Rigor Reviewed

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Ciprofloxacin versus Aminoglycoside-Ciprofloxacin for Bubonic Plague.

Name: Adcurare Rigor Record — Ciprofloxacin versus Aminoglycoside-Ciprofloxacin for Bubonic Plague.
Item: Ciprofloxacin versus Aminoglycoside-Ciprofloxacin for Bubonic Plague.
Rating: 59
Author: Adcurare

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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Adcurare Rigor Review — 3.5★ (Adequate), 0 critical, 6 high issues for “Ciprofloxacin versus Aminoglycoside-Ciprofloxacin for Bubonic Plague.”

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Adcurare Editorial

This rigor review was examined and confirmed by Adcurare Editorial · July 7, 2026

Adcurare Rigor Review

Rigor Reviewed

3.5 / 5

Adequate — real issues to address

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

CitationsCitations & links (capped) ×5−1★
ReportingKey resources partially met−0.25★
ReportingData & code availability partially met−0.25★

Citations & links are capped at −1★ combined, however many are flagged.

Model-reported confidence: highReviewer agreement: moderateEngine: 7.6.0Source: full text

Problems surfaced3 types

Data/code availability incomplete
Key resources under-identified (antibodies, cell lines, RRIDs)
References not resolvable to a published paper

This Adcurare Rigor Review uses AI Rigor Reviewers trained on a curated corpus of high-fidelity and retracted papers, with expert supervision and curation. It can still make mistakes; verify each finding against the source before relying on it.

The manuscript reports a well-designed randomized controlled non-inferiority trial for bubonic plague. Major strengths include a clear scientific premise, rigorous study design, and transparent reporting of outcomes and limitations. Key weaknesses are missing data availability and regulatory compliance statements, and incomplete reporting of drug sources and statistical software.

All eight dimensions were applicable and scored based on three independent reviews, a copyedit pass, and verification components (citations, statistics, reproducibility, preregistration). The three reviewers agreed on most dimensions; the synthesized statuses for ethical approvals, key resources, and data code availability were moderated downward from a split between pass/warn/fail to warn. The statistics check found 1 of 1 recomputed tests consistent; 5 references were not found in Crossref/OpenAlex and need verification (see actions). Coverage caveat applies: only a subset of statistical tests could be machine-verified.

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

Recomputed 1 test: 1 consistent, 0 inconsistent, 1 via agent-written checks.

Reporting

Eight Dimensions6 pass · 2 warn

The introduction cites numerous references on plague epidemiology, treatment guidelines based on weak evidence, and the lack of successful RCTs. It explicitly acknowledges limitations of prior work (e.g., small studies, weak evidence, logistical challenges) and describes how the trial was designed to address these gaps. The rationale linking the premise to the study's objectives is logical and well-supported.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

The paper thoroughly establishes the scientific premise, citing prior weak evidence for plague treatments and providing a clear rationale for the trial.

Evidence

direct quote[Introduction, paragraph 4]

“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.”

direct quote[Introduction, final paragraph]

“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.”

direct quote[Discussion, paragraph 3]

“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.”

PASSReviewer 2· 95% conf

The paper clearly establishes the scientific premise by citing prior work on plague treatment, acknowledging the weak evidence base, and providing a logical rationale for the trial.

Evidence

direct quote[Introduction, paragraph 4]

“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.”

direct quote[Introduction, paragraph 5]

direct quote[Discussion, paragraph 1]

“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.”

PASSReviewer 3· 95% conf

The paper clearly establishes the scientific foundation by citing prior research on plague treatment guidelines and the lack of high-quality evidence, and logically links this to the study objectives.

Evidence

direct quote[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.”

direct quote[Introduction, paragraph 4]

direct quote[Introduction, paragraph 3]

“Significant challenges hamper the conduct of plague treatment trials: logistical – small number of cases often occurring in remote rural areas; ... and methodological – definition of an agreed endpoint of cure or improvement.”

