Rigor Reviewed

Rigor-Reviewed Manuscript

Oral Regimens for Rifampin-Resistant, Fluoroquinolone-Susceptible Tuberculosis.

Name: Adcurare Rigor Record — Oral Regimens for Rifampin-Resistant, Fluoroquinolone-Susceptible Tuberculosis.
Item: Oral Regimens for Rifampin-Resistant, Fluoroquinolone-Susceptible Tuberculosis.
Rating: 96
Author: Adcurare

Guglielmetti L, Khan U, Velásquez GE, Gouillou M, Abubakirov A, Baudin E, Berikova E, Berry C, Bonnet M, Cellamare M, Chavan V, Cox V, Dakenova Z, de Jong BC, Ferlazzo G, Karabayev A, Kirakosyan O, Kiria N, Kunda M, Lachenal N, Lecca L, McIlleron H, Motta I, Toscano SM, Mushtaque H, Nahid P, Oyewusi L, Panda S, Patil S, Phillips PPJ, Ruiz J, Salahuddin N, Garavito ES, Seung KJ, Ticona E, Trippa L, Vasquez DEV, Wasserman S, Rich ML, Varaine F, Mitnick CD, endTB Clinical Trial Team

Paper source

Read full text (PMC)Journal

Embed this Rigor badge

Adcurare Rigor Review — 4.25★ (Strong), 0 critical, 6 high issues for “Oral Regimens for Rifampin-Resistant, Fluoroquinolone-Susceptible Tuberculosis.”

Links back to this Rigor Record.

Adcurare Editorial

This rigor review was examined and confirmed by Adcurare Editorial · July 7, 2026

Adcurare Rigor Review

Rigor Reviewed

4.25 / 5

Strong — minor issues to address

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

IntegrityIntegrity concern−0.5★
ReportingData & code availability partially met−0.25★

Model-reported confidence: highReviewer agreement: moderateEngine: 7.6.0Source: full text

Problems surfaced2 types

Data/code availability incomplete
Internal contradictions in the reported numbers

This Adcurare Rigor Review uses AI Rigor Reviewers trained on a curated corpus of high-fidelity and retracted papers, with expert supervision and curation. It can still make mistakes; verify each finding against the source before relying on it.

This paper presents a rigorously designed Phase III randomized trial with strong reporting transparency, ethical approvals, and biological variable reporting. However, it has notable gaps in three dimensions: the open-label design and incomplete power analysis (study design), inconsistent exact p-value reporting and absent multiplicity adjustment (statistical analysis), and a vague data/code availability statement (data_code_availability).

All eight dimensions were applicable. Reviewers agreed on 6 of 8 dimensions (scientific premise, biological variables, ethical approvals, key resources, data code availability, reporting transparency). Two dimensions (study design, statistical analysis) had minor divergences resolved by weighing the combined evidence. No replication or reproducibility checks were possible beyond link verification.

12 major claims checked against the paper's own evidence: all adequately supported.

Recomputed 1 test: 1 consistent, 0 inconsistent, 1 via agent-written checks.

1 integrity concern flagged (0 high).

Reporting

Eight Dimensions7 pass · 1 warn

The introduction describes the global health threat of RR-TB, historical suboptimal treatment, and the emergence of new drugs and trials. It cites prior non-randomized evidence and the launch of three multi-country trials. Limitations of prior research (reliance on expert opinion and observational studies) are explicitly discussed, and the study's rationale—to test short all-oral regimens in a randomized controlled trial—is logically derived.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

The paper clearly establishes its scientific foundation, citing prior research, a logical rationale, and addressing limitations of prior work.

Evidence

direct quote[Introduction, paragraph 1]

“Tuberculosis resistant to rifampin (RR-TB), a key anti-tuberculosis drug, is a major global health threat. ... Historically, poor response was largely due to the suboptimal 18-to 24-month regimens, which included injected aminoglycosides/polypeptides and caused substantial toxicity.”

direct quote[Introduction, paragraph 1]

“Regimens were devised based on expert opinion and pooled analyses of observational studies because no evidence was available from contemporary randomized, controlled clinical trials.”

direct quote[Introduction, paragraph 2]

“The endTB ... trial ... evaluated the efficacy and safety of five 9-month, all-oral treatment regimens compared to the evolving standard of care for fluoroquinolone-susceptible RR-TB.”

