A pragmatic trial with an optimized dose of rifampicin and moxifloxacin for the treatment of drug-susceptible pulmonary tuberculosis: A study protocol for open-label, randomized phase III trial (OptiRiMoxTB)

A pragmatic trial with an optimized dose of rifampicin and moxifloxacin for the treatment of drug-susceptible pulmonary tuberculosis: A study protocol for open-label, randomized phase III trial (OptiRiMoxTB) | 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 Research Article A pragmatic trial with an optimized dose of rifampicin and moxifloxacin for the treatment of drug-susceptible pulmonary tuberculosis: A study protocol for open-label, randomized phase III trial (OptiRiMoxTB) Hamu Joseph Mlyuka, Alphonce Liyoyo, Belinda Nyaulingo, Emmanuel Mpolya, and 16 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7238156/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 30 Jan, 2026 Read the published version in Trials → Version 1 posted 5 You are reading this latest preprint version Abstract Background Current combination antibiotic treatment for drug-susceptible tuberculosis (DS-TB) usually takes six months to complete. This long duration can compromise clinical outcomes. Although a four-month regimen including an optimized dose of rifapentine plus moxifloxacin is non-inferior to standard therapy, rifapentine is hard to source globally and adoption of this regimen has been slow. This trial investigates the efficacy and safety of a four-month DS-TB treatment including the more readily available rifamycin, rifampicin 35mg/kg, with or without moxifloxacin 400mg. Methods This multi-centre phase III randomized open-label clinical trial will be conducted across four African countries (Gabon, Malawi, Mozambique, and Tanzania). A total of 414 newly diagnosed consenting adult participants will be block randomized, after stratification by chest radiograph cavitation, to two experimental and one control arm at a ratio of 1:1:1. The first experimental group will receive optimized dose rifampicin (35mg/kg) with routine weight-banded doses of isoniazid, pyrazinamide, and ethambutol once daily for four-months. The second experimental group will receive optimized dose rifampicin (35mg/kg) and moxifloxacin 400mg once daily alongside routine doses of isoniazid and pyrazinamide. The control group will receive six-month standard of care therapy: rifampicin (10mg/kg) plus weight banded dose of isoniazid, pyrazinamide, and ethambutol for two months, followed by the same doses of rifampicin and isoniazid for four months. Participants will be followed until the allocation of efficacy (TB-free survival) and safety (proportion of severe adverse events) outcomes. Secondary outcomes will also include the evaluation of the Tuberculosis Molecular Bacterial Load Assay (TB-MBLA) for microbiological treatment monitoring. Discussion This study will evaluate whether four-month duration multi-drug treatment including an optimized dose of rifampicin with or without moxifloxacin have non-inferior efficacy and safety outcomes compared to standard of care DS-TB therapy in Africa. Trial registration: ClinicalTrials.gov, ID: NCT05575518 registered on 10th October 2022. Optimized dose rifampicin moxifloxacin drug susceptible TB TB-MBLA Figures Figure 1 Figure 2 Figure 3 Introduction Background and rationale {6a} Tuberculosis (TB) is a major public health problem, particularly in low- and middle-income countries (LMICs). Timely administration and completion of effective treatment is crucial for TB control. Currently, most short course chemotherapy for drug susceptible (DS)-TB takes 26 weeks (6 months); an 8-week intensive phase of rifampicin (at a standard daily dose of 10mg/kg), isoniazid, pyrazinamide, and ethambutol and a 16-week continuation phase of rifampicin and isoniazid. Treatment success is reported at 80% (95% Confidence Interval [CI]: 78.4–81.7) overall, and 71% (95% CI: 63.7-77.8) for TB patients living with HIV (1). This is below the World Health Organization (WHO) target of treatment success in 90% of cases (2). Prolonged DS-TB therapy presents adherence challenges. Interventions such as Directly Observed Therapy (DoT) are difficult, expensive and only partially successful (3). Medication side-effects including drug-induced liver injury (DILI) add complexity, which is further amplified for patients receiving anti-TB medicines alongside anti-retroviral therapy (ART) for Human Immunodeficiency Virus (HIV) (4). Interruption or premature discontinuation of TB treatment increases the risk of drug resistance and unfavourable outcomes. Mathematical models estimate that potent, shorter regimens will reduce TB incidence and deaths (5). The international Phase 3 clinical trials, REMoxTB and RIFAQUIN, showed that four-month experimental regimens containing the 8-methoxyfluoroquinolone, moxifloxacin and a standard-dose rifamycin (either rifampicin or rifapentine) achieved faster sputum sterilization than standard 6-month therapy for pulmonary TB, but improved clinical outcomes were thwarted by higher post-treatment relapse rates (6,7). Accumulative evidence from pre-clinical studies (8-10) and early-phase clinical trials have revealed improved bactericidal efficacy from rifampicin dose escalation (11), described safety of rifampicin doses up to 40mg/kg (12-14), and reported compatibility of rifampicin 35mg/kg with dolutegravir-based ART (15). Dose escalation studies of rifapentine (from 600mg to 1200mg daily) have provided similar results (16). A Phase 2 Multi-Arm Multi-Stage (MAMS) study run by the Pan-African Consortium for the Evaluation of Anti-tuberculosis Antibiotics (PanACEA) suggested that a regimen containing both moxifloxacin and optimized dose rifampicin has treatment-shortening potential (14). In 2021, the pivotal Phase 3 Study 31/A5349 trial confirmed that four-month treatment containing optimized rifapentine 1200mg plus moxifloxacin 400mg is non-inferior to the standard six-month TB approach (17). Although this regimen has since been incorporated within WHO guidelines (18) global uptake has been slow, largely due to implementation challenges including limited worldwide availability of rifapentine (19). Most national TB programmes still rely on rifampicin-based DS-TB treatment, so it is important to establish whether rifampicin can replace rifapentine in regimens of four months or shorter. Primary and secondary microbiological endpoints in Phase 2 and 3 clinical trials of new anti-TB regimens are conventionally based on conversion from positive to negative, or the rate of bacillary clearance, from sputum culture. However, the laboratory methods used for mycobacterial culture are difficult to perform, generate results slowly, and provide data that correlate only modestly with long-term clinical outcomes (20). The TB Molecular Bacterial Load Assay (TB-MBLA) is a molecular test based on specific Mycobacterium tuberculosis 16S ribosomal RNA ( Mtb 16S-rRNA) quantification (21), which reads out much more quickly and is suitable for evaluation as a new microbiological tool to monitor treatment response and compare regimens. Here we present OptiRiMoxTB, a Phase 3 clinical trial, conducted across four African countries to assess whether a four-month treatment containing optimized dose of rifampicin (35mg/kg), with or without moxifloxacin (400mg) is as effective and safe as standard six-month therapy. A successful outcome will facilitate rapid implementation scale-up for public health impact. The secondary aims of the study include the evaluation of the TB-MBLA as a treatment response biomarker. Objectives {7} The OptiRiMoxTB trial aims to show whether one or both of two experimental regimens given for 16 weeks are non-inferior to standard treatment for DS-TB given for 26 weeks and could replace this under programmatic conditions. Primary and secondary efficacy outcomes will be outlined in detail below. In brief, the primary efficacy objective will be evaluation of participant survival, free of tuberculosis 12 months after initiation of therapy. The primary safety objective will be to evaluate whether the experimental regimens are as safe and tolerable as standard treatment, based on assessment of the frequency of adverse events (AEs) of at least Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 severity. Secondary effectiveness objectives include assessment of longer-term TB-free survival out to 12 months after treatment completion, microbiological measurement of bacterial clearance (including TB-MBLA measurements) and clinical response incorporating participant reported health status. Secondary safety objectives include more detailed AE comparisons between study arms such as the proportion of treatment discontinuations or interruptions related to these. Trial Design {8} This is a pragmatic phase 3 multi-center, open-label, non-inferiority randomized controlled clinical trial with three parallel arms (two experimental regimens and control) and randomization by central allocation in a 1:1:1 ratio. Methods: Participants, interventions and outcomes Study settings {9} As shown in Table 1, six clinical sites in four sub-Saharan African countries with moderate to high burden of TB and HIV incidence (22) will participate. All sites in Gabon, Malawi, Mozambique, and Tanzania are established clinical infectious disease research centres with appropriate facilities and capacity to recruit participants from rural and urban settings. These locations provide a good representation of populations across west, east, and southern Africa. Eligibility criteria {10} Participants must fulfil all the following inclusion criteria prior to enrolment: 1. Provide oral informed consent for study participation, including HIV testing if HIV status is unknown. 2. Have a diagnosis of pulmonary TB established by an Xpert MTB/RIF® result which confirms “low” “medium” or “high” level detection of M tuberculosis and does not detect rifampicin resistance. 3. Be aged ≥ 18 years (in Tanzania, Malawi and Mozambique) and ≥21 year (in Gabon) on the day of providing informed consent. 4. Have a body weight in light clothing and without shoes of ≥ 35kg 5. Have a negative urine or serum pregnancy test ≤ 7 days prior to screening, and consent to practice an effective method of contraception until completion of therapy (Female participants of child-bearing potential only). 6. Have a verifiable residence location and telephone number for contact during follow-up. Individuals for whom one of the following criteria is met will be excluded from the trial: 1. Any circumstances raise concern about provision of free, informed consent to study. 2. Sputum Xpert MTB/RIF® assay result is “negative”, “trace”, or “very low” positive. 3. Any pre-treatment M tuberculosis isolate, either cultured or detected through molecular assays from sputum, is resistant to one or more of rifampicin, isoniazid, pyrazinamide, ethambutol, or fluoroquinolones. 4. Poor general condition where delay in treatment cannot be tolerated, or death within three months is likely, as assessed by the investigator. 5. A nose/throat swab is positive for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2), on Polymerase Chain Reaction (PCR) or a rapid diagnostic test within 14 days of enrolment. 6. Pregnancy or breast-feeding (female participants only). 7. Unable to take oral medications. 8. Received any investigational drug in the past three months. 9. Received more than five days of treatment directed against active tuberculosis within 6 months of enrolment. 10. Known intolerance or contraindications to any of the study drugs. 11. Unwilling or unable to adhere to requirements regarding restricted use of other medications during the study. Restricted medications will include medications which prolong the QTc interval, and CYP450 inhibitors or inducers. 12. Due to initiate, or requires continuation of, non-efavirenz, non-dolutegravir-based anti-retroviral therapy for HIV infection. 13. Decompensated liver disease and/or aminotransaminases >3x upper limit of normal (ULN), serum total bilirubin level >1.5x ULN or serum/plasma creatinine level >x2 ULN. 14. A baseline QTc interval of >450ms on electrocardiograph (ECG). 15. Being, or about to be, treated for malaria. 16. Co-existent medical conditions that, in the investigator’s judgement, make study participation not in the individual’s best interest. Who will take informed consent? {26a} Information about the trial will be provided by study doctors and nurses who have completed Good Clinical Practice in Research (GCP) and study protocol training. Participants will be invited for screening if they are suspected to have pulmonary TB based on sputum smear microscopy or GeneXpert MTB/RIF done within the government or private health sector. Screening may continue for a maximum of five days. After providing valid informed consent, participants will be screened using all inclusion and exclusion criteria. The study database will contain a record of every screening, irrespective of outcome. Individuals who are successfully recruited will be randomised. Those who are ineligible will be referred for routine TB or other appropriate medical care. Additional consent provisions for collection and use of participant data and biological specimens {26b} Additional consent form will be provided to participant requesting to use their leftover sputum and blood samples stored in the lab for future studies to advance TB research. Interventions Explanation for the choice of comparators {6b} The choice of rifampicin dose (35mg/kg) in both experimental arms is based on prior studies designed to optimise efficacy and safety of this drug, particularly in African populations. However, some recent meta-analyses have also reported increased rifampicin tolerability concerns at doses above 20-30mg/kg (24,25) so particular care will be given to analysis of tolerability and toxicity data in this study. Both the PanACEA-MAMS trial (14) and Study 31/A5349 (17) indicated that combining optimised dose rifamycins with moxifloxacin is likely to confer additional benefit, perhaps because of high fluoroquinolone penetration into pathological TB lesions (26). Therefore, one experimental arm contains both optimized dose rifampicin and moxifloxacin. The six-month control comparator of rifampicin (10mg/kg)-isoniazid-pyrazinamide-ethambutol was chosen as it remains the most commonly used DS-TB regimen worldwide. Intervention description {11a} Details of each treatment arm are shown in Figure 1. Study medications will be administered as a mixture of fixed dose combination (FDC) and single drug formulation tablets. In experimental Arm 1, participants will receive optimized dose of rifampicin (35mg/kg/day) plus standard weight banded dose of isoniazid, pyrazinamide and ethambutol administered orally once a day for a duration of four months (4R 35 HZE). Arm 2 is similar to arm one except ethambutol is replaced by moxifloxacin 400mg (4R 35 HZM). The six-month control arm regimen consists of standard dose of rifampicin (10mg/kg/day) plus isoniazid with or without pyrazinamide and ethambutol administered orally once a day for two months rifampicin followed by four months of rifampicin 10mg/kg with weight banded dose of isoniazid (4R 10 