Protocol for a phase 2, partially-blinded, randomised trial assessing the safety and efficacy of sorfequiline or bedaquiline, in combination with pretomanid and linezolid in adult participants with newly diagnosed, drug-sensitive, smear-positive pulmonary tuberculosis (NC-009)

Protocol for a phase 2, partially-blinded, randomised trial assessing the safety and efficacy of sorfequiline or bedaquiline, in combination with pretomanid and linezolid in adult participants with newly diagnosed, drug-sensitive, smear-positive pulmonary tuberculosis (NC-009) | 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 Protocol for a phase 2, partially-blinded, randomised trial assessing the safety and efficacy of sorfequiline or bedaquiline, in combination with pretomanid and linezolid in adult participants with newly diagnosed, drug-sensitive, smear-positive pulmonary tuberculosis (NC-009) Morounfolu Olugbosi, Maria Beumont, Leandra Lombard, Jerry Nedelman, and 13 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7298866/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 06 Jan, 2026 Read the published version in Trials → Version 1 posted 5 You are reading this latest preprint version Abstract Introduction : In 2023, tuberculosis (TB) returned to being the world’s leading cause of death from a single infectious agent. Current standard of care for drug-sensitive tuberculosis (DS-TB) treatment has a long duration with risk of poor compliance and outcomes, and increased risk of development of resistant strains. Sorfequiline (S) is a second generation diarylquinoline with the potential to contribute both to increased efficacy and improved safety, and to a shorter TB treatment regimen for both DS-TB and drug-resistant (DR-TB). Methods and analysis : NC-009 is a phase 2, multi-centre, partially blinded, randomised clinical trial conducted in 5 treatment arms, including 3 doses of sorfequiline in combination with pretomanid and linezolid for 8 weeks followed by 7 or 18 weeks of HR depending on the participant meeting criteria to stop treatment at week 15. There is also a BPaL arm and standard of care arm, both for 26 weeks treatment duration. Study population is smear-positive, DS-TB. The primary objective of the study is to determine the optimal dose of sorfequiline to move forward to a potential phase 3 study based on efficacy and safety data. The study is being conducted in Georgia, South Africa, Tanzania, Uganda and the Philippines in accordance with ICH-GCP and after approval of all relevant country Health Authorities and Ethics Committees. Discussion : NC-009 is a first-in-patient, dose-ranging, phase 2 trial of sorfequiline, with an innovative design combining ph2a, ph2b, and ph2c elements that simultaneously allows for dose selection, preliminary evaluation of treatment duration, robust collection of safety data, evaluation of drug-drug interaction with antiretroviral medications and pharmacokinetic assessment of study drugs. The study is currently ongoing. Trial registration number {4} : ClinicalTrials.gov: NCT 06058299; Registered 09 September 2023; (URL: https://clinicaltrials.gov/study/NCT06058299?cond=tuberculosis&term=NC-009&rank=1 ) Protocol version {2}: 03 Feb 2023 Version 1.0 (NC-009) Sorfequiline Bedaquiline Pretomanid Linezolid Drug-Sensitive TB Clinical trial Figures Figure 1 STRENGHTS AND LIMITATIONS OF THIS STUDY This is a unique study that combines dose selection for a next generation diarylquinoline (3 doses of sorfequiline evaluated) using efficacy and safety data, plus evaluation of potential duration of treatment based on ability to stop treatment at week 15 based on meeting certain criteria. This study also evaluates the potential drug-drug interaction of sorfequiline on dolutegravir and tenofovir. The study is not powered to compare *sorfequiline and bedaquiline, both in combination with pretomanid and linezolid. INTRODUCTION Background and rationale {6a} Tuberculosis (TB) is a preventable and usually curable disease. Yet in 2023, TB returned to being the world’s leading cause of death from a single infectious agent, following 3 years in which it was replaced by coronavirus disease (COVID-19) (1). Existing drug sensitive TB (DS-TB) treatment regimens are efficacious but lengthy in duration and involve multidrug therapy combinations i.e., an intensive phase of 2 months of isoniazid (H), rifampicin (R), pyrazinamide (Z), and ethambutol (E) followed by a continuation phase of 4 months of isoniazid and rifampicin (HRZE/HR); this treatment regimen was first introduced as the standard of care more than 40 years ago (2). Long and complex treatments lead to high rates of non-adherence, which often result in unfavourable outcomes, emergence of drug resistance, continued spread of disease, and increased mortality. Drug-drug interactions caused by rifampicin’s potent induction of CYP enzymes are another major challenge with the HRZE/HR regimen, particularly for women on hormonal contraception and TB participants co-infected with HIV taking anti-retroviral therapies (ARVs). While a 4-month rifapentine-based regimen for treatment of pulmonary DS-TB is now recommended by the WHO as a possible alternative to HRZE/HR but with very limited global roll-out (3), there is a need for new TB drugs and drug regimens that are efficacious, safe, well-tolerated, simpler, and that can further shorten the overall treatment duration, thereby improving adherence and patient outcomes. The combination of bedaquiline, a first generation diarylquinoline, with pretomanid (a nitroimidazole), and linezolid (an oxazolidinone) administered for 26 weeks has been extensively studied and is referred to as the BPaL regimen. The BPaL regimen demonstrated robust efficacy (>90% relapse-free cure) in adults with pulmonary XDR-TB and TI/NR MDR-TB (pre-WHO 2021 definitions) when linezolid was dosed at 1200 mg daily (4). When the linezolid dose was decreased to 600 mg daily, efficacy was retained, and the regimen demonstrated improved tolerability (5). BPaL (plus moxifloxacin in patients with fluoroquinolone-susceptible TB) for 6 months is currently recommended for patients with drug resistant TB (DR-TB) sensitive to all components of the regimen (6). The high potency of the BPaL regimen has potential to also shorten treatment for DS-TB (7). Sorfequiline (S) is a second generation diarylquinoline selected for development based on initial positive nonclinical results. In vitro and in vivo studies have shown the increased potency of sorfequiline over bedaquiline. The sorfequiline minimum inhibitory concentration (MIC) against a phylogenetically diverse panel of 96 clinical strains was approximately 10-fold lower than the corresponding bedaquiline MICs and in the acute and chronic mouse models of TB, sorfequiline was superior to bedaquiline when administered as monotherapy or in combination with PaL. Crucially, the activity of sorfequiline against the most common type of bedaquiline resistant mutant (Rv0678 mutant) was similar to that of bedaquiline against a wild type strain, both in vitro and in the mouse model(8) . Based on in vitro cardiac potassium channel current inhibition screening studies (hERG assay) and in vivo cardiovascular safety assessments, sorfequiline has shown a reduced risk for QTc prolongation compared with bedaquiline(9) . Sorfequiline thus has the potential to contribute both to increased efficacy and improved safety, and to a shorter TB treatment regimen for both DS-TB and DR-TB. OBJECTIVES {7} List of primary, key secondary, secondary and exploratory objectives and associated endpoints are described in Table 1. TRIAL DESIGN {8} This is a phase 2, multi-center, partially blinded, randomised clinical trial where at least 300 participants with DS‑TB who meet all the inclusion criteria and none of the exclusion criteria, aged 18 to 65, will be randomised to receive 1 of the 5 active treatment regimens (at least 60 participants per regimen). Participants will be randomised in equally, using an interactive response technology (IRT) that stratifies based on country and severity of disease (AFB 3+ and/or bilateral cavitation) to 1 of the 5 daily treatment regimens. The trial consists of the following periods: Screening Period : Screening visit up to 11 days prior to randomisation (Day 1) Treatment Period 1 (TP1): Day 1 through Week 8 (SPaL or BPaL or HRZE) Treatment Period 2 (TP2): Week 9 through Week 15 (participants in the SPaL arms that meet criteria for early completion of treatment). Week 9 through Week 26 (participants in the HRZE/HR or BPaL arms, and participants in the SPaL arms who do not meet criteria for early completion of treatment). Post end of treatment (EOT) Follow-up Period : 52 weeks after EOT After receiving 8 weeks of treatment, participants in the SPaL arms and in the control arm (HRZE/HR) will continue treatment with HR, and participants randomised to BPaL will continue treatment with BPaL. Treatment completion will be allowed at week 15 in participants randomised to the SPaL arms, if thecriteria below are met : Week 8 sputum Mycobacterial Growth Indicator Tube (MGIT) culture is negative, and The participant has no TB-related symptoms by Week 15. If the MGIT result is MTB positive and/or there are still TB symptom(s), participants will continue to receive HR (in the SPaL arms) and will complete a total of 26 weeks of treatment. Note: The inability to produce sputum will be considered as a negative MGIT culture result and therefore can be used to determine the participants’ eligibility to complete treatment at Week 15. For all participants except those on HRZE/HR, blood samples to assess the pharmacokinetics (PK) of study drugs are collected weekly pre-dose and at 1, 3, and 5 hours post-dose at Day 15 and Week 8. Participants at some sites may volunteer for 24-hour intensive sampling at Day 15. In addition, pre-dose samples are collected at Days 1 and 8 and Weeks 4 and 8 to assess the PK of tenofovir and dolutegravir. See Figure 1 for NC-009 Trial Design. Re-Treatment {30} Participants randomised to the 3 SPaL arms and BPaL arm who relapse or experience treatment failure (see definition of relapse and treatment failure in Table 2) will be re-treated with HRZE/HR, provided that drug susceptibility data do not reveal emergence of resistance or the participant has a contraindication for receiving HRZE/HR, in which case they will be referred to the local national TB programme (NTP) for further management. Participants who are re-treated will be followed for 26 weeks after the end of their re-treatment. In the case of treatment failure or relapse in participants randomised to the control arm (HRZE/HR), the participant will be referred to the local NTP for further management, and the treating physicians will be provided with the DST results and medical report from the investigator, should an individualized regimen be indicated. Participants who early discontinue from the study for reasons other than relapse/re-infection or treatment failure, where possible, would complete an early discontinuation visit and be referred to the local NTP. No additional follow-up visits are required except where unscheduled visits are needed for ongoing AEs that led to discontinuation from trial and for pregnancies. TB Alliance certifies that it has liability insurance coverage for itself and will provide an associated certificate upon request. The insurance does not relieve the investigators of the obligation to maintain their own liability insurance as required by applicable law. TB Alliance does not assume any obligation for the medical treatment of other injuries and illnesses but in certain instances, compassionate support is provided to participants as required. METHODS AND ANALYSIS Study setting {9} The trial will be performed at multiple centres globally including Georgia, the Philippines, South Africa, Tanzania, and Uganda. These are a total of 22 clinical trial units recruiting participants from TB clinics in catchment areas. See Table 3 for list of countries, cities and site names. Eligibility criteria {10} The key inclusion and exclusion criteria are listed below: Inclusion Criteria: Signed informed consent DS-TB is defined as sensitive to rifampicin and isoniazid by rapid sputum-based test AND either newly diagnosed for TB or have a history of being untreated for at least 3 years after cure from a previous episode of TB Of non-childbearing potential OR using effective birth control methods Body weight ≥ 35 kg Exclusion Criteria: Karnofsky score < 60 at screening Any evidence of extrapulmonary TB Cardiovascular or QT prolongation risk factors Pregnant or breastfeeding Any of the following lab toxicities: Platelets 1.3 x ULN Haemoglobin <9.5 g/dL or <95 g/L Absolute neutrophil count 1 x ULN Haemoglobin A1c ≥8.0% Total lipase ≥1.5 x ULN Total amylase ≥1.5 x ULN CPK >3 x ULN (if >3 x ULN, enquire about the participant’s recent strenuous activity and consider repeating the test within the screening window) TSH >1 x ULN Positive results at screening for HBsAg, HAV IgM, or hepatitis C antibodies For participants living with HIV only: CD4+ count <200 cells/μL WHO Clinical Stage 4 HIV disease Participant does not agree to use DTG/TFV/3TC during trial if ARV therapy is indicated, and randomised to the Sorfequiline or the BPaL regimen If initiation of ARV therapy is indicated, participants who are known to be intolerant, non-responsive to DTG/TFV/3TC or have DTG/TFV/3TC as a contraindication Consent or assent {26a} Informed consent forms are approved by the relevant ethics committee and regulatory authority. Written informed consent will be obtained from each screened participant, and the process is conducted in the participants’ preferred local languages in each country. In cases where a participant is illiterate, an impartial witness will be present throughout the informed consent process to ensure that the information in the consent form was accurately explained to, and understood by the participant, and that informed consent was freely given by the participant. Additional consent provisions for collection and use of participant data and biological specimens {26b} Additional consents to be signed by participants are: Pharmacokinetic Sampling (for participants willing to participate in 24hrs of PK sample collection at Day 15, PK subgroup) Biostorage for: The storage of all unused blood, sputum, and urine samples (as available) for long-term storage. Additional blood and urine samples for exploratory research will be collected at Day 1, weeks 4, 8, 15, and 26. Pharmacogenetic testing for participants not randomised to the HRZE/HR arm to collect a blood sample at Day 1 for possible exploratory pharmacogenetic testing. INTERVENTIONS Explanation for choice of comparator {6b} The 6-month treatment regimen is composed of four first-line TB medicines – HRZE/HR per weight band. This regimen is well known and has been widely adopted worldwide for decades; while using it, about 85% of participants will have a successful treatment outcome (1). This regimen is based on seminal TB treatment studies conducted by the British Medical Research Council in the second half of the 20th century (10). Intervention description {11a} Treatment will be administered by the site to the participant at scheduled trial visits. In between scheduled site visits, the participants will be responsible for the administration of their own investigation medicinal product (IMP). 1 st 3 treatment arms : 25 mg/ 50 mg/ 100 mg of sorfequiline + 200 mg pretomanid + 600 mg linezolid for 8 weeks (TP1) followed by 7 weeks or 18 weeks of HR based on participant meeting criteria to stop treatment at week 15 (TP2). 4 th treatment arm : 200 mg bedaquiline + 200mg pretomanid + 600 mg linezolid for 1st 8 weeks (TP1) followed by 100 mg bedaquiline + 200mg pretomanid + 600 mg linezolid for 18 weeks (TP2). 