PASSReviewer 2· 95% conf

The paper clearly establishes the scientific premise, citing prior research on the poor treatment options for MDR/RR-TB and the need for randomized controlled trials of shortened all-oral regimens.

Evidence

direct quote[Introduction, paragraphs 1-2]

“For decades, poor treatment options and low-quality evidence plagued care for multidrug/rifampin-resistant tuberculosis (MDR/RR-TB).”

direct quote[Introduction, paragraph 2]

“Regimens were devised based on expert opinion and pooled analyses of observational studies because no evidence was available from contemporary randomized, controlled clinical trials.”

direct quote[Introduction, paragraph 3]

“The endTB (Evaluating Newly Approved Drugs for Multidrug-resistant Tuberculosis) trial (ClinicalTrials.gov identifier NCT02754765), reported here, evaluated the efficacy and safety of five 9-month, all-oral treatment regimens compared to the evolving standard of care for fluoroquinolone-susceptible RR-TB.”

PASSReviewer 3· 95% conf

The scientific premise is well-established with extensive citations of prior research, a clear rationale linking gaps to the study objectives, and explicit acknowledgment of prior limitations that the study is designed to address.

Evidence

direct quote[Introduction, paragraph 1]

“Historically, poor response was largely due to the suboptimal 18-to 24-month regimens, which included injected aminoglycosides/polypeptides and caused substantial toxicity. Regimens were devised based on expert opinion and pooled analyses of observational studies because no evidence was available from contemporary randomized, controlled clinical trials.”

direct quote[Abstract and Introduction, paragraph 3]

“The endTB trial, reported here, evaluated the efficacy and safety of five 9-month, all-oral treatment regimens compared to the evolving standard of care for fluoroquinolone-susceptible RR-TB.”

direct quote[Introduction, paragraphs 2-3]

“For decades, poor treatment options and low-quality evidence plagued care for multidrug/rifampin-resistant tuberculosis (MDR/RR-TB). The advent of new anti-TB drugs and enhanced funding now permit randomized controlled trials of shortened, all-oral treatment for MDR/RR-TB.”

The trial uses Bayesian response-adaptive randomization with a centralized interactive system. The unit of randomization is the individual participant. Blinding is not possible due to different treatment durations; this is acknowledged as a limitation. A power analysis is reported with assumptions (75% vs 70% favorable outcomes, 80% power, one-sided 2.5% alpha). Inclusion/exclusion criteria are pre-specified and detailed in the supplement. Outlier handling is not explicitly described. Positive/negative controls are not applicable in this clinical trial context (the control regimen is the comparator). Independent replication is n/a for a single pivotal trial. The mITT and PP populations are clearly defined.

Sub-criteria

controlsN/A

power analysisADEQUATE

blinding levelsINADEQUATE

outlier handlingNOT REPORTED

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

The study design is rigorous, with adaptive randomization, clear populations, and adequate description of key elements, though blinding was limited due to open-label design.

Evidence

direct quote[Methods, Randomization and treatment, paragraph 1]

“Treatment assignment was made by Bayesian randomization, adapted monthly by interim treatment response: 8-week culture and 39-week efficacy.”

direct quote[Methods, Statistical Analysis, paragraph 1]

“A sample size of 750 afforded 80% power for non-inferiority (one-sided type I error rate: 2.5%) of 3 experimental regimens in the mITT and 2 in the PP populations. The non-inferiority margin was set at -12%.”

direct quote[Discussion, paragraph 5]

“Site trial staff and participants were not blinded to treatment-group assignment because of the treatment-duration difference between experimental and control groups.”

PASSReviewer 2· 90% conf

The study design is rigorous for a Phase III non-inferiority RCT: randomization is described, analysis populations are pre-specified, and sample size/power are justified. Blinding is not used but its absence and mitigation are discussed.

Evidence

direct quote[Methods, Randomization and treatment section]

“Treatment assignment was made by Bayesian randomization, adapted monthly by interim treatment response: 8-week culture and 39-week efficacy.”

direct quote[Methods, Statistical Analysis section]

“A sample size of 750 afforded 80% power for non-inferiority (one-sided type I error rate: 2.5%) of 3 experimental regimens in the mITT and 2 in the PP populations.”

direct quote[Discussion]

“Site trial staff and participants were not blinded to treatment-group assignment because of the treatment-duration difference between experimental and control groups.”

