Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

Zoliflodacin versus ceftriaxone plus azithromycin for treatment of uncomplicated urogenital gonorrhoea: an international, randomised, controlled, open-label, phase 3, non-inferiority clinical trial.

Name: Kaimen Rigor review — Zoliflodacin versus ceftriaxone plus azithromycin for treatment of uncomplicated urogenital gonorrhoea: an international, randomised, controlled, open-label, phase 3, non-inferiority clinical trial.
Item: Zoliflodacin versus ceftriaxone plus azithromycin for treatment of uncomplicated urogenital gonorrhoea: an international, randomised, controlled, open-label, phase 3, non-inferiority clinical trial.
Rating: 59
Author: Alpha1

Luckey A, Balasegaram M, Barbee LA, Batteiger TA, Broadhurst H, Cohen SE, Delany-Moretlwe S, de Vries HJC, Dionne JA, Gill K, Kenyon C, Kittiyaowamarn R, Lewis D, Mueller JP, Naicker V, O'Brien S, O'Donnell JP, Phanuphak N, Spooner E, Srinivasan S, Taylor SN, Unemo M, Zwane Z, Hook EW 3rd, Zoliflodacin Phase 3 Study Group

Paper source

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Kaimen Rigor review — 1.25★ (Critical), 0 critical, 4 high issues for “Zoliflodacin versus ceftriaxone plus azithromycin for treatment of uncomplicated urogenital gonorrhoea: an international, randomised, controlled, open-label, phase 3, non-inferiority clinical trial.”

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

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Zoliflodacin versus ceftriaxone plus azithromycin for treatment of uncomplicated urogenital gonorrhoea: an international, randomised, controlled, open-label, phase 3, non-inferiority clinical trial.

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DOI

10.1016/S0140-6736(25)01953-1

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Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

Zoliflodacin versus ceftriaxone plus azithromycin for treatment of uncomplicated urogenital gonorrhoea: an international, randomised, controlled, open-label, phase 3, non-inferiority clinical trial.

Paper source

Zoliflodacin versus ceftriaxone plus azithromycin for treatment of uncomplicated urogenital gonorrhoea: an international, randomised, controlled, open-label, phase 3, non-inferiority clinical trial.

Read full text (PMC)

Embed this Rigor badge

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Alpha1 Editorial

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

Kaimen Rigor review

Kaimen Rigor reviewed

1.25 / 5

Critical — serious problems across many checks

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

StatisticsStatistic did not reproduce ×2−1★
IntegrityIntegrity concern ×2−1★
ClaimsOverstated claim−0.5★
ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
ClaimsTreatment effect not shown to be clinically meaningful−0.5★
CitationsUnresolved reference−0.25★

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

Not verified in this report

The numeric-impossibility checks (GRIM/GRIMMER/DEBIT/SPRITE) did not run: 3 reported means were read, and their group size is not stated where the values are printed (this source has no machine-readable table structure). These checks need the count the mean was averaged over, so none was performed.

Biggest issues

01Printed percentage does not match its own count
highArithmeticrecomputedFull detail
5% does not match the reported count 61/619
“61 (10%); 65”
Table 4Find in source
02Reported statistic does not recompute
highArithmeticrecomputedFull detail
Post-hoc logistic regression p-value for male sex association with neutropenia.
“male sex (0·24, 0·11–0·53, p=0·0029)”
Find in source
03Efficacy rests on an unvalidated surrogate endpoint
highOverreachreviewer-assessedFull detail
The primary efficacy endpoint is microbiological cure, defined as eradication of Neisseria gonorrhoeae determined by culture at the urogenital site. This is a surrogate marker for clinical cure and prevention of complications. The paper does not provide evidence linking microbiological cure to hard clinical outcomes such as prevention of pelvic inflammatory disease, epididymitis, or disseminated gonococcal infection. Additionally, while the dose was selected based on phase 1 PK/PD studies, the paper does not explicitly demonstrate target engagement at the tested dose in this trial, nor does it cite validated evidence that microbiological cure at day 6 predicts long-term clinical outcomes.
“The primary endpoint was the proportion of participants with microbiological cure (negative or indeterminate N gonorrhoeae culture) at the urogenital site at TOC among participants included in the microbiological intention-to-treat (urogenital) population.”
Find in source
04Treatment effect not shown to be clinically meaningful
highOverreachreviewer-assessedFull detail
The primary efficacy result shows a microbiological cure rate of 90.9% for zoliflodacin versus 96.2% for comparator, with a difference of 5.3% (95% CI 1.4–8.6). Although the non-inferiority margin was met, the effect size is not anchored to a minimal clinically important difference or to the clinical significance of a 5.3% absolute difference in cure rates. The paper does not discuss whether this difference is clinically meaningful, and the lower bound of the CI is above zero, indicating a statistically significant inferiority of zoliflodacin. The clinical relevance of this difference is not addressed.
“The estimated difference between groups (comparator minus zoliflodacin) was 5·3% (95% CI 1·4–8·6) and the upper confidence interval limit was within the prespecified non-inferiority margin of less than 12%.”
Find in source
05Conclusion reaches beyond the evidence
mediumOverreachreviewer-assessedFull detail
Zoliflodacin might reduce antibiotic selection pressure and help preserve the effectiveness of other antibiotic classes.
“Furthermore, as a new antibiotic class with a novel bacterial target and a distinct mechanism of action, zoliflodacin might reduce antibiotic selection pressure and help preserve the effectiveness of other antibiotic classes, notably, ceftriaxone.”
Discussion ¶5Find in source

