Rigor Reviewed

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Trial of High-Dose Oral Rifampin in Adults with Tuberculous Meningitis.

Name: Adcurare Rigor Record — Trial of High-Dose Oral Rifampin in Adults with Tuberculous Meningitis.
Item: Trial of High-Dose Oral Rifampin in Adults with Tuberculous Meningitis.
Rating: 79
Author: Adcurare

Meya DB, Cresswell FV, Dai B, Engen N, Naidoo K, Ganiem AR, Imran D, Kabahubya M, Lessells RJ, Yunivita V, Estiasari R, Tugume L, Hlabisa B, Kurniawati MY, Sagita N, Kagimu E, Maharani K, Gakuru J, Gaharu MN, Mugabi T, Kimuda S, Namombwe S, Te Brake L, Aarnoutse R, Svensson EM, Bangdiwala AS, Namanda S, Bahr NC, Musubire AK, Moosa MYS, Hamers RL, Marais S, Boulware DR, van Crevel R, Ruslami R, HARVEST Trial Team

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Adcurare Rigor Review — 3.75★ (Adequate), 0 critical, 7 high issues for “Trial of High-Dose Oral Rifampin in Adults with Tuberculous Meningitis.”

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Adcurare Editorial

This rigor review was examined and confirmed by Adcurare Editorial · July 6, 2026

Adcurare Rigor Review

Rigor Reviewed

3.75 / 5

Adequate — real issues to address

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

IntegrityIntegrity concern ×2−1★
ReportingData & code availability partially met−0.25★

Model-reported confidence: moderateReviewer agreement: lowEngine: 7.6.0Source: full text

Problems surfaced3 types

Data/code availability incomplete
Implausibly large reported effect
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 phase III RCT is well-designed in terms of randomization, blinding, and eligibility criteria, and it reports comprehensive baseline characteristics and a thorough discussion of limitations. However, several reporting gaps exist: no data availability statement, no manufacturer details for the investigational drug, no statistical software identified, inexact p-values for some analyses, and a generic ethics statement that does not name the approving committees. Additionally, the power analysis assumes an implausibly large effect size, which should be acknowledged as a design limitation.

The three independent reviewers converged on most dimensions but disagreed on study design (pass vs. fail), ethical approvals (pass vs. warn), and data code availability (fail vs. warn). The synthesized judgments reflect a careful weighing of the detailed evidence. The copyedit pass identified 11 minor issues, the most concerning being a potential percentage-count inconsistency in Table 1. Statistics recomputations were consistent for 5/5 checks, but coverage was limited to tests with full test statistics or effect size+CI. No retracted or missing references were found.

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

Recomputed 5 tests: 5 consistent, 0 inconsistent, 5 via agent-written checks.

2 integrity concerns flagged (0 high).

Reporting

Eight Dimensions7 pass · 1 warn

The Introduction clearly describes the poor prognosis of tuberculous meningitis, the limited CNS penetration of standard rifampicin, and the mixed evidence from prior dose-finding studies. It acknowledges the limitations of earlier work (e.g., a null Vietnamese trial and a meta-analysis with large uncertainty) and justifies the need for a well-powered trial.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

The scientific premise is well established, citing prior phase II trials and meta-analyses that support the rationale for testing high-dose rifampicin.

Evidence

direct quote[Introduction, paragraph 4]

“Four phase II trials have shown a dose-exposure relationship for rifampicin, with higher doses enhancing plasma and CSF drug concentrations.”

direct quote[Introduction, last paragraph]

“We hypothesized that a daily dose of ~35 mg per kg of oral rifampicin given for 8 weeks, combined with the standard anti-tuberculosis regimen, would improve 6-month survival compared with the standard ~10 mg per kg rifampicin dose.”

direct quote[Introduction, paragraph 4]

“Given mixed evidence, a well powered randomized clinical trial evaluating high-dose rifampicin was deemed necessary.”

PASSReviewer 2· 95% conf

The paper clearly establishes the scientific premise, cites relevant prior work including conflicting evidence, and provides a logical rationale for the trial.

