{"paper_id":"e6bdf0ff-ff89-4d63-9314-2c9e0daa2ab8","body_text":"panTB-HM: a clinical trial of a pan-TB regimen targeting both host and microbe | 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 panTB-HM: a clinical trial of a pan-TB regimen targeting both host and microbe Don Mudzengi, S Mashatole, Q Xiang, C Adrion, N Glover, T Ngwanto, and 28 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5943039/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 27 Feb, 2026 Read the published version in Trials → Version 1 posted 5 You are reading this latest preprint version Abstract Background Newer oxazolidinones will be required to advance regimens in pan-TB indications. The addition of host-directed agents may help promote the recovery of lung function during TB treatment and prevent post-TB lung disease. Methods The panTB-HM trial assesses the capacity of regimens containing the oxazolidinone sutezolid and the anti-oxidant N-acetylcysteine to meet the target criteria proposed by WHO for pan-TB indications in a phase 2C trial. Discussion This trial is ground-breaking in its objectives and design for a pan-TB indication and its evaluation of lung function recovery. Trial registration The protocol was first registered on clinicaltrials.gov as NCT05686356 on 13 Jan 2023. Figures Figure 1 Figure 2 Figure 3 Figure 4 Administrative Information The current protocol version is 7.0, 1 Aug 2024. Funding is through RIA2019AMR-2647 of the EDCTP2 Programme supported by the European Union. The Funder has no responsibility for the execution, analysis, or publication of study findings. Funding requires that the trial results are published, and that anonymized patient-level data be made available to outside investigators after the conclusion of the trial. The Aurum Institute serves as the trial Sponsor, and RSW as Sponsor’s Representative. The trial is considered an Academic trial in that the Sponsor has no financial, intellectual property or other ownership of sutezolid, N-acetylcysteine, or other study treatments. The panTB-HM Consortium jointly has the responsibility for study design; collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication. The trial received regulatory approvals from SAHPRA (ZA), TMDA (TZ), and ANARME (MZ), and ethics approvals from the Wits HREC, NMRI, and INS ethics committees in those countries. The trial is enrolling participants at the time of this submission. Participant evaluation and data analysis are expected to continue through the end of 2025. Introduction Tuberculosis is a leading global cause of morbidity and mortality ( 1 ). Current treatments are inadequate, requiring patients to closely adhere to multi-drug regimens that are long, complex, and often poorly tolerated and/or ineffective. Even if cured, most patients are left with bronchiectasis and fibrosis, permanent conditions that impair lung function and increase long-term mortality. These concerns are greatly magnified in rifampin-resistant (RIF-R) TB, for which the likelihood of microbiologic cure is reduced, and that of permanent lung impairment increased ( 1 – 3 ). In 2016, a WHO expert committee released a seminal report describing target profiles for new TB regimens (TRPs) ( 4 ). In addition to describing TRPs for rifampin-susceptible and rifampin-resistant disease, the report described characteristics of a third type of regimen, termed ‘pan-TB’, that could be used without knowledge of RIF susceptibility (Table 1 ). The targets for the optimal panTB regimen have since been updated to include yet shorter durations, but most characteristics (including the 4-month duration) remain highly relevant ( 5 ). Table 1 WHO priority attributes for pan-TB regimens. Excerpted from ( 4 ) Minimal Optimal Purpose: Potential go/no-go decision point. Needed to achieve greater global impact. Indication: 1st-line treatment without the requirement of determining RIF resistance. 1st-line treatment without the requirement of determining RIF resistance. Population: Adults and children irrespective of HIV status. Adults and children irrespective of HIV status. Efficacy: Not inferior to the RIF-S-TB standard of care in a 6-month regimen. Not inferior to the RIF-S-TB standard of care in a regimen of 4 months or less. Safety & Tolerability: Adverse events no worse than RIF-S standard of care. No more than monthly clinical monitoring and no laboratory monitoring for drug toxicity except in special populations. Adverse events better than RIF-S standard of care. No active clinical monitoring and no laboratory monitoring for drug toxicity except in special populations. No ECG monitoring of QT interval required. We here describe a study of a pan-TB regimen targeting both host and microbe (panTB-HM) in a parallel arm, open-label phase 2C clinical trial. The trial objectives are to determine the efficacy, safety, tolerability, and suitability of sutezolid, bedaquiline, pretomanid, and NAC (SBPN) in novel pan-TB regimens; to assess sutezolid daily doses of 1200 and 1600 mg with respect to safety and efficacy; to determine the contribution of NAC with respect to lung function, hepatic safety, and microbiologic efficacy of the regimen; to assess the hazard ratio for stable sputum culture conversion (HR-SCC) as a predictor of relapse risk in the context of TB regimen development; and to better understand the PK/PD and PK/TD (toxicodynamic) relationships of sutezolid and its metabolite in TB. The issues regarding the protocol discussed in this manuscript include: 1) the regimen composition and treatment arms; 2) the trial design; 3) the patient population; 4) the rationale for and definitions of the main endpoints; 5) safety considerations; and 6) the statistical analysis plan and sample size estimates. The full protocol, model consent form, and SPIRIT checklist accompany this manuscript as online supplements. Methods Regimen composition and treatment arms Success in a pan-TB indication requires that the new regimen be comprised of new drugs that lack pre-existing resistance; have a high barrier to new resistance; and show satisfactory efficacy, safety, and tolerability compared to the current standard of care. The drugs comprising the panTB-HM regimen were specifically selected to meet these criteria. Sutezolid . Oxazolidinones as a class demonstrate an extraordinarily high barrier to new resistance. This is perhaps best illustrated by the rarity of resistance to linezolid in S aureus isolates, despite the use of linezolid as a single agent to treat a wide range of serious methicillin-resistant staphylococcal infections for over 2 decades. Sutezolid (originally U-100480) differs from linezolid in only 1 atom. It has demonstrated safety and efficacy as a TB candidate in multiple preclinical studies ( 6 – 8 ) and in 4 phase 1 & 2 trials ( 9 – 12 ). Sutezolid has an active sulfoxide metabolite (U-100603) that is excreted renally. Sutezolid and U-100603 have minimal protein binding, no known PK DDIs, and no effect on hERG signalling or the QT interval. Sutezolid has a 9-fold lower MTB MIC 50 and a 3-fold higher IC 50 for inhibition of mitochondrial protein synthesis (MPS) vs linezolid, yielding a 24-fold improved therapeutic index (TI, 258 vs 11). This may account for the absence of hematologic toxicity in subjects given sutezolid at a total daily dose of 1200mg for 1–3 months during phase 1 and 2 trials ( 11 , 12 ). Linezolid, in contrast, typically causes thrombocytopenia, an early signal of mitochondrial toxicity, after 2 weeks at this dose ( 13 ). The optimal dosing schedule of sutezolid is not yet known. Dosing at 600mg BID and 1200mg QD showed similar early bactericidal activity ( 9 ). When given in combination with bedaquiline, delamanid, and moxifloxacin in the SUDOCU trial, doses of sutezolid up to 800mg BID were associated with increasing MGIT TTP slope, without an evident plateau ( 12 ). Sutezolid doses of 1200mg and 1600mg daily were selected for this trial. Bedaquiline and pretomanid. Sutezolid will be given in combination with the approved TB drugs bedaquiline (an inhibitor of mycobacterial ATP synthesis) and pretomanid (a nitroimidazole inhibitor of mycolic acid synthesis). In choosing a nitroimidazole, we considered pretomanid and delamanid as similarly safe and efficacious, although the two drugs have not yet been directly compared ( 14 – 16 ). Possible concerns regarding the hepatic safety of pretomanid were raised during the STAND trial conducted by the TB Alliance, in which 3 deaths due to acute liver failure occurred in approximately 216 patients receiving pretomanid, moxifloxacin, and pyrazinamide. However, subsequent studies of pretomanid, including Nix, ZeNix, and TB-Practecal, have not shown this safety signal. For example, in TB Practecal, grade 3 or higher hepatic disorders occurred in 10 of 73 control participants, but in only 3 of 72 participants receiving pretomanid, bedaquiline, linezolid plus moxifloxacin. In retrospect, the hepatic safety concerns of the STAND trial may have uniquely occurred due to the combination of pretomanid plus pyrazinamide. Patients in panTB-HM will not receive this combination. Bedaquiline and pretomanid will be used at approved doses: bedaquiline at 400mg QD for 14 days followed by 200mg TIW, and pretomanid at 200mg daily. N-acetylcysteine (NAC) has the distinction of being both a non-prescription anti-oxidant health supplement and a WHO essential medicine. Its main clinical use for the past half-century has been to prevent death due to massive hepatic necrosis after paracetamol (acetaminophen) poisoning. Widely-used protocols for this indication describe both oral and iv routes of administration ( 17 ). The FDA-recommended oral regimen typically gives a total of 90 grams of NAC over 72 hrs. NAC acts by restoring cellular levels of the reduced (free) form of glutathione (GSH), which is required to protect cells against damage by reactive oxygen species (ROS). ROS are produced in excess by MTB-infected cells. The oxidation and dimerization of GSH (2GSH + O − →GSSG + H 2 O) converts ROS to water, thereby protecting cells and tissues from pro-inflammatory necrotic death ( 18 , 19 ). However, the reaction consumes GSH. GSH synthesis requires cysteine, a sulfur-containing amino acid. Cysteine is a conditionally essential amino acid, as its rate of synthesis is insufficient to restore GSH lost during periods of sustained or severe oxidative stress. Cysteine is present in rather limited amounts in most omnivore diets and is nearly absent from vegetarian and vegan diets. NAC is a temperature-stable, orally bioavailable form of cysteine that can support GSH synthesis under conditions of sustained oxidative stress. The optimal dosing of NAC to restore GSH and promote recovery of lung function in TB is not known. In the NAC-TB trial, NAC 1200mg BID given during days 1-112 of TB treatment increased whole blood GSH and promoted recovery of FEV1 and FVC( 20 ). However, the effect on GSH was partial and did not persist after NAC treatment ceased (Fig. 1 ). NAC will be given at a dose of 1800mg BID in this trial. Treatment arms in the panTB-HM trial therefore consist of the following: 4S 1200 BP, 4S 1600 BP, 4S 1600 BPN, and 2HRZE/4HR. In this nomenclature, the numerals shown in ordinary script indicate nominal (4 week) months; those shown in subscript indicate the sutezolid dose in mg/day. The trial schema appears in Fig. 2 . We diverged from a full factorial design in omitting an S 1200 BPN arm, as we expected that similar benefits of NAC would be evident regardless of the sutezolid dose. Individuals meeting all entry criteria are randomly assigned to one of the 4 arms at a ratio of 1:1:1:1, with stratification by radiographic extent of disease and HIV status. Randomization was performed in blocks of 8 using an online system as part of the Viedoc trial database maintained by Tecro Research. A checklist of the SPIRIT reporting guidelines accompanies this manuscript as an online supplement ( 21 ). Patient population Participants will be persons aged 18 to 65 years of age, with RIF-S-TB diagnosed by molecular testing and confirmed by culture and phenotypic testing. Persons over age 65 years have been excluded due to age-related loss of FEV1; children have been excluded due to insufficient PK and safety data for sutezolid. RIF-S-TB is specified so that the efficacy and safety of the new regimen can be compared to standard TB treatment, thereby facilitating assessments specified in the WHO target regimen profile (Table 1 ). We anticipate that a future pivotal trial will include individuals with RIF-R-TB, to demonstrate similar results regardless of RIF susceptibility. HIV + TB cases are permitted, thereby ensuring that findings may be generalized to areas of the world where HIV co-infection is common in persons with active tuberculosis. Individuals with CD4 + T cell counts < 100/ul are excluded, due to the expectation that opportunistic infections that are common in this subpopulation may require diagnostic testing or specialized treatments that may not be uniformly available in low-resource settings. Individuals with a positive test for hepatitis B surface antigen are also excluded, as such individuals are at greater risk of superimposed drug-induced liver injury. We anticipate that such individuals would be included in a future pivotal trial. Trial endpoints The primary endpoint will be the proportions of participants achieving durable (non-relapsing) cure, assessed at 1 year post-end-of-treatment. We anticipate that relapse will be the main potential adverse outcome preventing durable cure in this trial, as it has in other trials of new short regimens such as REMox. By definition, accrual of relapses can only begin after treatment has ended. The cumulative likelihood of relapse increases with the duration of follow-up. For this reason, the main measurement of this outcome will be determined at week 72 for the control arm and at week 64 for the experimental arms. A sensitivity analysis will examine outcomes at week 72 across all arms. Relapse will be classified according to 3 levels of certainty: 1) confirmed, based on whole genome sequencing (WGS); 2) possible, based on MTB culture (requiring positive results from 2 specimens); and 3) suspected, based on clinical evidence. Initial and recurrence strains will be compared by whole genome sequence analysis to distinguish relapse from disease due to reinfection. Experimental treatments will be compared to control in a non-inferiority (NI) test. We have selected this endpoint despite the study’s relatively small sample size to best determine if any of the arms can meet WHO efficacy criteria for a pan-TB indication, showing a 4-month regimen to be non-inferior to a 6-month standard of care (HRZE). The most important secondary endpoints will be those assessing lung function, particularly FEV1, the maximal 1-second exhaled volume. FEV1 is most simply expressed as a volume, but it may be more meaningfully presented after adjustment for age, sex, race and height. Adjusted values may then be expressed as a percentage of predicted values, or as a Z-score (indicating the number of standard deviations from the mean) ( 22 – 27 ). Values expressed as % of expected values have the advantage that they are readily understood by a diverse readership; they have the disadvantage that some journals require that graphs of this parameter scale the vertical axis with limits of zero and 100%, despite the lack of clinical significance of these values. FEV1 loss has profound long-term health consequences regardless of the method used for presentation. Large cohort studies have confirmed that even sub-clinical loss of FEV1 is associated with excess mortality risk, even in persons without recognized lung disease ( 28 , 29 ). This is most pronounced in low-income countries where TB is most prevalent ( 28 ). Lung function endpoints in the experimental arms will be compared to those in the control arm in superiority comparisons. Safety outcomes. Optic neuropathy is an uncommon adverse effect of oxazolidinone treatment, most often occurring in linezolid-treated patients with MDR-TB ( 30 ). Risks increase in relation to cumulative linezolid dose and trough plasma concentrations and is thought to occur due to inhibition of mitochondrial protein synthesis. In one small study, mitochondrial toxicity occurred in all patients with linezolid trough levels > 2 mg/L ( 31 ). Most reported cases of linezolid optic neuropathy evolve over several weeks and improve after treatment is stopped. Sparse reports describe normal-appearing optic nerves on MRI, as is typical of toxic optic neuropathies generally ( 32 – 34 ). Neuromyelitis Optica (NMO) spectrum disorder is an uncommon antibody-mediated demyelinating disease manifesting as episodes of optic neuritis and transverse myelitis, often following viral or bacterial infections, including tuberculosis ( 35 ). Shortly after the start of enrolment, a trial participant experienced rapid vision loss and paralysis that ultimately was determined to be due to NMO, unrelated to the study treatment. The NMO diagnosis was confirmed by MRI, which showed characteristic diffuse symmetrical increased T2 signal throughout both optic nerves from the pre-chiasmal through retrobulbar portions, with corresponding diffuse gadolinium enhancement of the T1 signal of these areas. The episode confirmed the need for routine testing of visual acuity and color perception in trials of new oxazolidinones (including this trial) and underscored the importance of advanced imaging methods to diagnose this rare illness and differentiate it from drug toxicity. The trial schedule of enrollment, interventions, and assessments (SPIRIT) are shown in Fig. 3 . Statistical analysis and sample size The intent-to-treat (ITT) population will include all randomized patients who received at least 1 dose of study drug. The modified ITT (mITT) population will include the ITT population but exclude those patients wrongly enrolled ( ie , not meeting entry criteria). The per protocol (PP) population will include the mITT population but exclude those who did not receive at least 85% of assigned treatments. The reasons for exclusion from any population will be summarized. The ITT population is the main population for safety evaluations. The PP population will be the main population for efficacy analyses. Secondary efficacy analyses will be performed using the mITT population. Subgroup analyses will be performed according to baseline radiographic extent of disease and HIV status. Enrolment will be stratified according to HIV status and radiographic extent of disease. Experimental arms will be compared individually to the control arm. We consider this as an exploratory study that will require confirmation. For this reason, we will not adjust for multiple comparisons. All confidence intervals (CIs) will be reported as two-sided at the 95% confidence level. All testing for significance will be two-sided, using a threshold of P = 0.05. The proportion of patients achieving durable (non-relapsing) cure will be tested by the chi-square test, after adjustment for baseline differences as above. Additional analyses will be performed for 1) confirmed relapses, based on whole genome sequencing (WGS); 2) possible relapses, based on MTB culture; and 3) suspected relapses, based on clinical evidence. Analyses will be performed separately for PP and mITT populations. The main efficacy objective of panTB-HM is to determine if a regimen comprised of SBPN can meet WHO target characteristics for a pan-TB indication, showing efficacy not inferior to a RIF-S-TB standard of care in a duration of 4 months or less. We therefore approached this problem from a phase 2c perspective, looking to obtain phase 3 endpoint data from a phase 2-sized study. The comparison to the standard of care described by the WHO TRP is a non-inferiority (NI) comparison. Like superiority comparisons, NI comparisons calculate the difference between point estimates of experimental and control arms, determine the confidence interval of that difference, and test whether that interval crosses zero. However, for NI comparisons, another factor, delta (or NI margin) is added. Delta permits the lower bound of the confidence interval to