Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

Phase 3 Results of Bepirovirsen Treatment for Chronic Hepatitis B Virus Infection.

Name: Kaimen Rigor review — Phase 3 Results of Bepirovirsen Treatment for Chronic Hepatitis B Virus Infection.
Item: Phase 3 Results of Bepirovirsen Treatment for Chronic Hepatitis B Virus Infection.
Rating: 96
Author: Alpha1

Hou J, Lim SG, Buti M, Yuen MF, Gane E, Lampertico P, Terrault N, Nguyen H, Yim HJ, Xie Q, Lin J, Qiu Y, Jeng WJ, Heo J, Peng CY, Chen CH, Chuang WL, Xie Y, Hlebowicz M, Idriz N, Mehta R, Agarwal K, Gomes da Silva MM, Franca A, Cernat R, Leerapun A, Coffin CS, Gadano A, Andreone P, Fujiyama S, Sevastianos V, Suzuki Y, Ratziu V, Riachi G, Stocker H, Lim TH, Asselah T, Tanaka Y, Holmes J, Liang X, Cremer J, Lukić T, Plein H, Quinn G, Tao Y, Paff M, Theodore D, Elston R, B-Well Study Group

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Kaimen Rigor review — 3.25★ (Adequate), 0 critical, 2 high issues for “Phase 3 Results of Bepirovirsen Treatment for Chronic Hepatitis B Virus Infection.”

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Phase 3 Results of Bepirovirsen Treatment for Chronic Hepatitis B Virus Infection.

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DOI

10.1056/NEJMoa2515131

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Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

Phase 3 Results of Bepirovirsen Treatment for Chronic Hepatitis B Virus Infection.

Paper source

Phase 3 Results of Bepirovirsen Treatment for Chronic Hepatitis B Virus Infection.

Read full text

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Links back to this Kaimen Rigor review.

Alpha1 Editorial

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

Kaimen Rigor review

Kaimen Rigor reviewed

3.25 / 5

Adequate — real issues to address

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

IntegrityIntegrity concern−0.5★
ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
ClaimsTreatment effect not shown to be clinically meaningful−0.5★
ReportingData & code availability partially met−0.25★

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

Not verified in this report

No data or code availability links were detected to verify.

Biggest issues

01Efficacy rests on an unvalidated surrogate endpoint
highOverreachreviewer-assessedFull detail
The primary efficacy endpoint is 'functional cure', defined as sustained HBV DNA below LLOQ and HBsAg loss (<0.05 IU/mL) for at least 24 weeks after discontinuing NA therapy. HBsAg loss is a surrogate biomarker for clinical outcomes (e.g., reduced risk of cirrhosis, hepatocellular carcinoma). Although the paper cites that HBsAg loss is associated with better clinical outcomes, it does not provide validated evidence linking this surrogate to hard clinical outcomes in the context of this trial, nor does it demonstrate target engagement at the tested dose (e.g., PK/PD data). The efficacy claim rests on this surrogate endpoint.
“A functional cure, defined as an HBV DNA level below the lower limit of quantification (LLOQ) and hepatitis B surface antigen (HBsAg) loss (i.e., a level of <0.05 IU per milliliter) for at least 24 weeks after finite (fixed-duration) therapy ... is the…”
Find in source
02Treatment effect not shown to be clinically meaningful
highOverreachreviewer-assessedFull detail
The primary outcome is a functional cure achieved in 20% and 19% of bepirovirsen-treated patients in the two trials, compared with 0% in placebo. While the difference is statistically significant, the absolute effect size is modest (about one in five patients). The paper does not anchor this effect size to a minimal clinically important difference or provide a clear biological/clinical meaningfulness threshold beyond statistical significance. The effect is presented as a positive result but lacks explicit anchoring to clinical meaningfulness.
“The percentage of patients with a functional cure at week 72 was significantly higher with bepirovirsen than with placebo both in the B-Well 1 trial (in 127 of 650 patients [20%] vs. none of 328 patients) and in the B-Well 2 trial (in 106 of 570 patients…”
Find in source

Findings by category

101ArithmeticNumerical inconsistencies 202OverreachOverstated conclusions 03AuthenticityNone found 104DisclosureReporting gaps 05AvailabilityNone found · partly checked 06Copyedit2 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 pair of replicate phase 3 randomized trials with strong methodology, clear reporting of demographics, ethics, and statistical methods. The main weakness is the vague data sharing statement, which lacks specific access details. Minor copyedit issues and a small N discrepancy in Table 1 are noted.

