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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

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, Zoliflodacin Phase 3 Study Group.

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Kaimen Rigor review — 2★ (Weak), 0 critical, 6 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 10, 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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Issued Aug 10, 2026Engine 7.29.0

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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

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Alpha1 Editorial

This rigor review was examined and confirmed by Alpha1 Editorial · August 10, 2026

Kaimen Rigor review

Kaimen Rigor reviewed

2 / 5

Weak — serious problems found

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

IntegrityIntegrity concern ×2−1★
ClaimsUnsupported claim (uncorroborated)−0.5★
ClaimsOverstated claim−0.5★
ReportingEthical approvals partially met−0.25★
ReportingKey resources partially met−0.25★
ReportingStatistical analysis partially met−0.25★
CitationsUnresolved reference−0.25★

Model-reported confidence: highReviewer agreement: highEngine: 7.29.0Source: full text

Biggest issues

01Conclusion not supported by the paper’s own evidence
highOverreachreviewer-assessedFull detail
This is the largest trial conducted to date in participants with N gonorrhoeae infection.
“A major strength of this study is its size; this is the largest trial conducted to date in participants with N gonorrhoeae infection.”
DiscussionFind in source
02Internal contradictions in the reported numbers
mediumArithmeticreviewer-assessedFull detail
The trial profile states 1011 participants were screened at 16 of 17 sites, with an additional 32 screened at a 17th site (31 randomized) and excluded after a GCP breach, yet the total randomized is 930 with only 81 screen failures. The arithmetic is ambiguous: if the 32 are outside the 1011, the total screened is 1043 and 1043−81=962, not 930; if they are inside, the excluded participants appear to remain in the randomized count.
“Between Nov 6, 2019, and March 16, 2023, 1011 participants were screened at 16 of the 17 sites. One site screened an additional 32 participants (31 of whom were randomly assigned and treated); however, after identification of a serious breach of Good Clinical…”
Abstract ¶1Find in source
03Internal contradictions in the reported numbers
mediumArithmeticreviewer-assessedFull detail
The text reports 455 participants from South Africa, but Table 1 sums to 424 (278 zoliflodacin + 146 comparator). The stated percentage (46%) is consistent with 424/930, not 455/930.
“Most participants were from South Africa (455 [46%] participants), followed by Thailand (270 [29%] participants), the USA (158 [17%] participants), and Europe (78 [8%] participants).”
Table 1Find in source
04Conclusion reaches beyond the evidence
mediumOverreachreviewer-assessedFull detail
Zoliflodacin might reduce antibiotic selection pressure and help preserve the effectiveness of other antibiotic classes, notably ceftriaxone.
“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 ¶3Find in source

Findings by category

101ArithmeticNumerical inconsistencies 202OverreachOverstated conclusions · partly checked 03AuthenticityNone found 304DisclosureReporting gaps 105AvailabilityBroken references and links 106CopyeditCopyediting

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

The paper reports a well-designed phase 3 trial with a clear scientific premise, robust randomization, and thorough statistical methods. Key reporting gaps include unnamed ethics committees, missing manufacturer details for investigational drugs, imprecise p-value reporting, and internal contradictions in participant counts (South Africa number and trial profile).

Synthesis based on two independent reviewer evaluations (same model, independent runs) that agreed on seven of eight dimensions; the statistical analysis divergence was resolved by weighing the imprecise p-value as a reporting deficiency. Copyedit findings and verification components (citation, statistics, reproducibility, integrity, claim audit) were integrated. The statistics verification covered only 2 tests; the citation check found one reference not located in the registry.

Numerical inconsistencies

1 finding · worst medium

Values that contradict each other or are impossible for the stated sample: recomputed p-values and test statistics, GRIM/GRIMMER checks on summary numbers, percentages against their own counts, totals against their parts, and estimates against their own confidence intervals.

Internal contradictions in the reported numbersAssessed

Recomputed 2 tests: 2 consistent, 0 inconsistent; 2 via agent-written checks.

Overstated conclusions

2 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.

Conclusions not supported by the paper’s own evidenceAssessed
Conclusions overstated beyond the evidenceAssessed

8 major claims checked against the paper's own evidence: 2 not fully backed by the presented evidence (unsupported or overstated).

Data authenticity concerns

None found

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

Checked — nothing surfaced.

