Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

Elebsiran and PEG-IFNα for chronic hepatitis B infection: a partially randomized, open-label, phase 2 trial

Name: Kaimen Rigor review — Elebsiran and PEG-IFNα for chronic hepatitis B infection: a partially randomized, open-label, phase 2 trial
Item: Elebsiran and PEG-IFNα for chronic hepatitis B infection: a partially randomized, open-label, phase 2 trial
Rating: 82
Author: Alpha1

Wong GL, Yuen MF, Lin B, Douglas MW, Hu P, Xie Q, Lv F, Tak WY, Leerapun A, Kim DJ, Tangkijvanich P, Lim YS, Dai CY, O'Beirne J, Weltman M, Khemnark S, Piratvisuth T, Manasirisuk W, Chen X, Liu CJ, Heo J, Lee J, Niu J, Kumar R, Kumar R, Zhu C, Cao K, Tian A, Chen X, Zhu Q, Margolis D, Jia J, Hong Z.

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Kaimen Rigor review — 4.25★ (Strong), 0 critical, 4 high issues for “Elebsiran and PEG-IFNα for chronic hepatitis B infection: a partially randomized, open-label, phase 2 trial”

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Alpha1 Editorial

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

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Elebsiran and PEG-IFNα for chronic hepatitis B infection: a partially randomized, open-label, phase 2 trial

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DOI

10.1038/s41591-025-04049-z

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Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

Elebsiran and PEG-IFNα for chronic hepatitis B infection: a partially randomized, open-label, phase 2 trial

Paper source

Elebsiran and PEG-IFNα for chronic hepatitis B infection: a partially randomized, open-label, phase 2 trial

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Links back to this Kaimen Rigor review.

Alpha1 Editorial

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

Kaimen Rigor review

Kaimen Rigor reviewed

4.25 / 5

Strong — minor issues to address

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

ReportingData & code availability not met−0.5★
ReportingKey resources partially met−0.25★

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

Not verified in this report

No reported statistical tests were found to recompute.
The numeric-impossibility checks (GRIM/GRIMMER/DEBIT/SPRITE) did not run on this paper: the pass that reads its reported means did not complete. No reported mean was checked for arithmetic impossibility.

Biggest issues

01Data and code not shared
highDisclosurereviewer-assessedFull detail
Data availability statement is vague (on request without a mechanism), and no analysis code is shared.
“No computer code was used for data collection.”
MethodsFind in source

Findings by category

01ArithmeticNone found 02OverreachNone found · partly checked 03AuthenticityNone found 204DisclosureReporting gaps 05AvailabilityNone found 06Copyedit4 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.

The paper is a well-conducted and clearly reported phase 2 trial with strong scientific premise, adequate randomization, detailed eligibility criteria, and transparent reporting of ethics, demographics, and limitations. The main weaknesses are reproducibility-related: a vague data-availability statement with no managed-access mechanism, no shared analysis code, threshold-only p-values, and missing manufacturer/source information for the investigational products.

All three independent reviewer runs were synthesized at the checklist level; the main divergences (study design pass vs warn; statistical analysis pass vs warn; data code availability fail vs warn) were resolved by weighing the specific evidence and the scoring rules. The statistics verification component recomputed 0 tests (none met the machine-verifiable criteria), so statistical correctness beyond the reported consistency is unverified. No retracted or non-findable references were flagged; the one reproducibility link checked was live.

Numerical inconsistencies

None found

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.

Checked — nothing surfaced.

Overstated conclusions

None found · partly checked

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.

Nothing surfaced — but not everything feeding this category ran (missing: surrogate-endpoint assessment), so read this as a partial clean bill.

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

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

2 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.

Data and code not sharedAssessed
Key resources under-identified (antibodies, cell lines, RRIDs)Assessed

Eight Dimensions6 pass · 1 warn · 1 fail

The paper cites prior studies on elebsiran, PEG-IFNα, and BRII-179, acknowledges the lack of a PEG-IFNα control in earlier work, and provides a logical rationale for the combination therapy and the use of BRII-179 for immunological profiling. Limitations of the current study and prior work are discussed.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

The scientific premise is well-established with citations to prior work, a clear rationale, and discussion of limitations of previous studies.

Evidence

paraphrase[Main text, paragraph 4]

“A prior study evaluating elebsiran in combination with PEG-IFNα reported an HBsAg loss rate of approximately 30% at the end of treatment (EOT) in participants with chronic HBV infection. However, this study lacked a PEG-IFNα monotherapy control, limiting direct comparison.”

paraphrase[Main text, paragraph 5]

“Therefore, we conducted an open-label, phase 2 study (ENSURE, NCT05970289) consisting of two parts... Part I was a randomized study... evaluating the efficacy and safety of elebsiran in combination with PEG-IFNα compared with PEG-IFNα monotherapy.”