Both reviewers classified the study as interventional, and no divergence was noted. The evaluation covered the full text, including methods, results, and discussion. Bench-specific criteria (e.g., cell line authentication) were not applicable. The statistics verification checked only 2 tests, so the broader statistical correctness is not fully verified.

Numerical inconsistencies

1 finding · worst low

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.

Efficacy rests on an unvalidated surrogate endpointAssessed
Treatment effect not shown to be clinically meaningfulAssessed

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

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

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

1 finding · worst medium

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.

Data/code availability incompleteAssessed

Eight Dimensions7 pass · 1 warn

The introduction cites prior research on HBV infection, functional cure definitions, and phase 2 bepirovirsen studies. The rationale for the trials is clearly linked to the need for finite therapies achieving functional cure. Limitations of prior research are implicitly addressed by the replicate trial design and the focus on a defined endpoint.

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 clear scientific premise with prior work and a logical rationale for the trials.

Evidence

paraphrase[Introduction, paragraph 1-3]

“Extended follow-up of the phase 2 bepirovirsen studies showed that some patients with a baseline HBsAg level of 3000 IU per milliliter or less who received a course of bepirovirsen were able to discontinue NA therapy and have a durable functional cure.”

paraphrase[Introduction, paragraph 3]

“In these trials, we assessed the percentage of patients who had a functional cure with 24 weeks of bepirovirsen therapy, as compared with placebo.”

paraphrase[Discussion, paragraph 2]

“The replicate trial design and multicountry enrollment across B-Well 1 and B-Well 2 provide robust evidence for the efficacy and safety of bepirovirsen in patients with chronic HBV infection worldwide.”

PASSReviewer 2· 95% conf

The paper establishes a clear scientific premise with prior work and a logical rationale for the trials.

Evidence

paraphrase[Introduction, paragraph 2]

paraphrase[Introduction, paragraph 3]

“In these trials, we assessed the percentage of patients who had a functional cure with 24 weeks of bepirovirsen therapy, as compared with placebo.”

paraphrase[Discussion, paragraph 2]

Randomization was performed via a central interactive response system with stratification by HBsAg level. The trials were double-blind. A power analysis is reported (≥750 patients per trial for >99% power). Inclusion/exclusion criteria are described. Missing data handling is specified (nonresponse imputation). The comparator is placebo, and the replicate design provides independent replication.

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 trials are well-designed with adequate randomization, blinding, power analysis, and inclusion/exclusion criteria.

Evidence

paraphrase[Methods, Randomization and Treatment]

“The patients were randomly assigned in a 2:1 ratio to receive bepirovirsen or placebo through a central interactive response system, with stratification according to the screening HBsAg level.”

paraphrase[Methods, Trial Design and Oversight]

“patients were recruited in the double-blind, placebo-controlled B-Well 1 and B-Well 2 trials”

“We determined that the enrollment of at least 750 patients in each of the B-Well trials would provide the trial with more than 99% power to determine the primary outcome with a two-sided alpha level of 0.05.”

Statistical analysisFind in source

PASSReviewer 2· 95% conf

The trials are well-designed with adequate randomization, blinding, power, and pre-specified criteria.

Evidence

paraphrase[Methods, Randomization and Treatment]

“The patients were randomly assigned in a 2:1 ratio to receive bepirovirsen or placebo through a central interactive response system, with stratification according to the screening HBsAg level.”

Statistical analysisFind in source

paraphrase[Methods, Statistical Analysis]

“Patients with missing data that precluded the efficacy assessment were classified as having a nonresponse.”

Table 1 reports age, sex, race, ethnicity, HBsAg levels, HBV DNA, HBeAg status, and ALT. Both sexes are enrolled, so sex justification is not applicable. Age and health status are reported. Demographics are comprehensive.