Reporting gaps

3 findings · worst high

Required detail the manuscript never states — study design, biological variables, ethics approval and consent, key resources, statistical reporting, data and code availability, and overall transparency.

Statistical reporting gaps (tests, assumptions, effect sizes)Assessed
Ethics/consent reporting incompleteAssessed
Key resources under-identified (antibodies, cell lines, RRIDs)Assessed

Eight Dimensions5 pass · 3 warn

The introduction and Research in context sections cite WHO incidence data, resistance trends, prior failed oral agents (solithromycin, delafloxacin), and ertapenem's limitations. The rationale linking the premise to the trial objective is explicit. The authors acknowledge the absence of a formal literature search before design, and they discuss weaknesses of prior treatments, satisfying the limitations-addressed criterion.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

The paper establishes a strong scientific foundation: the global burden of gonorrhoea, antimicrobial resistance concerns, the mechanism and prior phase 1/2 data for zoliflodacin, and the rationale for a phase 3 non-inferiority trial.

Evidence

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

IntroductionFind in source

“A phase 2 study found zoliflodacin efficacious in treating uncomplicated urogenital gonorrhoea, warranting further clinical investigation.”

Research in contextFind in source

“Before study conception and design, no formal literature search was undertaken, given the paucity of clinical development underway at the time. Instead, scientific advice was sought from global experts.”

Research in contextFind in source

PASSReviewer 2· 95% conf

The scientific premise is well-established with extensive prior work cited, a clear rationale, and limitations of prior research acknowledged.

Evidence

paraphrase[Introduction, paragraphs 1-4]

“Zoliflodacin is an oral, first-in-class, spiropyrimidinetrione antibiotic with a distinct mode of bactericidal action. ... Phase 1 safety and pharmacokinetic studies, and pharmacokinetic and pharmacodynamic modelling, support a single oral 3 g treatment regimen, which was subsequently shown to be well tolerated and efficacious in treating uncomplicated urogenital gonorrhoea in a phase 2 study.”

“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, paragraph 1Find in source

For a human RCT, the applicable sub-criteria are randomization method, randomization unit, blinding levels, power analysis, inclusion/exclusion, and outlier handling (analysis population/missing data). All are reported adequately. The open-label design is acknowledged with a rationale, microbiology laboratory staff and sponsor central team were masked, and the sample size calculation with 90% power and a 12% non-inferiority margin is explicit. Non-assessable TOC outcomes were handled as failures with multiple imputation sensitivity analyses.

Sub-criteria

controlsN/A

power analysisADEQUATE

blinding levelsADEQUATE

outlier handlingADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

The trial design is rigorous and well reported: computer-generated randomization with permuted blocks and stratification, explicit masking of laboratory staff, a priori power calculation, and pre-specified inclusion/exclusion criteria and missing-data handling.

Evidence

paraphrase[Methods, Randomisation and masking]

“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. Randomisation was done using random permutated blocks of three, six, and nine with stratification by assigned sex at birth.”

“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

“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”

Statistical analysisFind in source

PASSReviewer 2· 95% conf

The study design is rigorous with adequate randomization, blinding rationale, power analysis, inclusion/exclusion criteria, and missing data handling.

Evidence

Methods ¶1Find in source

Statistical analysis ¶1Find in source

“Participants included in the microbiological intention-to-treat who had non-assessable outcomes at TOC (eg, missed or out-of-window TOC visits, or samples taken as per protocol but without results) were analysed as microbiological failures.”

Statistical analysis ¶2Find in source

For a human interventional trial, sex_reported, age_weight_health, and demographics apply. Sex and demographics are reported adequately. Health status is described through eligibility criteria and HIV status, but weight is not reported; therefore age_weight_health is judged reported_but_inadequate. Since 2 of 3 applicable sub-criteria are adequate, the dimension passes.

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthINADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Sex, age, race/ethnicity, region, and HIV status are reported in the text and Table 1; both sexes were enrolled so sex justification is not applicable. Body weight is not reported, but this does not compromise the overall assessment.

Evidence

“815 (88%) of 930 participants were assigned male at birth and 115 (12%) participants were assigned female at birth.”

ResultsFind in source

“The mean participant age was 29·7 years (SD 9·4).”

ResultsFind in source

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

ResultsFind in source

PASSReviewer 2· 85% conf

Sex and demographics are adequately reported; age is reported but weight/health status are partially reported (HIV status provided, but not general health or weight).

