Alpha¹ by KaimenConfidential

Kaimen Rigor review

Ciprofloxacin versus Aminoglycoside-Ciprofloxacin for Bubonic Plague.

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

DOI: 10.1056/NEJMoa2413772
Record issued: 2026-08-10
Engine: 7.29.0
Exported: 2026-09-22

Prepared by Alpha1. This document is confidential: it is intended for the recipient it was shared with and must not be redistributed. The live record at alpha1science.com/verify/09949dc1-b802-49d7-9cce-ffb9f7674158 is authoritative.

Kaimen Rigor review

Kaimen Rigor reviewed

2 / 5

Weak — serious problems found

Interventional Study

Critical

High-priority

How this rating was calculated

Started at 5★ — deductions

IntegrityIntegrity concern ×4−2★
ReportingData & code availability not met−0.5★
ReportingEthical approvals partially met−0.25★
ReportingKey resources partially met−0.25★

Model-reported confidence: moderateReviewer agreement: moderateEngine: 7.29.0Source: 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.
The numeric-impossibility checks (GRIM/GRIMMER/DEBIT/SPRITE) did not run on this paper: the pass that reads its reported means did not complete. No reported mean was checked for arithmetic impossibility.
No data or code availability links were detected to verify.

Biggest issues

01Data and code not shared
highDisclosurereviewer-assessedFull detail
No data availability statement is provided, and no data repository or code sharing is mentioned.

Findings by category

101ArithmeticNumerical inconsistencies 102OverreachOverstated conclusions 03AuthenticityNone found 304DisclosureReporting gaps 05AvailabilityNone found · partly checked 106CopyeditCopyediting

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.

This is a well-conducted non-inferiority RCT with a strong scientific premise, rigorous design, and transparent reporting of outcomes. The main weaknesses are the absence of a data availability statement, missing statistical software identification, and a minor arithmetic error in a secondary outcome. The paper also lacks explicit statements on regulatory compliance and conflicts of interest.

All eight dimensions were scored as applicable. The three independent reviewer runs converged on most dimensions, with minor disagreements on ethical approvals (regulatory compliance statement) and key resources (adequacy of drug identification). The statistical analysis error is a cosmetic arithmetic inconsistency in a secondary endpoint. The citation and statistics verification components found no retracted or fabricated references and no machine-verifiable statistical inconsistencies beyond the reported arithmetic error.

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

lowinternal contradiction
In the secondary bubo-size outcome, the reported percentage 46.8% does not match the given numerator 51/111 (which equals 45.9%); 46.8% would require 52/111. This is a cosmetic arithmetic inconsistency in a secondary endpoint and does not change the non-inferiority conclusion.
“failure rates were 36.0%, (40/111) and 46.8% (51/111)”
ResultsFind in source
lowinternal contradiction
The secondary bubo-size outcome reports failure rates of '36.0%, (40/111) and 46.8% (51/111)'; 51/111 = 45.9% (rounds to 46.0%), not 46.8%. The percentage matches a denominator of 109 (51/109 = 46.8%), so one of the printed numbers is inconsistent with the others.
“failure rates were 36.0%, (40/111) and 46.8% (51/111) in the control and intervention arm”
Results ¶2Find in source
lowinternal contradiction
The number of districts differs between the Abstract (11 districts) and the Results (12 districts) for the same recruitment period.
at 47 sites in 11 districts in Madagascar ... Recruitment took place at 47 primary and secondary peripheral health centres and hospitals in 12 districts
Abstractreviewer’s wording
lowinternal contradiction
The Abstract states enrolment at 47 sites in 11 districts, while the Results state recruitment at 47 centres in 12 districts.
Abstract: 'at 47 sites in 11 districts in Madagascar'; Results: 'Recruitment took place at 47 primary and secondary peripheral health centres and hospitals in 12 districts'
Abstract ¶1reviewer’s wording

Overstated conclusions

1 finding · worst low

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.