5 th treatment arm : HRZE for 8 weeks followed by HR for 18 weeks. Intervention modifications {11b} At no time should the participant be treated with a single agent. If any of the components other than linezolid need to be interrupted, the entire regimen must be interrupted. Dose adjustments are not allowed for sorfequiline, bedaquiline, pretomanid, or HRZE/HR. Linezolid can be reduced from 600 mg to 300mg or temporarily interrupted or permanently discontinued. No minimum number of doses of linezolid is specified in the protocol. During TP1 and 2, the full regimen can be interrupted for up to 14 and 28 cumulative doses for drug related toxicities respectively. Strategies to improve adherence to interventions {11c} Participants are reminded at each dispensing visit about the importance of adherence and compliance to the IMP. Site staff encourage participants to contact them between visits if they have any questions about their medications or if they are feeling unwell. The site contact details (24 hours) are provided to the participant at the screening visit via a ‘Participant Contact Card’. Concomitant care that is permitted or prohibited during the trial {11d} All therapies (prescriptions or over-the-counter medications, including vitamins and herbal supplements) different from the trial drugs are recorded in the concomitant therapy section of the Direct Data Capturing (DDC) platform. Prohibited Concomitant Medications : The following therapies are not allowed during the trial: All medicinal products used to treat pulmonary TB; isoniazid prophylaxis as treatment preventive therapy (TPT) preventative for participants living with HIV; Monoamine Oxidase Inhibitors (due to linezolid, applicable to SPaL and BPaL regimens). Concomitant Medication to be avoided : The following concomitant medications should be avoided during and for 14 days after treatment with IMP to prevent possible drug interactions with the IMP: any drug known to be hepatotoxic (applicable for all treatment regimens) e.g. NSAIDS, acetaminophens; any drug known to prolong QTc interval (applicable to SPaL and BPaL regimens) e.g. chloroquine, amiodarone; any drug known to induce significant myelosuppression (due to linezolid, applicable to SPaL and BPaL regimens) e.g. chloramphenicol; systemic use of strong CYP3A4 inhibitors, for more than 14 consecutive days (applicable to SPaL and BPaL regimens) e.g. azole antifungals; systemic use of strong and moderate CYP3A4 inducers should be avoided 14 days before and during treatment (applicable to SPaL and BPaL regimens) e.g. phenytoin, carbamazepine serotonergic antidepressants (SPaL and BPaL regimens) e.g. fluoxetine, paroxetine; strong P-gp inhibitors for more than 3 consecutive days (applicable to SPaL and BPaL regimens) e.g. cyclosporine. Provision of post-trial care {30} Participants who early discontinue from the study for reasons other than relapse/re-infection or treatment failure, where possible, would complete an early discontinuation visit and be referred to the local NTP. No additional follow-up visits are required except where unscheduled visits are needed for ongoing adverse events (AEs) that led to discontinuation from trial and for pregnancies. Outcomes {12} See table 1 for study objective and relevant outcomes/end points. See table 2 for Study Outcome Definitions. Participant timelines {13} See Trial Flow Chart in NC-009 protocol (supplementary materials). Sample size {14} Sample size for this trial will be at least 60 participants per treatment regimen. Sample size assumptions below are selected to be conservative to achieve adequate power given expected minimal dropout prior to Week 8. Based on data from previous trials of DS-TB, it is assumed that the probability of participants achieving stable sputum culture conversion to negative status by Week 8 to TP1 in the control regimen (HRZE/HR) is 0.50 (11, 12). The number of events and power required is based on comparison of the primary endpoint i.e. time to stable sputum culture conversion to negative status using data from weekly cultures through Week 8 to TP1. The trial will require approximately 76 events (stable sputum culture conversion to negative status) among approximately 120 randomised participants. This number ensures that a 2-sided, α = 0.05 logrank test procedure will have 80% power when the true hazard ratio of sorfequiline vs. HRZE is 2.0 and 90% power when the hazard ratio is 2.2. It is assumed that calculations are sufficiently conservative to ensure that the required number of events will be observed by the time the analysis is conducted using Week 8 data. To minimize Type I error, the comparisons for inference will be ordered starting with the highest sorfequiline dose regimen. Recruitment - Strategies for achieving adequate participant randomisation to reach target sample size {15} Participating sites foster and maintain positive working relationships with the local TB clinics in their areas via the Community Engagement (CE) teams and activities. Before a trial commences, the site CE team meets with and informs community stakeholders e.g. Community Advisory Board (CAB), TB clinic nurses and doctors about the trial. When the trial starts, the TB clinics identify patients who have been newly diagnosed with DS-TB, and they inform the site CE contact person. The CE contact person talks with the patient to find out if they would like to know more about the trial, and if they agree, they invite them to the site. The CE team arranges transportation for the participant from their home or TB clinic to the site while they still test positive for TB. This process facilitates a good relationship between CAB, TB clinics and trial sites, and as a consequence hopefully good recruitment to the trial. Who will be blinded {17a} The trial is partially blinded i.e. sorfequiline and bedaquiline will be blinded during the first 8 weeks of trial treatment; participants randomised to the sorfequiline or bedaquiline arms will receive open label pretomanid and linezolid. After the Week 8 visit, participants will be unblinded if they are randomised to sorfequiline or bedaquiline but the dose of sorfequiline remains blinded throughout the study. Participants randomised to the HRZE/HR arm will receive open label IMP. Only the unblinded statistician will have access to unblinded data. Blinding (masking): emergency unblinding {17b} The blind for a participant must not be broken by the site or TB Alliance except in the case of a medical emergency, where treatment of a participant is influenced by the knowledge of what dose of sorfequiline or bedaquiline the participant is receiving. The investigator should discuss this with the TB Alliance’s Study Physician prior to breaking the blind unless knowledge of the treatment regimen is required urgently for a safety concern. TB Alliance’s Study Physician should be informed of the blind break within 24 hours if not discussed prior to unblinding. DATA COLLECTION AND MANAGEMENT Data collection plan {18a} This study utilized a Direct Data Capturing (DDC) system, which negates the needs, in most cases, for a paper source document at the site. Safety lab tests are performed by a central laboratory vendor which involves shipping of samples to affiliated local labs; results available are sent to the sites via a central e-platform. Sputum samples are analysed by a central laboratory in South Africa, and the results available are sent to sites via the laboratory e-platform. In non-South African sites, local mycobacteriology labs affiliated with the sites are used and data is entered directly into the DDC system. ECGs taken at the site and associated readings are transmitted to a central ECG system to undergo quality checks, blinded central review and cardiologist reporting. All data capture and laboratory information systems conform to the Code of Federal Regulations Title 21, Part 11 (21 CFR Part 11) requirements. The data are mapped and transmitted directly from the laboratory information system into the corresponding SDTM datasets. Plans to promote participant retention and complete follow ‑ up {18b} Each site develops their own ‘Recruitment and Retention’ plan, specific to their community and location. Participants are reimbursed for their transport, and any other reasonable expense, to and from the site for all trial visits as approved by EC/IRB. The site also provides the participant with a ‘cellular / phone voucher’ to ensure that the participant has the monetary means to contact the site at any time, if they need to. Site staff contact the participant telephonically between trial visits and just before the next scheduled visit to ask them how they are doing and to remind them of the upcoming visit. Data management {19} A DDC system was designed to collect all the data required by the protocol. Delegated site staff enter data collected per study visit in the DDC system (tablets). Any correction or changes in entry in the DDC are tracked electronically via an audit trail. Safety lab, Myco lab, ECG & IRT data are all programmatically integrated into the corresponding SDTM datasets. Adverse events are coded using the Medical dictionary for regulatory activities (MedDRA) terminology. Concomitant medications will be summarised per Anatomical Therapeutic Chemical (ATC) level 2 and level 4 code. Medications that cannot be assigned a level 2 or level 4 code will be identified in the table as missing the coding level. The Data Manager, or their delegate, regularly reviews the DDC data entered by investigator staff for completeness and accuracy. Confidentiality {27} All laboratory specimens, including stored specimens, as well as trial reports, data collection tools, and administrative documents are identified by using only the participant’s unique trial number. All local and central databases are secured with password-protected access systems. The investigators ensure anonymity of the participant and that all documents are anonymised before being transmitted to TB Alliance. Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33} For study participants not randomised to HRZE/HR and who sign a separate informed consent, a blood sample will be drawn at Day 1 (or at other time point during the trial if not obtained at Day 1) for possible exploratory pharmacogenetic testing. The sample may be used to identify genes that contribute to pharmacokinetic (PK) variability of sorfequiline and bedaquiline, i.e., variability in blood levels of those drugs and their metabolites, such as (but not necessarily restricted to) genes for drug-metabolizing enzymes or drug-transport proteins. STATISTICAL METHODS Statistical methods for primary and secondary outcomes {20a} Demographic and screening/baseline characteristics of the randomised participants will be summarised by treatment arm. There are 3 analysis population utilized in this protocol i.e.: Intent-to-treat (ITT) Population (include all randomised participants who took at least 1 dose of trial drug) Modified Intent-to-treat (MITT) Population (participants who are randomised and take at least 1 dose of trial drug, without late exclusions i.e. the lack of MTB culture positive on day 1 and discrepancies between screening rapid test result and corresponding culture/WGS) Per Protocol Population (MITT population excluding participants with major protocol deviations) The MITT population is the primary population for all efficacy analyses and ITT for all safety analysis. The primary endpoint is time to stable sputum culture conversion to negative status over 8 weeks using data from weekly cultures up to and including Week 8 in the sorfequiline regimens. Stable sputum culture conversion to negative status is defined as 2 negative results (at least 7 days apart without an intervening MTB positive). The primary hypothesis is that for participants randomised to a sorfequiline-containing regimen (at least 1 sorfequiline regimen), the time to culture negativity by 8 weeks will be superior, compared to the participants who are treated with the standard HRZE regimen. Time to stable sputum culture conversion to negative status will also be summarized using the Kaplan-Meier method and displayed graphically. Median event times (and other quartiles) and 2-sided 95% CI for each time will be provided. The key secondary analysis is the proportion of participants with a favourable outcome at 26 weeks after end of treatment (EOT) based on the MITT population for BPaL vs. HRZE/HR. The proportion of participants who meet the criteria to stop treatment at Week 15 in the 3 sorfequiline arms will be summarized based on the MITT population. Relapse rates at 26 weeks after EOT, and separately at 52 weeks after the EOT follow-up period based on the MITT population will be summarized. An analysis of the bactericidal activity over 2 weeks, BA TTP (1-15), of sorfequiline or bedaquiline in combination with pretomanid and linezolid, relative to HRZE, as determined by the rate of change in TTP over Days 1 to 15 of treatment, represented by the model-fitted log(TTP) as calculated by the regression of the observed log(TTP) counts over time. A similar analysis will be performed to assess bactericidal activity over 8 weeks [BA TTP (1-56)]. Change from baseline in measurements of biomarker assays (potentially LAM and other assays), through the course of treatment and the post-treatment follow-up period relative to treatment outcome will be evaluated. Key safety analysis will be performed including incidence of adverse events (AE), study drug modifications, clinical laboratory evaluation, ECGs, concomitant medications etc. For study drugs, plasma concentrations will be summarized, and exposure metrics such as C max and AUC will be computed and summarized. Relationships will be explored between exposure metrics and efficacy and safety endpoints. Trough concentrations of dolutegravir and tenofovir will be summarized for participants living with HIV and will be compared with standard ranges to assess possible interactions with study drugs. Interim analysis {21b} There will be 1 planned unblinded interim analysis which will contain results by treatment group in aggregate and will include the primary analysis. This will occur after all participants have completed 8 weeks of treatment. The study team and Data Safety Monitoring Committee (DSMC) will have access to the primary end-point analysis. Statistics: additional analyses {20b} A stratified logrank test will be used to compare time to stable sputum culture conversion to negative status between the 2 regimens with the stratification factors country and severity of disease (AFB 3+ and/or bilateral cavitation). All subgroup analyses will be performed on the ITT, mITT and PP populations. Additionally, post hoc analyses not originally described in the protocol will be mentioned in the statistical analysis plan (SAP). SAP in supplementary material. Methods in analysis to handle protocol non ‑ adherence and any statistical methods to handle missing data {20c} Participants with Clinical Study Report (CSR) reportable deviations as evaluated and determined by a review committee prior to database lock will be excluded from the PP population. Plans to give access to the full protocol, participant ‑ level data and statistical code {31c} It is the intention that de-identified SDTM datasets including an associated data dictionary will be made available via TB PACTS hosted by CPATH (https://c-path.org/tools-platforms/tb-pacts/). The full protocol and statistical analysis plan will be made available as appendices during the publication of the trial results. OVERSIGHT AND MONITORING Composition of the coordinating centre and trial steering committee {5d} The trial is led by: TB Alliance Study Physician who leads the core team composed of biostatistician, medical monitors, mycobacteriologist, and non-clinical group. TB Alliance Clinical Project Manager who leads the clinical operations group consisting of a partner Clinical Research Organization overseeing trial monitoring, vendor management, data management, drug and non-drug supplies, and the finance team. There is also a Data Safety Monitoring Committee (DSMC). Composition of the data safety monitoring committee, its role and reporting structure {21a} The DSMC is independent of TB Alliance and all project collaborators. It is governed by the DSMC Charter which describes its purpose and terms of reference. It consists of a chairperson and other seasoned TB disease and trial specialists, a statistician and a country representative from Tanzania (per Tanzania Medi requirements). The DSMC meeting will be held approximately every 6 months after the first randomised participant. Ad-hoc meetings can be called by TB Alliance or the DSMC based on the rates of SAEs, SAEs of particular concern, or any safety concerns that arise during the trial The DSMC acts in an advisory capacity to TB Alliance, to safeguard the interest of trial participants by monitoring participant safety, participant risk versus benefit, and general evaluation of the study progress. See DSMC Charter in supplementary material. Adverse events reporting and harms {22} Adverse events reporting applies to both investigational and control arms in the trial. All AEs and serious adverse events (SAEs) will be collected from the signing of the ICF until the follow-up Week 52 visit (end of trial). Treatment-emergent AEs are defined as any AE that occurs after the first dose of IMP and within 28 days after the last dose of IMP. All AEs are recorded in the AE section of the DDC. AEs can be spontaneously reported or elicited during open-ended questioning, examination, or evaluation of a trial participant. The investigator must also promptly review all results of assessments performed as part of the trial, such as laboratory assessment results, ECGs, vital sign monitoring, physical examinations, etc. and assess them for clinical significance. Each AE is evaluated to determine the severity grade: Grade 1–4 as per the latest version of the DAIDS Severity Grading Scale, its duration (start and end dates or if continuing at the end-of-study visit), its relationship to the study treatment, action taken with respect to study treatment (treatment maintained, dose reduced, permanently discontinued, temporarily discontinued, not applicable), whether medication or therapy was taken/given in relation to the AE and whether it is a serious adverse event (SAE). All AEs will be followed until satisfactory clinical resolution or stabilization, or the end of the follow-up period or early discontinuation of the trial. All SAEs (including updated or significant follow up information) will be recorded and reported to TB Alliance immediately and within 24 hours of awareness. TB Alliance has a legal responsibility to notify the relevant regulatory authority, IRB/EC, and investigators about the safety of an IMP under clinical investigation. Frequency and plans for auditing trial conduct {23} A risk-based approach is used for quality assurance audits to evaluate if the trial was conducted and the data generated in compliance with the protocol, GCP and applicable regulatory and ethics committee requirements. Prior to the conduct of work, independent auditors conduct qualification audits for significant trial vendors to evaluate and confirm the vendor’s capability to perform the planned work in accordance with required standards. During the trial independent auditors conduct routine requalification audits. The frequency of audit is based on the risk tier assigned to each vendor, with the highest risk vendors subject to an audit every 2 years, ranging to the lowest risk vendors which are audited every 10 years. Dissemination plan {31a} Results of this research will be submitted for publication as soon as feasible upon completion of the trial in the form of a joint publication(s) between TB Alliance and investigator(s), including site clinical and laboratory investigators, as appropriate. Publication and authorship will be in accord with the International Association of Journal Editors. Because the trial is funded, in whole or in part, by the Bill and Melinda Gates Foundation (the “Foundation”), all peer-reviewed published research relating to the trial must comply with the Foundation’s Open Access Policy as described from time to time at http://www.gatesfoundation.org/How-We-Work/General-Information/Open-Access-Policy. Specifically, (a) all peer-reviewed published research relating to the trial must be submitted for publication by TB Alliance through the Chronos Open Access Publishing Service established by the Foundation to ensure the immediate and unrestricted access and reuse of all peer-reviewed published research funded, in whole or in part, by the Foundation without any embargo period, and (b) all data underlying the peer-reviewed published research results must be immediately made accessible and open to the public in accordance with the Foundation’s Open Access Policy. DISCUSSION Tuberculosis continues to be one of the most formidable global health threats, especially in the context of rising