Evidence

“815 (88%) of 930 participants were assigned male at birth and 115 (12%) participants were assigned female at birth.”

Results ¶2Find in source

“The mean participant age was 29·7 years (SD 9·4).”

Table 1Find in source

paraphrase[Table 1]

“Race: Black or African American 349 (56%), Asian 193 (31%), White 66 (11%) ... Region: South Africa 278 (45%), Thailand 181 (29%), USA 107 (17%), Europe 55 (9%) ... HIV status: Positive 134 (22%)”

The paper states that the protocol was approved by the institutional review board or ethics committee of all participating centres, but does not name the specific bodies. A reference to a supplementary table containing the names is implied but not explicitly provided in the main text. Informed consent is adequately described as written. Regulatory compliance with FDA guidance is stated. The lack of a named approving body triggers a warn status.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementINADEQUATE

regulatory complianceADEQUATE

Per reviewer (2) — the votes behind the verdict

WARNReviewer 1· 65% conf

The paper states that the protocol was approved by the IRB/ethics committee of all participating centres and that written informed consent was obtained, but it does not name the approving bodies or provide protocol numbers, falling short of the named-body requirement.

Evidence

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

WARNReviewer 2· 80% conf

Informed consent and regulatory compliance are adequately reported, but the IRB/ethics committee approval statement does not name the specific approving body, which is inadequate per the criteria.

Evidence

Methods ¶1Find in source

“all participants provided written informed consent.”

Methods ¶1Find 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 and advice from research and public health bodies.”

Methods ¶1Find in source

Zoliflodacin is described as '3 g (granules as oral suspension)' and comparator as 'ceftriaxone 500 mg (intramuscular) plus azithromycin 1 g (oral)', but no manufacturers or catalog numbers are provided. For a drug trial, the investigational product should be identified with manufacturer. SAS version 9.4 is adequately identified. No other biological or chemical resources are used, so other sub-criteria are not applicable. The proportion of applicable criteria adequate is 1/2 (50%), resulting in a warn.

Sub-criteria

mycoplasma testingN/A

reagents identifiedINADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedADEQUATE

Per reviewer (2) — the votes behind the verdict

WARNReviewer 1· 75% conf

The investigational drugs are specified with dose, route, and formulation but without manufacturer or source, and SAS 9.4 is identified with its vendor; no other bench resources apply.

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

WARNReviewer 2· 85% conf

The investigational products (zoliflodacin, ceftriaxone, azithromycin) are described but not fully identified with manufacturer/source, while statistical software (SAS) is 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”

Methods ¶1Find in source

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

Statistical analysis ¶3Find in source

All applicable sub-criteria are adequate except exact_p_values: the primary analysis uses CIs, but the post-hoc logistic regression reports p<0.0001 for race, which is a threshold rather than an exact value. Tests are named (Clopper–Pearson, Newcombe score, logistic regression), assumptions are handled by the analysis design, effect sizes with CIs are reported throughout, software is identified, data presentation includes n/N and CIs, and the reported percentages and counts are internally consistent (e.g., 460/506=90.9%, Table 1 sums agree). Per the scoring rule, the threshold-only p-value makes the dimension a warn.

Sub-criteria

tests namedADEQUATE

exact p valuesINADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedADEQUATE

mathematical plausibilityPASS

Per reviewer (2) — the votes behind the verdict

WARNReviewer 1· 80% conf

Statistical methods are thorough and the primary endpoint is reported by estimation with 95% CIs, but one post-hoc p-value is reported only as a threshold (p<0.0001), which is imprecise reporting. Mathematical plausibility checks of the reported proportions were all consistent.

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

“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)”

ResultsFind in source

“460/506 | 90·9% (88·1–93·3) | 229/238 | 96·2% (92·9–98·3) | 5·3% (1·4–8·6)”

Table 2Find in source

PASSReviewer 2· 95% conf

All applicable statistical criteria are adequately reported; tests are named, assumptions are handled by design, effect sizes with CIs are provided, software is identified, data presentation is complete, and mathematical plausibility checks pass.

Evidence

“For the primary endpoint analysis, the proportion of participants with microbiological cure at TOC was calculated for the microbiological intention-to-treat (urogenital) population, and 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 analysis ¶2Find in source

“Microbiological cure rates at TOC in the microbiological intention-to-treat (urogenital) population (primary efficacy endpoint) were 460 (90·9%, 95% CI 88·1–93·3) of 506 participants for zoliflodacin and 229 (96·2%, 92·9–98·3) of 238 participants for comparator.”