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· 95% conf

Demographic and clinical characteristics are well reported, including sex, age, race, and key disease markers.

Evidence

“Age — yr 50.2±11.8 49.2±10.6 48.7±10.4 49.2±11.4 Male sex — no. (%) 461 (71) 227 (69) 414 (73) 202 (71)”

Table 1Find in source

“Race or ethnic group — no. (%)† Asian 440 (67) 229 (70) 388 (68) 195 (68)”

Table 1Find in source

PASSReviewer 2· 95% conf

Demographic and clinical characteristics are well reported, including sex, age, and disease-related variables.

Evidence

“Male sex — no. (%) 461 (71) 227 (69) 414 (73) 202 (71)”

Table 1Find in source

“Race or ethnic group — no. (%)† Asian 440 (67) 229 (70) 388 (68) 195 (68)”

Table 1Find in source

“Hepatitis B surface antigen‡ Mean — IU/ml 952±1047 914±760 955±741 919±691”

Table 1Find in source

The protocols were approved by the relevant institutional review board or ethics committee at each site, and all patients provided written informed consent. Regulatory compliance is implied by the trial conduct and reporting.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

Ethics approval and informed consent are adequately reported.

Evidence

paraphrase[Methods, Trial Design and Oversight]

“The trial protocols (available with the full text of this article at NEJM.org) were approved by the relevant institutional review board or ethics committee at each site.”

“All the patients provided written informed consent.”

MethodsFind in source

PASSReviewer 2· 95% conf

Ethics approval and informed consent are adequately reported.

Evidence

paraphrase[Methods, Trial Design and Oversight]

“The trial protocols (available with the full text of this article at NEJM.org) were approved by the relevant institutional review board or ethics committee at each site.”

“All the patients provided written informed consent.”

MethodsFind in source

Bepirovirsen is named as an antisense oligonucleotide, and the dose and regimen are specified. Assays (COBAS, Elecsys) are identified with manufacturers. As a drug trial, the investigational product is the key resource and is adequately identified.

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedNOT REPORTED

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The investigational product (bepirovirsen) and key assays are identified, though some details are in the supplementary appendix.

Evidence

“Bepirovirsen (at a dose of 300 mg) or placebo was administered through weeks 1 to 24 as weekly subcutaneous injections”

MethodsFind in source

paraphrase[Methods, Randomization and Treatment]

“as assessed with the COBAS assay [Roche]... as assessed with the Elecsys HBsAg II assay [Roche]”

PASSReviewer 2· 90% conf

The investigational product (bepirovirsen) and key assays are identified, though some details are in the supplementary appendix.

Evidence

paraphrase[Methods, Randomization and Treatment]

“Bepirovirsen (at a dose of 300 mg) or placebo was administered through weeks 1 to 24 as weekly subcutaneous injections (two injections per administration), with a loading dose on days 4 and 11.”

paraphrase[Methods, Randomization and Treatment]

“as assessed with the COBAS assay [Roche] ... as assessed with the Elecsys HBsAg II assay [Roche]”

The primary analysis uses the Miettinen–Nurminen method for risk differences with 95% CIs. P-values are reported as <0.001. Missing data are handled by nonresponse imputation. The statistical software is not explicitly named, but this is a minor omission. Data presentation includes per-group n and confidence intervals.

Sub-criteria

tests namedADEQUATE

exact p valuesINADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedNOT REPORTED

assumptions verifiedADEQUATE

mathematical plausibilityN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Statistical methods are appropriate and well-described, with exact p-values and confidence intervals.

Evidence

“We calculated the common risk difference using the summary Miettinen–Nurminen method across the two baseline HBsAg strata”

Statistical analysisFind in source

“P<0.001 for both comparisons”

ResultsFind in source

paraphrase[Results, Functional Cure at Week 72]

“The common risk difference ... was 17.5 percentage points (95% confidence interval [CI], 14.6 to 20.3) in B-Well 1 and 13.3 percentage points (95% CI, 10.4 to 16.1) in B-Well 2”

PASSReviewer 2· 90% conf

Statistical methods are appropriate and well-described, with exact p-values and confidence intervals.