Findings by category

301ArithmeticNumerical inconsistencies 302OverreachOverstated conclusions 103AuthenticityData authenticity concerns 04DisclosureNone found 105AvailabilityBroken references and links 06Copyedit6 minor suggestions

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

This is a well-conducted and transparently reported phase 3 non-inferiority trial. The main methodological strengths are the rigorous design, comprehensive reporting of biological variables, and clear data availability. The primary weakness is a minor statistical inconsistency in a post-hoc analysis p-value, and a few copyedit typos.

Both reviewers agreed on study type (interventional) and on all dimension statuses except statistical analysis, where the deterministic recomputation overrode the reviewers' pass. Non-applicable sub-criteria (e.g., animal housing, cell lines) were excluded. The statistics check covered only 3 tests; the rest are unverified.

Numerical inconsistencies

3 findings · worst high

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.

Reported statistics do not recomputeRecomputed
Summary statistic impossible for the stated N (GRIM/GRIMMER)Recomputed
Internal contradictions in the reported numbersAssessed

Recomputed 2 tests: 1 consistent, 1 inconsistent; 2 via agent-written checks. 1 reported summary statistic mathematically impossible for the stated N (PERCENT).

Overstated conclusions

3 findings · worst high

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.

Efficacy rests on an unvalidated surrogate endpointAssessed
Treatment effect not shown to be clinically meaningfulAssessed
Conclusions overstated beyond the evidenceAssessed

5 major claims checked against the paper's own evidence: 1 not fully backed by the presented evidence (unsupported or overstated).

Premise concern: surrogate not validated for clinical benefit; effect size not shown to be clinically meaningful.

Data authenticity concerns

1 finding · worst low

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.

Other integrity concernAssessed

2 integrity concerns flagged (0 high).

Reporting gaps

None found

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.

Checked — nothing surfaced.

Eight Dimensions8 pass

The introduction and 'Research in context' section cite WHO data on gonorrhoea burden, antimicrobial resistance trends, and prior clinical trials of other antibiotics. The rationale for zoliflodacin is well-supported by its mechanism of action and phase 2 data. Limitations of prior research (e.g., failures of solithromycin, delafloxacin, gentamicin, fosfomycin) are explicitly discussed, and the study design addresses these gaps.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The paper establishes a strong scientific premise with extensive prior work cited, a clear rationale, and acknowledgment of prior research limitations.

Evidence

“In 2020, WHO estimated that Neisseria gonorrhoeae caused 82·4 million new cases of gonorrhoea among those aged 15–49 years worldwide.”

Introduction ¶1Find in source

“Phase 3 studies investigating two new oral treatments, solithromycin and delafloxacin, as well as the older antibiotics, gentamicin and fosfomycin, had not shown non-inferiority to standard of care, ceftriaxone.”

Research in context, Evidence before th…Find in source

“Zoliflodacin is an oral, first-in-class, spiropyrimidinetrione antibiotic with a distinct mode of bactericidal action.”

Introduction ¶3Find in source

PASSReviewer 2· 90% conf

The paper establishes a strong scientific premise with extensive prior work cited, a clear rationale, and addresses limitations of prior research.

Evidence

“In 2020, WHO estimated that Neisseria gonorrhoeae caused 82·4 million new cases of gonorrhoea among those aged 15–49 years worldwide.”

Introduction ¶1Find in source

“Zoliflodacin is an oral, first-in-class, spiropyrimidinetrione antibiotic with a distinct mode of bactericidal action.”

Introduction ¶3Find in source

Research in context, Evidence before th…Find in source

Randomization used computer-generated random numbers with permuted blocks and stratification by sex. Blinding was partial but justified: participants and clinicians were unblinded due to different formulations, while microbiology lab staff and sponsor central team were masked. Power analysis was pre-specified with a 90% power assumption. Inclusion/exclusion criteria were detailed, and the analysis populations (microbiological ITT, evaluable, per-protocol) were clearly defined. Outlier handling was addressed through sensitivity analyses and multiple imputation for missing data.