“This study has some limitations. Approximately 1.5 years, on average, elapsed between the BRII-179-835-001 study and the ENSURE study, and the impact of this gap in time is unknown.”

Discussion ¶6Find in source

PASSReviewer 2· 95% conf

The study clearly establishes its scientific foundation by citing prior work on HBV functional cure, limitations of existing therapies, and prior studies on elebsiran and BRII-179.

Evidence

paraphrase[Main text, paragraph 2]

“Approved treatment options for chronic HBV are limited... PEG-IFNα offers a finite-duration treatment with modest functional cure (<10%)... These limitations highlight the urgent need for effective, short-duration therapies.”

paraphrase[Main text, paragraph 3]

“A prior study evaluating elebsiran in combination with PEG-IFNα reported an HBsAg loss rate of approximately 30%... However, this study lacked a PEG-IFNα monotherapy control, limiting direct comparison.”

paraphrase[Main text, paragraph 3-4]

“The study hypothesizes that combining elebsiran with PEG-IFNα will enhance HBsAg loss, and that prior response to BRII-179 may identify patients more likely to benefit.”

PASSReviewer 3· 95% conf

The paper clearly establishes the scientific premise by citing relevant prior work, acknowledging limitations, and providing a logical rationale for the study.

Evidence

paraphrase[Introduction, paragraph 4]

“A prior study evaluating elebsiran in combination with PEG-IFNα reported an HBsAg loss rate of approximately 30% ... However, this study lacked a PEG-IFNα monotherapy control, limiting direct comparison.”

paraphrase[Introduction, paragraph 5]

“The rationale is that combining viral suppression (elebsiran) with immune stimulation (PEG-IFNα) may increase functional cure rates, and that prior BRII-179 response may identify patients with better immune fitness.”

paraphrase[Introduction, paragraph 5]

“The study design includes a PEG-IFNα monotherapy control arm to address the lack of a control in prior studies.”

The randomized part I uses a validated computerized system for randomization, stratified by HBsAg levels. Participants are the unit of randomization. The open-label nature is stated in the title and methods but no rationale for lack of blinding is provided. A Bayesian sample size calculation is presented. Detailed inclusion/exclusion criteria are given. Analysis sets (mITT, modified efficacy, safety) are pre-specified. The PEG-IFNα monotherapy arm serves as an active control.

Sub-criteria

controlsADEQUATE

power analysisADEQUATE

blinding levelsINADEQUATE

outlier handlingADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

The study design is rigorous for a phase 2 trial, with randomization, a control arm, pre-specified eligibility criteria, and a Bayesian sample size justification. The open-label design is stated but not justified.

Evidence

“The randomization code was generated through a validated computerized system.”

MethodsFind in source

“open-label, phase 2 trial”

MethodsFind in source

“The actual sample size was informed by a Bayesian statistical model. Specifically, with 15 participants per cohort, the lower bounds of the 95% CrI would exclude a response rate of 10%, provided the observed response rate was greater than 27%.”

Statistical analysisFind in source

WARNReviewer 2· 90% conf

The study design is partially rigorous: randomization and inclusion/exclusion criteria are well reported, but blinding is absent without justification, the sample size justification lacks a traditional power analysis, and outlier handling is not specified.

Evidence

“The randomization code was generated through a validated computerized system.”

MethodsFind in source

“Elebsiran and PEG-IFNα for chronic hepatitis B infection: a partially randomized, open-label, phase 2 trial”

MethodsFind in source

Statistical analysisFind in source

PASSReviewer 3· 85% conf

The study design is adequately described with randomization method, sample size justification, and inclusion/exclusion criteria. However, the open-label design lacks a stated rationale, and outlier handling is not explicitly addressed.

Evidence

paraphrase[Methods, Study design, paragraph 2]

“Eligible participants were randomized at 1:1:1 to cohort 1... using an Interactive Response Technology system. The randomization code was generated through a validated computerized system.”

“open-label, phase 2 study”

AbstractFind in source

paraphrase[Methods, Statistical methods, paragraph 2]

“Up to 75 participants were planned to be randomized... The actual sample size was informed by a Bayesian statistical model. Specifically, with 15 participants per cohort, the lower bounds of the 95% CrI would exclude a response rate of 10%...”

Table 1 provides sex, age, BMI, race, HBsAg levels, anti-HBs, ALT, HBeAg status for all cohorts. The study enrolls both sexes (mostly male) and reports demographics adequately.

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

Biological variables including sex, age, BMI, race, and health status are reported in baseline tables.

Evidence

paraphrase[Table 1]

“Male n (%) ... Female n (%)”

paraphrase[Table 1]

“Mean (s.d.) age ... BMI at baseline”

paraphrase[Table 1]

“Race n (%) ... HBeAg at baseline n (%)”

PASSReviewer 2· 95% conf

Biological variables and subject characteristics are well reported, including sex, age, BMI, race, and baseline HBsAg levels.