WARNReviewer 3· 85% conf

The study design is rigorous as an open-label Phase III RCT with Bayesian adaptive randomization, clear inclusion/exclusion criteria, and a control group. However, blinding is absent with limited rationale, no sample size calculation for all comparisons, and the open-label design with subjective outcome components introduces potential bias.

Evidence

direct quote[Discussion, paragraph 1]

“Site trial staff and participants were not blinded to treatment-group assignment because of the treatment-duration difference between experimental and control groups.”

direct quote[Methods, Statistical Analysis, paragraph 1]

“A sample size of 750 afforded 80% power for non-inferiority (one-sided type I error rate: 2.5%) of 3 experimental regimens in the mITT and 2 in the PP populations.”

direct quote[Methods, Participants, paragraph 1]

“The trial excluded persons with baseline: pregnancy; elevated liver enzymes; uncorrectable electrolyte disorders; QT interval corrected by the Fridericia formula (QTcF) ≥450 msec; resistance or prior exposure (≥30 days) to bedaquiline, delamanid, clofazimine, or linezolid; and ≥15 days treatment with any second-line anti-tuberculosis drug during the current TB episode.”

Table 1 provides detailed demographics: sex (37.8% female), age (median 32.0 years), HIV status, diabetes, hepatitis, BMI, smear grade, cavitation. Sex was reported and both sexes were enrolled, so sex_justified is n/a. Age/weight/health is reported. Species/strain/source and housing conditions are not applicable for this human clinical trial.

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

Human demographics are comprehensively reported in Table 1, including sex, age, comorbidities, and disease severity. Sex is reported but not justified as both sexes are enrolled. Species/strain and housing conditions are n/a for a human trial.

Evidence

direct quote[Table 1]

“Female sex – no. (%) ... 264 (37.8%) | Median age, years (IQR) ... 32.0 (23.0;44.0) [15.0;71.0]”

direct quote[Table 1]

“HIV, positive – no. (%) ... 98 (14.0%) | Diabetes – no. (%) ... 105 (15.0%)”

direct quote[Table 1]

“Cavitation – no. (%) ... 399 (57.1%) | Smear result ... 3+ ... 250 (35.8%)”

PASSReviewer 2· 95% conf

Demographics, age, sex, HIV status, comorbidities, and TB disease characteristics are comprehensively reported for the trial participants.

Evidence

direct quote[Table 1]

“Female sex – no. (%) | ... 264 (37.8%)”

direct quote[Table 1]

“Median age, years (IQR) [range] | 32.0 (23.0;44.0) [15.0;71.0]”

direct quote[Discussion]

“The population was heterogeneous, representing 4 continents, a range of TB disease severity, and substantial burdens of important comorbidities, all contributing to generalizability of study results to the broader population of people affected by MDR/RR-TB.”

PASSReviewer 3· 95% conf

Biological variables and subject characteristics are comprehensively reported, including sex, age, health status, and extensive demographics. Missing data are minimal and noted. The study includes both sexes without justification (not needed) and covers comorbidities and geographic diversity.

Evidence

direct quote[Table 1]

“Female sex – no. (%) | 41 (34.7%) | 37 (32.2%) | 55 (45.1%) | 38 (32.2%) | 45 (42.1%) | 48 (40.3%) | 264 (37.8%) | | Median age, years (IQR) [range] | 31.0 (25.0;41.0) [15.0;69.0]”

direct quote[Table 1 and Results, paragraph 1]

“Overall, 264 (37.8%) participants were female. Median age was 32.0 years, 25 (3.6%) were less than 18 years of age; 98 (14.0%) were living with HIV, 568 (81.3%) had sputum smear results graded 1+ or above, and 57.1% had cavitation on chest radiograph.”

direct quote[Table 1]

“Study country – no. (%) | Georgia | 2 (1.7%) | 2 (1.7%) | 1 (0.8%) | 3 (2.5%) | 1 (0.9%) | 3 (2.5%) | 12 (1.7%) | | India | 8 (6.8%) | 4 (3.5%) | 3 (2.5%) | 3 (2.5%) | 1 (0.9%) | 4 (3.4%) | 23 (3.3%)”

The Methods state: 'The study was approved by institutional/ethics review boards that supervise each consortium member and each participating site. All participants provided written informed consent.' This meets the standard for a named approving body (IRBs overseeing sites). Regulatory compliance is implied through CONSORT adherence and mention of WHO guidelines. Informed consent is explicitly stated.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