H). Participants in Arms 1 and 2 will be advised to take their medications early in the morning with a light meal to reduce the risk of gastrointestinal irritation with optimized dose rifampicin. Those in the control arm will be advised to take their medications with a glass of water first thing in the morning on an empty stomach (one hour before or two hours after food) for best rifampicin absorption. If medication upsets the stomach when taken fasted, it may be taken with a small amount of food. Manufacturers of trial medications are: Lupin Limited, India (for FDC RHZE and RH tablets); Macleods Pharm Ltd, India (for rifampicin 150mg and 300mg capsules); Oxalis Lab, India (for pyrazinamide 400mg tablets) and; MSN Laboratories Pvt Ltd, India (for Moxifloxacin 400mg tablets). All manufacturers are certified and adheres to good manufacturing practice. IMP supply will be handled by the Global Drug Facility, in accordance with manufacturers’ specifications. Criteria for discontinuing or modifying allocated interventions {11b} Participants may be withdrawn from the trial during treatment or follow-up because of withdrawal of informed consent, late exclusion (identification of information confirming that one or more exclusion criteria are met after full enrolment), safety concerns by site investigators (including adverse events or concern about worsening TB and/or bacteriological failure/relapse that requires a change in TB treatment), pregnancy, at the request of the sponsor, or loss to follow-up. Participants withdrawn from the trial will not routinely be replaced. Strategies to improve adherence to interventions {11c} At site pharmacies, study medications will be repacked into daily doses and dispensed by trial pharmacists or trained dispensers who are also responsible for documentation in source data and on dispensing and adherence eCRFs. Trial medications will be provided to participants during follow-up visits on day 14, 28, 56, 84, 112, and 168. Adherence to interventions will be assessed using pill counts during each clinic visit and automatically calculated in the adherence eCRF. Adherence to trial medications will be reinforced by routine counselling, study staff observing uptake of one dose during each visit while the rest of doses will be taken at home under support of identified relative or friend treatment supervisor. Relevant concomitant care permitted or prohibited during the trial {11d} Absorption of moxifloxacin is reduced by multivalent cation-containing medications e.g. aluminium and magnesium containing antacids. Proton pump inhibitors, e.g. omeprazole, are preferred antacids. TB patients living with HIV are eligible if they are already taking or newly initiating ART regimens composed of two nucleosides (or nucleotide) reverse transcriptase inhibitors (other than stavudine and didanosine) plus efavirenz/dolutegravir. Those taking dolutegravir will be required to increase the dose to 50mg twice daily for the duration of TB treatment. New TB patients who are being, or are about to be, treated for malaria will be excluded from enrolment. Should a participant develop malaria during the trial, anti-malarial treatment may be offered in accordance with national malaria treatment guidelines but careful consideration must be given to electrocardiographic QTc-prolonging potential and drug-drug interactions involving available anti-malarial drugs. Individuals who have received QTc prolonging medications within 30 days of the first dose of study drugs will be excluded, to avoid the risk of QTc exacerbation with moxifloxacin (27). Exceptions may be made for those who have received 3 daily doses or less, and at least 5 elimination half‐lives of the drug have passed before first dose of study treatment. The list of medications with risk of QTc prolongation is accessible in https://crediblemeds.org. Provisions for post-trial care {30} Participants who leave the study due to adverse events or unfavourable TB treatment outcomes will be referred locally for appropriate medical care or ongoing TB management via National TB Programmes. Outcomes {12} The primary efficacy endpoint for this trial is participant survival, free of tuberculosis 12 months after randomisation. For this favourable outcome to be allocated, all the following criteria will require to be met: 1. Completed assigned treatment and known to be alive 2. Stable sputum culture conversion, or clinically well without features of ongoing active TB and unable to provide a sputum culture result, either because sputum can no longer be produced or because the only available sample is contaminated without evidence of Mtb 3. Have not met criteria for treatment failure or relapse 4. Not in need of TB treatment and having required no substantial treatment modifications or additional treatment for TB outside the study regimen. Unfavourable primary efficacy outcomes will be allocated to participants who exit the study under any of the following circumstances: 1. Completed assigned treatment in the absence of bacteriological cure. This typically occurs as a consequence of treatment failure (defined as submitting two sputum samples with positive culture for Mtb on different visits, when the first of these samples was collected at or after two weeks prior to the scheduled end of treatment) or TB relapse (defined as submitting two sputum samples with positive culture for Mtb on different visits, when the first of these samples was collected after completion of scheduled TB therapy and where at least one of the Mtb isolates is genetically similar to the baseline strain). 2. Completed assigned treatment with a single positive culture for Mtb when last seen, but not confirmed by a second sample, unless the positive culture is deemed to represent re-infection. 3. Death from any cause during study treatment, except violent or accidental death (e.g., road traffic accident.) 4. Extension or alteration of TB treatment beyond that permitted by the protocol. Circumstances during the study which may result in unassessable outcomes include: 1. Failure to complete treatment 2. Completion of assigned treatment, then loss to follow-up, with the last reported culture being negative for Mtb 3. Women becoming pregnant during TB therapy and withdrawing from the trial 4. Death from a violent or accidental cause 5. Detection of TB re-infection, after successful completion of their assigned therapy, with a new strain of Mtb , demonstrated to be genetically different from that identified at study entry. The following secondary efficacy endpoints will be reported · Participant survival, free of tuberculosis at 12 months after treatment completion following extended follow-up arranged beyond the formal project end. · Microbiological response using BD Mycobacteria Growth Indicator Tube 960®liquid culture time to positivity (MGIT-TTP) · Microbiological response using the TB-MBLA (including time to conversion to negative, and rate of decline in estimated Colony Forming Units/ml of sputum). · Clinical response to therapy, including change from baseline clinical measurement of weight, body mass index (BMI), TB symptoms and Patient Reported Health Status. The primary safety outcome for this trial will be the occurrence of AEs of CTCAE Grade 3 severity or higher. The following secondary safety outcomes will also be reported: · Occurrence of AEs of any grade reported and regarded as definitely, probably, or possibly related to study drugs · Treatment discontinuations or interruptions related to AEs · Frequency, severity, and type of AEs During each visit at day 14, 28, 56, 84, 112, 182, month 9 and 12 participants will undergo assessments including self-reported health status, physical examination, routine clinical laboratory tests particularly serum creatinine, total bilirubin, alanine transaminase (ALT), blood count (Hb, WBC and platelet count). Participant timeline {13} Participants will be followed according to the schedule of events elaborated in Figure 2. Sample size {14} Sample size has been calculated based on the primary efficacy outcome of participant survival free of TB 12 months after initiation of treatment. Based on previous trials of new DST-TB therapy in similar populations (the REMoxTB (6) and STAND (28) studies) in similar populations it was been estimated that 6% and 10% of participants will have unfavourable primary and non-assessable primary efficacy outcomes respectively. For OptiRiMoxTB, with power (β) set at 90%, a non-inferiority margin of 10%, and a type I error (α) of 5%, a total of 414 participants (138 participants per arm in a 1:1:1) across all sites will be required to show non-inferiority of either of the experimental regimens to control. Recruitment {15} All sites will recruit via networks of satellite centres particularly primary and secondary health facilities. This will be achieved through meetings with healthcare providers at potential health centres and use public liaison activities designed during our prior experience of clinical trial conduct at the same sites . Available information on rates of new TB diagnoses at clinics affiliated with each study site, informed pre-trial projections of likely participant numbers in each study country to be set as follows: Gabon, 50; Malawi, 104; Mozambique, 100; and Tanzania, 160. Assignment of interventions: allocation Sequence generation {16a} Randomisation of eligible participants will be stratified according to the presence or absence of cavitation on chest radiograph. Stratified randomization will be undertaken within Research Electronic Data Capture (REDCap) software (29) on a 1:1:1 allocation ratio using a permuted block randomization procedure with block sizes of 3, 6 and 9. Concealment mechanism {16b} Allocation concealment to reduce selection bias at randomization is fostered by REDCap which provides a randomization number only after all screening information has been provided on the CRF. Following randomization, the study will be open label with treatment allocation known to participants and healthcare providers. Implementation {16c} The allocation sequence generation will be released automatically by REDCap software upon confirmation of participant eligibility on the eCRF. Assignment of interventions: Blinding Who will be blinded {17a} Not Applicable. Not applicable because, this is an open-label trial, so site investigators and participants will be aware of treatment allocations. Procedure for unblinding if needed {17b} Not Applicable. Not applicable because, this is open label trial, so site investigators and participants will be aware of treatment allocations. Data collection and management Plans for assessment and collection of outcomes {18a} Study endpoints are based on a combination of objective clinical observations and microbiological measurements. An outcome allocation committee, comprising the Principal Investigators, study statistician and independent medical experts appointed by the Sponsor will meet at study completion to confirm assignment of final outcomes for each participant. Plans to promote participant retention and complete follow-up {18b} Careful participant counselling and community engagement will reinforce the importance of study visit attendance from the point of screening onwards. Participants will have clear contact details for local site investigators to report any concerns as soon as they arise. If visits are missed, at least three attempts at contact via telephone or home visits will be undertaken before any participant is allocated as lost to follow-up. In general, participants who withdraw from the study for reasons other than withdrawal of consent or loss to follow-up shall continue to follow study assessments as laid down in the schedule of events, to make them evaluable for long-term outcomes. Data Management {19} All study data will be entered into eCRF forms, created for each participant in REDCap. Physical source data, including participant’s case records, chest radiographs, and safety and microbiology laboratory results will be retained and made available for verification. Accuracy and completeness of data will be checked by pre-programmed edit checks in the REDCap database that will flag out of range values and by at least two visits to each site by independent monitors. Site lead investigators be responsible to ensure that study documents are maintained in accordance with International Conference on Harmonisation of Good Clinical Practice (ICH-GCP) guidelines. Upon trial completion essential documents will be retained for a duration of not less than 10 years or as required by local regulation. Confidentiality {27} In the trial database and on all study forms participants will only be identified by a study number comprising three letters which represent the site and three numbers which represent their enrolment number. A participant identification log will be kept in a securely locked separate trial file at each site, that only delegated staff will have access to. The ICF has a clause granting permission for the review of participants’ source documents by site lead investigators or a competent delegated person if necessary. The trial database will be encrypted and stored on secure servers with regular back-up and access control. Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33} Sputum samples at screening and enrolment will be used to confirm the diagnosis of pulmonary tuberculosis by sputum smear microscopy and/or Xpert MTB/RIF, and to perform rapid drug susceptibility testing for rifampicin. Sputum from all timepoints will be used for mycobacterial liquid (MGIT) culture and the molecular bacterial load assay (TB-MBLA). M tuberculosis isolates from these cultures will be stored and may be used for additional drug susceptibility testing. Isolates from participants who remain sputum culture positive at end of treatment or develop recurrent TB after treatment completion will be stored for Whole Genome Sequencing to confirm whether it is a relapse or reinfection. Statistical methods Statistical methods for primary and secondary outcomes {20a} Study analysis groups will be defined and analysed as shown in Table 2. The primary efficacy outcome will be assessed by comparing each of the experimental regimens with the control arm in the modified intention-to-treat (mITT) population. In each comparison non-inferiority will be assessed by comparing the upper bound of a 95%, two-sided confidence interval for the difference between the proportion of participants who were classified with an unfavourable outcome on the control and experimental regimen to the pre-defined non-inferiority margin of 10%. The primary safety outcome will be assessed by comparing the proportion of participants with CTCAE grade 3 or higher AEs in each experimental regimens versus control regimen, in the pre-defined safety population. Table 2: OptiRiMoxTB study analysis populations All enrolled participants who receive a treatment assignment Participants with an unassessable primary efficacy outcome will be assumed to have had an unfavourable outcome All ITT participants except late exclusions This is the primary analysis population for efficacy analyses. Participants with an unassessable primary efficacy outcome will be assumed to have had an unfavourable outcome All participants who completed the study without protocol deviations and had an outcome assigned. Participants with an unassessable outcome will be excluded from the analysis. All ITT participants that receive at least one dose of study medication This is the primary analysis population of interest for safety analyses In secondary efficacy analyses, the primary efficacy endpoint will be assessed in the PP population, and the secondary efficacy endpoints will be assessed in both mITT and PP populations. Both experimental regimens will be compared with the control regimen. Secondary analyses will include those directed towards identification of clinical and microbiological factors associated with favourable and unfavourable outcomes. Mixed effects models will be used to analyse microbiological culture and TB-MBLA data on bacillary clearance rates. Time to unfavourable outcome and time to microbiology-negative status will be analysed using Kaplan-Meier plots and Cox proportional hazards regression methods. Multivariate logistics regression modelling will be used to assess relationships between co-variates and clinical outcomes. As with the primary safety outcome, all secondary safety outcomes will be assessed in the pre-defined safety population. Interim analyses {21b} Not Applicable. Not applicable because, there will be no interim analysis apart from Data and Safety Monitoring Committee (DSMC) reports which will be generated following review of unblinded data in closed meetings. Methods for additional analyses (e.g. subgroup analyses) {20b} Sub-group analyses (with tests for interaction) of the primary endpoint will be performed according to age, gender, weight, BMI, country, HIV status, smoking history and history of diabetes, the presence or absence of cavitation (cavitation will be defined as a gas-containing lucent space at least 1 cm in diameter within the lung parenchyma surrounded by an infiltrate or fibrotic wall greater than 1 mm thick seen on the chest radiograph), extent of cavitation on baseline chest radiograph, MGIT days to detection, initial bacterial load in sputum as indicated by baseline MIGT-TTP result (low bacterial load = MIGT-TTP≥ median, high bacterial load = MIGT-TTP < median) and GeneXpert MTB/RIF Cycle threshold. The test for an interaction between the covariate and treatment will be done using logistic regression comparing the model including the interaction term and the model with only marginal terms using the likelihood ratio test to evaluate the statistical significance of inclusion of the interaction term in the model. Methods in analysis to handle protocol non ‑ adherence and any statistical methods to handle missing data {20c} Although the primary study analysis will be the mITT population, sensitivity analyses will be undertaken to consider the effect of missing data on study outcomes. These will include primary efficacy analyses on ITT and PP populations. To minimise missing information, following data entry into eCRFs, completeness and consistency checks will be performed by sponsor’s data management. All resulting queries will be sent through the database query system to leave an audit trail. Plans to give access to the full protocol, patient level ‑ data and statistical code {31c} With exception of participant-identifying information which will not be shared, all other data from this trial will be released through public use data set. Oversight and monitoring Composition of the coordinating centre and trial steering committee {5d} A trial Operational Team (OT) chaired by the Trial Project Manager, comprising two co-Principal Investigators, Sponsor Trial Manager, and all site Lead Investigators, alongside data, microbiology/biomarker and pharmacy project leads will meet every two weeks to co-ordinate day-to-day operations. Additionally, a Trial Steering Committee (TSC), comprising a sponsor representative, the trial statistician, and two expert clinicians who are independent of trial conduct will convene on an ad hoc basis throughout the trial, reporting to the sponsor. A Medical Monitoring Team (MMT) comprising two co-Principal Investigators and two independent clinicians, from experienced African TB trial sites which are not involved in OptiRiMoxTB will provide real-time oversight (with response time to queries of 24 hours) of clinical activities at all sites: primarily offering guidance on management and reporting of safety events, including decisions on participant withdrawal from the study. The MMT will report directly to the Sponsor and may present at OT or TSC meetings as required. On request the MMT may compile information or provide reports to the Data Safety Monitoring Committee (DSMC). Composition of data safety monitoring committee, its role and reporting structure {21a} The DSMC will consist of five members: two trial statisticians (one of whom has extensive experience of TB trials, and will be chair), and three clinicians (one Infectious Disease physician, one Respiratory Medicine physician and one Clinical Pharmacologist). The DSMC will be balanced by gender and geography (with African and European members who are experienced not only in clinical TB research but the specific study settings and context). DSMC members will be independent of the sponsor and study investigators and have no competing interest. They will meet on a prespecified schedule; before initiation of recruitment, after month 6, and then when one-third, two-thirds and all participants have been enrolled. Addition ad hoc meetings will be convened if required by the sponsor. The DSMC acts in advisory capacity to the Sponsor through TSC to safeguard the integrity of trial conduct and participant safety. After each assessment, the DSMC will make recommendations to the Sponsor about continuation, modification, or termination of the entire study, or of individual arms . Adverse event reporting and harms {22} All participants will be counselled during informed consent to report any AEs experienced at any time during the study. Additionally, information on AEs will be proactively sought during each study visit by direct clinical assessment (interview and physical examination and laboratory investigations as outlined in Figure 2. Severity of AEs will be classified on a scale of 1-5 according to the United States (U.S) National Institutes of Health CTCAE 5.0(30). Site lead investigators will categorise causal relationships of AEs to study drugs as ‘unrelated’, ‘unlikely’, ‘possible’, ‘probable’ and ‘certain’. The MMT will be used as a resource to assess and manage AEs. All AEs will be recorded. Those with a severity grading of 3-5 will be defined as severe adverse events (SAEs) which carries an obligation to report to the Sponsor, regulatory authorities and independent ethical committees within 24 hours of first identification. All women of child-bearing age will be counselled to contact their site investigator immediately if they suspect that they might be pregnant at any time. If pregnancy is confirmed, the participant will be withdrawn from the trial and referred to their National TB Program for ongoing care. Investigators will also report to the Sponsor follow-up information regarding the outcome of the pregnancy, including perinatal and neonatal outcomes. Adverse events involving hepatotoxicity are of particular interest in this trial, and specific Hepatotoxicity Management Guidelines will be used. Participants with aminotransaminases ≥ 3x ULN or bilirubin ≥ 2x ULN will be instructed to withhold all trial medications, with further guidance based on repeat blood tests, clinical condition and MMT consultation. Frequency and plans for auditing trial conduct {23} Qualified independent trial monitors, appointed prior to trial initiation by the Sponsor, will visit each site at least twice during the trial to audit performance. Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25} All changes to the protocol will be completed by means of amendments, which will be submitted to applicable ethical committees and regulatory agencies prior to implementation. Amendments of trial protocol will be updated in ClinicalTrials.gov, ID: NCT05575518. Protocol amendment training will be performed as necessary. Dissemination of results {31a} The findings from this trial will be important to study participants, communities affected by TB, and to clinicians, public health policymakers, and researchers working on TB treatment and control. Results will be disseminated to each group by appropriate means including aggregate data reports to study participants and community advisory boards, scientific conference presentations, and submission of manuscripts for publication in open access peer-reviewed journals. Discussion The OptiRiMoxTB trial builds on previous work, including some of the same group that described the tolerability of rifampicin doses up to 35mg/kg in Africa populations by offering Phase 3 evaluation of DS-TB treatment regimens using that dose. It also builds on the important work of the TBTC Study 31/ATCG5349 trial which indicated that optimised dose rifamycins may need to be accompanied by lesion-penetrating 8-methoxyfluoroquinolones to achieve the goal of treatment-shortening ( 6 ). Since initiation of this protocol, the RIFASHORT trial has published results indicating that flat-dosing of 1200mg and 1800mg rifampicin (equivalent to 20mg/kg and 30mg/kg respectively in a 60kg adult) combined with other first-line TB drugs did not achieve non-inferiority compared to standard of care therapy ( 30 ). OptiRiMoxTB advances on that work by weight-based rifampicin dose escalation and incorporation of an experimental arm containing moxifloxacin. In order to generate data which is generalisable to programmatic delivery of routine TB care in high-burden countries and which may accelerate implementation of successful study regimens, the trial will be conducted in African study sites with moderate-to-high HIV prevalence and the study design has been kept as pragmatic as possible: eligibility criteria have been kept as broad as possible, there are no specific HIV severity or CD4-count threshold based exclusion criteria, and procedures at study visits have been rationalised to those which are deemed essential. Since protocol initiation, systematic reviews have ongoing uncertainty on the optimal tolerable dose of rifampicin ( 24 , 25 ), underpinning the need for the careful safety monitoring, which will be provided by site investigators, the MMT and the independent DSMC. The primary efficacy endpoint of this trial is clinical, but secondary microbiological endpoints will include measurements using conventional MGIT-TTP and also the novel TB-MBLA assay. Comparative performance of these assays will be important for the design and conduct of future Phase 2 and 3 clinical trials and may also provide insights on the value of TB-MBLA for treatment monitoring in routine TB care. The open-label design of this trial is driven by the complexity and pill burden which would be generated by placebo-controls but does poses a risk of reporting bias at the point of outcome allocation. This will be mitigated by use of standard prospective outcome definitions, incorporating objective laboratory evidence of stable culture conversion, and appointment of an outcome allocation committee containing independent medical experts. Primary endpoints for this trial will be measured 12 months after participant randomisation, partly because this timepoint was deemed practically achievable during the prescribed funding window at the time of study design. Acknowledging that post-treatment relapse is an important component of long-term outcome in Phase 3 TB trials, secondary outcomes do include scope for longer-term outcomes (until at least 12 months after treatment completion). Sufficient resources are now in place for extended follow-up and a further protocol amendment (v3.0) is in process to approve data collection for this. Ultimately, this pragmatic Phase 3 trial will establish whether four-month DS-TB treatment incorporating optimised dose rifampicin (35mg/kg) with or without moxifloxacin (400mg) is efficacious and safe compared to six-month standard treatment with rifampicin 10mg/kg. The study design, based on routine care delivery to a representative patient population, and use of a readily available rifamycin may pave the way for accelerated programmatic implementation. Trial status OptiRiMoxTB was registered at ClinicalTrials.gov, ID: NCT05575518 with trial version 1.0 on 10th October 2022. Four clinical sites were included at that time (CERMEL,Gabon; KUHeS, Malawi; INS, Mozambique; KIDH, Tanzania) At KIDH recruitment started on August 2023. The protocol was amended to version 2.0 on 30th November 2023, primarily to allow site expansion to include IHI and NIMR-Mwanza in Tanzania. These sites started recruitment in 2024. The protocol was further amended to version 3.0 on 8th January 2025 to increase follow-up time from 12 to 18 months post-randomisation. Recruitment of the first participant was on 11th August 2023 and the last participant was recruited on 6th January 2025. Currently participants are being followed up expecting the last participant last visit to be on 25th May 2026. Abbreviations 16S 16Svedberg unit 2R 10 HZE Two months duration of standard daily Rifampicin (R) 10mg/kg plus standard weight banded dose of Isoniazid (I), Pyrazinamide (Z) and Ethambutol (E) 4R 10 H Four months duration of standard daily Rifampicin (R) 10mg/kg plus standard weight banded dose of Isoniazid (I) 4R 35 HZE Four months duration of daily Rifampicin (R) 35mg/kg plus standard weight banded dose of Isoniazid (I), Pyrazinamide (Z) and Ethambutol (E) 4R 35 HZM Four months duration of daily Rifampicin (R) 35mg/kg plus standard weight banded dose of Isoniazid (I), Pyrazinamide (Z) and Moxifloxacin(M) AEs Adverse Events ALT Alanine Transaminase ART Anti-Retroviral Therapy BD MGIT 960® Becton, Dickinson Mycobacteria Growth Indicator Tube 960® BD MGIT-TTP 960® Becton, Dickinson Mycobacteria Growth Indicator Tube 960® liquid culture time to positivity BMI Body Mass Index CD4 Cluster of Differentiation 4 CERMEL Centre de Recherches Médicales de Lambaréné CH-GCP International Conference on Harmonization of Good Clinical Practice CISPOC Polana Caniço Health Research and Training Center COVID-19 Coronavirus Disease-19 CRF Case Report Form CTCAE Common Terminology Criteria for Adverse Events CYP450 Cytochrome P450 DILI Drug-Induced Liver Injury DoT Directly Observed Therapy DSMC Data and Safety Monitoring Committee DS-TB Drug-Susceptible Tuberculosis ECG Electrocardiograph eCRF Electronic-Case Report Form EDCTP2 Europe and Developing Countries Clinical Trials-2 EN Enrollment FDC Fixed Dose Combination FDC RH Fixed Combination of Rifampicin (R) 150mg and Isoniazid (H) 75mg FDC RHZE Fixed Dose Combination of Rifampicin (R) 150mg, Isoniazid (H) 75mg, Pyrazinamide (Z) 400mg and Ethambutol (E) 275mg GCP Good Clinical Practice in Research Hb Hemoglobin HIV Human Immunodeficiency Virus ICF Informed Consent Form IHI Ifakara Health Institute INS Instituto Nacional de Saúde ITT Intention- To Ttreat KIDH Kibong’oto Infectious Diseases Hospital KUHeS Kamuzu University