Evidence

“Table 1 Demographics and baseline characteristics”

Table 1Find in source

“ALT and AST ≤ ULN”

MethodsFind in source

PASSReviewer 3· 95% conf

Biological variables including sex, age, BMI, health status, and demographics are well reported in Table 1.

Evidence

paraphrase[Table 1]

“Sex n (%) Male 16 (88.9) ... Mean (s.d.) age 45.2 (8.5) ... Mean (s.d.) BMI 24.3 (3.4) ... HBeAg negative 15 (83.3)”

The study was approved by an independent ethics committee or institutional review board at each site (list provided in supplement), conducted in accordance with the Declaration of Helsinki and ICH-GCP, and all participants provided written informed consent.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

Ethical approval, informed consent, and regulatory compliance are clearly stated.

Evidence

paraphrase[Methods, 'Study design' paragraph]

“The study was approved by an independent ethics committee or institutional review board at each site (see ‘Ethics committees/institutional review boards that approved the study protocol’ in the Supplementary Information) and was conducted in accordance with the Declaration of Helsinki and International Conference on Harmonisation Good Clinical Practice.”

“All participants provided written informed consent to participate in the study before any study-specific procedures were conducted.”

MethodsFind in source

PASSReviewer 2· 95% conf

Ethical approvals, informed consent, and regulatory compliance are clearly documented.

Evidence

paraphrase[Methods, Study design]

“The study was approved by an independent ethics committee or institutional review board at each site... All participants provided written informed consent to participate in the study before any study-specific procedures were conducted.”

“conducted in accordance with the Declaration of Helsinki and International Conference on Harmonisation Good Clinical Practice.”

MethodsFind in source

PASSReviewer 3· 90% conf

Ethical approvals, informed consent, and regulatory compliance are adequately reported.

Evidence

paraphrase[Methods, Study design, paragraph 1]

“All participants provided written informed consent to participate in the study before any study-specific procedures were conducted.”

Methods ¶1Find in source

“conducted in accordance with the Declaration of Helsinki and International Conference on Harmonisation Good Clinical Practice.”

Methods ¶1Find in source

Reagents_identified is scored against the investigational products. Elebsiran and PEG-IFNα are named with doses, but no manufacturer, catalog number, or lot number is provided. Software (SAS version 9.4) is adequately identified. All other resource categories are not applicable.

Sub-criteria

mycoplasma testingN/A

reagents identifiedINADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedADEQUATE

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 85% conf

Investigational products (elebsiran, PEG-IFNα, BRII-179) are named and dosed but not fully identified with manufacturer/source; software is identified.

Evidence

paraphrase[Main text, paragraph 4]

“Elebsiran (BRII-835/VIR-2218) is a triantennary N-acetyl galactosamine (GalNAc)-conjugated small interfering RNA (siRNA)...”

“PEG-IFNα 180 μg administered subcutaneously (SC) every week”

MethodsFind in source

“SAS version 9.4 was used for data analyses in this study.”

Statistical analysisFind in source

WARNReviewer 2· 90% conf

The investigational products (elebsiran and PEG-IFNα) are named but not identified by manufacturer or source. Statistical software is adequately identified.

Evidence

paraphrase[Methods, Study design]

“elebsiran 200 mg administered SC every 4 weeks (Q4W)... PEG-IFNα 180 μg administered subcutaneously (SC) every week (QW)”

“SAS version 9.4 was used for data analyses in this study.”

Statistical analysisFind in source

WARNReviewer 3· 85% conf

The investigational products (elebsiran and PEG-IFNα) are named with dose and regimen but manufacturer/source is not provided. Statistical software (SAS 9.4) is identified.

Evidence

paraphrase[Methods, Study design, paragraph 2]

“Elebsiran (BRII-835/VIR-2218) and PEG-IFNα 180 μg are named with dose and regimen, but no manufacturer or source is given.”

“SAS version 9.4 was used for data analyses in this study.”

Statistical analysis ¶3Find in source

The primary analysis uses Bayesian estimation with credible intervals, which is acceptable. The mixed model for repeated measures is named. Assumptions are handled by design. Effect sizes are reported with CIs. Data presentation includes per-group n and error bars. The only shortcoming is that the reported p-value is imprecise ('P < 0.05').

Sub-criteria

tests namedADEQUATE

exact p valuesINADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedADEQUATE

mathematical plausibilityN/A

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 85% conf

Statistical methods are appropriate and software is identified, but exact p-values are not reported (only threshold 'P < 0.05') for the mixed model.