Table 2Find in source

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

Statistical analysis ¶3Find in source

The data availability statement names a specific route (datasharing@gardp.org), states that data will be available within 6 months of first regulatory approval, and describes anonymisation and a data sharing agreement. For identifiable patient-level data, repository deposit and accession numbers are not applicable, and no custom code is mentioned, so code sharing is not applicable. The single applicable criterion is adequate, giving a pass.

Sub-criteria

code sharingN/A

accession numbersN/A

repository depositN/A

data availability statementADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

A concrete data-sharing statement is provided with a named contact, timeline, and conditions for accessing anonymised participant-level data, which is adequate for patient-level clinical trial data.

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. A signed data sharing agreement might be required.”

Data availabilityFind in source

PASSReviewer 2· 90% conf

A data availability statement is present and adequate, providing a concrete mechanism for data access. Repository deposit and code sharing are not applicable due to the nature of the data and standard analysis.

Evidence

“The data underlying the results of this study and related study documents (eg, study protocol, statistical analysis plan, and informed consent form) can be made available upon request. 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. A signed data sharing agreement might be required.”

Data availabilityFind in source

Methods are complete and the protocol and SAP are publicly linked. Registration is provided (NCT03959527, EudraCT 2019-000990-22). All pre-specified outcomes are reported, including negative/null findings and secondary analyses. Limitations are discussed at length, conclusions are balanced, and funding sources and conflicts of interest are detailed. The only gap is that no CONSORT checklist is referenced, so reporting_guideline is not_reported; the percentage of adequate sub-criteria is still above 60%.

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineNOT REPORTED

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The manuscript is transparent and complete: trial registration numbers, detailed methods with linked protocol/SAP, thorough limitations, proportional conclusions, and funding/COI disclosures are all present. A CONSORT checklist is not explicitly referenced.

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.”

DiscussionFind in source

paraphrase[Acknowledgments and Declaration of interests]

“This trial was sponsored and led by GARDP ... with support from Germany's Federal Ministry of Research, Technology and Space (grant 03KA1831)”

PASSReviewer 2· 90% conf

Reporting is generally transparent with complete methods, trial registration, all outcomes reported, limitations discussed, proportional conclusions, and funding/COI statements. The only gap is the absence of a specific reporting guideline mention (e.g., CONSORT).

Evidence

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

Methods ¶1Find in source

Discussion ¶5Find in source

“This trial was sponsored and led by GARDP (registered under the legal name GARDP Foundation) and was fully publicly funded, with support from Germany's Federal Ministry of Research, Technology and Space (grant 03KA1831), the UK Department of Health and Social Care as part of the Global Antimicrobial Resistance Innovation Fund, Japan's Ministry of Health, Labour and Welfare, the Government of The Netherlands' Ministry of Health, Welfare and Sport and Directorate-General for International Cooperation, the Government of Switzerland, and the Canton of Geneva, Switzerland.”

FundingFind 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).

3 data/code links checked; 3 live.

Copyediting

1 finding · worst low

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

Wording or formatting errors that need correctingAssessed

8 copyedit issues flagged (2 major): mostly typo, consistency, grammar.

Kaimen Rigor Action ItemsFinal pass before journal submission

As a post-publication audit, the paper is generally robust but has several reporting inconsistencies that undermine confidence in the reported numbers. The internal contradictions in participant counts and the unsupported superlative claim warrant a formal correction or erratum. An informed reader should weigh the ambiguities in the trial profile and the South Africa participant count, as well as the lack of named ethics committees.