cross zero by a specified amount yet still claim non-inferiority. Two justifications are given for the introduction of the delta. Regulators would like to know if a new drug is superior to a placebo, as this would be the most direct basis for licensing. However, they acknowledge that comparisons to placebo may become unethical once effective treatments are available. From this perspective, historical data may be used to estimate the efficacy of a placebo, and a value for delta selected to retain some portion of the difference from placebo. Clinicians, on the other hand, would like to know if a new drug has some unique other advantage, in which case a small reduction in efficacy might be considered an acceptable trade-off. This is particularly the case for treatment shortening in TB. This issue arose when the TB Alliance submitted the STAND trial (NCT02342886) to FDA for review. The trial sought to shorten treatment to 4 months with a regimen comprised of pretomanid, moxifloxacin, and pyrazinamide, with HRZE as the control regimen. The delta of 12% agreed by FDA is based on the clinical and public health value of a 4-month regimen, and the inclusion in the regimen of 2 new drugs (one new chemical entity, and one repurposed drug not yet approved for TB). These arguments are equally applicable to SBPN, which similarly is a 4-month regimen with one new and one repurposed drug. Most importantly, the new regimen brings to the table the possibility of superior recovery of lung function and prevention of long-term pulmonary morbidity and mortality. These outcomes have not previously been considered in trials of new TB drugs and regimens. We, therefore, examined the sample size requirements for a trial in a NI comparison with delta = 12%, using an online calculator based on the method of Blackwelder ( 36 , 37 ). The results, shown in Fig. 4 , indicate that the required sample size varies according to the success rate of the control arm and the difference between experimental and control. The x-axis indicates the efficacy in the control arm, and the lines with different colors represent the relative efficacy between the experimental and control arm. Given an expected success rate between 92–94% in the control arm, at 80% power, a trial with 80 subjects per arm is likely to be able to demonstrate non-inferiority so long as the point estimate of the experimental arm is no more than 1% worse than that of the control arm. If the success rate of the control arm is 95% or above, it could be up to 2% worse. These are acceptable parameters to proceed with the proposed sample size of 80 evaluable subjects per arm. The total sample size for this study would therefore ordinarily be 352 subjects, allowing for 10% lost or unevaluable. Trial status and timeline The project experienced several unexpected delays. We found it necessary to identify a new pharma partner to manufacture sutezolid due to changes in industry priorities regarding antimicrobial research and development. We ultimately were assisted in this regard through existing contracts of the TB Alliance. Recruitment began on 24 July 2023, but shortly afterwards a pause in enrollment was required by the Funders while a review of the findings of the SUDOCU was undertaken. Enrollment was again paused voluntarily while a review of the NMO SAE was completed. These delays amounted to a total of over 6 months. Additional sites in Rustenburg, Durban, and George were activated to compensate, but it remained unlikely that all participants would finish a full year of post-treatment follow-up within the funding period. To address this concern, we turned to a review by Nunn et al that examined results from 15 tuberculosis treatment trials initiated by the BMRC between 1970 and 1983 in Africa and East Asia involving 7305 participants ( 38 ). Of 574 relapses, 525 (91%) occurred within 12 months of stopping treatment; of these, 447 (85%) occurred within 6 months. The authors suggested that investigators should consider terminating follow-up after the last enrolled patient completes 6 months following treatment while continuing to follow patients enrolled earlier until that time. The authors concluded that compared to following all patients to 24 months, this approach would permit the total trial duration to be reduced by 18 months, with no increase in patient numbers in a non-inferiority design. We have adopted a similar strategy for the DRTB-HDT trial, permitting the period of post-treatment follow-up to be as short as 6 months for those participants enrolled in the last year of the trial. Readers will note from Fig. 3 that statistical power increases as the relapse rate in the control arm decreases. In our case, we felt this decrease was most accurately considered an artifact of the shortened duration of follow-up of some participants. We, therefore, increased the planned total enrolment to 374 to maintain the expected total number of recurrence cases. Enrollment was completed on 4 February 2025. The current protocol version is 7.0, 1 Aug 2024. Analysis of repeated lung function measurements Spirometry will be performed at multiple time points during and after treatment to broadly assess changes in respiratory function over time. Parameters will include FEV1, FVC, and FEV1/FVC, expressed as a Z score and as % of predicted. The longitudinal evolution of the outcomes of interest in the secondary endpoints will be evaluated using the linear mixed effect models with a hinge to reflect the change of the curve of lung function. We anticipate the hinge will be located at month 6 based on the evolution of lung function over time in the NAC-TB trial ( 20 ). This approach takes full advantage of repeated measurements without requiring the imputation of missing values. It exhibits substantially greater statistical power compared to testing at specific time points. Discussion Oxazolidinones with safety profiles superior to linezolid will be required to permit their use for pan-TB indications. Regimens with host-directed components may be best suited to help promote recovery of lung function and prevent post-TB lung disease. This trial will determine the potential for regimens containing sutezolid and NAC to meet the safety and efficacy criteria targeted by WHO in new pan-TB indications. We anticipate that one of the experimental arms will be selected to be advanced to a phase 3 trial. Declarations Acknowledgements The authors wish to thank the funders, our respective organizations, and the trial participants for making this effort possible. Authors' contributions RSW was responsible for obtaining funding and preparing the initial draft of this manuscript and of the trial protocol. DM was responsible for trial management, collecting authors' comments, and creating the final manuscript version. All the authors participated in regular meetings of the Trial Steering Committee and contributed to, reviewed and approved this manuscript. Funding Funding was provided by RIA2019AMR-2647 of the EDCTP2 Programme supported by the European Union. Availability of data and material Anonymized patient-level data will be made available to qualified investigators after the conclusion of the trial and the publication of its main findings. Ethics approval and consent to participate Ethics approval and written informed consent was obtained according to ICH and GCP guidelines. Consent for publication All authors give consent for publication. Competing interests None of the authors has any competing interests to declare. References World Health Organization. Global tuberculosis report. Geneva: WHO; 2023. Di Naso FC, Pereira JS, Schuh SJ, Unis G. [Functional evaluation in patients with pulmonary tuberculosis sequelae]. Rev Port Pneumol. 2011;17(5):216–21. Byrne AL, Marais BJ, Mitnick CD, Garden FL, Lecca L, Contreras C et al. Chronic airflow obstruction after successful treatment of multidrug-resistant tuberculosis. ERJ Open Res. 2017;3(3). WHO. Target regimen profiles for TB treatment. Geneva: WHO; 2016. Report No.: WHO/HTM/TB/2016.16. Lienhardt C, Dooley KE, Nahid P, Wells C, Ryckman TS, Kendall EA, et al. Target regimen profiles for tuberculosis treatment. Bull World Health Organ. 2024;102(8):600–7. Williams KN, Brickner SJ, Stover CK, Zhu T, Ogden A, Tasneen R, et al. Addition of PNU-100480 to first-line drugs shortens the time needed to cure murine tuberculosis. Am J Respir Crit Care Med. 2009;180(4):371–6. Williams KN, Stover CK, Zhu T, Tasneen R, Tyagi S, Grosset JH, et al. Promising anti-tuberculosis activity of the oxazolidinone PNU-100480 relative to linezolid in the murine model. Antimicrob Agents Chemother. 2009;53(4):1314–9. Wallis RS, Jakubiec W, Mitton-Fry M, Ladutko L, Campbell S, Paige D, et al. Rapid Evaluation in Whole Blood Culture of Regimens for XDR-TB Containing PNU-100480 (Sutezolid), TMC207, PA-824, SQ109, and Pyrazinamide. PLoS ONE. 2012;7(1):e30479. Wallis RS, Dawson R, Friedrich SO, Venter A, Paige D, Zhu T, et al. Mycobactericidal activity of sutezolid (PNU-100480) in sputum (EBA) and blood (WBA) of patients with pulmonary tuberculosis. PLoS ONE. 2014;9(4):e94462. Wallis RS, Jakubiec W, Kumar V, Bedarida G, Silvia A, Paige D, et al. Biomarker assisted dose selection for safety and efficacy in early development of PNU-100480 for tuberculosis. Antimicrob Agents Chemother. 2011;55(2):567–74. Wallis RS, Jakubiec W, Kumar V, Silvia AM, Paige D, Dimitrova D, et al. Pharmacokinetics and whole blood bactericidal activity against Mycobacterium tuberculosis of single ascending doses of PNU-100480 in healthy volunteers. J Infect Dis. 2010;202(5):745–51. Heinrich N, Manyama C, Ntinginya EN, Mpagama S, Liyoyo A, Mhimbira F, Feb et al. 19, 2023; Seattle. Seattle2023. French G. Safety and tolerability of linezolid. J Antimicrob Chemother. 2003;51(Suppl 2):ii45–53. Olayanju O, Esmail A, Limberis J, Dheda K. A regimen containing bedaquiline and delamanid compared to bedaquiline in patients with drug resistant tuberculosis. Eur Respir J. 2019. Conradie F, Diacon AH, Ngubane N, Howell P, Everitt D, Crook AM, et al. Treatment of Highly Drug-Resistant Pulmonary Tuberculosis. N Engl J Med. 2020;382(10):893–902. Dooley KE, Rosenkranz SL, Conradie F, Moran L, Hafner R, von Groote-Bidlingmaier F, et al. QT effects of bedaquiline, delamanid, or both in patients with rifampicin-resistant tuberculosis: a phase 2, open-label, randomised, controlled trial. Lancet Infect Dis. 2021;21(7):975–83. Smilkstein MJ, Knapp GL, Kulig KW, Rumack BH. Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. Analysis of the national multicenter study (1976 to 1985). N Engl J Med. 1988;319(24):1557–62. Amaral EP, Conceição EL, Costa DL, Rocha MS, Marinho JM, Cordeiro-Santos M, et al. N-acetyl-cysteine exhibits potent anti-mycobacterial activity in addition to its known anti-oxidative functions. BMC Microbiol. 2016;16(1):251. Palanisamy GS, Kirk NM, Ackart DF, Shanley CA, Orme IM, Basaraba RJ. Evidence for oxidative stress and defective antioxidant response in guinea pigs with tuberculosis. PLoS ONE. 2011;6(10):e26254. Wallis RS, Sabi I, Lalashowi J, Bakuli A, Mapamba D, Olomi W, et al. Adjunctive N-Acetylcysteine and Lung Function in Pulmonary Tuberculosis. NEJM Evid. 2024;3(9):EVIDoa2300332. Chan AW, Tetzlaff JM, Altman DG, Laupacis A, Gotzsche PC, Krle AJK, et al. SPIRIT 2013 Statement: defining standard protocol items for clinical trials. Rev Panam Salud Publica. 2015;38(6):506–14. Willcox PA, Ferguson AD. Chronic obstructive airways disease following treated pulmonary tuberculosis. Respir Med. 1989;83(3):195–8. Ralph AP, Kenangalem E, Waramori G, Pontororing GJ, Sandjaja, Tjitra E, et al. High morbidity during treatment and residual pulmonary disability in pulmonary tuberculosis: under-recognised phenomena. PLoS ONE. 2013;8(11):e80302. Meghji J, Simpson H, Squire SB, Mortimer K. A Systematic Review of the Prevalence and Pattern of Imaging Defined Post-TB Lung Disease. PLoS ONE. 2016;11(8):e0161176. Ross J, Ehrlich RI, Hnizdo E, White N, Churchyard GJ. Excess lung function decline in gold miners following pulmonary tuberculosis. Thorax. 2010;65(11):1010–5. Ehrlich RI, White N, Norman R, Laubscher R, Steyn K, Lombard C, et al. Predictors of chronic bronchitis in South African adults. Int J Tuberc Lung Dis. 2004;8(3):369–76. Byrne AL, Marais BJ, Mitnick CD, Lecca L, Marks GB. Tuberculosis and chronic respiratory disease: a systematic review. Int J Infect Dis. 2015;32:138–46. Duong M, Islam S, Rangarajan S, Leong D, Kurmi O, Teo K, et al. Mortality and cardiovascular and respiratory morbidity in individuals with impaired FEV1 (PURE): an international, community-based cohort study. Lancet Glob Health. 2019;7(5):e613–23. Schunemann HJ, Dorn J, Grant BJ, Winkelstein W Jr., Trevisan M. Pulmonary function is a long-term predictor of mortality in the general population: 29-year follow-up of the Buffalo Health Study. Chest. 2000;118(3):656–64. 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. Song T, Lee M, Jeon HS, Park Y, Dodd LE, Dartois V, et al. Linezolid Trough Concentrations Correlate with Mitochondrial Toxicity-Related Adverse Events in the Treatment of Chronic Extensively Drug-Resistant Tuberculosis. EBioMedicine. 2015;2(11):1627–33. Lee E, Burger S, Shah J, Melton C, Mullen M, Warren F, et al. Linezolid-associated toxic optic neuropathy: a report of 2 cases. Clin Infect Dis. 2003;37(10):1389–91. Agashe P, Doshi A. Linezolid induced optic neuropathy in a child treated for extensively drug resistant tuberculosis: A case report and review of literature. Saudi J Ophthalmol. 2019;33(2):188–91. Kanda T, Miyazaki A, Zeng F, Ueno Y, Sofue K, Maeda T, et al. Magnetic resonance imaging of intraocular optic nerve disorders: review article. Pol J Radiol. 2020;85:e67–81. Sellner J, Hemmer B, Muhlau M. The clinical spectrum and immunobiology of parainfectious neuromyelitis optica (Devic) syndromes. J Autoimmun. 2010;34(4):371–9. Sealed Envelope Ltd. Power calculator for binary outcome non-inferiority trials. 2012. Blackwelder WC. Proving the null hypothesis in clinical trials. Control Clin Trials. 1982;3(4):345–53. Nunn AJ, Phillips PP, Mitchison DA. Timing of relapse in short-course chemotherapy trials for tuberculosis. Int J Tuberc Lung Dis. 2010;14(2):241–2. Supplementary Files SPIRITchecklist.pdf panTBHMprotocolv729jul24clean.pdf Cite Share Download PDF Status: Published Journal Publication published 27 Feb, 2026 Read the published version in Trials → Version 1 posted Editorial decision: Minor revision 08 Sep, 2025 Reviewers agreed at journal 21 Jul, 2025 Reviewers invited by journal 09 May, 2025 Editor assigned by journal 06 Apr, 2025 First submitted to journal 03 Apr, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Funding is through RIA2019AMR-2647 of the EDCTP2 Programme supported by the European Union. The Funder has no responsibility for the execution, analysis, or publication of study findings. Funding requires that the trial results are published, and that anonymized patient-level data be made available to outside investigators after the conclusion of the trial. The Aurum Institute serves as the trial Sponsor, and RSW as Sponsor’s Representative. The trial is considered an Academic trial in that the Sponsor has no financial, intellectual property or other ownership of sutezolid, N-acetylcysteine, or other study treatments. The panTB-HM Consortium jointly has the responsibility for study design; collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication. The trial received regulatory approvals from SAHPRA (ZA), TMDA (TZ), and ANARME (MZ), and ethics approvals from the Wits HREC, NMRI, and INS ethics committees in those countries. The trial is enrolling participants at the time of this submission. Participant evaluation and data analysis are expected to continue through the end of 2025.\\u003c/p\\u003e\"},{\"header\":\"Introduction\",\"content\":\"\\u003cp\\u003eTuberculosis is a leading global cause of morbidity and mortality (\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e). Current treatments are inadequate, requiring patients to closely adhere to multi-drug regimens that are long, complex, and often poorly tolerated and/or ineffective. Even if cured, most patients are left with bronchiectasis and fibrosis, permanent conditions that impair lung function and increase long-term mortality. These concerns are greatly magnified in rifampin-resistant (RIF-R) TB, for which the likelihood of microbiologic cure is reduced, and that of permanent lung impairment increased (\\u003cspan additionalcitationids=\\\"CR2\\\" citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003eIn 2016, a WHO expert committee released a seminal report describing target profiles for new TB regimens (TRPs) (\\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e). In addition to describing TRPs for rifampin-susceptible and rifampin-resistant disease, the report described characteristics of a third type of regimen, termed \\u0026lsquo;pan-TB\\u0026rsquo;, that could be used without knowledge of RIF susceptibility (Table \\u003cspan refid=\\\"Tab1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e). The targets for the optimal panTB regimen have since been updated to include yet shorter durations, but most characteristics (including the 4-month duration) remain highly relevant (\\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab1\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 1\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eWHO priority attributes for pan-TB regimens. Excerpted from (\\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e)\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"3\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eMinimal\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eOptimal\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003ePurpose:\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003ePotential go/no-go decision point.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eNeeded to achieve greater global impact.\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eIndication:\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e1st-line treatment without the requirement of determining RIF resistance.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e1st-line treatment without the requirement of\\u0026nbsp;determining RIF resistance.\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003ePopulation:\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eAdults and children irrespective of HIV status.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eAdults and children irrespective of HIV status.\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eEfficacy:\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eNot inferior to the RIF-S-TB standard of care in a \\u003c/p\\u003e \\u003cp\\u003e\\u003cb\\u003e6-month\\u003c/b\\u003e regimen.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eNot inferior to the RIF-S-TB standard of care in a regimen of \\u003cb\\u003e4 months\\u003c/b\\u003e or less.\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eSafety \\u0026amp;\\u0026nbsp; \\u003c/p\\u003e \\u003cp\\u003eTolerability:\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eAdverse events \\u003cb\\u003eno worse\\u003c/b\\u003e than RIF-S standard of care. No more than monthly clinical monitoring and\\u0026nbsp;no laboratory monitoring for drug toxicity except in special populations.\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eAdverse events \\u003cb\\u003ebetter than\\u003c/b\\u003e RIF-S standard of care. No active clinical monitoring and no laboratory monitoring for drug toxicity except in special populations. No ECG monitoring of QT interval required.\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003cp\\u003eWe here describe a study of a pan-TB regimen targeting both host and microbe (panTB-HM) in a parallel arm, open-label phase 2C clinical trial. The trial objectives are to determine the efficacy, safety, tolerability, and suitability of sutezolid, bedaquiline, pretomanid, and NAC (SBPN) in novel pan-TB regimens; to assess sutezolid daily doses of 1200 and 1600 mg with respect to safety and efficacy; to determine the contribution of NAC with respect to lung function, hepatic safety, and microbiologic efficacy of the regimen; to assess the hazard ratio for stable sputum culture conversion (HR-SCC) as a predictor of relapse risk in the context of TB regimen development; and to better understand the PK/PD and PK/TD (toxicodynamic) relationships of sutezolid and its metabolite in TB.