of Health Sciences LMICs Low- and Middle-Income Countries M tuberculosis Mycobacterium tuberculosis M2, M4, M6 Month Two, Month Four, Month Six MAMS Multi-Arm Multi-Stage MDR/RR TB Multi Drug Resistant/Rifampicin Resistant Tuberculosis mITT modified intention-to-treat MMT Medical Monitoring Team Mtb Mycobacterium tuberculosis NIMR National Institute for Medical Research OT Operational Team PanACEA Pan-African Consortium for the Evaluation of Anti-tuberculosis Antibiotics PCR Polymerase Chain Reaction PP Per -Protocol REDCap Research Electronic Data Capture RNA Ribonucleic acid rRNA Ribosomal Ribonucleic acid SAEs Severe Adverse Events SARS-CoV2 Severe Acute Respiratory Syndrome Coronavirus 2 SCR Screening SPIRIT Standard Protocol Items: Recommendations for Interventional Trials TB Tuberculosis TB-MBLA Tuberculosis Molecular Bacterial Load Assay TSC Trial Steering Committee ULN Upper Limit of Normal US United States WBC White Blood Count WHO World Health Organization Declarations Protocol version: The manuscript has been developed based on protocol version 2.0 of 30 th November 2022. Acknowledgements The authors would like to acknowledge members of the DSMC (Associate Professor Patrick Phillips, Dr Polycarp Mogeni, Professor Kogie Naidoo, Professor Mark Lipman and Professor Catriona Waitt) and the MMT (Dr Caryn Upton, Dr Daniella Ross and Dr Tina Minja). We would also like to thank Dr Angela Crook and Professor Rob Aarnoutse who advised our statistical and pharmacy teams respectively, in addition to all clinical site teams, community engagement groups, and participants so far. Authors’ contributions {31b} The trial was conceptualized by DJS, SM and SHG. The study design was conceived by DJS and SM. SHG who also wrote the protocol and HM, DJS, SGM, and SHG wrote this manuscript. Study set-up and conduct is being undertaken by HM, AL, EM, OLK, SL, HS, TDMcH, LW, WS, BRA, ML, CK, PM, BM, KJ and SGM. All authors read and approved the final manuscript. Funding {4} The trial is funded by the Europe and Developing Countries Clinical Trials-2 (EDCTP2) Simplified short treatment for tuberculosis grant RIA2017S-2012. The funder had no role in the design of the study and writing this manuscript. Also, the funder will have no role in data collection, analysis, interpretation and reporting the trial findings. Availability of data and materials {29} All parties conducting the trial will have access to the final dataset. Ethical approval and consent to participate {24} Ethical approvals for this trial have been thought from all sites’ local and or national ethical committees; Tanzania (KIDH and National Institute of Medical Research (NIMR)), Gabon (CERMEL and National Research Ethics Committee), Malawi (KUHeS Ethical Committee) and Mozambique (INS Institutional Review Board and Comité Nacional de Bioética para Saúde). Also, the trial has received clinical trial authorization from medicines regulatory authorities in all participating countries namely; Tanzania Medicines and Medical Devices Authority (TMDA), Malawi Pharmacy and Medicines Regulatory Authority (PMRA), Gabon Directorate of Medicines and Pharmacy (DMP) and Mozambique Autoridade Nacional Regulatoria de Medicamentos (ANARME). Consent for publication {32} Written informed consent will be obtained from all participants prior to enrolment. Original ICFs will be kept in regulatory binders at each site and will be available on request. Competing interests {28} None of the authors has any competing interest to declare. In addition, the funder has no influence on design, implementation and reporting of this clinical trial research. Authors’ information (optional) Not Applicable. Not applicable because, authors affiliations information have been stated in Author details {5a}. 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U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES, National Institutes of Health, National Cancer Institute. Published: November 27; 2017. Cite Share Download PDF Status: Published Journal Publication published 30 Jan, 2026 Read the published version in Trials → Version 1 posted Editorial decision: Accept 14 Jan, 2026 Reviewers agreed at journal 02 Oct, 2025 Reviewers invited by journal 02 Oct, 2025 Editor assigned by journal 28 Aug, 2025 First submitted to journal 26 Aug, 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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https://gisgeography.com\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7238156/v1/f57d546e5d4f1bec3fad35c8.png"},{"id":93618130,"identity":"8bbd20e7-181e-4b2a-a035-8029b1dad541","added_by":"auto","created_at":"2025-10-15 17:18:48","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":867565,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eOptiRiMoxTB study schematic and drug dosing\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7238156/v1/46bb613ee202ccfdeb561fbd.jpeg"},{"id":93617703,"identity":"55fb94f6-e0c0-4d4b-9345-07dd6e25cde0","added_by":"auto","created_at":"2025-10-15 17:10:47","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":118800,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSchedule of enrolment, intervention and assessment\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7238156/v1/39010019da140f8622136281.png"},{"id":101690778,"identity":"d7bbb0b5-4f3b-47f7-bbec-f3912edfa574","added_by":"auto","created_at":"2026-02-02 16:08:31","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3039530,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7238156/v1/9f75a440-1e9b-461d-8079-cbb446d54963.pdf"}],"financialInterests":"","formattedTitle":"A pragmatic trial with an optimized dose of rifampicin and moxifloxacin for the treatment of drug-susceptible pulmonary tuberculosis: A study protocol for open-label, randomized phase III trial (OptiRiMoxTB)","fulltext":[{"header":"Introduction","content":"\u003cp\u003e\u003cstrong\u003eBackground and rationale {6a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTuberculosis (TB) is a major public health problem, particularly in low- and middle-income countries (LMICs). Timely administration and completion of effective treatment is crucial for TB control. Currently, most short course chemotherapy for drug susceptible (DS)-TB takes 26 weeks (6 months); an 8-week intensive phase of rifampicin (at a standard daily dose of 10mg/kg), isoniazid, pyrazinamide, and ethambutol and a 16-week continuation phase of rifampicin and isoniazid. Treatment success is reported at 80% (95% Confidence Interval [CI]: 78.4\u0026ndash;81.7) overall, and 71% (95% CI: 63.7-77.8) for TB patients living with HIV (1). This is below the World Health Organization (WHO) target of treatment success in 90% of cases (2).\u003c/p\u003e\n\u003cp\u003eProlonged DS-TB therapy presents adherence challenges. Interventions such as Directly Observed Therapy (DoT) are difficult, expensive and only partially successful (3). Medication side-effects including drug-induced liver injury (DILI) add complexity, which is further amplified for patients receiving anti-TB medicines alongside anti-retroviral therapy (ART) for\u0026nbsp;Human Immunodeficiency Virus (HIV)\u0026nbsp;(4). Interruption or premature discontinuation of TB treatment increases the risk of drug resistance and unfavourable outcomes. Mathematical models estimate that potent, shorter regimens will reduce TB incidence and deaths (5).\u003c/p\u003e\n\u003cp\u003eThe international Phase 3 clinical trials, REMoxTB and RIFAQUIN, showed that four-month experimental regimens containing the 8-methoxyfluoroquinolone, moxifloxacin and a standard-dose rifamycin (either rifampicin or rifapentine) achieved faster sputum sterilization than standard 6-month therapy for pulmonary TB, but improved clinical outcomes were thwarted by higher post-treatment relapse rates (6,7).\u0026nbsp;Accumulative evidence from pre-clinical studies (8-10) and early-phase clinical trials have revealed improved bactericidal efficacy from rifampicin dose escalation (11), described safety of rifampicin doses up to 40mg/kg (12-14), and reported compatibility of rifampicin 35mg/kg with dolutegravir-based ART (15). Dose escalation studies of rifapentine (from 600mg to 1200mg daily) have provided similar results (16). A Phase 2 Multi-Arm Multi-Stage (MAMS) study run by the Pan-African Consortium for the Evaluation of Anti-tuberculosis Antibiotics (PanACEA) suggested that a regimen containing both moxifloxacin and optimized dose rifampicin has treatment-shortening potential (14).\u003c/p\u003e\n\u003cp\u003eIn 2021, the pivotal Phase 3 Study 31/A5349 trial confirmed that four-month treatment containing optimized rifapentine 1200mg plus moxifloxacin 400mg is non-inferior to the standard six-month TB approach (17). Although this regimen has since been incorporated within WHO guidelines (18) global uptake has been slow, largely due to implementation challenges including limited worldwide availability of rifapentine\u0026nbsp;(19). Most national TB programmes still rely on rifampicin-based DS-TB treatment, so it is important to establish whether rifampicin can replace rifapentine in regimens of four months or shorter.\u003c/p\u003e\n\u003cp\u003ePrimary and secondary microbiological endpoints in Phase 2 and 3 clinical trials of new anti-TB regimens are conventionally based on conversion from positive to negative, or the rate of bacillary clearance, from sputum culture. However, the laboratory methods used for mycobacterial culture are difficult to perform, generate results slowly, and provide data that correlate only modestly with long-term clinical outcomes (20). The TB Molecular Bacterial Load Assay (TB-MBLA) is a molecular test based on specific \u003cem\u003eMycobacterium tuberculosis\u0026nbsp;\u003c/em\u003e16S ribosomal RNA (\u003cem\u003eMtb\u0026nbsp;\u003c/em\u003e16S-rRNA) quantification (21), which reads out much more quickly and is suitable for evaluation as a new microbiological tool to monitor treatment response and compare regimens.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHere we present OptiRiMoxTB, a Phase 3 clinical trial, conducted across four African countries to assess whether a four-month treatment containing optimized dose of rifampicin (35mg/kg), with or without moxifloxacin (400mg) is as effective and safe as standard six-month therapy.\u0026nbsp;A successful outcome will facilitate rapid implementation scale-up for public health impact. The secondary aims of the study include the evaluation of the TB-MBLA as a treatment response biomarker.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjectives {7}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe OptiRiMoxTB trial aims to show whether one or both of two experimental regimens given for 16 weeks are non-inferior to standard treatment for DS-TB given for 26 weeks and could replace this under programmatic conditions.\u003c/p\u003e\n\u003cp\u003ePrimary and secondary efficacy outcomes will be outlined in detail below. In brief, the primary efficacy objective will be\u0026nbsp;evaluation of participant survival, free of tuberculosis 12 months after initiation of therapy. The primary safety objective\u0026nbsp;will be to evaluate whether the experimental regimens are as safe and tolerable as standard treatment, based on assessment of the frequency of adverse events (AEs) of at least Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 severity.\u003c/p\u003e\n\u003cp\u003eSecondary effectiveness objectives include assessment of longer-term TB-free survival out to 12 months after treatment completion, microbiological measurement of bacterial clearance (including TB-MBLA measurements) and clinical response incorporating participant reported health status. Secondary safety objectives include more detailed AE comparisons between study arms such as the proportion of treatment discontinuations or interruptions related to these.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial Design {8}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis is a pragmatic phase 3 multi-center, open-label, non-inferiority randomized controlled clinical trial with three parallel arms (two experimental regimens and control) and randomization by central allocation in a 1:1:1 ratio.\u003c/p\u003e"},{"header":"Methods: Participants, interventions and outcomes","content":"\u003cp\u003e\u003cstrong\u003eStudy settings {9}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAs shown in Table 1, six clinical sites in four sub-Saharan African countries with moderate to high burden of TB and HIV incidence (22) will participate. All sites in Gabon, Malawi, Mozambique, and Tanzania are established clinical infectious disease research centres with appropriate facilities and capacity to recruit participants from rural and urban settings. These locations provide a good representation of populations across west, east, and southern Africa.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eEligibility criteria {10}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipants must fulfil all\u0026nbsp;the following inclusion criteria prior to enrolment:\u003c/p\u003e\n\u003cp\u003e1. \u0026nbsp; \u0026nbsp;Provide oral informed consent for study participation, including HIV testing if HIV status is unknown.\u003c/p\u003e\n\u003cp\u003e2. \u0026nbsp; \u0026nbsp;Have a diagnosis of pulmonary TB established by an Xpert MTB/RIF\u0026reg; result which confirms \u0026ldquo;low\u0026rdquo;\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u0026ldquo;medium\u0026rdquo; or \u0026ldquo;high\u0026rdquo; level detection of \u003cem\u003eM tuberculosis\u0026nbsp;\u003c/em\u003eand does not detect rifampicin resistance.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e3. Be aged \u0026ge; 18 years (in Tanzania, Malawi and Mozambique) and \u0026ge;21 year (in Gabon) on the day of providing informed consent.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e4. \u0026nbsp; \u0026nbsp;Have a body weight in light clothing and without shoes of \u0026ge; 35kg\u003c/p\u003e\n\u003cp\u003e5. Have a negative urine or serum pregnancy test \u0026le; 7 days prior to screening, and consent to practice an effective method of contraception until completion of therapy (Female participants of child-bearing potential only).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e6. \u0026nbsp; \u0026nbsp;Have a verifiable residence location and telephone number for contact during follow-up.\u003c/p\u003e\n\u003cp\u003eIndividuals for whom one of the following criteria is met will be excluded from the trial:\u003c/p\u003e\n\u003cp\u003e1. \u0026nbsp; \u0026nbsp;Any circumstances raise concern about provision of free, informed consent to study.\u003c/p\u003e\n\u003cp\u003e2. \u0026nbsp; \u0026nbsp;Sputum Xpert MTB/RIF\u0026reg; assay result is \u0026ldquo;negative\u0026rdquo;, \u0026ldquo;trace\u0026rdquo;, or \u0026ldquo;very low\u0026rdquo; positive.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e3. \u0026nbsp; \u0026nbsp;Any pre-treatment \u003cem\u003eM tuberculosis\u003c/em\u003e isolate, either cultured or detected through molecular assays from sputum, is resistant to one or more of rifampicin, isoniazid, pyrazinamide, ethambutol, or fluoroquinolones.