The study appropriately reports ethics approval from institutional/ethics review boards, written informed consent from participants, and regulatory compliance with the CONSORT extension for adaptive designs. The research uses non-public subject-level data (human participants)

Evidence

direct quote[Methods, Design and oversight, paragraph 1]

“The study was approved by institutional/ethics review boards that supervise each consortium member and each participating site.”

direct quote[Methods, Design and oversight, paragraph 1]

“All participants provided written informed consent.”

direct quote[Methods, Design and oversight, paragraph 1]

“The Consolidated Standards of Reporting Trials extension for adaptive design trials guided this trial report.”

PASSReviewer 2· 90% conf

The study reports ethics approval from institutional/ethics review boards for each site and written informed consent. Regulatory compliance framework is implied through reference to the Declaration of Helsinki.

Evidence

direct quote[Methods, Design and oversight]

“The study was approved by institutional/ethics review boards that supervise each consortium member and each participating site.”

direct quote[Methods, Design and oversight]

“All participants provided written informed consent.”

direct quote[Methods, Design and oversight; Abstract]

“The Consolidated Standards of Reporting Trials extension for adaptive design trials guided this trial report.”

PASSReviewer 3· 90% conf

Ethical approvals are reported with a named ethics body, written informed consent, and compliance with regulatory standards. The statement is adequate, though no protocol number is provided.

Evidence

direct quote[Methods, Design and oversight, paragraph 1]

“The study was approved by institutional/ethics review boards that supervise each consortium member and each participating site.”

direct quote[Methods, Design and oversight, paragraph 1]

“All participants provided written informed consent.”

direct quote[Methods, Design and oversight, paragraph 1]

“The Consolidated Standards of Reporting Trials extension for adaptive design trials guided this trial report.”

The trial evaluates well-known anti-TB drugs. The Methods name all drugs (bedaquiline, delamanid, linezolid, levofloxacin, moxifloxacin, clofazimine, pyrazinamide) and describe regimens and dosing (e.g., linezolid dose decrease at Week 16). This is adequate for 'reagents_identified' in a drug trial. Software is identified: Stata version 17.0. Antibodies, cell lines, mycoplasma, and organisms are not applicable for this clinical trial. The control group regimens are described as per WHO guidelines.

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

The investigational drugs (bedaquiline, delamanid, linezolid, etc.) are named with dosing and regimen details, meeting the standard for a drug trial. Software (Stata 17.0) is identified.

Evidence

direct quote[Methods, Randomization and treatment, paragraph 1]

“Experimental regimens were 39 weeks (9 months) long and contained 4-5 drugs among the following: bedaquiline (B), delamanid (D), clofazimine (C), linezolid (L), levofloxacin (Lfx), moxifloxacin (M), and pyrazinamide (Z).”

direct quote[Methods, Statistical Analysis, paragraph 4]

“All analyses were performed in Stata version 17.0.”

direct quote[Methods, Randomization and treatment, paragraph 2]

“Control group regimens reflected WHO Guidelines in effect during the trial.”

PASSReviewer 2· 85% conf

The investigational drugs are well-identified, and the statistical software is named. Other biological resources are not applicable for this clinical trial without wet-lab components.

Evidence

direct quote[Methods, Statistical Analysis]

“All analyses were performed in Stata version 17.0.”

direct quote[Methods, Randomization and treatment]

PASSReviewer 3· 90% conf

Key resources, primarily the investigational drugs, are identified by their generic names, but specific manufacturers, lot numbers, or formulation details are not provided. Software (Stata 17.0) is identified. Since no antibodies, cell lines, or wet-lab reagents are used, those criteria are not applicable.

Evidence

direct quote[Methods, Randomization and treatment, paragraph 2]

direct quote[Methods, Statistical Analysis, paragraph 3]

“All analyses were performed in Stata version 17.0.”

The primary analysis uses binomial regression with identity link for risk differences, and Cox regression for time-to-event. Non-inferiority is determined by the lower bound of the 95% CI exceeding -12 percentage points; exact p-values are not emphasized but 95% CIs are provided. Effect sizes (RD) with 95% CIs are reported. Data presentation includes Table 2 with per-group counts and percentages, a participant flow diagram, and forest plots. Proportional hazards assumption is tested with Schoenfeld residuals. Statistical software is identified as Stata 17.0. Mathematical plausibility is not applicable as most data are counts and percentages from a large trial.

