Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

Daily Mosnodenvir as Dengue Prophylaxis in a Controlled Human Infection Model.

Name: Kaimen Rigor review — Daily Mosnodenvir as Dengue Prophylaxis in a Controlled Human Infection Model.
Item: Daily Mosnodenvir as Dengue Prophylaxis in a Controlled Human Infection Model.
Rating: 84
Author: Alpha1

Durbin AP, Van Wesenbeeck L, Pierce KK, Herrera-Taracena G, Ebone L, Buelens A, Lutton P, Sabundayo BP, Van Eygen V, De Clerck K, Fetter I, Voge NV, Fang X, Goeyvaerts N, Vandendijck Y, Mayfield J, Lenz O, De Meyer S, Kakuda TN, He H, Amaro-Carambot E, Akli RD, Carmolli M, De Marez T, Whitehead SS, Van Loock M, Rasschaert F

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Kaimen Rigor review — 1.25★ (Critical), 0 critical, 0 high issues for “Daily Mosnodenvir as Dengue Prophylaxis in a Controlled Human Infection Model.”

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Alpha1 Editorial

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

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Daily Mosnodenvir as Dengue Prophylaxis in a Controlled Human Infection Model.

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DOI

10.1056/NEJMoa2500179

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Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

Daily Mosnodenvir as Dengue Prophylaxis in a Controlled Human Infection Model.

Paper source

Daily Mosnodenvir as Dengue Prophylaxis in a Controlled Human Infection Model.

Read full text (PMC)

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Alpha1 Editorial

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

Kaimen Rigor review

Kaimen Rigor reviewed

1.25 / 5

Critical — serious problems across many checks

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

IntegrityIntegrity concern ×4−2★
ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
ClaimsTreatment effect not shown to be clinically meaningful−0.5★
ReportingData & code availability not met−0.5★
ReportingStatistical analysis partially met−0.25★

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

Not verified in this report

Statistics were not checked: no recomputable values were found in this text — no test statistic reported with its degrees of freedom, no effect estimate printed with both a 95% CI and a p-value, and no percentage printed with both its count and its denominator.

Biggest issues

01Efficacy rests on an unvalidated surrogate endpoint
highOverreachreviewer-assessedFull detail
Primary efficacy endpoint is DENV-3 RNA viral load AUC, a surrogate outcome. No validated evidence linking this surrogate to clinical benefit is provided, and target engagement at the tested dose is not demonstrated.
“The primary objective was to assess the antiviral activity of mosnodenvir versus placebo in terms of reduction of DENV-3 RNA by evaluating the area under the DENV-3 RNA viral load (VL) concentration-time curves from immediately before inoculation (D1) until…”
Find in source
02Treatment effect not shown to be clinically meaningful
highOverreachreviewer-assessedFull detail
The reported effect is reduction in viral RNA AUC, with 60% of high-dose participants having undetectable RNA vs 0% in placebo. The magnitude is not anchored to a minimal clinically important difference or clinical benefit.
“The proportion of participants without signs of DENV-3 infection was 0% (0/6), 17% (1/6), 60% (6/10) in low-, medium-, high-dose regimens, respectively, versus 0% (0/7) in the placebo arm.”
Find in source
03Data and code not shared
highDisclosurereviewer-assessedFull detail
No data availability statement, repository deposit, accession numbers, or code-sharing mechanism is reported in the manuscript.

Findings by category

101ArithmeticNumerical inconsistencies 302OverreachOverstated conclusions 103AuthenticityData authenticity concerns 204DisclosureReporting gaps 05AvailabilityNone found 106CopyeditCopyediting

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

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

Overstated conclusions

3 findings · worst high

Conclusions that reach past what the paper's own results support — including a significance claim that no longer holds when the statistic is recomputed, and efficacy resting on an unvalidated surrogate endpoint.

Efficacy rests on an unvalidated surrogate endpointAssessed
Treatment effect not shown to be clinically meaningfulAssessed
Conclusions only partially backed by the presented evidenceAssessed

12 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

1 finding · worst low

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

Methods and results do not matchAssessed

4 integrity concerns flagged (0 high).

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
Statistical reporting gaps (tests, assumptions, effect sizes)Assessed

Eight Dimensions6 pass · 1 warn · 1 fail

The introduction cites dengue epidemiology, the limitations of current vaccines, and mosnodenvir's mechanism (NS3-NS4B inhibition) with in vitro, mouse, and NHP efficacy data. The study objective follows logically from this premise. The discussion explicitly acknowledges CHIM limitations and the need for field confirmation, satisfying the limitations-addressed criterion.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

The paper establishes a clear scientific premise: dengue lacks antiviral prophylaxis/treatment, mosnodenvir has a defined mechanism and promising preclinical and first-in-human data, and a CHIM is an appropriate early-stage model.

