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
- 2026-08-15
- Engine
- 7.39.0
- Exported
- 2026-09-20
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/d8f9d942-03bc-4d49-b7c9-951b1feb745b is authoritative.
How this rating was calculated
- IntegrityIntegrity concern−0.5★
- ReportingData & code availability partially met−0.25★
- 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.
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 lowValues 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 contradictionThe abstract states 11 districts, while the results state 12 districts.
Abstract: '47 sites in 11 districts'; Results: '47 primary and secondary peripheral health centres and hospitals in 12 districts'
Abstractreviewer’s wording
Overstated conclusions
None foundConclusions 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.
- supportedReviewers 1, 2Ciprofloxacin oral monotherapy for 10 days is non-inferior to aminoglycoside-ciprofloxacin sequential combination for treating bubonic plague.The primary analysis shows the upper bound of the CI is below the non-inferiority margin, and results are consistent across sensitivity analyses.Evidence: Primary ITTI analysis: 9.0% vs 8.1% failure, risk difference 0.9% (95% CI -6.0 to 7.8), upper bound 7.8% < 15%.
“Ciprofloxacin oral monotherapy for 10 days is non-inferior to aminoglycoside-ciprofloxacin sequential combination for treating bubonic plague.”
ConclusionFind in source - supportedReviewers 1, 2Both treatments were effective, with 90% efficacy and 4% CFR overall.The failure rates of ~9% imply ~91% efficacy, and the CFR is 4.5% (5/111) in the intervention arm, consistent with the claim.Evidence: Treatment failure rates of 8.1% and 9.0% in the ITTI population; deaths 4 and 5 per arm.
“Both treatments were effective, with 90% efficacy and 4% CFR overall.”
Discussion ¶1Find in source - supportedReviewer 1The risk of selection bias was reduced by eligibility criteria that excluded only pregnancy and known prior adverse reactions.The eligibility criteria are broad and the study population is representative of typical cases, supporting the claim.Evidence: Eligibility criteria described in Methods; discussion notes enrollment of 61% of confirmed/probable cases in the districts.
“The risk of selection bias was reduced by eligibility criteria that excluded only pregnancy (different treatment guidelines) and known prior adverse reactions to study drugs.”
Discussion ¶2Find in source - supportedReviewer 1Ciprofloxacin was added as first-line treatment in the most recent treatment guidelines of the WHO and CDC, but based on weak evidence.The paper cites that ciprofloxacin is approved by FDA and included in guidelines, and notes the weak evidence base, which is consistent.Evidence: Discussion cites WHO and CDC guidelines and FDA approval.
“Ciprofloxacin was added as first-line treatment in the most recent treatment guidelines of the World Health Organization (WHO) and the United States Centers for Disease Control and Prevention (CDC)”
Discussion ¶4Find in source - supportedReviewer 2The trial's study population is representative of the typical bubonic plague case occurring in Madagascar.The paper provides evidence that the trial enrolled a large proportion of confirmed cases in the districts.Evidence: IMASOY enrolled 220 (61%) of the total 358 confirmed/probable cases in the districts.
“IMASOY’s study population is representative of the typical bubonic plague case occurring in Madagascar: 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 2Ciprofloxacin is an effective alternative to a regimen requiring gentamicin injections.The non-inferiority result supports this conclusion.Evidence: Primary analysis shows non-inferiority.
“In conclusion, 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 endpointThe primary endpoint is a composite of hard clinical outcomes: death, fever, secondary pneumonic plague, or receipt of alternative/prolonged treatment. These are direct clinical outcomes, not surrogate biomarkers. The trial also reports mortality and secondary pneumonic plague rates, which are clinically meaningful.
“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.”
- ADEQUATEEffect sizeThe trial demonstrates non-inferiority of ciprofloxacin monotherapy to the control regimen, with treatment failure rates of 9.0% vs 8.1% (risk difference 0.9%, 95% CI -6.0 to 7.8%). The non-inferiority margin was pre-specified as 15%, and the upper bound of the CI (7.8%) is well below this. The effect is anchored to clinical outcomes (death, secondary pneumonic plague) and the trial was powered to detect non-inferiority. The absolute failure rates are low and comparable to historical data.