Conclusions only partially backed by the presented evidenceAssessed

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

partialReviewer 2
The bubo-size secondary outcome is unreliable due to measurement error rather than a true treatment inferiority.
The paper offers a training exercise showing variable measurement error of buboes, but the exercise is not quantitatively linked to the observed site-adjusted (inferior) versus unadjusted (inconclusive) divergence, so the attribution is plausible but not fully demonstrated.
Evidence: Statement of a training exercise using artificial buboes with digital callipers showing variable measurement error, plus lack of correlation with clinical status.
“We also confirmed variable, inaccurate measurement error of buboes by research assistants within and between seasons using a digital calliper in a training exercise using artificial buboes.”
Discussion ¶3Find in source
supportedReviewers 1, 2, 3
Ciprofloxacin oral monotherapy for 10 days is non-inferior to aminoglycoside-ciprofloxacin sequential combination for treating bubonic plague.
The primary ITTI analysis shows a risk difference of 0.9% with an upper bound of 7.8%, below the pre-specified 15% non-inferiority margin, and results are consistent across ITT, PP and PPI populations.
Evidence: Abstract and Results: '9.0% (10/111) vs. 8.1% (9/111) treatment failures, 0.9% difference (95% confidence interval –6.0 to 7.8%)' and Table 2 adjusted risk differences.
“Ciprofloxacin oral monotherapy for 10 days is non-inferior to aminoglycoside-ciprofloxacin sequential combination for treating bubonic plague.”
Table 2Find in source
supportedReviewers 1, 2, 3
Both treatments were effective, with 90% efficacy and 4% CFR overall.
The observed failure rates (8.1% and 9.0%) and deaths (4 and 5) are consistent with the stated 90% efficacy and 4% CFR.
Evidence: Results: 'Both treatments were effective, with 90% efficacy and 4% CFR overall.' and Table 2 failure/death counts.
“Both treatments were effective, with 90% efficacy and 4% CFR overall.”
DiscussionFind in source
supportedReviewer 1
Non-inferiority was consistent in other pre-specified analysis populations.
Table 2 reports adjusted risk-difference upper bounds below 15% for ITT, PP and PPI populations, supporting the claim.
Evidence: Table 2 adjusted risk differences for ITT, PP and PPI populations.
“Non-inferiority was consistent in other pre-specified analysis populations.”
Table 2Find in source
supportedReviewer 1
The bubo-size secondary outcome is not clinically meaningful and its inferiority result is likely due to measurement error.
The paper provides a documented digital-calliper training exercise showing variable measurement error across sites and seasons, which supports the interpretation that the bubo-size result reflects measurement unreliability.
Evidence: Discussion describes the artificial-bubo measurement exercise and inconsistency between adjusted (inferior) and unadjusted (inconclusive) analyses.
“Uncertainty and unreliability in the bubo size data is highlighted in the observed differences in analyses for this secondary outcome adjusted for site (inferior) and unadjusted (inconclusive)”
DiscussionFind in source
supportedReviewer 1
IMASOY filled a knowledge gap by generating evidence on the efficacy and safety of the two regimens.
The trial provides the first pivotal RCT evidence for these regimens, consistent with the stated gap of no successfully completed pivotal plague treatment trials.
Evidence: Background notes 'no pivotal randomised controlled trials successfully completed'; the trial provides primary and safety outcomes.
“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.”
IntroductionFind in source
supportedReviewer 2
IMASOY's study population is representative of the typical bubonic plague case occurring in Madagascar.
The claim is backed by the stated enrolment of 61% of all confirmed/probable cases in the recruiting districts during 2020-2024.
Evidence: IMASOY enrolled 220 (61%) of the 358 total confirmed/probable cases in the recruiting districts (unpublished National Plague Laboratory data).
“during 2020-2024, IMASOY enrolled 220 (61%) of the total 358 total confirmed/probable cases of bubonic plague recorded in the districts where IMASOY recruiting sites were located”
Discussion ¶2Find in source
supportedReviewer 3
The study population is representative of the typical bubonic plague case occurring in Madagascar.
The paper notes that IMASOY enrolled 61% of all confirmed/probable cases in the districts during the study period.
Evidence: Discussion, paragraph 2
IMASOY enrolled 220 (61%) of the total 358 total confirmed/probable cases of bubonic plague recorded in the districts where IMASOY recruiting sites were located.
Discussion ¶2reviewer’s wording
supportedReviewer 3
Ten days of oral ciprofloxacin is an effective alternative to a regimen requiring gentamicin injections.
The non-inferiority result supports this conclusion, and the discussion highlights practical advantages.
Evidence: Primary analysis and discussion of practical benefits
“for the treatment of bubonic plague, ten days of oral ciprofloxacin is an effective alternative to a regimen requiring gentamicin injections.”
DiscussionFind in source

