Non-Inferiority Stepped Wedge Cluster Randomized Controlled Trial on All-Oral Shorter Regimens for Rifampicin Resistant/Multidrug-Resistant TB in Pakistan – A Study Protocol

Non-Inferiority Stepped Wedge Cluster Randomized Controlled Trial on All-Oral Shorter Regimens for Rifampicin Resistant/Multidrug-Resistant TB in Pakistan – A Study Protocol | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Study protocol Non-Inferiority Stepped Wedge Cluster Randomized Controlled Trial on All-Oral Shorter Regimens for Rifampicin Resistant/Multidrug-Resistant TB in Pakistan – A Study Protocol Nida Khan, Muhammad Ahmar Khan, Naila Muzaffar, Ahmad Ismail, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6156079/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 07 May, 2025 Read the published version in BMC Infectious Diseases → Version 1 posted 4 You are reading this latest preprint version Abstract Introduction: Pakistan has one of the largest burdens of rifampicin-resistant/ multidrug-resistant TB according to the global estimates. Novel all oral treatment regimens containing new antibiotics with reduced treatment duration are available. World Health Organization guidelines recommend the use of shorter all-oral regimens under operational research. To guide recommendations, we will compare two all-oral, short (≤11 months) regimens for the outcomes of efficacy, safety, cost, and health-related quality of life under programmatic conditions in Pakistan. Methods: This is a stepped wedge, cluster randomized controlled trial with economic evaluation and health related quality of life sub-studies. Modified all-oral 9-month regimen will be sequentially rolled-out compared with the standard all-oral 11-month regimen at 12 sites in Punjab, Islamabad and Azad Jammu and Kashmir region, Pakistan. A total of 400 eligible participants will be enrolled in both study arms. The primary outcome is difference in efficacy as measured by the proportion of patients with treatment success without recurrence at 12 months after the end of treatment between regimens using a non-inferiority design with a margin of 12%. The intention to treat analysis principle will be employed and a marginal mean model with Poisson generalized estimation equations, and a log-link will be used to assess the relative risk. The economic evaluation will be carried out from the healthcare providers perspective; linear mixed models will be used to estimate differences in costs between arms. Health related quality of life will be measured with the EQ-5D-3L quality of life questionnaire at four time points during the study period. The impact will be assessed by calculating the changes for each participant between time points. Ethical approval for this study has been obtained from provincial bioethics committee in Punjab, Pakistan (Ref: No.4-87/NBC-491/20/48). Discussion: The study's findings will be disseminated to physicians, program implementers, scientific audiences, and policymakers on both a national and international level via reports, presentations, and scientific publications. Trial registration: ISRCTN registry. ISRCTN17334530, ‘retrospectively registered’ on 8 th February 2021. ‘Clinical trial number: not applicable.’ rifampicin-resistant/ multidrug-resistant TB stepped wedge cluster randomized controlled trial non-inferiority health related quality of life all-oral short regimen economic evaluation treatment efficacy safety Figures Figure 1 BACKGROUNG AND RATIONALE The World Health Organization (WHO) END TB goals, established in 2015, envision reductions of 90% and 95% in tuberculosis (TB) incidence and deaths, respectively, by the year 2035 1 . Yet global trajectories remain off track, and TB remains a leading cause of global mortality, and over 10 million people fall ill with TB disease each year, more than 500,000 of whom are infected with TB strains resistant to rifampicin (i.e., rifampicin-resistant TB [RR-TB]) 2 . RR-TB is characterized by resistance to only rifampicin, whereas when resistance extends to at least both rifampicin and isoniazid, TB is categorized as multidrug-resistant TB (MDR-TB) 3 ; as treatment for both RR-TB and MDR-TB are typically the same, they are commonly referred to synonymously (i.e., RR/MDR-TB). Global data from 2019 identified China, India, and Pakistan as the top three countries with highest burden of RR/MDR-TB 4 , with an estimated 15,000 people with RR/MDR-TB in Pakistan alone 5 . RR/MDR-TB poses a significant public health challenge, as individuals are infected with strains resistant to the two strongest anti-TB drugs and are hence left with treatment options which are usually of prolonged duration, less effective, costly, and produce a range of side effects, thus making it even more difficult to combat the disease 6 . Historically RR/MDR-TB was treated with a combination of oral and injectable drugs for a minimum of eighteen months, making it physically and psychologically burdensome for most individuals. These long treatment regimens had poor treatment outcomes with less than 60% success rate and high mortality, and loss to follow-up rates. Additionally, studies report that approximately one-third of the RR/MDR-TB patients either die or experience a recurrent disease episode when followed up within 2 to 6 years of initial diagnosis 7 , 8 . Efforts have been made globally to introduce novel all oral treatment regimens containing new antibiotics such as linezolid and bedaquiline with reduced treatment duration ranging from 6 to 12 months 9 . In 2019, WHO revised its guidelines and recommended the use of shorter all-oral bedaquiline containing regimen for the treatment of RR/MDR-TB with a certain eligibility criterion. Subsequently, modified versions of all-oral shorter regimen were suggested under operational research conditions to generate evidence on effectiveness, safety, acceptability, feasibility, and cost implications through the ShORRT (Short, all-Oral Regimens for Rifampicin-Resistant Tuberculosis) research package 10 . In Pakistan, the National TB Program (NTP) established PMDT (Programmatic Management of Drug-Resistant Tuberculosis) sites in 2010 to manage the burden and spread of drug-resistant TB (DR-TB). These sites are funded by the GFTAM (Global Fund to Fight AIDS, Tuberculosis and Malaria) and WHO and are operated by the private partners who work in close collaboration with the national and provincial TB programs. The Association for Social Development (ASD) is responsible for the implementation and monitoring of the PMDT sites in Punjab province which bears 51% of the total RR/MDR-TB case load in the country. These PMDT sites offer core clinical and diagnostic services as well as DR-TB drugs free of cost. Since the initiation of PMDT sites, the NTP has been adopting novel strategies for the treatment of RR/MDR-TB 11 . Considering WHO findings and recommendations in support of RR/MDR-TB treatment shortening with regimens containing bedaquiline, the NTP issued an advisory in 2020 for all PMDT sites to start implementing an 11-month all-oral, bedaquiline-containing RR/MDR-TB regimen —substantially shorter than the previous 18-month standard of care regimen. Since 2020, several other iterations of short RR/MDR-TB regimens emerged. Thus, to guide recommendations on use of these regimens, we adapted the ShORRT research package to compare two all-oral, short (≤ 11 months) regimens for the outcomes of non-inferiority, safety, cost, and health-related quality of life under programmatic conditions in Pakistan. This study protocol follows the SPIRIT guidelines 12 . Primary objective To compare the efficacy of modified all-oral 9-month regimen against the standard all-oral 11-month regimen for the treatment of RR/MDR-TB. Secondary objectives To compare 1) the proportion of deaths and treatment failure during treatment, 2) recurrent TB episode and cure without permanent disability within one year post treatment, 3) treatment adherence, 4) proportion of patients with adverse effects and serious adverse effects, 5) impact on health related quality of life and 6) cost implications of modified all-oral 9-month regimen against the standard all-oral 11-month regimen for the treatment of RR/MDR-TB. Study design A cluster randomized non-inferiority trial with stepped wedge recruitment design. METHODS Study setting and population This study will be conducted at 12 PMDT sites in Punjab, Islamabad and Azad Jammu and Kashmir region, Pakistan. Each PMDT site has a designated staff of eight members to provide treatment to RR/MDR-TB patients. The staff includes a physician, pharmacist, directly observed treatment facilitator / case management person, social support person, treatment coordinator, lab attendant, psychologist, and program data assistant. Each person being treated for RR/MDR-TB, along with their treatment supporter, visits the PMDT site on monthly basis, to: a) be medically assessed; and b) receive TB medications (one-month supply) and social support (cash allowance). The inclusion and exclusion criteria for study participants is given in Table 1 . Table 1 Inclusion and exclusion criteria of study participants Inclusion criteria Exclusion criteria 15 or more years of age Fluoroquinolone resistance Willingness and ability to give informed consent to be enrolled in the research study and for follow- up (signed or witnessed consent if the patient is illiterate). Unable to take oral medication. Bacteriologically or molecularly confirmed TB with evidence of resistance to at least rifampicin. Known allergy to any of the drugs in the study regimen. QT interval with Fredericia correction (QTcF) interval of ≥ 500 msec at the time of registration that does not correct with medical management Requires medications for other health conditions contraindicated with the medicines in the study regimen. Eligible, consented individuals will be offered the standard of care regimen or intervention regimen (as per stepped-wedge design) for 11 or 9 months, respectively, and will be followed for 12 months after the successful completion of treatment. People who decline participation in the study or are not eligible will be referred for standard of care treatment with no negative consequences. The study timetable (Table 2 ) details the investigations and observations to conduct at each visit. Table 2. Schedule of examinations during treatment and follow-up phases of the study Investigation/Observation Baseline assessment & screening Treatment Phase (M=Month) Post-treatment Follow-Up M T 1 M T 2 M T 3 M T 4 M T 5 M T 6 M T 7 M T 8 M T 9/11 M F 6 M F 12 Clinical evaluation Demographics, Medical History X Written informed consent X Clinical Examination X X X X X X X X X X X X Treatment adherence X X X X X X X X X Concomitant treatment X X X X X X X X X X Adverse events X X X X X X X X X X Bacteriology Y Sputum smear X X X X X .X X X X X X X Sputum culture X X X X X X X X X X X X DST (FQ) X Laboratory tests Hemoglobin/platelets count / White blood count X X X X X X X X X X Serum liver enzymes X X X X X X X X X X Serum creatinine (at baseline and if clinically indicated or ECG abnormalities) X Serum potassium (at baseline and if clinically indicated or ECG abnormalities) X Pregnancy test (female) X HIV testing X Other ECG X X β X X X X X X X X Visual acuity & BPNS (Note: for patients receiving Lzd and high-dose INH/EMB) X (X) (X) (X) (X) (X) (X) (X) (X) (X) Chest X-ray X Disability assessment X X X Health Related Quality of Life assessment X X X X β Baseline ECG should be obtained and additional ECGs conducted at week 1 and 2 after starting treatment and thereafter monthly throughout treatment.. Sample size: The number of participants to be included in this study has been estimated based on surveillance data from the NTP, specifically the number of people with bacteriologically confirmed RR/MDR-TB. The sample size was calculated using the stepped wedge cluster level power calculations in STATA (statistical software package). A sample of 400 RR/MDR-TB patients (i.e. 200 in each arm) will be required for a non-inferiority margin of 12% on the primary outcome of treatment success without recurrence at 12 months after the end of treatment while maintaining 80% power and type I error rate of 5%. The average number of RR/MDR-TB patients in the clusters will be 20 and will be included in the trial in four steps excluding baseline. Interventions Both the regimens under investigation are adapted from the WHO recommended dose of drugs 13 , Table 3 . Intervention care The intervention care is the modified all-oral shorter regimen for the duration of 9 months. 2 Lzd-Bdq-Lfx -Cfz-Z-E-H(high dose) / 4 Bdq- Lfx -Cfz-Z-E-H(high dose) / 3 Lfx -Cfz-Z-E Standard of care The standard of care is the all-oral shorter regimen for the duration of 11 months. 6 Bdq- Lfx -Cfz-Eto-Z-E-H(high dose) / 5 Lfx-Cfz-Z-E Table 3 Daily drug dosage by patient weight (above 14 years old) Drug Weight-based daily dose Formulation 30–35 kg 36–45 kg 46–55 kg 56–70 kg > 70 kg Usual upper daily dose Bedaquiline 100 mg tab 4 tabs od first two weeks, then 2 tabs od M/W/F for 22 weeks 400 mg Levofloxacin 250 mg tab 3 3 4 4 4 1.5 g 500 mg tab 1.5 1.5 2 2 2 1.5 g 750 mg tab 1 1 1.5 1.5 1.5 1.5 g Ethionamide 15–20 mg/kg 250 mg tab 2 2 3 3 4 1 g Clofazimine 50 mg cps or tab 2 2 2 2 2 100 mg 100 mg cps or tab 1 1 1 1 1 100 mg Pyrazinamide 20–30 mg/kg 400 mg tab 3 4 4 4 5 500 mg tab 2 3 3 3 4 Isoniazid (high dose) 10–15 mg/kg 300 mg tab 1.5 1.5 2 2 2 Ethambutol 15–25 mg/kg 400 mg tab 2 2 3 3 3 Linezolid 600 mg tab < 15 years < 15 years 1 1 1 1.2 g Adapted from https://iris.who.int/bitstream/handle/10665/311389/9789241550529-eng.pdf Outcomes Primary outcomes There are two primary outcomes of interest: a) Treatment efficacy : the proportion of RR/MDR-TB patients who have a favorable treatment outcome. This is defined as “cured” or “treatment completed” without recurrence during 12 months after successful treatment Secondary outcomes The secondary outcomes of interest include: The proportion of RR/MDR-TB patients who died while on treatment. The proportion of RR/MDR-TB patients who had a treatment failure. The proportion of RR/MDR-TB patients who had a recurrent episode of RR/MDR-TB during the 12- month follow-up. The proportion of RR/MDR-TB patients who are “cured without permanent disability” (up to one year after the end of the treatment). The proportion of RR/MDR-TB patients who complete at least 90% of doses (intake adherence indicator to be included as deem feasible in the given context). The average number of adverse events of interest experienced by RR/MDR-TB patients. The proportion of RR/MDR-TB patients experiencing each adverse event of interest. The proportion of RR/MDR-TB patients who experience serious adverse events. Key definitions of study outcomes are given in Table 4 . Table 4 Definitions of study outcomes. Outcomes Definition Favorable outcome Composite outcome corresponding to the combination of “cured” + “treatment completed” (= treatment success) without recurrence over the 12-month follow-up period. Note: this outcome can also be defined as “recurrence-free cure” Cured A patient with bacteriologically confirmed MDR/RR-TB who has completed 9–12 months of treatment by 9/12-month regimen protocol without evidence of failure AND at least two consecutive cultures taken at least 30 days apart are negative at the end of the treatment and at least one month earlier. Treatment Completed A patient who completes 9–12 months of treatment by 9/12-month regimen protocol without evidence of failure BUT without bacteriological evidence (negative culture at the end of the treatment phase and at least one month earlier). Treatment Failed Treatment terminated or need for permanent change of the regimen protocol of at least two anti-TB drugs because of: • lack of sputum culture conversion after 4 months of treatment, or • bacteriological reversion of sputum culture after 5 months of treatment in a patient with previous culture conversion to negative, or • evidence of additional acquired resistance to drugs in the study, or • adverse drug reactions (ADRs) (leading to the change of at least two anti-TB drugs in the regimen) Died A patient who dies for any reason during treatment. Lost to follow-up A patient whose treatment was interrupted for 2 consecutive months or more. Not evaluated A patient for whom no treatment outcome is assigned (this includes cases “transferred out” to another treatment unit and whose treatment outcome is unknown/can’t be assessed) Withdrawn A patient is taken off the 9/12-month regimen for any reason other than treatment failure (for example, baseline second-line drug resistance, withdrawn patient informed consent or other reasons) and referred to the PMDT program for routine care. Recurrence Cure or treatment completion followed by two consecutive positive cultures during post- treatment follow-up (without genotyping information on baseline and recurrent strain), or one positive culture with clinical signs and symptoms or radiographic deterioration. Conversion (to negative) Cultureisconsideredtohaveconvertedtonegativewhentwoconsecutiveculturestaken at least 30 days apart are found to be negative. In such case, the specimen collection date of the first negative culture is used as the date of conversion. In case patients were culture negative at baseline, a negative culture result at month 4 may be considered as “initial conversion”. Reversion (to positive) Culture is considered to have reverted to positive when after an initial conversion, two consecutive cultures taken at least 30 days apart are found to be positive. In case of patients who are culture negative at baseline, a positive culture result at month 4 may be considered as “initial conversion”. Treatment adherence 90% of the treatment doses were taken based on staff notes in the treatment cards, measured over