\u003c/p\u003e\n\u003cp\u003e4. \u0026nbsp; \u0026nbsp;Poor general condition where delay in treatment cannot be tolerated, or death within three months is likely, as assessed by the investigator.\u003c/p\u003e\n\u003cp\u003e5. \u0026nbsp; \u0026nbsp;A nose/throat swab is positive for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2), on Polymerase Chain Reaction (PCR) or a rapid diagnostic test within 14 days of enrolment.\u003c/p\u003e\n\u003cp\u003e6. \u0026nbsp; \u0026nbsp;Pregnancy or breast-feeding (female participants only).\u003c/p\u003e\n\u003cp\u003e7. \u0026nbsp; \u0026nbsp;Unable to take oral medications.\u003c/p\u003e\n\u003cp\u003e8. \u0026nbsp; \u0026nbsp;Received any investigational drug in the past three months.\u003c/p\u003e\n\u003cp\u003e9. \u0026nbsp; \u0026nbsp;Received more than five days of treatment directed against active tuberculosis within 6 months of enrolment.\u003c/p\u003e\n\u003cp\u003e10.\u0026nbsp;Known intolerance or contraindications to any of the study drugs.\u003c/p\u003e\n\u003cp\u003e11.\u0026nbsp;Unwilling or unable to adhere to requirements regarding restricted use of other medications during the study. Restricted medications will include medications which prolong the QTc interval, and CYP450 inhibitors or inducers.\u003c/p\u003e\n\u003cp\u003e12.\u0026nbsp;Due to initiate, or requires continuation of, non-efavirenz, non-dolutegravir-based anti-retroviral therapy for HIV infection.\u003c/p\u003e\n\u003cp\u003e13.\u0026nbsp;Decompensated liver disease and/or aminotransaminases \u0026gt;3x upper limit of normal (ULN), serum total bilirubin level \u0026gt;1.5x ULN or serum/plasma creatinine level \u0026gt;x2 ULN.\u003c/p\u003e\n\u003cp\u003e14. A baseline QTc interval of \u0026gt;450ms on electrocardiograph (ECG).\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e15.\u0026nbsp;Being, or about to be, treated for malaria.\u003c/p\u003e\n\u003cp\u003e16.\u0026nbsp;Co-existent medical conditions that, in the investigator\u0026rsquo;s judgement, make study participation not in the individual\u0026rsquo;s best interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWho will take informed consent? {26a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInformation about the trial will be provided by study doctors and nurses who have completed Good Clinical Practice in Research (GCP) and study protocol training. Participants will be invited for screening if they are suspected to have pulmonary TB based on sputum smear microscopy or GeneXpert MTB/RIF done within the government or private health sector. Screening may continue for a maximum of five days. After providing valid informed consent, participants will be screened using all inclusion and exclusion criteria. The study database will contain a record of every screening, irrespective of outcome. Individuals who are successfully recruited will be randomised.\u0026nbsp;Those who are ineligible will be referred for routine TB or other appropriate medical care.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdditional consent provisions for collection and use of participant data and biological specimens {26b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAdditional consent form will be provided to participant requesting to use their leftover sputum and blood samples stored in the lab for future studies to advance TB research. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInterventions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExplanation for the choice of comparators {6b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe choice of rifampicin dose (35mg/kg) in both experimental arms is based on prior studies designed to optimise efficacy and safety of this drug, particularly in African populations. However, some recent meta-analyses have also reported increased rifampicin tolerability concerns at doses above 20-30mg/kg (24,25) so particular care will be given to analysis of tolerability and toxicity data in this study.\u003c/p\u003e\n\u003cp\u003eBoth the PanACEA-MAMS trial (14) and Study 31/A5349 (17) indicated that combining optimised dose rifamycins with moxifloxacin is likely to confer additional benefit, perhaps because of high fluoroquinolone penetration into pathological TB lesions (26). Therefore, one experimental arm contains both optimized dose rifampicin and moxifloxacin.\u003c/p\u003e\n\u003cp\u003eThe six-month control comparator of rifampicin (10mg/kg)-isoniazid-pyrazinamide-ethambutol was chosen as it remains the most commonly used DS-TB regimen worldwide.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIntervention description {11a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDetails of each treatment arm are shown in Figure 1. Study medications will be administered as a mixture of fixed dose combination (FDC) and single drug formulation tablets.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn experimental Arm 1, participants will receive optimized dose of rifampicin (35mg/kg/day) plus standard weight banded dose of isoniazid, pyrazinamide and ethambutol administered orally once a day for a duration of four months (4R\u003csub\u003e35\u003c/sub\u003eHZE). Arm 2 is similar to arm one except ethambutol is replaced by moxifloxacin 400mg (4R\u003csub\u003e35\u003c/sub\u003eHZM). The six-month control arm regimen consists of standard dose of rifampicin (10mg/kg/day) plus isoniazid with or without pyrazinamide and ethambutol administered orally once a day for two months rifampicin followed by four months of rifampicin 10mg/kg with weight banded dose of isoniazid (4R\u003csub\u003e10\u003c/sub\u003eH).\u003c/p\u003e\n\u003cp\u003eParticipants in Arms 1 and 2 will be advised to take their medications early in the morning with a light meal to reduce the risk of gastrointestinal irritation with optimized dose rifampicin. Those in the control arm will be advised to take their medications with a glass of water first thing in the morning on an empty stomach (one hour before or two hours after food) for best rifampicin absorption. If medication upsets the stomach when taken fasted, it may be taken with a small amount of food.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eManufacturers of trial medications are: Lupin Limited, India (for FDC RHZE and RH tablets); Macleods Pharm Ltd, India (for rifampicin 150mg and 300mg capsules); Oxalis Lab, India (for pyrazinamide 400mg tablets) and; MSN Laboratories Pvt Ltd, India (for Moxifloxacin 400mg tablets). All manufacturers are certified and adheres to good manufacturing practice. IMP supply will be handled by the Global Drug Facility, in accordance with manufacturers\u0026rsquo; specifications.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCriteria for discontinuing or modifying allocated interventions {11b}\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipants may be withdrawn from the trial during treatment or follow-up because of withdrawal of informed consent, late exclusion (identification of information confirming that one or more exclusion criteria are met after full enrolment), safety concerns by site investigators (including adverse events or concern about worsening TB and/or bacteriological failure/relapse that requires a change in TB treatment), pregnancy, at the request of the sponsor, or loss to follow-up.\u003c/p\u003e\n\u003cp\u003eParticipants withdrawn from the trial will not routinely be replaced.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStrategies to improve adherence to interventions {11c}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAt site pharmacies, study medications will be repacked into daily doses and dispensed by trial pharmacists or trained dispensers who are also responsible for documentation in source data and on dispensing and adherence eCRFs. Trial medications will be provided to participants during follow-up visits on day 14, 28, 56, 84, 112, and 168. Adherence to interventions will be assessed using pill counts during each clinic visit and automatically calculated in the adherence eCRF. Adherence to trial medications will be reinforced by routine counselling, study staff observing uptake of one dose during each visit while the rest of doses will be taken at home under support of identified relative or friend treatment supervisor.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRelevant concomitant care permitted or prohibited during the trial {11d}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAbsorption of moxifloxacin is reduced by multivalent cation-containing medications e.g. aluminium and magnesium containing antacids. Proton pump inhibitors, e.g. omeprazole, are preferred antacids.\u003c/p\u003e\n\u003cp\u003eTB patients living with HIV are eligible if they are already taking or newly initiating ART regimens composed of two nucleosides (or nucleotide) reverse transcriptase inhibitors (other than stavudine and didanosine) plus efavirenz/dolutegravir. Those taking dolutegravir will be required to increase the dose to 50mg twice daily for the duration of TB treatment.\u003c/p\u003e\n\u003cp\u003eNew TB patients who are being, or are about to be, treated for malaria will be excluded from enrolment. Should a participant develop malaria during the trial, anti-malarial treatment may be offered in accordance with national malaria treatment guidelines but careful consideration must be given to electrocardiographic QTc-prolonging potential and drug-drug interactions involving available anti-malarial drugs.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIndividuals who have received QTc prolonging medications within 30 days of the first dose of study drugs will be excluded, to avoid the risk of QTc exacerbation with moxifloxacin (27). Exceptions may be made for those who have received 3 daily doses or less, and at least 5 elimination half‐lives of the drug have passed before first dose of study treatment. The list of medications with risk of QTc prolongation is accessible in https://crediblemeds.org.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eProvisions for post-trial care {30}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipants who leave the study due to adverse events or unfavourable TB treatment outcomes will be referred locally for appropriate medical care or ongoing TB management via National TB Programmes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcomes {12}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary efficacy endpoint for this trial is participant survival, free of tuberculosis 12 months after randomisation. For this favourable outcome to be allocated, all the following criteria will require to be met:\u003c/p\u003e\n\u003cp\u003e1. Completed assigned treatment and known to be alive\u003c/p\u003e\n\u003cp\u003e2. Stable sputum culture conversion, or clinically well without features of ongoing active TB and unable to provide a sputum culture result, either because sputum can no longer be produced or because the only available sample is contaminated without evidence of \u003cem\u003eMtb\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e3. Have not met criteria for treatment failure or relapse\u003c/p\u003e\n\u003cp\u003e4. Not in need of TB treatment and having required no substantial treatment modifications or additional treatment for TB outside the study regimen.\u003c/p\u003e\n\u003cp\u003eUnfavourable primary efficacy outcomes will be allocated to participants who exit the study under any of the following circumstances:\u003c/p\u003e\n\u003cp\u003e1. \u0026nbsp; \u0026nbsp;Completed assigned treatment in the absence of bacteriological cure. This typically occurs as a consequence of treatment failure (defined as submitting two sputum samples with positive culture for \u003cem\u003eMtb\u003c/em\u003e on different visits, when the first of these samples was collected at or after two weeks prior to the scheduled end of treatment) or TB relapse (defined as submitting two sputum samples with positive culture for \u003cem\u003eMtb\u003c/em\u003e on different visits, when the first of these samples was collected after completion of scheduled TB therapy and where at least one of the \u003cem\u003eMtb\u003c/em\u003e isolates is genetically similar to the baseline strain).\u003c/p\u003e\n\u003cp\u003e2. \u0026nbsp; Completed assigned treatment with a single positive culture for \u003cem\u003eMtb\u003c/em\u003e when last seen, but not confirmed by a second sample, unless the positive culture is deemed to represent re-infection.\u003c/p\u003e\n\u003cp\u003e3. \u0026nbsp; Death from any cause during study treatment, except violent or accidental death (e.g., road traffic accident.)\u003c/p\u003e\n\u003cp\u003e4. Extension or alteration of TB treatment beyond that permitted by the protocol.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCircumstances during the study which may result in unassessable outcomes include:\u003c/p\u003e\n\u003cp\u003e1. Failure to complete treatment\u003c/p\u003e\n\u003cp\u003e2. \u0026nbsp; Completion of assigned treatment, then loss to follow-up, with the last reported culture being negative for \u003cem\u003eMtb\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e3. Women becoming pregnant during TB therapy and withdrawing from the trial\u003c/p\u003e\n\u003cp\u003e4. Death from a violent or accidental cause\u003c/p\u003e\n\u003cp\u003e5. Detection of TB re-infection, after successful completion of their assigned therapy, with a new strain of \u003cem\u003eMtb\u003c/em\u003e, demonstrated to be genetically different from that identified at study entry.\u003c/p\u003e\n\u003cp\u003eThe following secondary efficacy endpoints will be reported\u003c/p\u003e\n\u003cp\u003e\u0026middot; Participant survival, free of tuberculosis at 12 months after treatment completion following extended follow-up arranged beyond the formal project end.\u003c/p\u003e\n\u003cp\u003e\u0026middot; Microbiological response using BD Mycobacteria Growth Indicator Tube 960\u0026reg;liquid culture time to positivity (MGIT-TTP)\u003c/p\u003e\n\u003cp\u003e\u0026middot; Microbiological response using the TB-MBLA (including time to conversion to negative, and rate of decline in estimated Colony Forming Units/ml of sputum).\u003c/p\u003e\n\u003cp\u003e\u0026middot; Clinical response to therapy, including change from baseline clinical measurement of weight, body mass index (BMI), TB symptoms and Patient Reported Health Status.\u003c/p\u003e\n\u003cp\u003eThe primary safety outcome for this trial will be the occurrence of AEs of CTCAE Grade 3 severity or higher.\u003c/p\u003e\n\u003cp\u003eThe following secondary safety outcomes will also be reported:\u003c/p\u003e\n\u003cp\u003e\u0026middot; Occurrence of AEs of any grade reported and regarded as definitely, probably, or possibly related to study drugs\u003c/p\u003e\n\u003cp\u003e\u0026middot; Treatment discontinuations or interruptions related to AEs\u003c/p\u003e\n\u003cp\u003e\u0026middot; Frequency, severity, and type of AEs\u003c/p\u003e\n\u003cp\u003eDuring each visit at day 14, 28, 56, 84, 112, 182, month 9 and 12 participants will undergo assessments including self-reported health status, physical examination, routine clinical laboratory tests particularly serum creatinine, total bilirubin, alanine transaminase (ALT), blood count (Hb, WBC and platelet count).