“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%).”
Data authenticity concerns
None foundAn 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 mediumRequired 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
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.
“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.”
“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.”
“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.”
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.
“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.”
“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.”
“Blinding of patients and the trial team to treatment allocation was not possible due to the different treatment administration routes.”
“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.”
“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.”
“Blinding of patients and the trial team to treatment allocation was not possible due to the different treatment administration routes.”
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.
“Male (%) | 267 (59.5) | 118 (53.2) | 63 (56.8) | 55 (49.5)”
“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)”
“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.”
“median (range) age 14 years (2-72)”
“Male (%) | 267 (59.5) | 118 (53.2) | 63 (56.8) | 55 (49.5)”
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.
“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).”
“Patients were randomised following consent by the trial team at participating sites”
“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).”
“Patients were randomised following consent by the trial team at participating sites”
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.
“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.”
“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.”
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.
“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.”
“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.”
“The risk difference adjusted for site was 0.9% with an upper confidence bound (UB) of 7.8%, meeting the criterion for non-inferiority”
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.
“Further details about the trial design can be found in the and in the protocol publications and at nejm.org (https://www.nejm.org/) .”
“Further details about the trial design can be found in the and in the protocol publications and at nejm.org (https://www.nejm.org/) .”
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.
“Trial registration number : NCT04110340”
“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.”
“This work was supported by the UK Foreign, Commonwealth and Development Office and Wellcome [216273/Z/19/Z].”
“Trial registration number : NCT04110340”
“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.”
“This work was supported by the UK Foreign, Commonwealth and Development Office and Wellcome [216273/Z/19/Z].”
Registered (1 ID: ClinicalTrials.gov). No reporting guideline cited.
Broken references and links
None foundReferences 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).
- NO DOIPlagueNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIPlague Outbreak ToolboxNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIReport 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 1898No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIManual for plague surveillance, diagnosis, prevention and controlNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIPlague around the world in 2019 – La peste dans le monde en 2019No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIPlague Bioterrorism Response ToolkitNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIAnimal Rule InformationNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIWHO 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 transmissionNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIAminoglycoside antibioticsNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIProducts Approved for Other Bioterrorism EmergenciesNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
1 data/code link found; not probed for liveness in this run.
- datahttps://www.nejm.org/UNVERIFIEDHTTP 403Liveness indeterminate — content not checked.
Copyediting
6 minorWording, 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.
- MINORtypoAbstract, Methods“2020-2024”→ Use en dash: 2020–2024Inconsistent use of hyphen vs en dash in date ranges.
- MINORconsistencyMethods, first paragraph“Further details about the trial design can be found in the and in the protocol publications”→ Remove 'the' or complete the sentence.Incomplete sentence.
- MINORconsistencyResults, paragraph 1“12 districts”→ Check if it should be 11 districts as in the abstract.Abstract says 11 districts, results say 12.
- MINORtypoAbstract“Trial registration number : NCT04110340”→ Remove extra space before colon.Minor formatting issue.
- MINORconsistencyMethods, first paragraph“Further details about the trial design can be found in the and in the protocol publications”→ Remove 'the' or specify the reference.Incomplete sentence.
- MINORclarityDiscussion, paragraph 5“approximately 14 US$ for intravenous and 6.5 US$ for intramuscular injections vs. 0.75 US$ for ciprofloxacin alone”→ Use consistent currency formatting (e.g., US$14, US$6.5, US$0.75).Minor formatting.
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 codeAdd 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 codeDeposit 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.HIGHreportingResolve 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.MEDIUMstatisticsIdentify 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.MEDIUMreportingMention 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.MEDIUMethicsAdd 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.MEDIUMreportingFix 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.LOWcopyeditUse 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.LOWcopyeditRemove the extra space before the colon in 'Trial registration number : NCT04110340'.Minor formatting issue flagged by the copyedit.
- 10.LOWcopyeditUse consistent currency formatting (e.g., US$14, US$6.5, US$0.75) in the Discussion.The copyedit flagged inconsistent currency formatting.
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.”
- 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.
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.