Evidence

direct quote[Introduction, paragraphs 1-3]

“Emerging evidence suggests that higher rifampicin doses may improve tuberculous meningitis treatment outcomes. Four phase II trials have shown a dose-exposure relationship for rifampicin, with higher doses enhancing plasma and CSF drug concentrations.”

direct quote[Introduction, paragraph 3]

“Given mixed evidence, a well powered randomized clinical trial evaluating high-dose rifampicin was deemed necessary.”

direct quote[Introduction, paragraph 4]

PASSReviewer 3· 93% conf

The scientific premise is well-established, citing prior evidence that standard rifampicin dosing achieves suboptimal CSF concentrations, and that higher doses may improve outcomes.

Evidence

direct quote[Introduction, paragraphs 1-3]

“Despite guidelines recommending isoniazid, pyrazinamide, ethambutol, and rifampicin (10 mg per kilogram/day), outcomes for tuberculous meningitis remain poor... rifampicin... has limited penetration into cerebrospinal fluid (CSF) achieving ~5% of plasma levels.”

direct quote[Introduction, paragraph 3]

“Given mixed evidence, a well powered randomized clinical trial evaluating high-dose rifampicin was deemed necessary.”

direct quote[Introduction, final paragraph]

The trial uses permuted-block randomization stratified by center, HIV status, and disease severity. Double-blind placebo control is ensured with identical-appearing tablets. A power analysis is provided, and inclusion/exclusion criteria are detailed, including late exclusion criteria. The primary analysis population (ITT) is defined, and a per-protocol analysis is mentioned.

Sub-criteria

controlsN/A

power analysisADEQUATE

blinding levelsADEQUATE

outlier handlingADEQUATE

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 clear randomization, blinding, sample size calculation, and eligibility criteria.

Evidence

direct quote[Methods, Randomization and Blinding]

“We randomized participants in a 1:1 ratio to either high-dose or standard-dose oral rifampicin, using permutated blocks with sizes of two or four.”

direct quote[Methods, Randomization and Blinding]

“Both participants and investigators were blinded to treatment allocation, with identical-appearing intervention and placebo tablets.”

direct quote[Methods, Statistical Analysis]

“Assuming 50% survival in the control group, an overall sample size of 500 participants (250 per group) provided 80% power with a two-sided 0.05 significance level to detect a hazard ratio for death of 0.68 (approximately 13% absolute survival improvement) while accounting for ≤5% loss-to-follow up.”

PASSReviewer 2· 95% conf

The design is rigorous: randomized, double-blind, placebo-controlled, with a pre-specified power analysis, clear inclusion/exclusion criteria, and appropriate blinding.

Evidence

direct quote[Methods, Randomization and Blinding]

“We randomized participants in a 1:1 ratio to either high-dose or standard-dose oral rifampicin, using permutated blocks with sizes of two or four. Randomization was stratified by trial centers, HIV status, and tuberculous meningitis severity”

direct quote[Methods, Randomization and Blinding]

“Both participants and investigators were blinded to treatment allocation, with identical-appearing intervention and placebo tablets.”

direct quote[Methods, Statistical Analysis]

FAILReviewer 3· 90% conf

Randomization, blinding, and inclusion/exclusion criteria are well-reported, and a priori power analysis is present, but the design is severely underpowered for the stated effect; only 1 of 5 applicable sub-criteria (inclusion_exclusion) is adequate.

Evidence

direct quote[Methods, Statistical Analysis]

direct quote[Methods, Randomization and Blinding]

“We randomized participants in a 1:1 ratio to either high-dose or standard-dose oral rifampicin, using permutated blocks with sizes of two or four.”

direct quote[Methods, Study population and setting]

“Eligibility criteria included microbiologically-confirmed... or suspected tuberculous meningitis based on abnormal CSF parameters and clinical findings with antituberculous treatment planned.”

The study reports sex, age, weight, HIV status, CD4 count, disease severity (MRC grade), Glasgow Coma Scale, and CSF parameters for both groups in Table 1. Sex is reported (44% female). Since both sexes are enrolled, a justification for sex is not applicable. Demographics are comprehensive. Species/strain and housing conditions are not applicable for a 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· 80% conf

Sex, age, weight, and key health variables are reported, but race/ethnicity is not explicitly stated.

Evidence

direct quote[Results, paragraph 1]

“222 of 499 (44%) were female.”

direct quote[Table 1]

“Median age (IQR), years: 38 (28-46) vs 35 (28-45). Median weight (IQR), kg: 54 (49-60) vs 55 (45-62).”

absence[Table 1 and Results]

Race/ethnicity is not explicitly reported.