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eParticipant timeline {13}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipants will be followed according to the schedule of events elaborated in Figure 2.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSample size {14}\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSample size has been calculated based on the primary efficacy outcome of participant survival free of TB 12 months after initiation of treatment. Based on previous trials of new DST-TB therapy in similar populations (the REMoxTB (6) and STAND (28) studies) in similar populations it was been estimated that 6% and 10% of participants will have unfavourable primary and non-assessable primary efficacy outcomes respectively. For OptiRiMoxTB, with power (\u0026beta;) set at 90%, a non-inferiority margin of 10%, and a type I error (\u0026alpha;) of 5%, a total of 414 participants (138 participants per arm in a 1:1:1) across all sites will be required to show non-inferiority of either of the experimental regimens to control.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRecruitment {15}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll sites will recruit via networks of satellite centres particularly primary and secondary health facilities. This will be achieved through meetings with healthcare providers at potential health centres and use public liaison activities designed during our prior experience of clinical trial conduct at the same sites\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAvailable information on rates of new TB diagnoses at clinics affiliated with each study site, informed pre-trial projections of likely participant numbers in each study country to be set as follows: Gabon, 50; Malawi, 104; Mozambique, 100; and Tanzania, 160.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAssignment of interventions: allocation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSequence generation {16a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRandomisation of eligible participants will be stratified according to the presence or absence of cavitation on chest radiograph. Stratified randomization will be undertaken within Research Electronic Data Capture (REDCap) software (29) on a 1:1:1 allocation ratio using a permuted block randomization procedure with block sizes of 3, 6 and 9.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConcealment mechanism {16b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAllocation concealment to reduce selection bias at randomization is fostered by REDCap which provides a randomization number only after all screening information has been provided on the CRF. Following randomization, the study will be open label with treatment allocation known to participants and healthcare providers.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eImplementation {16c}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe allocation sequence generation will be released automatically by REDCap software upon confirmation of participant eligibility on the eCRF.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAssignment of interventions: Blinding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWho will be blinded {17a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot Applicable. Not applicable because, this is an open-label trial, so site investigators and participants will be aware of treatment allocations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eProcedure for unblinding if needed {17b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot Applicable. Not applicable because, this is open label trial, so site investigators and participants will be aware of treatment allocations.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData collection and management\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans for assessment and collection of outcomes {18a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStudy endpoints are based on a combination of objective clinical observations and microbiological measurements. An outcome allocation committee, comprising the Principal Investigators, study statistician and independent medical experts appointed by the Sponsor will meet at study completion to confirm assignment of final outcomes for each participant.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans to promote participant retention and complete follow-up {18b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCareful participant counselling and community engagement will reinforce the importance of study visit attendance from the point of screening onwards. Participants will have clear contact details for local site investigators to report any concerns as soon as they arise. If visits are missed, at least three attempts at contact via telephone or home visits will be undertaken before any participant is allocated as lost to follow-up.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn general, participants who withdraw from the study for reasons other than withdrawal of consent or loss to follow-up shall continue to follow study assessments as laid down in the schedule of events, to make them evaluable for long-term outcomes.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Management {19}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll study data will be entered into eCRF forms, created for each participant in REDCap. Physical source data, including participant\u0026rsquo;s case records, chest radiographs, and safety and microbiology laboratory results will be retained and made available for verification. Accuracy and completeness of data will be checked by pre-programmed edit checks in the REDCap database that will flag out of range values and by at least two visits to each site by independent monitors.\u003c/p\u003e\n\u003cp\u003eSite lead investigators be responsible to ensure that study documents are maintained in accordance with International Conference on Harmonisation of Good Clinical Practice (ICH-GCP) guidelines. Upon trial completion essential documents will be retained for a duration of not less than 10 years or as required by local regulation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConfidentiality {27}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn the trial database and on all study forms participants will only be identified by a study number comprising three letters which represent the site and three numbers which represent their enrolment number. A participant identification log will be kept in a securely locked separate trial file at each site, that only delegated staff will have access to. The ICF has a clause granting permission for the review of participants\u0026rsquo; source documents by site lead investigators or a competent delegated person if necessary. The trial database will be encrypted and stored on secure servers with regular back-up and access control.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSputum samples at screening and enrolment will be used to confirm the diagnosis of pulmonary tuberculosis by sputum smear microscopy and/or Xpert MTB/RIF, and to perform rapid drug susceptibility testing for rifampicin. Sputum from all timepoints will be used for mycobacterial liquid (MGIT) culture and the molecular bacterial load assay (TB-MBLA). M tuberculosis isolates from these cultures will be stored and may be used for additional drug susceptibility testing. Isolates from participants who remain sputum culture positive at end of treatment or develop recurrent TB after treatment completion will be stored for Whole Genome Sequencing to confirm whether it is a relapse or reinfection. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical methods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical methods for primary and secondary outcomes {20a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStudy analysis groups will be defined and analysed as shown in Table 2. The primary efficacy outcome will be assessed by comparing each of the experimental regimens with the control arm in the modified intention-to-treat (mITT) population. In each comparison non-inferiority will be assessed by comparing the upper bound of a 95%, two-sided confidence interval for the difference between the proportion of participants who were classified with an unfavourable outcome on the control and experimental regimen to the pre-defined non-inferiority margin of 10%.\u003c/p\u003e\n\u003cp\u003eThe primary safety outcome will be assessed by comparing the proportion of participants with CTCAE grade 3 or higher AEs in each experimental regimens versus control regimen, in the pre-defined safety population.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2: OptiRiMoxTB study analysis populations\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 141px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 460px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 141px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 460px;\"\u003e\n \u003cp\u003eAll enrolled participants who receive a treatment assignment\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eParticipants with an unassessable primary efficacy outcome will be assumed to have had an unfavourable outcome\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 141px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 460px;\"\u003e\n \u003cp\u003eAll ITT participants except late exclusions\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eThis is the primary analysis population for efficacy analyses.\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eParticipants with an unassessable primary efficacy outcome will be assumed to have had an unfavourable outcome\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 141px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 460px;\"\u003e\n \u003cp\u003eAll participants who completed the study without protocol deviations and had an outcome assigned.\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eParticipants with an unassessable outcome will be excluded from the analysis.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 141px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 460px;\"\u003e\n \u003cp\u003eAll ITT participants that receive at least one dose of study medication\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eThis is the primary analysis population of interest for safety analyses\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn secondary efficacy analyses, the primary efficacy endpoint will be assessed in the PP population, and the secondary efficacy endpoints will be assessed in both mITT and PP populations. Both experimental regimens will be compared with the control regimen. Secondary analyses will include those directed towards identification of clinical and microbiological factors associated with favourable and unfavourable outcomes. Mixed effects models will be used to analyse microbiological culture and TB-MBLA data on bacillary clearance rates. Time to unfavourable outcome and time to microbiology-negative status will be analysed using Kaplan-Meier plots and Cox proportional hazards regression methods. Multivariate logistics regression modelling will be used to assess relationships between co-variates and clinical outcomes. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAs with the primary safety outcome, all secondary safety outcomes will be assessed in the pre-defined safety population.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInterim analyses {21b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot Applicable. Not applicable because, there will be no interim analysis apart from Data and Safety Monitoring Committee (DSMC) reports which will be generated following review of unblinded data in closed meetings.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods for additional analyses (e.g. subgroup analyses) {20b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSub-group analyses (with tests for interaction) of the primary endpoint will be performed according to age, gender, weight, BMI, country, HIV status, smoking history and history of diabetes, the presence or absence of cavitation (cavitation will be defined as a gas-containing lucent space at least 1 cm in diameter within the lung parenchyma surrounded by an infiltrate or fibrotic wall greater than 1 mm thick seen on the chest radiograph), extent of cavitation on baseline chest radiograph, MGIT days to detection, initial bacterial load in sputum as indicated by baseline MIGT-TTP result (low bacterial load = MIGT-TTP\u0026ge; median, high bacterial load = MIGT-TTP \u0026lt; median) and GeneXpert MTB/RIF Cycle threshold. The test for an interaction between the covariate and treatment will be done using logistic regression comparing the model including the interaction term and the model with only marginal terms using the likelihood ratio test to evaluate the statistical significance of inclusion of the interaction term in the model.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods in analysis to handle protocol non\u003c/strong\u003e\u003cstrong\u003e‑\u003c/strong\u003e\u003cstrong\u003eadherence and any statistical methods to handle missing data {20c}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAlthough the primary study analysis will be the mITT population, sensitivity analyses will be undertaken to consider the effect of missing data on study outcomes. These will include primary efficacy analyses on ITT and PP populations.\u003c/p\u003e\n\u003cp\u003eTo minimise missing information, following data entry into eCRFs, completeness and consistency checks will be performed by sponsor\u0026rsquo;s data management. All resulting queries will be sent through the database query system to leave an audit trail.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans to give access to the full protocol, patient level\u003c/strong\u003e\u003cstrong\u003e‑\u003c/strong\u003e\u003cstrong\u003edata and statistical code {31c}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWith exception of participant-identifying information which will not be shared, all other data from this trial will be released through public use data set.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOversight and monitoring\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eComposition of the coordinating centre and trial steering committee {5d}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA trial Operational Team (OT) chaired by the Trial Project Manager, comprising two co-Principal Investigators, Sponsor Trial Manager, and all site Lead Investigators, alongside data, microbiology/biomarker and pharmacy project leads will meet every two weeks to co-ordinate day-to-day operations. Additionally, a Trial Steering Committee (TSC), comprising a sponsor representative, the trial statistician, and two expert clinicians who are independent of trial conduct will convene on an ad hoc basis throughout the trial, reporting to the sponsor. \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA Medical Monitoring Team (MMT) comprising two co-Principal Investigators and two independent clinicians, from experienced African TB trial sites which are not involved in OptiRiMoxTB will provide real-time oversight (with response time to queries of 24 hours) of clinical activities at all sites: primarily offering guidance on management and reporting of safety events, including decisions on participant withdrawal from the study. The MMT will report directly to the Sponsor and may present at OT or TSC meetings as required. On request the MMT may compile information or provide reports to the Data Safety Monitoring Committee (DSMC).