the entire treatment period. Permanent disability A combined outcome, using the modified Medical Research Council Dyspnea scale (mMRC) based on which patients with a score above 2 are considered permanently disabled in terms of their pneumological function. A score of 2 describes that the on level ground, the person walks slower than people of same age because of breathlessness, or have to stop for breath when walking at own pace on the level. In addition, all serious adverse events by system organ class that are not resolved at the end of treatment, should be summarized by treatment regimen. This is a measure of a programme’s ability to start treatment promptly and treat patients effectively. Clustering The randomization unit or cluster in this trial is PMDT site. All patients meeting the eligibility criteria at the respective PMDT site will be randomised to the same trial arm. Taking PMDT site as unit of randomization will avoid the risk of contamination. Randomization and blinding The study biostatistician will create the randomization sequence using STATA14.2 statistical software. The first three sites will be designated to enter the intervention after 3 months of the standard-of-care phase, the second three after 6 months, the third group after 9 months, and the last three after 12 months (Fig. 1). For the first three months of the study, all investigators will be kept blinded about the allocation sequence, allowing all sites to begin using standard-of-care without knowing when the intervention phase will begin. Then, the biostatistician will inform which three sites will be chosen randomly to begin the first phase of the intervention. Before moving on to the intervention phase, the three study sites will go through a transition phase for one week in which the site staff will be trained on research protocols and the administration of new treatment; along with that, logistic preparations (drug procurement, etc.) will also be done. The standard-of-care will be maintained at all other study sites, and they will be blinded to the time when the intervention will begin. The study design prevents blinding of the site investigators following exposure to intervention arm. When moving from the standard of care to the intervention treatment regimen, the patients who started the standard of care treatment will continue until the end of the treatment, but the newly diagnosed RR/MDR-TB patients will be treated with the intervention treatment regimen. Discontinuation of the study regimen In case the study regimen must be discontinued, participants will be evaluated by a clinical committee and switched to an individualized regimen, as per the national guidelines. The most common situations in which the regimen may be discontinued are included in box 1: Box 1: Situations to discontinue study treatment regimen : a) Acquired resistance to any drug in the regimen : If resistance to any drug in the regimen is acquired after treatment is initiated, it may be necessary to modify, extend or discontinue the regimen. b) Severe toxicity : One or more drugs may need to be suspended permanently due to severe toxicity. In such cases, the clinical committee will review the medical history carefully to determine how the regimen should be modified. c) Treatment failure : If clinical and bacteriological responses to treatment are poor (informed by culture result), a change in the treatment regimen might be considered. DST will be repeated, whether the regimen is changed, to inform future management decisions. Post-treatment follow-up After completion of treatment, participants will be informed of the risk of recurrent TB disease and advised to return for clinical assessment and sputum collection (at PMDT site) at 6 and 12 months after completion of treatment or at any time after the end of the treatment if experiencing TB clinical symptoms. In case participants are unable to visit the PMDT site, a telephonic survey encompassing clinical evaluation will be conducted. Safety monitoring and management Participants will be screened and managed monthly by PMDT site physicians and/or pharmacists trained in the diagnosis and management of adverse events (AE). AEs severity and seriousness will be judged based on the national guidelines for AEs recording and reporting (See Annexure 1&2 for details on AEs diagnosis and management). Data collection and analysis The study data will be regularly retrieved from the program electronic medical records and will be reviewed by the MDR program coordinator to look for any discrepancies or protocol deviations. The analysis will be done using the intention to treat analysis principle and non-inferiority will be declared if the lower-bound of the 95% confidence interval of the difference in treatment success without recurrence at 12 months after the end of treatment between the intervention and control group is greater than − 12%. Participants with no information during the 12-month follow-up will be classified as “not assessable”. Baseline characteristics of the participants will be reported by treatments and groups of sites. Frequencies and percentages will summarize the categorical variables, whereas the quantitative variables (such as the age) will be described through mean and standard deviation (SD). The Chi-square, Fisher’s exact, Mann-Whitney or Kruskal-Wallis tests will be employed to detect any imbalances in baseline characteristics across regimen treatment, with a level of significance of 5%. For the primary outcome, a marginal mean model with Poisson generalized estimation equations (GEE) 14 , and a log-link will assess the relative risk (RR), by comparing the two treatment regimens. The group of sites will be considered as a cluster effect. The period will be added in the list of predictors and will be considered as a categorical variable 15 . The models will be adjusted at least on age and gender: the selection of covariables. To correct the inflated type I error rates due to the small number of clusters, the Fay and Graubard (FG) correction will be applied to the standard errors 16 . 95% confidence intervals (CI) will be displayed. The upper limit of the CI will be compared with the non-inferiority margin of 12% (i.e. a RR equal to 1.12). Different structures of the covariance matrix will be looked at and be selected with a tool developed in R 17 . The secondary outcomes will be described by treatment regimens, with frequencies and percentages for categorical variables, and with mean and SD for continuous variable. The analysis will be executed through the R software version 2023.06.1 Health economic evaluation The non-inferiority design of the trial warrants employing a cost-minimization analysis. We will estimate the cost of administering the two regimens from the providers perspective. All costs of providing healthcare services to participants will be considered. This includes costs of medications, costs of laboratory and monitoring tests, salary costs of healthcare personnel, costs of hospitalization, and costs of managing adverse events. We will collect costs of medications at various doses and formulations from procurement records of the NTP. Costs of laboratory and monitoring tests will be as reported from participating PMDT sites. For costs of healthcare personnel, we will use nationally representative salaries and administer time estimation questionnaires to healthcare personnel at all sites for 10 consecutive days. These questionnaires ask healthcare personnel about their time spent doing specific tasks related to RR/MDR-TB care. We will use the average time spent on specific tasks and annual salaries, to arrive at a dollar value for time spent on specific activities (e.g., initial or follow-up visits). Costs of per day of hospitalization will be estimated from tertiary level facilities from the WHO-CHOICE 18 . Finally, we will estimate costs of adverse event management by micro-costing per-protocol management of different grades and types of adverse events. We will use the above costs to arrive at costs of specific activities that occur during treatment and multiply these values by the number of occurrences of each activity during treatment based on events and activities reported in case report forms for each participant. We will then sum up all costs over the course of treatment for each participant to arrive at an overall cost per participant. We will calculate the arithmetic mean, standard deviation, and 95% confidence interval for RR/MDR-TB treatment by arm. To estimate differences in costs between arms, we will perform multivariable analysis. This analysis will use linear mixed models, with the PMDT site as the clustering variable, and will be adjusted for treatment arm, as well as demographic and clinical characteristics. Prior to regression, costs will be log-transformed as they are very likely to be skewed and this gives them better properties for regression. Resultant model estimates will be back-transformed and are interpreted as cost ratios; we will also use the NLESTIMATE function in SAS to convert these cost ratios to absolute differences. We will perform this analysis on the modified intention to treat population. We will determine if there is a significant difference in costs by treatment arm and demographic and clinical characteristics based on the estimated 95% confidence intervals in the fully adjusted model (i.e., for cost ratios if they cross 1.0, there is no significant difference). If non-inferiority is demonstrated, we will assume that the less expensive regimen is the preferred regimen from a purely economic perspective. Health Related Quality of Life (HRQoL) HRQoL measures the physical and functional status and social and emotional well-being of an individual. We will conduct a sub-study to assess the HRQoL of RR/MDR-TB patients receiving the two all-oral shorter RR/MDR-TB treatment regimens. The study will be conducted on all participants recruited in the trial. This assessment will adopt a longitudinal design with data collection at four-time points i.e., at enrolment, 4 months, end of treatment, and twelve months after the end of treatment. HRQoL will be assessed through the Urdu translated version of Euro quality of life questionnaire, EQ-5D-3L 19 . This instrument will be composed by a system describing five dimensions (Mobility, self-care, usual activities, pain/discomfort and anxiety/depression) and by a visual analogue scale (EQ-VAS). For each time point and for each treatment regimen, the EQ-VAS will be summarized by mean and standard deviation, while the dimensions will be reported in frequencies and percentages by level (no problems, some problems, and extreme problems). The impact of the all-oral shorter treatment regimens will be assessed by calculating the changes in the EQ-VAS for each participant between time points (between baseline and 4 months, baseline and end of treatment, baseline and end of follow-up, and end of treatment and end of follow-up). The frequencies and percentages of the trajectories of participants will be displayed based on the Paretian Classification of Health Change (PCHC). For each dimension, each participant will be classified into no change/no problems, no change/any problems, better and worse, based on the measures between time points (the same as for the EQ-VAS) 20 . Ethics approval The research protocols were submitted for approval by Provincial Bioethics Committee in Punjab and ethical approval for conducting this study has been received (Ref: No.4–87/NBC-491/20/48). The protection of patient confidentiality is essential, and the study will follow the principles of the 2018 Declaration of Helsinki 21 . DISCUSSION The proposed trial, and associated sub studies, will be conducted at 12 PMDT sites where core diagnostic, laboratory and clinical inputs, social support, and medications are being, and will continue to be, managed through the ongoing GFTAM project support. A stepped-wedge cluster-randomized trial design was chosen for this study due to its robustness in demonstrating the effectiveness of intervention during routine implementation. Prior studies suggest that stepped wedge design is often suitable to accommodate the logistical challenges of implementing interventions at a large scale 22 . Since the WHO guidelines suggest already established efficacy of the modified treatment regimen, it is imperative not to withhold the intervention from the study participants. This study design will take care of such ethical considerations by allowing all participants to receive the intervention eventually 23 . Each cluster will be exposed to both the control and intervention care, this will contribute to increasing the statistical power of the study by making within cluster comparisons 24 . We will follow RR/MDR TB patients for 9–11 months during treatment and for one year after the successful completion of treatment, the stepped wedge cluster trial design will additionally support the investigation of temporal effect by introducing intervention at different time points. The data analysis, however, will require careful considerations keeping in view the complexities produced by the study design. Moreover, it will take longer to achieve the trial outcomes 25 . The current study primarily aims to evaluate the non-inferiority of an all-oral modified shorter treatment against the all-oral standard shorter treatment for RR/MDR TB patients. Previous evaluations of the standard all-oral short treatment regimen suggest promising results, with up to 80% treatment success rate. Based on WHO recommendations this study will further contribute towards generating evidence on the non-inferiority of a 9 month long modified all-oral treatment regimen. The shorter treatment length (9 months against 11 months) is not only expected to demonstrate a similar treatment success rate but will also minimize number of visits to health facility leading to better treatment adherence, reduced cost and improved quality of life of patients 26 . The primary outcome will be declared after twelve months post successful treatment completion to understand the sustained effects of treatment. We will report data on proportion of patients who remained cured, experienced relapse or re-infection and died within one year post treatment, thus will contribute to enriching data on the impact of RR/MDR TB treatment following cure 8 . Literature suggests that second line anti-TB drugs cause adverse drugs effects in greater number of patients than the first line drugs, which warrant a more closer and regular safety monitoring during the treatment span 27 . Nevertheless, data quality and reporting has been identified as a challenge during routine program setting 28 . We anticipate that during this trial we will develop and implement stringent protocols to ensure pharmacovigilance, rigorous reporting and timely response. This will help us to generate evidence on the safety of modified regimen as well as establish improved pharmacovigilance mechanisms within TB care in the country. The criteria of good clinical practice shall be followed rigorously to maintain the validity and integrity of trial 29 . The Trial Steering Committee (TSC) will be responsible for the direct management and monitoring of research operations and will oversee the research personnel on the ground. The study researchers have received comprehensive training on data collection, monitoring tools, and Standard Operating Procedures (SOPs) related to the protocol, ensuring that the study is conducted with the highest level of scientific and ethical rigor. Evidence from this research will inform programmatic implementation in Pakistan and provide crucial data to the global TB community, strengthening the evidence base necessary to inform future treatment guidance. The study's findings will be disseminated to physicians, program implementers, scientific audiences, and policymakers on both a national and international level via reports, presentations, and scientific publications. Demonstrating the benefit of integrating a shorter all-oral regimen at PMDT sites will provide strong supportive evidence to accelerate the widespread implementation of this intervention across Pakistan and in similar settings. Abbreviations WHO World health organization TB Tuberculosis MDR-TB Multidrug resistant tuberculosis RR-TB Rifampicin resistant tuberculosis PMDT Programmatic management of drug-resistant tuberculosis NTP National tuberculosis program ShORRT Short, all-oral regimens for rifampicin-resistant tuberculosis AE Adverse events Declarations Availability of data and materials This is a study protocol manuscript, not applicable. Funding statement This research project received financial support from the UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR), grant number [PO202606230]. Competing interest statement Authors declare no competing interests Trial status At the time of the manuscript submission, the intervention has been rolled out and patients are being followed-up for the primary outcome. A delay in submission of this manuscript is due to resource limitations and long-term impact of COVID-19, which necessitated redirection of efforts to keeping the trial going rather than writing a protocol for scientific publication. Data sharing statement The authors plan to disseminate the findings on main study outcomes in a single paper after completing data collection, cleaning and analysis. Additional scientific publication on economic evaluation is anticipated after publishing trial results. Human ethics and consent to participate declaration The research protocols were submitted for approval by Provincial Bioethics Committee in Punjab, Pakistan and ethical approval for conducting this study was received (Ref: No.4-87/NBC-491/20/48). Protection of patient confidentiality is essential, and the study will follow the principles of the 2018 Declaration of Helsinki. Informed written consent will be obtained from patients or a guardian in the case of minors, as defined by local legal requirements. Those who do not consent to participate in this research will receive treatment as per national guidelines. Consent for publication This is a study protocol, does not require consent to publish, Not applicable. Author contributions NK designed the study, did sample size calculations, contributed to the ethics approval of study and drafted original manuscript. MAK and AI will lead the study implementation, NM contributed in the ethics approval of the study, drafted original manuscript and will be involved in study implementation and data analysis. AG conceptualized the study and contributed to the design, development and operationalization of intervention and other care protocols. ZN will be involved in trial data analysis. CSM conceptualized the study and contributed to writing, review and editing of the manuscript. JRC contributed to writing, review and editing of the manuscript and is leading the economic evaluation and analysis. GLC contributed to writing, review and editing of the manuscript and is leading primary statistical analysis. MAK conceptualized the study and led the team in design, development and operationalization of intervention and other care protocols. Disclaimer CSM is currently a staff member of the World Health Organization; the author alone is responsible for the views expressed in this publication and they do not necessarily represent the decisions, policy or views of the WHO. References Matteelli A, Rendon A, Tiberi S, Al-Abri S, Voniatis C, Carvalho AC, Centis R, D'Ambrosio L, Visca D, Spanevello A, Migliori GB. Tuberculosis elimination: where are we now?. European Respiratory Review. 