Evidence

paraphrase[Extended Data Table 3 footnote]

“P < 0.05”

paraphrase[Methods, 'Statistical methods' paragraph]

“A Bayesian hierarchical model was used as the primary analysis... For cohorts 1–3, changes from baseline in HBsAg (on a log10 scale) at all scheduled visits were statistically analyzed using a mixed model for repeated measures.”

paraphrase[Tables 2, 3, Extended Data Table 3]

“Point estimate of response, % (95% CrI) ... LSMD and 95% CI”

PASSReviewer 2· 85% conf

Statistical methods are generally appropriate and well described, though exact p-values are not reported (only thresholds).

Evidence

paraphrase[Methods, Statistical methods]

“A Bayesian hierarchical model was used... For cohorts 1–3, changes from baseline in HBsAg... were statistically analyzed using a mixed model for repeated measures.”

paraphrase[Results, Key secondary efficacy outcomes]

“The mean change from baseline in serum HBsAg level through week 72 was substantially greater (P < 0.05; Extended Data Table)”

“Point estimate of response, % (95% CrI)”

Table 2Find in source

PASSReviewer 3· 85% conf

Statistical methods are adequately described, including Bayesian analysis and mixed models. Effect sizes with credible/confidence intervals are reported. However, p-values are sometimes reported as thresholds (P < 0.05) rather than exact values.

Evidence

paraphrase[Methods, Statistical methods, paragraph 2]

“A Bayesian hierarchical model was used as the primary analysis... For cohorts 1–3, changes from baseline in HBsAg... were statistically analyzed using a mixed model for repeated measures.”

“P < 0.05; Extended Data Table”

Results ¶1Find in source

“Point estimate of response, % (95% CrI) | 5.4 (0.1, 18.1) | 26.2 (10.3, 45.4) | 33.3 (17.1, 49.5)”

Table 2Find in source

The data availability statement says deidentified individual participant data will be shared on request or after trial completion, but does not name a managed-access platform or data-access committee. The study protocol and SAP are available. No code was shared; the paper states no computer code was used for data collection, but analysis code (SAS) is not mentioned.

Sub-criteria

code sharingNOT REPORTED

accession numbersN/A

repository depositN/A

data availability statementINADEQUATE

Per reviewer (3) — the votes behind the verdict

FAILReviewer 1· 90% conf

Data availability statement is vague (on request without a mechanism), and no analysis code is shared.

Evidence

paraphrase[Data availability section]

“Owing to the ongoing nature of the ENSURE study, the deidentified individual participant data that underlie the results reported in this Article will be shared on request, or after the completion of the trial within the timeframe as required by ClinicalTrial.gov (NCT05970289).”

“No computer code was used for data collection.”

MethodsFind in source

WARNReviewer 2· 90% conf

A data availability statement exists but is vague, lacking a concrete data access mechanism or platform.

Evidence

paraphrase[Data availability section]

FAILReviewer 3· 80% conf

The data availability statement is vague ('on request' with a timeframe but no concrete platform), and no analysis code is shared. No applicable criterion is adequately reported.

Evidence

paraphrase[Data availability section]

“the deidentified individual participant data that underlie the results reported in this Article will be shared on request, or after the completion of the trial within the timeframe as required by ClinicalTrial.gov (NCT05970289).”

“No computer code was used for data collection.”

Methods ¶1Find in source

The methods are sufficiently detailed for replication. The trial is registered (NCT05970289). CONSORT adherence is stated. All primary and secondary outcomes are reported. Limitations are discussed in the Discussion. Conclusions are proportional to the evidence. Funding and competing interests are declared.

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineADEQUATE

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

The manuscript is well-reported with CONSORT adherence, trial registration, funding/COI disclosure, and proportional conclusions. Some secondary outcomes (pharmacokinetics, antidrug antibodies) are not reported in this paper.

Evidence

“ClinicalTrials.gov registration: NCT05970289”

AbstractFind in source

“The study adhered to the Consolidated Standards of Reporting Trials (CONSORT) guidelines.”

MethodsFind in source

“Secondary objectives were to assess the antiviral activity of elebsiran and PEG-IFNα combination therapy, and to assess elebsiran pharmacokinetics exposure (endpoint: plasma concentrations of elebsiran and its metabolite at selected time points) and evaluate antidrug antibody to elebsiran (endpoint: the occurrence of antidrug antibody to elebsiran and associated titer, if positive).”

MethodsFind in source

PASSReviewer 2· 95% conf

The manuscript is well reported: methods are detailed, trial is registered, CONSORT guidelines are followed, all outcomes are reported, limitations are discussed, conclusions are proportional, and funding/COI are disclosed.

Evidence

“ClinicalTrials.gov registration: NCT05970289”

AbstractFind in source

“The study adhered to the Consolidated Standards of Reporting Trials (CONSORT) guidelines.”