drug resistance and the setbacks from the COVID-19 pandemic. In response, the TB Alliance initiated protocol NC-009, a phase 2, multi-arm clinical trial that introduces several pioneering features aimed at improving treatment outcomes for drug-sensitive TB (DS-TB). This article explores the innovative aspects of the NC-009 study design, emphasizing its methodological sophistication and translational impact. At the heart of the NC-009 protocol is its five-arm, partially-blinded, randomized trial design. This allows the evaluation of: Three different doses (25 mg, 50 mg, 100 mg) of the novel diarylquinoline sorfequiline Comparison with bedaquiline (200 mg), the current standard among diarylquinolines, First trial to evaluate BPaL in DS-TB population and, Benchmarking against the HRZE/HR standard of care. The partially-blinded methodology balances methodological rigor with operational feasibility. An important innovation is the adaptive treatment duration based on early treatment response. Participants in the SPaL arms can transition from treatment to follow-up at 15 weeks, provided they meet pre-defined microbiological and symptomatic recovery criteria. This approach tests the hypothesis that treatment for DS-TB can be safely and effectively shortened for some participants, improving adherence and reducing resource use. Unlike many trials that focus predominantly on clinical outcomes, NC-009 robustly incorporates pharmacokinetic/pharmacodynamic (PK/PD) modeling, using both sparse and intensive sampling strategies. This allows for: Correlation of drug exposure with bactericidal activity and adverse events. Identification of the optimal dose of sorfequiline with a favorable efficacy-safety profile. Assessment of drug-drug interactions in participants co-infected with HIV. A pragmatic and ethical innovation is the inclusion of a pre-planned re-treatment pathway i.e. participants randomized to the S/ BPaL arms who relapse are offered standard re-treatment with HRZE/HR, and outcomes are monitored for an additional 26 weeks, as part of the study. This strategy ensures participant safety while enabling long-term outcome assessment and avoids overburdening the local NTP clinics. The protocol introduces detailed criteria for treatment modification and toxicity monitoring (including visual acuity and neuropathy assessments), critical for regimens containing linezolid. It also includes QTc interval evaluation, providing an opportunity to compare sorfequiline to bedaquiline regarding this safety concern of the latter. These measures ensure participant safety without compromising the study's scientific goals. TRIAL STATUS The study is being conducted according to the initial protocol Version 1 dated 3 February 2023. No protocol amendments have been generated. Recruitment started on 24 October 2023 and completed on 30 August 2024, including a total of 309 randomised and eligible participants. The last treatment visit was conducted on 10 March 2025 and the planned ‘Last Participant Last Follow-up Visit’ is due on 27 February 2026. All ongoing participants are currently in the follow-up phase of the trial. Three DSMC meetings were held on 5 February 2024, 8 April 2024, and 4 November 2024 and the recommendation was to continue trial unmodified. The Clinical Study Report (CSR) is planned to be completed by 25 September 2026 following the planned final database lock on 8 May 2026. Abbreviations 3TC: Lamivudine; AE: Adverse Event; AFB: Acid-fast bacilli; ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; ARV: Antiretroviral; AST: Aspartate transaminase; AUC: Area under the curve; BATTP: Bactericidal activity measured by TTP; BPaL: bedaquiline, pretomanid, linezolid; CFR: Code of federal regulations; Cmax: maximum plasma concentration; CPK: Creatine phosphokinase; CV: Coefficient of variation; CYP: cytochrome P450; DAIDS: Divisions of AIDS; DR-TB: Drug-resistant tuberculosis; DSMC: Data Safety Monitoring Committee; DS-TB: drug-sensitive tuberculosis; DTG: Dolutegravir; EC: Ethics committee; ECG: electrocardiogram; EOT: End of treatment; GCP: Good clinical practice; HAV: Hepatitis A virus; HbsAg: Hepatitis B surface antigen; HBV: Hepatitis B virus; HCV: Hepatitis C virus; HIV: Human immunodeficiency virus; HRZE: Isoniazid, rifampicin, pyrazinamide, ethambutol; HR: Isoniazid, rifampicin; IB: Investigator’s Brochure; ICF: Informed consent form; ICH: International Council on Harmonisation; IMP: Investigational medicinal product; IRB: Institutional Review Board; IRT: Interactive response technology; ITT: Intent to treat; IUATLD: International Union Against Tuberculosis and Lung Disease; LAM: Lipoarabinomannan; MAD: multiple ascending dose; MDR-TB: Multi-drug resistant tuberculosis; MedDRA: Medical Dictionary for Regulatory Activities; MGIT: Mycobacteria growth indicator tube; MIC: Minimum inhibitory concentration; MITT: Modified intent-to-treat; MTB: Mycobacterium tuberculosis; NTP: National TB program; PCR: Polymerase chain reaction; PD: Pharmacodynamics; PK: Pharmacokinetics; PP: Per protocol; QTcF: QT interval corrected using Fridericia’s formula; SAD: Single ascending dose; SAE: Serious adverse event; SAP: Statistical analysis plan; SD: Standard deviation; SDTM: Study Data Tabulation Model; SmPC: Summary of product characteristics; TB: Tuberculosis; TEAE: Treatment-emergent adverse event; TFV: Tenofovir; TI/NR MDR-TB: Treatment-intolerant/non-responsive MDR-TB; TPT: TB preventive treatment; TSH: Thyroid stimulating hormone; TTP: Time to positive; ULN: Upper limit of normal; WGS: Whole genome sequencing, WHO: World Health Organization; XDR-TB: Extensively drug-resistant tuberculosis. Declarations Supplementary information The supplementary material is available in the online version. Authors contributions {31b} OM, BM, LL, NJ, TJ, BT, BR, HD, LA, BeM, EE, ML, HJ, SS, FS, BnM, SE initiated the study design and implemented the study. OM is study physician, and LL is clinical project manager. NJ is pharmacokinetics, BT is biologist, TJ is microbiologist, BeM is clinical data manager, EE is back up clinical project manager & medical writer, ML is drug supply manager, HJ oversees quality assurance, SS is community engagement manager. All authors contributed to refinement of the study protocol and approved the final manuscript. Funding {4} This work was supported by TB Alliance (Global Alliance for TB Drug Development) with funding from Australia’s Department of Foreign Affairs and Trade, the Gates Foundation [OPP1129600], the Foreign, Commonwealth and Development Office (United Kingdom), Germany’s Federal Ministry of Education and Research through KfW, Irish Aid, and the United States Agency for International Development. This work was supported in part by the Gates Foundation [OPP1129600]. The conclusions and opinions expressed in this work are those of the author(s) alone and shall not be attributed to the Foundation. Under the grant conditions of the Foundation, a Creative Commons Attribution 4.0 License has already been assigned to the Author Accepted Manuscript version that might arise from this submission. Please note works submitted as a preprint have not undergone a peer review process. Availability of data and materials {29} The trial data will be made available after primary publication. All unpublished information/data given to the investigator by TB Alliance shall not be published or disclosed to a third party, other than to the responsible IRB/EC, with the understanding of the confidentiality of their nature, without the prior written consent of TB Alliance. Ethics approval and consent to participate {24} All relevant country ethics committee / institutional review board (REC/ IRB) approvals were obtained before commencement of this study. The study protocol, the participant Information and Consent Form (ICF), the DDC, up-to-date versions of the Investigator Brochures or Summary of Product Characteristics (SmPC), as well as Principal Investigators qualifications has been submitted and approved by the ethical boards and regulatory authorities listed in Table 4. Informed consent materials {32} Informed consent materials in supplementary materials Competing interests {28} There are no financial or other conflicts of interest for principal investigators or DSMC committee members. Authors details 1 TB Alliance, South Africa 2 TB Alliance, USA 3 RTI International, USA References WHO. Global tuberculosis report. Geneva: World Health Organization. 2024. Report No.: ISBN 978-92-4-010154-8. WHO. WHO Operational handbook on tuberculosis. Worlsd Health Organization. 2022. Contract No.: ISBN: 978-92-4-006312-9. WHO. Rapid communication on updated guidance on the management of TB in children and adolescents. 2021. Conradie F, Everitt D, Crook AM. Treatment of Highly Drug-Resistant Pulmonary Tuberculosis. Reply. N Engl J Med. 2020;382(24):2377. Conradie F, Bagdasaryan TR, Borisov S, Howell P, Mikiashvili L, Ngubane N, et al. Bedaquiline-Pretomanid-Linezolid Regimens for Drug-Resistant Tuberculosis. N Engl J Med. 2022;387(9):810–23. WHO. Rapid communication: key changes to the treatment of drug-resistant tuberculosis. online: World Health Organization; 2022 May 2022. Report No.: WHO Reference Number: WHO/UCN/TB/2022.2. Tanseen RB, Tyagi F, Li S, Williams D, Converse K, Dartois P, Yang V, Mendel T, Midliuli C, Nuermberger K. Contribution of Oxazolidinones to Efficacy of Novel Regimens containing Bedaquilinie and Pretomanid in a Mouse Model of Tuberculosis. Antimicrob Agents Chemother. 2016;60(1):17. Almeida DCP, Li S, Upton AM, Fotouhi N, Nuerrmberger EL. Comparative Efficacy of the Novel Diarylquinoline TBAJ-876 and Bedaquiline against a Resistant Rv0678 Mutant in a Mouse Model of Tuberculosis. Antimicrob Agents Chemother. 2021. Sutherland HS, Tong AST, Choi PJ, Blaser A, Conole D, Franzblau SG, et al. 3,5-Dialkoxypyridine analogues of bedaquiline are potent antituberculosis agents with minimal inhibition of the hERG channel. Bioorg Med Chem. 2019;27(7):1292–307. Fox W, Ellard GA, Mitchison DA. Studies on the treatment of tuberculosis undertaken by the British Medical Research Council tuberculosis units, 1946–1986, with relevant subsequent publications. Int J Tuberc Lung Dis. 1999;3(10 Suppl 2):S231–79. Gillespie 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):1577–87. Dorman SE, Nahid P, Kurbatova EV, Phillips PPJ, Bryant K, Dooley KE, et al. Four-Month Rifapentine Regimens with or without Moxifloxacin for Tuberculosis. N Engl J Med. 2021;384(18):1705–18. Tables Table 1: List of primary, key secondary, secondary and exploratory objectives and associated end-points. Objectives Endpoints Primary To evaluate the efficacy of 3 dose levels of sorfequiline in combination with pretomanid and linezolid, relative to 2HRZE, during 8 weeks of treatment in adult participants with newly diagnosed, smear-positive, pulmonary DS-TB as measured by time to stable sputum culture conversion to negative status. Time to stable sputum culture conversion to negative status using data from weekly cultures through 8 weeks of treatment. Key Secondary To evaluate the safety and efficacy at 26 weeks after the EOT of B-Pa-L relative to 2HRZE/4HR in adult participants with newly diagnosed, smear-positive, pulmonary DS-TB. Proportion of participants with a favourable outcome at 26 weeks after the EOT. Secondary To evaluate the efficacy of 3 dose levels of sorfequiline in combination with pretomanid and linezolid, in adult participants with newly diagnosed, smear-positive, pulmonary DS-TB, as measured by meeting the criteria to stop treatment at Week 15. Proportion of participants who meet the criteria to stop treatment at Week 15. To evaluate the safety and efficacy of 3 dose levels of sorfequiline in combination with pretomanid and linezolid at 26 weeks and 52 weeks after end of treatment relative to 2HRZE/4HR for the overall arms and key subgroups by stratification factors and total treatment duration, in adult participants with newly diagnosed, smear-positive, pulmonary DS-TB. Proportion of participants with a favourable outcome at 26 weeks and 52 weeks after the EOT. To evaluate the safety and efficacy at 52 weeks after the EOT of B-Pa-L relative to 2HRZE/4HR in adult participants with newly diagnosed, smear-positive, pulmonary DS-TB. Proportion of participants with a favourable outcome at 52 weeks after the EOT. To evaluate the efficacy of 3 dose levels of sorfequiline in combination with pretomanid and linezolid, B-Pa-L, and 2HRZE/4HR, at 26 weeks and 52 weeks after the EOT, as measured by relapse rates in participants that enter follow up with a favourable response at the EOT for the overall arms and key subgroups by stratification factors and total treatment duration. Relapse rates at 26 weeks and 52 weeks after the EOT. To evaluate the efficacy of B-Pa-L, relative to 2HRZE, during 8 weeks of treatment in adult participants with newly diagnosed, smear-positive, pulmonary DS‑TB as measured by time to stable sputum culture conversion to negative status. Time to stable sputum culture conversion to negative status using data from weekly cultures through 8 weeks of treatment. To assess the bactericidal activity over 2 weeks of 3 dose levels of sorfequiline in combination with pretomanid and linezolid or B-Pa-L, relative to 2HRZE, in adult participants with newly diagnosed, smear-positive, pulmonary DS-TB. BA TTP (1-15) as determined by the rate of change in TTP over Days 1 to 15 of treatment, represented by the model-fitted log(TTP) as calculated by the regression of the observed log(TTP) counts over time. To assess the bactericidal activity over 8 weeks of 3 dose levels of sorfequiline in combination with pretomanid and linezolid or B-Pa-L, relative to 2HRZE, in adult participants with newly diagnosed, smear-positive, pulmonary DS-TB. BA TTP (1-56) as determined by the rate of change in TTP over 8 weeks of treatment, represented by the model-fitted log(TTP) results as calculated by the regression of the observed log(TTP) results over time. To evaluate stable sputum culture conversion to negative status over time during the treatment period. Proportion of participants with stable sputum culture conversion to negative status at Weeks 4, 6, 8, 12, 15, 20, and 26. To assess the safety and tolerability of the 3 dose levels of sorfequiline in combination with pretomanid and linezolid or B‑Pa‑L regimens at different time points, relative to 2HRZE/4HR, in adult participants with newly diagnosed, smear-positive, pulmonary DS‑TB. Incidence of TEAEs, by severity, drug relatedness, seriousness, leading to early discontinuation, and leading to death; and ECG, vital signs, and quantitative and qualitative clinical laboratory result measurements, changes in ophthalmic exam for visual acuity and changes noted in peripheral neuropathy, including observed and changes from baseline at Weeks 8, 26, and 26 weeks after the EOT. To evaluate the systemic exposure of sorfequiline, bedaquiline, pretomanid, and linezolid. Plasma concentrations of sorfequiline, bedaquiline, pretomanid, linezolid, and selected metabolites from sparse samples in all participants assigned those treatments and from an intensive profile on Day 15 in a sub-group of participants. Exploratory To assess if changes in measurements of biomarker assays through the course of treatment and the post-treatment follow-up period are associated with treatment outcome. Change from baseline in biomarker assay through the course of treatment and the post-treatment follow-up period relative to treatment outcome. To correlate various endpoints measured with MGIT with AFB smear and exploratory biomarkers at Day 1 and Weeks 4, 8, 15, and 26. Parameters derived from modelling various endpoints measured with MGIT (e.g. MGIT negative [yes/no], quantitative outcomes) relative to AFB smear and exploratory biomarkers at Day 1 and Weeks 4, 8, 15, and 26 To correlate MGIT culture results at Weeks 2, 4, and 8 with favorable outcome at 26 weeks and 52 weeks after the EOT. Parameters derived from modelling MGIT culture results at Weeks 2, 4, and 8 (e.g. MGIT negative [yes/no], quantitative outcomes) relative to favourable outcome at 26 weeks and 52 weeks after the EOT. To explore predictors of MGIT negative culture at Week 8 of treatment. MGIT negative at Week 8 of treatment (yes/no) relative to key baseline characteristics. To explore the population PK and exposure-response relationships of sorfequiline, bedaquiline, pretomanid, and linezolid. Population-PK models, summary metrics of exposure (e.g., AUC) derived from those models, and models for relationships between exposure and efficacy and safety outcomes. To explore the systemic exposure of dolutegravir and tenofovir when co-administered with 3 dose levels of sorfequiline in combination with pretomanid and linezolid, B-Pa-L or 2HRZE. Trough concentrations of dolutegravir and tenofovir from participants living with HIV assigned treatments. To explore the impact on quality of life of 3 dose levels of sorfequiline in combination with pretomanid and linezolid, B-Pa-L, and 2HRZE/4HR Time to improvement of quality of life measurements, proportion of participants with improved measurements on quality of life at different time points during and after treatment. Table 2: Study Outcome Definitions Definition Treatment Failure TREATMENT FAILURE DIAGNOSED by the end of treatment IF ≥2 of A, B, or C are satisfied; OR if D is satisfied Clinical Disease Persistence Persistent TB symptoms or signs without an alternative explanation. Chest X-ray Progression Abnormalities that are compatible with active TB disease (cavitation, infiltrates, consolidation) with clear evidence of no improvement or progression compared with start of treatment without an alternative, more likely explanation. Unconfirmed positive MGIT Sputum sample result after having achieved culture negative status (defined as 2 negative culture results at least 7 days apart). Confirmed MTB positive sputum culture Failure to attain culture negative status by the end of treatment or failure to maintain culture negative status (defined as 2 positive culture results at least 7 days apart after achieving culture negative status). Relapse or Reinfection RELAPSE or RE-INFECTION DIAGNOSED during follow up in participants with culture negative status by the EOT, IF ≥2 of A, B, or C are satisfied; OR if D is satisfied Clinical Disease Progression New or recurrent TB symptoms or signs after complete resolution at the EOT without an alternative, more