Evidence

paraphrase[Methods, Statistical Analysis]

“We calculated the common risk difference using the summary Miettinen–Nurminen method across the two baseline HBsAg strata.”

“P<0.001 for both comparisons”

ResultsFind in source

paraphrase[Results, Functional Cure at Week 72]

“The common risk difference ... was 17.5 percentage points (95% confidence interval [CI], 14.6 to 20.3) in B-Well 1 and 13.3 percentage points (95% CI, 10.4 to 16.1) in B-Well 2”

The paper states 'A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.' This is vague and does not specify the access mechanism. No repository or accession numbers are provided in the text.

Sub-criteria

code sharingN/A

accession numbersNOT REPORTED

repository depositNOT REPORTED

data availability statementINADEQUATE

Per reviewer (2) — the votes behind the verdict

WARNReviewer 1· 80% conf

A data sharing statement is mentioned but not detailed in the provided text.

Evidence

“A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.”

End of articleFind in source

WARNReviewer 2· 80% conf

A data sharing statement is mentioned but not detailed in the text; no repository or accession numbers are provided.

Evidence

“A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.”

End of articleFind in source

The trials are registered (ClinicalTrials.gov numbers provided). Limitations are discussed. Conclusions are proportional to the results. Funding and COI are disclosed. Methods are detailed enough for replication.

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· 95% conf

The manuscript is transparent with trial registration, limitations, and funding disclosures.

Evidence

“ClinicalTrials.gov numbers, NCT05630807 and NCT05630820”

AbstractFind in source

paraphrase[Discussion, paragraph 3]

“Limitations of the phase 3 trials include the relatively small numbers of patients who were included in subgroup analyses and the small numbers in certain racial and ethnic groups”

“Supported by GSK.”

End of articleFind in source

PASSReviewer 2· 95% conf

The paper is transparent, with trial registration, limitations, and proportional conclusions.

Evidence

“ClinicalTrials.gov numbers, NCT05630807 and NCT05630820”

AbstractFind in source

paraphrase[Discussion, paragraph 3]

“Limitations of the phase 3 trials include the relatively small numbers of patients who were included in subgroup analyses and the small numbers in certain racial and ethnic groups.”

“Supported by GSK. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.”

End of articleFind in source

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

Broken references and links

None found · partly checked

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.

Nothing surfaced — but not everything feeding this category ran (missing: data/code link verification), so read this as a partial clean bill.

Checked 29 references by DOI: 1 verified — 28 no DOI (shown, not verified).

Copyediting

2 minor

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

No major wording or formatting errors. 2 minor suggestions below.

2 copyedit issues flagged: mostly typo, consistency.

Kaimen Rigor Action ItemsFinal pass before journal submission

The published work is robust and well-reported, with only minor reporting gaps. An informed reader should weigh the vague data sharing statement and the minor N discrepancy in Table 1, but these do not undermine the main conclusions. No erratum is warranted for the core findings, though clarifying the data sharing mechanism and the N discrepancy would improve transparency.

1.
HIGHdata code
In the data sharing statement (end of article), specify the access mechanism (e.g., via a data access committee or platform) and conditions, rather than a vague reference to a statement available at NEJM.org.
The current statement is vague and does not meet the expectation for concrete data availability, which is a common reviewer concern.
2.
HIGHreporting
In Table 1 footnote, clarify why the HBsAg values are for 570 patients in the bepirovirsen group in B-Well 2 while the column header indicates N=571.
The N discrepancy is an internal contradiction that could raise questions about data integrity.
3.
MEDIUMstatistics
In the Methods, Statistical Analysis section, explicitly name the statistical software used (e.g., SAS version).
Identifying the software is standard for reproducibility and was flagged by both reviewers.
4.
MEDIUMreporting
Add a statement about adherence to reporting guidelines (e.g., CONSORT) in the Methods or supplementary material.
Mentioning CONSORT adherence is expected for randomized trials and was flagged as not reported.
5.
MEDIUMstatistics
In the Results, consider reporting exact p-values (e.g., P=0.001) instead of only 'P<0.001' where possible.
Exact p-values provide more precision, though threshold reporting is common in clinical trials.
6.
LOWcopyedit
In the Abstract, Results, add 'patients' after 'none' for clarity: 'vs. none of 328 patients'.
Minor grammatical omission that could be clarified.