\\u003c/p\\u003e \\u003cp\\u003eThe issues regarding the protocol discussed in this manuscript include: 1) the regimen composition and treatment arms; 2) the trial design; 3) the patient population; 4) the rationale for and definitions of the main endpoints; 5) safety considerations; and 6) the statistical analysis plan and sample size estimates. The full protocol, model consent form, and SPIRIT checklist accompany this manuscript as online supplements.\\u003c/p\\u003e\"},{\"header\":\"Methods\",\"content\":\"\\u003cp\\u003eRegimen composition and treatment arms\\u003c/p\\u003e \\u003cp\\u003eSuccess in a pan-TB indication requires that the new regimen be comprised of new drugs that lack pre-existing resistance; have a high barrier to new resistance; and show satisfactory efficacy, safety, and tolerability compared to the current standard of care. The drugs comprising the panTB-HM regimen were specifically selected to meet these criteria.\\u003c/p\\u003e \\u003cp\\u003e \\u003cem\\u003eSutezolid\\u003c/em\\u003e. Oxazolidinones as a class demonstrate an extraordinarily high barrier to new resistance. This is perhaps best illustrated by the rarity of resistance to linezolid in \\u003cem\\u003eS aureus\\u003c/em\\u003e isolates, despite the use of linezolid as a single agent to treat a wide range of serious methicillin-resistant staphylococcal infections for over 2 decades. Sutezolid (originally U-100480) differs from linezolid in only 1 atom. It has demonstrated safety and efficacy as a TB candidate in multiple preclinical studies (\\u003cspan additionalcitationids=\\\"CR7\\\" citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e) and in 4 phase 1 \\u0026amp; 2 trials (\\u003cspan additionalcitationids=\\\"CR10 CR11\\\" citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e). Sutezolid has an active sulfoxide metabolite (U-100603) that is excreted renally. Sutezolid and U-100603 have minimal protein binding, no known PK DDIs, and no effect on hERG signalling or the QT interval. Sutezolid has a 9-fold lower MTB MIC\\u003csub\\u003e50\\u003c/sub\\u003e and a 3-fold higher IC\\u003csub\\u003e50\\u003c/sub\\u003e for inhibition of mitochondrial protein synthesis (MPS) \\u003cem\\u003evs\\u003c/em\\u003e linezolid, yielding a 24-fold improved therapeutic index (TI, 258 \\u003cem\\u003evs\\u003c/em\\u003e 11). This may account for the absence of hematologic toxicity in subjects given sutezolid at a total daily dose of 1200mg for 1\\u0026ndash;3 months during phase 1 and 2 trials (\\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e). Linezolid, in contrast, typically causes thrombocytopenia, an early signal of mitochondrial toxicity, after 2 weeks at this dose (\\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003eThe optimal dosing schedule of sutezolid is not yet known. Dosing at 600mg BID and 1200mg QD showed similar early bactericidal activity (\\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e). When given in combination with bedaquiline, delamanid, and moxifloxacin in the SUDOCU trial, doses of sutezolid up to 800mg BID were associated with increasing MGIT TTP slope, without an evident plateau (\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e). Sutezolid doses of 1200mg and 1600mg daily were selected for this trial.\\u003c/p\\u003e \\u003cp\\u003e \\u003cem\\u003eBedaquiline and pretomanid.\\u003c/em\\u003e Sutezolid will be given in combination with the approved TB drugs bedaquiline (an inhibitor of mycobacterial ATP synthesis) and pretomanid (a nitroimidazole inhibitor of mycolic acid synthesis). In choosing a nitroimidazole, we considered pretomanid and delamanid as similarly safe and efficacious, although the two drugs have not yet been directly compared (\\u003cspan additionalcitationids=\\\"CR15\\\" citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR16\\\" class=\\\"CitationRef\\\"\\u003e16\\u003c/span\\u003e). Possible concerns regarding the hepatic safety of pretomanid were raised during the STAND trial conducted by the TB Alliance, in which 3 deaths due to acute liver failure occurred in approximately 216 patients receiving pretomanid, moxifloxacin, and pyrazinamide. However, subsequent studies of pretomanid, including Nix, ZeNix, and TB-Practecal, have not shown this safety signal. For example, in TB Practecal, grade 3 or higher hepatic disorders occurred in 10 of 73 control participants, but in only 3 of 72 participants receiving pretomanid, bedaquiline, linezolid plus moxifloxacin. In retrospect, the hepatic safety concerns of the STAND trial may have uniquely occurred due to the combination of pretomanid plus pyrazinamide. Patients in panTB-HM will not receive this combination.\\u003c/p\\u003e \\u003cp\\u003eBedaquiline and pretomanid will be used at approved doses: bedaquiline at 400mg QD for 14 days followed by 200mg TIW, and pretomanid at 200mg daily.\\u003c/p\\u003e \\u003cp\\u003e\\u003cem\\u003eN-acetylcysteine\\u003c/em\\u003e (NAC) has the distinction of being both a non-prescription anti-oxidant health supplement and a WHO essential medicine. Its main clinical use for the past half-century has been to prevent death due to massive hepatic necrosis after paracetamol (acetaminophen) poisoning. Widely-used protocols for this indication describe both oral and iv routes of administration (\\u003cspan citationid=\\\"CR17\\\" class=\\\"CitationRef\\\"\\u003e17\\u003c/span\\u003e). The FDA-recommended oral regimen typically gives a total of 90 grams of NAC over 72 hrs. NAC acts by restoring cellular levels of the reduced (free) form of glutathione (GSH), which is required to protect cells against damage by reactive oxygen species (ROS). ROS are produced in excess by MTB-infected cells. The oxidation and dimerization of GSH (2GSH\\u0026thinsp;+\\u0026thinsp;O\\u003csup\\u003e\\u0026minus;\\u003c/sup\\u003e\\u0026rarr;GSSG\\u0026thinsp;+\\u0026thinsp;H\\u003csub\\u003e2\\u003c/sub\\u003eO) converts ROS to water, thereby protecting cells and tissues from pro-inflammatory necrotic death (\\u003cspan citationid=\\\"CR18\\\" class=\\\"CitationRef\\\"\\u003e18\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR19\\\" class=\\\"CitationRef\\\"\\u003e19\\u003c/span\\u003e). However, the reaction consumes GSH. GSH synthesis requires cysteine, a sulfur-containing amino acid. Cysteine is a conditionally essential amino acid, as its rate of synthesis is insufficient to restore GSH lost during periods of sustained or severe oxidative stress. Cysteine is present in rather limited amounts in most omnivore diets and is nearly absent from vegetarian and vegan diets. NAC is a temperature-stable, orally bioavailable form of cysteine that can support GSH synthesis under conditions of sustained oxidative stress.\\u003c/p\\u003e \\u003cp\\u003eThe optimal dosing of NAC to restore GSH and promote recovery of lung function in TB is not known. In the NAC-TB trial, NAC 1200mg BID given during days 1-112 of TB treatment increased whole blood GSH and promoted recovery of FEV1 and FVC(\\u003cspan citationid=\\\"CR20\\\" class=\\\"CitationRef\\\"\\u003e20\\u003c/span\\u003e). However, the effect on GSH was partial and did not persist after NAC treatment ceased (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e). NAC will be given at a dose of 1800mg BID in this trial.\\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003cp\\u003e \\u003cem\\u003eTreatment arms\\u003c/em\\u003e in the panTB-HM trial therefore consist of the following: 4S\\u003csub\\u003e1200\\u003c/sub\\u003eBP, 4S\\u003csub\\u003e1600\\u003c/sub\\u003eBP, 4S\\u003csub\\u003e1600\\u003c/sub\\u003eBPN, and 2HRZE/4HR. In this nomenclature, the numerals shown in ordinary script indicate nominal (4 week) months; those shown in subscript indicate the sutezolid dose in mg/day. The trial schema appears in Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e. We diverged from a full factorial design in omitting an S\\u003csub\\u003e1200\\u003c/sub\\u003eBPN arm, as we expected that similar benefits of NAC would be evident regardless of the sutezolid dose. Individuals meeting all entry criteria are randomly assigned to one of the 4 arms at a ratio of 1:1:1:1, with stratification by radiographic extent of disease and HIV status. Randomization was performed in blocks of 8 using an online system as part of the Viedoc trial database maintained by Tecro Research.\\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003cp\\u003eA checklist of the SPIRIT reporting guidelines accompanies this manuscript as an online supplement (\\u003cspan citationid=\\\"CR21\\\" class=\\\"CitationRef\\\"\\u003e21\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003ePatient population\\u003c/p\\u003e \\u003cp\\u003eParticipants will be persons aged 18 to 65 years of age, with RIF-S-TB diagnosed by molecular testing and confirmed by culture and phenotypic testing. Persons over age 65 years have been excluded due to age-related loss of FEV1; children have been excluded due to insufficient PK and safety data for sutezolid. RIF-S-TB is specified so that the efficacy and safety of the new regimen can be compared to standard TB treatment, thereby facilitating assessments specified in the WHO target regimen profile (Table \\u003cspan refid=\\\"Tab1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e). We anticipate that a future pivotal trial will include individuals with RIF-R-TB, to demonstrate similar results regardless of RIF susceptibility. HIV\\u0026thinsp;+\\u0026thinsp;TB cases are permitted, thereby ensuring that findings may be generalized to areas of the world where HIV co-infection is common in persons with active tuberculosis. Individuals with CD4\\u0026thinsp;+\\u0026thinsp;T cell counts\\u0026thinsp;\\u0026lt;\\u0026thinsp;100/ul are excluded, due to the expectation that opportunistic infections that are common in this subpopulation may require diagnostic testing or specialized treatments that may not be uniformly available in low-resource settings. Individuals with a positive test for hepatitis B surface antigen are also excluded, as such individuals are at greater risk of superimposed drug-induced liver injury. We anticipate that such individuals would be included in a future pivotal trial.