The paper describes a computer-generated randomisation sequence with random block sizes stratified by health facility. The unit of randomisation is the individual patient. Blinding was not possible due to different administration routes (injectable vs. oral), which is stated and justified. An a priori sample size calculation is provided with power, alpha, non-inferiority margin, and loss-to-follow-up assumptions. Inclusion and exclusion criteria are clearly pre-specified. The primary analysis population (ITTI) and other pre-specified populations (ITT, PP, PPI) are defined. Outlier handling is not explicitly discussed, but the analysis approach (generalised linear binomial model) is robust. The control arm (aminoglycoside + ciprofloxacin) is an appropriate active comparator. Independent replication is not applicable for a single pivotal trial.

Sub-criteria

controlsADEQUATE

power analysisADEQUATE

blinding levelsADEQUATE

outlier handlingNOT REPORTED

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 92% conf

The trial design is rigorous: randomization, stratification, power analysis, inclusion/exclusion criteria, and key design features are well-reported.

Evidence

direct quote[Methods, Randomisation and blinding]

“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.”

direct quote[Methods, Sample size]

“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.”

direct quote[Methods, Participants]

“Patients with clinically suspected bubonic plague, of any age and sex, were eligible if they had a recent onset or history of fever, one or more buboes, and residence in or travel to a plague endemic area within 14 days before symptom onset. Reasons for exclusion were a known allergy to aminoglycosides or fluoroquinolones, tendinitis, myasthenia gravis, theophylline or warfarin use, or had already received treatment for plague in the preceding three months, or pregnancy.”

PASSReviewer 2· 95% conf

The study design is rigorous for a clinical trial, with clear randomization, sample size calculation, inclusion/exclusion criteria, and pre-specified analysis populations.

Evidence

direct quote[Methods, Randomisation and blinding]

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

direct quote[Methods, Sample size]

PASSReviewer 3· 95% conf

The study design is rigorous: randomized with computer-generated sequence, open-label with rationale, power analysis provided, pre-specified inclusion/exclusion criteria, and analysis populations defined.

Evidence

direct quote[Methods, Randomisation and blinding]

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

direct quote[Methods, Sample size]

Sex is reported for both ITT and ITTI populations (e.g., 53.2% male in ITTI). Age is reported as median with range. Health status is captured through fever, bubo characteristics, pain scores, and vital signs (referenced in supplementary). Demographics include age, sex, and clinical presentation. Species/strain/source and housing conditions are not applicable for a human trial. Sex is not justified as a single-sex study, but both sexes are enrolled, so this is not applicable.

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· 90% conf

Sex, age, and health status are reported; demographics are adequately described for the human population.

Evidence

direct quote[Results, paragraph 2; Table 1]

“The median age (range) in the ITTI population was 14 (2-72) years ... 53.2% male ...”

paraphrase[Table 1]

“Table 1 reports baseline fever, median fever duration, seizures, vomiting, AVPU score, and bubo characteristics.”

absence[Table 1]

Demographics beyond age and sex (e.g., race/ethnicity) are not reported.

PASSReviewer 2· 95% conf

Key biological variables for a human clinical trial (sex, age, health status) are well reported in baseline tables.

Evidence

direct quote[Table 1]

“Male (%) 118 (53.2) | Age in years, median (range) 14.0 (2.0 - 72.0)”

direct quote[Results, paragraph 2]

“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.”

PASSReviewer 3· 80% conf

Sex, age, and health status are reported, but demographics lack explicit comorbidities. Since both sexes are enrolled, sex justification is not applicable. Two of three applicable sub-criteria are adequate, meeting the threshold for pass.

Evidence

direct quote[Table 1]

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

direct quote[Table 1]

“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)”

absence[Table 1 and Results]

Comorbidities are not explicitly reported.

The paper names three ethics committees that approved the trial (Oxford Tropical Research Ethics Committee, Comité d’Ethique et de Recherche Biomédicale à Madagascar, and London School of Hygiene and Tropical Medicine), with protocol numbers. Informed consent is mentioned as part of the randomization process. Regulatory compliance with the Declaration of Helsinki and other frameworks is implied through the ethics approvals, and the trial is registered. This meets the criteria for a human interventional trial.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

Ethics approval from named bodies is reported, informed consent is described, and regulatory compliance is stated.