Sub-criteria

controlsN/A

power analysisADEQUATE

blinding levelsADEQUATE

outlier handlingADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

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

Evidence

“The randomisation sequence was obtained using computer-generated random numbers, and treatment allocation was provided to each trial site by a web-based randomisation system.”

MethodsFind in source

“The local or regional and central microbiology analytical laboratory staff who did primary endpoint microbiological analysis and the sponsor's central study team members were masked to treatment allocation until after database lock.”

MethodsFind in source

“the microbiological intention-to-treat (urogenital) sample size was calculated as 696 participants, with a 2:1 allocation ratio, to provide 90% power to show that zoliflodacin was non-inferior to the comparator”

Statistical analysisFind in source

PASSReviewer 2· 95% conf

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

Evidence

“The randomisation sequence was obtained using computer-generated random numbers, and treatment allocation was provided to each trial site by a web-based randomisation system.”

MethodsFind in source

“Assuming a 90% cure rate in the comparator group, a –4% treatment difference, and a prespecified non-inferiority margin of less than 12% for the upper bound of the two-sided 95% CI for the primary endpoint, the microbiological intention-to-treat (urogenital) sample size was calculated as 696 participants, with a 2:1 allocation ratio, to provide 90% power to show that zoliflodacin was non-inferior to the comparator with respect to microbiological cure rate at TOC.”

Statistical analysisFind in source

Sex assigned at birth, gender, age, race, and region are reported in Table 1. Age and health status (HIV status) are also reported. Since both sexes were enrolled, sex_justified is not applicable. Species/strain and housing conditions are not applicable for a human trial.

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Demographic and clinical characteristics are comprehensively reported, including sex, age, race, and HIV status.

Evidence

paraphrase[Results, paragraph 2]

“815 (88%) of 930 participants were assigned male at birth and 115 (12%) participants were assigned female at birth. The mean participant age was 29·7 years (SD 9·4).”

“514 (55%) of 930 participants were Black or African American, 285 (31%) were Asian, and 113 (12%) were White.”

Results ¶2Find in source

“199 (21%) were living with HIV”

Results ¶2Find in source

PASSReviewer 2· 90% conf

Demographic and baseline characteristics are comprehensively reported, including sex, age, race, and HIV status.

Evidence

paraphrase[Results, paragraph 2]

“815 (88%) of 930 participants were assigned male at birth and 115 (12%) participants were assigned female at birth. The mean participant age was 29·7 years (SD 9·4).”

“514 (55%) of 930 participants were Black or African American, 285 (31%) were Asian, and 113 (12%) were White.”

Results ¶2Find in source

paraphrase[Table 1]

“HIV status: Negative 455 (73%) | Positive 134 (22%) | Missing 32 (5%)”

The paper states that the protocol was approved by the institutional review board or ethics committee of all participating centres, and all participants provided written informed consent. This satisfies both irb_ethics_statement and informed_consent. Regulatory compliance is implied by adherence to FDA guidance and Good Clinical Practice.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

Ethical approval and informed consent are adequately documented.

Evidence

“The study protocol and its amendments were approved by the institutional review board or ethics committee of all participating centres”

MethodsFind in source

“all participants provided written informed consent”

MethodsFind in source

“This phase 3, multinational, open-label, randomised, controlled, non-inferiority trial was designed and conducted in accordance with US Food and Drug Administration (FDA) guidance”

MethodsFind in source

PASSReviewer 2· 95% conf

Ethical approvals and informed consent are adequately reported.

Evidence

“The study protocol and its amendments were approved by the institutional review board or ethics committee of all participating centres”

MethodsFind in source

“all participants provided written informed consent.”

MethodsFind in source

“This phase 3, multinational, open-label, randomised, controlled, non-inferiority trial was designed and conducted in accordance with US Food and Drug Administration (FDA) guidance”

MethodsFind in source

Zoliflodacin and the comparator (ceftriaxone plus azithromycin) are identified with doses and routes. The central laboratory (JMI Laboratories) is named. Since this is a drug trial, antibodies, cell lines, mycoplasma, and organisms are not applicable. Software used for statistical analysis (SAS version 9.4) is identified.

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The investigational products are adequately identified, and the central laboratory is named.

Evidence

“either a single oral dose of zoliflodacin 3 g (granules as oral suspension) or the comparator, a single intramuscular 500 mg dose of ceftriaxone plus a single oral 1 g dose of azithromycin”

MethodsFind in source

“Statistical analyses were done by Plus-Project (Knutsford, UK) using SAS version 9.4.”

Statistical analysisFind in source

PASSReviewer 2· 90% conf

The investigational products and central laboratory are adequately identified.

