Rigor Reviewed

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One Dose versus Three Doses of Benzathine Penicillin G in Early Syphilis.

Name: Adcurare Rigor Record — One Dose versus Three Doses of Benzathine Penicillin G in Early Syphilis.
Item: One Dose versus Three Doses of Benzathine Penicillin G in Early Syphilis.
Rating: 59
Author: Adcurare

Hook EW 3rd, Dionne JA, Workowski K, McNeil CJ, Taylor SN, Batteiger TA, Dombrowski JC, Mayer KH, Seña AC, Hamill MM, Wiesenfeld HC, Zhu C, Perlowski C, Mejia-Galvis JE, Newman LM

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Adcurare Rigor Review — 1★ (Critical), 0 critical, 10 high issues for “One Dose versus Three Doses of Benzathine Penicillin G in Early Syphilis.”

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Adcurare Editorial

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

Adcurare Rigor Review

Rigor Reviewed

1 / 5

Critical — a demonstrable failure

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

IntegrityIntegrity concern ×4−2★
CitationsCitations & links (capped) ×7−1★
ReportingKey resources not met−0.5★
ReportingData & code availability not met−0.5★
ReportingStudy design partially met−0.25★
ReportingEthical approvals partially met−0.25★
ReportingStatistical analysis partially met−0.25★

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

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

Not verified in this report

No reported statistical tests were found to recompute.
Declared data/code links were not checked for liveness or content.

Problems surfaced7 types

Data and code not shared
Key resources not identified
Statistical reporting gaps (tests, assumptions, effect sizes)
Ethics/consent reporting incomplete
Internal contradictions in the reported numbers
Study-design details incomplete (controls, blinding, power)
References not resolvable to a published paper

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

The paper presents a well-designed multicenter RCT, but several reporting gaps reduce its rigor: the trial is not registered, randomization method is unspecified, statistical software is not identified, and a data availability statement for patient-level data is missing. Table sum discrepancies and missing regulatory compliance statement also need attention.

Both reviewers agreed on study type and most dimensions, but diverged on study design, ethical approvals, key resources, and data/code availability. The synthesis weighed specific evidence: e.g., open-label lacking rationale, power analysis incomplete, and missing regulatory compliance statement. The verification components identified internal contradictions in Table 1 and 7 references not found in registries, the latter requiring verification.

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

4 integrity concerns flagged (0 high).

Reporting

Eight Dimensions3 pass · 3 warn · 2 fail

The introduction cites historical and contemporary literature on syphilis treatment, HIV co-infection, and the ongoing debate about single vs. multiple BPG doses. It acknowledges the limitations of prior research, including concerns about single-dose efficacy in immunocompromised persons, and states the rationale for the trial. The hypothesis (non-inferiority of single dose) follows logically from the cited evidence.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

The paper clearly establishes the scientific foundation by citing prior research on syphilis treatment and the controversy over optimal BPG duration for persons with HIV.

Evidence

direct quote[Introduction, paragraphs 1-3]

“While a single dose of benzathine penicillin G (BPG) has been the accepted standard for therapy of early syphilis for decades, concerns about the adequacy of single dose BPG for treatment of early syphilis for persons with HIV (PWH) are longstanding.”

direct quote[Introduction, paragraph 2]

“Despite CDC recommendations for single dose BPG therapy, many clinicians treat PLWH with multiple doses of BPG.”

direct quote[Introduction, paragraph 3]

“To address the continuing controversy regarding the optimal duration of BPG for early syphilis treatment, we conducted a multicenter randomized non-inferiority clinical trial (RCT) comparing single dose therapy with 2.4 million units (MU) of BPG to therapy with three doses of 2.4MU BPG administered at successive weekly intervals.”

PASSReviewer 2· 90% conf

The study establishes its scientific foundation by citing prior work on syphilis therapy and the controversy regarding optimal duration, especially for persons with HIV.

Evidence

paraphrase[Introduction, paragraphs 1-3]

“The paper cites CDC recommendations, the Rolfs et al study, and concerns about treatment duration for PWH.”

paraphrase[Discussion, paragraph 1]

“The paper mentions that clinicians question single-dose therapy for PWH and that BPG shortages exist, but does not systematically assess prior study weaknesses.”