PASSReviewer 2· 95% conf

Key biological variables for humans (age, sex, HIV status, disease severity) are well-reported in Table 1.

Evidence

direct quote[Table 1]

“Female sex, no. (%) | 101 (40.6) | 121 (48.4)”

direct quote[Results, paragraph 2]

“Overall, 304 of 499 (61%) were persons living with HIV; 125 of 304 (41%) were receiving antiretroviral therapy, and 115 of 226 (51%) had CD4 counts <100 cells/mm3.”

PASSReviewer 3· 90% conf

Key biological variables for a human clinical trial are adequately reported, including sex, age, weight, HIV status, and comorbidities.

Evidence

direct quote[Results, Table 1]

“Median age (IQR), years | 38 (28-46) | 35 (28-45) | Female sex, no. (%) | 101 (40.6) | 121 (48.4) | Median weight (IQR), kg | 54 (49-60) | 55 (45-62)”

direct quote[Results, Table 1 and text]

“Overall, 304 of 499 (61%) were persons living with HIV; 125 of 304 (41%) were receiving antiretroviral therapy, and 115 of 226 (51%) had CD4 counts <100 cells/mm3.”

The paper states 'Research ethics committees and relevant regulatory approvals occurred at all sites' and provides the trial registration. Informed consent is described: 'Written informed consent was obtained from all participants, or surrogates for people lacking capacity to consent.' The study uses a named trial registration (ISRCTN). While a specific ethics committee name is not given in the text (the IRB statement is somewhat generic), the statement is adequate for a multi-national trial reported in a journal that requires ethics approval. The confidence is high, but the evidence for a *named* body is slightly indirect (inferred from the trial registration and regulatory statement). The paper states compliance with guidelines by referencing 'international guidelines' for corticosteroids.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 85% conf

Ethics approval is mentioned but the approving bodies are not named, and compliance with a recognized ethical framework is not explicitly stated.

Evidence

direct quote[Methods, Study Design]

“Research ethics committees and relevant regulatory approvals occurred at all sites.”

direct quote[Methods, Study population and setting]

“Written informed consent was obtained from all participants, or surrogates for people lacking capacity to consent.”

absence[Methods]

Regulatory compliance is not explicitly stated (e.g., Declaration of Helsinki).

PASSReviewer 2· 90% conf

Ethical approvals are reported, informed consent is documented, and regulatory compliance with the Declaration of Helsinki can be inferred.

Evidence

direct quote[Methods, Study Design]

“Research ethics committees and relevant regulatory approvals occurred at all sites.”

direct quote[Methods, Study population and setting]

“Written informed consent was obtained from all participants, or surrogates for people lacking capacity to consent.”

PASSReviewer 3· 85% conf

The paper reports ethics committee approval and informed consent, but does not name the specific committees or grant protocol numbers, which would be needed for a fully 'adequate' rating; however, the generic statement plus regulatory compliance is sufficient for a pass.

Evidence

direct quote[Methods, Study Design]

“Research ethics committees and relevant regulatory approvals occurred at all sites.”

direct quote[Methods, Study population and setting]

“Written informed consent was obtained from all participants, or surrogates for people lacking capacity to consent.”

The investigational product is high-dose rifampicin, and the paper names the diagnostic test 'Xpert MTB/RIF Ultra (Cepheid, CA)' and 'mycobacterial growth indicator tube culture (Becton Dickinson, NJ)'. The dosing formulation is described (extra rifampicin tablets, fixed-dose combination tablets, matched placebo). Software tools are partially identified (SAS/Stata likely used but not explicitly named in the main text; the statistical methods section mentions an unadjusted Cox regression but no software version). However, for a clinical trial of an approved drug, this is adequate. The placebo matching is described. Antibodies, cell lines, mycoplasma, and organisms are not applicable.

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedINADEQUATE

Per reviewer (3) — the votes behind the verdict

FAILReviewer 1· 90% conf

The investigational product (rifampicin) is not fully identified (manufacturer missing), and statistical software is not named.

Evidence

direct quote[Methods, Intervention]

“extra rifampicin tablets (900 mg if ≤38 kilograms, otherwise 1200 mg) in addition to the standard tuberculosis fixed-dose combination tablets”

absence[Methods, Statistical Analysis]

Statistical software is not identified.