Full text (51,248 chars)Analyzed: Aug 15, 2026

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Phase 3 Results of Bepirovirsen Treatment for Chronic Hepatitis B Virus Infection.

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DOI

10.1056/NEJMoa2515131

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Record fingerprint

3bc11d913f90a09390e8ebff030b92929cd47c40d07c8241e6e20771371e0201

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

3.25 / 5

Adequate — real issues to address

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

IntegrityIntegrity concern−0.5★
ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
ClaimsTreatment effect not shown to be clinically meaningful−0.5★
ReportingData & code availability partially met−0.25★

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

Not verified in this report

No data or code availability links were detected to verify.

Biggest issues

01Efficacy rests on an unvalidated surrogate endpoint
highOverreachreviewer-assessedFull detail
The primary efficacy endpoint is 'functional cure', defined as sustained HBV DNA below LLOQ and HBsAg loss (<0.05 IU/mL) for at least 24 weeks after discontinuing NA therapy. HBsAg loss is a surrogate biomarker for clinical outcomes (e.g., reduced risk of cirrhosis, hepatocellular carcinoma). Although the paper cites that HBsAg loss is associated with better clinical outcomes, it does not provide validated evidence linking this surrogate to hard clinical outcomes in the context of this trial, nor does it demonstrate target engagement at the tested dose (e.g., PK/PD data). The efficacy claim rests on this surrogate endpoint.
“A functional cure, defined as an HBV DNA level below the lower limit of quantification (LLOQ) and hepatitis B surface antigen (HBsAg) loss (i.e., a level of <0.05 IU per milliliter) for at least 24 weeks after finite (fixed-duration) therapy ... is the…”
Find in source
02Treatment effect not shown to be clinically meaningful
highOverreachreviewer-assessedFull detail
The primary outcome is a functional cure achieved in 20% and 19% of bepirovirsen-treated patients in the two trials, compared with 0% in placebo. While the difference is statistically significant, the absolute effect size is modest (about one in five patients). The paper does not anchor this effect size to a minimal clinically important difference or provide a clear biological/clinical meaningfulness threshold beyond statistical significance. The effect is presented as a positive result but lacks explicit anchoring to clinical meaningfulness.
“The percentage of patients with a functional cure at week 72 was significantly higher with bepirovirsen than with placebo both in the B-Well 1 trial (in 127 of 650 patients [20%] vs. none of 328 patients) and in the B-Well 2 trial (in 106 of 570 patients…”
Find in source

Findings by category

101ArithmeticNumerical inconsistencies 202OverreachOverstated conclusions 03AuthenticityNone found 104DisclosureReporting gaps 05AvailabilityNone found · partly checked 06Copyedit2 minor suggestions

Numerical inconsistencies

1 finding · worst low

Internal contradictions in the reported numbersAssessed

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

Overstated conclusions

2 findings · worst high

Efficacy rests on an unvalidated surrogate endpointAssessed
Treatment effect not shown to be clinically meaningfulAssessed

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

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

Data authenticity concerns

None found

Checked — nothing surfaced.

Reporting gaps

1 finding · worst medium

Data/code availability incompleteAssessed

Eight Dimensions7 pass · 1 warn

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 clear scientific premise with prior work and a logical rationale for the trials.

Evidence

paraphrase[Introduction, paragraph 1-3]

paraphrase[Introduction, paragraph 3]

“In these trials, we assessed the percentage of patients who had a functional cure with 24 weeks of bepirovirsen therapy, as compared with placebo.”

paraphrase[Discussion, paragraph 2]

PASSReviewer 2· 95% conf

The paper establishes a clear scientific premise with prior work and a logical rationale for the trials.

Evidence

paraphrase[Introduction, paragraph 2]

paraphrase[Introduction, paragraph 3]

“In these trials, we assessed the percentage of patients who had a functional cure with 24 weeks of bepirovirsen therapy, as compared with placebo.”

paraphrase[Discussion, paragraph 2]

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 trials are well-designed with adequate randomization, blinding, power analysis, and inclusion/exclusion criteria.

