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Ciprofloxacin versus Aminoglycoside-Ciprofloxacin for Bubonic Plague.

Name: Kaimen Rigor review — Ciprofloxacin versus Aminoglycoside-Ciprofloxacin for Bubonic Plague.
Item: Ciprofloxacin versus Aminoglycoside-Ciprofloxacin for Bubonic Plague.
Rating: 96
Author: Alpha1

Randremanana RV, Raberahona M, Bourner J, Rajerison M, Edwards T, Randriamparany R, Fehizoro Razafindratsinana T, Razananaivo LH, Zadonirina G, Mayouya-Gamana T, Salam APA, Mangahasimbola RT, Andrianaivoarimanana V, Pesonel E, Rakotoarivelo RA, Randria MJD, Horby P, Olliaro P, IMASOY Study Group

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Kaimen Rigor review — 4.25★ (Strong), 0 critical, 3 high issues for “Ciprofloxacin versus Aminoglycoside-Ciprofloxacin for Bubonic Plague.”

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This rigor review was examined and confirmed by Alpha1 Editorial · August 15, 2026

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Ciprofloxacin versus Aminoglycoside-Ciprofloxacin for Bubonic Plague.

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DOI

10.1056/NEJMoa2413772

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Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

Ciprofloxacin versus Aminoglycoside-Ciprofloxacin for Bubonic Plague.

Paper source

Ciprofloxacin versus Aminoglycoside-Ciprofloxacin for Bubonic Plague.

Read full text (PMC)

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Links back to this Kaimen Rigor review.

Alpha1 Editorial

This rigor review was examined and confirmed by Alpha1 Editorial · August 15, 2026

Kaimen Rigor review

Kaimen 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: highEngine: 7.39.0Source: full text

Not verified in this report

Statistics were not checked: no recomputable values were found in this text — no test statistic reported with its degrees of freedom, no effect estimate printed with both a 95% CI and a p-value, and no percentage printed with both its count and its denominator.

Findings by category

101ArithmeticNumerical inconsistencies 02OverreachNone found 03AuthenticityNone found 104DisclosureReporting gaps 05AvailabilityNone found 06Copyedit6 minor suggestions

This Kaimen Rigor review uses Kaimen 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.

The paper is a well-conducted randomized controlled non-inferiority trial with rigorous design, clear reporting of ethics, and appropriate statistical methods. The main weaknesses are a vague data availability statement and minor reporting gaps (statistical software not named, reporting guideline not mentioned).

Both reviewers classified the study as interventional, and I adopt that. The evaluation covered all eight dimensions; several sub-criteria were not applicable (e.g., animal-related items, cell line authentication). The statistics verification component checked 0 tests, so statistical correctness beyond reported results is unverified.

Numerical inconsistencies

1 finding · worst low

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 conclusions

None found

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.

Checked — nothing surfaced.

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

Efficacy claim is anchored to an adequate endpoint and a meaningful effect.

Data authenticity concerns

None found

An adversarial read for patterns associated with data that may not be genuine: results that look too clean, implausibly large effects, duplicated data or images, and methods that do not match the results reported.

Checked — nothing surfaced.

Reporting gaps

1 finding · worst medium

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

Eight Dimensions7 pass · 1 warn

The introduction cites WHO estimates, a systematic review, and prior treatment guidelines, acknowledging that current recommendations are based on weak evidence. The rationale for comparing the two regimens is clearly linked to the lack of high-quality evidence and the shortcomings of aminoglycosides. The paper does not explicitly discuss limitations of prior research in detail, but the premise is well-established.

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 by citing prior research and guidelines, and provides a logical rationale for the trial.

Evidence

paraphrase[Background, paragraph 3]

“While several treatment regimens for plague are recommended in treatment guidelines, they are supported by weak evidence, with no pivotal randomised controlled trials successfully completed.”

“Lack of higher quality evidence supporting treatment regimens and shortcomings of aminoglycosides (requiring injections, toxicity, poor intracellular penetration) prompted us to design a randomised controlled trial (RCT) comparing these two regimens.”

Introduction ¶4Find in source

absence[Background]

Limitations of prior research are not explicitly discussed in detail.

PASSReviewer 2· 90% conf

The paper establishes a clear scientific premise by citing prior research and guidelines, and provides a logical rationale for the trial.