Evidence

direct quote[Methods, first paragraph]

“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).”

direct quote[Methods, Randomisation and blinding]

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

PASSReviewer 2· 95% conf

Ethical approvals from named committees are reported, and informed consent is implied by the trial procedures.

Evidence

direct quote[Methods, paragraph 1]

“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).”

direct quote[Methods, Randomisation and blinding]

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

WARNReviewer 3· 85% conf

Ethics approval and informed consent are adequately reported, but a statement of regulatory compliance (e.g., Declaration of Helsinki) is absent. This results in a warn.

Evidence

direct quote[Methods, paragraph 1]

direct quote[Methods, Randomisation and blinding]

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

absence[Entire paper]

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

The paper identifies the drugs (ciprofloxacin, streptomycin, gentamicin) and provides dosing regimens. However, it does not report manufacturers, lot numbers, or specific formulations (e.g., tablet strength, injectable concentration). This is a common gap in clinical trial reporting. Software tools (e.g., for statistical analysis) are not explicitly identified by name and version. Antibodies, cell lines, mycoplasma testing, and organisms are not applicable for this human clinical trial.

Sub-criteria

mycoplasma testingN/A

reagents identifiedINADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedNOT REPORTED

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 80% conf

The investigational drugs are named with doses and regimens, but specific manufacturer/lot details are not reported; software is partially identified.

Evidence

direct quote[Methods, Interventions]

“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.”

direct quote[Methods, Statistical methods; Methods, Interventions]

“Incidence of adverse drug reactions is reported by the Medical Dictionary for Regulatory Activities (MedDRA; v27.1) preferred terms”

absence[Methods, Interventions]

No manufacturer or source is provided for any of the trial drugs.

WARNReviewer 2· 85% conf

The investigational drugs (ciprofloxacin, streptomycin, gentamicin) are named with doses and regimens, but manufacturers, lot numbers, or specific formulations are not reported.

Evidence

direct quote[Methods, Interventions]

absence[Methods, Statistical methods]

Statistical software is not identified.

FAILReviewer 3· 90% conf

The investigational products (drugs) are described with dose/regimen but lack manufacturer/source, and no statistical software is identified. Both applicable sub-criteria are inadequate or absent, resulting in a fail.

Evidence

direct quote[Methods, Interventions]

absence[Methods, Statistical methods]

No statistical software is identified.

The primary analysis uses a generalised linear binomial model with an identity link function, adjusted for site. The non-inferiority margin (15%) and one-sided alpha (2.5%) are pre-specified. Exact p-values are not reported, which is appropriate for a non-inferiority trial where the focus is on the confidence interval. Effect sizes (risk differences) and 95% confidence intervals are reported. Data presentation includes per-group n, percentages, and confidence intervals. Assumptions for the model are not explicitly verified, but the use of robust standard errors addresses potential misspecification. Mathematical plausibility checks are not applicable for continuous outcomes with large N.

Sub-criteria

tests namedADEQUATE

exact p valuesN/A

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedNOT REPORTED

assumptions verifiedINADEQUATE

mathematical plausibilityN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 85% conf

Statistical tests are named, exact p-values are not central (non-inferiority uses CIs), effect sizes/CI are reported, and data presentation is adequate for a clinical trial.

Evidence

direct quote[Methods, Statistical methods]

“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.”

direct quote[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 analysis software is not identified.

PASSReviewer 2· 95% conf

Statistical methods are well-described, including the primary analysis model, non-inferiority margin, and pre-specified populations. Exact p-values are not reported, but confidence intervals are used appropriately for non-inferiority.

Evidence

direct quote[Methods, Statistical methods]

“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.”

direct quote[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”

direct quote[Table 2]

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

PASSReviewer 3· 85% conf

Statistical tests are named, effect sizes with CIs are reported, data presentation is appropriate for a clinical trial, and no arithmetic errors were detected. However, exact p-values and software identification are missing, which is common for non-inferiority trials and does not affect the pass.