MethodsFind in source

“This study has some limitations. Approximately 1.5 years, on average, elapsed between the BRII-179-835-001 study and the ENSURE study, and the impact of this gap in time is unknown.”

DiscussionFind in source

PASSReviewer 3· 95% conf

The manuscript is well-structured, includes trial registration, CONSORT adherence, discusses limitations, reports all outcomes, and provides funding and conflict of interest statements.

Evidence

“ClinicalTrials.gov registration: NCT05970289”

AbstractFind in source

“The study adhered to the Consolidated Standards of Reporting Trials (CONSORT) guidelines.”

Methods ¶1Find in source

“This study has some limitations. Approximately 1.5 years, on average, elapsed between the BRII-179-835-001 study and the ENSURE study, and the impact of this gap in time is unknown.”

Discussion ¶6Find in source

Registered (1 ID: ClinicalTrials.gov). Reporting guideline cited: CONSORT.

Broken references and links

None found

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.

Checked — nothing surfaced.

Checked 24 references by DOI: 19 verified — 5 no DOI (shown, not verified).

1 data/code link checked; 1 live.

Copyediting

4 minor

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

No major wording or formatting errors. 4 minor suggestions below.

4 copyedit issues flagged: mostly consistency, clarity, punctuation.

Kaimen Rigor Action ItemsFinal pass before journal submission

Post-publication: the published work is methodologically sound and its core clinical findings can be read with reasonable confidence, but the vague data-sharing statement and absence of analysis code materially weaken reproducibility, and the threshold p-values obscure effect-size precision. An informed reader should weigh the open-label design without justification and the unreported secondary PK/antidrug-antibody endpoints. These issues would warrant a correction or data-supplement update (data-sharing mechanism, exact p-values, product sourcing) rather than a retraction or re-analysis.

1.
HIGHdata code
Replace the vague 'on request' data availability statement in the Data availability section with a named managed-access platform (e.g., Vivli, YODA) or a data-access committee with explicit conditions and timeline.
The current statement provides no concrete mechanism for accessing deidentified IPD, undermining the reproducibility of the published results.
2.
HIGHdata code
Deposit the SAS analysis code in a public repository (e.g., Zenodo, GitHub) with a DOI and cite it in the Methods or Data availability section.
Sharing the analysis code enables independent verification of the reported Bayesian and mixed-model analyses.
3.
HIGHstatistics
Report exact p-values (e.g., 'P = 0.023') instead of 'P < 0.05' for the mixed-model comparisons in the main text and Extended Data tables.
Threshold-only p-values obscure the strength of evidence and are a recognized reporting deficiency.
4.
HIGHother
Add the manufacturer/source (and lot numbers if available) for elebsiran, PEG-IFNα, and BRII-179 in the Methods.
Reagents identification is currently inadequate, hindering replication and proper attribution.
5.
MEDIUMother
Add a brief rationale for the open-label design in the Methods (e.g., feasibility of blinding subcutaneous injections).
The absence of a justification for the lack of blinding is a reporting gap in an interventional trial.
6.
MEDIUMstatistics
Describe the handling of missing data and outliers (e.g., imputation methods, sensitivity analyses) in the statistical methods.
Outlier and missing-data approaches are not pre-specified, which is a reproducibility gap.
7.
MEDIUMreporting
Report the pre-specified secondary endpoints of elebsiran pharmacokinetics and antidrug antibodies, or explicitly state where they will be reported.
Not all pre-specified secondary outcomes appear in this paper, which is a transparency concern.
8.
MEDIUMcopyedit
Correct the truncated reference title in the References (line 24) so it begins 'Hepatitis B virus infection...'.
The reference appears cut off, which is an integrity/consistency error in the citation list.
9.
LOWcopyedit
Complete the pointer to the supplementary file for the ethics committee approval list (e.g., 'see Supplementary Information').
The current placeholder text appears incomplete.
10.
LOWcopyedit
Ensure consistent hyphenation of 'PEG-IFNα' throughout the manuscript.
Minor terminology consistency issue flagged by the copyedit pass.
11.
LOWcopyedit
Clarify in the statistical methods that the sample size was determined by a Bayesian approach rather than a frequentist power analysis.
Reduces reader confusion about the absence of a conventional power calculation.

Full text (64,019 chars)Analyzed: Aug 10, 2026

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Elebsiran and PEG-IFNα for chronic hepatitis B infection: a partially randomized, open-label, phase 2 trial

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DOI

10.1038/s41591-025-04049-z

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Record fingerprint

97d71e52d1a2b0bab83096520fa91e988fb31dc68958d4ff4c62efcb149b807f

Verify via API

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

4.25 / 5

Strong — minor issues to address

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

ReportingData & code availability not met−0.5★
ReportingKey resources partially met−0.25★

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

Not verified in this report

No reported statistical tests were found to recompute.
The numeric-impossibility checks (GRIM/GRIMMER/DEBIT/SPRITE) did not run on this paper: the pass that reads its reported means did not complete. No reported mean was checked for arithmetic impossibility.