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eComposition of data safety monitoring committee, its role and reporting structure {21a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe DSMC will consist of five members: two trial statisticians (one of whom has extensive experience of TB trials, and will be chair), and three clinicians (one Infectious Disease physician, one Respiratory Medicine physician and one Clinical Pharmacologist). The DSMC will be balanced by gender and geography (with African and European members who are experienced not only in clinical TB research but the specific study settings and context). DSMC members will be independent of the sponsor and study investigators and have no competing interest. They will meet on a prespecified schedule; before initiation of recruitment, after month 6, and then when one-third, two-thirds and all participants have been enrolled. Addition ad hoc meetings will be convened if required by the sponsor. The DSMC acts in advisory capacity to the Sponsor through TSC to safeguard the integrity of trial conduct and participant safety. After each assessment, the DSMC will make recommendations to the Sponsor about continuation, modification, or termination of the entire study, or of individual arms\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdverse event reporting and harms {22}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll participants will be counselled during informed consent to report any AEs experienced at any time during the study. Additionally, information on AEs will be proactively sought during each study visit by direct clinical assessment (interview and physical examination and laboratory investigations as outlined in Figure 2. Severity of AEs will be classified on a scale of 1-5 according to the United States (U.S) National Institutes of Health CTCAE 5.0(30). Site lead investigators will categorise causal relationships of AEs to study drugs as \u0026lsquo;unrelated\u0026rsquo;, \u0026lsquo;unlikely\u0026rsquo;, \u0026lsquo;possible\u0026rsquo;, \u0026lsquo;probable\u0026rsquo; and \u0026lsquo;certain\u0026rsquo;. The MMT will be used as a resource to assess and manage AEs. All AEs will be recorded. Those with a severity grading of 3-5 will be defined as severe adverse events (SAEs) which carries an obligation to report to the Sponsor, regulatory authorities and independent ethical committees within 24 hours of first identification.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll women of child-bearing age will be counselled to contact their site investigator immediately if they suspect that they might be pregnant at any time. If pregnancy is confirmed, the participant will be withdrawn from the trial and referred to their National TB Program for ongoing care. Investigators will also report to the Sponsor follow-up information regarding the outcome of the pregnancy, including perinatal and neonatal outcomes.\u003c/p\u003e\n\u003cp\u003eAdverse events involving hepatotoxicity are of particular interest in this trial, and specific Hepatotoxicity Management Guidelines will be used. Participants with aminotransaminases\u0026nbsp;\u0026ge; 3x ULN or bilirubin \u0026ge; 2x ULN will be instructed to withhold all trial medications, with further guidance based on repeat blood tests, clinical condition and MMT consultation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFrequency and plans for auditing trial conduct {23}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eQualified independent trial monitors, appointed prior to trial initiation by the Sponsor, will visit each site at least twice during the trial to audit performance.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll changes to the protocol will be completed by means of amendments, which will be submitted to applicable ethical committees and regulatory agencies prior to implementation. Amendments of trial protocol will be updated in ClinicalTrials.gov, ID: NCT05575518. Protocol amendment training will be performed as necessary.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDissemination of results {31a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe findings from this trial will be important to study participants, communities affected by TB, and to clinicians, public health policymakers, and researchers working on TB treatment and control. Results will be disseminated to each group by appropriate means including aggregate data reports to study participants and community advisory boards, scientific conference presentations, and submission of manuscripts for publication in open access peer-reviewed journals.\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe OptiRiMoxTB trial builds on previous work, including some of the same group that described the tolerability of rifampicin doses up to 35mg/kg in Africa populations by offering Phase 3 evaluation of DS-TB treatment regimens using that dose. It also builds on the important work of the TBTC Study 31/ATCG5349 trial which indicated that optimised dose rifamycins may need to be accompanied by lesion-penetrating 8-methoxyfluoroquinolones to achieve the goal of treatment-shortening (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Since initiation of this protocol, the RIFASHORT trial has published results indicating that flat-dosing of 1200mg and 1800mg rifampicin (equivalent to 20mg/kg and 30mg/kg respectively in a 60kg adult) combined with other first-line TB drugs did not achieve non-inferiority compared to standard of care therapy (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). OptiRiMoxTB advances on that work by weight-based rifampicin dose escalation and incorporation of an experimental arm containing moxifloxacin.\u003c/p\u003e\u003cp\u003eIn order to generate data which is generalisable to programmatic delivery of routine TB care in high-burden countries and which may accelerate implementation of successful study regimens, the trial will be conducted in African study sites with moderate-to-high HIV prevalence and the study design has been kept as pragmatic as possible: eligibility criteria have been kept as broad as possible, there are no specific HIV severity or CD4-count threshold based exclusion criteria, and procedures at study visits have been rationalised to those which are deemed essential. Since protocol initiation, systematic reviews have ongoing uncertainty on the optimal tolerable dose of rifampicin (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e), underpinning the need for the careful safety monitoring, which will be provided by site investigators, the MMT and the independent DSMC.\u003c/p\u003e\u003cp\u003eThe primary efficacy endpoint of this trial is clinical, but secondary microbiological endpoints will include measurements using conventional MGIT-TTP and also the novel TB-MBLA assay. Comparative performance of these assays will be important for the design and conduct of future Phase 2 and 3 clinical trials and may also provide insights on the value of TB-MBLA for treatment monitoring in routine TB care.\u003c/p\u003e\u003cp\u003eThe open-label design of this trial is driven by the complexity and pill burden which would be generated by placebo-controls but does poses a risk of reporting bias at the point of outcome allocation. This will be mitigated by use of standard prospective outcome definitions, incorporating objective laboratory evidence of stable culture conversion, and appointment of an outcome allocation committee containing independent medical experts.\u003c/p\u003e\u003cp\u003ePrimary endpoints for this trial will be measured 12 months after participant randomisation, partly because this timepoint was deemed practically achievable during the prescribed funding window at the time of study design. Acknowledging that post-treatment relapse is an important component of long-term outcome in Phase 3 TB trials, secondary outcomes do include scope for longer-term outcomes (until at least 12 months after treatment completion). Sufficient resources are now in place for extended follow-up and a further protocol amendment (v3.0) is in process to approve data collection for this.\u003c/p\u003e\u003cp\u003eUltimately, this pragmatic Phase 3 trial will establish whether four-month DS-TB treatment incorporating optimised dose rifampicin (35mg/kg) with or without moxifloxacin (400mg) is efficacious and safe compared to six-month standard treatment with rifampicin 10mg/kg. The study design, based on routine care delivery to a representative patient population, and use of a readily available rifamycin may pave the way for accelerated programmatic implementation.\u003c/p\u003e\n\u003ch3\u003eTrial status\u003c/h3\u003e\n\u003cp\u003eOptiRiMoxTB was registered at ClinicalTrials.gov, ID: NCT05575518 with trial version 1.0 on 10th October 2022. Four clinical sites were included at that time (CERMEL,Gabon; KUHeS, Malawi; INS, Mozambique; KIDH, Tanzania) At KIDH recruitment started on August 2023. The protocol was amended to version 2.0 on 30th November 2023, primarily to allow site expansion to include IHI and NIMR-Mwanza in Tanzania. These sites started recruitment in 2024. The protocol was further amended to version 3.0 on 8th January 2025 to increase follow-up time from 12 to 18 months post-randomisation. Recruitment of the first participant was on 11th August 2023 and the last participant was recruited on 6th January 2025. Currently participants are being followed up expecting the last participant last visit to be on 25th May 2026.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e16S\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003e16Svedberg unit\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e2R\u003csub\u003e10\u003c/sub\u003eHZE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eTwo months duration of standard daily Rifampicin (R) 10mg/kg plus standard weight banded dose of Isoniazid (I), Pyrazinamide (Z) and Ethambutol (E)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e4R\u003csub\u003e10\u003c/sub\u003eH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eFour months duration of standard daily Rifampicin (R) 10mg/kg plus standard weight banded dose of Isoniazid (I)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e4R\u003csub\u003e35\u003c/sub\u003eHZE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eFour months duration of daily Rifampicin (R) 35mg/kg plus standard weight banded dose of Isoniazid (I), Pyrazinamide (Z) and Ethambutol (E)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e4R\u003csub\u003e35\u003c/sub\u003eHZM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eFour months duration of daily Rifampicin (R) 35mg/kg plus standard weight banded dose of Isoniazid (I), Pyrazinamide (Z) and Moxifloxacin(M)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eAEs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eAdverse Events\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eALT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eAlanine Transaminase\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eART\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eAnti-Retroviral Therapy\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eBD MGIT 960\u0026reg;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eBecton, Dickinson Mycobacteria Growth Indicator Tube 960\u0026reg;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eBD MGIT-TTP 960\u0026reg;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eBecton, Dickinson Mycobacteria Growth Indicator Tube 960\u0026reg; liquid culture time to positivity\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eBMI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eBody Mass Index\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eCD4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eCluster of Differentiation 4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eCERMEL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eCentre de Recherches M\u0026eacute;dicales de Lambar\u0026eacute;n\u0026eacute;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eCH-GCP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eInternational Conference on Harmonization of Good Clinical Practice\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eCISPOC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003ePolana Cani\u0026ccedil;o Health Research and Training Center\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eCOVID-19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eCoronavirus Disease-19\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eCRF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eCase Report Form\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eCTCAE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eCommon Terminology Criteria for Adverse Events\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eCYP450\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eCytochrome P450\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eDILI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eDrug-Induced Liver Injury\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eDoT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eDirectly Observed Therapy\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eDSMC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eData and Safety Monitoring Committee\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eDS-TB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eDrug-Susceptible Tuberculosis\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eECG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eElectrocardiograph\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eeCRF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eElectronic-Case Report Form\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eEDCTP2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eEurope and Developing Countries Clinical Trials-2\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eEN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eEnrollment\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eFDC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eFixed Dose Combination\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eFDC RH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eFixed Combination of Rifampicin (R) 150mg and Isoniazid (H) 75mg\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eFDC RHZE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eFixed Dose Combination of Rifampicin (R) 150mg, Isoniazid (H) 75mg, Pyrazinamide (Z) 400mg and Ethambutol (E) 275mg\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eGCP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eGood