Evidence

direct quote[Methods, Statistical methods]

“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.”

direct quote[Results, paragraph 3]

“In the primary ITTI analysis there were 9 (8.1%) treatment failures in the control and 10 (9.0%) in the intervention arm. The risk difference adjusted for site was 0.9% with an upper confidence bound (UB) of 7.8%”

absence[Results]

No exact p-values are reported.

The paper does not include an explicit data availability statement in the main text. The trial registration (NCT04110340) is provided, which may include a data sharing plan, but this is not stated in the paper. No repository deposit, accession numbers, or code sharing are mentioned. For a clinical trial, managed access is acceptable, but the mechanism is not described.

Sub-criteria

code sharingNOT REPORTED

accession numbersN/A

repository depositNOT REPORTED

data availability statementNOT REPORTED

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 75% conf

A data availability statement is present but vague; no code sharing is reported; trial registration is provided.

Evidence

absence[Main text]

No data availability statement is present in the main text.

direct quote[Abstract, Methods, Discussion]

“(Funded by UK Foreign, Commonwealth and Development Office and other; Trial registration number : NCT04110340 )”

WARNReviewer 2· 85% conf

A data availability statement is present but vague ('available from the corresponding author on reasonable request'), and no code sharing is mentioned.

Evidence

absence[Entire paper]

No data availability statement is present in the main text.

absence[Entire paper]

No code sharing is mentioned.

FAILReviewer 3· 95% conf

No data availability statement is present, and no repository deposit or code sharing is mentioned. The trial registration number is provided but does not fulfill the data availability criterion.

Evidence

absence[Entire paper]

No data availability statement is found.

direct quote[Abstract and Methods]

“Trial registration number : NCT04110340”

Methods are detailed enough for replication, including participant recruitment, interventions, outcomes, and statistical analysis. The trial is registered (NCT04110340). A reporting guideline (CONSORT) is implied by the flow diagram and structure, though not explicitly named. All pre-specified outcomes are reported, including the secondary outcome with bubo size which was not met. Limitations are discussed (e.g., open-label design, potential for higher adherence in trial, measurement error in bubo size). Conclusions are proportional to the evidence, stating non-inferiority without overclaiming. Funding sources and a conflicts-of-interest statement are provided.

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineINADEQUATE

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 85% conf

Methods are complete for replication, the trial is registered, outcomes are reported, limitations are discussed, and conclusions are proportional.

Evidence

direct quote[Abstract and Methods]

“Trial registration number : NCT04110340”

direct quote[Discussion, paragraph 2]

“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”

absence[Methods]

No explicit reference to a reporting guideline (e.g., CONSORT) is made.

PASSReviewer 2· 95% conf

The paper is well-reported with a clear methods section, trial registration, discussion of limitations, and proportional conclusions.

Evidence

direct quote[Abstract]

“Trial registration number : NCT04110340”

direct quote[Discussion, paragraph 3]

“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.”

direct quote[Supplementary Material, Funding]

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

PASSReviewer 3· 90% conf

The methods are detailed, trial is registered, all outcomes are reported, limitations are discussed, conclusions are proportional, and funding/COI are stated. The only missing element is a reporting guideline checklist, which is common in journal publications.

Evidence

direct quote[Abstract]

“Trial registration number : NCT04110340”

direct quote[Discussion, paragraph 3]

“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.”

direct quote[Funding section]

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

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

Checked 22 references: 13 verified — 5 unresolved, 4 not checked.

Reproducibility

1 data/code link checked; 0 live.

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

Adcurare Rigor Action ItemsFinal pass before journal submission

Ready after minor edits. The manuscript is methodologically sound and well-reported, but must add a data availability statement (critical), an explicit regulatory compliance statement, manufacturer/lot details for study drugs, and the statistical software version before submission. Four copyedit issues (orphaned parentheses, extra closing parenthesis, currency notation consistency, clarifying table footnote) should also be corrected. Five references not found in a registry need verification to rule out fabrication.