Biggest issues

01Data and code not shared
highDisclosurereviewer-assessedFull detail
Data availability statement is vague (on request without a mechanism), and no analysis code is shared.
“No computer code was used for data collection.”
MethodsFind in source

Findings by category

01ArithmeticNone found 02OverreachNone found · partly checked 03AuthenticityNone found 204DisclosureReporting gaps 05AvailabilityNone found 06Copyedit4 minor suggestions

Numerical inconsistencies

None found

Checked — nothing surfaced.

Overstated conclusions

None found · partly checked

Nothing surfaced — but not everything feeding this category ran (missing: surrogate-endpoint assessment), so read this as a partial clean bill.

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

Data authenticity concerns

None found

Checked — nothing surfaced.

Reporting gaps

2 findings · worst high

Data and code not sharedAssessed
Key resources under-identified (antibodies, cell lines, RRIDs)Assessed

Eight Dimensions6 pass · 1 warn · 1 fail

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

The scientific premise is well-established with citations to prior work, a clear rationale, and discussion of limitations of previous studies.

Evidence

paraphrase[Main text, paragraph 4]

paraphrase[Main text, paragraph 5]

“This study has some limitations. Approximately 1.5 years, on average, elapsed between the BRII-179-835-001 study and the ENSURE study, and the impact of this gap in time is unknown.”

Discussion ¶6Find in source

PASSReviewer 2· 95% conf

The study clearly establishes its scientific foundation by citing prior work on HBV functional cure, limitations of existing therapies, and prior studies on elebsiran and BRII-179.

Evidence

paraphrase[Main text, paragraph 2]

paraphrase[Main text, paragraph 3]

paraphrase[Main text, paragraph 3-4]

“The study hypothesizes that combining elebsiran with PEG-IFNα will enhance HBsAg loss, and that prior response to BRII-179 may identify patients more likely to benefit.”

PASSReviewer 3· 95% conf

The paper clearly establishes the scientific premise by citing relevant prior work, acknowledging limitations, and providing a logical rationale for the study.

Evidence

paraphrase[Introduction, paragraph 4]

“A prior study evaluating elebsiran in combination with PEG-IFNα reported an HBsAg loss rate of approximately 30% ... However, this study lacked a PEG-IFNα monotherapy control, limiting direct comparison.”

paraphrase[Introduction, paragraph 5]

“The study design includes a PEG-IFNα monotherapy control arm to address the lack of a control in prior studies.”

Sub-criteria

controlsADEQUATE

power analysisADEQUATE

blinding levelsINADEQUATE

outlier handlingADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

Evidence

“The randomization code was generated through a validated computerized system.”

MethodsFind in source

“open-label, phase 2 trial”

MethodsFind in source

Statistical analysisFind in source

WARNReviewer 2· 90% conf

Evidence

“The randomization code was generated through a validated computerized system.”

MethodsFind in source

“Elebsiran and PEG-IFNα for chronic hepatitis B infection: a partially randomized, open-label, phase 2 trial”

MethodsFind in source

Statistical analysisFind in source

PASSReviewer 3· 85% conf

Evidence

paraphrase[Methods, Study design, paragraph 2]

“Eligible participants were randomized at 1:1:1 to cohort 1... using an Interactive Response Technology system. The randomization code was generated through a validated computerized system.”

“open-label, phase 2 study”

AbstractFind in source

paraphrase[Methods, Statistical methods, paragraph 2]

Table 1 provides sex, age, BMI, race, HBsAg levels, anti-HBs, ALT, HBeAg status for all cohorts. The study enrolls both sexes (mostly male) and reports demographics adequately.

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

Biological variables including sex, age, BMI, race, and health status are reported in baseline tables.

Evidence

paraphrase[Table 1]

“Male n (%) ... Female n (%)”

paraphrase[Table 1]

“Mean (s.d.) age ... BMI at baseline”

paraphrase[Table 1]

“Race n (%) ... HBeAg at baseline n (%)”

PASSReviewer 2· 95% conf

Biological variables and subject characteristics are well reported, including sex, age, BMI, race, and baseline HBsAg levels.

Evidence

“Table 1 Demographics and baseline characteristics”

Table 1Find in source

“ALT and AST ≤ ULN”

MethodsFind in source

PASSReviewer 3· 95% conf

Biological variables including sex, age, BMI, health status, and demographics are well reported in Table 1.