2018 Jun 30;27(148). World Health Organization. WHO consolidated guidelines on drug-resistant tuberculosis treatment. World Health Organization; 2019. Singh R, Dwivedi SP, Gaharwar US, Meena R, Rajamani P, Prasad T. Recent updates on drug resistance in Mycobacterium tuberculosis. Journal of applied microbiology. 2020 Jun 1;128(6):1547-67. Lv H, Zhang X, Zhang X, Bai J, You S, Li X, Li S, Wang Y, Zhang W, Xu Y. Global prevalence and burden of multidrug-resistant tuberculosis from 1990 to 2019. BMC Infectious Diseases. 2024 Feb 22;24(1):243. Ali S, Khan MT, Khan AS, Mohammad N, Khan MM, Ahmad S, Noor S, Jabbar A, Daire C, Hassan F. Prevalence of multi-drug resistant Mycobacterium tuberculosis in Khyber Pakhtunkhwa–a high tuberculosis endemic area of Pakistan. Polish journal of microbiology. 2020 Jan 1;69(2):133-7. Taylor HA, Dowdy DW, Searle AR, Stennett AL, Dukhanin V, Zwerling AA, Merritt MW. Disadvantage and the experience of treatment for multidrug-resistant tuberculosis (MDR-TB). SSM-Qualitative Research in Health. 2022 Dec 1;2:100042. Surie D, Sathyanarayanan MK, Lavanya J, Smith JP, Shanmugam SK, Tamilzhalagan S, Selvaraj A, Ramesh G, Tripathy S, Khaparde SD, Ho CS. Long-term follow-up of persons diagnosed with multidrug-resistant TB in Chennai, India, 2013–2020. The international journal of tuberculosis and lung disease: the official journal of the International Union against Tuberculosis and Lung Disease. 2024 Jan 1;28(1):54. Cox H, Kebede Y, Allamuratova S, Ismailov G, Davletmuratova Z, Byrnes G, Stone C, Niemann S, Rüsch-Gerdes S, Blok L, Doshetov D. Tuberculosis recurrence and mortality after successful treatment: impact of drug resistance. PLoS medicine. 2006 Oct;3(10):e384. Morgan H, Ndjeka N, Hasan T, Gegia M, Mirzayev F, Nguyen LN, Schumacher S, Schlub TE, Naidoo K, Fox GJ. Treatment of multidrug-resistant or rifampicin-resistant tuberculosis with an all-oral 9-month regimen containing linezolid or ethionamide in South Africa: A retrospective cohort study. Clinical Infectious Diseases. 2024 Jun 15;78(6):1698-706. World Health Organization. WHO operational handbook on tuberculosis: module 4: treatment: drug-resistant tuberculosis treatment. World Health Organization; 2020. Khan MA, Bilal W, Asim H, Rahmat ZS, Essar MY, Ahmad S. MDR-TB in Pakistan: Challenges, efforts, and recommendations. Annals of Medicine and Surgery. 2022 Jul 1;79:104009. Moher D, Chan AW. SPIRIT (standard protocol items: recommendations for interventional trials). Guidelines for Reporting Health Research: a user's manual. 2014 Jul 25:56-67. World Health Organization. WHO consolidated guidelines on tuberculosis: module 4: treatment: drug-resistant tuberculosis treatment: online annexes. World Health Organization; 2020. Yelland LN, Salter AB, Ryan P. Performance of the modified Poisson regression approach for estimating relative risks from clustered prospective data. American journal of epidemiology. 2011 Oct 15;174(8):984-92. Hussey MA, Hughes JP. Design and analysis of stepped wedge cluster randomized trials. Contemporary clinical trials. 2007 Feb 1;28(2):182-91. Thompson JA, Hemming K, Forbes A, Fielding K, Hayes R. Comparison of small-sample standard-error corrections for generalised estimating equations in stepped wedge cluster randomised trials with a binary outcome: a simulation study. Statistical methods in medical research. 2021 Feb;30(2):425-39. Westgate PM, West BT. Tools for selecting working correlation structures when using weighted GEE to model longitudinal survey data. Journal of survey statistics and methodology. 2021 Feb 1;9(1):141-58. Bertram MY, Lauer JA, Stenberg K, Edejer TT. Methods for the economic evaluation of health care interventions for priority setting in the health system: an update from WHO CHOICE. International Journal of Health Policy and Management. 2021 Nov;10(11):673. Group TE. EuroQol-a new facility for the measurement of health-related quality of life. Health policy. 1990 Dec 1;16(3):199-208. Devlin NJ, Parkin D, Browne J. Patient‐reported outcome measures in the NHS: new methods for analysing and reporting EQ‐5D data. Health economics. 2010 Aug;19(8):886-905. Shrestha B, Dunn L. The declaration of Helsinki on medical research involving human subjects: a review of seventh revision. Brown CA, Lilford RJ. The stepped wedge trial design: a systematic review. BMC medical research methodology. 2006 Dec;6:1-9. Zhan Z, van den Heuvel ER, Doornbos PM, Burger H, Verberne CJ, Wiggers T, de Bock GH. Strengths and weaknesses of a stepped wedge cluster randomized design: its application in a colorectal cancer follow-up study. Journal of clinical epidemiology. 2014 Apr 1;67(4):454-61. de Hoop E, van der Tweel I, van der Graaf R, Moons KG, van Delden JJ, Reitsma JB, Koffijberg H. The need to balance merits and limitations from different disciplines when considering the stepped wedge cluster randomized trial design. BMC medical research methodology. 2015 Dec;15:1-3. Mdege ND, Man MS, Taylor CA, Torgerson DJ. Systematic review of stepped wedge cluster randomized trials shows that design is particularly used to evaluate interventions during routine implementation. Journal of clinical epidemiology. 2011 Sep 1;64(9):936-48. Chakaya J, Khan M, Ntoumi F, Aklillu E, Fatima R, Mwaba P, Kapata N, Mfinanga S, Hasnain SE, Katoto PD, Bulabula AN. Global Tuberculosis Report 2020–Reflections on the Global TB burden, treatment and prevention efforts. International journal of infectious diseases. 2021 Dec 1;113:S7-12. Atif M, Ahmed W, Nouman Iqbal M, Ahmad N, Ahmad W, Malik I, Al-Worafi YM. Frequency and factors associated with adverse events among multi-drug resistant tuberculosis patients in Pakistan: A retrospective study. Frontiers in Medicine. 2022 Mar 1;8:790718. Massud A, Syed Sulaiman SA, Ahmad N, Shafqat M, Chiau Ming L, Khan AH. Frequency and management of adverse drug reactions among drug-resistant tuberculosis patients: analysis from a prospective study. Frontiers in Pharmacology. 2022 Jun 2;13:883483. Sprumont D. Legal protection of human research subjects in Europe. European Journal of Health Law. 1999 Mar 1;6(1):25-43. Additional Declarations No competing interests reported. Supplementary Files completedSPIRITchecklist1.docx Annexure.docx Cite Share Download PDF Status: Published Journal Publication published 07 May, 2025 Read the published version in BMC Infectious Diseases → Version 1 posted Editorial decision: Revision requested 14 Mar, 2025 Editor assigned by journal 12 Mar, 2025 Submission checks completed at journal 12 Mar, 2025 First submitted to journal 04 Mar, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6156079","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Study protocol","associatedPublications":[],"authors":[{"id":428514004,"identity":"5edaf571-d9ef-407d-b654-2800496b96b6","order_by":0,"name":"Nida Khan","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA1klEQVRIiWNgGAWjYDACZgYDxsYGBgZ+IFsCIsRGpBbJBqK1MEC1GBwgVos5O/PGjzN32OUZHz/+8AZDjU00g3RbAl4tls1sxZIbzyQXm53JMbZgOJaW2yBz7AB+Vx3mMZB82MacuO1ADpsEY8Ph3AaJ9AZCWox/PmyrT9zc//wZ0VrMJDe2HU7cIJFgBtWSRshhbGWWM9uOJ8648cbYIgHolzaZYwn4tZw/vPlmb1t1Yn9/+sMbH2pscvul2wzwakEFIOPZJEjQAAVkaBkFo2AUjILhDQA3mkrJWrFNcwAAAABJRU5ErkJggg==","orcid":"","institution":"Association for Social Development","correspondingAuthor":true,"prefix":"","firstName":"Nida","middleName":"","lastName":"Khan","suffix":""},{"id":428514005,"identity":"0e66717e-60c2-4387-8f1a-c9cbf86d771a","order_by":1,"name":"Muhammad Ahmar Khan","email":"","orcid":"","institution":"Association for Social Development","correspondingAuthor":false,"prefix":"","firstName":"Muhammad","middleName":"Ahmar","lastName":"Khan","suffix":""},{"id":428514006,"identity":"cbef54c6-4ad7-4403-acff-e3f1840f44e9","order_by":2,"name":"Naila Muzaffar","email":"","orcid":"","institution":"Association for Social Development","correspondingAuthor":false,"prefix":"","firstName":"Naila","middleName":"","lastName":"Muzaffar","suffix":""},{"id":428514007,"identity":"5636bbe1-e6d0-44a5-bc97-34d1439d852b","order_by":3,"name":"Ahmad Ismail","email":"","orcid":"","institution":"Association for Social Development","correspondingAuthor":false,"prefix":"","firstName":"Ahmad","middleName":"","lastName":"Ismail","suffix":""},{"id":428514008,"identity":"24b5d471-b669-432e-a51c-18ca688f1b0c","order_by":4,"name":"Abdul Ghafoor","email":"","orcid":"","institution":"National TB Control Programme","correspondingAuthor":false,"prefix":"","firstName":"Abdul","middleName":"","lastName":"Ghafoor","suffix":""},{"id":428514009,"identity":"f0a94066-8a3a-47f3-9435-7b5199342e8a","order_by":5,"name":"Jonathon R. Campbell","email":"","orcid":"","institution":"McGill University","correspondingAuthor":false,"prefix":"","firstName":"Jonathon","middleName":"R.","lastName":"Campbell","suffix":""},{"id":428514010,"identity":"212d617f-5ce8-4619-91f6-f3ae54192901","order_by":6,"name":"Gwenaelle Le Coroller","email":"","orcid":"","institution":"Luxembourg Institute of Health","correspondingAuthor":false,"prefix":"","firstName":"Gwenaelle","middleName":"Le","lastName":"Coroller","suffix":""},{"id":428514011,"identity":"06f8a95b-7553-4289-8cd6-f52f81d47870","order_by":7,"name":"Zia Un Nisa","email":"","orcid":"","institution":"Association for Social Development","correspondingAuthor":false,"prefix":"","firstName":"Zia","middleName":"Un","lastName":"Nisa","suffix":""},{"id":428514012,"identity":"7c8160b8-ed9f-4f57-a360-9bf41bc743a4","order_by":8,"name":"Corinne Simone Merle","email":"","orcid":"","institution":"World Health Organization","correspondingAuthor":false,"prefix":"","firstName":"Corinne","middleName":"Simone","lastName":"Merle","suffix":""},{"id":428514013,"identity":"7c3830be-e5e1-4cfa-908b-f7ce696372bd","order_by":9,"name":"Muhammad Amir Khan","email":"","orcid":"","institution":"Association for Social Development","correspondingAuthor":false,"prefix":"","firstName":"Muhammad","middleName":"Amir","lastName":"Khan","suffix":""}],"badges":[],"createdAt":"2025-03-04 16:53:09","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6156079/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6156079/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12879-025-11068-1","type":"published","date":"2025-05-07T15:57:06+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":78689852,"identity":"a45e6dc9-d143-473e-953d-b7d532223fb1","added_by":"auto","created_at":"2025-03-17 16:13:33","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":28628,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eTransition period from control to intervention arm\u003c/em\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6156079/v1/d544db2ba7c01a0a841e4be1.png"},{"id":82537443,"identity":"89d301ae-72b5-4b00-9004-0b0c13ce735a","added_by":"auto","created_at":"2025-05-12 16:06:34","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1340571,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6156079/v1/46cd5634-5a1c-41c7-b687-6cda1dee81c4.pdf"},{"id":78689752,"identity":"29a19e51-9a65-413b-8b76-ea927351e121","added_by":"auto","created_at":"2025-03-17 16:13:16","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":29473,"visible":true,"origin":"","legend":"","description":"","filename":"completedSPIRITchecklist1.docx","url":"https://assets-eu.researchsquare.com/files/rs-6156079/v1/6e272e054333a7ad8f898fe8.docx"},{"id":78689868,"identity":"97bb1087-c30a-4bfb-9da0-3acc41f05b7b","added_by":"auto","created_at":"2025-03-17 16:13:41","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":22286,"visible":true,"origin":"","legend":"","description":"","filename":"Annexure.docx","url":"https://assets-eu.researchsquare.com/files/rs-6156079/v1/be3064c26dc07761603185f6.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Non-Inferiority Stepped Wedge Cluster Randomized Controlled Trial on All-Oral Shorter Regimens for Rifampicin Resistant/Multidrug-Resistant TB in Pakistan – A Study Protocol ","fulltext":[{"header":"BACKGROUNG AND RATIONALE","content":"\u003cp\u003eThe World Health Organization (WHO) END TB goals, established in 2015, envision reductions of 90% and 95% in tuberculosis (TB) incidence and deaths, respectively, by the year 2035\u003csup\u003e1\u003c/sup\u003e. Yet global trajectories remain off track, and TB remains a leading cause of global mortality, and over 10\u0026nbsp;million people fall ill with TB disease each year, more than 500,000 of whom are infected with TB strains resistant to rifampicin (i.e., rifampicin-resistant TB [RR-TB])\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. RR-TB is characterized by resistance to only rifampicin, whereas when resistance extends to at least both rifampicin and isoniazid, TB is categorized as multidrug-resistant TB (MDR-TB)\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e; as treatment for both RR-TB and MDR-TB are typically the same, they are commonly referred to synonymously (i.e., RR/MDR-TB). Global data from 2019 identified China, India, and Pakistan as the top three countries with highest burden of RR/MDR-TB\u003csup\u003e4\u003c/sup\u003e, with an estimated 15,000 people with RR/MDR-TB in Pakistan alone\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eRR/MDR-TB poses a significant public health challenge, as individuals are infected with strains resistant to the two strongest anti-TB drugs and are hence left with treatment options which are usually of prolonged duration, less effective, costly, and produce a range of side effects, thus making it even more difficult to combat the disease\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. Historically RR/MDR-TB was treated with a combination of oral and injectable drugs for a minimum of eighteen months, making it physically and psychologically burdensome for most individuals. These long treatment regimens had poor treatment outcomes with less than 60% success rate and high mortality, and loss to follow-up rates. Additionally, studies report that approximately one-third of the RR/MDR-TB patients either die or experience a recurrent disease episode when followed up within 2 to 6 years of initial diagnosis\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eEfforts have been made globally to introduce novel all oral treatment regimens containing new antibiotics such as linezolid and bedaquiline with reduced treatment duration ranging from 6 to 12 months\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. In 2019, WHO revised its guidelines and recommended the use of shorter all-oral bedaquiline containing regimen for the treatment of RR/MDR-TB with a certain eligibility criterion. Subsequently, modified versions of all-oral shorter regimen were suggested under operational research conditions to generate evidence on effectiveness, safety, acceptability, feasibility, and cost implications through the ShORRT (Short, all-Oral Regimens for Rifampicin-Resistant Tuberculosis) research package\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn Pakistan, the National TB Program (NTP) established PMDT (Programmatic Management of Drug-Resistant Tuberculosis) sites in 2010 to manage the burden and spread of drug-resistant TB (DR-TB). These sites are funded by the GFTAM (Global Fund to Fight AIDS, Tuberculosis and Malaria) and WHO and are operated by the private partners who work in close collaboration with the national and provincial TB programs. The Association for Social Development (ASD) is responsible for the implementation and monitoring of the PMDT sites in Punjab province which bears 51% of the total RR/MDR-TB case load in the country. These PMDT sites offer core clinical and diagnostic services as well as DR-TB drugs free of cost. Since the initiation of PMDT sites, the NTP has been adopting novel strategies for the treatment of RR/MDR-TB\u003csup\u003e11\u003c/sup\u003e. Considering WHO findings and recommendations in support of RR/MDR-TB treatment shortening with regimens containing bedaquiline, the NTP issued an advisory in 2020 for all PMDT sites to start implementing an 11-month all-oral, bedaquiline-containing RR/MDR-TB regimen \u0026mdash;substantially shorter than the previous 18-month standard of care regimen.