likely explanation. Chest X-ray Progression Abnormalities that are compatible with active TB disease (cavitation, infiltrates, consolidation) with clear evidence of progression compared with the EOT without an alternative, more likely explanation. Microbiological Evidence of Recurrence Sputum sample taken after the EOT is smear positive OR GeneXpert positive (if >26 weeks after EOT); OR unconfirmed MGIT MTB positive culture;. Confirmed MTB Positive Sputum Culture Sputum culture MTB positive on 2 consecutive samples, at least 7 days apart,. Stable Culture Conversion 2 negative results (at least 7 days apart without an intervening MTB positive). If the first negative result occurs at Week 8, the Week 9 culture result can be used for the confirmatory negative result. Lost to Follow Up Should a participant not be reachable to attend trial visits, the following should be conducted and documented in the site trial records before confirming a participant is lost to follow-up: Three documented telephone contact attempts (participant and/or relative). Letter to be sent to the participant’s physical address via courier, or a similar process (adapted per country specific requirements/circumstances). If no feedback is received within 30 days of courier confirmation of letter delivery to and receipt by the participant, then the participant may be considered lost to follow-up. Table 3: List of countries, cities and site names. Country City Site Name Georgia Tbilisi National Center for Tuberculosis and Lung Diseases Philippines Manila Tropical Disease Foundation Lung Center of Philippines Care Clinical Trial Group, Inc. South Africa Brits Madibeng Centre for Research Cape Town Desmond Tutu Health Foundation TASK Clinical Trials University of Cape Town Lung Institute Durban Enhancing Care Foundation TB and HIV Investigative Network East London Synergy Biomed Research Institute George TASK Eden Johannesburg Clinical HIV Research Unit, Helen Joseph Hospital Klerksdorp Prenatal HIV Research Unit, Tshepong Hospital Port Elizabeth Isango Lethemba TB Research Unit Pretoria Setshaba Research Centre Rustenburg The Aurum Institute Tanzania Mbeya National Institute for Medical Research, Mbeya Moshi Kilimanjaro Clinical Research Institute Mwanza National Institute for Medical Research, Mwanza Uganda Kampala Joint Clinical Research Institute Case Western Reserve University, Makerere University Table 4. Country RA: Regulatory Authority EC: Ethics Committee Name of RA or EC Reference Number Approval Georgia Local EC JSC National Centre of Tuberculosis and Lung Diseases Independent Ethics Committee 817/01-17 26 Mar 2023 Georgia RA LEPL Regulation Agency for Medical and Pharmaceutical Activities of Ministry of Internally Displaced Persons from the Occupied Territories, Labor, Health and Social Affairs of Georgia #000924 13 May 2023 Philippines Local EC Makati Medical Centre Institutional Review Board MMCIRB20 23-083 16 Aug 2023 Philippines Local EC Lung Centre Philippines Institutional Review Board LCP-CT-015-2023 4 Jul 2023 Philippines Local EC Batangas Medical Centre Research Ethics Review Committee BatMC RERC 2024- 002 2 Jul 2024 Philippines Central EC Single Joint Research Ethics Board SJREB-2023-62 16 Aug 23 Philippines RA Philippine Food and Drug Administration 2023-CT0791 9 Oct 2023 South Africa Central EC Wits Health Research Ethics Committee 230305 23 Jun 2023 South Africa Local EC University of Cape Town, Faculty of Human Sciences Human Research Ethics Committee 280/2023 7 Aug 2023 South Africa Local EC University of Cape Town, Faculty of Human Sciences Human Research Ethics Committee 699/2023 28 Sep 2023 South Africa Central EC Pharma-Ethics Health Research Ethics Committee 240626487-62 29 Jul 2024 South Africa RA South African Health Products Regulatory Authority 20230301 19 Apr 2023 Tanzania Local EC Mbeya Medical Research and Ethics Review Committee SZEC – 2439/ R.A/ V.1/ 175 30 Mar 2023 Tanzania Local EC Kilimanjaro Christian Medical Centre Research Ethics Committee Proposal number 1421 21 Jun 2023 Tanzania Central EC National Institute for Medical Research N/A 26 May 2023 Tanzania RA Tanzania Medicines and Medical Devices Authority BC.69/96/64/3 14 Sep 2023 Uganda Local EC Joint Clinical Research Centre Research Ethics Committee JCRC-2023-43 3 May 2023 Uganda Central EC Uganda National Council for Science and Technology HS2928ES 7 Aug 2023 Uganda RA Uganda National Drug Authority CTC 0248/2023 9 Aug 2023 Supplementary Files 2023.02.03MasterHIVV0.1.docx 2023.06.02MasterBiostorageV1.0.docx 2023.06.13MasterPGtICFV1.0Final.docx 2023.06.16MasterMainV1.0Final.docx 2023.10.05Master24HrPKV1.0.docx 2024.09.30SAPV2.pdf NC009DSMCCharterV1.027Sep2023.pdf NC009ProtocolV1.003FEB2023.pdf NC009TrialFlowChartSPIRITFigure.pdf SPIRITchecklistNC009ManuscriptAug2025.docx Cite Share Download PDF Status: Published Journal Publication published 06 Jan, 2026 Read the published version in Trials → Version 1 posted Reviewers agreed at journal 08 Dec, 2025 Reviewers invited by journal 03 Dec, 2025 Editor assigned by journal 09 Sep, 2025 First submitted to journal 09 Sep, 2025 Editorial decision: Minor revision 21 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. 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diagnosed, drug-sensitive, smear-positive pulmonary tuberculosis (NC-009)","fulltext":[{"header":"STRENGHTS AND LIMITATIONS OF THIS STUDY","content":"\n\u003cul\u003e\n \u003cli\u003eThis is a unique study that combines dose selection for a next generation diarylquinoline (3 doses of sorfequiline evaluated) using efficacy and safety data, plus evaluation of potential duration of treatment based on ability to stop treatment at week 15 based on meeting certain criteria.\u003c/li\u003e\n \u003cli\u003eThis study also evaluates the potential drug-drug interaction of sorfequiline on dolutegravir and tenofovir.\u003c/li\u003e\n \u003cli\u003eThe study is not powered to compare *sorfequiline and bedaquiline, both in combination with pretomanid and linezolid.\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"INTRODUCTION","content":"\u003cp\u003e\u003cu\u003eBackground and rationale {6a}\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eTuberculosis (TB) is a preventable and usually curable disease. Yet in 2023, TB returned to being the world’s leading cause of death from a single infectious agent, following 3 years in which it was replaced by coronavirus disease (COVID-19)\u0026nbsp;(1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eExisting drug sensitive TB (DS-TB) treatment regimens are efficacious but lengthy in duration and involve multidrug therapy combinations i.e., an intensive phase of 2 months of isoniazid (H), rifampicin (R), pyrazinamide (Z), and ethambutol (E) followed by a continuation phase of 4 months of isoniazid and rifampicin (HRZE/HR); this treatment regimen was first introduced as the standard of care more than 40 years ago (2). \u0026nbsp;Long and complex treatments lead to high rates of non-adherence, which often result in unfavourable outcomes, emergence of drug resistance, continued spread of disease, and increased mortality. \u0026nbsp;Drug-drug interactions caused by rifampicin’s potent induction of CYP enzymes are another major challenge with the HRZE/HR regimen, particularly for women on hormonal contraception and TB participants co-infected with HIV taking anti-retroviral therapies (ARVs). \u0026nbsp;While a 4-month rifapentine-based regimen for treatment of pulmonary DS-TB is now recommended by the WHO as a possible alternative to HRZE/HR but with very limited global roll-out\u0026nbsp;(3), there is a need for new TB drugs and drug regimens that are efficacious, safe, well-tolerated, simpler, and that can further shorten the overall treatment duration, thereby improving adherence and patient outcomes.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe combination of bedaquiline, a first generation diarylquinoline, with pretomanid (a nitroimidazole), and linezolid (an oxazolidinone) administered for 26 weeks has been extensively studied and is referred to as the BPaL regimen. \u0026nbsp;The BPaL regimen demonstrated robust efficacy (\u0026gt;90% relapse-free cure) in adults with pulmonary XDR-TB and TI/NR MDR-TB (pre-WHO 2021 definitions) when linezolid was dosed at 1200 mg daily\u0026nbsp;(4). When the linezolid dose was decreased to 600 mg daily, efficacy was retained, and the regimen demonstrated improved tolerability (5). \u0026nbsp;BPaL (plus moxifloxacin in \u0026nbsp;patients with fluoroquinolone-susceptible TB) for 6 months is currently recommended for \u0026nbsp;patients with drug resistant TB (DR-TB) sensitive to all components of the regimen\u0026nbsp;(6). \u0026nbsp;The high potency of the BPaL regimen has potential to also shorten treatment for DS-TB\u0026nbsp;(7).\u003c/p\u003e\n\u003cp\u003eSorfequiline (S) is a second generation diarylquinoline selected for development based on initial positive nonclinical results. \u0026nbsp;In vitro and in vivo studies have shown the increased potency of sorfequiline over bedaquiline. The sorfequiline minimum inhibitory concentration (MIC) against a phylogenetically diverse panel of \u0026nbsp;96 clinical strains was approximately 10-fold lower than the corresponding bedaquiline MICs and in the acute and chronic mouse models of TB, sorfequiline was superior to bedaquiline when administered as monotherapy or in combination with PaL. Crucially, the activity of sorfequiline against the most common type of bedaquiline resistant mutant (Rv0678 mutant) was similar to that of bedaquiline against a wild type strain, both in vitro and in the mouse model(8) . Based on in vitro cardiac potassium channel current inhibition screening studies (hERG assay) and in vivo cardiovascular safety assessments, sorfequiline has shown a reduced risk for QTc prolongation compared with bedaquiline(9)\u0026nbsp;. Sorfequiline thus has the potential to contribute both to increased efficacy and improved safety, and to a shorter TB treatment regimen for both DS-TB and DR-TB.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOBJECTIVES {7}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eList of primary, key secondary, secondary and exploratory objectives and associated endpoints are described in Table 1.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTRIAL DESIGN {8}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis is a phase 2, multi-center, partially blinded, randomised clinical trial where at least 300 participants with DS‑TB who meet all the inclusion criteria and none of the exclusion criteria, aged 18 to 65, will be randomised to receive 1 of the 5 active treatment regimens (at least 60 participants per regimen). \u0026nbsp;Participants will be randomised in equally, using an interactive response technology (IRT) that stratifies based on country and severity of disease (AFB 3+ and/or bilateral cavitation) to 1 of the 5 daily treatment regimens.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe trial consists of the following periods:\u003c/p\u003e\n\u003cul type=\"disc\"\u003e\n \u003cli\u003e\u003cem\u003eScreening Period\u003c/em\u003e: Screening visit up to 11 days prior to randomisation (Day 1)\u003c/li\u003e\n \u003cli\u003e\u003cem\u003eTreatment Period 1 (TP1):\u003c/em\u003e Day 1 through Week 8 (SPaL or BPaL or HRZE)\u003c/li\u003e\n \u003cli\u003e\u003cem\u003eTreatment Period 2 (TP2): \u0026nbsp;\u003c/em\u003e\n \u003cul type=\"circle\"\u003e\n \u003cli\u003eWeek 9 through Week 15 (participants in the SPaL arms that meet criteria for early completion of treatment).\u003c/li\u003e\n \u003cli\u003eWeek 9 through Week 26 (participants in the HRZE/HR or BPaL arms, and participants in the SPaL arms who do not meet criteria for early completion of treatment).\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/li\u003e\n \u003cli\u003e\u003cem\u003ePost end of treatment (EOT) Follow-up Period\u003c/em\u003e: 52 weeks after EOT\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eAfter receiving 8 weeks of treatment, participants in the SPaL arms and in the control arm (HRZE/HR) will continue treatment with HR, and participants randomised to BPaL will continue treatment with BPaL. \u0026nbsp;Treatment completion will be allowed at week 15 in participants randomised to the SPaL arms, if thecriteria below are met\u003cem\u003e:\u003c/em\u003e\u003c/p\u003e\n\u003cul type=\"disc\"\u003e\n \u003cli\u003eWeek 8 sputum Mycobacterial Growth Indicator Tube (MGIT) culture is negative, and\u003c/li\u003e\n \u003cli\u003eThe participant has no TB-related symptoms by Week 15.\u0026nbsp;\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eIf the MGIT result is MTB positive and/or there are still TB symptom(s), participants will continue to receive HR (in the SPaL arms) and will complete a total of 26 weeks of treatment. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNote: \u0026nbsp;The inability to produce sputum will be considered as a negative MGIT culture result and therefore can be used to determine the participants’ eligibility to complete treatment at Week 15. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFor all participants except those on HRZE/HR, blood samples to assess the pharmacokinetics (PK) of study drugs are collected weekly pre-dose and at 1, 3, and 5 hours post-dose at Day 15 and Week 8. Participants at some sites may volunteer for 24-hour intensive sampling at Day 15. In addition, pre-dose samples are collected at Days 1 and 8 and Weeks 4 and 8 to assess the PK of tenofovir and dolutegravir.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSee Figure 1\u0026nbsp;for NC-009 Trial Design.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eRe-Treatment {30}\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eParticipants randomised to the 3 SPaL arms and BPaL arm who relapse or experience treatment failure (see definition of relapse and treatment failure in\u0026nbsp;Table 2) will be re-treated with HRZE/HR, provided that drug susceptibility data do not reveal emergence of resistance or the participant has a contraindication for receiving HRZE/HR, in which case they will be referred to the local national TB programme (NTP) for further management. \u0026nbsp;Participants who are re-treated will be followed for 26 weeks after the end of their re-treatment. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the case of treatment failure or relapse in participants randomised to the control arm (HRZE/HR), the participant will be referred to the local NTP for further management, and the treating physicians will be provided with the DST results and medical report from the investigator, should an individualized regimen be indicated. \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eParticipants who early discontinue from the study for reasons other than relapse/re-infection or treatment failure, where possible, would complete an early discontinuation visit and be referred to the local NTP. No additional follow-up visits are required except where unscheduled visits are needed for ongoing AEs that led to discontinuation from trial and for pregnancies.\u003c/p\u003e\n\u003cp\u003eTB Alliance certifies that it has liability insurance coverage for itself and will provide an associated certificate upon request. The insurance does not relieve the investigators of the obligation to maintain their own liability insurance as required by applicable law. \u0026nbsp;TB Alliance does not assume any obligation for the medical treatment of other injuries and illnesses but in certain instances, compassionate support is provided to participants as required.\u003c/p\u003e"},{"header":"METHODS AND ANALYSIS","content":"\u003cp\u003e\u003cu\u003eStudy setting {9}\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eThe trial will be performed at multiple centres globally including Georgia, the Philippines, South Africa, Tanzania, and Uganda. These are a total of 22 clinical trial units recruiting participants from TB clinics in catchment areas. See Table 3\u0026nbsp;for list of countries, cities and site names.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eEligibility criteria {10}\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eThe key inclusion and exclusion criteria are listed below:\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eInclusion Criteria:\u003c/em\u003e\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eSigned informed consent\u003c/li\u003e\n \u003cli\u003eDS-TB is defined as sensitive to rifampicin and isoniazid by rapid sputum-based test AND either newly diagnosed for TB or have a history of being untreated for at least 3 years after cure from a previous episode of TB\u003c/li\u003e\n \u003cli\u003eOf non-childbearing potential OR using effective birth control methods\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eBody weight \u0026ge; 35 kg\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cem\u003eExclusion Criteria:\u003c/em\u003e\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eKarnofsky score \u0026lt; 60 at screening\u003c/li\u003e\n \u003cli\u003eAny evidence of extrapulmonary TB\u003c/li\u003e\n \u003cli\u003eCardiovascular or QT prolongation risk factors\u003c/li\u003e\n \u003cli\u003ePregnant or breastfeeding\u003c/li\u003e\n \u003cli\u003eAny of the following lab toxicities:\u003cul\u003e\n \u003cli\u003ePlatelets \u0026lt;100,000/mm\u0026sup3;\u003c/li\u003e\n \u003cli\u003eCreatinine \u0026gt;1.3 x ULN\u003c/li\u003e\n \u003cli\u003eHaemoglobin \u0026lt;9.5 g/dL or \u0026lt;95 g/L\u003c/li\u003e\n \u003cli\u003eAbsolute neutrophil count \u0026lt;800/mm\u0026sup3;\u003c/li\u003e\n \u003cli\u003eSerum potassium less than the lower limit of normal for the laboratory\u003c/li\u003e\n \u003cli\u003eALT and/or AST \u0026ge;2.5 x ULN\u003c/li\u003e\n \u003cli\u003eTotal bilirubin \u0026ge;1.6 x ULN\u003c/li\u003e\n \u003cli\u003eDirect bilirubin \u0026gt;1 x ULN\u003c/li\u003e\n \u003cli\u003eHaemoglobin A1c \u0026ge;8.0%\u003c/li\u003e\n \u003cli\u003eTotal lipase \u0026ge;1.5 x ULN\u003c/li\u003e\n \u003cli\u003eTotal amylase \u0026ge;1.5 x ULN\u003c/li\u003e\n \u003cli\u003eCPK \u0026gt;3 x ULN (if \u0026gt;3 x ULN, enquire about the participant\u0026rsquo;s recent strenuous activity and consider repeating the test within the screening window)\u003c/li\u003e\n \u003cli\u003eTSH \u0026gt;1 x ULN\u003c/li\u003e\n \u003cli\u003ePositive results at screening for HBsAg, HAV IgM, or hepatitis C antibodies\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/li\u003e\n \u003cli\u003eFor participants living with HIV only:\u003cul\u003e\n \u003cli\u003eCD4+ count \u0026lt;200 cells/\u0026mu;L\u003c/li\u003e\n \u003cli\u003eWHO Clinical Stage 4 HIV disease\u003c/li\u003e\n \u003cli\u003eParticipant does not agree to use DTG/TFV/3TC during trial if ARV therapy is indicated, and randomised to the Sorfequiline or the BPaL regimen\u003c/li\u003e\n \u003cli\u003eIf initiation of ARV therapy is indicated, participants who are known to be intolerant, non-responsive to DTG/TFV/3TC or have DTG/TFV/3TC as a contraindication\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cu\u003eConsent or assent {26a}\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eInformed consent forms are approved by the relevant ethics committee and regulatory authority. Written informed consent will be obtained from each screened participant, and the process is conducted in the participants\u0026rsquo; preferred local languages in each country. In cases where a participant is illiterate, an impartial witness will be present throughout the informed consent process to ensure that the information in the consent form was accurately explained to, and understood by the participant, and that informed consent was freely given by the participant.