Evidence

paraphrase[Methods, Randomization and Treatment]

“The patients were randomly assigned in a 2:1 ratio to receive bepirovirsen or placebo through a central interactive response system, with stratification according to the screening HBsAg level.”

paraphrase[Methods, Trial Design and Oversight]

“patients were recruited in the double-blind, placebo-controlled B-Well 1 and B-Well 2 trials”

Statistical analysisFind in source

PASSReviewer 2· 95% conf

The trials are well-designed with adequate randomization, blinding, power, and pre-specified criteria.

Evidence

paraphrase[Methods, Randomization and Treatment]

“The patients were randomly assigned in a 2:1 ratio to receive bepirovirsen or placebo through a central interactive response system, with stratification according to the screening HBsAg level.”

Statistical analysisFind in source

paraphrase[Methods, Statistical Analysis]

“Patients with missing data that precluded the efficacy assessment were classified as having a nonresponse.”

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· 95% conf

Demographic and clinical characteristics are well reported, including sex, age, race, and key disease markers.

Evidence

“Age — yr 50.2±11.8 49.2±10.6 48.7±10.4 49.2±11.4 Male sex — no. (%) 461 (71) 227 (69) 414 (73) 202 (71)”

Table 1Find in source

“Race or ethnic group — no. (%)† Asian 440 (67) 229 (70) 388 (68) 195 (68)”

Table 1Find in source

PASSReviewer 2· 95% conf

Demographic and clinical characteristics are well reported, including sex, age, and disease-related variables.

Evidence

“Male sex — no. (%) 461 (71) 227 (69) 414 (73) 202 (71)”

Table 1Find in source

“Race or ethnic group — no. (%)† Asian 440 (67) 229 (70) 388 (68) 195 (68)”

Table 1Find in source

“Hepatitis B surface antigen‡ Mean — IU/ml 952±1047 914±760 955±741 919±691”

Table 1Find in source

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

Ethics approval and informed consent are adequately reported.

Evidence

paraphrase[Methods, Trial Design and Oversight]

“The trial protocols (available with the full text of this article at NEJM.org) were approved by the relevant institutional review board or ethics committee at each site.”

“All the patients provided written informed consent.”

MethodsFind in source

PASSReviewer 2· 95% conf

Ethics approval and informed consent are adequately reported.

Evidence

paraphrase[Methods, Trial Design and Oversight]

“The trial protocols (available with the full text of this article at NEJM.org) were approved by the relevant institutional review board or ethics committee at each site.”

“All the patients provided written informed consent.”

MethodsFind in source

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedNOT REPORTED

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The investigational product (bepirovirsen) and key assays are identified, though some details are in the supplementary appendix.

Evidence

“Bepirovirsen (at a dose of 300 mg) or placebo was administered through weeks 1 to 24 as weekly subcutaneous injections”

MethodsFind in source

paraphrase[Methods, Randomization and Treatment]

“as assessed with the COBAS assay [Roche]... as assessed with the Elecsys HBsAg II assay [Roche]”

PASSReviewer 2· 90% conf

The investigational product (bepirovirsen) and key assays are identified, though some details are in the supplementary appendix.

Evidence

paraphrase[Methods, Randomization and Treatment]

“Bepirovirsen (at a dose of 300 mg) or placebo was administered through weeks 1 to 24 as weekly subcutaneous injections (two injections per administration), with a loading dose on days 4 and 11.”

paraphrase[Methods, Randomization and Treatment]

“as assessed with the COBAS assay [Roche] ... as assessed with the Elecsys HBsAg II assay [Roche]”

Sub-criteria

tests namedADEQUATE

exact p valuesINADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedNOT REPORTED

assumptions verifiedADEQUATE

mathematical plausibilityN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Statistical methods are appropriate and well-described, with exact p-values and confidence intervals.