Randomization is stated but method not described. Blinding is open-label without justification. Power analysis was originally for 420 but terminated early; futility analysis claimed 80% power. Inclusion/exclusion criteria well-defined. ITT and per-protocol analyses are clearly described. Comparator arm is appropriate.

Sub-criteria

controlsADEQUATE

power analysisINADEQUATE

blinding levelsINADEQUATE

outlier handlingADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodINADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The study is an open-label RCT with a non-inferiority design. Randomization is described, but the method is not detailed. Blinding is not used (open-label) with a rationale. Power analysis is reported. Inclusion/exclusion criteria are specified. Controls are appropriate. The study was stopped early due to slow enrollment, but futility analysis is provided.

Evidence

direct quote[Methods, first paragraph]

“This open label RCT was conducted at ten U.S. sites.”

direct quote[Methods, Statistical Analyses paragraph]

“The pre-specified non-inferiority margin was 10%. ... a sample size of 420 participants (210 per treatment group) was sought. ... Futility analyses performed at that time indicated that when response rates for the two treatment groups were similar at approximately 0.789, available data could still provide 80% power.”

direct quote[Methods, first paragraph]

“Participants were ≥18 years of age and had early syphilis ... Participants were excluded if they were pregnant, had taken antibiotics active against Treponema pallidum in the preceding 30 days...”

WARNReviewer 2· 80% conf

The study design is generally sound but has several reporting gaps: randomization method not specified, open-label without rationale, power analysis incomplete due to early stopping, and missing blinding information.

Evidence

absence[Methods, paragraph 'Treatment']

Randomization method not specified.

direct quote[Methods, first sentence]

“This open label RCT was conducted at ten U.S. sites.”

direct quote[Methods, 'Statistical Analyses']

“a sample size of 420 participants (210 per treatment group) was sought... The study was halted... Futility analyses... could still provide 80% power.”

The study reports sex at birth (97% male, 3% female), age (mean 35, range 19-66), race, ethnicity, HIV status, CD4 counts, syphilis stage, and prior syphilis history. The low number of women is acknowledged as a limitation but single-sex justification is n/a since both sexes were enrolled. For a human interventional study, species_strain_source and housing_conditions are n/a. Demographics and age/weight/health are reported. Sex_justified is n/a because both sexes are included.

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

Human demographics (age, sex, race, HIV status, syphilis stage) are thoroughly reported. Sex is reported and the study enrolled both sexes, though the number of women was low and limitations are discussed. Age and health status (HIV, CD4 counts) are reported. Species/strain and housing conditions are n/a for a human trial.

Evidence

direct quote[Results, Table 1]

“Male 123 (98%) vs 119 (96%) in three-dose and one-dose groups; Median Age 31 vs 33 years; Black 64% vs 60%”

direct quote[Results, Table 1 and text]

“Among 153 PWH in the ITT population, 92% reported taking anti-retroviral therapy (ART)... CD4 lymphocyte concentrations at the time of treatment were >350 cells/mm3 in 110 (77%).”

direct quote[Discussion, paragraph 3]

“The number of women in the trial was low. The data are insufficient to evaluate response to therapy in women and there are no data on outcomes of therapy for pregnant persons.”

PASSReviewer 2· 80% conf

Biological variables are adequately reported: sex, age, race/ethnicity, HIV status, and syphilis stage are all detailed in Table 1.

Evidence

direct quote[Table 1]

“Male: 123 (98%) and 119 (96%)”

direct quote[Table 1]

“Median Age in Years (IQR): 32 (27,42)”

absence[Table 1]

Health status limited to HIV; weight not reported.

Written informed consent obtained. The UAB IRB approved the protocol, and each site's IRB provided approval. However, no mention of compliance with Declaration of Helsinki, ICH-GCP, or other regulations.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceNOT REPORTED

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

The paper reports IRB approval from a named board (UAB IRB) with protocol approval at each site, written informed consent from all participants, and compliance with regulatory standards.

Evidence

direct quote[Methods, Human Subjects paragraph]

“The master protocol was approved by the UAB Institutional Review Board (IRB) for Human Subjects and subsequently by IRBs at each study site.”

direct quote[Methods, Human Subjects paragraph]

“Written informed consent was obtained from all participants.”

direct quote[Methods, Human Subjects paragraph]

“During the trial National Institutes of Allergy and Infectious Diseases (NIAID) convened a Data Safety and Monitoring Board (DSMB) to review study progress and participant safety on three occasions.”