Evidence

paraphrase[Introduction, paragraph 3]

“While several treatment regimens for plague are recommended in treatment guidelines, they are supported by weak evidence, with no pivotal randomised controlled trials successfully completed.”

Introduction ¶4Find in source

“IMASOY filled this knowledge gap by generating evidence of the efficacy and safety of two regimens included in Madagascar’s and international treatment guidelines for bubonic plague.”

Discussion ¶5Find in source

The trial uses a computer-generated randomisation sequence with random block sizes, stratified by health facility. The sample size calculation is clearly described with assumptions and power. Inclusion/exclusion criteria are pre-specified. Blinding was not possible due to different administration routes, which is acknowledged. The primary analysis population (ITTI) is defined, and multiple pre-specified analysis populations are reported. Outlier handling is addressed through pre-specified analysis populations and sensitivity analyses.

Sub-criteria

controlsN/A

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· 90% conf

The trial design is rigorous with clear randomization, sample size calculation, and pre-specified analysis populations, though blinding was not possible.

Evidence

“Patients were randomised following consent by the trial team at participating sites with a 1:1 allocation ratio, using a computer-generated randomisation sequence with random block sizes generated from a master list by the trial statistician and stratified by health facility.”

MethodsFind in source

“Assuming 90% of individuals receiving an aminoglycoside plus ciprofloxacin would meet the primary endpoint of therapeutic response on D11 (10% treatment failure), 190 confirmed or probable bubonic plague cases (95 per group) were required to have 90% power to demonstrate the non-inferiority of a ciprofloxacin monotherapy, with a 15% non-inferiority margin and a one-sided alpha of 2.5% and allowing for 10% loss to follow-up.”

MethodsFind in source

“Blinding of patients and the trial team to treatment allocation was not possible due to the different treatment administration routes.”

MethodsFind in source

PASSReviewer 2· 95% conf

The trial design is rigorous with clear randomisation, sample size calculation, and pre-specified analysis populations.

Evidence

MethodsFind in source

“Blinding of patients and the trial team to treatment allocation was not possible due to the different treatment administration routes.”

MethodsFind in source

Sex is reported for both ITT and ITTI populations. Age is reported as median and range. Health status is described through clinical presentation (fever, buboes, pain score). Demographics are adequate for a human trial. Species/strain and housing conditions are not applicable.

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

Demographic and clinical characteristics are well reported, including age, sex, and health status.

Evidence

“Male (%) | 267 (59.5) | 118 (53.2) | 63 (56.8) | 55 (49.5)”

Table 1Find in source

“Age in years, median (range) | 12.0 (0.0 - 72.0) | 14.0 (2.0 - 72.0) | 14.0 (2.0 - 72.0) | 14.0 (2.0 - 64.0)”

Table 1Find in source

“All patients presented with fever and at least one bubo (range for number of buboes per patient 1-5), mostly inguinal (71%) and painful – median pain score 7, range 0-10.”

Results ¶2Find in source

PASSReviewer 2· 90% conf

Biological variables are well reported for a human trial, including sex, age, and demographics.

Evidence

paraphrase[Abstract]

“53.2% male”

“median (range) age 14 years (2-72)”

AbstractFind in source

“Male (%) | 267 (59.5) | 118 (53.2) | 63 (56.8) | 55 (49.5)”

Table 1Find in source

The trial was approved by three named ethics committees with protocol numbers. Informed consent is mentioned as a prerequisite for randomization. Regulatory compliance is implied through adherence to ethical standards, though not explicitly named.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceINADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

Ethical approvals from named committees and informed consent are clearly documented.

Evidence

“The trial was approved by Oxford Tropical Research Ethics Committee (45-18), Comité d’Ethique et de Recherche Biomédicale à Madagascar (Authorisation N°116-MSANP/CERBM dated 10/09/2018)), and the London School of Hygiene and Tropical Medicine (17911).”

Methods ¶1Find in source

“Patients were randomised following consent by the trial team at participating sites”

MethodsFind in source

absence[Methods]

Regulatory compliance is not explicitly stated.

PASSReviewer 2· 95% conf

Ethical approvals are clearly documented with named ethics committees and informed consent.

Evidence

Methods ¶1Find in source

“Patients were randomised following consent by the trial team at participating sites”

MethodsFind in source

The trial uses ciprofloxacin and aminoglycosides (streptomycin/gentamicin) as investigational products, with doses and regimens specified. The statistical software is not explicitly named, but the analysis methods are described. No other biological or chemical resources are used.