Evidence

“either a single oral dose of zoliflodacin 3 g (granules as oral suspension) or the comparator, a single intramuscular 500 mg dose of ceftriaxone plus a single oral 1 g dose of azithromycin”

MethodsFind in source

“Presumptive N gonorrhoeae isolates were frozen and shipped to the central laboratory (JMI Laboratories; Iowa City, IA, USA)”

MethodsFind in source

“Statistical analyses were done by Plus-Project (Knutsford, UK) using SAS version 9.4.”

Statistical analysisFind in source

The primary analysis used Clopper-Pearson CIs and Newcombe score method for the difference, which is appropriate for non-inferiority. Exact p-values are reported for the post-hoc logistic regression (p<0.0001, p=0.0029). Effect sizes are reported with 95% CIs throughout. Software is identified. Data presentation includes per-group n and CIs. Mathematical plausibility checks were not performed due to large N and continuous outcomes.

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedADEQUATE

mathematical plausibilityN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

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

Evidence

“95% CIs were calculated using the Clopper–Pearson method. The point estimate for the treatment difference (comparator minus zoliflodacin) and the two-sided 95% CI were calculated using the Newcombe score method.”

Statistical analysisFind in source

“Black or African American odds ratio 109·70, 90% CI 20·91–575·53; p<0·0001) and male sex (0·24, 0·11–0·53, p=0·0029)”

Results ¶8Find in source

“The estimated difference between groups was 5·3% (95% CI 1·4–8·6)”

Results ¶3Find in source

PASSReviewer 2· 90% conf

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

Evidence

Statistical analysisFind in source

“Post-hoc multivariate logistic regression analysis revealed a strong association of neutropenia with race (Black or African American odds ratio 109·70, 90% CI 20·91–575·53; p<0·0001) and male sex (0·24, 0·11–0·53, p=0·0029)”

Results ¶8Find in source

“The estimated difference between groups (comparator minus zoliflodacin) was 5·3% (95% CI 1·4–8·6)”

Results ¶3Find in source

The data sharing statement provides a specific email address (datasharing@gardp.org) and describes the process for requesting data, including anonymization and timeframe. This meets the criteria for a managed-access platform. Repository deposit and accession numbers are not applicable for patient-level data. Code sharing is not applicable as no bespoke code is mentioned.

Sub-criteria

code sharingN/A

accession numbersN/A

repository depositN/A

data availability statementADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Data availability is adequately described with a concrete access route.

Evidence

“Requests from researchers should be sent to GARDP at datasharing@gardp.org for consideration. If granted, relevant individual participant data will be anonymised and securely transferred. Participant-level data will be made available within 6 months of first regulatory approval.”

Data availabilityFind in source

PASSReviewer 2· 90% conf

Data availability is adequately described with a concrete access route.

Evidence

Data availabilityFind in source

The trial is registered with ClinicalTrials.gov and EudraCT. Methods are detailed enough for replication. Limitations are explicitly discussed, including open-label design and low enrollment of women/adolescents. Conclusions are proportional to the evidence. Funding sources and conflicts of interest are fully disclosed. A reporting guideline is not explicitly mentioned, but the paper follows CONSORT-like structure.

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineINADEQUATE

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

The manuscript is transparent with trial registration, detailed methods, limitations, and funding/COI statements.

Evidence

“The trial is registered with ClinicalTrials.gov (http://ClinicalTrials.gov) , NCT03959527 (https://clinicaltrials.gov/ct2/show/NCT03959527) , and EudraCT, 2019-000990-22.”

MethodsFind in source

“Limitations of the study include the open-label study design, which was necessary due to the different formulations of study treatments and the unacceptability and operational burden of placebo injections required to mask the study.”

Discussion ¶6Find in source

“The institutions or affiliated institutions of LAB, TAB, SEC, SD-M, HJCdV, JAD, KG, CK, RK, VN, NP, ES, SNT, and ZZ received funding from GARDP for the trial.”

AcknowledgementsFind in source

PASSReviewer 2· 95% conf

Reporting is transparent with trial registration, comprehensive methods, and proportional conclusions.

Evidence

“The trial is registered with ClinicalTrials.gov (http://ClinicalTrials.gov) , NCT03959527 (https://clinicaltrials.gov/ct2/show/NCT03959527) , and EudraCT, 2019-000990-22.”

MethodsFind in source

Discussion ¶7Find in source

“The institutions or affiliated institutions of LAB, TAB, SEC, SD-M, HJCdV, JAD, KG, CK, RK, VN, NP, ES, SNT, and ZZ received funding from GARDP for the trial.”

Declaration of interestsFind in source

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

Broken references and links

1 finding · worst low

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.

References not resolvable to a published paperRecomputed

Checked 34 references by DOI: 27 verified — 1 DOI unresolved, 6 no DOI (shown, not verified).

2 data/code links checked; 2 live.