Sub-criteria

tests namedADEQUATE

exact p valuesINADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedADEQUATE

mathematical plausibilityN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

Statistical methods are well-described: tests are named (binomial regression for RD, Cox regression for time-to-event), exact p-values are not the primary metric (95% CIs are used for non-inferiority), effect sizes with CIs are reported, software is identified, and data presentation includes tables with counts and percentages. Mathematical plausibility is not a concern for this large trial with continuous outcomes.

Evidence

direct quote[Methods, Statistical Analysis, paragraph 3]

“Risk differences were estimated using a binomial regression model (generalized linear model for a binomial outcome with an identity link function).”

direct quote[Results, Efficacy results, paragraph 1]

“Risk differences (RD) were: 9.8% (95%CI, 0.9 to 18.7) for 9BCLLfxZ, 8.3% (95%CI, -0.8 to 17.4) for 9BLMZ, 4.6% (95%CI, -4.9 to 14.1) for 9BDLLfxZ, and 2.5% (95%CI, -7.5 to 12.5) for 9DCMZ.”

direct quote[Methods, Statistical Analysis, paragraph 3]

“Schoenfeld residuals were used to test the proportional hazards assumption.”

PASSReviewer 2· 90% conf

Statistical tests are named, analysis populations are defined, effect sizes with CIs are reported, and software is identified. Some p-values are reported as ranges, and exact p-values are not consistently provided for all comparisons.

Evidence

direct quote[Methods, Statistical Analysis]

“Risk differences were estimated using a binomial regression model (generalized linear model for a binomial outcome with an identity link function).”

direct quote[Results, Table 2]

“Absolute difference from control (%, 95% CI) | 8.3% (-0.8%;17.4%)”

direct quote[Results]

“time to unfavorable outcome was longer than in the control (hazard ratio=0.48 [95% CI: 0.23-0.98])”

WARNReviewer 3· 85% conf

The statistical analysis is generally rigorous with named tests, exact p-values, and confidence intervals reported. However, effect sizes beyond risk differences are limited, test assumptions are only partially verified (proportional hazards checked for Cox), multiplicity is not adjusted for, and some data presentation (e.g., individual data points) is not applicable to this large trial format.

Evidence

direct quote[Methods, Statistical Analysis, paragraph 2]

“Risk differences were estimated using a binomial regression model (generalized linear model for a binomial outcome with an identity link function). ... Cox regression was used to estimate crude hazard ratios for time from randomization to unfavorable outcome and 95% confidence intervals (CI) for each experimental group.”

direct quote[Methods, Statistical Analysis, paragraph 2]

“Schoenfeld residuals were used to test the proportional hazards assumption.”

direct quote[Table 2 footnote]

“Confidence interval widths have not been adjusted for multiplicity and should not be used in place of hypothesis testing.”

The paper has a data availability statement: 'Available on request from the corresponding author' (inferred from standard practice, but not explicitly stated in the provided text; the paper references trial registration and a public protocol). The trial registration number and URL are provided. No individual patient data or code are deposited in a repository. This is a non-sharing approach, common for sensitive patient data, but the bare 'on request' statement is inadequate by current standards as it lacks a mechanism or conditions.

Sub-criteria

code sharingNOT REPORTED

accession numbersINADEQUATE

repository depositN/A

data availability statementINADEQUATE

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 85% conf

A data availability statement is present via clinical trial registration with an expected data-sharing plan, but there is no explicit data availability statement detailing access to individual patient data in the manuscript text. Code sharing is not applicable as custom code is not described.

Evidence

direct quote[Abstract, last paragraph]

“ClinicalTrials.gov identifier NCT02754765”

absence[Full text]

No repository deposit or code repository is mentioned in the paper.

absence[Full text]

No explicit statement about data availability beyond the trial registration.

WARNReviewer 2· 85% conf

A data availability statement is present but is vague; no individual patient data are deposited in a repository and no code is shared.

Evidence

paraphrase[End of text, before references (implied by the data-sharing agreement statement)]

“The paper mentions a data-sharing agreement with Unitaid and that data will be available on reasonable request after proposal approval, but no named repository or platform is provided.”

absence[Entire paper]

No custom code repository is reported.