\u003c/p\u003e \u003cp\u003eSince 2020, several other iterations of short RR/MDR-TB regimens emerged. Thus, to guide recommendations on use of these regimens, we adapted the ShORRT research package to compare two all-oral, short (\u0026le;\u0026thinsp;11 months) regimens for the outcomes of non-inferiority, safety, cost, and health-related quality of life under programmatic conditions in Pakistan. This study protocol follows the SPIRIT guidelines\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003ePrimary objective\u003c/h3\u003e\n\u003cp\u003eTo compare the efficacy of modified all-oral 9-month regimen against the standard all-oral 11-month regimen for the treatment of RR/MDR-TB.\u003c/p\u003e\n\u003ch3\u003eSecondary objectives\u003c/h3\u003e\n\u003cp\u003eTo compare 1) the proportion of deaths and treatment failure during treatment, 2) recurrent TB episode and cure without permanent disability within one year post treatment, 3) treatment adherence, 4) proportion of patients with adverse effects and serious adverse effects, 5) impact on health related quality of life and 6) cost implications of modified all-oral 9-month regimen against the standard all-oral 11-month regimen for the treatment of RR/MDR-TB.\u003c/p\u003e\n\u003ch3\u003eStudy design\u003c/h3\u003e\n\u003cp\u003eA cluster randomized non-inferiority trial with stepped wedge recruitment design.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003eStudy setting and population\u003c/h2\u003e\n \u003cp\u003eThis study will be conducted at 12 PMDT sites in Punjab, Islamabad and Azad Jammu and Kashmir region, Pakistan. Each PMDT site has a designated staff of eight members to provide treatment to RR/MDR-TB patients. The staff includes a physician, pharmacist, directly observed treatment facilitator / case management person, social support person, treatment coordinator, lab attendant, psychologist, and program data assistant.\u003c/p\u003e\n \u003cp\u003eEach person being treated for RR/MDR-TB, along with their treatment supporter, visits the PMDT site on monthly basis, to: a) be medically assessed; and b) receive TB medications (one-month supply) and social support (cash allowance). The inclusion and exclusion criteria for study participants is given in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003cdiv align=\"left\" class=\"colspec\"\u003e\u003cbr\u003e\u003c/div\u003e\u0026nbsp;\u0026nbsp;\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eInclusion and exclusion criteria of study participants\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eInclusion criteria\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eExclusion criteria\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15 or more years of age\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFluoroquinolone resistance\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWillingness and ability to give informed consent to be enrolled in the research study and for follow- up (signed or witnessed consent if the patient is illiterate).\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUnable to take oral medication.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"3\"\u003e\n \u003cp\u003eBacteriologically or molecularly confirmed TB with evidence of resistance to at least rifampicin.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eKnown allergy to any of the drugs in the study regimen.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eQT interval with Fredericia correction (QTcF) interval of \u0026ge;\u0026thinsp;500 msec at the time of registration that does not correct with medical management\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRequires medications for other health conditions contraindicated with the medicines in the study regimen.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003eEligible, consented individuals will be offered the standard of care regimen or intervention regimen (as per stepped-wedge design) for 11 or 9 months, respectively, and will be followed for 12 months after the successful completion of treatment. People who decline participation in the study or are not eligible will be referred for standard of care treatment with no negative consequences. The study timetable (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e) details the investigations and observations to conduct at each visit.\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003cdiv align=\"left\" class=\"colspec\"\u003e\u003cem\u003eTable 2. Schedule of examinations during treatment and follow-up phases of the study\u003c/em\u003e\u003c/div\u003e\n \u003cdiv align=\"left\" class=\"colspec\"\u003e\u003cbr\u003e\u003c/div\u003e\n \u003ctable style=\"margin-left: -32.5pt;border-collapse: collapse;border: none;width: 689px;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 20.55pt;border: 1pt solid black;padding: 0in;height: 26.35pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 189.05pt;border-top: 1pt solid black;border-right: 1pt solid black;border-bottom: 1pt solid black;border-image: initial;border-left: none;padding: 0in;height: 26.35pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style=\"font-size:12px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style=\"font-size:12px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:7.75pt;margin-right:0in;margin-bottom:.0001pt;margin-left:27.65pt;'\u003e\u003cstrong\u003e\u003cspan style='font-size:11px;font-family: \"Arial\",sans-serif;'\u003eInvestigation/Observation\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 0.5in;border-top: 1pt solid black;border-right: 1pt solid black;border-bottom: 1pt solid black;border-image: initial;border-left: none;background: rgb(234, 240, 221);padding: 0in;height: 26.35pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:5.45pt;margin-right:3.65pt;margin-bottom:.0001pt;margin-left:5.6pt;line-height:9.5pt;'\u003e\u003cstrong\u003e\u003cspan style='font-size:11px;font-family:\"Arial\",sans-serif;color:black;'\u003eBaseline\u0026nbsp;assessment\u0026nbsp;\u0026amp;\u0026nbsp;screening\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"9\" style=\"width: 221.3pt;border-top: 1pt solid black;border-right: 1pt solid black;border-bottom: 1pt solid black;border-image: initial;border-left: none;background: rgb(247, 202, 172);padding: 0in;height: 26.35pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:.25pt;'\u003e\u003cspan style=\"font-size:9px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-left:27.65pt;'\u003e\u003cstrong\u003e\u003cspan style='font-size:11px;font-family: \"Arial\",sans-serif;color:black;'\u003eTreatment\u0026nbsp;Phase\u0026nbsp;(M=Month)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 48.65pt;border-top: 1pt solid black;border-right: 1pt solid black;border-bottom: 1pt solid black;border-image: initial;border-left: none;padding: 0in;height: 26.35pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:.25pt;'\u003e\u003cspan style=\"font-size:9px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-left:2.85pt;'\u003e\u003cstrong\u003e\u003cspan style='font-size:11px;font-family: \"Arial\",sans-serif;'\u003ePost-treatment Follow-Up\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 24.6pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 28.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:5.6pt;margin-right: 2.75pt;margin-bottom:.0001pt;margin-left:5.9pt;text-align: center;'\u003e\u003cstrong\u003e\u003cspan style='font-size:11px;font-family:\"Arial\",sans-serif;color:black;'\u003eM \u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-size:8px;font-family:\"Arial\",sans-serif;color:black;'\u003eT\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:.95pt;margin-right: 0in;margin-bottom:.0001pt;margin-left:3.1pt;text-align: center;'\u003e\u003cstrong\u003e\u003cspan style='font-size:11px;font-family:\"Arial\",sans-serif;color:black;'\u003e1\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.45pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 28.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:5.6pt;margin-right: .55pt;margin-bottom:.0001pt;margin-left:.05in;text-align: center;'\u003e\u003cstrong\u003e\u003cspan style='font-size:11px;font-family:\"Arial\",sans-serif;color:black;'\u003eM \u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-size:8px;font-family:\"Arial\",sans-serif;color:black;'\u003eT\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:.95pt;margin-right: 0in;margin-bottom:.0001pt;margin-left:3.0pt;text-align: center;'\u003e\u003cstrong\u003e\u003cspan style='font-size:11px;font-family:\"Arial\",sans-serif;color:black;'\u003e2\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.55pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 28.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:5.6pt;margin-right: 2.95pt;margin-bottom:.0001pt;margin-left:5.95pt;text-align: center;'\u003e\u003cstrong\u003e\u003cspan style='font-size:11px;font-family:\"Arial\",sans-serif;color:black;'\u003eM \u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-size:8px;font-family:\"Arial\",sans-serif;color:black;'\u003eT\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:.95pt;margin-right: 0in;margin-bottom:.0001pt;margin-left:3.0pt;text-align: center;'\u003e\u003cstrong\u003e\u003cspan style='font-size:11px;font-family:\"Arial\",sans-serif;color:black;'\u003e3\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.45pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 28.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:5.6pt;margin-right: .4pt;margin-bottom:.0001pt;margin-left:.05in;text-align: center;'\u003e\u003cstrong\u003e\u003cspan style='font-size:11px;font-family:\"Arial\",sans-serif;color:black;'\u003eM \u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-size:8px;font-family:\"Arial\",sans-serif;color:black;'\u003eT\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:.95pt;margin-right: 0in;margin-bottom:.0001pt;margin-left:3.2pt;text-align: center;'\u003e\u003cstrong\u003e\u003cspan style='font-size:11px;font-family:\"Arial\",sans-serif;color:black;'\u003e4\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.6pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 28.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:5.6pt;margin-right: 2.75pt;margin-bottom:.0001pt;margin-left:5.85pt;text-align: center;'\u003e\u003cstrong\u003e\u003cspan style='font-size:11px;font-family:\"Arial\",sans-serif;color:black;'\u003eM \u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-size:8px;font-family:\"Arial\",sans-serif;color:black;'\u003eT\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:.95pt;margin-right: 0in;margin-bottom:.0001pt;margin-left:3.1pt;text-align: center;'\u003e\u003cstrong\u003e\u003cspan style='font-size:11px;font-family:\"Arial\",sans-serif;color:black;'\u003e5\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.5pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 28.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:5.6pt;margin-right: 2.75pt;margin-bottom:.0001pt;margin-left:6.05pt;text-align: center;'\u003e\u003cstrong\u003e\u003cspan style='font-size:11px;font-family:\"Arial\",sans-serif;color:black;'\u003eM \u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-size:8px;font-family:\"Arial\",sans-serif;color:black;'\u003eT\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:.95pt;margin-right: 0in;margin-bottom:.0001pt;margin-left:3.25pt;text-align: center;'\u003e\u003cstrong\u003e\u003cspan style='font-size:11px;font-family:\"Arial\",sans-serif;color:black;'\u003e6\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.6pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 28.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:5.6pt;margin-right: 2.6pt;margin-bottom:.0001pt;margin-left:6.0pt;text-align: center;'\u003e\u003cstrong\u003e\u003cspan style='font-size:11px;font-family:\"Arial\",sans-serif;color:black;'\u003eM \u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-size:8px;font-family:\"Arial\",sans-serif;color:black;'\u003eT\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:.95pt;margin-right: 0in;margin-bottom:.0001pt;margin-left:3.35pt;text-align: center;'\u003e\u003cstrong\u003e\u003cspan style='font-size:11px;font-family:\"Arial\",sans-serif;color:black;'\u003e7\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.6pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 28.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:5.6pt;margin-right: 2.75pt;margin-bottom:.0001pt;margin-left:5.9pt;text-align: center;'\u003e\u003cstrong\u003e\u003cspan style='font-size:11px;font-family:\"Arial\",sans-serif;color:black;'\u003eM \u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-size:8px;font-family:\"Arial\",sans-serif;color:black;'\u003eT\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:.95pt;margin-right: 0in;margin-bottom:.0001pt;margin-left:3.1pt;text-align: center;'\u003e\u003cstrong\u003e\u003cspan style='font-size:11px;font-family:\"Arial\",sans-serif;color:black;'\u003e8\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.95pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 28.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:6.3pt;margin-right:4.75pt;margin-bottom:.0001pt;margin-left:2.6pt;text-indent:2.75pt;line-height:95%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:11px;line-height:95%;font-family: \"Arial\",sans-serif;color:black;'\u003eM\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-size:8px;line-height:95%;font-family: \"Arial\",sans-serif;color:black;'\u003eT \u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-size:11px;line-height:95%;font-family: \"Arial\",sans-serif;color:black;'\u003e9/11\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.15pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 0in;height: 28.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:6.1pt;margin-right:4.35pt;margin-bottom:.0001pt;margin-left:10.85pt;text-indent:-2.8pt;'\u003e\u003cstrong\u003e\u003cspan style='font-size:11px;font-family: \"Arial\",sans-serif;'\u003eM\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-size:7px;font-family:\"Arial\",sans-serif;'\u003eF \u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-size:11px;font-family: \"Arial\",sans-serif;'\u003e6\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.5pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 0in;height: 28.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:6.1pt;margin-right:4.4pt;margin-bottom:.0001pt;margin-left:8.95pt;text-indent:-.6pt;'\u003e\u003cstrong\u003e\u003cspan style='font-size:11px;font-family: \"Arial\",sans-serif;'\u003eM\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-size:7px;font-family:\"Arial\",sans-serif;'\u003eF \u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-size:11px;font-family: \"Arial\",sans-serif;'\u003e12\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"6\" style=\"width: 20.55pt;border-right: 1pt solid black;border-bottom: 1pt solid black;border-left: 1pt solid black;border-image: initial;border-top: none;padding: 0in;height: 15.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:6.05pt;margin-right:0in;margin-bottom:.0001pt;margin-left:5.6pt;'\u003e\u003cstrong\u003e\u003cspan style='font-size:11px;font-family: \"Arial\",sans-serif;'\u003eClinical\u0026nbsp;evaluation\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 189.05pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 0in;height: 15.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:4.0pt;margin-right:0in;margin-bottom:.0001pt;margin-left:6.2pt;'\u003e\u003cspan style=\"font-size:11px;\"\u003eDemographics,\u0026nbsp;Medical\u0026nbsp;History\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0.5in;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(234, 240, 221);padding: 0in;height: 15.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:4.0pt;margin-right: 0in;margin-bottom:.0001pt;margin-left:1.7pt;text-align: center;'\u003e\u003cspan style=\"font-size:11px;color:black;\"\u003eX\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.6pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 15.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.45pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 15.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.55pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 15.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.45pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 15.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.6pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 15.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.5pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 15.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.6pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 15.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.6pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 15.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.95pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 15.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.15pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 0in;height: 15.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.5pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 0in;height: 15.