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eAdditional consent provisions for collection and use of participant data and biological specimens {26b}\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eAdditional consents to be signed by participants are:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003ePharmacokinetic Sampling (for participants willing to participate in 24hrs of PK sample collection at Day 15, PK subgroup)\u003c/li\u003e\n \u003cli\u003eBiostorage for:\u003c/li\u003e\n \u003cli\u003eThe storage of all unused blood, sputum, and urine samples (as available) for long-term storage.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eAdditional blood and urine samples for exploratory research will be collected at Day 1, weeks 4, 8, 15, and 26.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003ePharmacogenetic testing for participants not randomised to the HRZE/HR arm to collect a blood sample at Day 1 for possible exploratory pharmacogenetic testing.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eINTERVENTIONS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExplanation for choice of comparator {6b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe 6-month treatment regimen is composed of four first-line TB medicines \u0026ndash; HRZE/HR per weight band. This regimen is well known and has been widely adopted worldwide for decades; while using it, about 85% of participants will have a successful treatment outcome (1). This regimen is based on seminal TB treatment studies conducted by the British Medical Research Council in the second half of the 20th century\u0026nbsp;(10).\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eIntervention description {11a}\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eTreatment will be administered by the site to the participant at scheduled trial visits. In between scheduled site visits, the participants will be responsible for the administration of their own investigation medicinal product (IMP).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e1\u003csup\u003est\u003c/sup\u003e 3 treatment arms\u003c/em\u003e: 25 mg/ 50 mg/ 100 mg of sorfequiline + 200 mg pretomanid + 600 mg linezolid for 8 weeks (TP1) followed by 7 weeks or 18 weeks of HR based on participant meeting criteria to stop treatment at week 15 (TP2).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e4\u003csup\u003eth\u003c/sup\u003e treatment arm\u003c/em\u003e: 200 mg bedaquiline + 200mg pretomanid + 600 mg linezolid for 1st 8 weeks (TP1) followed by 100 mg bedaquiline + 200mg pretomanid + 600 mg linezolid for 18 weeks (TP2).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e5\u003csup\u003eth\u003c/sup\u003e treatment arm\u003c/em\u003e: HRZE for 8 weeks followed by HR for 18 weeks.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eIntervention modifications {11b}\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eAt no time should the participant be treated with a single agent. \u0026nbsp; If any of the components other than linezolid need to be interrupted, the entire regimen must be interrupted. \u0026nbsp;Dose adjustments are not allowed for sorfequiline, bedaquiline, pretomanid, or HRZE/HR. Linezolid can be reduced from 600 mg to 300mg or temporarily interrupted or permanently discontinued. No minimum number of doses of linezolid is specified in the protocol.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDuring TP1 and 2, the full regimen can be interrupted for up to 14 and 28 cumulative doses for drug related toxicities respectively.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eStrategies to improve adherence to interventions {11c}\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eParticipants are reminded at each dispensing visit about the importance of adherence and compliance to the IMP. Site staff encourage participants to contact them between visits if they have any questions about their medications or if they are feeling unwell. The site contact details (24 hours) are provided to the participant at the screening visit via a \u0026lsquo;Participant Contact Card\u0026rsquo;.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eConcomitant care that is permitted or prohibited during the trial {11d}\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eAll therapies (prescriptions or over-the-counter medications, including vitamins and herbal supplements) different from the trial drugs are recorded in the concomitant therapy section of the Direct Data Capturing (DDC) platform.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eProhibited Concomitant Medications\u003c/em\u003e:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe following therapies are not allowed during the trial: All medicinal products used to treat pulmonary TB; isoniazid prophylaxis as treatment preventive therapy (TPT) preventative for participants living with HIV; Monoamine Oxidase Inhibitors (due to linezolid, applicable to SPaL and BPaL regimens).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eConcomitant Medication to be avoided\u003c/em\u003e: \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe following concomitant medications should be avoided during and for 14 days after treatment with IMP to prevent possible drug interactions with the IMP: any drug known to be hepatotoxic (applicable for all treatment regimens) e.g. NSAIDS, acetaminophens; any drug known to prolong QTc interval (applicable to SPaL and BPaL regimens) e.g. chloroquine, amiodarone; any drug known to induce significant myelosuppression (due to linezolid, applicable to SPaL and BPaL regimens) e.g. chloramphenicol; systemic use of strong CYP3A4 inhibitors, for more than 14 consecutive days (applicable to SPaL and BPaL regimens) e.g. azole antifungals; systemic use of strong and moderate CYP3A4 inducers should be avoided 14 days before and during treatment (applicable to SPaL and BPaL regimens) e.g. phenytoin, carbamazepine serotonergic antidepressants (SPaL and BPaL regimens) e.g. fluoxetine, paroxetine; strong P-gp inhibitors for more than 3 consecutive days (applicable to SPaL and BPaL regimens) e.g. cyclosporine.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eProvision of post-trial care {30}\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eParticipants who early discontinue from the study for reasons other than relapse/re-infection or treatment failure, where possible, would complete an early discontinuation visit and be referred to the local NTP. \u0026nbsp;No additional follow-up visits are required except where unscheduled visits are needed for ongoing adverse events (AEs) that led to discontinuation from trial and for pregnancies.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eOutcomes {12}\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eSee table 1\u0026nbsp;for study objective and relevant outcomes/end points. See table 2 for Study Outcome Definitions.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eParticipant timelines {13}\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eSee Trial Flow Chart in NC-009 protocol (supplementary materials).\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eSample size {14}\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eSample size for this trial will be at least 60 participants per treatment regimen. \u0026nbsp; Sample size assumptions below are selected to be conservative to achieve adequate power given expected minimal dropout prior to Week 8.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBased on data from previous trials of DS-TB, it is assumed that the probability of participants achieving stable sputum culture conversion to negative status by Week 8 to TP1 in the control regimen (HRZE/HR) is 0.50\u0026nbsp;(11, 12). \u0026nbsp;The number of events and power required is based on comparison of the primary endpoint i.e. time to stable sputum culture conversion to negative status using data from weekly cultures through Week 8 to TP1.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe trial will require approximately 76 events (stable sputum culture conversion to negative status) among approximately 120 randomised participants. \u0026nbsp;This number ensures that a 2-sided, \u0026alpha; = 0.05 logrank test procedure will have 80% power when the true hazard ratio of sorfequiline vs. HRZE is 2.0 and 90% power when the hazard ratio is 2.2. \u0026nbsp;It is assumed that calculations are sufficiently conservative to ensure that the required number of events will be observed by the time the analysis is conducted using Week 8 data. \u0026nbsp;To minimize Type I error, the comparisons for inference will be ordered starting with the highest sorfequiline dose regimen.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eRecruitment - Strategies for achieving adequate participant randomisation to reach target sample size {15}\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eParticipating sites foster and maintain positive working relationships with the local TB clinics in their areas via the Community Engagement (CE) teams and activities. Before a trial commences, the site CE team meets with and informs community stakeholders e.g. Community Advisory Board (CAB), TB clinic nurses and doctors about the trial. \u0026nbsp;When the trial starts, the TB clinics identify patients who have been newly diagnosed with DS-TB, and they inform the site CE contact person. The CE contact person talks with the patient to find out if they would like to know more about the trial, and if they agree, they invite them to the site. \u0026nbsp;The CE team arranges transportation for the participant from their home or TB clinic to the site while they still test positive for TB. This process facilitates a good relationship between CAB, TB clinics and trial sites, and as a consequence hopefully good recruitment to the trial.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eWho will be blinded {17a}\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eThe trial is partially blinded i.e. sorfequiline and bedaquiline will be blinded during the first 8 weeks of trial treatment; participants randomised to the sorfequiline or bedaquiline arms will receive open label pretomanid and linezolid. After the Week 8 visit, participants will be unblinded if they are randomised to sorfequiline or bedaquiline but the dose of sorfequiline remains blinded throughout the study. Participants randomised to the HRZE/HR arm will receive open label IMP. Only the unblinded statistician will have access to unblinded data.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eBlinding (masking): emergency unblinding {17b}\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eThe blind for a participant must not be broken by the site or TB Alliance except in the case of a medical emergency, where treatment of a participant is influenced by the knowledge of what dose of sorfequiline or bedaquiline the participant is receiving. The investigator should discuss this with the TB Alliance\u0026rsquo;s Study Physician prior to breaking the blind unless knowledge of the treatment regimen is required urgently for a safety concern. TB Alliance\u0026rsquo;s Study Physician should be informed of the blind break within 24 hours if not discussed prior to unblinding.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDATA COLLECTION AND MANAGEMENT\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eData collection plan {18a}\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eThis study utilized a Direct Data Capturing (DDC) system, which negates the needs, in most cases, for a paper source document at the site. Safety lab tests are performed by a central laboratory vendor which involves shipping of samples to affiliated local labs; results available are sent to the sites via a central e-platform. Sputum samples are analysed by a central laboratory in South Africa, and the results available are sent to sites via the laboratory e-platform. In non-South African sites, local mycobacteriology labs affiliated with the sites are used and data is entered directly into the DDC system. ECGs taken at the site and associated readings are transmitted to a central ECG system to undergo quality checks, blinded central review and cardiologist reporting. All data capture and laboratory information systems conform to the Code of Federal Regulations Title 21, Part 11 (21 CFR Part 11) requirements. The data are mapped and transmitted directly from the laboratory information system into the corresponding SDTM datasets.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003ePlans to promote participant retention and complete follow\u003c/u\u003e\u003cu\u003e‑\u003c/u\u003e\u003cu\u003eup {18b}\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eEach site develops their own \u0026lsquo;Recruitment and Retention\u0026rsquo; plan, specific to their community and location. Participants are reimbursed for their transport, and any other reasonable expense, to and from the site for all trial visits as approved by EC/IRB. The site also provides the participant with a \u0026lsquo;cellular / phone voucher\u0026rsquo; to ensure that the participant has the monetary means to contact the site at any time, if they need to.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSite staff contact the participant telephonically between trial visits and just before the next scheduled visit to ask them how they are doing and to remind them of the upcoming visit.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eData management {19}\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eA DDC system was designed to collect all the data required by the protocol. Delegated site staff enter data collected per study visit in the DDC system (tablets). Any correction or changes in entry in the DDC are tracked electronically via an audit trail. Safety lab, Myco lab, ECG \u0026amp; IRT data are all programmatically integrated into the corresponding SDTM datasets.\u003c/p\u003e\n\u003cp\u003eAdverse events are coded using the Medical dictionary for regulatory activities (MedDRA) terminology. Concomitant medications will be summarised per Anatomical Therapeutic Chemical (ATC) level 2 and level 4 code. Medications that cannot be assigned a level 2 or level 4 code will be identified in the table as missing the coding level.\u003c/p\u003e\n\u003cp\u003eThe Data Manager, or their delegate, regularly reviews the DDC data entered by investigator staff for completeness and accuracy.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eConfidentiality {27}\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eAll laboratory specimens, including stored specimens, as well as trial reports, data collection tools, and administrative documents are identified by using only the participant\u0026rsquo;s unique trial number. All local and central databases are secured with password-protected access systems. The investigators ensure anonymity of the participant and that all documents are anonymised before being transmitted to TB Alliance.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003ePlans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eFor study participants not randomised to HRZE/HR and who sign a separate informed consent, a blood sample will be drawn at Day 1 (or at other time point during the trial if not obtained at Day 1) for possible exploratory pharmacogenetic testing. \u0026nbsp; The sample may be used to identify genes that contribute to pharmacokinetic (PK) variability of sorfequiline and bedaquiline, i.e., variability in blood levels of those drugs and their metabolites, such as (but not necessarily restricted to) genes for drug-metabolizing enzymes or drug-transport proteins. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSTATISTICAL METHODS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eStatistical methods for primary and secondary outcomes {20a}\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eDemographic and screening/baseline characteristics of the randomised participants will be summarised by treatment arm. There are 3 analysis population utilized in this protocol i.e.:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\u003cem\u003eIntent-to-treat (ITT) Population\u003c/em\u003e (include all randomised participants who took at least 1 dose of trial drug)\u003c/li\u003e\n \u003cli\u003e\u003cem\u003eModified Intent-to-treat (MITT) Population\u003c/em\u003e (participants who are randomised and take at least 1 dose of trial drug, without late exclusions i.e. the lack of MTB culture positive on day 1 and discrepancies between screening rapid test result and corresponding culture/WGS)\u003c/li\u003e\n \u003cli\u003e\u003cem\u003ePer Protocol Population\u003c/em\u003e (MITT population excluding participants with major protocol deviations)\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eThe MITT population is the primary population for all efficacy analyses and ITT for all safety analysis.