Rigor Reviewed

Rigor-Reviewed Manuscript

Levofloxacin Preventive Treatment in Children Exposed to MDR Tuberculosis.

Name: Αlpha¹ Rigor Record — Levofloxacin Preventive Treatment in Children Exposed to MDR Tuberculosis.
Item: Levofloxacin Preventive Treatment in Children Exposed to MDR Tuberculosis.
Rating: 96
Author: Αlpha¹

Hesseling AC, Purchase SE, Martinson NA, Fairlie L, Schaaf HS, Brigden J, Staples S, Gibb DM, Garcia-Prats A, Conradie F, McGowan C, Layton C, Batist E, Demers AM, Nyamathe S, Frigati L, Turner R, Duong T, Seddon JA

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Αlpha¹ Rigor Review — 3.75★ (Adequate), 0 critical, 2 high issues for “Levofloxacin Preventive Treatment in Children Exposed to MDR Tuberculosis.”

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Αlpha¹ Editorial

This rigor review was examined and confirmed by Αlpha¹ Editorial · August 16, 2026

Αlpha¹ 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−0.5★
ClaimsTreatment effect not shown to be clinically meaningful−0.5★
ReportingData & code availability partially met−0.25★

Model-reported confidence: highReviewer agreement: highEngine: 7.39.0Source: full text

Not verified in this report

No data or code availability links were detected to verify.

Problems surfaced4 types

Numerical inconsistencies1

Values that contradict each other or are impossible for the stated sample: recomputed p-values and test statistics, GRIM/GRIMMER checks on summary numbers, percentages against their own counts, totals against their parts, and estimates against their own confidence intervals.

Internal contradictions in the reported numbersAssessed

Overstated conclusions2

Conclusions that reach past what the paper's own results support — including a significance claim that no longer holds when the statistic is recomputed, and efficacy resting on an unvalidated surrogate endpoint.

Treatment effect not shown to be clinically meaningfulAssessed
Conclusions only partially backed by the presented evidenceAssessed

Reporting gaps1

Required detail the manuscript never states — study design, biological variables, ethics approval and consent, key resources, statistical reporting, data and code availability, and overall transparency.

Data/code availability incompleteAssessed

This Αlpha¹ 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 is a well-conducted cluster-randomized trial with rigorous design, clear reporting of biological variables, and appropriate statistical methods. The main weakness is the lack of a clear data availability statement and code sharing, which limits reproducibility.

Both reviewers agreed on the study type and all dimension statuses. The statistics verification component recomputed 9 tests, all consistent, but coverage is limited to tests with test statistics or effect estimates with CIs. The citation check found no retracted or unresolved references.

8 major claims checked against the paper's own evidence: 3 only partially supported (evidence backs part of the claim; gaps or caveats remain); the rest adequately supported.

Premise concern: effect size not shown to be clinically meaningful.

Recomputed 9 tests: 9 consistent, 0 inconsistent; 2 recomputed directly from the reported test statistics, 7 via agent-written checks.

1 integrity concern flagged (0 high).

Reporting

Eight Dimensions7 pass · 1 warn

The introduction cites prior observational data and WHO conditional recommendations, and clearly states the lack of randomized controlled trial evidence for MDR-TB preventive treatment. The rationale for the trial is logically derived from the high risk of disease progression in young children and the need for trial data. Limitations of prior research are implicitly addressed by the trial design, though not explicitly detailed.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedINADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The paper establishes a clear scientific premise, citing prior research and identifying the evidence gap for MDR-TB preventive treatment in children.

Evidence

paraphrase[Introduction, paragraph 1]

“There is good evidence for the efficacy and safety of TB preventive treatment for individuals exposed to drug-susceptible TB, but data from randomized-controlled trials for MDR-TB are lacking.”

paraphrase[Introduction, paragraph 2]

“Young children, particularly those <5 years, are an important population for TB preventive treatment given their higher risk of faster disease progression following TB exposure and risk of severe forms of TB.”

absence[Introduction]

Limitations of prior research are not explicitly discussed in the introduction.

PASSReviewer 2· 90% conf

The paper establishes a clear scientific premise with adequate citation of prior work and a logical rationale for the trial.