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 189.05pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 0in;height: 15.15pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:4.0pt;margin-right:0in;margin-bottom:.0001pt;margin-left:6.2pt;'\u003e\u003cspan style=\"font-size:11px;\"\u003eWritten\u0026nbsp;informed\u0026nbsp;consent\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0.5in;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(234, 240, 221);padding: 0in;height: 15.15pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:3.85pt;margin-right: 0in;margin-bottom:.0001pt;margin-left:1.7pt;text-align: center;'\u003e\u003cspan style=\"font-size:11px;color:black;\"\u003eX\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.6pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 15.15pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.45pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 15.15pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.55pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 15.15pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.45pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 15.15pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.6pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 15.15pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.5pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 15.15pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.6pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 15.15pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n 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black;border-right: 1pt solid black;padding: 0in;height: 15.15pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.5pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 0in;height: 15.15pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 189.05pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 0in;height: 15.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:3.9pt;margin-right:0in;margin-bottom:.0001pt;margin-left:6.2pt;line-height:10.5pt;'\u003e\u003cspan style=\"font-size:11px;\"\u003eClinical\u0026nbsp;Examination\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0.5in;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(234, 240, 221);padding: 0in;height: 15.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:3.85pt;margin-right: 0in;margin-bottom:.0001pt;margin-left:1.7pt;text-align: center;'\u003e\u003cspan style=\"font-size:11px;color:black;\"\u003eX\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.6pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 15.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:3.85pt;margin-right: 0in;margin-bottom:.0001pt;margin-left:3.05pt;text-align: center;'\u003e\u003cspan style=\"font-size:11px;color:black;\"\u003eX\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.45pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 15.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:3.85pt;margin-right: 0in;margin-bottom:.0001pt;margin-left:2.95pt;text-align: center;'\u003e\u003cspan style=\"font-size:11px;color:black;\"\u003eX\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.55pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 15.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:3.85pt;margin-right: 0in;margin-bottom:.0001pt;margin-left:2.9pt;text-align: center;'\u003e\u003cspan style=\"font-size:11px;color:black;\"\u003eX\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.45pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 15.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:3.85pt;margin-right: 0in;margin-bottom:.0001pt;margin-left:3.1pt;text-align: center;'\u003e\u003cspan style=\"font-size:11px;color:black;\"\u003eX\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.6pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 15.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:3.85pt;margin-right: 0in;margin-bottom:.0001pt;margin-left:3.0pt;text-align: center;'\u003e\u003cspan style=\"font-size:11px;color:black;\"\u003eX\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.5pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 15.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:3.85pt;margin-right: 0in;margin-bottom:.0001pt;margin-left:3.2pt;text-align: center;'\u003e\u003cspan style=\"font-size:11px;color:black;\"\u003eX\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.6pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 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rgb(247, 202, 172);padding: 0in;height: 15.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:3.85pt;margin-right:0in;margin-bottom:.0001pt;margin-left:10.85pt;'\u003e\u003cspan style=\"font-size:11px;color:black;\"\u003eX\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.15pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 0in;height: 15.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:3.85pt;margin-right: 3.1pt;margin-bottom:.0001pt;margin-left:5.95pt;text-align: center;'\u003e\u003cspan style=\"font-size:11px;\"\u003eX\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.5pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 0in;height: 15.4pt;vertical-align: top;\"\u003e\n 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MT\",sans-serif;margin-top:3.85pt;margin-right:23.95pt;margin-bottom:.0001pt;margin-left:6.2pt;line-height:9.0pt;'\u003e\u003cspan style=\"font-size:11px;\"\u003eSerum\u0026nbsp;creatinine\u0026nbsp;(at\u0026nbsp;baseline\u0026nbsp;and\u0026nbsp;if\u0026nbsp;clinically\u0026nbsp;indicated\u0026nbsp;or ECG\u0026nbsp;abnormalities)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0.5in;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(234, 240, 221);padding: 0in;height: 23.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:4.0pt;margin-right: 0in;margin-bottom:.0001pt;margin-left:1.7pt;text-align: center;'\u003e\u003cspan style=\"font-size:11px;color:black;\"\u003eX\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.6pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 23.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.45pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 23.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.55pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 23.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.45pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 23.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.6pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 23.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.5pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 23.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.6pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 23.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.6pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 23.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.95pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 23.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.15pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 0in;height: 23.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.5pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 0in;height: 23.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 189.05pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 0in;height: 22.35pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:3.2pt;margin-right:21.2pt;margin-bottom:.0001pt;margin-left:6.2pt;line-height:9.1pt;'\u003e\u003cspan style=\"font-size:11px;\"\u003eSerum potassium (at baseline and if clinically\u0026nbsp;indicated\u0026nbsp;or ECG\u0026nbsp;abnormalities)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0.5in;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(234, 240, 221);padding: 0in;height: 22.35pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:4.1pt;margin-right: 0in;margin-bottom:.0001pt;margin-left:1.7pt;text-align: center;'\u003e\u003cspan style=\"font-size:11px;color:black;\"\u003eX\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.6pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 22.35pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.45pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 22.35pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.55pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 22.35pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.45pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 22.35pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.6pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 22.35pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.5pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 22.35pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.6pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 22.35pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.6pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 22.35pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.95pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 22.35pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.15pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 0in;height: 22.35pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.5pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 0in;height: 22.35pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 189.05pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 0in;height: 14.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:4.1pt;margin-right:0in;margin-bottom:.0001pt;margin-left:6.2pt;'\u003e\u003cspan style=\"font-size:11px;\"\u003ePregnancy\u0026nbsp;test\u0026nbsp;(female)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0.5in;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(234, 240, 221);padding: 0in;height: 14.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:3.9pt;margin-right: 0in;margin-bottom:.0001pt;margin-left:1.7pt;text-align: center;'\u003e\u003cspan style=\"font-size:11px;color:black;\"\u003eX\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.6pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 14.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.45pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 14.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.55pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 14.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan 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black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 14.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.95pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 14.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.15pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 0in;height: 14.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.5pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 0in;height: 14.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 189.05pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 0in;height: 18.05pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:4.0pt;margin-right:0in;margin-bottom:.0001pt;margin-left:6.2pt;'\u003e\u003cspan style=\"font-size:11px;\"\u003eHIV\u0026nbsp;testing\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0.5in;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(234, 240, 221);padding: 0in;height: 18.05pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:4.95pt;margin-right: 6.75pt;margin-bottom:.0001pt;margin-left:8.7pt;text-align: center;'\u003e\u003cspan style=\"font-size:11px;color:black;\"\u003eX\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.6pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 18.05pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.45pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 18.05pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.55pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 18.05pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.45pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 18.05pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.6pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 18.05pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.5pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 18.05pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.6pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 18.05pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.6pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 18.05pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.95pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 18.05pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.15pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 0in;height: 18.05pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.5pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 0in;height: 18.05pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"4\" style=\"width: 20.55pt;border-top: none;border-left: 1pt solid black;border-bottom: none;border-right: 1pt solid black;padding: 0in;height: 16.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:6.05pt;margin-right: 31.0pt;margin-bottom:.0001pt;margin-left:26.35pt;text-align:center;'\u003e\u003cstrong\u003e\u003cspan style='font-size:11px;font-family:\"Arial\",sans-serif;'\u003eOther\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 189.05pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 0in;height: 16.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:4.2pt;margin-right:0in;margin-bottom:.0001pt;margin-left:6.2pt;'\u003e\u003cspan style=\"font-size:11px;\"\u003eECG\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0.5in;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(234, 240, 221);padding: 0in;height: 16.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:5.2pt;margin-right: 0in;margin-bottom:.0001pt;margin-left:1.7pt;text-align: center;'\u003e\u003cspan style=\"font-size:11px;color:black;\"\u003eX\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.6pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 16.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:5.2pt;margin-right: 2.75pt;margin-bottom:.0001pt;margin-left:5.8pt;text-align: center;'\u003e\u003cspan style=\"font-size:11px;color:black;\"\u003eX\u003c/span\u003e\u003cstrong\u003e\u003cspan style='font-size:11px;font-family:\"Arial\",sans-serif;color:#C00000;'\u003e\u0026beta;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.45pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 16.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:5.2pt;margin-right: 0in;margin-bottom:.0001pt;margin-left:2.95pt;text-align: center;'\u003e\u003cspan style=\"font-size:11px;color:black;\"\u003eX\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.55pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 16.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:5.2pt;margin-right: 0in;margin-bottom:.0001pt;margin-left:2.9pt;text-align: center;'\u003e\u003cspan style=\"font-size:11px;color:black;\"\u003eX\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.45pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 16.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:5.2pt;margin-right: 0in;margin-bottom:.0001pt;margin-left:3.1pt;text-align: center;'\u003e\u003cspan style=\"font-size:11px;color:black;\"\u003eX\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.6pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 16.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:5.2pt;margin-right: 0in;margin-bottom:.0001pt;margin-left:3.0pt;text-align: center;'\u003e\u003cspan style=\"font-size:11px;color:black;\"\u003eX\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.5pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 16.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:5.2pt;margin-right: 0in;margin-bottom:.0001pt;margin-left:3.2pt;text-align: center;'\u003e\u003cspan style=\"font-size:11px;color:black;\"\u003eX\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.6pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 16.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:5.2pt;margin-right: 0in;margin-bottom:.0001pt;margin-left:3.3pt;text-align: center;'\u003e\u003cspan style=\"font-size:11px;color:black;\"\u003eX\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.6pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 16.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:5.2pt;margin-right: 0in;margin-bottom:.0001pt;margin-left:3.05pt;text-align: center;'\u003e\u003cspan style=\"font-size:11px;color:black;\"\u003eX\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.95pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 16.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:5.2pt;margin-right:0in;margin-bottom:.0001pt;margin-left:10.85pt;'\u003e\u003cspan style=\"font-size:11px;color:black;\"\u003eX\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.15pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 0in;height: 16.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.5pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 0in;height: 16.