PASSReviewer 2· 90% conf

The investigational drug (rifampicin) and key diagnostics (Xpert MTB/RIF Ultra) are identified with manufacturers.

Evidence

direct quote[Methods, Study population and setting]

“microbiologically-confirmed (positive CSF Xpert MTB/Rif Ultra (Cepheid, CA), mycobacterial growth indicator tube culture (Becton Dickinson, NJ))”

direct quote[Methods, Intervention]

“This dose was achieved by providing extra rifampicin tablets (900 mg if ≤38 kilograms, otherwise 1200 mg) in addition to the standard tuberculosis fixed-dose combination tablets that included rifampicin (~10 mg per kilogram)”

absence[Methods, Statistical Analysis]

Statistical software is not explicitly named in the main text.

PASSReviewer 3· 80% conf

For this clinical trial of a drug, the key resource is the investigational product (rifampicin and placebo), which is described with dose and regimen, though not with manufacturer/lot numbers. The diagnostic test (Xpert MTB/RIF Ultra) is named with manufacturer.

Evidence

direct quote[Methods, Intervention]

“Participants in the intervention arm received high-dose oral rifampicin of ~35 mg per kilogram daily, administered for 8 weeks. This dose was achieved by providing extra rifampicin tablets (900 mg if ≤38 kilograms, otherwise 1200 mg) in addition to the standard tuberculosis fixed-dose combination tablets”

direct quote[Methods, Study population and setting]

“microbiologically-confirmed (positive CSF Xpert MTB/Rif Ultra (Cepheid, CA)... mycobacterial growth indicator tube culture (Becton Dickinson, NJ))”

The primary analysis uses Cox regression with HR and 95% CI. Exact p-values are reported (P=0.25, P=0.007). Effect sizes are given (HR 1.17, 95% CI 0.89-1.54). The software is not explicitly named. Data presentation uses Kaplan-Meier curves and tables with group-wise N. Assumptions for Cox regression are handled by the analysis approach (proportional hazards is implicit). The power analysis is reported. Effect sizes and confidence intervals are reported. Mathematical plausibility checks: the numbers provided are typical for a clinical trial and no demonstrable arithmetic impossibilities are apparent in the primary analysis. The p-value for the primary outcome can be recomputed (see statistics_checks).

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedINADEQUATE

assumptions verifiedINADEQUATE

mathematical plausibilityN/A

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 80% conf

Statistical tests are named, effect sizes with CIs are reported, and data presentation is adequate, but assumptions are not verified, exact p-values are not provided for all analyses, and software is not identified.

Evidence

direct quote[Methods, Statistical Analysis]

“The treatment effect of high-dose rifampicin vs standard-dose rifampicin was estimated via hazard ratio from an unadjusted Cox regression.”

direct quote[Results, Figure 2]

“Kaplan-Meier Curves for 6-month Survival by Treatment Group and Key Subgroups”

direct quote[Results, Primary Outcome]

“Hazard Ratio, 1.17; 95% confidence interval, 0.89 to 1.54; P=0.25”

PASSReviewer 2· 90% conf

Statistical tests are mostly named, key analyses are pre-specified, and data presentation is adequate for a large clinical trial.

Evidence

direct quote[Abstract, Results]

“hazard ratio, 1.17; 95% confidence interval, 0.89-1.54; p=0.25”

direct quote[Results, Safety]

“Total bilirubin (≥2.6x upper limit of normal) | 24 (9.6) | 9 (3.6) | 0.007”

absence[Methods, Statistical Analysis]

Statistical software version is not provided.

PASSReviewer 3· 85% conf

Statistical methods are well-described and appropriate for the study design, but p-values are not reported for the primary analysis (only 'P=0.25'), and no effect sizes are reported alongside CIs for most comparisons.

Evidence

direct quote[Results, Primary Outcome]

“Hazard Ratio, 1.17; 95% confidence interval [CI], 0.89 to 1.54; P=0.25”

direct quote[Methods, Statistical Analysis]

“The primary analysis was based on the intention-to-treat population... Survival distributions and 6-month mortality were estimated via Kaplan-Meier estimators. The treatment effect... was estimated via hazard ratio from an unadjusted Cox regression.”

absence[Methods, Statistical Analysis]

No statistical software is named in the main text.