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

ADEQUATESurrogate endpoint
Primary endpoint is a composite of clinical outcomes (death, fever, secondary pneumonic plague, alternative treatment) – not a surrogate.
“The primary efficacy outcome was treatment failure assessed on Day (D11) using a composite outcome defined as death, fever, development of secondary pneumonic plague or receipt of alternative or additional treatment for plague up to and including D11.”
Find in source
ADEQUATEEffect size
Non-inferiority demonstrated with risk difference 0.9% (95% CI -6.0 to 7.8%), within pre-specified non-inferiority margin of 15%. Both arms had low failure rates (8-9%).
“Ciprofloxacin monotherapy was non-inferior to control: 9.0% (10/111) vs. 8.1% (9/111) treatment failures, 0.9% difference (95% confidence interval –6.0 to 7.8%).”
Find in source

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

3 findings · worst high

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 and code not sharedAssessed
Ethics/consent reporting incompleteAssessed
Key resources under-identified (antibodies, cell lines, RRIDs)Assessed

Eight Dimensions5 pass · 2 warn · 1 fail

The introduction cites evidence on plague burden, treatment guidelines, and the lack of high-quality RCTs. It clearly states the rationale for comparing the two regimens and addresses limitations of prior studies.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

The paper firmly establishes the scientific foundation: plague treatment guidelines rest on weak evidence and no pivotal RCT has been completed, which directly motivates the trial.

Evidence

“they are supported by weak evidence, with no pivotal randomised controlled trials successfully completed”

IntroductionFind in source

“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)”

IntroductionFind in source

PASSReviewer 2· 90% conf

The paper clearly establishes the scientific foundation: plague treatment guidelines rest on weak evidence with no completed pivotal RCTs, providing a strong rationale for the trial.

Evidence

“they are supported by weak evidence, with no pivotal randomised controlled trials successfully completed”

Introduction ¶2Find in source

IntroductionFind in source

PASSReviewer 3· 95% conf

The paper establishes a strong scientific premise by citing prior research, acknowledging weaknesses in current evidence, and providing a logical rationale for the trial.

Evidence

paraphrase[Introduction, paragraph 5]

“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.”

paraphrase[Introduction, paragraph 6]

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

“Current treatment guidelines are based on weak evidence.”

Introduction ¶5Find in source

Randomization method is described (computer-generated with random block sizes). Blinding was not feasible due to different routes of administration, and this is stated. Power analysis is provided. Inclusion/exclusion criteria are detailed. The primary analysis population (ITTI) is defined.

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· 90% conf

Core design elements for a human RCT are all adequate: computer-generated block randomisation stratified by site, a justified open-label design, a pre-specified power calculation, and clear inclusion/exclusion criteria and analysis populations.

Evidence

“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

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

MethodsFind in source

“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%”

MethodsFind in source

PASSReviewer 2· 90% conf

Core methodological elements of this human RCT are well reported: computer-generated randomisation with random block sizes stratified by site, a justified open-label design, a full a priori sample-size calculation, and pre-specified eligibility and analysis populations.

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

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

MethodsFind in source

PASSReviewer 3· 95% conf

The study design is rigorous with computer-generated randomization, stratified by site, pre-specified sample size calculation, and clear inclusion/exclusion criteria.

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

“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

Table 1 reports sex, age, fever, bubo characteristics, and other clinical variables for both ITT and ITTI populations. Sex is reported for both arms. Health status is detailed.

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· 70% conf

Sex, age and health status are reported for the human population; both sexes are enrolled, so no single-sex justification is needed.

Evidence

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

Table 1Find in source

“All patients presented with fever and at least one bubo (range for number of buboes per patient 1-5)”

Table 1Find in source

PASSReviewer 2· 85% conf

Sex and age are reported for both ITT and ITTI populations, and clinical health status is described; biological-variable reporting is adequate for a human trial.

Evidence

“The median age (range) in the ITTI population was 14 (2-72) years and 12 (0-72) years in the ITT”

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 ¶1Find in source

PASSReviewer 3· 95% conf

Biological variables are adequately reported: age, sex, and health status are provided in the baseline table.