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 189.05pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 0in;height: 24.65pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:2.95pt;margin-right:26.65pt;margin-bottom:.0001pt;margin-left:6.2pt;line-height:9.0pt;'\u003e\u003cspan style=\"font-size:11px;\"\u003eVisual acuity \u0026amp; BPNS\u003c/span\u003e\u003cspan style=\"font-size:13px;color:red;\"\u003e\u0026nbsp;\u003c/span\u003e\u003cem\u003e\u003cspan style='font-size:11px;font-family: \"Arial\",sans-serif;'\u003e(Note:\u0026nbsp;for\u0026nbsp;patients\u0026nbsp;receiving\u0026nbsp;Lzd\u0026nbsp;and high-dose\u0026nbsp;INH/EMB)\u003c/span\u003e\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0.5in;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(234, 240, 221);padding: 0in;height: 24.65pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:4.95pt;margin-right: 0in;margin-bottom:.0001pt;margin-left:1.7pt;text-align: center;'\u003e\u003cspan style=\"font-size:11px;color:black;\"\u003eX\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.6pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 24.65pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:4.95pt;margin-right: 2.75pt;margin-bottom:.0001pt;margin-left:5.75pt;text-align: center;'\u003e\u003cspan style=\"font-size:11px;color:black;\"\u003e(X)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.45pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 24.65pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:4.95pt;margin-right: .55pt;margin-bottom:.0001pt;margin-left:3.45pt;text-align: center;'\u003e\u003cspan style=\"font-size:11px;color:black;\"\u003e(X)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.55pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 24.65pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:4.95pt;margin-right: 2.95pt;margin-bottom:.0001pt;margin-left:5.8pt;text-align: center;'\u003e\u003cspan style=\"font-size:11px;color:black;\"\u003e(X)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.45pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 24.65pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:4.95pt;margin-right: .55pt;margin-bottom:.0001pt;margin-left:.05in;text-align: center;'\u003e\u003cspan style=\"font-size:11px;color:black;\"\u003e(X)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.6pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 24.65pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:4.95pt;margin-right: 2.75pt;margin-bottom:.0001pt;margin-left:5.7pt;text-align: center;'\u003e\u003cspan style=\"font-size:11px;color:black;\"\u003e(X)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.5pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 24.65pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:4.95pt;margin-right: 2.75pt;margin-bottom:.0001pt;margin-left:5.9pt;text-align: center;'\u003e\u003cspan style=\"font-size:11px;color:black;\"\u003e(X)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.6pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 24.65pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:4.95pt;margin-right: 2.75pt;margin-bottom:.0001pt;margin-left:6.0pt;text-align: center;'\u003e\u003cspan style=\"font-size:11px;color:black;\"\u003e(X)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.6pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 24.65pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:4.95pt;margin-right: 2.75pt;margin-bottom:.0001pt;margin-left:5.75pt;text-align: center;'\u003e\u003cspan style=\"font-size:11px;color:black;\"\u003e(X)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.95pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 24.65pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:4.95pt;margin-right: 5.0pt;margin-bottom:.0001pt;margin-left:0in;text-align: right;'\u003e\u003cspan style=\"font-size:11px;color:black;\"\u003e(X)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.15pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 0in;height: 24.65pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.5pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 0in;height: 24.65pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 189.05pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 0in;height: 19pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:3.95pt;margin-right:0in;margin-bottom:.0001pt;margin-left:6.2pt;'\u003e\u003cspan style=\"font-size:11px;\"\u003eChest\u0026nbsp;X-ray\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0.5in;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(234, 240, 221);padding: 0in;height: 19pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:4.95pt;margin-right: 0in;margin-bottom:.0001pt;margin-left:1.7pt;text-align: center;'\u003e\u003cspan style=\"font-size:11px;color:black;\"\u003eX\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.6pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 19pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.45pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 19pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.55pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 19pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.45pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 19pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.6pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 19pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.5pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 19pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.6pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 19pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.6pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 19pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.95pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 19pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.15pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 0in;height: 19pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.5pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 0in;height: 19pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 189.05pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 0in;height: 17.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:3.95pt;margin-right:0in;margin-bottom:.0001pt;margin-left:6.2pt;'\u003e\u003cspan style=\"font-size:11px;\"\u003eDisability assessment\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0.5in;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(234, 240, 221);padding: 0in;height: 17.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:4.95pt;margin-right: 0in;margin-bottom:.0001pt;margin-left:1.7pt;text-align: center;'\u003e\u003cspan style=\"font-size:11px;color:black;\"\u003eX\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.6pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 17.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.45pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 17.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.55pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 17.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.45pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 17.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.6pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 17.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.5pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 17.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.6pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 17.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.6pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 17.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.95pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 17.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:4.95pt;margin-right:0in;margin-bottom:.0001pt;margin-left:10.85pt;'\u003e\u003cspan style=\"font-size:11px;color:black;\"\u003eX\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.15pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 0in;height: 17.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:4.95pt;margin-right: 0in;margin-bottom:.0001pt;margin-left:3.05pt;text-align: center;'\u003e\u003cspan style=\"font-size:11px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.5pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 0in;height: 17.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:4.95pt;margin-right: 0in;margin-bottom:.0001pt;margin-left:3.15pt;text-align: center;'\u003e\u003cspan style=\"font-size:11px;\"\u003eX\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 20.55pt;border-right: 1pt solid black;border-bottom: 1pt solid black;border-left: 1pt solid black;border-image: initial;border-top: none;padding: 0in;height: 17.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-size:1px;line-height:107%;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 189.05pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 0in;height: 17.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:3.95pt;margin-right:0in;margin-bottom:.0001pt;margin-left:6.2pt;'\u003e\u003cspan style=\"font-size:11px;\"\u003eHealth Related Quality of Life assessment\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0.5in;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(234, 240, 221);padding: 0in;height: 17.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:4.95pt;text-align: center;'\u003e\u003cspan style=\"font-size:11px;color:black;\"\u003eX\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.6pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 17.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.45pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 17.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.55pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 17.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.45pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 17.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;text-align:center;'\u003e\u003cspan style=\"font-size:11px;color:black;\"\u003eX\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.6pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 17.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.5pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 17.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.6pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 17.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.6pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 17.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;'\u003e\u003cspan style='font-size:11px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.95pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;background: rgb(247, 202, 172);padding: 0in;height: 17.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:4.95pt;margin-right:0in;margin-bottom:.0001pt;margin-left:10.85pt;'\u003e\u003cspan style=\"font-size:11px;color:black;\"\u003eX\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.15pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 0in;height: 17.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:4.95pt;margin-right: 0in;margin-bottom:.0001pt;margin-left:3.05pt;text-align: center;'\u003e\u003cspan style=\"font-size:11px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.5pt;border-top: none;border-left: none;border-bottom: 1pt solid black;border-right: 1pt solid black;padding: 0in;height: 17.2pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Arial MT\",sans-serif;margin-top:4.95pt;margin-right: 0in;margin-bottom:.0001pt;margin-left:3.15pt;text-align: center;'\u003e\u003cspan style=\"font-size:11px;\"\u003eX\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:normal;'\u003e\u003cstrong\u003e\u003cspan style='font-size:11px;font-family:\"Arial\",sans-serif;color:#C00000;'\u003e\u0026beta;\u003c/span\u003e\u003c/strong\u003e\u003cem\u003e\u003cspan style=\"font-size:12px;\"\u003eBaseline ECG should be obtained and additional ECGs conducted at week 1 and 2 after starting treatment and thereafter monthly throughout treatment..\u003c/span\u003e\u003c/em\u003e\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003ch3\u003eSample size:\u003c/h3\u003e\n\u003cp\u003eThe number of participants to be included in this study has been estimated based on surveillance data from the NTP, specifically the number of people with bacteriologically confirmed RR/MDR-TB.\u003c/p\u003e\n\u003cp\u003eThe sample size was calculated using the stepped wedge cluster level power calculations in STATA (statistical software package). A sample of 400 RR/MDR-TB patients (i.e. 200 in each arm) will be required for a non-inferiority margin of 12% on the primary outcome of treatment success without recurrence at 12 months after the end of treatment while maintaining 80% power and type I error rate of 5%. The average number of RR/MDR-TB patients in the clusters will be 20 and will be included in the trial in four steps excluding baseline.\u003c/p\u003e\n\u003ch3\u003eInterventions\u003c/h3\u003e\n\u003cp\u003eBoth the regimens under investigation are adapted from the WHO recommended dose of drugs\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e, Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003eIntervention care\u003c/h2\u003e\n \u003cp\u003eThe intervention care is the modified all-oral shorter regimen for the duration of 9 months.\u003c/p\u003e\n \u003cp\u003e2 Lzd-Bdq-Lfx -Cfz-Z-E-H(high dose) / 4 Bdq- Lfx -Cfz-Z-E-H(high dose) / 3 Lfx -Cfz-Z-E\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n \u003ch2\u003eStandard of care\u003c/h2\u003e\n \u003cp\u003eThe standard of care is the all-oral shorter regimen for the duration of 11 months.\u003c/p\u003e\n \u003cp\u003e6 Bdq- Lfx -Cfz-Eto-Z-E-H(high dose) / 5 Lfx-Cfz-Z-E\u003c/p\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eDaily drug dosage by patient weight (above 14 years old)\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDrug\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eWeight-based daily dose\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eFormulation\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e30\u0026ndash;35 kg\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e36\u0026ndash;45 kg\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e46\u0026ndash;55 kg\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e56\u0026ndash;70 kg\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u0026gt;\u0026thinsp;70 kg\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eUsual upper daily dose\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBedaquiline\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e100 mg tab\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"5\"\u003e\n \u003cp\u003e4 tabs od first two weeks, then 2 tabs od M/W/F for 22 weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e400 mg\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"3\"\u003e\n \u003cp\u003eLevofloxacin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"3\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e250 mg tab\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.5 g\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e500 mg tab\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.5 g\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e750 mg tab\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.5 g\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEthionamide\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15\u0026ndash;20 mg/kg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e250 mg tab\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 g\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eClofazimine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e50 mg cps or tab\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e100 mg\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e100 mg cps or tab\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e100 mg\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003ePyrazinamide\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e20\u0026ndash;30 mg/kg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e400 mg tab\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e500 mg tab\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIsoniazid (high dose)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10\u0026ndash;15 mg/kg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e300 mg tab\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEthambutol\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15\u0026ndash;25 mg/kg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e400 mg tab\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLinezolid\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e600 mg tab\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;15 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;15 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.2 g\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"9\"\u003eAdapted from \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://iris.who.int/bitstream/handle/10665/311389/9789241550529-eng.pdf\u003c/span\u003e\u003c/span\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n \u003ch2\u003eOutcomes\u003c/h2\u003e\n \u003cdiv id=\"Sec14\" class=\"Section3\"\u003e\n \u003ch3\u003ePrimary outcomes\u003c/h3\u003e\n \u003cp\u003eThere are two primary outcomes of interest:\u003c/p\u003e\n \u003cp\u003e\u003cspan\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003ea) Treatment efficacy\u003c/strong\u003e: the proportion of RR/MDR-TB patients who have a favorable treatment outcome. This is defined as \u0026ldquo;cured\u0026rdquo; or \u0026ldquo;treatment completed\u0026rdquo; without recurrence during 12 months after successful treatment\u003c/p\u003e\n \u003cp\u003e\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\n \u003ch2\u003eSecondary outcomes\u003c/h2\u003e\n \u003cp\u003eThe secondary outcomes of interest include:\u003c/p\u003e\n \u003col style=\"list-style-type: lower-alpha;\"\u003e\n \u003cli\u003eThe proportion of RR/MDR-TB patients who died while on treatment.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eThe proportion of RR/MDR-TB patients who had a treatment failure.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eThe proportion of RR/MDR-TB patients who had a recurrent episode of RR/MDR-TB during the 12- month follow-up.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eThe proportion of RR/MDR-TB patients who are \u0026ldquo;cured without permanent disability\u0026rdquo; (up to one year after the end of the treatment).\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eThe proportion of RR/MDR-TB patients who complete at least 90% of doses (intake adherence indicator to be included as deem feasible in the given context).\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eThe average number of adverse events of interest experienced by RR/MDR-TB patients.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eThe proportion of RR/MDR-TB patients experiencing each adverse event of interest.