For a clinical trial of this nature, individual patient data is not expected to be publicly deposited (privacy/consent), but a data availability statement describing managed access through a data access committee is the current best practice and is absent. The trial registration (ISRCTN15668391) is provided, and the protocol is referenced to nejm.org, but these do not constitute a data availability statement. No code sharing is mentioned.

Sub-criteria

code sharingNOT REPORTED

accession numbersN/A

repository depositN/A

data availability statementNOT REPORTED

Per reviewer (3) — the votes behind the verdict

FAILReviewer 1· 90% conf

No data availability statement is present, and no code or data repositories are mentioned.

Evidence

absence[End of manuscript]

No data availability statement is present.

WARNReviewer 2· 85% conf

The trial is registered, but there is no explicit data availability statement, repository deposit, or code sharing mentioned in the main text.

Evidence

absence[Throughout paper]

No data availability statement is found.

direct quote[Methods, Study population and setting]

“Full details of study conduct can be found in the protocol at nejm.org (https://www.nejm.org/).”

WARNReviewer 3· 90% conf

The paper provides a trial registration number and mentions that the protocol is available at NEJM.org, but does not include a data availability statement, repository deposit, or code sharing for the anonymized patient data or analysis code.

Evidence

absence[Entire paper]

No data availability statement is provided.

direct quote[Methods, Study Design and Results]

“ISRCTN15668391”

The trial is registered (ISRCTN15668391). Methods are sufficiently detailed for replication. All pre-specified outcomes are reported, including negative results. Limitations are discussed, and conclusions are drawn conservatively. Funding and COI disclosures are provided. The only omission is an explicit statement of adherence to CONSORT or another reporting guideline, though a CONSORT diagram is included.

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineNOT REPORTED

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

The trial is registered, methods are detailed, limitations are discussed, and conclusions are proportional. However, no adherence to a reporting guideline is stated.

Evidence

direct quote[Abstract, Methods]

“Clinical Trial number ISRCTN15668391”

direct quote[Discussion, paragraph 4]

“The major limitation common to all tuberculous meningitis studies is the potential for misdiagnosis.”

direct quote[Abstract, Conclusions]

“There is no evidence of beneficial effect from high-dose rifampicin for tuberculous meningitis, and the potential for a harmful effect cannot be ruled out.”

PASSReviewer 2· 90% conf

The paper reports comprehensively, including negative results, limitations, and proportional conclusions.

Evidence

direct quote[Abstract]

“Clinical Trial numberISRCTN15668391”

direct quote[Discussion, paragraph 1]

“This randomized double-blind trial demonstrated no benefit of high-dose rifampicin as prescribed among adults with tuberculous meningitis with respect to 6-month survival or any prespecified secondary endpoints or subgroups.”

direct quote[Support Statement]

“Funded by the Department of Health and Social Care, the Foreign, Commonwealth & Development Office, the United Kingdom Medical Research Council, and Wellcome Trust Medical Research Council Joint Global Health Trials (MR/S004963/1).”

PASSReviewer 3· 90% conf

Reporting is comprehensive: methods are detailed, limitations are discussed, conclusions are proportional, and funding/COI disclosures are provided. Trial registration is present, but no formal reporting guideline (CONSORT) is explicitly cited.

Evidence

direct quote[Methods, Study Design]

“(ISRCTN15668391)”

direct quote[Discussion, paragraph 4]

“The major limitation common to all tuberculous meningitis studies is the potential for misdiagnosis.”

direct quote[End of paper, Support Statement and Disclosure forms]

11 copyedit issues flagged: mostly consistency, punctuation, typo.

Checked 33 references: 32 verified — 1 not checked.

Reproducibility

1 data/code link checked; 0 live.

Registered (1 ID: ISRCTN). Reporting guideline cited: CONSORT.

Adcurare Rigor Action ItemsFinal pass before journal submission

The paper is not ready for submission in its current form. The absence of a data availability statement (fail) and the generic ethics committee statement (warn) are critical reporting gaps that will likely be flagged by editors. The Table 1 inconsistency (count 144 but percentage 45.8%) must be corrected, and the implausibly optimistic power analysis should be acknowledged as a limitation. After these fixes and the other medium-priority actions (adding software name, exact p-values, manufacturer of drug), the paper would be ready for submission.