\u003c/p\u003e\n\u003cp\u003eThe primary endpoint is time to stable sputum culture conversion to negative status over 8 weeks using data from weekly cultures up to and including Week 8 in the sorfequiline regimens. \u0026nbsp;Stable sputum culture conversion to negative status is defined as 2 negative results (at least 7 days apart without an intervening MTB positive). \u0026nbsp;The primary hypothesis is that for participants randomised to a sorfequiline-containing regimen (at least 1 sorfequiline regimen), the time to culture negativity by 8 weeks will be superior, compared to the participants who are treated with the standard HRZE regimen. Time to stable sputum culture conversion to negative status will also be summarized using the Kaplan-Meier method and displayed graphically. \u0026nbsp;Median event times (and other quartiles) and 2-sided 95% CI for each time will be provided.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe key secondary analysis is the proportion of participants with a favourable outcome at 26 weeks after end of treatment (EOT) based on the MITT population for BPaL vs. HRZE/HR.\u003c/p\u003e\n\u003cp\u003eThe proportion of participants who meet the criteria to stop treatment at Week 15 in the 3 sorfequiline arms will be summarized based on the MITT population.\u003c/p\u003e\n\u003cp\u003eRelapse rates at 26 weeks after EOT, and separately at 52 weeks after the EOT follow-up period based on the MITT population will be summarized.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAn analysis of the bactericidal activity over 2 weeks, BA\u003csub\u003eTTP\u003c/sub\u003e(1-15), of sorfequiline or bedaquiline in combination with pretomanid and linezolid, relative to HRZE, as determined by the rate of change in TTP over Days 1 to 15 of treatment, represented by the model-fitted log(TTP) as calculated by the regression of the observed log(TTP) counts over time. \u0026nbsp;A similar analysis will be performed to assess bactericidal activity over 8 weeks [BA\u003csub\u003eTTP\u003c/sub\u003e(1-56)].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eChange from baseline in measurements of biomarker assays (potentially LAM and other assays), through the course of treatment and the post-treatment follow-up period relative to treatment outcome will be evaluated. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eKey safety analysis will be performed including incidence of adverse events (AE), study drug modifications, clinical laboratory evaluation, ECGs, concomitant medications etc.\u003c/p\u003e\n\u003cp\u003eFor study drugs, plasma concentrations will be summarized, and exposure metrics such as C\u003csub\u003emax\u003c/sub\u003e and AUC will be computed and summarized. Relationships will be explored between exposure metrics and efficacy and safety endpoints.\u003c/p\u003e\n\u003cp\u003eTrough concentrations of dolutegravir and tenofovir will be summarized for participants living with HIV and will be compared with standard ranges to assess possible interactions with study drugs.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eInterim analysis {21b}\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eThere will be 1 planned unblinded interim analysis which will contain results by treatment group in aggregate and will include the primary analysis. This will occur after all participants have completed 8 weeks of treatment. \u0026nbsp;The study team and Data Safety Monitoring Committee (DSMC) will have access to the primary end-point analysis.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eStatistics: additional analyses {20b}\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eA stratified logrank test will be used to compare time to stable sputum culture conversion to negative status between the 2 regimens with the stratification factors country and severity of disease (AFB 3+ and/or bilateral cavitation). \u0026nbsp;All subgroup analyses will be performed on the ITT, mITT and PP populations. Additionally, post hoc analyses not originally described in the protocol will be mentioned in the statistical analysis plan (SAP). SAP in supplementary material.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eMethods in analysis to handle protocol non\u003c/u\u003e\u003cu\u003e‑\u003c/u\u003e\u003cu\u003eadherence and any statistical methods to handle missing data {20c}\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eParticipants with Clinical Study Report (CSR) reportable deviations as evaluated and determined by a review committee prior to database lock will be excluded from the PP population.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003ePlans to give access to the full protocol, participant\u003c/u\u003e\u003cu\u003e‑\u003c/u\u003e\u003cu\u003elevel data and statistical code {31c}\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eIt is the intention that de-identified SDTM datasets including an associated data dictionary will be made available via TB PACTS hosted by CPATH (https://c-path.org/tools-platforms/tb-pacts/).\u0026nbsp;The full protocol and statistical analysis plan will be made available as appendices during the publication of the trial results.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOVERSIGHT AND MONITORING\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eComposition of the coordinating centre and trial steering committee {5d}\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eThe trial is led by:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eTB Alliance Study Physician who leads the core team composed of biostatistician, medical monitors, mycobacteriologist, and non-clinical group.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eTB Alliance Clinical Project Manager who leads the clinical operations group consisting of a partner Clinical Research Organization overseeing trial monitoring, vendor management, data management, drug and non-drug supplies, and the finance team.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eThere is also a Data Safety Monitoring Committee (DSMC).\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eComposition of the data safety monitoring committee, its role and reporting structure {21a}\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eThe DSMC is independent of TB Alliance and all project collaborators. It is governed by the DSMC Charter which describes its purpose and terms of reference. It consists of a chairperson and other seasoned TB disease and trial specialists, a statistician and a country representative from Tanzania (per Tanzania Medi requirements). The DSMC meeting will be held approximately every 6 months after the first randomised participant. Ad-hoc meetings can be called by TB Alliance or the DSMC based on the rates of SAEs, SAEs of particular concern, or any safety concerns that arise during the trial\u003c/p\u003e\n\u003cp\u003eThe DSMC acts in an advisory capacity to TB Alliance, to safeguard the interest of trial participants by monitoring participant safety, participant risk versus benefit, and general evaluation of the study progress.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSee DSMC Charter in supplementary material.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eAdverse events reporting and harms {22}\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eAdverse events reporting applies to both investigational and control arms in the trial. All AEs and serious adverse events (SAEs) will be collected from the signing of the ICF until the follow-up Week 52 visit (end of trial). \u0026nbsp;Treatment-emergent AEs are defined as any AE that occurs after the first dose of IMP and within 28 days after the last dose of IMP. All AEs are recorded in the AE section of the DDC. AEs can be spontaneously reported or elicited during open-ended questioning, examination, or evaluation of a trial participant. The investigator must also promptly review all results of assessments performed as part of the trial, such as laboratory assessment results, ECGs, vital sign monitoring, physical examinations, etc. and assess them for clinical significance. Each AE is evaluated to determine the severity grade: Grade 1\u0026ndash;4 as per the latest version of the DAIDS Severity Grading Scale, its duration (start and end dates or if continuing at the end-of-study visit), its relationship to the study treatment, action taken with respect to study treatment (treatment maintained, dose reduced, permanently discontinued, temporarily discontinued, not applicable), whether medication or therapy was taken/given in relation to the AE and whether it is a serious adverse event (SAE). All AEs will be followed until satisfactory clinical resolution or stabilization, or the end of the follow-up period or early discontinuation of the trial. All SAEs (including updated or significant follow up information) will be recorded and reported to TB Alliance immediately and within 24 hours of awareness. \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTB Alliance has a legal responsibility to notify the relevant regulatory authority, IRB/EC, and investigators about the safety of an IMP under clinical investigation. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eFrequency and plans for auditing trial conduct {23}\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eA risk-based approach is used for quality assurance audits to evaluate if the trial was conducted and the data generated in compliance with the protocol, GCP and applicable regulatory and ethics committee requirements. \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePrior to the conduct of work, independent auditors conduct qualification audits for significant trial vendors to evaluate and confirm the vendor\u0026rsquo;s capability to perform the planned work in accordance with required standards. During the trial independent auditors conduct routine requalification audits. The frequency of audit is based on the risk tier assigned to each vendor, with the highest risk vendors subject to an audit every 2 years, ranging to the lowest risk vendors which are audited every 10 years.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eDissemination plan {31a}\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eResults of this research will be submitted for publication as soon as feasible upon completion of the trial in the form of a joint publication(s) between TB Alliance and investigator(s), including site clinical and laboratory investigators, as appropriate. Publication and authorship will be in accord with the International Association of Journal Editors.\u003c/p\u003e\n\u003cp\u003eBecause the trial is funded, in whole or in part, by the Bill and Melinda Gates Foundation (the \u0026ldquo;Foundation\u0026rdquo;), all peer-reviewed published research relating to the trial must comply with the Foundation\u0026rsquo;s Open Access Policy as described from time to time at http://www.gatesfoundation.org/How-We-Work/General-Information/Open-Access-Policy. \u0026nbsp;Specifically, (a) all peer-reviewed published research relating to the trial must be submitted for publication by TB Alliance through the Chronos Open Access Publishing Service established by the Foundation to ensure the immediate and unrestricted access and reuse of all peer-reviewed published research funded, in whole or in part, by the Foundation without any embargo period, and (b) all data underlying the peer-reviewed published research results must be immediately made accessible and open to the public in accordance with the Foundation\u0026rsquo;s Open Access Policy.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eTuberculosis continues to be one of the most formidable global health threats, especially in the context of rising drug resistance and the setbacks from the COVID-19 pandemic. In response, the TB Alliance initiated protocol NC-009, a phase 2, multi-arm clinical trial that introduces several pioneering features aimed at improving treatment outcomes for drug-sensitive TB (DS-TB). This article explores the innovative aspects of the NC-009 study design, emphasizing its methodological sophistication and translational impact.\u003c/p\u003e\n\u003cp\u003eAt the heart of the NC-009 protocol is its five-arm, partially-blinded, randomized trial design. This allows the evaluation of:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eThree different doses (25 mg, 50 mg, 100 mg) of the novel diarylquinoline sorfequiline\u003c/li\u003e\n \u003cli\u003eComparison with bedaquiline (200 mg), the current standard among diarylquinolines,\u003c/li\u003e\n \u003cli\u003eFirst trial to evaluate BPaL in DS-TB population and,\u003c/li\u003e\n \u003cli\u003eBenchmarking against the HRZE/HR standard of care.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eThe partially-blinded methodology balances methodological rigor with operational feasibility.\u003c/p\u003e\n\u003cp\u003eAn important innovation is the adaptive treatment duration based on early treatment response. Participants in the SPaL arms can transition from treatment to follow-up at 15 weeks, provided they meet pre-defined microbiological and symptomatic recovery criteria. This approach tests the hypothesis that treatment for DS-TB can be safely and effectively shortened for some participants, improving adherence and reducing resource use.\u003c/p\u003e\n\u003cp\u003eUnlike many trials that focus predominantly on clinical outcomes, NC-009 robustly incorporates pharmacokinetic/pharmacodynamic (PK/PD) modeling, using both sparse and intensive sampling strategies. This allows for:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eCorrelation of drug exposure with bactericidal activity and adverse events.\u003c/li\u003e\n \u003cli\u003eIdentification of the optimal dose of sorfequiline with a favorable efficacy-safety profile.\u003c/li\u003e\n \u003cli\u003eAssessment of drug-drug interactions in participants co-infected with HIV.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eA pragmatic and ethical innovation is the inclusion of a pre-planned re-treatment pathway i.e. participants randomized to the S/ BPaL arms who relapse are offered standard re-treatment with HRZE/HR, and outcomes are monitored for an additional 26 weeks, as part of the study. This strategy ensures participant safety while enabling long-term outcome assessment and avoids overburdening the local NTP clinics.\u003c/p\u003e\n\u003cp\u003eThe protocol introduces detailed criteria for treatment modification and toxicity monitoring (including visual acuity and neuropathy assessments), critical for regimens containing linezolid. It also includes QTc interval evaluation, providing an opportunity to compare sorfequiline to bedaquiline regarding this safety concern of the latter. These measures ensure participant safety without compromising the study's scientific goals.\u003c/p\u003e"},{"header":"TRIAL STATUS","content":"\u003cp\u003eThe study is being conducted according to the initial protocol Version 1 dated 3 February 2023. No protocol amendments have been generated.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRecruitment started on 24 October 2023 and completed on 30 August 2024, including a total of 309 randomised and eligible participants. The last treatment visit was conducted on 10 March 2025 and the planned \u0026lsquo;Last Participant Last Follow-up Visit\u0026rsquo; is due on 27 February 2026. All ongoing participants are currently in the follow-up phase of the trial.\u003c/p\u003e\n\u003cp\u003eThree DSMC meetings were held on 5 February 2024, 8 April 2024, and 4 November 2024 and the recommendation was to continue trial unmodified. The Clinical Study Report (CSR) is planned to be completed by 25 September 2026 following the planned final database lock on 8 May 2026.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e3TC: Lamivudine; AE: Adverse Event; AFB: Acid-fast bacilli; ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; ARV: Antiretroviral; AST: Aspartate transaminase; AUC: Area under the curve; BATTP: Bactericidal activity measured by TTP; BPaL: bedaquiline, pretomanid, linezolid; CFR: Code of federal regulations; Cmax: maximum plasma concentration; CPK: Creatine phosphokinase; CV: Coefficient of variation; CYP: cytochrome P450; DAIDS: Divisions of AIDS; DR-TB: Drug-resistant tuberculosis; DSMC: Data Safety Monitoring Committee; DS-TB: drug-sensitive tuberculosis; DTG: Dolutegravir; EC: Ethics committee; ECG: electrocardiogram; EOT: End of treatment; GCP: Good clinical practice; HAV: Hepatitis A virus; HbsAg: Hepatitis B surface antigen; HBV: Hepatitis B virus; HCV: Hepatitis C virus; HIV: Human immunodeficiency virus; HRZE: Isoniazid, rifampicin, pyrazinamide, ethambutol; HR: Isoniazid, rifampicin; IB: Investigator\u0026rsquo;s Brochure; ICF: Informed consent form; ICH: International Council on Harmonisation; IMP: Investigational medicinal product; IRB: Institutional Review Board; IRT: Interactive response technology; ITT: Intent to treat; IUATLD: International Union Against Tuberculosis and Lung Disease; LAM: Lipoarabinomannan; MAD: multiple ascending dose; MDR-TB: Multi-drug resistant tuberculosis; MedDRA: Medical Dictionary for Regulatory Activities; MGIT: Mycobacteria growth indicator tube; MIC: Minimum inhibitory concentration; MITT: Modified intent-to-treat; MTB: Mycobacterium tuberculosis; NTP: National TB program; PCR: Polymerase chain reaction; PD: Pharmacodynamics; PK: Pharmacokinetics; PP: Per protocol; QTcF: QT interval corrected using Fridericia\u0026rsquo;s formula; SAD: Single ascending dose; SAE: Serious adverse event; SAP: Statistical analysis plan; SD: Standard deviation; SDTM: Study Data Tabulation Model; SmPC: Summary of product characteristics; TB: Tuberculosis; TEAE: Treatment-emergent adverse event; TFV: Tenofovir; TI/NR MDR-TB: Treatment-intolerant/non-responsive MDR-TB; TPT: TB preventive treatment; TSH: Thyroid stimulating hormone; TTP: Time to positive; ULN: Upper limit of normal; WGS: Whole genome sequencing, WHO: World Health Organization; XDR-TB: Extensively drug-resistant tuberculosis.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cu\u003eSupplementary information\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eThe supplementary material is available in the online version.