\\u003c/p\\u003e \\u003cp\\u003eTrial endpoints\\u003c/p\\u003e \\u003cp\\u003e \\u003cem\\u003eThe primary endpoint\\u003c/em\\u003e will be the proportions of participants achieving durable (non-relapsing) cure, assessed at 1 year post-end-of-treatment. We anticipate that relapse will be the main potential adverse outcome preventing durable cure in this trial, as it has in other trials of new short regimens such as REMox. By definition, accrual of relapses can only begin after treatment has ended. The cumulative likelihood of relapse increases with the duration of follow-up. For this reason, the main measurement of this outcome will be determined at week 72 for the control arm and at week 64 for the experimental arms. A sensitivity analysis will examine outcomes at week 72 across all arms. Relapse will be classified according to 3 levels of certainty: 1) confirmed, based on whole genome sequencing (WGS); 2) possible, based on MTB culture (requiring positive results from 2 specimens); and 3) suspected, based on clinical evidence. Initial and recurrence strains will be compared by whole genome sequence analysis to distinguish relapse from disease due to reinfection. Experimental treatments will be compared to control in a non-inferiority (NI) test. We have selected this endpoint despite the study\\u0026rsquo;s relatively small sample size to best determine if any of the arms can meet WHO efficacy criteria for a pan-TB indication, showing a 4-month regimen to be non-inferior to a 6-month standard of care (HRZE).\\u003c/p\\u003e \\u003cp\\u003e \\u003cem\\u003eThe most important secondary endpoints\\u003c/em\\u003e will be those assessing lung function, particularly FEV1, the maximal 1-second exhaled volume. FEV1 is most simply expressed as a volume, but it may be more meaningfully presented after adjustment for age, sex, race and height. Adjusted values may then be expressed as a percentage of predicted values, or as a Z-score (indicating the number of standard deviations from the mean) (\\u003cspan additionalcitationids=\\\"CR23 CR24 CR25 CR26\\\" citationid=\\\"CR22\\\" class=\\\"CitationRef\\\"\\u003e22\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR27\\\" class=\\\"CitationRef\\\"\\u003e27\\u003c/span\\u003e). Values expressed as % of expected values have the advantage that they are readily understood by a diverse readership; they have the disadvantage that some journals require that graphs of this parameter scale the vertical axis with limits of zero and 100%, despite the lack of clinical significance of these values. FEV1 loss has profound long-term health consequences regardless of the method used for presentation. Large cohort studies have confirmed that even sub-clinical loss of FEV1 is associated with excess mortality risk, even in persons without recognized lung disease (\\u003cspan citationid=\\\"CR28\\\" class=\\\"CitationRef\\\"\\u003e28\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR29\\\" class=\\\"CitationRef\\\"\\u003e29\\u003c/span\\u003e). This is most pronounced in low-income countries where TB is most prevalent (\\u003cspan citationid=\\\"CR28\\\" class=\\\"CitationRef\\\"\\u003e28\\u003c/span\\u003e). Lung function endpoints in the experimental arms will be compared to those in the control arm in superiority comparisons.\\u003c/p\\u003e \\u003cp\\u003e \\u003cem\\u003eSafety outcomes.\\u003c/em\\u003e Optic neuropathy is an uncommon adverse effect of oxazolidinone treatment, most often occurring in linezolid-treated patients with MDR-TB (\\u003cspan citationid=\\\"CR30\\\" class=\\\"CitationRef\\\"\\u003e30\\u003c/span\\u003e). Risks increase in relation to cumulative linezolid dose and trough plasma concentrations and is thought to occur due to inhibition of mitochondrial protein synthesis. In one small study, mitochondrial toxicity occurred in all patients with linezolid trough levels\\u0026thinsp;\\u0026gt;\\u0026thinsp;2 mg/L (\\u003cspan citationid=\\\"CR31\\\" class=\\\"CitationRef\\\"\\u003e31\\u003c/span\\u003e). Most reported cases of linezolid optic neuropathy evolve over several weeks and improve after treatment is stopped. Sparse reports describe normal-appearing optic nerves on MRI, as is typical of toxic optic neuropathies generally (\\u003cspan additionalcitationids=\\\"CR33\\\" citationid=\\\"CR32\\\" class=\\\"CitationRef\\\"\\u003e32\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR34\\\" class=\\\"CitationRef\\\"\\u003e34\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003eNeuromyelitis Optica (NMO) spectrum disorder is an uncommon antibody-mediated demyelinating disease manifesting as episodes of optic neuritis and transverse myelitis, often following viral or bacterial infections, including tuberculosis (\\u003cspan citationid=\\\"CR35\\\" class=\\\"CitationRef\\\"\\u003e35\\u003c/span\\u003e). Shortly after the start of enrolment, a trial participant experienced rapid vision loss and paralysis that ultimately was determined to be due to NMO, unrelated to the study treatment. The NMO diagnosis was confirmed by MRI, which showed characteristic diffuse symmetrical increased T2 signal throughout both optic nerves from the pre-chiasmal through retrobulbar portions, with corresponding diffuse gadolinium enhancement of the T1 signal of these areas. The episode confirmed the need for routine testing of visual acuity and color perception in trials of new oxazolidinones (including this trial) and underscored the importance of advanced imaging methods to diagnose this rare illness and differentiate it from drug toxicity.\\u003c/p\\u003e \\u003cp\\u003eThe trial schedule of enrollment, interventions, and assessments (SPIRIT) are shown in Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig4\\\" class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003e.\\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003cp\\u003eStatistical analysis and sample size\\u003c/p\\u003e \\u003cp\\u003eThe intent-to-treat (ITT) population will include all randomized patients who received at least 1 dose of study drug. The modified ITT (mITT) population will include the ITT population but exclude those patients wrongly enrolled (\\u003cem\\u003eie\\u003c/em\\u003e, not meeting entry criteria). The per protocol (PP) population will include the mITT population but exclude those who did not receive at least 85% of assigned treatments. The reasons for exclusion from any population will be summarized. The ITT population is the main population for safety evaluations. The PP population will be the main population for efficacy analyses. Secondary efficacy analyses will be performed using the mITT population. Subgroup analyses will be performed according to baseline radiographic extent of disease and HIV status.\\u003c/p\\u003e \\u003cp\\u003eEnrolment will be stratified according to HIV status and radiographic extent of disease. Experimental arms will be compared individually to the control arm. We consider this as an exploratory study that will require confirmation. For this reason, we will not adjust for multiple comparisons. All confidence intervals (CIs) will be reported as two-sided at the 95% confidence level. All testing for significance will be two-sided, using a threshold of P\\u0026thinsp;=\\u0026thinsp;0.05. The proportion of patients achieving durable (non-relapsing) cure will be tested by the chi-square test, after adjustment for baseline differences as above. Additional analyses will be performed for 1) confirmed relapses, based on whole genome sequencing (WGS); 2) possible relapses, based on MTB culture; and 3) suspected relapses, based on clinical evidence. Analyses will be performed separately for PP and mITT populations.\\u003c/p\\u003e \\u003cp\\u003eThe main efficacy objective of panTB-HM is to determine if a regimen comprised of SBPN can meet WHO target characteristics for a pan-TB indication, showing efficacy not inferior to a RIF-S-TB standard of care in a duration of 4 months or less. We therefore approached this problem from a phase 2c perspective, looking to obtain phase 3 endpoint data from a phase 2-sized study. The comparison to the standard of care described by the WHO TRP is a non-inferiority (NI) comparison. Like superiority comparisons, NI comparisons calculate the difference between point estimates of experimental and control arms, determine the confidence interval of that difference, and test whether that interval crosses zero. However, for NI comparisons, another factor, delta (or NI margin) is added. Delta permits the lower bound of the confidence interval to cross zero by a specified amount yet still claim non-inferiority. Two justifications are given for the introduction of the delta. Regulators would like to know if a new drug is superior to a placebo, as this would be the most direct basis for licensing. However, they acknowledge that comparisons to placebo may become unethical once effective treatments are available. From this perspective, historical data may be used to estimate the efficacy of a placebo, and a value for delta selected to retain some portion of the difference from placebo. Clinicians, on the other hand, would like to know if a new drug has some unique other advantage, in which case a small reduction in efficacy might be considered an acceptable trade-off. This is particularly the case for treatment shortening in TB.