Evidence

“We calculated the common risk difference using the summary Miettinen–Nurminen method across the two baseline HBsAg strata”

Statistical analysisFind in source

“P<0.001 for both comparisons”

ResultsFind in source

paraphrase[Results, Functional Cure at Week 72]

“The common risk difference ... was 17.5 percentage points (95% confidence interval [CI], 14.6 to 20.3) in B-Well 1 and 13.3 percentage points (95% CI, 10.4 to 16.1) in B-Well 2”

PASSReviewer 2· 90% conf

Statistical methods are appropriate and well-described, with exact p-values and confidence intervals.

Evidence

paraphrase[Methods, Statistical Analysis]

“We calculated the common risk difference using the summary Miettinen–Nurminen method across the two baseline HBsAg strata.”

“P<0.001 for both comparisons”

ResultsFind in source

paraphrase[Results, Functional Cure at Week 72]

“The common risk difference ... was 17.5 percentage points (95% confidence interval [CI], 14.6 to 20.3) in B-Well 1 and 13.3 percentage points (95% CI, 10.4 to 16.1) in B-Well 2”

Sub-criteria

code sharingN/A

accession numbersNOT REPORTED

repository depositNOT REPORTED

data availability statementINADEQUATE

Per reviewer (2) — the votes behind the verdict

WARNReviewer 1· 80% conf

A data sharing statement is mentioned but not detailed in the provided text.

Evidence

“A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.”

End of articleFind in source

WARNReviewer 2· 80% conf

A data sharing statement is mentioned but not detailed in the text; no repository or accession numbers are provided.

Evidence

“A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.”

End of articleFind 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· 95% conf

The manuscript is transparent with trial registration, limitations, and funding disclosures.

Evidence

“ClinicalTrials.gov numbers, NCT05630807 and NCT05630820”

AbstractFind in source

paraphrase[Discussion, paragraph 3]

“Limitations of the phase 3 trials include the relatively small numbers of patients who were included in subgroup analyses and the small numbers in certain racial and ethnic groups”

“Supported by GSK.”

End of articleFind in source

PASSReviewer 2· 95% conf

The paper is transparent, with trial registration, limitations, and proportional conclusions.

Evidence

“ClinicalTrials.gov numbers, NCT05630807 and NCT05630820”

AbstractFind in source

paraphrase[Discussion, paragraph 3]

“Limitations of the phase 3 trials include the relatively small numbers of patients who were included in subgroup analyses and the small numbers in certain racial and ethnic groups.”

“Supported by GSK. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.”

End of articleFind in source

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

Broken references and links

None found · partly checked

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.

Nothing surfaced — but not everything feeding this category ran (missing: data/code link verification), so read this as a partial clean bill.

Checked 29 references by DOI: 1 verified — 28 no DOI (shown, not verified).

Copyediting

2 minor

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

No major wording or formatting errors. 2 minor suggestions below.

2 copyedit issues flagged: mostly typo, consistency.

Kaimen Rigor Action ItemsFinal pass before journal submission

1.
HIGHdata code
In the data sharing statement (end of article), specify the access mechanism (e.g., via a data access committee or platform) and conditions, rather than a vague reference to a statement available at NEJM.org.
The current statement is vague and does not meet the expectation for concrete data availability, which is a common reviewer concern.
2.
HIGHreporting
In Table 1 footnote, clarify why the HBsAg values are for 570 patients in the bepirovirsen group in B-Well 2 while the column header indicates N=571.
The N discrepancy is an internal contradiction that could raise questions about data integrity.
3.
MEDIUMstatistics
In the Methods, Statistical Analysis section, explicitly name the statistical software used (e.g., SAS version).
Identifying the software is standard for reproducibility and was flagged by both reviewers.
4.
MEDIUMreporting
Add a statement about adherence to reporting guidelines (e.g., CONSORT) in the Methods or supplementary material.
Mentioning CONSORT adherence is expected for randomized trials and was flagged as not reported.
5.
MEDIUMstatistics
In the Results, consider reporting exact p-values (e.g., P=0.001) instead of only 'P<0.001' where possible.
Exact p-values provide more precision, though threshold reporting is common in clinical trials.
6.
LOWcopyedit
In the Abstract, Results, add 'patients' after 'none' for clarity: 'vs. none of 328 patients'.
Minor grammatical omission that could be clarified.

Full text (51,248 chars)Analyzed: Aug 15, 2026