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eAuthors contributions {31b}\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eOM, BM, LL, NJ, TJ, BT, BR, HD, LA, BeM, EE, ML, HJ, SS, FS, BnM, SE initiated the study design and implemented the study. OM is study physician, and LL is clinical project manager. NJ is pharmacokinetics, BT is biologist, TJ is microbiologist, BeM is clinical data manager, EE is back up clinical project manager \u0026amp; medical writer, ML is drug supply manager, HJ oversees quality assurance, SS is community engagement manager. All authors contributed to refinement of the study protocol and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eFunding {4}\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by TB Alliance (Global Alliance for TB Drug Development) with funding from Australia\u0026rsquo;s Department of Foreign Affairs and Trade, the Gates Foundation [OPP1129600], the Foreign, Commonwealth and Development Office (United Kingdom), Germany\u0026rsquo;s Federal Ministry of Education and Research through KfW, Irish Aid, and the United States Agency for International Development. This work was supported in part by the Gates Foundation [OPP1129600]. The conclusions and opinions expressed in this work are those of the author(s) alone and shall not be attributed to the Foundation. Under the grant conditions of the Foundation, a Creative Commons Attribution 4.0 License has already been assigned to the Author Accepted Manuscript version that might arise from this submission. Please note works submitted as a preprint have not undergone a peer review process.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eAvailability of data and materials {29}\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eThe trial data will be made available after primary publication. All unpublished information/data given to the investigator by TB Alliance shall not be published or disclosed to a third party, other than to the responsible IRB/EC, with the understanding of the confidentiality of their nature, without the prior written consent of TB Alliance.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eEthics approval and consent to participate {24}\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eAll relevant country ethics committee / institutional review board (REC/ IRB) approvals were obtained before commencement of this study.\u003c/p\u003e\n\u003cp\u003eThe study protocol, the participant Information and Consent Form (ICF), the DDC, up-to-date versions of the Investigator Brochures or Summary of Product Characteristics (SmPC), as well as Principal Investigators qualifications has been submitted and approved by the ethical boards and regulatory authorities listed in Table 4.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eInformed consent materials {32}\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eInformed consent materials in supplementary materials\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eCompeting interests {28}\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eThere are no financial or other conflicts of interest for principal investigators or DSMC committee members.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eAuthors details\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e1\u003c/sup\u003e TB Alliance, South Africa\u003csup\u003e\u0026nbsp;2\u003c/sup\u003e TB Alliance, USA \u003csup\u003e3\u003c/sup\u003e RTI International, USA\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eWHO. Global tuberculosis report. Geneva: World Health Organization. 2024. Report No.: ISBN 978-92-4-010154-8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWHO. WHO Operational handbook on tuberculosis. Worlsd Health Organization. 2022. Contract No.: ISBN: 978-92-4-006312-9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWHO. Rapid communication on updated guidance on the management of TB in children and adolescents. 2021.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eConradie F, Everitt D, Crook AM. Treatment of Highly Drug-Resistant Pulmonary Tuberculosis. Reply. N Engl J Med. 2020;382(24):2377.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eConradie F, Bagdasaryan TR, Borisov S, Howell P, Mikiashvili L, Ngubane N, et al. Bedaquiline-Pretomanid-Linezolid Regimens for Drug-Resistant Tuberculosis. N Engl J Med. 2022;387(9):810\u0026ndash;23.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWHO. Rapid communication: key changes to the treatment of drug-resistant tuberculosis. online: World Health Organization; 2022 May 2022. Report No.: WHO Reference Number: WHO/UCN/TB/2022.2.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTanseen RB, Tyagi F, Li S, Williams D, Converse K, Dartois P, Yang V, Mendel T, Midliuli C, Nuermberger K. Contribution of Oxazolidinones to Efficacy of Novel Regimens containing Bedaquilinie and Pretomanid in a Mouse Model of Tuberculosis. Antimicrob Agents Chemother. 2016;60(1):17.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAlmeida DCP, Li S, Upton AM, Fotouhi N, Nuerrmberger EL. Comparative Efficacy of the Novel Diarylquinoline TBAJ-876 and Bedaquiline against a Resistant Rv0678 Mutant in a Mouse Model of Tuberculosis. Antimicrob Agents Chemother. 2021.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSutherland HS, Tong AST, Choi PJ, Blaser A, Conole D, Franzblau SG, et al. 3,5-Dialkoxypyridine analogues of bedaquiline are potent antituberculosis agents with minimal inhibition of the hERG channel. Bioorg Med Chem. 2019;27(7):1292\u0026ndash;307.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFox W, Ellard GA, Mitchison DA. Studies on the treatment of tuberculosis undertaken by the British Medical Research Council tuberculosis units, 1946\u0026ndash;1986, with relevant subsequent publications. Int J Tuberc Lung Dis. 1999;3(10 Suppl 2):S231\u0026ndash;79.\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\u003eDorman SE, Nahid P, Kurbatova EV, Phillips PPJ, Bryant K, Dooley KE, et al. Four-Month Rifapentine Regimens with or without Moxifloxacin for Tuberculosis. N Engl J Med. 2021;384(18):1705\u0026ndash;18.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1: List of primary, key secondary, secondary and exploratory objectives and associated end-points.\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"96%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 272px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eObjectives\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 308px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEndpoints\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 272px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePrimary\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 308px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 272px;\"\u003e\n \u003cp\u003eTo evaluate the efficacy of 3 dose levels of sorfequiline in combination with pretomanid and linezolid, relative to 2HRZE, during 8 weeks of treatment in adult participants with newly diagnosed, smear-positive, pulmonary DS-TB as measured by time to stable sputum culture conversion\u0026nbsp;to negative status.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 308px;\"\u003e\n \u003cp\u003eTime to stable sputum culture conversion to negative status using data from weekly cultures through 8 weeks of treatment.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 272px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eKey Secondary\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 308px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 272px;\"\u003e\n \u003cp\u003eTo evaluate the safety and efficacy at 26 weeks after the EOT of B-Pa-L relative to 2HRZE/4HR\u0026nbsp;in adult participants with newly diagnosed, smear-positive, pulmonary DS-TB.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 308px;\"\u003e\n \u003cp\u003eProportion of participants with a favourable outcome at 26 weeks after the EOT.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 272px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSecondary\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 308px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 272px;\"\u003e\n \u003cp\u003eTo evaluate the efficacy of 3 dose levels of sorfequiline in combination with pretomanid and linezolid, in adult participants with newly diagnosed, smear-positive, pulmonary DS-TB, as measured by meeting the criteria to stop treatment at Week 15.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 308px;\"\u003e\n \u003cp\u003eProportion of participants who meet the criteria to stop treatment at Week 15.\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 272px;\"\u003e\n \u003cp\u003eTo evaluate the safety and efficacy of 3 dose levels of sorfequiline in combination with pretomanid and linezolid at 26 weeks and 52\u0026nbsp;weeks after end of treatment relative to 2HRZE/4HR for the overall arms and key subgroups by stratification factors and total treatment duration,\u0026nbsp;in adult participants with newly diagnosed, smear-positive, pulmonary DS-TB.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 308px;\"\u003e\n \u003cp\u003eProportion of participants with a favourable outcome at 26 weeks and 52 weeks after the EOT.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 272px;\"\u003e\n \u003cp\u003eTo evaluate the safety and efficacy at 52 weeks after the EOT of B-Pa-L relative to 2HRZE/4HR\u0026nbsp;in adult participants with newly diagnosed, smear-positive, pulmonary DS-TB.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 308px;\"\u003e\n \u003cp\u003eProportion of participants with a favourable outcome at 52 weeks after the EOT.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 272px;\"\u003e\n \u003cp\u003eTo evaluate the efficacy of 3 dose levels of sorfequiline in combination with pretomanid and linezolid, B-Pa-L, and 2HRZE/4HR, at 26 weeks and 52 weeks after the EOT, as measured by relapse rates in participants that enter follow up with a favourable response at the EOT for the overall arms and key subgroups by stratification factors and total treatment duration.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 308px;\"\u003e\n \u003cp\u003eRelapse rates at 26 weeks and 52 weeks after the EOT.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 272px;\"\u003e\n \u003cp\u003eTo evaluate the efficacy of B-Pa-L, relative to 2HRZE, during 8 weeks of treatment in adult participants with newly diagnosed, smear-positive, pulmonary DS‑TB as measured by time to stable sputum culture conversion\u0026nbsp;to negative status.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 308px;\"\u003e\n \u003cp\u003eTime to stable sputum culture conversion to negative status using data from weekly cultures through 8 weeks of treatment.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 272px;\"\u003e\n \u003cp\u003eTo assess the bactericidal activity over 2 weeks of 3 dose levels of sorfequiline in combination with pretomanid and linezolid or B-Pa-L, relative to 2HRZE, in adult participants with newly diagnosed, smear-positive, pulmonary DS-TB.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 308px;\"\u003e\n \u003cp\u003eBA\u003csub\u003eTTP\u003c/sub\u003e(1-15) as determined by the rate of change in TTP over Days 1 to 15 of treatment, represented by the model-fitted log(TTP) as calculated by the regression of the observed log(TTP) counts over time.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 272px;\"\u003e\n \u003cp\u003eTo assess the bactericidal activity over 8 weeks of 3 dose levels of sorfequiline in combination with pretomanid and linezolid or B-Pa-L, relative to 2HRZE, in adult participants with newly diagnosed, smear-positive, pulmonary DS-TB.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 308px;\"\u003e\n \u003cp\u003eBA\u003csub\u003eTTP\u003c/sub\u003e(1-56) as determined by the rate of change in TTP over 8\u0026nbsp;weeks of treatment, represented by the model-fitted log(TTP) results as calculated by the regression of the observed log(TTP) results over time.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 272px;\"\u003e\n \u003cp\u003eTo evaluate stable sputum culture conversion to negative status over time during the treatment period.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 308px;\"\u003e\n \u003cp\u003eProportion of participants with stable sputum culture conversion to negative status at Weeks 4, 6, 8, 12, 15, 20, and 26.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 272px;\"\u003e\n \u003cp\u003eTo assess the safety and tolerability of the 3 dose levels of sorfequiline in combination with pretomanid and linezolid or B‑Pa‑L regimens at different time points, relative to 2HRZE/4HR, in adult participants with newly diagnosed, smear-positive, pulmonary DS‑TB.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 308px;\"\u003e\n \u003cp\u003eIncidence of TEAEs, by severity, drug relatedness, seriousness, leading to early discontinuation, and leading to death; and ECG, vital signs, and quantitative and qualitative clinical laboratory result measurements, changes in ophthalmic exam for visual acuity and changes noted in peripheral neuropathy, including observed and changes from baseline at Weeks 8, 26, and 26\u0026nbsp;weeks after the EOT.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 272px;\"\u003e\n \u003cp\u003eTo evaluate the systemic exposure of sorfequiline, bedaquiline, pretomanid, and linezolid.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 308px;\"\u003e\n \u003cp\u003ePlasma concentrations of sorfequiline, bedaquiline, pretomanid, linezolid, and selected metabolites from sparse samples in all participants assigned those treatments and from an intensive profile on Day 15 in a sub-group of participants.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 272px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eExploratory\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 308px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 272px;\"\u003e\n \u003cp\u003eTo assess if changes in measurements of biomarker assays through the course of treatment and the post-treatment follow-up period are associated with treatment outcome.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 308px;\"\u003e\n \u003cp\u003eChange from baseline in biomarker assay through the course of treatment and the post-treatment follow-up period relative to treatment outcome.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 272px;\"\u003e\n \u003cp\u003eTo correlate various endpoints measured with MGIT with AFB smear and exploratory biomarkers at Day 1 and Weeks 4, 8, 15, and 26.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 308px;\"\u003e\n \u003cp\u003eParameters derived from modelling various endpoints measured with MGIT (e.g. MGIT negative [yes/no], quantitative outcomes) relative to AFB smear and exploratory biomarkers at Day 1 and Weeks 4, 8, 15, and 26\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 272px;\"\u003e\n \u003cp\u003eTo correlate MGIT culture results at Weeks 2, 4, and 8 with favorable outcome at 26 weeks and 52 weeks after the EOT.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 308px;\"\u003e\n \u003cp\u003eParameters derived from modelling MGIT culture results at Weeks 2, 4, and 8 (e.g. MGIT negative [yes/no], quantitative outcomes) relative to favourable outcome at 26 weeks and 52 weeks after the EOT.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 272px;\"\u003e\n \u003cp\u003eTo explore predictors of MGIT negative culture at Week 8 of treatment.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 308px;\"\u003e\n \u003cp\u003eMGIT negative at Week 8 of treatment (yes/no) relative to key baseline characteristics.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 272px;\"\u003e\n \u003cp\u003eTo explore the population PK and exposure-response relationships of sorfequiline, bedaquiline, pretomanid, and linezolid.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 308px;\"\u003e\n \u003cp\u003ePopulation-PK models, summary metrics of exposure (e.g., AUC) derived from those models, and models for relationships between exposure and efficacy and safety outcomes.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 272px;\"\u003e\n \u003cp\u003eTo explore the systemic exposure of dolutegravir and tenofovir when co-administered with 3 dose levels of sorfequiline in combination with pretomanid and linezolid, B-Pa-L or 2HRZE.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 308px;\"\u003e\n \u003cp\u003eTrough concentrations of dolutegravir and tenofovir from participants living with HIV assigned treatments.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 272px;\"\u003e\n \u003cp\u003eTo explore the impact on quality of life of 3 dose levels of sorfequiline in combination with pretomanid and linezolid, B-Pa-L, and 2HRZE/4HR\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 308px;\"\u003e\n \u003cp\u003eTime to improvement of quality of life measurements, proportion of participants with improved measurements on quality of life at different time points during and after treatment.\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\u003e\u003cstrong\u003eTable 2: Study Outcome Definitions\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: 157px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 444px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDefinition\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTreatment Failure\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 444px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTREATMENT FAILURE DIAGNOSED \u003cu\u003eby the end of treatment\u0026nbsp;\u003c/u\u003eIF \u0026ge;2 of A, B, or C are satisfied; OR if D is satisfied\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003col start=\"1\" type=\"A\"\u003e\n \u003cli\u003e\u003cstrong\u003eClinical Disease Persistence\u003c/strong\u003e\u003c/li\u003e\n \u003c/ol\u003e\n \u003cp\u003ePersistent TB symptoms or signs without an alternative explanation.\u003c/p\u003e\n \u003col start=\"2\" type=\"A\"\u003e\n \u003cli\u003e\u003cstrong\u003eChest X-ray Progression\u003c/strong\u003e\u003c/li\u003e\n \u003c/ol\u003e\n \u003cp\u003eAbnormalities that are compatible with active TB disease (cavitation, infiltrates, consolidation) with clear evidence of no improvement or progression compared with start of treatment without an alternative, more likely explanation.\u003c/p\u003e\n \u003col start=\"3\" type=\"A\"\u003e\n \u003cli\u003eUnconfirmed positive MGIT Sputum sample result after having achieved culture negative status (defined as 2 negative culture results at least 7 days apart).