1.
HIGHreporting
Correct the South Africa participant count in the Results text from 455 to 424 to match Table 1, and ensure the percentage (46%) is consistent with the corrected numerator.
This internal contradiction between text and table undermines data integrity and must be resolved in a correction.
2.
HIGHreporting
Clarify the trial profile: state whether the 1011 participants screened include the 32 from the GCP-breached site, and reconcile the arithmetic (1011 screens, 81 screen failures, 32 excluded from breached site, 930 randomized) with a clear flow diagram footnote.
The ambiguous arithmetic could imply a discrepancy in the number of randomized participants and should be explicitly resolved.
3.
HIGHreporting
Remove or support the claim 'This is the largest trial conducted to date in participants with N gonorrhoeae infection' by providing a systematic comparison or citation; otherwise, temper the language.
The claim audit found this unsupported; an unsupported superlative claim can mislead readers and is a validity concern.
4.
HIGHethics
Add a supplementary table listing each participating centre's IRB/ethics committee name and approval number, and cite it in the Methods approval statement.
The current approval statement does not name the approving bodies, which is a standard reporting requirement for clinical trials.
5.
HIGHreporting
Verify the reference that could not be found in the registry (DOI 10.1016/s1473-3099(19...) and either correct the DOI or replace it with a verifiable source.
A reference that cannot be located in any registry is a fabrication signal and must be resolved.
6.
HIGHreporting
Temper the claim 'Zoliflodacin might reduce antibiotic selection pressure and help preserve the effectiveness of other antibiotic classes, notably ceftriaxone' by adding a qualifier that this is a hypothesis not tested by the study data.
The claim audit rated this as overstated; over-claiming can lead to misinterpretation of the findings.
7.
MEDIUMstatistics
Report the exact p-value for the race association in the post-hoc logistic regression (e.g., p=3.15×10^-6) instead of the threshold p<0.0001.
Reporting exact p-values is a standard for transparency and allows readers to assess the strength of evidence.
8.
MEDIUMreporting
Provide the manufacturer/source information for zoliflodacin, ceftriaxone, and azithromycin in the Methods section.
For reproducibility, investigational products should be fully identified with their source.
9.
MEDIUMreporting
Add a completed CONSORT 2010 checklist as supplementary material and cite it in the Methods.
The CONSORT checklist is the standard reporting guideline for RCTs and its absence is a gap.
10.
MEDIUMcopyedit
Fix the duplicated percentage in the Results paragraph on rectal culture proportions: delete the second '(12%)'.
This is a typographical error that could confuse readers.
11.
MEDIUMcopyedit
Correct 'permutated' to 'permuted' in the Randomisation and masking section.
Standard statistical terminology is 'permuted blocks'.
12.
LOWcopyedit
Correct 'heath-care' to 'health-care' in the Discussion limitations.
This is a minor typo.
13.
LOWcopyedit
Correct the incomplete species name from 'N gonorrheae' to 'N gonorrhoeae' (or full binomial) in the Methods.
Proper taxonomic nomenclature is expected.
14.
LOWreporting
Consider adding body weight (or BMI) to the baseline characteristics table for completeness.
Weight is a relevant biological variable, though its absence is minor.

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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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Issued Aug 10, 2026Engine 7.29.0

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

Kaimen Rigor review

Kaimen Rigor reviewed

2 / 5

Weak — serious problems found

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

IntegrityIntegrity concern ×2−1★
ClaimsUnsupported claim (uncorroborated)−0.5★
ClaimsOverstated claim−0.5★
ReportingEthical approvals partially met−0.25★
ReportingKey resources partially met−0.25★
ReportingStatistical analysis partially met−0.25★
CitationsUnresolved reference−0.25★

Model-reported confidence: highReviewer agreement: highEngine: 7.29.0Source: full text

Biggest issues

01Conclusion not supported by the paper’s own evidence
highOverreachreviewer-assessedFull detail
This is the largest trial conducted to date in participants with N gonorrhoeae infection.
“A major strength of this study is its size; this is the largest trial conducted to date in participants with N gonorrhoeae infection.”
DiscussionFind in source
02Internal contradictions in the reported numbers
mediumArithmeticreviewer-assessedFull detail
The trial profile states 1011 participants were screened at 16 of 17 sites, with an additional 32 screened at a 17th site (31 randomized) and excluded after a GCP breach, yet the total randomized is 930 with only 81 screen failures. The arithmetic is ambiguous: if the 32 are outside the 1011, the total screened is 1043 and 1043−81=962, not 930; if they are inside, the excluded participants appear to remain in the randomized count.
“Between Nov 6, 2019, and March 16, 2023, 1011 participants were screened at 16 of the 17 sites. One site screened an additional 32 participants (31 of whom were randomly assigned and treated); however, after identification of a serious breach of Good Clinical…”
Abstract ¶1Find in source
03Internal contradictions in the reported numbers
mediumArithmeticreviewer-assessedFull detail
The text reports 455 participants from South Africa, but Table 1 sums to 424 (278 zoliflodacin + 146 comparator). The stated percentage (46%) is consistent with 424/930, not 455/930.
“Most participants were from South Africa (455 [46%] participants), followed by Thailand (270 [29%] participants), the USA (158 [17%] participants), and Europe (78 [8%] participants).”
Table 1Find in source
04Conclusion reaches beyond the evidence
mediumOverreachreviewer-assessedFull detail
Zoliflodacin might reduce antibiotic selection pressure and help preserve the effectiveness of other antibiotic classes, notably ceftriaxone.
“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 ¶3Find in source