Copyediting

6 minor

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

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

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

Kaimen Rigor Action ItemsFinal pass before journal submission

The published work is robust overall, but readers should weigh the minor p-value inconsistency in the post-hoc neutropenia analysis and the lack of an explicit CONSORT statement. No erratum is urgently required, but a correction to the p-value and typo fixes would improve accuracy.

1.
HIGHstatistics
In Results, paragraph 8, correct the reported p-value for the male sex association with neutropenia from p=0.0029 to the recomputed p=0.0291, or provide the exact model specification that yields the reported value.
The deterministic recomputation found an inconsistency; an incorrect p-value in a published paper is a validity concern that should be corrected or explained.
2.
HIGHreporting
Add an explicit statement in the Methods (or a supplementary file) that the trial adheres to the CONSORT reporting guideline, and include the CONSORT flow diagram.
Both reviewers flagged the reporting guideline as inadequate; explicit adherence improves transparency and reproducibility.
3.
HIGHstatistics
In Methods, Statistical analysis, provide a detailed description of the post-hoc multivariate logistic regression, including variable selection, model building, and diagnostics.
Both reviewers noted the post-hoc analysis is under-described; this is needed for readers to assess the validity of the neutropenia findings.
4.
HIGHreporting
Verify and correct the reference 'Gonococcal antimicrobial susceptibility surveillance in the European Union/European Economic Area, summary of results for 2022' (DOI 10.1016/s1473-3099(19...), which could not be found in any registry; if it is a real publication, provide the correct DOI and full citation.
A reference that cannot be found in Crossref/OpenAlex may be fabricated or have an incorrect DOI; this is an integrity concern that must be resolved.
5.
MEDIUMcopyedit
In Results, paragraph 2, fix the typographical error '114 (12%) of 930 (12%)' to '114 (12%) of 930'.
The duplicated percentage is a clear typo that could confuse readers.
6.
MEDIUMcopyedit
In Discussion, paragraph 6, correct the typo 'heath-care' to 'health-care'.
A simple typo that should be fixed for professionalism.
7.
MEDIUMcopyedit
In the Abstract and Methods, remove the extra space before the comma in the ClinicalTrials.gov registration statement and ensure consistent URL formatting.
Minor formatting inconsistency flagged by the copyedit pass.
8.
MEDIUMreporting
In the Discussion, temper the claim that 'Zoliflodacin might reduce antibiotic selection pressure and help preserve the effectiveness of other antibiotic classes' to explicitly note that this is a speculative benefit not directly measured in the trial.
The claim audit rated this as overstated; the paper should not overstate benefits beyond the evidence.
9.
MEDIUMreporting
In the Discussion, add a note about the generalizability of the results to populations not well represented in the trial, such as women and adolescents.
Both reviewers suggested this; it addresses a known limitation and helps readers interpret the findings.
10.
LOWreporting
In the Methods or Data sharing section, add a statement about the availability of statistical analysis code, even if not applicable, to enhance transparency.
Reviewer 2 suggested this; it is a nice-to-have for reproducibility.
11.
LOWreporting
In the Results, provide a breakdown of the 81 participants who did not meet screening criteria to improve transparency.
Reviewer 1 suggested this; it would help readers understand the screening process.
12.
LOWreporting
In the Methods, clarify the role of the data safety monitoring board and any interim analyses conducted.
Reviewer 1 suggested this; it is relevant for a phase 3 trial.

Full text (66,107 chars)Analyzed: Aug 15, 2026

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Zoliflodacin versus ceftriaxone plus azithromycin for treatment of uncomplicated urogenital gonorrhoea: an international, randomised, controlled, open-label, phase 3, non-inferiority clinical trial.

Read full text (PMC)

DOI

10.1016/S0140-6736(25)01953-1

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  <img src="https://alpha1science.com/verify/ee286851-3a6f-45b8-9d6c-34866784236b/badge" alt="Kaimen Rigor review — 1.25★ (Critical), 0 critical, 4 high issues for “Zoliflodacin versus ceftriaxone plus azithromycin for treatment of uncomplicated urogenital gonorrhoea: an international, randomised, controlled, open-label, phase 3, non-inferiority clinical trial.”" width="440" height="104" style="max-width:100%;height:auto" />
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Record fingerprint

112a92768ed832a507fb34017129a531ccb2f0691730f39005d9ccaeac054c12

Verify via API

Issued Aug 15, 2026Engine 7.39.0

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

Kaimen Rigor review

Kaimen Rigor reviewed

1.25 / 5

Critical — serious problems across many checks

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

StatisticsStatistic did not reproduce ×2−1★
IntegrityIntegrity concern ×2−1★
ClaimsOverstated claim−0.5★
ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
ClaimsTreatment effect not shown to be clinically meaningful−0.5★
CitationsUnresolved reference−0.25★

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

Not verified in this report

The numeric-impossibility checks (GRIM/GRIMMER/DEBIT/SPRITE) did not run: 3 reported means were read, and their group size is not stated where the values are printed (this source has no machine-readable table structure). These checks need the count the mean was averaged over, so none was performed.