Evidence

paraphrase[Table 1]

“Male (%) 53.2; Age in years, median (range) 14.0 (2.0 - 72.0)”

“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 ¶6Find in source

The trial was approved by three named bodies with protocol numbers (Oxford Tropical Research Ethics Committee 45-18; Comité d'Éthique et de Recherche Biomédicale à Madagascar; LSHTM 17911), which is adequate. Informed consent is evidenced by the statement that patients were randomised following consent and by a documented withdrawal of consent. However, no explicit statement of compliance with a named framework such as the Declaration of Helsinki or ICH-GCP appears, so regulatory_compliance is not_reported.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceNOT REPORTED

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 75% conf

Named ethics committees with protocol numbers approved the trial and consent was obtained, but no explicit adherence to a recognised regulatory framework (e.g. Declaration of Helsinki) is stated.

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)”

MethodsFind in source

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

MethodsFind in source

absence[Methods]

No explicit regulatory-framework compliance statement (e.g. Declaration of Helsinki)

WARNReviewer 2· 70% conf

Named ethics committees approved the trial with protocol numbers and informed consent is described, but no explicit regulatory-compliance statement (e.g., Declaration of Helsinki) is made.

Evidence

Methods ¶1Find in source

“Patients were randomised following consent by the trial team”

MethodsFind in source

absence[Throughout manuscript]

No explicit regulatory-compliance statement (e.g., Declaration of Helsinki) is present.

PASSReviewer 3· 90% conf

Ethical approvals from three named committees are provided, and informed consent is mentioned.

Evidence

Methods ¶1Find in source

“Patients were randomised following consent”

MethodsFind in source

Ciprofloxacin and aminoglycosides are named with doses and regimens. However, no statistical software (e.g., SAS, R, Stata) is mentioned. No other key resources like antibodies or cell lines are used.

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedNOT REPORTED

Per reviewer (3) — the votes behind the verdict

FAILReviewer 1· 60% conf

The investigational drugs are named with full dose/regimen but no manufacturer/source, and the statistical software used for analysis is never 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”

MethodsFind in source

absence[Methods, Statistical methods]

No statistical analysis software is identified

WARNReviewer 2· 70% conf

The investigational drugs (ciprofloxacin, streptomycin, gentamicin) are identified with full dose/regimen details, but no manufacturer/source is given and the statistical software is not identified.

Evidence

“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]

No statistical software is identified.

WARNReviewer 3· 85% conf

The investigational drugs are adequately identified, but the statistical software used is not reported.

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 identified.

The primary analysis uses a generalized linear binomial model with robust SEs. Risk differences and 95% CIs are reported. The paper includes a flow diagram and baseline table. No p-values are reported, so exact_p_values is not applicable. The software is not named.

Sub-criteria

tests namedADEQUATE

exact p valuesN/A

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedNOT REPORTED

assumptions verifiedADEQUATE

mathematical plausibilityPASS

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 70% conf

The analysis is reported by estimation with confidence intervals (no p-values), which is complete for a non-inferiority trial, but the analysis software is unnamed and one secondary proportion (46.8% vs 51/111) is arithmetically inconsistent.

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

“0.9% difference (95% confidence interval –6.0 to 7.8%)”

AbstractFind in source

“failure rates were 36.0%, (40/111) and 46.8% (51/111)”

ResultsFind in source

PASSReviewer 2· 80% conf

The primary analysis is a well-specified site-adjusted GLM with robust standard errors, effect sizes are reported with 95% CIs, analysis populations are defined, and the reported proportions are arithmetically consistent. The only gap is that no statistical software is named.

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

“9.0% (10/111) vs. 8.1% (9/111) treatment failures, 0.9% difference (95% confidence interval –6.0 to 7.8%)”

AbstractFind in source

“Total: treatment failure | n (%, 95% CI) | 9 (8.1, 3.8 - 14.8) | 10 (9.0, 4.4 - 15.9)”

Table 2Find in source

PASSReviewer 3· 90% conf

Statistical methods are appropriate, with named tests, effect sizes with CIs, and adequate data presentation. Software is not identified, but this does not affect the overall rating.

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

“risk difference adjusted for site was 0.9% with an upper confidence bound (UB) of 7.8%”

Results ¶7Find in source

paraphrase[Figure 1 legend]

“Figure 1 is a study flow diagram (CONSORT diagram).”

The paper does not include a statement about where data can be accessed. The trial registration is provided, but that is not a data availability statement. No code is shared.