\\u003c/p\\u003e \\u003cp\\u003eThis issue arose when the TB Alliance submitted the STAND trial (NCT02342886) to FDA for review. The trial sought to shorten treatment to 4 months with a regimen comprised of pretomanid, moxifloxacin, and pyrazinamide, with HRZE as the control regimen. The delta of 12% agreed by FDA is based on the clinical and public health value of a 4-month regimen, and the inclusion in the regimen of 2 new drugs (one new chemical entity, and one repurposed drug not yet approved for TB). These arguments are equally applicable to SBPN, which similarly is a 4-month regimen with one new and one repurposed drug. Most importantly, the new regimen brings to the table the possibility of superior recovery of lung function and prevention of long-term pulmonary morbidity and mortality. These outcomes have not previously been considered in trials of new TB drugs and regimens.\\u003c/p\\u003e \\u003cp\\u003eWe, therefore, examined the sample size requirements for a trial in a NI comparison with delta\\u0026thinsp;=\\u0026thinsp;12%, using an online calculator based on the method of Blackwelder (\\u003cspan citationid=\\\"CR36\\\" class=\\\"CitationRef\\\"\\u003e36\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR37\\\" class=\\\"CitationRef\\\"\\u003e37\\u003c/span\\u003e). The results, shown in Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig5\\\" class=\\\"InternalRef\\\"\\u003e4\\u003c/span\\u003e, indicate that the required sample size varies according to the success rate of the control arm and the difference between experimental and control. The x-axis indicates the efficacy in the control arm, and the lines with different colors represent the relative efficacy between the experimental and control arm. Given an expected success rate between 92\\u0026ndash;94% in the control arm, at 80% power, a trial with 80 subjects per arm is likely to be able to demonstrate non-inferiority so long as the point estimate of the experimental arm is no more than 1% worse than that of the control arm. If the success rate of the control arm is 95% or above, it could be up to 2% worse. These are acceptable parameters to proceed with the proposed sample size of 80 evaluable subjects per arm. The total sample size for this study would therefore ordinarily be 352 subjects, allowing for 10% lost or unevaluable.\\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003cp\\u003eTrial status and timeline\\u003c/p\\u003e \\u003cp\\u003eThe project experienced several unexpected delays. We found it necessary to identify a new pharma partner to manufacture sutezolid due to changes in industry priorities regarding antimicrobial research and development. We ultimately were assisted in this regard through existing contracts of the TB Alliance. Recruitment began on 24 July 2023, but shortly afterwards a pause in enrollment was required by the Funders while a review of the findings of the SUDOCU was undertaken. Enrollment was again paused voluntarily while a review of the NMO SAE was completed. These delays amounted to a total of over 6 months. Additional sites in Rustenburg, Durban, and George were activated to compensate, but it remained unlikely that all participants would finish a full year of post-treatment follow-up within the funding period. To address this concern, we turned to a review by Nunn \\u003cem\\u003eet al\\u003c/em\\u003e that examined results from 15 tuberculosis treatment trials initiated by the BMRC between 1970 and 1983 in Africa and East Asia involving 7305 participants (\\u003cspan citationid=\\\"CR38\\\" class=\\\"CitationRef\\\"\\u003e38\\u003c/span\\u003e). Of 574 relapses, 525 (91%) occurred within 12 months of stopping treatment; of these, 447 (85%) occurred within 6 months. The authors suggested that investigators should consider terminating follow-up after the last enrolled patient completes 6 months following treatment while continuing to follow patients enrolled earlier until that time. The authors concluded that compared to following all patients to 24 months, this approach would permit the total trial duration to be reduced by 18 months, with no increase in patient numbers in a non-inferiority design. We have adopted a similar strategy for the DRTB-HDT trial, permitting the period of post-treatment follow-up to be as short as 6 months for those participants enrolled in the last year of the trial. Readers will note from Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig4\\\" class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003e that statistical power increases as the relapse rate in the control arm decreases. In our case, we felt this decrease was most accurately considered an artifact of the shortened duration of follow-up of some participants. We, therefore, increased the planned total enrolment to 374 to maintain the expected total number of recurrence cases. Enrollment was completed on 4 February 2025.\\u003c/p\\u003e \\u003cp\\u003eThe current protocol version is 7.0, 1 Aug 2024.\\u003c/p\\u003e \\u003cp\\u003eAnalysis of repeated lung function measurements\\u003c/p\\u003e \\u003cp\\u003eSpirometry will be performed at multiple time points during and after treatment to broadly assess changes in respiratory function over time. Parameters will include FEV1, FVC, and FEV1/FVC, expressed as a Z score and as % of predicted. The longitudinal evolution of the outcomes of interest in the secondary endpoints will be evaluated using the linear mixed effect models with a hinge to reflect the change of the curve of lung function. We anticipate the hinge will be located at month 6 based on the evolution of lung function over time in the NAC-TB trial (\\u003cspan citationid=\\\"CR20\\\" class=\\\"CitationRef\\\"\\u003e20\\u003c/span\\u003e). This approach takes full advantage of repeated measurements without requiring the imputation of missing values. It exhibits substantially greater statistical power compared to testing at specific time points.\\u003c/p\\u003e\"},{\"header\":\"Discussion\",\"content\":\"\\u003cp\\u003eOxazolidinones with safety profiles superior to linezolid will be required to permit their use for pan-TB indications. Regimens with host-directed components may be best suited to help promote recovery of lung function and prevent post-TB lung disease. This trial will determine the potential for regimens containing sutezolid and NAC to meet the safety and efficacy criteria targeted by WHO in new pan-TB indications. We anticipate that one of the experimental arms will be selected to be advanced to a phase 3 trial.\\u003c/p\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003ch2\\u003eAcknowledgements\\u003c/h2\\u003e\\n\\u003cp\\u003eThe authors wish to thank the funders, our respective organizations, and the trial participants for making this effort possible.\\u003c/p\\u003e\\n\\u003ch2\\u003eAuthors' contributions\\u003c/h2\\u003e\\n\\u003cp\\u003eRSW was responsible for obtaining funding and preparing the initial draft of this manuscript and of the trial protocol. DM was responsible for trial management, collecting authors' comments, and creating the final manuscript version. All the authors participated in regular meetings of the Trial Steering Committee and contributed to, reviewed and approved this manuscript.\\u003c/p\\u003e\\n\\u003ch2\\u003eFunding\\u003c/h2\\u003e\\n\\u003cp\\u003eFunding was provided by RIA2019AMR-2647 of the EDCTP2 Programme supported by the European Union.\\u003c/p\\u003e\\n\\u003ch2\\u003eAvailability of data and material\\u003c/h2\\u003e\\n\\u003cp\\u003eAnonymized patient-level data will be made available to qualified investigators after the conclusion of the trial and the publication of its main findings.\\u003c/p\\u003e\\n\\u003ch2\\u003eEthics approval and consent to participate\\u003c/h2\\u003e\\n\\u003cp\\u003eEthics approval and written informed consent was obtained according to ICH and GCP guidelines.\\u003c/p\\u003e\\n\\u003ch2\\u003eConsent for publication\\u003c/h2\\u003e\\n\\u003cp\\u003eAll authors give consent for publication.\\u003c/p\\u003e\\n\\u003ch2\\u003eCompeting interests\\u003c/h2\\u003e\\n\\u003cp\\u003eNone of the authors has any competing interests to declare.\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\u003cli\\u003e\\u003cspan\\u003eWorld Health Organization. Global tuberculosis report. Geneva: WHO; 2023.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eDi Naso FC, Pereira JS, Schuh SJ, Unis G. [Functional evaluation in patients with pulmonary tuberculosis sequelae]. Rev Port Pneumol. 2011;17(5):216\\u0026ndash;21.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eByrne AL, Marais BJ, Mitnick CD, Garden FL, Lecca L, Contreras C et al. Chronic airflow obstruction after successful treatment of multidrug-resistant tuberculosis. ERJ Open Res. 2017;3(3).\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eWHO. Target regimen profiles for TB treatment. Geneva: WHO; 2016. Report No.: WHO/HTM/TB/2016.16.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eLienhardt C, Dooley KE, Nahid P, Wells C, Ryckman TS, Kendall EA, et al. Target regimen profiles for tuberculosis treatment. Bull World Health Organ. 2024;102(8):600\\u0026ndash;7.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eWilliams KN, Brickner SJ, Stover CK, Zhu T, Ogden A, Tasneen R, et al. Addition of PNU-100480 to first-line drugs shortens the time needed to cure murine tuberculosis. Am J Respir Crit Care Med. 2009;180(4):371\\u0026ndash;6.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eWilliams KN, Stover CK, Zhu T, Tasneen R, Tyagi S, Grosset JH, et al. Promising anti-tuberculosis activity of the oxazolidinone PNU-100480 relative to linezolid in the murine model. Antimicrob Agents Chemother. 2009;53(4):1314\\u0026ndash;9.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eWallis RS, Jakubiec W, Mitton-Fry M, Ladutko L, Campbell S, Paige D, et al. Rapid Evaluation in Whole Blood Culture of Regimens for XDR-TB Containing PNU-100480 (Sutezolid), TMC207, PA-824, SQ109, and Pyrazinamide. PLoS ONE. 2012;7(1):e30479.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eWallis RS, Dawson R, Friedrich SO, Venter A, Paige D, Zhu T, et al. Mycobactericidal activity of sutezolid (PNU-100480) in sputum (EBA) and blood (WBA) of patients with pulmonary tuberculosis. PLoS ONE. 2014;9(4):e94462.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eWallis RS, Jakubiec W, Kumar V, Bedarida G, Silvia A, Paige D, et al. Biomarker assisted dose selection for safety and efficacy in early development of PNU-100480 for tuberculosis. Antimicrob Agents Chemother. 