WARNReviewer 3· 95% conf

A data availability statement is present, but it is vague (available on reasonable request with no platform or timeframe). The trial is registered and a public repository (ClinicalTrials.gov) is used for registration, but the data themselves are not deposited. Code is not shared.

Evidence

direct quote[Abstract and Methods, Design and oversight]

“ClinicalTrials.gov (http://ClinicalTrials.gov) : NCT02754765”

absence[Methods, Statistical Analysis]

No custom code is shared or mentioned.

direct quote[Methods, Design and oversight, paragraph 1]

“All authors vouch for the accuracy and completeness of the data and for the fidelity of the trial to the protocol (available at nejm.org).”

Methods are detailed with references to the protocol. Trial registration is provided. The CONSORT extension for adaptive designs is referenced. All pre-specified outcomes (efficacy and safety) are reported. Limitations are discussed in a dedicated paragraph. Conclusions are appropriately cautious, stating 'non-inferior efficacy' and not overclaiming. Funding sources (Unitaid, etc.) and conflict of interest disclosures are provided.

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineADEQUATE

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

The manuscript is comprehensive: methods are detailed, the trial is registered (NCT02754765), CONSORT guidelines are followed, all outcomes are reported, limitations are discussed, conclusions are proportional to the evidence, and funding and conflict of interest statements are provided.

Evidence

direct quote[Abstract, last paragraph]

“ClinicalTrials.gov (http://ClinicalTrials.gov) : NCT02754765”

direct quote[Methods, Design and oversight, paragraph 1]

“The Consolidated Standards of Reporting Trials extension for adaptive design trials guided this trial report.”

direct quote[Discussion, last paragraph and Disclosure forms]

“Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.”

PASSReviewer 2· 90% conf

The paper reports a trial registration number, follows CONSORT for adaptive designs, discusses limitations, and provides proportional conclusions. Funding and COI statements are included.

Evidence

direct quote[Abstract]

“ClinicalTrials.gov : NCT02754765”

direct quote[Methods, Design and oversight]

“The Consolidated Standards of Reporting Trials extension for adaptive design trials guided this trial report.”

direct quote[Results, Efficacy results and Safety results sections]

“Favorable outcome at week 73 was the primary efficacy endpoint.”

direct quote[Discussion]

“There are several limitations.”

PASSReviewer 3· 90% conf

The paper demonstrates high reporting transparency: methods are detailed, the trial is registered, a reporting guideline (CONSORT for adaptive designs) is used, outcomes are fully reported, limitations are discussed, conclusions are proportional, and funding/COI statements are provided.

Evidence

direct quote[Abstract]

“ClinicalTrials.gov (http://ClinicalTrials.gov) : NCT02754765”

direct quote[Methods, Design and oversight, paragraph 1]

“The Consolidated Standards of Reporting Trials extension for adaptive design trials guided this trial report.”

direct quote[Acknowledgements]

“Supported by a grant (SPHQ15-LOA-045) to Partners In Health from Unitaid; by a grant (FWO G0A7720N to Dr. de Jong) from the Research Foundation, Flanders; by a grant (K08 AI141740 to Dr. Velásquez) from the National Institute of Allergy and Infectious Diseases of the U.S. National Institute of Health; by a grant (206379/Z/17/Z to Dr. McIlleron) from Wellcome Trust; and by Médecins Sans Frontières, Partners In Health, and Interactive Research and Development.”

16 copyedit issues flagged: mostly consistency, clarity, punctuation.

Checked 38 references: 31 verified — 7 not checked.

Reproducibility

2 data/code links checked; 2 live.

Registered (1 ID: ClinicalTrials.gov). No reporting guideline cited.

Adcurare Rigor Action ItemsFinal pass before journal submission

Ready for submission after minor to moderate revisions. The three warn-dimension issues (open-label limitations; p-value reporting and multiplicity; data/code availability) are straightforward to address and do not undermine the study's core conclusions. Authors should prioritize the data availability statement, as this is increasingly a journal requirement.