Evidence

paraphrase[Table 1]

“Sex n (%) Male 16 (88.9) ... Mean (s.d.) age 45.2 (8.5) ... Mean (s.d.) BMI 24.3 (3.4) ... HBeAg negative 15 (83.3)”

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

Ethical approval, informed consent, and regulatory compliance are clearly stated.

Evidence

paraphrase[Methods, 'Study design' paragraph]

“All participants provided written informed consent to participate in the study before any study-specific procedures were conducted.”

MethodsFind in source

PASSReviewer 2· 95% conf

Ethical approvals, informed consent, and regulatory compliance are clearly documented.

Evidence

paraphrase[Methods, Study design]

“conducted in accordance with the Declaration of Helsinki and International Conference on Harmonisation Good Clinical Practice.”

MethodsFind in source

PASSReviewer 3· 90% conf

Ethical approvals, informed consent, and regulatory compliance are adequately reported.

Evidence

paraphrase[Methods, Study design, paragraph 1]

“All participants provided written informed consent to participate in the study before any study-specific procedures were conducted.”

Methods ¶1Find in source

“conducted in accordance with the Declaration of Helsinki and International Conference on Harmonisation Good Clinical Practice.”

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 (3) — the votes behind the verdict

WARNReviewer 1· 85% conf

Investigational products (elebsiran, PEG-IFNα, BRII-179) are named and dosed but not fully identified with manufacturer/source; software is identified.

Evidence

paraphrase[Main text, paragraph 4]

“Elebsiran (BRII-835/VIR-2218) is a triantennary N-acetyl galactosamine (GalNAc)-conjugated small interfering RNA (siRNA)...”

“PEG-IFNα 180 μg administered subcutaneously (SC) every week”

MethodsFind in source

“SAS version 9.4 was used for data analyses in this study.”

Statistical analysisFind in source

WARNReviewer 2· 90% conf

The investigational products (elebsiran and PEG-IFNα) are named but not identified by manufacturer or source. Statistical software is adequately identified.

Evidence

paraphrase[Methods, Study design]

“elebsiran 200 mg administered SC every 4 weeks (Q4W)... PEG-IFNα 180 μg administered subcutaneously (SC) every week (QW)”

“SAS version 9.4 was used for data analyses in this study.”

Statistical analysisFind in source

WARNReviewer 3· 85% conf

The investigational products (elebsiran and PEG-IFNα) are named with dose and regimen but manufacturer/source is not provided. Statistical software (SAS 9.4) is identified.

Evidence

paraphrase[Methods, Study design, paragraph 2]

“Elebsiran (BRII-835/VIR-2218) and PEG-IFNα 180 μg are named with dose and regimen, but no manufacturer or source is given.”

“SAS version 9.4 was used for data analyses in this study.”

Statistical analysis ¶3Find in source

Sub-criteria

tests namedADEQUATE

exact p valuesINADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedADEQUATE

mathematical plausibilityN/A

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 85% conf

Statistical methods are appropriate and software is identified, but exact p-values are not reported (only threshold 'P < 0.05') for the mixed model.

Evidence

paraphrase[Extended Data Table 3 footnote]

“P < 0.05”

paraphrase[Methods, 'Statistical methods' paragraph]

paraphrase[Tables 2, 3, Extended Data Table 3]

“Point estimate of response, % (95% CrI) ... LSMD and 95% CI”

PASSReviewer 2· 85% conf

Statistical methods are generally appropriate and well described, though exact p-values are not reported (only thresholds).

Evidence

paraphrase[Methods, Statistical methods]

“A Bayesian hierarchical model was used... For cohorts 1–3, changes from baseline in HBsAg... were statistically analyzed using a mixed model for repeated measures.”

paraphrase[Results, Key secondary efficacy outcomes]

“The mean change from baseline in serum HBsAg level through week 72 was substantially greater (P < 0.05; Extended Data Table)”

“Point estimate of response, % (95% CrI)”

Table 2Find in source

PASSReviewer 3· 85% conf

Evidence

paraphrase[Methods, Statistical methods, paragraph 2]

“A Bayesian hierarchical model was used as the primary analysis... For cohorts 1–3, changes from baseline in HBsAg... were statistically analyzed using a mixed model for repeated measures.”

“P < 0.05; Extended Data Table”

Results ¶1Find in source

“Point estimate of response, % (95% CrI) | 5.4 (0.1, 18.1) | 26.2 (10.3, 45.4) | 33.3 (17.1, 49.5)”

Table 2Find in source

Sub-criteria

code sharingNOT REPORTED

accession numbersN/A

repository depositN/A

data availability statementINADEQUATE

Per reviewer (3) — the votes behind the verdict

FAILReviewer 1· 90% conf

Data availability statement is vague (on request without a mechanism), and no analysis code is shared.

Evidence

paraphrase[Data availability section]

“No computer code was used for data collection.”