2011;55(2):567\\u0026ndash;74.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eWallis RS, Jakubiec W, Kumar V, Silvia AM, Paige D, Dimitrova D, et al. Pharmacokinetics and whole blood bactericidal activity against Mycobacterium tuberculosis of single ascending doses of PNU-100480 in healthy volunteers. J Infect Dis. 2010;202(5):745\\u0026ndash;51.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eHeinrich N, Manyama C, Ntinginya EN, Mpagama S, Liyoyo A, Mhimbira F, Feb et al. 19, 2023; Seattle. Seattle2023.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eFrench G. Safety and tolerability of linezolid. J Antimicrob Chemother. 2003;51(Suppl 2):ii45\\u0026ndash;53.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eOlayanju O, Esmail A, Limberis J, Dheda K. A regimen containing bedaquiline and delamanid compared to bedaquiline in patients with drug resistant tuberculosis. Eur Respir J. 2019.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eConradie F, Diacon AH, Ngubane N, Howell P, Everitt D, Crook AM, et al. Treatment of Highly Drug-Resistant Pulmonary Tuberculosis. N Engl J Med. 2020;382(10):893\\u0026ndash;902.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eDooley KE, Rosenkranz SL, Conradie F, Moran L, Hafner R, von Groote-Bidlingmaier F, et al. QT effects of bedaquiline, delamanid, or both in patients with rifampicin-resistant tuberculosis: a phase 2, open-label, randomised, controlled trial. Lancet Infect Dis. 2021;21(7):975\\u0026ndash;83.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eSmilkstein MJ, Knapp GL, Kulig KW, Rumack BH. Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. Analysis of the national multicenter study (1976 to 1985). N Engl J Med. 1988;319(24):1557\\u0026ndash;62.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eAmaral EP, Concei\\u0026ccedil;\\u0026atilde;o EL, Costa DL, Rocha MS, Marinho JM, Cordeiro-Santos M, et al. N-acetyl-cysteine exhibits potent anti-mycobacterial activity in addition to its known anti-oxidative functions. BMC Microbiol. 2016;16(1):251.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003ePalanisamy GS, Kirk NM, Ackart DF, Shanley CA, Orme IM, Basaraba RJ. Evidence for oxidative stress and defective antioxidant response in guinea pigs with tuberculosis. PLoS ONE. 2011;6(10):e26254.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eWallis RS, Sabi I, Lalashowi J, Bakuli A, Mapamba D, Olomi W, et al. Adjunctive N-Acetylcysteine and Lung Function in Pulmonary Tuberculosis. NEJM Evid. 2024;3(9):EVIDoa2300332.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eChan AW, Tetzlaff JM, Altman DG, Laupacis A, Gotzsche PC, Krle AJK, et al. SPIRIT 2013 Statement: defining standard protocol items for clinical trials. Rev Panam Salud Publica. 2015;38(6):506\\u0026ndash;14.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eWillcox PA, Ferguson AD. Chronic obstructive airways disease following treated pulmonary tuberculosis. Respir Med. 1989;83(3):195\\u0026ndash;8.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eRalph AP, Kenangalem E, Waramori G, Pontororing GJ, Sandjaja, Tjitra E, et al. High morbidity during treatment and residual pulmonary disability in pulmonary tuberculosis: under-recognised phenomena. PLoS ONE. 2013;8(11):e80302.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eMeghji J, Simpson H, Squire SB, Mortimer K. A Systematic Review of the Prevalence and Pattern of Imaging Defined Post-TB Lung Disease. PLoS ONE. 2016;11(8):e0161176.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eRoss J, Ehrlich RI, Hnizdo E, White N, Churchyard GJ. Excess lung function decline in gold miners following pulmonary tuberculosis. Thorax. 2010;65(11):1010\\u0026ndash;5.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eEhrlich RI, White N, Norman R, Laubscher R, Steyn K, Lombard C, et al. Predictors of chronic bronchitis in South African adults. Int J Tuberc Lung Dis. 2004;8(3):369\\u0026ndash;76.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eByrne AL, Marais BJ, Mitnick CD, Lecca L, Marks GB. Tuberculosis and chronic respiratory disease: a systematic review. Int J Infect Dis. 2015;32:138\\u0026ndash;46.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eDuong M, Islam S, Rangarajan S, Leong D, Kurmi O, Teo K, et al. Mortality and cardiovascular and respiratory morbidity in individuals with impaired FEV1 (PURE): an international, community-based cohort study. Lancet Glob Health. 2019;7(5):e613\\u0026ndash;23.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eSchunemann HJ, Dorn J, Grant BJ, Winkelstein W Jr., Trevisan M. Pulmonary function is a long-term predictor of mortality in the general population: 29-year follow-up of the Buffalo Health Study. Chest. 2000;118(3):656\\u0026ndash;64.\\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\\u003eSong T, Lee M, Jeon HS, Park Y, Dodd LE, Dartois V, et al. Linezolid Trough Concentrations Correlate with Mitochondrial Toxicity-Related Adverse Events in the Treatment of Chronic Extensively Drug-Resistant Tuberculosis. EBioMedicine. 2015;2(11):1627\\u0026ndash;33.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eLee E, Burger S, Shah J, Melton C, Mullen M, Warren F, et al. Linezolid-associated toxic optic neuropathy: a report of 2 cases. Clin Infect Dis. 2003;37(10):1389\\u0026ndash;91.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eAgashe P, Doshi A. Linezolid induced optic neuropathy in a child treated for extensively drug resistant tuberculosis: A case report and review of literature. Saudi J Ophthalmol. 2019;33(2):188\\u0026ndash;91.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eKanda T, Miyazaki A, Zeng F, Ueno Y, Sofue K, Maeda T, et al. Magnetic resonance imaging of intraocular optic nerve disorders: review article. Pol J Radiol. 2020;85:e67\\u0026ndash;81.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eSellner J, Hemmer B, Muhlau M. The clinical spectrum and immunobiology of parainfectious neuromyelitis optica (Devic) syndromes. J Autoimmun. 2010;34(4):371\\u0026ndash;9.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eSealed Envelope Ltd. Power calculator for binary outcome non-inferiority trials. 2012.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eBlackwelder WC. Proving the null hypothesis in clinical trials. Control Clin Trials. 1982;3(4):345\\u0026ndash;53.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eNunn AJ, Phillips PP, Mitchison DA. Timing of relapse in short-course chemotherapy trials for tuberculosis. Int J Tuberc Lung Dis. 2010;14(2):241\\u0026ndash;2.\\u003c/span\\u003e\\u003c/li\\u003e\\u003c/ol\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":false,\"hideJournal\":false,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":true,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":true,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"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\":\"\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-5943039/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-5943039/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003cp\\u003e\\u003cstrong\\u003eBackground\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eNewer oxazolidinones will be required to advance regimens in pan-TB indications. The addition of host-directed agents may help promote the recovery of lung function during TB treatment and prevent post-TB lung disease.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eMethods\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe panTB-HM trial assesses the capacity of regimens containing the oxazolidinone sutezolid and the anti-oxidant N-acetylcysteine to meet the target criteria proposed by WHO for pan-TB indications in a phase 2C trial.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eDiscussion\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThis trial is ground-breaking in its objectives and design for a pan-TB indication and its evaluation of lung function recovery.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eTrial registration\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe protocol was first registered on clinicaltrials.gov as NCT05686356 on 13 Jan 2023.\\u003c/p\\u003e\",\"manuscriptTitle\":\"panTB-HM: a clinical trial of a pan-TB regimen targeting both host and microbe\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2025-05-14 06:49:36\",\"doi\":\"10.21203/rs.3.rs-5943039/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0},{\"type\":\"decision\",\"content\":\"Minor revision\",\"date\":\"2025-09-08T18:30:49+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"\",\"date\":\"2025-07-21T18:16:32+00:00\",\"index\":0,\"fulltext\":\"\"},{\"type\":\"reviewersInvited\",\"content\":\"\",\"date\":\"2025-05-09T11:19:59+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorAssigned\",\"content\":\"\",\"date\":\"2025-04-06T06:36:59+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"submitted\",\"content\":\"Trials\",\"date\":\"2025-04-03T16:47:12+00:00\",\"index\":\"\",\"fulltext\":\"\"}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"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\":\"ca792a91-f0a8-4a28-86d4-8c83521f77f6\",\"owner\":[],\"postedDate\":\"May 14th, 2025\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"published-in-journal\",\"subjectAreas\":[],\"tags\":[],\"updatedAt\":\"2026-03-02T16:02:48+00:00\",\"versionOfRecord\":{\"articleIdentity\":\"rs-5943039\",\"link\":\"https://doi.org/10.1186/s13063-026-09568-9\",\"journal\":{\"identity\":\"trials\",\"isVorOnly\":false,\"title\":\"Trials\"},\"publishedOn\":\"2026-02-27 15:57:14\",\"publishedOnDateReadable\":\"February 27th, 2026\"},\"versionCreatedAt\":\"2025-05-14 06:49:36\",\"video\":\"\",\"vorDoi\":\"10.1186/s13063-026-09568-9\",\"vorDoiUrl\":\"https://doi.org/10.1186/s13063-026-09568-9\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-5943039\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-5943039\",\"identity\":\"rs-5943039\",\"version\":[\"v1\"]},\"buildId\":\"8U1c8b4HqxoKbykW_rLl7\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}