WARNReviewer 2· 90% conf

Informed consent and IRB approval are adequately documented, but regulatory compliance with a recognized framework (e.g., Declaration of Helsinki) is not stated.

Evidence

direct quote[Methods, 'Human Subjects']

“The master protocol was approved by the UAB Institutional Review Board (IRB) for Human Subjects and subsequently by IRBs at each study site.”

direct quote[Methods, 'Human Subjects']

“Written informed consent was obtained from all participants.”

absence[Methods, 'Human Subjects']

No regulatory framework cited.

Benzathine penicillin G is described but no source or formulation details beyond dose. The RPR and TPPA tests are named with vendors. No software is mentioned for statistical analysis.

Sub-criteria

mycoplasma testingN/A

reagents identifiedINADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedNOT REPORTED

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 85% conf

The investigational product (benzathine penicillin G) is identified, and the software/tools used for analysis are not specified in detail, but the paper refers to a protocol and SAP with full details. For a drug trial, reagents_identified (investigational product) is adequate; software_tools_identified is reported but could be more specific.

Evidence

direct quote[Title, Abstract, Methods]

“Benzathine Penicillin G, 1 vs 3 Weekly Doses, for Early Syphilis Treatment”

direct quote[Methods, paragraph 1]

“reactive rapid plasma reagin (RPR) tests (BD Macro-Vue) confirmed by a TPPA (Treponema pallidum particle agglutination) test (SERODIA TPPA, Fujirebio Diagnostics)”

direct quote[Methods, Statistical Analyses paragraph; also Methods paragraph 1]

“Full details of study conduct can be found in the protocol and SAP at nejm.org”

FAILReviewer 2· 90% conf

The investigational drug (BPG) is identified only by name and dose, lacking manufacturer, lot number, or catalog number. Statistical software is not identified. Diagnostic tests are adequately identified.

Evidence

direct quote[Methods, 'Treatment']

“intramuscular injections of 1.2 MU of BPG in each buttock.”

direct quote[Methods, first paragraph]

“reactive rapid plasma reagin (RPR) tests (BD Macro-Vue)”

absence[Methods, 'Statistical Analyses']

Statistical software not identified.

The primary analysis uses the Farrington-Manning test for non-inferiority. The paper reports the difference and 90% CI for the ITT and per-protocol populations but does not report exact p-values; it relies on the CI vs. non-inferiority margin. Effect sizes (e.g., risk difference) are provided along with CIs. Assumptions for the test (e.g., normality) are not discussed; for a large trial this is acceptable as per the guide. Statistical software (e.g., SAS, R) is not identified. Data presentation is adequate for a clinical trial: Kaplan-Meier curves are not shown as the primary endpoint is binary, but response rates are graphed in Figure 2. Mathematical_plausibility: some minor inconsistencies in Table 1 (e.g., HIV status percentages sum to 98% due to missing data, which is stated) and RPR titer counts appear to have row label alignment issues that are likely copyediting errors, not arithmetic errors. No demonstrable errors found. The warn is due to the lack of software identification and the absence of exact p-values (though appropriate for a non-inferiority trial that uses CIs).

Sub-criteria

tests namedADEQUATE

exact p valuesINADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedNOT REPORTED

assumptions verifiedINADEQUATE

mathematical plausibilityWARN

Per reviewer (2) — the votes behind the verdict

WARNReviewer 1· 85% conf

The statistical tests are named (Farrington-Manning test), and exact p-values are not reported for the primary comparison (difference and 90% CI given). Effect sizes are not reported as a standardized metric. Assumptions are not verified. Software is not identified. Data presentation includes individual data points in figures and group n's are stated. Mathematical plausibility checks show some table structure issues but no demonstrable errors.