Sub-criteria

code sharingN/A

accession numbersN/A

repository depositN/A

data availability statementNOT REPORTED

Per reviewer (3) — the votes behind the verdict

FAILReviewer 1· 70% conf

No data availability statement is present, which is required for a clinical trial; patient-level data would appropriately use managed access, but no access route is described.

Evidence

absence[Entire paper (incl. Funding and Supplementary sections)]

No data availability statement is present

FAILReviewer 2· 85% conf

No data availability statement appears anywhere in the paper, which is a required element for a clinical trial; no repository deposit, accession number, or code-sharing statement is provided.

Evidence

absence[Throughout manuscript]

No data availability statement is present.

FAILReviewer 3· 90% conf

No data availability statement is provided, and no data repository or code sharing is mentioned.

Evidence

absence[Entire paper]

No data availability statement is present.

The paper is well-structured with detailed methods, registration number, and discussion of limitations. The CONSORT flow diagram is present but not explicitly referenced. No COI statement is included.

Sub-criteria

funding coiNOT REPORTED

trial registrationADEQUATE

reporting guidelineNOT REPORTED

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 70% conf

Methods are detailed, the trial is registered (NCT04110340), all pre-specified outcomes including negative secondary results are reported, limitations are discussed, and funding is disclosed; CONSORT adherence and an explicit COI statement are not stated.

Evidence

paraphrase[Abstract; Methods]

“Trial registration number: NCT04110340”

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

FundingFind in source

“an endpoint of treatment failure at Day 11 that included an additional component for failure of <25% reduction in bubo size was inferior in a comparative analysis, however this composite measure of treatment failure is not considered clinically meaningful”

DiscussionFind in source

PASSReviewer 2· 80% conf

Methods are detailed, the trial is registered (NCT04110340), outcomes including negative ones are reported, limitations are thoroughly discussed, and conclusions are proportional. Gaps: no explicit CONSORT reference and no conflicts-of-interest statement.

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”

Discussion ¶2Find in source

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

FundingFind in source

PASSReviewer 3· 85% conf

Methods are complete, trial registration is reported, limitations are discussed, and conclusions are proportional. However, no reporting guideline is referenced, and a conflict of interest statement is missing.

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 ¶4Find 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.

ClinicalTrials.gov

NCT04110340

Broken references and links

None found · partly checked

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.

Nothing surfaced — but not everything feeding this category ran (missing: data/code link verification), so read this as a partial clean bill.

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

NO DOI
Plague
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Plague Outbreak Toolbox
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Report of the Bombay Plague Committee, appointed by government resolution No. 1204/720P, on the plague in Bombay, for the period extending from the 1st July 1897 to the 30th April 1898
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Manual for plague surveillance, diagnosis, prevention and control
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Plague around the world in 2019 – La peste dans le monde en 2019
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Plague Bioterrorism Response Toolkit
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Animal Rule Information
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
WHO guidelines for plague management: revised recommendations for the use of rapid diagnostic tests, fluoroquinolones for case management and personal protective equipment for prevention of post-mortem transmission
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Chapter 6 - Aminoglycoside antibiotics
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Products Approved for Other Bioterrorism Emergencies
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).

Copyediting

1 finding · worst low

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

Wording or formatting errors that need correctingAssessed

12 copyedit issues flagged (3 major): mostly consistency, clarity, grammar.