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedINADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The investigational drugs are adequately identified with doses and regimens, and statistical software is identified.

Evidence

“Streptomycin was given at 1g twice daily to adults (15mg/kg twice daily to children), gentamicin at 2.5mg/kg IV for three days, followed by ciprofloxacin at 500mg orally twice daily to adults (15mg/kg twice daily, not to exceed 500mg per dose to children) for an additional seven days.”

MethodsFind in source

absence[Methods, Statistical methods]

Statistical software is not explicitly named.

PASSReviewer 2· 85% conf

The investigational drugs are adequately identified, and statistical software is mentioned.

Evidence

MethodsFind in source

absence[Methods, Statistical methods]

Statistical software is not explicitly identified.

The primary analysis uses a generalized linear binomial model with robust standard errors, adjusted for site. Effect sizes are reported as risk differences with 95% CIs. Exact p-values are not reported, but the trial uses a non-inferiority design with confidence intervals, which is appropriate. Data presentation includes per-group n and confidence intervals. Mathematical plausibility checks are not applicable due to continuous outcomes and large N.

Sub-criteria

tests namedADEQUATE

exact p valuesN/A

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedINADEQUATE

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 effect sizes and confidence intervals reported; p-values are not the primary focus.

Evidence

“The primary analysis of the primary efficacy outcome was adjusted for trial site using robust standard errors in a generalised linear binomial model with an identity link function.”

Statistical analysisFind in source

paraphrase[Results, paragraph 3]

“The risk difference adjusted for site was 0.9% with an upper confidence bound (UB) of 7.8%, meeting the criterion for non-inferiority.”

absence[Methods, Statistical methods]

Statistical software is not identified.

PASSReviewer 2· 90% conf

Statistical methods are appropriate and well-described, with effect sizes and confidence intervals reported.

Evidence

“The primary analysis of the primary efficacy outcome was adjusted for trial site using robust standard errors in a generalised linear binomial model with an identity link function.”

Statistical analysisFind in source

“The risk difference adjusted for site was 0.9% with an upper confidence bound (UB) of 7.8%, meeting the criterion for non-inferiority”

Results ¶4Find in source

absence[Methods, Statistical methods]

Statistical software is not identified.

The paper mentions that further details are available in protocol publications and at nejm.org, but does not provide a clear data availability statement with a concrete access route. No repository deposit or accession numbers are provided. Code sharing is not applicable as no bespoke code is mentioned.

Sub-criteria

code sharingN/A

accession numbersN/A

repository depositNOT REPORTED

data availability statementINADEQUATE

Per reviewer (2) — the votes behind the verdict

WARNReviewer 1· 80% conf

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

Evidence

“Further details about the trial design can be found in the and in the protocol publications and at nejm.org (https://www.nejm.org/) .”

Methods ¶1Find in source

absence[Entire paper]

No repository deposit is mentioned.

WARNReviewer 2· 80% conf

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

Evidence

absence[End of paper]

No explicit data availability statement is present.

“Further details about the trial design can be found in the and in the protocol publications and at nejm.org (https://www.nejm.org/) .”

Methods ¶1Find in source

The trial is registered with NCT04110340. Methods are detailed enough for replication. Limitations are discussed, including adherence and bubo measurement issues. Conclusions are proportional to the evidence. Funding and COI are stated. Reporting guideline adherence is not explicitly mentioned.

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

“Trial registration number : NCT04110340”

AbstractFind in source

“However, patient’s adherence to the prescribed regimen might be higher in the trial than in practice as all cases were hospitalised for the first three days of treatment and were subsequently seen daily by village health workers, which might not be routine practice.”

Discussion ¶3Find in source

“This work was supported by the UK Foreign, Commonwealth and Development Office and Wellcome [216273/Z/19/Z].”

FundingFind in source

PASSReviewer 2· 90% conf

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

Evidence

“Trial registration number : NCT04110340”

AbstractFind in source

Discussion ¶3Find in source

“This work was supported by the UK Foreign, Commonwealth and Development Office and Wellcome [216273/Z/19/Z].”

FundingFind in source

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

Broken references and links

None found

References checked against Crossref, OpenAlex and Retraction Watch for retractions and resolvability, plus declared data and code links probed for whether they resolve to content matching the paper.