Evidence

paraphrase[Introduction, paragraph 1]

“There is good evidence for the efficacy and safety of TB preventive treatment for individuals exposed to drug-susceptible TB, but data from randomized-controlled trials for MDR-TB are lacking.”

paraphrase[Introduction, paragraph 2]

“We undertook a clinical trial to compare levofloxacin versus placebo in children/adolescents exposed to a person with infectious MDR-TB in their household.”

Randomization was at household level, stratified by site, using computer-generated block randomization. The trial was double-blind with placebo control. A power calculation was provided (80% power to detect 60% reduction, assuming 7% incidence). Inclusion/exclusion criteria were described, and the modified intention-to-treat population was defined. Outlier handling is addressed through the pre-specified analysis population and censoring rules. Controls are inherent in the placebo arm. Independent replication is not applicable for a single pivotal trial.

Sub-criteria

controlsADEQUATE

power analysisADEQUATE

blinding levelsADEQUATE

outlier handlingADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

The trial design is rigorous with appropriate randomization, blinding, power calculation, and pre-specified analysis populations.

Evidence

paraphrase[Methods, Trial design]

“Randomization was at household-level, stratified by site, with 1:1 allocation to either levofloxacin or placebo. Randomization was by a computer-generated randomization list prepared by the trial statistician using block randomization with varying block size, incorporated in a centralized web-based database.”

paraphrase[Methods, Trial design]

“TB-CHAMP was a multi-site, cluster-randomized, double-blind placebo-controlled trial”

paraphrase[Methods, Statistical Analysis]

“We calculated that 1009 participants would provide 80% power to detect a 60% reduction in incident TB by 48-weeks, at a two-sided significance level of 5%.”

PASSReviewer 2· 95% conf

The trial design is rigorous with adequate randomization, blinding, power analysis, and pre-specified analysis populations.

Evidence

paraphrase[Methods, Trial design]

paraphrase[Methods, Statistical Analysis]

“We calculated that 1009 participants would provide 80% power to detect a 60% reduction in incident TB by 48-weeks, at a two-sided significance level of 5%.”

paraphrase[Abstract]

“TB-CHAMP was a community-based multi-site household cluster-randomized double-blind placebo-controlled trial”

Sex, age, HIV status, IGRA status, and BCG vaccination are reported in Table 1. Since both sexes were enrolled, sex justification is not applicable. Age and health status are reported. Demographics include ethnicity and site. Species/strain and housing conditions are not applicable for a human trial.

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Key biological variables including sex, age, HIV status, and IGRA status are reported in baseline characteristics.

Evidence

direct quote[Table 1]

“Sex Male 213 (47%) 241 (51%) 454 (49%) Female 240 (53%) 228 (49%) 468 (51%)”

View in source

paraphrase[Table 1]

“HIV status Positive 10 (2%) 9 (2%) 19 (2%) HIV-exposed uninfected 153 (34%) 160 (34%) 313 (34%) HIV-unexposed 288 (64%) 298 (64%) 586 (64%)”

direct quote[Table 1]

“Ethnicity Black 362 (80%) 381 (81%) 743 (81%) South African mixed 81 (18%) 78 (17%) 159 (17%)”

View in source

PASSReviewer 2· 90% conf

Biological variables are well reported for a pediatric trial, including sex, age, HIV status, and IGRA status.

Evidence

direct quote[Table 1]

“Sex Male 213 (47%) 241 (51%) 454 (49%) Female 240 (53%) 228 (49%) 468 (51%)”

View in source

direct quote[Table 1]

“Ethnicity Black 362 (80%) 381 (81%) 743 (81%)”

View in source

The paper states that the study was approved by all institutional and national ethics committees, and informed consent was obtained from parents/caregivers, with assent from older children. However, the specific ethics committee names are not provided in the main text (likely in the supplement). Regulatory compliance is implied by adherence to standard trial practices.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementINADEQUATE

regulatory complianceINADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 85% conf

Ethical approval and informed consent are reported, though the specific ethics committee is not named in the main text.

Evidence

direct quote[Methods, Trial design]

“The study was approved by all institutional and national ethics committees (Supplement).”

View in source

paraphrase[Methods, Trial design]

“Children <5 years were recruited following written informed consent from their parent/caregiver if exposure to the MDR-TB index patient had been substantial in the preceding 6 months.”

absence[Methods]

Regulatory compliance is not explicitly stated.

PASSReviewer 2· 85% conf

Ethical approvals and consent are adequately reported.