Clinical Practice in Research\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eHb\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eHemoglobin\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eHIV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eHuman Immunodeficiency Virus\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eICF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eInformed Consent Form\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eIHI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eIfakara Health Institute\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eINS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eInstituto Nacional de Sa\u0026uacute;de\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eITT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eIntention- To Ttreat\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eKIDH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eKibong\u0026rsquo;oto Infectious Diseases Hospital\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eKUHeS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eKamuzu University of Health Sciences\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eLMICs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eLow- and Middle-Income Countries\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eM tuberculosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eMycobacterium tuberculosis\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eM2, M4, M6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eMonth Two, Month Four, Month Six\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eMAMS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eMulti-Arm Multi-Stage\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eMDR/RR TB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eMulti Drug Resistant/Rifampicin Resistant Tuberculosis\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003emITT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003emodified intention-to-treat\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eMMT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eMedical Monitoring Team\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eMtb\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eMycobacterium tuberculosis\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eNIMR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eNational Institute for Medical Research\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eOT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eOperational Team\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003ePanACEA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003ePan-African Consortium for the Evaluation of Anti-tuberculosis Antibiotics\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003ePCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003ePolymerase Chain Reaction\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003ePP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003ePer -Protocol\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eREDCap\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eResearch Electronic Data Capture\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eRibonucleic acid\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003erRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eRibosomal Ribonucleic acid\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eSAEs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eSevere Adverse Events\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eSARS-CoV2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eSevere Acute Respiratory Syndrome Coronavirus 2\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eSCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eScreening\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eSPIRIT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eStandard Protocol Items: Recommendations for Interventional Trials\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eTB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eTuberculosis\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eTB-MBLA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eTuberculosis Molecular Bacterial Load Assay\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eTSC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eTrial Steering Committee\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eULN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eUpper Limit of Normal\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eUS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eUnited States\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eWBC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eWhite Blood Count\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eWHO\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 504px;\"\u003e\n \u003cp\u003eWorld Health Organization\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eProtocol version:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe manuscript has been developed based on protocol version 2.0 of 30\u003csup\u003eth\u003c/sup\u003e November 2022.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to acknowledge members of the DSMC (Associate Professor Patrick Phillips, Dr Polycarp Mogeni, Professor Kogie Naidoo, Professor Mark Lipman and Professor Catriona Waitt) and the MMT (Dr Caryn Upton, Dr Daniella Ross and Dr Tina Minja). We would also like to thank Dr Angela Crook and Professor Rob Aarnoutse who advised our statistical and pharmacy teams respectively, in addition to all clinical site teams, community engagement groups, and participants so far.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions {31b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe trial was conceptualized by DJS, SM and SHG. The study design was conceived by DJS and SM. SHG who also wrote the protocol and HM, DJS, SGM, and SHG wrote this manuscript. Study set-up and conduct is being undertaken by HM, AL, EM, OLK, SL, HS, TDMcH, LW, WS, BRA, ML, CK, PM, BM, KJ and SGM. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding {4}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe trial is funded by the Europe and Developing Countries Clinical Trials-2 (EDCTP2) Simplified short treatment for tuberculosis grant RIA2017S-2012. The funder had no role in the design of the study and writing this manuscript. Also, the funder will have no role in data collection, analysis, interpretation and reporting the trial findings.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials {29}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll parties conducting the trial will have access to the final dataset.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval and consent to participate {24}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthical approvals for this trial have been thought from all sites\u0026rsquo; local and or national ethical committees; Tanzania (KIDH and National Institute of Medical Research (NIMR)), Gabon (CERMEL and National Research Ethics Committee), Malawi (KUHeS Ethical Committee) and Mozambique (INS Institutional Review Board and\u0026nbsp;Comit\u0026eacute; Nacional de Bio\u0026eacute;tica para Sa\u0026uacute;de). Also, the trial has received clinical trial authorization from medicines regulatory authorities in all participating countries namely; Tanzania Medicines and Medical Devices Authority (TMDA), Malawi Pharmacy and Medicines Regulatory Authority (PMRA), Gabon Directorate of Medicines and Pharmacy (DMP) and Mozambique Autoridade Nacional Regulatoria de Medicamentos (ANARME).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication {32}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent will be obtained from all \u003cstrong\u003eparticipants\u003c/strong\u003e prior to enrolment. Original ICFs will be kept in regulatory binders at each site and will be available on request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests {28}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone of the authors has any competing interest to declare. In addition, the funder has no influence on design, implementation and reporting of this clinical trial research.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; information (optional)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot Applicable. Not applicable because, authors affiliations information have been stated in Author details {5a}.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eChaves Torres NM, Quijano Rodr\u0026iacute;guez JJ, Porras Andrade PS, Arriaga MB, Netto EM. Factors predictive of the success of tuberculosis treatment: A systematic review with meta-analysis. PLoS ONE. 2019;14(12):e0226507.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWorld Health Organisation. WHO End TB Strategy: Global strategy and targets for tuberculosis prevention, care and control after 2015. 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Proc Natl Acad Sci USA. 2009;106:13980\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGillespie SH, Crook AM, McHugh TD, Mendel CM, Meredith SK, Murray SR, et al. Four Month Moxifloxacin-Based Regimens for Drug-Sensitive Tuberculosis. N Engl J Med. 2014;371(17):1577\u0026ndash;87.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJindani A, Harrison TS, Nunn AJ, Phillips PPJ, Churchyard GJ, Charalambous S, et al. High-Dose Rifapentine with Moxifloxacin for Pulmonary Tuberculosis. N Engl J Med. 2014;371(17):1599\u0026ndash;608.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJayaram R, Shandil RK, Gaonkar S, Kaur P, Suresh BL, Mahesh BN, et al. Isoniazid pharmacokinetics-pharmacodynamics in an aerosol infection model of tuberculosis. Antimicrob Agents Chemother. 2004;48(8):2951\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRosenthal IM, Tasneen R, Peloquin CA, Zhang M, Almeida D, Mdluli KE, et al. 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PLoS Med 16(4): e1002773.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTulkens PM, Arvis P, Kruesmann F. Moxifloxacin safety: An analysis of 14 years of clinical data. Drugs R D. 2012;12(2):71\u0026ndash;100.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTweed CD, Wills GH, Crook AM, Amukoye E, Balanag V, Ban AYL, et al. A partially randomised trial of pretomanid, moxifloxacin and pyrazinamide for pulmonary TB. Int J Tuberc Lung Dis. 2021;25(4):305\u0026ndash;14.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHarris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap) \u0026ndash; A metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inf. 2009;42(2):37.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCommon Terminology Criteria for Adverse Events (CTCAE). Version 5.0. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES, National Institutes of Health, National Cancer Institute. Published: November 27; 2017.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"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":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Optimized dose rifampicin, moxifloxacin, drug susceptible TB, TB-MBLA","lastPublishedDoi":"10.21203/rs.3.rs-7238156/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7238156/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eCurrent combination antibiotic treatment for drug-susceptible tuberculosis (DS-TB) usually takes six months to complete. This long duration can compromise clinical outcomes. Although a four-month regimen including an optimized dose of rifapentine plus moxifloxacin is non-inferior to standard therapy, rifapentine is hard to source globally and adoption of this regimen has been slow. This trial investigates the efficacy and safety of a four-month DS-TB treatment including the more readily available rifamycin, rifampicin 35mg/kg, with or without moxifloxacin 400mg.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eThis multi-centre phase III randomized open-label clinical trial will be conducted across four African countries (Gabon, Malawi, Mozambique, and Tanzania). A total of 414 newly diagnosed consenting adult participants will be block randomized, after stratification by chest radiograph cavitation, to two experimental and one control arm at a ratio of 1:1:1. The first experimental group will receive optimized dose rifampicin (35mg/kg) with routine weight-banded doses of isoniazid, pyrazinamide, and ethambutol once daily for four-months. The second experimental group will receive optimized dose rifampicin (35mg/kg) and moxifloxacin 400mg once daily alongside routine doses of isoniazid and pyrazinamide. The control group will receive six-month standard of care therapy: rifampicin (10mg/kg) plus weight banded dose of isoniazid, pyrazinamide, and ethambutol for two months, followed by the same doses of rifampicin and isoniazid for four months. Participants will be followed until the allocation of efficacy (TB-free survival) and safety (proportion of severe adverse events) outcomes. Secondary outcomes will also include the evaluation of the Tuberculosis Molecular Bacterial Load Assay (TB-MBLA) for microbiological treatment monitoring.\u003c/p\u003e\u003ch2\u003eDiscussion\u003c/h2\u003e\u003cp\u003eThis study will evaluate whether four-month duration multi-drug treatment including an optimized dose of rifampicin with or without moxifloxacin have non-inferior efficacy and safety outcomes compared to standard of care DS-TB therapy in Africa.\u003c/p\u003e\u003ch2\u003eTrial registration:\u003c/h2\u003e\u003cp\u003eClinicalTrials.gov, ID: NCT05575518 registered on 10th October 2022.\u003c/p\u003e","manuscriptTitle":"A pragmatic trial with an optimized dose of rifampicin and moxifloxacin for the treatment of drug-susceptible pulmonary tuberculosis: A study protocol for open-label, randomized phase III trial (OptiRiMoxTB)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-15 17:02:43","doi":"10.21203/rs.3.rs-7238156/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Accept","date":"2026-01-14T14:39:37+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2025-10-02T15:13:48+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-10-02T13:53:35+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-08-28T05:37:39+00:00","index":"","fulltext":""},{"type":"submitted","content":"Trials","date":"2025-08-26T17:49:35+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"abd9078a-da58-41c8-b206-c77c9d3de49d","owner":[],"postedDate":"October 15th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-02-02T16:05:35+00:00","versionOfRecord":{"articleIdentity":"rs-7238156","link":"https://doi.org/10.1186/s13063-026-09466-0","journal":{"identity":"trials","isVorOnly":false,"title":"Trials"},"publishedOn":"2026-01-30 15:58:35","publishedOnDateReadable":"January 30th, 2026"},"versionCreatedAt":"2025-10-15 17:02:43","video":"","vorDoi":"10.1186/s13063-026-09466-0","vorDoiUrl":"https://doi.org/10.1186/s13063-026-09466-0","workflowStages":[]},"version":"v1","identity":"rs-7238156","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7238156","identity":"rs-7238156","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}