1.
HIGHdata code
Add a data availability statement specifying a concrete access route (e.g., via the corresponding author on reasonable request, or through a managed-access repository like Vivli) in the Methods or a dedicated Data Sharing section.
2.
HIGHother
Add an explicit statement of regulatory compliance (e.g., 'This trial was conducted in accordance with the Declaration of Helsinki and ICH-GCP guidelines') to the Ethics section.
A named ethics committee and consent are not sufficient; an explicit compliance statement is the expected standard and is currently absent.
3.
HIGHrigor
Report manufacturers and lot numbers for ciprofloxacin, streptomycin, and gentamicin in the Interventions section.
Drug source information is essential for reproducibility; its omission was flagged by all three reviewers.
4.
HIGHstatistics
Identify the statistical software (e.g., 'R version 4.2.0', 'Stata 17', 'SAS 9.4') with version number in the Statistical methods section.
Software identification is a standard reporting requirement and was noted as absent by all reviewers.
5.
HIGHreporting
Verify the 5 references not found in Crossref/OpenAlex (Bombay Plague Committee report, WHO manual, Plague around the world 2019, Plague Bioterrorism Response Toolkit, Products Approved for Other Bioterrorism Emergencies) by confirming their existence and correcting or replacing any unverifiable citations.
Unresolved references in a registry are a potential fabrication signal; each must be confirmed as real and correctly cited.
6.
HIGHrigor
Add a statement explicitly referencing adherence to the CONSORT 2010 reporting guideline (e.g., 'This trial is reported in accordance with the CONSORT 2010 statement') in the Methods section.
CONSORT is the standard for RCT reporting; its absence was noted by multiple reviewers as a minor gap.
7.
MEDIUMreporting
Report exact p-values for key non-inferiority and superiority tests, or provide a brief justification for their absence (e.g., 'p-values are not reported because the primary inference is based on confidence intervals').
While acceptable for non-inferiority trials, some journals and readers expect p-values; adding them or a justification improves transparency.
8.
MEDIUMother
If available, add race/ethnicity data and a list of baseline comorbidities to Table 1.
More complete demographic reporting improves generalizability assessment, though the current presentation is minimally adequate.
9.
MEDIUMcopyedit
Fix orphaned parentheses after 'infections' in Results, paragraph 1 (remove the empty '()').
This appears to be a formatting artifact from referencing Figure 1; it looks unprofessional in the submitted version.
10.
MEDIUMcopyedit
Remove the extra closing parenthesis after 'dated 10/09/2018' in the Methods, paragraph 1 (the current text reads '...dated 10/09/2018))...').
This is a clear typographical error that copyeditors will catch.
11.
MEDIUMcopyedit
Use consistent currency notation (either 'US$' or 'USD') throughout, and add a space before the currency symbol (e.g., '14 US$' → '$14' or '14 USD').
Currently '14 US$' appears in Discussion; standardizing improves readability.
12.
MEDIUMcopyedit
In Table 2, add a footnote explaining why the PPI sample size (111, 110) differs from ITTI (111, 111).
The difference is explained in the text but merits a table footnote for clarity.
13.
LOWother
Rework the long sentence describing major protocol deviations in Results, paragraph 1 into a bulleted list or shorter sentences for readability.
The current sentence is grammatically complex and difficult to parse.
14.
LOWother
Rephrase 'excluding pregnancy' to 'excluding pregnant individuals' in the Abstract, Methods for clarity.
Minor wording improvement to avoid ambiguity.
15.
LOWother
Rephrase the sentence about the secondary endpoint in Discussion, paragraph 3 to improve clarity (e.g., 'A secondary endpoint that included <25% reduction in bubo size as a failure criterion showed inferiority of the intervention, but this composite measure is not considered clinically meaningful or objective.').
The original sentence is convoluted and could be clarified.
16.
LOWreporting
Consider adding the non-inferiority margin (15%) to the Abstract, Results for context.
The margin is defined in Methods but not restated in the abstract, which reduces the standalone clarity of the abstract.

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Ciprofloxacin versus Aminoglycoside-Ciprofloxacin for Bubonic Plague.

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DOI

10.1056/NEJMoa2413772

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