Checked — nothing surfaced.

Checked 22 references by DOI: 12 verified — 10 no DOI (shown, not verified).

1 data/code link found; not probed for liveness in this run.

Copyediting

6 minor

Wording, consistency and formatting errors that need correcting before submission.

No major wording or formatting errors. 6 minor suggestions below.

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

Kaimen Rigor Action ItemsFinal pass before journal submission

The published work is robust overall, but an informed reader should weigh the vague data availability statement and the minor internal inconsistency (11 vs 12 districts) as reporting gaps. No evidence of statistical errors or retracted citations was found, but the statistics were not independently recomputed.

1.
HIGHdata code
Add a clear data availability statement in the Methods or a dedicated section, specifying where de-identified data can be accessed (e.g., a repository or managed access process) and any conditions.
The current statement is vague and does not provide a concrete access route, which is a reporting gap for a data-driven trial.
2.
HIGHdata code
Deposit the de-identified dataset in a public repository (e.g., Dryad, Zenodo) with a DOI, or provide a data access committee contact and procedure.
No repository deposit is mentioned, which limits reproducibility and transparency.
3.
HIGHreporting
Resolve the internal contradiction between the abstract (11 districts) and the results (12 districts) by verifying the correct number and correcting one of them.
An internal contradiction in a key descriptive statistic undermines reader trust and may warrant an erratum.
4.
MEDIUMstatistics
Identify the statistical software used (e.g., R version, Stata version) in the Statistical methods section.
Both reviewers flagged that the statistical software is not named, which is a minor reporting gap for reproducibility.
5.
MEDIUMreporting
Mention adherence to a reporting guideline such as CONSORT in the Methods or a separate statement.
The paper does not explicitly state adherence to a reporting guideline, which is expected for a randomized trial.
6.
MEDIUMethics
Add a statement on regulatory compliance, e.g., 'The trial was conducted in accordance with the Declaration of Helsinki and ICH-GCP guidelines.'
Reviewer 1 noted that regulatory compliance is not explicitly stated, which is a minor ethics reporting gap.
7.
MEDIUMreporting
Fix the incomplete sentence in the Methods first paragraph: 'Further details about the trial design can be found in the and in the protocol publications' by removing the stray 'the' or completing the sentence.
The copyedit flagged this as an incomplete sentence, which is a clarity issue.
8.
LOWcopyedit
Use en dashes for date ranges (e.g., 2020–2024) consistently throughout the manuscript.
The copyedit flagged inconsistent use of hyphens vs en dashes in date ranges.
9.
LOWcopyedit
Remove the extra space before the colon in 'Trial registration number : NCT04110340'.
Minor formatting issue flagged by the copyedit.
10.
LOWcopyedit
Use consistent currency formatting (e.g., US$14, US$6.5, US$0.75) in the Discussion.
The copyedit flagged inconsistent currency formatting.

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Ciprofloxacin versus Aminoglycoside-Ciprofloxacin for Bubonic Plague.

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DOI

10.1056/NEJMoa2413772

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Record fingerprint

97e2851259e99b3b0ace4724084fae5b3999f46899bdd7d4f125fc98ec0fa929

Verify via API

Issued Aug 15, 2026Engine 7.39.0

Alpha1 assesses methodological rigor, not the importance of the findings. See how we calibrate →

Kaimen Rigor review

Kaimen 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: highEngine: 7.39.0Source: full text

Not verified in this report

Statistics were not checked: no recomputable values were found in this text — no test statistic reported with its degrees of freedom, no effect estimate printed with both a 95% CI and a p-value, and no percentage printed with both its count and its denominator.

Findings by category

101ArithmeticNumerical inconsistencies 02OverreachNone found 03AuthenticityNone found 104DisclosureReporting gaps 05AvailabilityNone found 06Copyedit6 minor suggestions

Numerical inconsistencies

1 finding · worst low

Internal contradictions in the reported numbersAssessed

Overstated conclusions

None found

Checked — nothing surfaced.

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

Efficacy claim is anchored to an adequate endpoint and a meaningful effect.

Data authenticity concerns

None found

Checked — nothing surfaced.

Reporting gaps

1 finding · worst medium

Data/code availability incompleteAssessed

Eight Dimensions7 pass · 1 warn

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 by citing prior research and guidelines, and provides a logical rationale for the trial.