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eThe proportion of RR/MDR-TB patients who experience serious adverse events.\u003c/li\u003e\n \u003c/ol\u003e\n \u003cp\u003eKey definitions of study outcomes are given in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e.\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u0026nbsp;\u003ctable id=\"Tab4\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eDefinitions of study outcomes.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eOutcomes\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDefinition\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eFavorable outcome\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eComposite outcome corresponding to the combination of \u0026ldquo;cured\u0026rdquo; + \u0026ldquo;treatment completed\u0026rdquo; (=\u0026thinsp;treatment success) without recurrence over the 12-month follow-up period.\u003c/p\u003e\n \u003cp\u003eNote: this outcome can also be defined as \u0026ldquo;recurrence-free cure\u0026rdquo;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eCured\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eA patient with bacteriologically confirmed MDR/RR-TB who has completed 9\u0026ndash;12 months of treatment by 9/12-month regimen protocol without evidence of failure AND at least two consecutive cultures taken at least 30 days apart are negative at the end of the treatment and at least one month earlier.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eTreatment Completed\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eA patient who completes 9\u0026ndash;12 months of treatment by 9/12-month regimen protocol without evidence of failure BUT without bacteriological evidence (negative culture at the end of the treatment phase and at least one month earlier).\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eTreatment Failed\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTreatment terminated or need for permanent change of the regimen protocol of at least two anti-TB drugs because of:\u003c/p\u003e\n \u003cp\u003e\u0026bull; lack of sputum \u003cstrong\u003eculture\u003c/strong\u003e conversion after 4 months of treatment, or\u003c/p\u003e\n \u003cp\u003e\u0026bull; bacteriological reversion of sputum \u003cstrong\u003eculture\u003c/strong\u003e after 5 months of treatment in a patient with previous culture conversion to negative, or\u003c/p\u003e\n \u003cp\u003e\u0026bull; evidence of additional acquired resistance to drugs in the study, or\u003c/p\u003e\n \u003cp\u003e\u0026bull; adverse drug reactions (ADRs) (leading to the change of at least two anti-TB drugs in the regimen)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eDied\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eA patient who dies for any reason during treatment.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eLost to follow-up\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eA patient whose treatment was interrupted for 2 consecutive months or more.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eNot evaluated\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eA patient for whom no treatment outcome is assigned (this includes cases \u0026ldquo;transferred out\u0026rdquo; to another treatment unit and whose treatment outcome is unknown/can\u0026rsquo;t be assessed)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eWithdrawn\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eA patient is taken off the 9/12-month regimen for any reason other than treatment failure (for example, baseline second-line drug resistance, withdrawn patient informed consent or other reasons) and referred to the PMDT program for routine care.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eRecurrence\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCure or treatment completion followed by two consecutive positive cultures during post- treatment follow-up (without genotyping information on baseline and recurrent strain), or one positive culture with clinical signs and symptoms or radiographic deterioration.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eConversion (to negative)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCultureisconsideredtohaveconvertedtonegativewhentwoconsecutiveculturestaken at least 30 days apart are found to be negative. In such case, the specimen collection date of the first negative culture is used as the date of conversion.\u003c/p\u003e\n \u003cp\u003eIn case patients were culture negative at baseline, a negative culture result at month 4 may be considered as \u0026ldquo;initial conversion\u0026rdquo;.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eReversion (to positive)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCulture is considered to have reverted to positive when after an initial conversion, two consecutive cultures taken at least 30 days apart are found to be positive.\u003c/p\u003e\n \u003cp\u003eIn case of patients who are culture negative at baseline, a positive culture result at month 4 may be considered as \u0026ldquo;initial conversion\u0026rdquo;.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eTreatment adherence\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e90% of the treatment doses were taken based on staff notes in the treatment cards, measured over the entire treatment period.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003ePermanent disability\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eA combined outcome, using the modified Medical Research Council Dyspnea scale (mMRC) based on which patients with a score above 2 are considered permanently disabled in terms of their pneumological function. A score of 2 describes that the on level ground, the person walks slower than people of same age because of breathlessness, or have to stop for breath when walking at own pace on the level.\u003c/p\u003e\n \u003cp\u003eIn addition, all serious adverse events by system organ class that are not resolved at the end of treatment, should be summarized by treatment regimen.\u003c/p\u003e\n \u003cp\u003eThis is a measure of a programme\u0026rsquo;s ability to start treatment promptly and treat patients effectively.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\n \u003ch2\u003eClustering\u003c/h2\u003e\n \u003cp\u003eThe randomization unit or cluster in this trial is PMDT site. All patients meeting the eligibility criteria at the respective PMDT site will be randomised to the same trial arm. Taking PMDT site as unit of randomization will avoid the risk of contamination.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\n \u003ch2\u003eRandomization and blinding\u003c/h2\u003e\n \u003cp\u003eThe study biostatistician will create the randomization sequence using STATA14.2 statistical software. The first three sites will be designated to enter the intervention after 3 months of the standard-of-care phase, the second three after 6 months, the third group after 9 months, and the last three after 12 months (Fig. 1). For the first three months of the study, all investigators will be kept blinded about the allocation sequence, allowing all sites to begin using standard-of-care without knowing when the intervention phase will begin. Then, the biostatistician will inform which three sites will be chosen randomly to begin the first phase of the intervention.\u003c/p\u003e\n \u003cp\u003eBefore moving on to the intervention phase, the three study sites will go through a transition phase for one week in which the site staff will be trained on research protocols and the administration of new treatment; along with that, logistic preparations (drug procurement, etc.) will also be done. The standard-of-care will be maintained at all other study sites, and they will be blinded to the time when the intervention will begin. The study design prevents blinding of the site investigators following exposure to intervention arm. When moving from the standard of care to the intervention treatment regimen, the patients who started the standard of care treatment will continue until the end of the treatment, but the newly diagnosed RR/MDR-TB patients will be treated with the intervention treatment regimen.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\n \u003ch2\u003eDiscontinuation of the study regimen\u003c/h2\u003e\n \u003cp\u003eIn case the study regimen must be discontinued, participants will be evaluated by a clinical committee and switched to an individualized regimen, as per the national guidelines. The most common situations in which the regimen may be discontinued are included in box 1:\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tabb\" border=\"1\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eBox 1: Situations to discontinue study treatment regimen\u003c/strong\u003e:\u003c/p\u003e\n \u003cp\u003ea) \u003cstrong\u003eAcquired resistance to any drug in the regimen\u003c/strong\u003e: If resistance to any drug in the regimen is acquired after treatment is initiated, it may be necessary to modify, extend or discontinue the regimen.\u003c/p\u003e\n \u003cp\u003eb) \u003cstrong\u003eSevere toxicity\u003c/strong\u003e: One or more drugs may need to be suspended permanently due to severe toxicity. In such cases, the clinical committee will review the medical history carefully to determine how the regimen should be modified.\u003c/p\u003e\n \u003cp\u003ec) \u003cstrong\u003eTreatment failure\u003c/strong\u003e: If clinical and bacteriological responses to treatment are poor (informed by culture result), a change in the treatment regimen might be considered. DST will be repeated, whether the regimen is changed, to inform future management decisions.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec19\" class=\"Section2\"\u003e\n \u003ch2\u003ePost-treatment follow-up\u003c/h2\u003e\n \u003cp\u003eAfter completion of treatment, participants will be informed of the risk of recurrent TB disease and advised to return for clinical assessment and sputum collection (at PMDT site) at 6 and 12 months after completion of treatment or at any time after the end of the treatment if experiencing TB clinical symptoms. In case participants are unable to visit the PMDT site, a telephonic survey encompassing clinical evaluation will be conducted.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec20\" class=\"Section2\"\u003e\n \u003ch2\u003eSafety monitoring and management\u003c/h2\u003e\n \u003cp\u003eParticipants will be screened and managed monthly by PMDT site physicians and/or pharmacists trained in the diagnosis and management of adverse events (AE). AEs severity and seriousness will be judged based on the national guidelines for AEs recording and reporting (See Annexure 1\u0026amp;2 for details on AEs diagnosis and management).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec21\" class=\"Section2\"\u003e\n \u003ch2\u003eData collection and analysis\u003c/h2\u003e\n \u003cp\u003eThe study data will be regularly retrieved from the program electronic medical records and will be reviewed by the MDR program coordinator to look for any discrepancies or protocol deviations. The analysis will be done using the intention to treat analysis principle and non-inferiority will be declared if the lower-bound of the 95% confidence interval of the difference in treatment success without recurrence at 12 months after the end of treatment between the intervention and control group is greater than \u0026minus;\u0026thinsp;12%. Participants with no information during the 12-month follow-up will be classified as \u0026ldquo;not assessable\u0026rdquo;.\u003c/p\u003e\n \u003cp\u003eBaseline characteristics of the participants will be reported by treatments and groups of sites. Frequencies and percentages will summarize the categorical variables, whereas the quantitative variables (such as the age) will be described through mean and standard deviation (SD). The Chi-square, Fisher\u0026rsquo;s exact, Mann-Whitney or Kruskal-Wallis tests will be employed to detect any imbalances in baseline characteristics across regimen treatment, with a level of significance of 5%.\u003c/p\u003e\n \u003cp\u003eFor the primary outcome, a marginal mean model with Poisson generalized estimation equations (GEE) \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e, and a log-link will assess the relative risk (RR), by comparing the two treatment regimens. The group of sites will be considered as a cluster effect. The period will be added in the list of predictors and will be considered as a categorical variable \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. The models will be adjusted at least on age and gender: the selection of covariables. To correct the inflated type I error rates due to the small number of clusters, the Fay and Graubard (FG) correction will be applied to the standard errors\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. 95% confidence intervals (CI) will be displayed. The upper limit of the CI will be compared with the non-inferiority margin of 12% (i.e. a RR equal to 1.12). Different structures of the covariance matrix will be looked at and be selected with a tool developed in R\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. The secondary outcomes will be described by treatment regimens, with frequencies and percentages for categorical variables, and with mean and SD for continuous variable. The analysis will be executed through the R software version 2023.06.1\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec22\" class=\"Section2\"\u003e\n \u003ch2\u003eHealth economic evaluation\u003c/h2\u003e\n \u003cp\u003eThe non-inferiority design of the trial warrants employing a cost-minimization analysis. We will estimate the cost of administering the two regimens from the providers perspective. All costs of providing healthcare services to participants will be considered. This includes costs of medications, costs of laboratory and monitoring tests, salary costs of healthcare personnel, costs of hospitalization, and costs of managing adverse events. We will collect costs of medications at various doses and formulations from procurement records of the NTP. Costs of laboratory and monitoring tests will be as reported from participating PMDT sites. For costs of healthcare personnel, we will use nationally representative salaries and administer time estimation questionnaires to healthcare personnel at all sites for 10 consecutive days. These questionnaires ask healthcare personnel about their time spent doing specific tasks related to RR/MDR-TB care. We will use the average time spent on specific tasks and annual salaries, to arrive at a dollar value for time spent on specific activities (e.g., initial or follow-up visits). Costs of per day of hospitalization will be estimated from tertiary level facilities from the WHO-CHOICE\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. Finally, we will estimate costs of adverse event management by micro-costing per-protocol management of different grades and types of adverse events.\u003c/p\u003e\n \u003cp\u003eWe will use the above costs to arrive at costs of specific activities that occur during treatment and multiply these values by the number of occurrences of each activity during treatment based on events and activities reported in case report forms for each participant. We will then sum up all costs over the course of treatment for each participant to arrive at an overall cost per participant.\u003c/p\u003e\n \u003cp\u003eWe will calculate the arithmetic mean, standard deviation, and 95% confidence interval for RR/MDR-TB treatment by arm. To estimate differences in costs between arms, we will perform multivariable analysis. This analysis will use linear mixed models, with the PMDT site as the clustering variable, and will be adjusted for treatment arm, as well as demographic and clinical characteristics. Prior to regression, costs will be log-transformed as they are very likely to be skewed and this gives them better properties for regression. Resultant model estimates will be back-transformed and are interpreted as cost ratios; we will also use the NLESTIMATE function in SAS to convert these cost ratios to absolute differences. We will perform this analysis on the modified intention to treat population. We will determine if there is a significant difference in costs by treatment arm and demographic and clinical characteristics based on the estimated 95% confidence intervals in the fully adjusted model (i.e., for cost ratios if they cross 1.0, there is no significant difference). If non-inferiority is demonstrated, we will assume that the less expensive regimen is the preferred regimen from a purely economic perspective.\u003c/p\u003e\n \u003cdiv id=\"Sec23\" class=\"Section3\"\u003e\n \u003ch2\u003eHealth Related Quality of Life (HRQoL)\u003c/h2\u003e\n \u003cp\u003eHRQoL measures the physical and functional status and social and emotional well-being of an individual. We will conduct a sub-study to assess the HRQoL of RR/MDR-TB patients receiving the two all-oral shorter RR/MDR-TB treatment regimens. The study will be conducted on all participants recruited in the trial. This assessment will adopt a longitudinal design with data collection at four-time points i.e., at enrolment, 4 months, end of treatment, and twelve months after the end of treatment. HRQoL will be assessed through the Urdu translated version of Euro quality of life questionnaire, EQ-5D-3L\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. This instrument will be composed by a system describing five dimensions (Mobility, self-care, usual activities, pain/discomfort and anxiety/depression) and by a visual analogue scale (EQ-VAS).\u003c/p\u003e\n \u003cp\u003eFor each time point and for each treatment regimen, the EQ-VAS will be summarized by mean and standard deviation, while the dimensions will be reported in frequencies and percentages by level (no problems, some problems, and extreme problems).