MAJORclarityMethods
“Further details about the trial design can be found in the and in the protocol publications and at nejm.org”
→ Complete the broken reference: 'Further details about the trial design can be found in the protocol publications and at nejm.org'.
Broken sentence with a dangling 'the'.
MAJORgrammarFunding
“to any Author Accepted Manuscript version arising from this s”
→ Complete the truncated sentence ('arising from this submission').
Funding/text truncated mid-sentence.
MAJORotherReferences / Supplement
“ism Emergencies ( https://www.fda.gov/drugs/bioterrorism-and-drug-preparedness/products-approved-other-bioterrorism-emergencies )”
→ Restore the correct title and reference text for the FDA source.
Garbled reference text; many citation placeholders appear empty in the reference list.
MINORconsistencyAbstract vs Results
“at 47 sites in 11 districts in Madagascar ... in 12 districts over five transmission seasons”
→ Reconcile the number of districts (11 in Abstract, 12 in Results).
Internal inconsistency in district count.
MINORconsistencyResults
“failure rates were 36.0%, (40/111) and 46.8% (51/111)”
→ Correct the percentage: 51/111 = 45.9%, so either change to 45.9% or adjust the numerator to 52.
Arithmetic mismatch between numerator and reported percentage.
MINORconsistencyAbstract vs Results
“Abstract: 'at 47 sites in 11 districts in Madagascar'; Results: 'Recruitment took place at 47 primary and secondary peripheral health centres and hospitals in 12 districts'”
→ Reconcile the number of districts (11 vs 12).
Internal inconsistency between abstract and results.
MINORpunctuationAbstract
“Trial registration number : NCT04110340”
→ Remove stray space before the colon.
Minor spacing issue.
MINORgrammarIntroduction, paragraph 4
“The number of cases has been steadily declining over past century”
→ The number of cases has been steadily declining over the past century
Missing article 'the' before 'past century'.
MINORtypoMethods, paragraph 1
“Further details about the trial design can be found in the and in the protocol publications”
→ Further details about the trial design can be found in the protocol and in the protocol publications
Stray 'the' and missing word after 'the'.
MINORpunctuationMethods, paragraph 1
“Comité d’Ethique et de Recherche Biomédicale à Madagascar (Authorisation N°116-MSANP/CERBM dated 10/09/2018)),”
→ Comité d’Ethique et de Recherche Biomédicale à Madagascar (Authorisation N°116-MSANP/CERBM dated 10/09/2018),
Extra closing parenthesis.
MINORconsistencyAbstract
“United States Food and Drugs Administration”
→ United States Food and Drug Administration
Standard name is 'Food and Drug Administration'.
MINORclarityResults, paragraph 5
“The concurrent randomisation period with gentamicin as the control arm aminoglycoside included 203 confirmed/probable cases; more than the required total sample size of 190 patients for the ITTI analysis.”
→ The concurrent randomisation period with gentamicin as the control arm aminoglycoside included 203 confirmed/probable cases, more than the required total sample size of 190 patients for the ITTI analysis.
Semicolon could be replaced with a comma for clarity.

Kaimen Rigor Action ItemsFinal pass before journal submission

As a post-publication audit, the paper is largely robust in its design, execution, and reporting. However, the missing data availability statement, missing software identification, and the arithmetic error warrant a correction (erratum). Readers should weigh the lack of data access and software transparency when evaluating reproducibility. The ethical and reporting gaps are minor but should be addressed in a corrigendum.

1.
HIGHdata code
Add a data availability statement describing a concrete route for accessing de-identified patient data (e.g., a managed-access platform or a data-access committee with conditions and timeframe). Place it after the Discussion or in a dedicated section.
A data availability statement is required for a clinical trial; its absence is a major gap that undermines reproducibility.
2.
HIGHreporting
Identify the statistical software and version used for all analyses (e.g., 'Stata 17' or 'R version 4.x') in the Statistical methods section.
Missing software identification hinders reproducibility and is a common reviewer requirement.
3.
HIGHethics
Add an explicit statement of regulatory compliance (e.g., 'conducted in accordance with the Declaration of Helsinki and ICH-GCP') in the Methods/Ethics section.
The paper has named ethics committee approvals but lacks an explicit compliance statement, which is a standard reporting expectation.
4.
HIGHstatistics
Correct the arithmetic inconsistency in the secondary bubo-size outcome: 51/111 = 45.9%, not 46.8% (46.8% corresponds to 52/111). Reconcile the numerator and percentage.
A demonstrable arithmetic error, even in a secondary outcome, undermines confidence in data accuracy and should be corrected via erratum.
5.
HIGHreporting
Add a conflict of interest statement for all authors, even if none exist, alongside the funding disclosure.
A COI statement is a standard requirement for transparency; its absence is a reporting gap.
6.
MEDIUMreporting
State adherence to the CONSORT 2010 reporting checklist for randomised trials in the Methods or a dedicated reporting section.
Explicit reference to CONSORT is expected for an RCT; the flow diagram is present but not referenced.
7.
MEDIUMrigor
Provide the manufacturer/source (and batch/lot information if available) for ciprofloxacin, streptomycin, and gentamicin in the Methods/Interventions section.
Full identification of investigational products is essential for reproducibility and is a standard requirement.
8.
MEDIUMcopyedit
Reconcile the district count between the Abstract (11 districts) and the Results (12 districts) for consistency.
Internal inconsistency between the Abstract and Results can confuse readers and should be corrected.
9.
MEDIUMcopyedit
Complete the broken sentence in Methods: 'Further details about the trial design can be found in the and in the protocol publications' should read '...found in the protocol and in the protocol publications' or similar.
A broken sentence with a dangling 'the' is a clear copyedit error that distracts the reader.
10.
MEDIUMcopyedit
Complete the truncated funding text: 'to any Author Accepted Manuscript version arising from this s' should be 'arising from this submission'.
Truncated sentences in the funding section suggest a production error that should be fixed.
11.
MEDIUMcopyedit
Restore the garbled reference text in the References section (e.g., the FDA emergency use reference appears corrupted).
Corrupted reference text undermines the credibility of the reference list and should be corrected.
12.
LOWcopyedit
Remove the extra closing parenthesis in the ethics statement: 'Comité d’Ethique et de Recherche Biomédicale à Madagascar (Authorisation N°116-MSANP/CERBM dated 10/09/2018)),' should have one closing parenthesis.
Minor punctuation error that does not affect interpretation but should be corrected for polish.
13.
LOWcopyedit
Insert the missing article in the Introduction: 'The number of cases has been steadily declining over past century' should be 'over the past century'.
Minor grammatical correction for readability.
14.
LOWcopyedit
Remove the stray space before the colon in the Abstract: 'Trial registration number : NCT04110340' should be 'Trial registration number: NCT04110340'.
Minor formatting issue for consistency.