Evidence

paraphrase[Background, paragraph 3]

“While several treatment regimens for plague are recommended in treatment guidelines, they are supported by weak evidence, with no pivotal randomised controlled trials successfully completed.”

Introduction ¶4Find in source

absence[Background]

Limitations of prior research are not explicitly discussed in detail.

PASSReviewer 2· 90% conf

The paper establishes a clear scientific premise by citing prior research and guidelines, and provides a logical rationale for the trial.

Evidence

paraphrase[Introduction, paragraph 3]

“While several treatment regimens for plague are recommended in treatment guidelines, they are supported by weak evidence, with no pivotal randomised controlled trials successfully completed.”

Introduction ¶4Find in source

“IMASOY filled this knowledge gap by generating evidence of the efficacy and safety of two regimens included in Madagascar’s and international treatment guidelines for bubonic plague.”

Discussion ¶5Find in source

Sub-criteria

controlsN/A

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· 90% conf

The trial design is rigorous with clear randomization, sample size calculation, and pre-specified analysis populations, though blinding was not possible.

Evidence

MethodsFind in source

“Blinding of patients and the trial team to treatment allocation was not possible due to the different treatment administration routes.”

MethodsFind in source

PASSReviewer 2· 95% conf

The trial design is rigorous with clear randomisation, sample size calculation, and pre-specified analysis populations.

Evidence

MethodsFind in source

“Blinding of patients and the trial team to treatment allocation was not possible due to the different treatment administration routes.”

MethodsFind in source

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

Demographic and clinical characteristics are well reported, including age, sex, and health status.

Evidence

“Male (%) | 267 (59.5) | 118 (53.2) | 63 (56.8) | 55 (49.5)”

Table 1Find in source

“Age in years, median (range) | 12.0 (0.0 - 72.0) | 14.0 (2.0 - 72.0) | 14.0 (2.0 - 72.0) | 14.0 (2.0 - 64.0)”

Table 1Find in source

“All patients presented with fever and at least one bubo (range for number of buboes per patient 1-5), mostly inguinal (71%) and painful – median pain score 7, range 0-10.”

Results ¶2Find in source

PASSReviewer 2· 90% conf

Biological variables are well reported for a human trial, including sex, age, and demographics.

Evidence

paraphrase[Abstract]

“53.2% male”

“median (range) age 14 years (2-72)”

AbstractFind in source

“Male (%) | 267 (59.5) | 118 (53.2) | 63 (56.8) | 55 (49.5)”

Table 1Find in source

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceINADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

Ethical approvals from named committees and informed consent are clearly documented.

Evidence

Methods ¶1Find in source

“Patients were randomised following consent by the trial team at participating sites”

MethodsFind in source

absence[Methods]

Regulatory compliance is not explicitly stated.

PASSReviewer 2· 95% conf

Ethical approvals are clearly documented with named ethics committees and informed consent.

Evidence

Methods ¶1Find in source

“Patients were randomised following consent by the trial team at participating sites”

MethodsFind in source

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedINADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The investigational drugs are adequately identified with doses and regimens, and statistical software is identified.

Evidence

MethodsFind in source

absence[Methods, Statistical methods]

Statistical software is not explicitly named.

PASSReviewer 2· 85% conf

The investigational drugs are adequately identified, and statistical software is mentioned.

Evidence

MethodsFind in source

absence[Methods, Statistical methods]

Statistical software is not explicitly identified.

Sub-criteria

tests namedADEQUATE

exact p valuesN/A

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedINADEQUATE

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 effect sizes and confidence intervals reported; p-values are not the primary focus.

Evidence

“The primary analysis of the primary efficacy outcome was adjusted for trial site using robust standard errors in a generalised linear binomial model with an identity link function.”

Statistical analysisFind in source

paraphrase[Results, paragraph 3]

“The risk difference adjusted for site was 0.9% with an upper confidence bound (UB) of 7.8%, meeting the criterion for non-inferiority.”

absence[Methods, Statistical methods]

Statistical software is not identified.

PASSReviewer 2· 90% conf

Statistical methods are appropriate and well-described, with effect sizes and confidence intervals reported.

Evidence

“The primary analysis of the primary efficacy outcome was adjusted for trial site using robust standard errors in a generalised linear binomial model with an identity link function.”