Biggest issues

01Printed percentage does not match its own count
highArithmeticrecomputedFull detail
5% does not match the reported count 61/619
“61 (10%); 65”
Table 4Find in source
02Reported statistic does not recompute
highArithmeticrecomputedFull detail
Post-hoc logistic regression p-value for male sex association with neutropenia.
“male sex (0·24, 0·11–0·53, p=0·0029)”
Find in source
03Efficacy rests on an unvalidated surrogate endpoint
highOverreachreviewer-assessedFull detail
The primary efficacy endpoint is microbiological cure, defined as eradication of Neisseria gonorrhoeae determined by culture at the urogenital site. This is a surrogate marker for clinical cure and prevention of complications. The paper does not provide evidence linking microbiological cure to hard clinical outcomes such as prevention of pelvic inflammatory disease, epididymitis, or disseminated gonococcal infection. Additionally, while the dose was selected based on phase 1 PK/PD studies, the paper does not explicitly demonstrate target engagement at the tested dose in this trial, nor does it cite validated evidence that microbiological cure at day 6 predicts long-term clinical outcomes.
“The primary endpoint was the proportion of participants with microbiological cure (negative or indeterminate N gonorrhoeae culture) at the urogenital site at TOC among participants included in the microbiological intention-to-treat (urogenital) population.”
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04Treatment effect not shown to be clinically meaningful
highOverreachreviewer-assessedFull detail
The primary efficacy result shows a microbiological cure rate of 90.9% for zoliflodacin versus 96.2% for comparator, with a difference of 5.3% (95% CI 1.4–8.6). Although the non-inferiority margin was met, the effect size is not anchored to a minimal clinically important difference or to the clinical significance of a 5.3% absolute difference in cure rates. The paper does not discuss whether this difference is clinically meaningful, and the lower bound of the CI is above zero, indicating a statistically significant inferiority of zoliflodacin. The clinical relevance of this difference is not addressed.
“The estimated difference between groups (comparator minus zoliflodacin) was 5·3% (95% CI 1·4–8·6) and the upper confidence interval limit was within the prespecified non-inferiority margin of less than 12%.”
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05Conclusion reaches beyond the evidence
mediumOverreachreviewer-assessedFull detail
Zoliflodacin might reduce antibiotic selection pressure and help preserve the effectiveness of other antibiotic classes.
“Furthermore, as a new antibiotic class with a novel bacterial target and a distinct mechanism of action, zoliflodacin might reduce antibiotic selection pressure and help preserve the effectiveness of other antibiotic classes, notably, ceftriaxone.”
Discussion ¶5Find in source

Findings by category

Numerical inconsistencies

3 findings · worst high

Reported statistics do not recomputeRecomputed
Summary statistic impossible for the stated N (GRIM/GRIMMER)Recomputed
Internal contradictions in the reported numbersAssessed

Recomputed 2 tests: 1 consistent, 1 inconsistent; 2 via agent-written checks. 1 reported summary statistic mathematically impossible for the stated N (PERCENT).

Overstated conclusions

3 findings · worst high

Efficacy rests on an unvalidated surrogate endpointAssessed
Treatment effect not shown to be clinically meaningfulAssessed
Conclusions overstated beyond the evidenceAssessed

5 major claims checked against the paper's own evidence: 1 not fully backed by the presented evidence (unsupported or overstated).

Premise concern: surrogate not validated for clinical benefit; effect size not shown to be clinically meaningful.

Data authenticity concerns

1 finding · worst low

Other integrity concernAssessed

2 integrity concerns flagged (0 high).

Reporting gaps

None found

Checked — nothing surfaced.

Eight Dimensions8 pass

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The paper establishes a strong scientific premise with extensive prior work cited, a clear rationale, and acknowledgment of prior research limitations.

Evidence

“In 2020, WHO estimated that Neisseria gonorrhoeae caused 82·4 million new cases of gonorrhoea among those aged 15–49 years worldwide.”

Introduction ¶1Find in source

Research in context, Evidence before th…Find in source

“Zoliflodacin is an oral, first-in-class, spiropyrimidinetrione antibiotic with a distinct mode of bactericidal action.”

Introduction ¶3Find in source

PASSReviewer 2· 90% conf

The paper establishes a strong scientific premise with extensive prior work cited, a clear rationale, and addresses limitations of prior research.

Evidence

“In 2020, WHO estimated that Neisseria gonorrhoeae caused 82·4 million new cases of gonorrhoea among those aged 15–49 years worldwide.”