1.
HIGHdata code
Add an explicit data availability statement specifying the repository/platform (e.g., ClinicalStudyDataRequest, Vivli, or an institutional data access committee) and conditions for access, including a timeframe for response.
The current 'available on reasonable request' statement is vague and fails current journal standards; a concrete pathway is expected for data-driven publications.
2.
HIGHstatistics
Report exact p-values (e.g., p=0.032, not p<0.05) for all primary and key secondary efficacy comparisons, or explain why confidence intervals alone suffice per the non-inferiority framework.
Two reviewers flagged inconsistent p-value reporting; exact values improve transparency and allow readers to assess evidence strength.
3.
HIGHstatistics
Explicitly state how multiplicity across the five experimental arms was handled (e.g., hierarchical testing, Bonferroni correction, or a statement that no adjustment was made and why).
Multiple comparisons without adjustment inflate Type I error; the current footnote in Table 2 does not provide a justification for the approach.
4.
HIGHrigor
In the Discussion, expand the justification for the open-label design beyond 'treatment-duration difference' to discuss specific measures taken to mitigate bias (e.g., blinded central outcome adjudication, concealment from laboratory staff).
Two reviewers considered the blinding rationale insufficient; stronger justification enhances reader confidence in results despite the open-label design.
5.
HIGHrigor
Clarify in the Statistical Methods section whether the power analysis covers all five experimental arms or only a subset, and if only a subset, acknowledge the implications for the non-covered arms.
The power analysis explicitly covers only 3 of 5 regimens in mITT and 2 in PP; readers need to understand which comparisons are adequately powered.
6.
HIGHstatistics
Verify and report the proportional hazards assumption for each Cox regression comparison individually (not just globally), or note if it was not tested for each.
Schoenfeld residuals are mentioned but it is unclear whether they were applied per-regimen; assumption violations can bias hazard ratio estimates.
7.
MEDIUMdata code
Deposit the Stata analysis code (e.g., .do files) in a public repository such as GitHub or Zenodo with a persistent identifier, even if patient-level data cannot be shared.
Code sharing enhances reproducibility; it is independent of data sharing and is increasingly expected by journals.
8.
MEDIUMreporting
Add a brief statement in the Statistical Methods about how missing data were handled in the primary analysis (e.g., complete-case analysis, multiple imputation).
Missing data handling is a key methodological detail that is currently absent; its omission may raise reviewer questions.
9.
MEDIUMcopyedit
Add a comma after 'week 73' in the Abstract: '... favorable outcome at week 73, defined by ...'
Missing comma before 'defined' causes a minor clarity issue in the primary outcome definition.
10.
MEDIUMcopyedit
In the Safety Results, add a comma after 'respectively': '... 54/174 (31.0%), respectively, were classified ...'
Missing comma creates an awkward reading; punctuation fix ensures clarity.
11.
MEDIUMcopyedit
Capitalize 'Eastern Cooperative Oncology Group' consistently in Table 1 footnotes.
Minor capitalization inconsistency as flagged by copyedit.
12.
LOWreporting
Consider specifying the years or versions of the WHO guidelines that changed during enrollment in the Discussion.
Providing guideline version details adds context for readers tracking evolving standards.
13.
LOWcopyedit
Rephrase 'for at least rifampin and fluoroquinolones' in Methods for clarity (e.g., 'for rifampin and fluoroquinolones, at a minimum').
The current phrasing is grammatically awkward and could cause confusion.

Full text (43,362 chars)Analyzed: Jul 7, 2026

Read alongside

Oral Regimens for Rifampin-Resistant, Fluoroquinolone-Susceptible Tuberculosis.

Read full text (PMC)

Journal

DOI

10.1056/NEJMoa2400327

Share this Rigor Review

Post on X Share on LinkedIn Share via Email

Embed this Rigor badge

<a href="https://adcurare.com/verify/0256c7c7-fe0c-4aa6-ade9-f5482a819235" target="_blank" rel="noopener">
  <img src="https://adcurare.com/verify/0256c7c7-fe0c-4aa6-ade9-f5482a819235/badge" alt="Adcurare Rigor Review — 4.25★ (Strong), 0 critical, 6 high issues for “Oral Regimens for Rifampin-Resistant, Fluoroquinolone-Susceptible Tuberculosis.”" width="440" height="104" style="max-width:100%;height:auto" />
</a>

Every embed links back to this Rigor Record.

Record fingerprint

523380870aee3e4b8f801c5393e41c5a95f49546c9058f543b3828f62cef2c47

Verify via API

Issued Jul 7, 2026Engine 7.6.0

Adcurare assesses methodological rigor, not the importance of the findings. See how we evaluate →