1.
HIGHdata code
Add a data availability statement to the manuscript (e.g., after the Discussion or before References) specifying that de-identified individual participant data can be requested through a managed access process (e.g., corresponding author, data access committee, or platform like Vivli).
A data availability statement is a journal requirement for clinical trials; its absence will cause the paper to be returned or rejected.
2.
HIGHethics
In the Methods section, replace the generic 'Research ethics committees and relevant regulatory approvals occurred at all sites' with the name(s) of the specific ethics committee(s) that approved the study, including protocol/approval numbers for each site.
Editors require traceable ethics approval; a generic statement is insufficient and may delay review or trigger a query.
3.
HIGHrigor
Correct the inconsistency in Table 1 for the high-dose group 'Definite TBM' row: if the count is 144, the percentage should read 57.8% (144/249); if the percentage (45.8%) is correct, the count should be ~114. Verify the source data and correct the table.
An internal numerical contradiction in a demographic table is a data-integrity issue that reviewers will catch and may raise concerns about data quality.
4.
HIGHreporting
In the Discussion/Limitations section, add a sentence acknowledging that the trial was powered for a hazard ratio of 0.68, which is a large effect for a single drug-dose modification, and that the wide confidence interval (0.89 to 1.54) cannot exclude either a clinically meaningful benefit or harm.
Transparency about the optimistic power assumption helps readers interpret the null result and prevents overstatement of the findings.
5.
HIGHstatistics
In the Methods (Statistical Analysis), name the statistical software used (e.g., 'SAS version 9.4' or 'R version 4.3.2') and, if any custom code was used, provide a link to a repository (e.g., GitHub) or state that it is available upon request.
Identifying the software is a standard reproducibility requirement; its absence is a common reviewer request.
6.
HIGHstatistics
Report exact p-values (e.g., 'P=0.2532' instead of 'P=0.25') for the primary analysis and for all subgroup and secondary analyses, either in the Results text or as a supplementary table.
Inexact p-values are less informative and can be misleading; exact values are standard for clinical trial reporting.
7.
HIGHreporting
At the end of the Methods, add a statement that the trial was reported in accordance with CONSORT guidelines (cite the CONSORT 2010 statement), even though a CONSORT diagram already appears as Figure 1.
Explicitly citing the reporting guideline is a CONSORT requirement and is expected by most journals.
8.
MEDIUMrigor
In the Methods (Statistical Analysis), describe how the proportional hazards assumption for the Cox regression was tested (e.g., scaled Schoenfeld residuals) or state that it is assumed.
Verifying assumptions of the primary model is a standard statistical practice; its omission may be noted by a statistical reviewer.
9.
MEDIUMrigor
In the Methods (Intervention), add the manufacturer (and lot numbers if available) of the rifampicin and placebo tablets used in the trial.
Identifying the source of the investigational product supports reproducibility and is required by many journals for drug trials.
10.
MEDIUMrigor
In the Results or Table 1, consider reporting the race/ethnicity of participants as a supplementary demographic variable, if the data were collected.
Race/ethnicity categories can be important for generalizability and are increasingly expected in clinical trial reporting.
11.
MEDIUMreporting
In the Methods (Study Design), add an explicit statement that the trial was conducted in compliance with the Declaration of Helsinki and/or ICH-GCP guidelines.
This formal regulatory compliance statement is expected by most journals and is a minor but missing detail.
12.
LOWcopyedit
Correct typographical error: change 'interquartile rage' to 'interquartile range' in the Results (Secondary Outcomes).
Minor typographical error.
13.
LOWcopyedit
Correct 'permutated blocks' to 'permuted blocks' in the Methods (Randomization and Blinding).
Standard statistical terminology.
14.
LOWcopyedit
In the Abstract (Results), rephrase 'Excess mortality occurred with high-dose group among those...' to 'Excess mortality occurred in the high-dose group among those...' for grammatical correctness.
Minor grammatical fix.
15.
LOWreporting
In the Results (Subgroup Analyses), consider including the p-value for the subgroup comparison of mortality in patients receiving ART at baseline (HR=2.01, 95% CI 1.07 to 3.78).
Adding the p-value improves completeness and clarity of subgroup reporting.

Full text (41,759 chars)Analyzed: Jul 6, 2026

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Trial of High-Dose Oral Rifampin in Adults with Tuberculous Meningitis.

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DOI

10.1056/NEJMoa2502866

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Issued Jul 6, 2026Engine 7.6.0

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