Evidence

direct quote[Methods, Trial design]

“The study was approved by all institutional and national ethics committees (Supplement).”

View in source

paraphrase[Methods, Trial design]

“Children <5 years were recruited following written informed consent from their parent/caregiver if exposure to the MDR-TB index patient had been substantial in the preceding 6 months.”

Levofloxacin and placebo are identified with manufacturer (Macleods Pharmaceuticals) and formulation. The IGRA assay (QuantiFERON-Gold Plus, Qiagen) is identified. Statistical software (Stata version 16.0) is named. Other bench resources are not applicable.

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The investigational product (levofloxacin) is identified with manufacturer and dosing, and statistical software is named.

Evidence

paraphrase[Methods, Treatment]

“Study medications were manufactured by Macleods Pharmaceuticals, India, as 250mg scored tablets levofloxacin or levofloxacin-placebo”

paraphrase[Methods, Trial design]

“interferon-gamma release assay (IGRA, QuantiFERON-Gold Plus, Qiagen)”

direct quote[Methods, Statistical Analysis]

“Analyses used Stata version 16.0 or later (StataCorp).”

View in source

PASSReviewer 2· 90% conf

The investigational product (levofloxacin) is adequately identified, and statistical software is named.

Evidence

paraphrase[Methods, Treatment]

“Study medications were manufactured by Macleods Pharmaceuticals, India, as 250mg scored tablets levofloxacin or levofloxacin-placebo”

direct quote[Methods, Statistical Analysis]

“Analyses used Stata version 16.0 or later (StataCorp).”

View in source

The primary analysis used Cox regression with cluster-robust variance, and the paper reports exact p-values (e.g., P=0.12) and hazard ratios with 95% CIs. Assumptions were checked via the Grambsch-Therneau test. Statistical software is identified. Data presentation includes Kaplan-Meier curves and tables with per-group n. Mathematical plausibility checks are not applicable for large-N continuous outcomes.

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedADEQUATE

mathematical plausibilityN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Statistical methods are appropriate and well-described, with exact p-values and effect sizes with confidence intervals.

Evidence

paraphrase[Methods, Statistical Analysis]

“We used Cox regression to estimate the hazard ratio (HR) comparing levofloxacin versus placebo, with cluster-robust variance accounting for intra-household correlation.”

paraphrase[Results, Primary Outcome]

“hazard ratio [HR] 0.44; 95% CI 0.15-1.25; P=0.12”

paraphrase[Methods, Statistical Analysis]

“We assessed for evidence of non-proportional hazards using the Grambsch-Therneau test based on scaled Schoenfeld residuals.”

PASSReviewer 2· 90% conf

Statistical methods are appropriate and well-reported, with exact p-values and effect sizes with confidence intervals.

Evidence

paraphrase[Results, Primary Outcome]

“hazard ratio [HR] 0.44; 95% CI 0.15-1.25; P=0.12”

paraphrase[Results, Primary Outcome]

“hazard ratio [HR] 0.44; 95% CI 0.15-1.25”

The paper does not include a specific data availability statement in the provided text. The trial is registered (ISRCTN92634082), but no data sharing mechanism is described. Since this is a clinical trial with patient data, managed access would be acceptable, but the absence of any statement is a gap.

Sub-criteria

code sharingN/A

accession numbersN/A

repository depositN/A

data availability statementNOT REPORTED

Per reviewer (2) — the votes behind the verdict

WARNReviewer 1· 80% conf

A data availability statement is present but vague, and no data or code repository is mentioned.

Evidence

absence[Entire paper]

No data availability statement is present.

WARNReviewer 2· 80% conf

A data availability statement is present but vague, and no data repository or code is provided.

Evidence

direct quote[Discussion, end]

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

View in source

The trial registration number is provided (ISRCTN92634082). Methods are detailed enough for replication. Limitations are explicitly discussed, including lower-than-expected event rate and generalizability. Conclusions are appropriately cautious, noting the lack of statistical significance. Funding and COI are disclosed.

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineNOT REPORTED

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The trial is registered, methods are detailed, limitations are discussed, and conclusions are proportional.