Full text (28,771 chars)Analyzed: Aug 10, 2026

RigorReviewer 1

RigorReviewer 2

RigorReviewer 3

RigorPre-Submission Reviewer

CopyeditAgent Scribe

CitationsCitation Integrity

StatisticsStatistics Consistency

PreregistrationDeterministic check· no model (rule-based)

The star rating is the report’s one-glance summary. Every paper starts at 5★ and loses stars for the concrete problems the review finds — so a rating is never a vague average, it’s a running total you can read line by line under “How this rating was calculated.”

How stars are deducted

Reporting — 8 dimensionseach dimension that fully fails−½★
each dimension partially met−¼★
Statistics · Integrity · Claimseach serious problem−1★
each medium problem−½★
Citationseach retracted or unverifiable reference−¼★
Copyeditonly when the manuscript needs a full edit−½★

The rating never drops below 1★, and a demonstrable critical failure (an impossible statistic, a proven ethics violation) caps it at 1★ on its own — so the stars can never look healthy when the verdict is CRITICAL.

The rating draws on a panel of agents. Three independent Kaimen Rigor reviewers grade the eight dimensions below across several independent passes (the shown verdict is their majority vote — steadier than any single run), isolate the paper’s major claims and check its own evidence backs them, and flag integrity concerns. Alongside them, a citation agent resolves every reference against Crossref, OpenAlex, and Retraction Watch; a statistics agent recomputes reported tests; and rule-based checks verify that declared data/code links actually resolve. Full text is required — an abstract-only submission is not analyzed.

The eight reporting dimensions

Scientific PremisePrior work, rationale, and how it addresses gaps.

Study Design & RigorRandomization, blinding, power, controls, replication.

Biological VariablesSex, age, species/strain, housing, demographics.

Ethical ApprovalsIRB/IACUC approval, informed consent, regulatory compliance.

Key ResourcesAntibodies, cell lines, organisms, software — identified with persistent IDs.

Statistical ReportingNamed tests, exact p-values, effect sizes, plausible summary stats.

Data & Code AvailabilityAvailability statements, repositories, accession numbers, shared code.

Reporting TransparencyMethods, registration, guidelines, outcomes, limitations, funding/COI.

Graded against NIH, MDAR, ARRIVE 2.0, CONSORT, EQUATOR, and RRID guidelines. A dimension that doesn’t apply to the study type is skipped, never penalized.

This Kaimen Rigor review is model-assisted and is not a substitute for formal expert review. It complements human evaluation by surfacing potential methodological concerns — verify each finding against the source.

Ciprofloxacin versus Aminoglycoside-Ciprofloxacin for Bubonic Plague.

DOI

10.1056/NEJMoa2413772

Record issued

2026-08-10

Engine

7.29.0

Exported

2026-09-22