Evidence

direct quote[Methods, Statistical Analyses]

“Differences in response rate using the Farrington-Manning test were compared without adjustment for HIV status.”

direct quote[Results, Response to therapy paragraph]

“The Farrington-Manning test result showed the difference in the proportion of participants with serological response between the two treatment groups as −0.06 [90% CI (−0.15, 0.03)].”

absence[Methods, Statistical Analyses]

Statistical software is not identified

WARNReviewer 2· 80% conf

Statistical tests are named and effect sizes with CIs are reported, but exact p-values are not provided and statistical software is not identified. Some table sums do not add to group totals, indicating data presentation issues.

Evidence

direct quote[Results, paragraph 'Response to therapy']

“The Farrington-Manning test result showed the difference in the proportion of participants with serological response between the two treatment groups as -0.06 [90% CI (-0.15, 0.03)].”

direct quote[Table 1]

“For three-dose: sums to 120, but n=125; for one-dose: sums to 120, but n=124.”

paraphrase[Methods, 'Statistical Analyses']

“The Farrington-Manning test is a standard method for comparing proportions, and no explicit assumption verification is needed per clinical trial conventions.”

The paper mentions 'Full details of study conduct can be found in the protocol and SAP at nejm.org' but does not state where data are available. No accession numbers or code repositories are mentioned.

Sub-criteria

code sharingN/A

accession numbersN/A

repository depositNOT REPORTED

data availability statementNOT REPORTED

Per reviewer (2) — the votes behind the verdict

WARNReviewer 1· 90% conf

A data availability statement is present, referring to the protocol and SAP at NEJM.org, but no raw data or code are deposited. No repository deposit or code sharing is reported.

Evidence

direct quote[Methods, first paragraph]

“Full details of study conduct can be found in the protocol and SAP at nejm.org”

absence[Full text]

No mention of data repository deposit or code sharing

FAILReviewer 2· 90% conf

No data availability statement is provided. The paper only refers to the protocol and SAP at NEJM.org, not the data. No repository deposit or code sharing occurs.

Evidence

absence[Methods and end of paper]

No data availability statement.

direct quote[Methods, last sentence]

“Full details of study conduct can be found in the protocol and SAP at nejm.org (http://www.nejm.org).”

Methods are detailed enough for replication. A CONSORT flow diagram is provided (Figure 1). Limitations are discussed in the Discussion, including low numbers of women, reliance on serological response, and limited data on advanced HIV. Conclusions are proportional: they state non-inferiority within the studied population. Trial registration is not reported; this is a significant omission for an interventional clinical trial. Funding (NIAID contract) and disclosure forms are mentioned. For an interventional clinical trial, trial_registration is applicable and not reported (reported_but_inadequate); reporting_guideline (CONSORT) is partially referenced via the flow diagram but not explicitly mentioned as a checklist; all_outcomes_reported seems adequate; limitations_discussed and conclusions_proportional are adequate; funding_coi is adequate.

Sub-criteria

funding coiADEQUATE

trial registrationNOT REPORTED

reporting guidelineINADEQUATE

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The paper provides detailed methods, includes a CONSORT diagram, discusses limitations, and offers conclusions proportional to the evidence. Clinical trial registration is not mentioned; however, for a trial that started enrollment in 2018, this would be expected. Funding and COI are disclosed.

Evidence

direct quote[Results, Figure 1]

“Figure 1. Disposition of Study Subjects Flow Chart (CONSORT Diagram)”

direct quote[Discussion, paragraphs 3-5]

“Our study had several limitations. The number of women in the trial was low. ... A further limitation of the study is our continued reliance upon serological response to therapy as an indicator of therapeutic effect.”

direct quote[Acknowledgements and Footnotes]

“This work was funded by the National Institute of Allergy and Infectious Diseases... Disclosure forms provided by the authors are available...”

PASSReviewer 2· 80% conf

Methods are detailed, limitations are discussed, conclusions are proportional, and funding/COI are stated. However, trial registration is not provided and CONSORT adherence is not explicitly claimed.

Evidence

absence[Abstract and Methods]

No trial registration number.

direct quote[Figure 1]

“Figure 1. Disposition of Study Subjects Flow Chart (CONSORT Diagram)”

direct quote[Discussion, second paragraph]

“Our study had several limitations.”

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

Checked 14 references: 4 verified — 7 unresolved, 3 not checked.

Reproducibility

No trial/study registration detected. Reporting guideline cited: CONSORT.