Findings by category

Numerical inconsistencies

1 finding · worst medium

Internal contradictions in the reported numbersAssessed

Recomputed 2 tests: 2 consistent, 0 inconsistent; 2 via agent-written checks.

Overstated conclusions

2 findings · worst high

Conclusions not supported by the paper’s own evidenceAssessed
Conclusions overstated beyond the evidenceAssessed

8 major claims checked against the paper's own evidence: 2 not fully backed by the presented evidence (unsupported or overstated).

Data authenticity concerns

None found

Checked — nothing surfaced.

Reporting gaps

3 findings · worst high

Statistical reporting gaps (tests, assumptions, effect sizes)Assessed
Ethics/consent reporting incompleteAssessed
Key resources under-identified (antibodies, cell lines, RRIDs)Assessed

Eight Dimensions5 pass · 3 warn

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

Evidence

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

IntroductionFind in source

“A phase 2 study found zoliflodacin efficacious in treating uncomplicated urogenital gonorrhoea, warranting further clinical investigation.”

Research in contextFind in source

PASSReviewer 2· 95% conf

The scientific premise is well-established with extensive prior work cited, a clear rationale, and limitations of prior research acknowledged.

Evidence

paraphrase[Introduction, paragraphs 1-4]

Research in context, paragraph 1Find 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

Evidence

paraphrase[Methods, Randomisation and masking]

MethodsFind in source

Statistical analysisFind in source

PASSReviewer 2· 95% conf

The study design is rigorous with adequate randomization, blinding rationale, power analysis, inclusion/exclusion criteria, and missing data handling.

Evidence

Methods ¶1Find in source

Statistical analysis ¶1Find in source

Statistical analysis ¶2Find in source

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthINADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Evidence

“815 (88%) of 930 participants were assigned male at birth and 115 (12%) participants were assigned female at birth.”

ResultsFind in source

“The mean participant age was 29·7 years (SD 9·4).”

ResultsFind in source

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

ResultsFind in source

PASSReviewer 2· 85% conf

Sex and demographics are adequately reported; age is reported but weight/health status are partially reported (HIV status provided, but not general health or weight).

Evidence

“815 (88%) of 930 participants were assigned male at birth and 115 (12%) participants were assigned female at birth.”

Results ¶2Find in source

“The mean participant age was 29·7 years (SD 9·4).”

Table 1Find in source

paraphrase[Table 1]

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementINADEQUATE

regulatory complianceADEQUATE

Per reviewer (2) — the votes behind the verdict

WARNReviewer 1· 65% conf

Evidence

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

WARNReviewer 2· 80% conf

Informed consent and regulatory compliance are adequately reported, but the IRB/ethics committee approval statement does not name the specific approving body, which is inadequate per the criteria.

Evidence

Methods ¶1Find in source

“all participants provided written informed consent.”

Methods ¶1Find in source

Sub-criteria

mycoplasma testingN/A

reagents identifiedINADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedADEQUATE

Per reviewer (2) — the votes behind the verdict

WARNReviewer 1· 75% conf

The investigational drugs are specified with dose, route, and formulation but without manufacturer or source, and SAS 9.4 is identified with its vendor; no other bench resources apply.

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

WARNReviewer 2· 85% conf

The investigational products (zoliflodacin, ceftriaxone, azithromycin) are described but not fully identified with manufacturer/source, while statistical software (SAS) is 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”

Methods ¶1Find in source

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

Statistical analysis ¶3Find in source

Sub-criteria

tests namedADEQUATE

exact p valuesINADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedADEQUATE

mathematical plausibilityPASS

Per reviewer (2) — the votes behind the verdict

WARNReviewer 1· 80% conf

Evidence

Statistical analysisFind in source

ResultsFind in source

“460/506 | 90·9% (88·1–93·3) | 229/238 | 96·2% (92·9–98·3) | 5·3% (1·4–8·6)”

Table 2Find in source

PASSReviewer 2· 95% conf

Evidence

Statistical analysis ¶2Find in source

Table 2Find in source

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

Statistical analysis ¶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· 95% conf

A concrete data-sharing statement is provided with a named contact, timeline, and conditions for accessing anonymised participant-level data, which is adequate for patient-level clinical trial data.