\u003c/p\u003e\n \u003cp\u003eThe impact of the all-oral shorter treatment regimens will be assessed by calculating the changes in the EQ-VAS for each participant between time points (between baseline and 4 months, baseline and end of treatment, baseline and end of follow-up, and end of treatment and end of follow-up). The frequencies and percentages of the trajectories of participants will be displayed based on the Paretian Classification of Health Change (PCHC). For each dimension, each participant will be classified into no change/no problems, no change/any problems, better and worse, based on the measures between time points (the same as for the EQ-VAS)\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec24\" class=\"Section2\"\u003e\n \u003ch2\u003eEthics approval\u003c/h2\u003e\n \u003cp\u003eThe research protocols were submitted for approval by Provincial Bioethics Committee in Punjab and ethical approval for conducting this study has been received (Ref: No.4\u0026ndash;87/NBC-491/20/48). The protection of patient confidentiality is essential, and the study will follow the principles of the 2018 Declaration of Helsinki\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThe proposed trial, and associated sub studies, will be conducted at 12 PMDT sites where core diagnostic, laboratory and clinical inputs, social support, and medications are being, and will continue to be, managed through the ongoing GFTAM project support.\u003c/p\u003e \u003cp\u003eA stepped-wedge cluster-randomized trial design was chosen for this study due to its robustness in demonstrating the effectiveness of intervention during routine implementation. Prior studies suggest that stepped wedge design is often suitable to accommodate the logistical challenges of implementing interventions at a large scale\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. Since the WHO guidelines suggest already established efficacy of the modified treatment regimen, it is imperative not to withhold the intervention from the study participants. This study design will take care of such ethical considerations by allowing all participants to receive the intervention eventually\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. Each cluster will be exposed to both the control and intervention care, this will contribute to increasing the statistical power of the study by making within cluster comparisons\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. We will follow RR/MDR TB patients for 9\u0026ndash;11 months during treatment and for one year after the successful completion of treatment, the stepped wedge cluster trial design will additionally support the investigation of temporal effect by introducing intervention at different time points. The data analysis, however, will require careful considerations keeping in view the complexities produced by the study design. Moreover, it will take longer to achieve the trial outcomes\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe current study primarily aims to evaluate the non-inferiority of an all-oral modified shorter treatment against the all-oral standard shorter treatment for RR/MDR TB patients. Previous evaluations of the standard all-oral short treatment regimen suggest promising results, with up to 80% treatment success rate. Based on WHO recommendations this study will further contribute towards generating evidence on the non-inferiority of a 9 month long modified all-oral treatment regimen. The shorter treatment length (9 months against 11 months) is not only expected to demonstrate a similar treatment success rate but will also minimize number of visits to health facility leading to better treatment adherence, reduced cost and improved quality of life of patients\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe primary outcome will be declared after twelve months post successful treatment completion to understand the sustained effects of treatment. We will report data on proportion of patients who remained cured, experienced relapse or re-infection and died within one year post treatment, thus will contribute to enriching data on the impact of RR/MDR TB treatment following cure\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eLiterature suggests that second line anti-TB drugs cause adverse drugs effects in greater number of patients than the first line drugs, which warrant a more closer and regular safety monitoring during the treatment span\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. Nevertheless, data quality and reporting has been identified as a challenge during routine program setting\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. We anticipate that during this trial we will develop and implement stringent protocols to ensure pharmacovigilance, rigorous reporting and timely response. This will help us to generate evidence on the safety of modified regimen as well as establish improved pharmacovigilance mechanisms within TB care in the country.\u003c/p\u003e \u003cp\u003eThe criteria of good clinical practice shall be followed rigorously to maintain the validity and integrity of trial\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e. The Trial Steering Committee (TSC) will be responsible for the direct management and monitoring of research operations and will oversee the research personnel on the ground. The study researchers have received comprehensive training on data collection, monitoring tools, and Standard Operating Procedures (SOPs) related to the protocol, ensuring that the study is conducted with the highest level of scientific and ethical rigor.\u003c/p\u003e \u003cp\u003eEvidence from this research will inform programmatic implementation in Pakistan and provide crucial data to the global TB community, strengthening the evidence base necessary to inform future treatment guidance. The study's findings will be disseminated to physicians, program implementers, scientific audiences, and policymakers on both a national and international level via reports, presentations, and scientific publications. Demonstrating the benefit of integrating a shorter all-oral regimen at PMDT sites will provide strong supportive evidence to accelerate the widespread implementation of this intervention across Pakistan and in similar settings.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eWHO\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eWorld health organization\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eTB\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eTuberculosis\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eMDR-TB\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMultidrug resistant tuberculosis\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eRR-TB\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eRifampicin resistant tuberculosis\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003ePMDT\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eProgrammatic management of drug-resistant tuberculosis\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eNTP\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eNational tuberculosis program\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eShORRT\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eShort, all-oral regimens for rifampicin-resistant tuberculosis\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eAE\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAdverse events\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis is a study protocol manuscript, not applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research project received financial support from the UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR), grant number [PO202606230].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interest statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAuthors declare no competing interests\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial status\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAt the time of the manuscript submission, the intervention has been rolled out and patients are being followed-up for the primary outcome. A delay in submission of this manuscript is due to resource limitations and long-term impact of COVID-19, which necessitated redirection of efforts to keeping the trial going rather than writing a protocol for scientific publication.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData sharing statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors plan to disseminate the findings on main study outcomes in a single paper after completing data collection, cleaning and analysis. Additional scientific publication on economic evaluation is anticipated after publishing trial results. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHuman ethics and consent to participate declaration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe research protocols were submitted for approval by Provincial Bioethics Committee in Punjab, Pakistan and ethical approval for conducting this study was received (Ref: No.4-87/NBC-491/20/48). Protection of patient confidentiality is essential, and the study will follow the principles of the 2018 Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003eInformed written consent will be obtained from patients or a guardian in the case of minors, as defined by local legal requirements. Those who do not consent to participate in this research will receive treatment as per national guidelines.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis is a study protocol, does not require consent to publish, Not applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNK designed the study, did sample size calculations, contributed to the ethics approval of study and drafted original manuscript. MAK and AI will lead the study implementation, NM contributed in the ethics approval of the study, drafted original manuscript and will be involved in study implementation and data analysis. AG conceptualized the study and contributed to the design, development and operationalization of intervention and other care protocols. ZN will be involved in trial data analysis. CSM conceptualized the study and contributed to writing, review and editing of the manuscript. JRC contributed to writing, review and editing of the manuscript and is leading the economic evaluation and analysis. GLC contributed to writing, review and editing of the manuscript and is leading primary statistical analysis. MAK conceptualized the study and led the team in design, development and operationalization of intervention and other care protocols. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclaimer\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCSM is currently a staff member of the World Health Organization; the author alone is responsible for the views expressed in this publication and they do not necessarily represent the decisions, policy or views of the WHO.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMatteelli A, Rendon A, Tiberi S, Al-Abri S, Voniatis C, Carvalho AC, Centis R, D'Ambrosio L, Visca D, Spanevello A, Migliori GB. Tuberculosis elimination: where are we now?. European Respiratory Review. 2018 Jun 30;27(148).\u003c/li\u003e\n\u003cli\u003eWorld Health Organization. WHO consolidated guidelines on drug-resistant tuberculosis treatment. 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Systematic review of stepped wedge cluster randomized trials shows that design is particularly used to evaluate interventions during routine implementation. Journal of clinical epidemiology. 2011 Sep 1;64(9):936-48.\u003c/li\u003e\n\u003cli\u003eChakaya J, Khan M, Ntoumi F, Aklillu E, Fatima R, Mwaba P, Kapata N, Mfinanga S, Hasnain SE, Katoto PD, Bulabula AN. Global Tuberculosis Report 2020\u0026ndash;Reflections on the Global TB burden, treatment and prevention efforts. International journal of infectious diseases. 2021 Dec 1;113:S7-12.\u003c/li\u003e\n\u003cli\u003eAtif M, Ahmed W, Nouman Iqbal M, Ahmad N, Ahmad W, Malik I, Al-Worafi YM. Frequency and factors associated with adverse events among multi-drug resistant tuberculosis patients in Pakistan: A retrospective study. Frontiers in Medicine. 2022 Mar 1;8:790718.\u003c/li\u003e\n\u003cli\u003eMassud A, Syed Sulaiman SA, Ahmad N, Shafqat M, Chiau Ming L, Khan AH. Frequency and management of adverse drug reactions among drug-resistant tuberculosis patients: analysis from a prospective study. Frontiers in Pharmacology. 2022 Jun 2;13:883483.\u003c/li\u003e\n\u003cli\u003eSprumont D. Legal protection of human research subjects in Europe. European Journal of Health Law. 1999 Mar 1;6(1):25-43.\u003c/li\u003e\n\u003c/ol\u003e\n"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-infectious-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"infd","sideBox":"Learn more about [BMC Infectious Diseases](http://bmcinfectdis.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/infd","title":"BMC Infectious Diseases","twitterHandle":"#bmcinfectdis","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"rifampicin-resistant/ multidrug-resistant TB, stepped wedge, cluster randomized controlled trial, non-inferiority, health related quality of life, all-oral, short regimen, economic evaluation, treatment efficacy, safety","lastPublishedDoi":"10.21203/rs.3.rs-6156079/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6156079/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eIntroduction: \u003c/strong\u003ePakistan has one of the largest burdens of rifampicin-resistant/ multidrug-resistant TB according to the global estimates. Novel all oral treatment regimens containing new antibiotics with reduced treatment duration are available. World Health Organization guidelines recommend the use of shorter all-oral regimens under operational research. To guide recommendations, we will compare two all-oral, short (≤11 months) regimens for the outcomes of efficacy, safety, cost, and health-related quality of life under programmatic conditions in Pakistan.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eThis is a stepped wedge, cluster randomized controlled trial with economic evaluation and health related quality of life sub-studies.\u0026nbsp; Modified all-oral 9-month regimen will be sequentially rolled-out compared with the standard all-oral 11-month regimen at 12 sites in Punjab, Islamabad and Azad Jammu and Kashmir region, Pakistan. A total of 400 eligible participants will be enrolled in both study arms. The primary outcome is difference in efficacy as measured by the proportion of patients with treatment success without recurrence at 12 months after the end of treatment between regimens using a non-inferiority design with a margin of 12%. The intention to treat analysis principle will be employed and a marginal mean model with Poisson generalized estimation equations, and a log-link will be used to assess the relative risk. The economic evaluation will be carried out from the healthcare providers perspective; linear mixed models will be used to estimate differences in costs between arms. Health related quality of life will be measured with the EQ-5D-3L quality of life questionnaire at four time points during the study period. The impact will be assessed by calculating the changes for each participant between time points. Ethical approval for this study has been obtained from provincial bioethics committee in Punjab, Pakistan (Ref: No.4-87/NBC-491/20/48).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDiscussion: \u003c/strong\u003eThe study's findings will be disseminated to physicians, program implementers, scientific audiences, and policymakers on both a national and international level via reports, presentations, and scientific publications.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration: \u003c/strong\u003eISRCTN registry. ISRCTN17334530, ‘retrospectively registered’ on 8\u003csup\u003eth\u003c/sup\u003e February 2021. ‘Clinical trial number: not applicable.’\u003c/p\u003e","manuscriptTitle":"Non-Inferiority Stepped Wedge Cluster Randomized Controlled Trial on All-Oral Shorter Regimens for Rifampicin Resistant/Multidrug-Resistant TB in Pakistan – A Study Protocol","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-03-17 16:04:19","doi":"10.21203/rs.3.rs-6156079/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-03-14T10:59:29+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-03-12T09:44:42+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-03-12T09:41:14+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Infectious Diseases","date":"2025-03-04T16:39:05+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-infectious-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"infd","sideBox":"Learn more about [BMC Infectious Diseases](http://bmcinfectdis.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/infd","title":"BMC Infectious Diseases","twitterHandle":"#bmcinfectdis","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"86ef882b-6105-4204-a76e-a932201ec9b8","owner":[],"postedDate":"March 17th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-05-12T15:59:18+00:00","versionOfRecord":{"articleIdentity":"rs-6156079","link":"https://doi.org/10.1186/s12879-025-11068-1","journal":{"identity":"bmc-infectious-diseases","isVorOnly":false,"title":"BMC Infectious Diseases"},"publishedOn":"2025-05-07 15:57:06","publishedOnDateReadable":"May 7th, 2025"},"versionCreatedAt":"2025-03-17 16:04:19","video":"","vorDoi":"10.1186/s12879-025-11068-1","vorDoiUrl":"https://doi.org/10.1186/s12879-025-11068-1","workflowStages":[]},"version":"v1","identity":"rs-6156079","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6156079","identity":"rs-6156079","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}