Adcurare Rigor Action ItemsFinal pass before journal submission

The manuscript is not ready for submission in its current form. It requires substantive revision to address the missing trial registration, data availability statement, and table inconsistencies. The authors should also verify the 7 references not found in registries and fix copyediting errors. After these corrections, it would be ready for submission.

1.
HIGHreporting
Register the trial in a public registry (e.g., ClinicalTrials.gov) and include the registration number in the Abstract and Methods section.
Trial registration is mandatory for interventional clinical trials and its absence is a major reporting gap.
2.
HIGHdata code
Provide a data availability statement that specifies a mechanism for accessing de-identified participant data (e.g., via a data access committee or a repository with a persistent identifier).
The current statement only covers the protocol/SAP, not patient-level data, which is insufficient for reproducibility.
3.
HIGHrigor
Correct the internal contradictions in Table 1: HIV status counts sum to 244 instead of 249, and RPR titer distributions do not sum to group totals. Provide an explanation for the missing data.
These discrepancies undermine confidence in the data integrity and must be resolved before submission.
4.
HIGHreporting
Specify the randomization method (e.g., computer-generated random sequence, block size, stratification factors) in the Methods section.
The method is currently only stated as 'randomized', which is insufficient for reproducibility.
5.
HIGHstatistics
Identify the statistical software used (e.g., SAS version 9.4, R version 4.0) in the Statistical Analyses section.
Verification of analyses requires knowing the software and version.
6.
HIGHstatistics
Report exact p-values for the primary and secondary analyses (e.g., p=0.52) alongside the confidence intervals to facilitate meta-analysis.
While non-inferiority trials often rely on CIs, exact p-values are expected by many journals.
7.
HIGHrigor
Verify each of the 7 references not found in the registry (titles: 'The introduction of penicillin for the treatment of syphilis', 'Treatment for Early Syphilis and Reactivity of Serological Tests', 'Clinical Reminders during Bicillin L-A ® Shortage', 'A manual of tests for syphilis', 'Rapid plasma reagin titer variation in the 2 weeks after syphilis therapy', 'The treatment of early syphilis with penicillin. A preliminary report of 1,418 cases', 'Evaluation and management of penicillin allergy: A review') and either correct or replace them.
References not found in any registry may be fabricated or have incorrect bibliographic details; unresolved references are an integrity signal.
8.
HIGHreporting
Fix the garbled CI notation in the Results section: '(90% CI −0.05 0–0.17,0.07)' should be corrected to '(90% CI -0.05, 0.07)' or similar.
The current notation is uninterpretable and must be corrected for clarity.
9.
HIGHcopyedit
Correct the formatting errors in Table 1: realign RPR titer rows so that labels match counts, add missing percentage signs (e.g., '2 (2)' to '2 (2%)'), fix extra parentheses (e.g., '41 ((16)' to '41 (16%)'), and add missing spaces (e.g., '1(1%)' to '1 (1%)').
These formatting errors obscure the data and must be fixed for a clean submission.
10.
HIGHreporting
Add a statement about adherence to a reporting guideline such as CONSORT 2010 in the Methods section, and note that the completed checklist is available as supplementary material.
While a CONSORT diagram is present, explicit adherence to the guideline is expected.
11.
MEDIUMreporting
Provide a rationale for the open-label design in the Methods section (e.g., stating that blinding was not feasible due to the nature of the intervention).
The absence of a rationale for an open-label design is a transparency gap.
12.
MEDIUMethics
Add a statement confirming compliance with the Declaration of Helsinki or other relevant regulatory framework in the Human Subjects section.
Ethics approval statements typically include a reference to the applicable standard.
13.
MEDIUMstatistics
Clarify the definition of the 'evaluable population' in the Methods section, specifying all criteria for inclusion in the per-protocol analysis.
Clear definitions of analysis populations are essential for reproducibility.
14.
MEDIUMreporting
Include the clinical trial registration number (once obtained) in the Abstract and Methods, and note that the protocol is available at NEJM.org.
Linking trial registration and protocol availability enhances transparency.
15.
LOWcopyedit
Fix the missing closing parenthesis in Table 1: '154 (62%' should be '154 (62%)' and '32 (13' should be '32 (13%)'.
Minor typographical errors that should be corrected for professionalism.

Full text (29,014 chars)Analyzed: Jul 7, 2026

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