Evidence

Data availabilityFind in source

PASSReviewer 2· 90% conf

Evidence

Data availabilityFind in source

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineNOT REPORTED

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

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

DiscussionFind in source

paraphrase[Acknowledgments and Declaration of interests]

“This trial was sponsored and led by GARDP ... with support from Germany's Federal Ministry of Research, Technology and Space (grant 03KA1831)”

PASSReviewer 2· 90% conf

Evidence

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

Methods ¶1Find in source

Discussion ¶5Find in source

FundingFind 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).

3 data/code links checked; 3 live.

Copyediting

1 finding · worst low

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

Wording or formatting errors that need correctingAssessed

8 copyedit issues flagged (2 major): mostly typo, consistency, grammar.

Kaimen Rigor Action ItemsFinal pass before journal submission

1.
HIGHreporting
Correct the South Africa participant count in the Results text from 455 to 424 to match Table 1, and ensure the percentage (46%) is consistent with the corrected numerator.
This internal contradiction between text and table undermines data integrity and must be resolved in a correction.
2.
HIGHreporting
Clarify the trial profile: state whether the 1011 participants screened include the 32 from the GCP-breached site, and reconcile the arithmetic (1011 screens, 81 screen failures, 32 excluded from breached site, 930 randomized) with a clear flow diagram footnote.
The ambiguous arithmetic could imply a discrepancy in the number of randomized participants and should be explicitly resolved.
3.
HIGHreporting
Remove or support the claim 'This is the largest trial conducted to date in participants with N gonorrhoeae infection' by providing a systematic comparison or citation; otherwise, temper the language.
The claim audit found this unsupported; an unsupported superlative claim can mislead readers and is a validity concern.
4.
HIGHethics
Add a supplementary table listing each participating centre's IRB/ethics committee name and approval number, and cite it in the Methods approval statement.
The current approval statement does not name the approving bodies, which is a standard reporting requirement for clinical trials.
5.
HIGHreporting
Verify the reference that could not be found in the registry (DOI 10.1016/s1473-3099(19...) and either correct the DOI or replace it with a verifiable source.
A reference that cannot be located in any registry is a fabrication signal and must be resolved.
6.
HIGHreporting
Temper the claim 'Zoliflodacin might reduce antibiotic selection pressure and help preserve the effectiveness of other antibiotic classes, notably ceftriaxone' by adding a qualifier that this is a hypothesis not tested by the study data.
The claim audit rated this as overstated; over-claiming can lead to misinterpretation of the findings.
7.
MEDIUMstatistics
Report the exact p-value for the race association in the post-hoc logistic regression (e.g., p=3.15×10^-6) instead of the threshold p<0.0001.
Reporting exact p-values is a standard for transparency and allows readers to assess the strength of evidence.
8.
MEDIUMreporting
Provide the manufacturer/source information for zoliflodacin, ceftriaxone, and azithromycin in the Methods section.
For reproducibility, investigational products should be fully identified with their source.
9.
MEDIUMreporting
Add a completed CONSORT 2010 checklist as supplementary material and cite it in the Methods.
The CONSORT checklist is the standard reporting guideline for RCTs and its absence is a gap.
10.
MEDIUMcopyedit
Fix the duplicated percentage in the Results paragraph on rectal culture proportions: delete the second '(12%)'.
This is a typographical error that could confuse readers.
11.
MEDIUMcopyedit
Correct 'permutated' to 'permuted' in the Randomisation and masking section.
Standard statistical terminology is 'permuted blocks'.
12.
LOWcopyedit
Correct 'heath-care' to 'health-care' in the Discussion limitations.
This is a minor typo.
13.
LOWcopyedit
Correct the incomplete species name from 'N gonorrheae' to 'N gonorrhoeae' (or full binomial) in the Methods.
Proper taxonomic nomenclature is expected.
14.
LOWreporting
Consider adding body weight (or BMI) to the baseline characteristics table for completeness.
Weight is a relevant biological variable, though its absence is minor.

Full text (66,107 chars)Analyzed: Aug 10, 2026