\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eConfirmed MTB positive sputum culture\u0026nbsp;\u003c/strong\u003e\u003c/li\u003e\n \u003c/ol\u003e\n \u003cp\u003eFailure to attain culture negative status by the end of treatment or failure to maintain culture negative status (defined as 2 positive culture results at least 7 days apart after achieving culture negative status). \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRelapse or Reinfection\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 444px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRELAPSE or RE-INFECTION DIAGNOSED \u003cu\u003eduring follow up\u003c/u\u003e\u0026nbsp;\u003c/strong\u003ein participants with culture negative status by the EOT,\u003cstrong\u003e\u0026nbsp;IF \u0026ge;2 of A, B, or C are satisfied; OR if D is satisfied\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003col start=\"1\" type=\"A\"\u003e\n \u003cli\u003e\u003cstrong\u003eClinical Disease Progression\u003c/strong\u003e\u003c/li\u003e\n \u003c/ol\u003e\n \u003cp\u003eNew or recurrent TB symptoms or signs after complete resolution at the EOT without an alternative, more likely explanation.\u003c/p\u003e\n \u003col start=\"2\" type=\"A\"\u003e\n \u003cli\u003e\u003cstrong\u003eChest X-ray Progression\u003c/strong\u003e\u003c/li\u003e\n \u003c/ol\u003e\n \u003cp\u003eAbnormalities that are compatible with active TB disease (cavitation, infiltrates, consolidation) with clear evidence of progression compared with the EOT without an alternative, more likely explanation.\u003c/p\u003e\n \u003col start=\"3\" type=\"A\"\u003e\n \u003cli\u003e\u003cstrong\u003eMicrobiological Evidence of Recurrence\u003c/strong\u003e\u003c/li\u003e\n \u003c/ol\u003e\n \u003cp\u003eSputum sample taken after the EOT is smear positive OR GeneXpert positive (if \u0026gt;26 weeks after EOT); OR unconfirmed MGIT MTB positive culture;.\u003c/p\u003e\n \u003col start=\"4\" type=\"A\"\u003e\n \u003cli\u003e\u003cstrong\u003eConfirmed MTB Positive Sputum Culture\u0026nbsp;\u003c/strong\u003e\u003c/li\u003e\n \u003c/ol\u003e\n \u003cp\u003eSputum culture MTB positive on 2 consecutive samples, at least 7 days apart,.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStable Culture Conversion\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 444px;\"\u003e\n \u003cp\u003e2 negative results (at least 7 days apart without an intervening MTB positive). \u0026nbsp;If the first negative result occurs at Week 8, the Week 9 culture result can be used for the confirmatory negative result.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 157px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLost to Follow Up\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 444px;\"\u003e\n \u003cp\u003eShould a participant not be reachable to attend trial visits, the following should be conducted and documented in the site trial records before confirming a participant is lost to follow-up:\u003c/p\u003e\n \u003cul type=\"disc\"\u003e\n \u003cli\u003eThree documented telephone contact attempts (participant and/or relative).\u003c/li\u003e\n \u003cli\u003eLetter to be sent to the participant\u0026rsquo;s physical address via courier, or a similar process (adapted per country specific requirements/circumstances).\u003c/li\u003e\n \u003c/ul\u003e\n \u003cp\u003eIf no feedback is received within 30 days of courier confirmation of letter delivery to and receipt by the participant, then the participant may be considered lost to follow-up.\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\u003e\u003cstrong\u003eTable 3: List of countries, cities and site names.\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: 93px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCountry\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 143px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCity\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSite Name\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003eGeorgia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 143px;\"\u003e\n \u003cp\u003eTbilisi\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003eNational Center for Tuberculosis and Lung Diseases\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003ePhilippines\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 143px;\"\u003e\n \u003cp\u003eManila\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003eTropical Disease Foundation\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 143px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003eLung Center of Philippines\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 143px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003eCare Clinical Trial Group, Inc.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003eSouth Africa\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 143px;\"\u003e\n \u003cp\u003eBrits\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003eMadibeng Centre for Research\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 143px;\"\u003e\n \u003cp\u003eCape Town\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003eDesmond Tutu Health Foundation\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 143px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003eTASK Clinical Trials\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 143px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003eUniversity of Cape Town Lung Institute\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 143px;\"\u003e\n \u003cp\u003eDurban\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003eEnhancing Care Foundation\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 143px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003eTB and HIV Investigative Network\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 143px;\"\u003e\n \u003cp\u003eEast London\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003eSynergy Biomed Research Institute\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 143px;\"\u003e\n \u003cp\u003eGeorge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003eTASK Eden\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 143px;\"\u003e\n \u003cp\u003eJohannesburg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003eClinical HIV Research Unit, Helen Joseph Hospital\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 143px;\"\u003e\n \u003cp\u003eKlerksdorp\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003ePrenatal HIV Research Unit, Tshepong Hospital\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 143px;\"\u003e\n \u003cp\u003ePort Elizabeth\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003eIsango Lethemba TB Research Unit\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 143px;\"\u003e\n \u003cp\u003ePretoria\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003eSetshaba Research Centre\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 143px;\"\u003e\n \u003cp\u003eRustenburg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003eThe Aurum Institute\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003eTanzania\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 143px;\"\u003e\n \u003cp\u003eMbeya\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003eNational Institute for Medical Research, Mbeya\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 143px;\"\u003e\n \u003cp\u003eMoshi\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003eKilimanjaro Clinical Research Institute\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 143px;\"\u003e\n \u003cp\u003eMwanza\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003eNational Institute for Medical Research, Mwanza\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003eUganda\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 143px;\"\u003e\n \u003cp\u003eKampala\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003eJoint Clinical Research Institute\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 143px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003eCase Western Reserve University, Makerere University\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;Table 4.\u003c/p\u003e\n \u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"614\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCountry\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRA: Regulatory Authority\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eEC: Ethics Committee\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 189px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eName of RA or EC\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eReference Number\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eApproval\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eGeorgia\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eLocal EC\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 189px;\"\u003e\n \u003cp\u003eJSC National Centre of Tuberculosis and Lung Diseases Independent Ethics Committee\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e817/01-17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e26 Mar 2023\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eGeorgia\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eRA\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 189px;\"\u003e\n \u003cp\u003eLEPL Regulation Agency for Medical and Pharmaceutical Activities of Ministry of Internally Displaced Persons from the Occupied Territories, Labor, Health and Social Affairs of Georgia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e#000924\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e13 May 2023\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003ePhilippines\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eLocal EC\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 189px;\"\u003e\n \u003cp\u003eMakati Medical Centre Institutional Review Board\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eMMCIRB20 23-083\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e16 Aug 2023\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003ePhilippines\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eLocal EC\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 189px;\"\u003e\n \u003cp\u003eLung Centre Philippines Institutional Review Board\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eLCP-CT-015-2023\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e4 Jul 2023\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003ePhilippines\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eLocal EC\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 189px;\"\u003e\n \u003cp\u003eBatangas Medical Centre Research Ethics Review Committee\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eBatMC RERC 2024-\u003c/p\u003e\n \u003cp\u003e002\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e2 Jul 2024\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003ePhilippines\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eCentral EC\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 189px;\"\u003e\n \u003cp\u003eSingle Joint Research Ethics Board\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eSJREB-2023-62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e16 Aug 23\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003ePhilippines\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eRA\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 189px;\"\u003e\n \u003cp\u003ePhilippine Food and Drug Administration\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e2023-CT0791\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e9 Oct 2023\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eSouth Africa\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eCentral EC\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 189px;\"\u003e\n \u003cp\u003eWits Health Research Ethics Committee\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e230305\u003c/p\u003e\n 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style=\"width: 189px;\"\u003e\n \u003cp\u003eUniversity of Cape Town, Faculty of Human Sciences Human Research Ethics Committee\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e699/2023\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e28 Sep 2023\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eSouth Africa\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eCentral EC\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 189px;\"\u003e\n \u003cp\u003ePharma-Ethics\u0026nbsp;Health Research Ethics Committee\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e240626487-62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e29 Jul 2024\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n 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132px;\"\u003e\n \u003cp\u003eSZEC \u0026ndash; 2439/ R.A/ V.1/ 175\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e30 Mar 2023\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eTanzania\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eLocal EC\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 189px;\"\u003e\n \u003cp\u003eKilimanjaro Christian Medical Centre Research Ethics Committee\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eProposal number 1421\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e21 Jun 2023\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eTanzania\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n 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style=\"width: 132px;\"\u003e\n \u003cp\u003eHS2928ES\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e7 Aug 2023\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eUganda\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003eRA\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 189px;\"\u003e\n \u003cp\u003eUganda National Drug Authority\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eCTC 0248/2023\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e9 Aug 2023\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\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":"Sorfequiline, Bedaquiline, Pretomanid, Linezolid, Drug-Sensitive TB, Clinical trial","lastPublishedDoi":"10.21203/rs.3.rs-7298866/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7298866/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eIntroduction\u003c/b\u003e: In 2023, tuberculosis (TB) returned to being the world\u0026rsquo;s leading cause of death from a single infectious agent. Current standard of care for drug-sensitive tuberculosis (DS-TB) treatment has a long duration with risk of poor compliance and outcomes, and increased risk of development of resistant strains. Sorfequiline (S) is a second generation diarylquinoline with the potential to contribute both to increased efficacy and improved safety, and to a shorter TB treatment regimen for both DS-TB and drug-resistant (DR-TB).\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods and analysis\u003c/b\u003e: NC-009 is a phase 2, multi-centre, partially blinded, randomised clinical trial conducted in 5 treatment arms, including 3 doses of sorfequiline in combination with pretomanid and linezolid for 8 weeks followed by 7 or 18 weeks of HR depending on the participant meeting criteria to stop treatment at week 15. There is also a BPaL arm and standard of care arm, both for 26 weeks treatment duration. Study population is smear-positive, DS-TB. The primary objective of the study is to determine the optimal dose of sorfequiline to move forward to a potential phase 3 study based on efficacy and safety data. The study is being conducted in Georgia, South Africa, Tanzania, Uganda and the Philippines in accordance with ICH-GCP and after approval of all relevant country Health Authorities and Ethics Committees.\u003c/p\u003e\u003cp\u003e\u003cb\u003eDiscussion\u003c/b\u003e: NC-009 is a first-in-patient, dose-ranging, phase 2 trial of sorfequiline, with an innovative design combining ph2a, ph2b, and ph2c elements that simultaneously allows for dose selection, preliminary evaluation of treatment duration, robust collection of safety data, evaluation of drug-drug interaction with antiretroviral medications and pharmacokinetic assessment of study drugs. The study is currently ongoing.\u003c/p\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eTrial registration number {4}\u003c/span\u003e: ClinicalTrials.gov: NCT 06058299; Registered 09 September 2023; (URL: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://clinicaltrials.gov/study/NCT06058299?cond=tuberculosis\u0026amp;term=NC-009\u0026amp;rank=1\u003c/span\u003e\u003cspan address=\"https://clinicaltrials.gov/study/NCT06058299?cond=tuberculosis\u0026amp;term=NC-009\u0026amp;rank=1\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e)\u003c/span\u003e\u003c/p\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eProtocol version\u003c/span\u003e {2}: 03 Feb 2023 Version 1.0 (NC-009)\u003c/p\u003e","manuscriptTitle":"Protocol for a phase 2, partially-blinded, randomised trial assessing the safety and efficacy of sorfequiline or bedaquiline, in combination with pretomanid and linezolid in adult participants with newly diagnosed, drug-sensitive, smear-positive pulmonary tuberculosis (NC-009)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-08 07:49:18","doi":"10.21203/rs.3.rs-7298866/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2025-12-08T11:16:21+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-12-03T11:58:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-09T10:44:46+00:00","index":"","fulltext":""},{"type":"submitted","content":"Trials","date":"2025-09-09T06:12:49+00:00","index":"","fulltext":""},{"type":"decision","content":"Minor revision","date":"2025-08-22T02:08:58+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":"99f10e78-ab59-4f1a-93e7-86bd807de0f7","owner":[],"postedDate":"December 8th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-01-12T16:15:35+00:00","versionOfRecord":{"articleIdentity":"rs-7298866","link":"https://doi.org/10.1186/s13063-025-09413-5","journal":{"identity":"trials","isVorOnly":false,"title":"Trials"},"publishedOn":"2026-01-06 15:58:47","publishedOnDateReadable":"January 6th, 2026"},"versionCreatedAt":"2025-12-08 07:49:18","video":"","vorDoi":"10.1186/s13063-025-09413-5","vorDoiUrl":"https://doi.org/10.1186/s13063-025-09413-5","workflowStages":[]},"version":"v1","identity":"rs-7298866","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7298866","identity":"rs-7298866","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}