Introduction ¶1Find in source

“Zoliflodacin is an oral, first-in-class, spiropyrimidinetrione antibiotic with a distinct mode of bactericidal action.”

Introduction ¶3Find in source

Research in context, Evidence before th…Find in source

Sub-criteria

controlsN/A

power analysisADEQUATE

blinding levelsADEQUATE

outlier handlingADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

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

Evidence

“The randomisation sequence was obtained using computer-generated random numbers, and treatment allocation was provided to each trial site by a web-based randomisation system.”

MethodsFind in source

Statistical analysisFind in source

PASSReviewer 2· 95% conf

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

Evidence

“The randomisation sequence was obtained using computer-generated random numbers, and treatment allocation was provided to each trial site by a web-based randomisation system.”

MethodsFind in source

Statistical analysisFind in source

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Demographic and clinical characteristics are comprehensively reported, including sex, age, race, and HIV status.

Evidence

paraphrase[Results, paragraph 2]

“815 (88%) of 930 participants were assigned male at birth and 115 (12%) participants were assigned female at birth. The mean participant age was 29·7 years (SD 9·4).”

“514 (55%) of 930 participants were Black or African American, 285 (31%) were Asian, and 113 (12%) were White.”

Results ¶2Find in source

“199 (21%) were living with HIV”

Results ¶2Find in source

PASSReviewer 2· 90% conf

Demographic and baseline characteristics are comprehensively reported, including sex, age, race, and HIV status.

Evidence

paraphrase[Results, paragraph 2]

“815 (88%) of 930 participants were assigned male at birth and 115 (12%) participants were assigned female at birth. The mean participant age was 29·7 years (SD 9·4).”

“514 (55%) of 930 participants were Black or African American, 285 (31%) were Asian, and 113 (12%) were White.”

Results ¶2Find in source

paraphrase[Table 1]

“HIV status: Negative 455 (73%) | Positive 134 (22%) | Missing 32 (5%)”

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

Ethical approval and informed consent are adequately documented.

Evidence

“The study protocol and its amendments were approved by the institutional review board or ethics committee of all participating centres”

MethodsFind in source

“all participants provided written informed consent”

MethodsFind in source

“This phase 3, multinational, open-label, randomised, controlled, non-inferiority trial was designed and conducted in accordance with US Food and Drug Administration (FDA) guidance”

MethodsFind in source

PASSReviewer 2· 95% conf

Ethical approvals and informed consent are adequately reported.

Evidence

“The study protocol and its amendments were approved by the institutional review board or ethics committee of all participating centres”

MethodsFind in source

“all participants provided written informed consent.”

MethodsFind in source

“This phase 3, multinational, open-label, randomised, controlled, non-inferiority trial was designed and conducted in accordance with US Food and Drug Administration (FDA) guidance”

MethodsFind in source

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The investigational products are adequately identified, and the central laboratory is named.

Evidence

“either a single oral dose of zoliflodacin 3 g (granules as oral suspension) or the comparator, a single intramuscular 500 mg dose of ceftriaxone plus a single oral 1 g dose of azithromycin”

MethodsFind in source

“Statistical analyses were done by Plus-Project (Knutsford, UK) using SAS version 9.4.”

Statistical analysisFind in source

PASSReviewer 2· 90% conf

The investigational products and central laboratory are adequately identified.

Evidence

“either a single oral dose of zoliflodacin 3 g (granules as oral suspension) or the comparator, a single intramuscular 500 mg dose of ceftriaxone plus a single oral 1 g dose of azithromycin”

MethodsFind in source

“Presumptive N gonorrhoeae isolates were frozen and shipped to the central laboratory (JMI Laboratories; Iowa City, IA, USA)”

MethodsFind in source

“Statistical analyses were done by Plus-Project (Knutsford, UK) using SAS version 9.4.”

Statistical analysisFind in source

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedADEQUATE

mathematical plausibilityN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

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

Evidence

Statistical analysisFind in source

“Black or African American odds ratio 109·70, 90% CI 20·91–575·53; p<0·0001) and male sex (0·24, 0·11–0·53, p=0·0029)”

Results ¶8Find in source

“The estimated difference between groups was 5·3% (95% CI 1·4–8·6)”

Results ¶3Find in source

PASSReviewer 2· 90% conf

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

Evidence

Statistical analysisFind in source

Results ¶8Find in source

“The estimated difference between groups (comparator minus zoliflodacin) was 5·3% (95% CI 1·4–8·6)”

Results ¶3Find in source

Sub-criteria

code sharingN/A

accession numbersN/A

repository depositN/A

data availability statementADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Data availability is adequately described with a concrete access route.

Evidence

Data availabilityFind in source

PASSReviewer 2· 90% conf

Data availability is adequately described with a concrete access route.