Statistical analysisFind in source

“The risk difference adjusted for site was 0.9% with an upper confidence bound (UB) of 7.8%, meeting the criterion for non-inferiority”

Results ¶4Find in source

absence[Methods, Statistical methods]

Statistical software is not identified.

Sub-criteria

code sharingN/A

accession numbersN/A

repository depositNOT REPORTED

data availability statementINADEQUATE

Per reviewer (2) — the votes behind the verdict

WARNReviewer 1· 80% conf

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

Evidence

“Further details about the trial design can be found in the and in the protocol publications and at nejm.org (https://www.nejm.org/) .”

Methods ¶1Find in source

absence[Entire paper]

No repository deposit is mentioned.

WARNReviewer 2· 80% conf

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

Evidence

absence[End of paper]

No explicit data availability statement is present.

“Further details about the trial design can be found in the and in the protocol publications and at nejm.org (https://www.nejm.org/) .”

Methods ¶1Find in source

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

“Trial registration number : NCT04110340”

AbstractFind in source

Discussion ¶3Find in source

“This work was supported by the UK Foreign, Commonwealth and Development Office and Wellcome [216273/Z/19/Z].”

FundingFind in source

PASSReviewer 2· 90% conf

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

Evidence

“Trial registration number : NCT04110340”

AbstractFind in source

Discussion ¶3Find in source

“This work was supported by the UK Foreign, Commonwealth and Development Office and Wellcome [216273/Z/19/Z].”

FundingFind in source

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

Broken references and links

None found

References checked against Crossref, OpenAlex and Retraction Watch for retractions and resolvability, plus declared data and code links probed for whether they resolve to content matching the paper.

Checked — nothing surfaced.

Checked 22 references by DOI: 12 verified — 10 no DOI (shown, not verified).

1 data/code link found; not probed for liveness in this run.

Copyediting

6 minor

Wording, consistency and formatting errors that need correcting before submission.

No major wording or formatting errors. 6 minor suggestions below.

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

Kaimen Rigor Action ItemsFinal pass before journal submission

1.
HIGHdata code
Add a clear data availability statement in the Methods or a dedicated section, specifying where de-identified data can be accessed (e.g., a repository or managed access process) and any conditions.
The current statement is vague and does not provide a concrete access route, which is a reporting gap for a data-driven trial.
2.
HIGHdata code
Deposit the de-identified dataset in a public repository (e.g., Dryad, Zenodo) with a DOI, or provide a data access committee contact and procedure.
No repository deposit is mentioned, which limits reproducibility and transparency.
3.
HIGHreporting
Resolve the internal contradiction between the abstract (11 districts) and the results (12 districts) by verifying the correct number and correcting one of them.
An internal contradiction in a key descriptive statistic undermines reader trust and may warrant an erratum.
4.
MEDIUMstatistics
Identify the statistical software used (e.g., R version, Stata version) in the Statistical methods section.
Both reviewers flagged that the statistical software is not named, which is a minor reporting gap for reproducibility.
5.
MEDIUMreporting
Mention adherence to a reporting guideline such as CONSORT in the Methods or a separate statement.
The paper does not explicitly state adherence to a reporting guideline, which is expected for a randomized trial.
6.
MEDIUMethics
Add a statement on regulatory compliance, e.g., 'The trial was conducted in accordance with the Declaration of Helsinki and ICH-GCP guidelines.'
Reviewer 1 noted that regulatory compliance is not explicitly stated, which is a minor ethics reporting gap.
7.
MEDIUMreporting
Fix the incomplete sentence in the Methods first paragraph: 'Further details about the trial design can be found in the and in the protocol publications' by removing the stray 'the' or completing the sentence.
The copyedit flagged this as an incomplete sentence, which is a clarity issue.
8.
LOWcopyedit
Use en dashes for date ranges (e.g., 2020–2024) consistently throughout the manuscript.
The copyedit flagged inconsistent use of hyphens vs en dashes in date ranges.
9.
LOWcopyedit
Remove the extra space before the colon in 'Trial registration number : NCT04110340'.
Minor formatting issue flagged by the copyedit.
10.
LOWcopyedit
Use consistent currency formatting (e.g., US$14, US$6.5, US$0.75) in the Discussion.
The copyedit flagged inconsistent currency formatting.

Full text (28,771 chars)Analyzed: Aug 15, 2026