Evidence

direct quote[Abstract]

“ISRCTN92634082”

View in source

paraphrase[Discussion]

“Our trial has limitations. The event rate in the placebo-arm was lower than anticipated. There are also limitations to generalizability.”

paraphrase[Acknowledgements]

“Funders UNITAID, through the BENEFIT Kids project grant (2019-36-SUN-MDR) to Stellenbosch University.”

PASSReviewer 2· 90% conf

The trial is registered, methods are complete, limitations are discussed, and conclusions are proportional.

Evidence

paraphrase[Abstract]

“(ISRCTN92634082.)”

paraphrase[Discussion, paragraph 5]

“Our trial has limitations. The event rate in the placebo-arm was lower than anticipated.”

20 copyedit issues flagged: mostly typo, consistency, clarity.

Checked 22 references by DOI: 17 verified — 5 no DOI (shown, not verified).

Reproducibility

Registered (2 IDs: ClinicalTrials.gov, ISRCTN). No reporting guideline cited.

Αlpha¹ Rigor Action ItemsFinal pass before journal submission

The published work is robust and well-reported, but readers should weigh the lack of a clear data availability statement and code sharing when assessing reproducibility. The minor copyedit issues and the vague data statement warrant attention, though they do not undermine the core findings.

1.
HIGHdata code
Add a clear data availability statement in the Methods or a dedicated section, specifying how de-identified data can be accessed (e.g., via a data access committee or repository) with conditions and timeframe.
The current statement is vague and does not provide a clear mechanism for data access, which is a key reproducibility gap.
2.
HIGHdata code
Deposit the statistical analysis code (e.g., Stata do-files) in a public repository and provide a link in the manuscript.
Sharing code enhances transparency and allows independent verification of the analyses.
3.
MEDIUMethics
Name the specific ethics committees that approved the study in the main text, not just in the supplement.
Naming the committees strengthens the ethics reporting and is expected by readers and journals.
4.
MEDIUMreporting
Explicitly state compliance with the Declaration of Helsinki or other regulatory framework in the Methods.
Explicit regulatory compliance statements are standard for clinical trials and reassure readers.
5.
MEDIUMreporting
Mention adherence to CONSORT reporting guidelines in the manuscript.
Explicitly stating CONSORT adherence helps readers assess the completeness of reporting.
6.
MEDIUMreporting
Clarify the handling of missing data for secondary outcomes, as the current statement only addresses the primary model.
Transparent missing data handling is important for interpreting secondary analyses.
7.
MEDIUMreporting
Include a statement on the availability of the full protocol and statistical analysis plan.
Providing access to the protocol and SAP enhances transparency and reproducibility.
8.
LOWcopyedit
Fix the typo in the Abstract: 'S ensitivity analyses' should be 'Sensitivity analyses'.
Minor typos detract from the professionalism of the manuscript.
9.
LOWcopyedit
Fix the typo in the Abstract: 'O ne child' should be 'One child'.
Minor typos detract from the professionalism of the manuscript.
10.
LOWcopyedit
Fix the extra space in 'P=0.12 )' in Results, Primary Outcome.
Minor formatting issues should be corrected for consistency.
11.
LOWcopyedit
Fix the extra space in 'P =0.14)' in Results, Secondary Outcomes.
Minor formatting issues should be corrected for consistency.
12.
LOWcopyedit
Fix the capitalization in 'w e recruited' in Discussion.
Minor typos detract from the professionalism of the manuscript.
13.
LOWcopyedit
Fix the extra spaces in 'rigorous ly', 'demonstra ted', 'inciden t TB', 'followe d regular ly', 'recruit ed', 'expanding late r' in Discussion.
Minor typos detract from the professionalism of the manuscript.
14.
LOWcopyedit
Fix the capitalization in 'S afety', 'C are', 'n ationally' in Discussion.
Minor typos detract from the professionalism of the manuscript.
15.
LOWcopyedit
Fix the symbol formatting in 'grade 3' to 'grade ≥3' in Discussion.
Proper symbol formatting is expected in scientific manuscripts.
16.
LOWcopyedit
Fix the typo 'account ing' to 'accounting' in Methods, Statistical Analysis.
Minor typos detract from the professionalism of the manuscript.
17.
LOWother
Clarify in Discussion, paragraph 4, that the systematic review demonstrating a 90% risk reduction is from observational data, not RCTs.
Clarifying the evidence source prevents misinterpretation.

Full text (30,579 chars)Analyzed: Aug 16, 2026

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