MethodsFind in source

WARNReviewer 2· 90% conf

A data availability statement exists but is vague, lacking a concrete data access mechanism or platform.

Evidence

paraphrase[Data availability section]

FAILReviewer 3· 80% conf

The data availability statement is vague ('on request' with a timeframe but no concrete platform), and no analysis code is shared. No applicable criterion is adequately reported.

Evidence

paraphrase[Data availability section]

“No computer code was used for data collection.”

Methods ¶1Find in source

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineADEQUATE

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

Evidence

“ClinicalTrials.gov registration: NCT05970289”

AbstractFind in source

“The study adhered to the Consolidated Standards of Reporting Trials (CONSORT) guidelines.”

MethodsFind in source

PASSReviewer 2· 95% conf

Evidence

“ClinicalTrials.gov registration: NCT05970289”

AbstractFind in source

“The study adhered to the Consolidated Standards of Reporting Trials (CONSORT) guidelines.”

MethodsFind in source

“This study has some limitations. Approximately 1.5 years, on average, elapsed between the BRII-179-835-001 study and the ENSURE study, and the impact of this gap in time is unknown.”

DiscussionFind in source

PASSReviewer 3· 95% conf

The manuscript is well-structured, includes trial registration, CONSORT adherence, discusses limitations, reports all outcomes, and provides funding and conflict of interest statements.

Evidence

“ClinicalTrials.gov registration: NCT05970289”

AbstractFind in source

“The study adhered to the Consolidated Standards of Reporting Trials (CONSORT) guidelines.”

Methods ¶1Find in source

“This study has some limitations. Approximately 1.5 years, on average, elapsed between the BRII-179-835-001 study and the ENSURE study, and the impact of this gap in time is unknown.”

Discussion ¶6Find in source

Registered (1 ID: ClinicalTrials.gov). Reporting guideline cited: CONSORT.

Broken references and links

None found

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.

Checked — nothing surfaced.

Checked 24 references by DOI: 19 verified — 5 no DOI (shown, not verified).

1 data/code link checked; 1 live.

Copyediting

4 minor

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

No major wording or formatting errors. 4 minor suggestions below.

4 copyedit issues flagged: mostly consistency, clarity, punctuation.

Kaimen Rigor Action ItemsFinal pass before journal submission

1.
HIGHdata code
Replace the vague 'on request' data availability statement in the Data availability section with a named managed-access platform (e.g., Vivli, YODA) or a data-access committee with explicit conditions and timeline.
The current statement provides no concrete mechanism for accessing deidentified IPD, undermining the reproducibility of the published results.
2.
HIGHdata code
Deposit the SAS analysis code in a public repository (e.g., Zenodo, GitHub) with a DOI and cite it in the Methods or Data availability section.
Sharing the analysis code enables independent verification of the reported Bayesian and mixed-model analyses.
3.
HIGHstatistics
Report exact p-values (e.g., 'P = 0.023') instead of 'P < 0.05' for the mixed-model comparisons in the main text and Extended Data tables.
Threshold-only p-values obscure the strength of evidence and are a recognized reporting deficiency.
4.
HIGHother
Add the manufacturer/source (and lot numbers if available) for elebsiran, PEG-IFNα, and BRII-179 in the Methods.
Reagents identification is currently inadequate, hindering replication and proper attribution.
5.
MEDIUMother
Add a brief rationale for the open-label design in the Methods (e.g., feasibility of blinding subcutaneous injections).
The absence of a justification for the lack of blinding is a reporting gap in an interventional trial.
6.
MEDIUMstatistics
Describe the handling of missing data and outliers (e.g., imputation methods, sensitivity analyses) in the statistical methods.
Outlier and missing-data approaches are not pre-specified, which is a reproducibility gap.
7.
MEDIUMreporting
Report the pre-specified secondary endpoints of elebsiran pharmacokinetics and antidrug antibodies, or explicitly state where they will be reported.
Not all pre-specified secondary outcomes appear in this paper, which is a transparency concern.
8.
MEDIUMcopyedit
Correct the truncated reference title in the References (line 24) so it begins 'Hepatitis B virus infection...'.
The reference appears cut off, which is an integrity/consistency error in the citation list.
9.
LOWcopyedit
Complete the pointer to the supplementary file for the ethics committee approval list (e.g., 'see Supplementary Information').
The current placeholder text appears incomplete.
10.
LOWcopyedit
Ensure consistent hyphenation of 'PEG-IFNα' throughout the manuscript.
Minor terminology consistency issue flagged by the copyedit pass.
11.
LOWcopyedit
Clarify in the statistical methods that the sample size was determined by a Bayesian approach rather than a frequentist power analysis.
Reduces reader confusion about the absence of a conventional power calculation.

Full text (64,019 chars)Analyzed: Aug 10, 2026