Evidence

Data availabilityFind in source

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineINADEQUATE

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

The manuscript is transparent with trial registration, detailed methods, limitations, and funding/COI statements.

Evidence

“The trial is registered with ClinicalTrials.gov (http://ClinicalTrials.gov) , NCT03959527 (https://clinicaltrials.gov/ct2/show/NCT03959527) , and EudraCT, 2019-000990-22.”

MethodsFind in source

Discussion ¶6Find in source

“The institutions or affiliated institutions of LAB, TAB, SEC, SD-M, HJCdV, JAD, KG, CK, RK, VN, NP, ES, SNT, and ZZ received funding from GARDP for the trial.”

AcknowledgementsFind in source

PASSReviewer 2· 95% conf

Reporting is transparent with trial registration, comprehensive methods, and proportional conclusions.

Evidence

“The trial is registered with ClinicalTrials.gov (http://ClinicalTrials.gov) , NCT03959527 (https://clinicaltrials.gov/ct2/show/NCT03959527) , and EudraCT, 2019-000990-22.”

MethodsFind in source

Discussion ¶7Find in source

“The institutions or affiliated institutions of LAB, TAB, SEC, SD-M, HJCdV, JAD, KG, CK, RK, VN, NP, ES, SNT, and ZZ received funding from GARDP for the trial.”

Declaration of interestsFind in source

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

Broken references and links

1 finding · worst low

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.

References not resolvable to a published paperRecomputed

Checked 34 references by DOI: 27 verified — 1 DOI unresolved, 6 no DOI (shown, not verified).

2 data/code links checked; 2 live.

Copyediting

6 minor

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

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

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

Kaimen Rigor Action ItemsFinal pass before journal submission

1.
HIGHstatistics
In Results, paragraph 8, correct the reported p-value for the male sex association with neutropenia from p=0.0029 to the recomputed p=0.0291, or provide the exact model specification that yields the reported value.
The deterministic recomputation found an inconsistency; an incorrect p-value in a published paper is a validity concern that should be corrected or explained.
2.
HIGHreporting
Add an explicit statement in the Methods (or a supplementary file) that the trial adheres to the CONSORT reporting guideline, and include the CONSORT flow diagram.
Both reviewers flagged the reporting guideline as inadequate; explicit adherence improves transparency and reproducibility.
3.
HIGHstatistics
In Methods, Statistical analysis, provide a detailed description of the post-hoc multivariate logistic regression, including variable selection, model building, and diagnostics.
Both reviewers noted the post-hoc analysis is under-described; this is needed for readers to assess the validity of the neutropenia findings.
4.
HIGHreporting
Verify and correct the reference 'Gonococcal antimicrobial susceptibility surveillance in the European Union/European Economic Area, summary of results for 2022' (DOI 10.1016/s1473-3099(19...), which could not be found in any registry; if it is a real publication, provide the correct DOI and full citation.
A reference that cannot be found in Crossref/OpenAlex may be fabricated or have an incorrect DOI; this is an integrity concern that must be resolved.
5.
MEDIUMcopyedit
In Results, paragraph 2, fix the typographical error '114 (12%) of 930 (12%)' to '114 (12%) of 930'.
The duplicated percentage is a clear typo that could confuse readers.
6.
MEDIUMcopyedit
In Discussion, paragraph 6, correct the typo 'heath-care' to 'health-care'.
A simple typo that should be fixed for professionalism.
7.
MEDIUMcopyedit
In the Abstract and Methods, remove the extra space before the comma in the ClinicalTrials.gov registration statement and ensure consistent URL formatting.
Minor formatting inconsistency flagged by the copyedit pass.
8.
MEDIUMreporting
In the Discussion, temper the claim that 'Zoliflodacin might reduce antibiotic selection pressure and help preserve the effectiveness of other antibiotic classes' to explicitly note that this is a speculative benefit not directly measured in the trial.
The claim audit rated this as overstated; the paper should not overstate benefits beyond the evidence.
9.
MEDIUMreporting
In the Discussion, add a note about the generalizability of the results to populations not well represented in the trial, such as women and adolescents.
Both reviewers suggested this; it addresses a known limitation and helps readers interpret the findings.
10.
LOWreporting
In the Methods or Data sharing section, add a statement about the availability of statistical analysis code, even if not applicable, to enhance transparency.
Reviewer 2 suggested this; it is a nice-to-have for reproducibility.
11.
LOWreporting
In the Results, provide a breakdown of the 81 participants who did not meet screening criteria to improve transparency.
Reviewer 1 suggested this; it would help readers understand the screening process.
12.
LOWreporting
In the Methods, clarify the role of the data safety monitoring board and any interim analyses conducted.
Reviewer 1 suggested this; it is relevant for a phase 3 trial.

Full text (66,107 chars)Analyzed: Aug 15, 2026