Evidence

“Licensed dengue treatments are currently unavailable and management consists of supportive measures, such as antipyretics and volume repletion.”

Introduction ¶1Find in source

paraphrase[Introduction, paragraph 3]

“Mosnodenvir is an oral, pan-serotype dengue small-molecule antiviral, that blocks viral replication by inhibiting de novo DENV nonstructural protein 3 (NS3)-NS4B interaction.”

“Findings from those studies must be confirmed in larger safety and efficacy studies in the target population since CHIM studies do not reflect field conditions.”

Discussion ¶5Find in source

PASSReviewer 2· 90% conf

The premise is well established: dengue burden, lack of antiviral treatment, vaccine limitations, and preclinical/first-in-human data on mosnodenvir are cited, with a clear rationale for a prophylactic antiviral and a stated hypothesis.

Evidence

“In contrast, an oral antiviral could be deployed in outbreaks, could limit cases in endemic areas through a prophylactic approach, and may be used for travelers and those who cannot receive a vaccine.”

Introduction ¶1Find in source

“Findings from those studies must be confirmed in larger safety and efficacy studies in the target population since CHIM studies do not reflect field conditions.”

DiscussionFind in source

PASSReviewer 3· 90% conf

The premise is firmly grounded in prior literature on dengue burden, vaccine limitations, and mosnodenvir's mechanism and preclinical efficacy, with a clear rationale for prophylaxis.

Evidence

“Mosnodenvir (also known as JNJ-64281802) is an oral, pan-serotype dengue small-molecule antiviral, that blocks viral replication by inhibiting de novo DENV nonstructural protein 3 (NS3)-NS4B interaction.”

IntroductionFind in source

“Findings from those studies must be confirmed in larger safety and efficacy studies in the target population since CHIM studies do not reflect field conditions.”

DiscussionFind in source

The randomized, double-blind design and unit of randomization (participant) are clear. A sample size simulation demonstrated >85% power for the primary endpoint. Inclusion/exclusion criteria are summarized and referenced to the protocol. Missing data were handled by pre-specified rules: one high-dose participant with a missing D29 sample was excluded from the primary analysis. The randomization method (e.g., block/stratified/computer-generated sequence) is not reported, so randomization_method is only partially adequate.

Sub-criteria

controlsN/A

power analysisADEQUATE

blinding levelsADEQUATE

outlier handlingADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodINADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 85% conf

Randomized, double-blind, placebo-controlled CHIM with a simulated power calculation, clear inclusion/exclusion criteria, and pre-specified handling of missing data; the specific randomization algorithm is not stated.

Evidence

“In this phase 2a, double-blind study, healthy adults were randomized to receive once daily oral mosnodenvir at different dose levels or placebo for 26 days”

AbstractFind in source

“Based on these simulations, the power to detect a relevant reduction of ≥ 30% on log 10 AUC D1-D29 (VL) at the 2-sided 10% significance level was calculated to be more than 85% with 6 participants in the placebo arm and 10 participants in the mosnodenvir high-dose arm.”

MethodsFind in source

“One participant in the high-dose mosnodenvir arm had a missing sample on D29 and was excluded from the primary analysis since the missing value could not be imputed according to pre-specified statistical analysis plan rules.”

Table 1Find in source

PASSReviewer 2· 80% conf

A pre-specified sample-size calculation, inclusion/exclusion criteria, double-blinding, and handling of missing data are reported; the main gap is that the randomization method (sequence generation) is not described.

Evidence

paraphrase[Methods, Study procedures]

“Participants were randomized to receive either high-dose mosnodenvir; (N=10) or matching placebo (N=6) (Group 1) or medium- (N=6) and low-dose (N=6) mosnodenvir or matching placebo (N=2) (Group 2).”

“the power to detect a relevant reduction of ≥ 30% on log 10 AUC D1-D29 (VL) at the 2-sided 10% significance level was calculated to be more than 85%”

MethodsFind in source

PASSReviewer 3· 80% conf

Core clinical trial design elements are well reported: double-blind, placebo-controlled, with sample-size simulation, inclusion/exclusion criteria, and a pre-specified missing-data rule.

Evidence

“This is a phase 2a, randomized, double-blind, placebo-controlled human infection model (CHIM) study”

MethodsFind in source

“the power to detect a relevant reduction of ≥ 30% on log 10 AUC D1-D29 (VL) at the 2-sided 10% significance level was calculated to be more than 85% with 6 participants in the placebo arm and 10 participants in the mosnodenvir high-dose arm.”

MethodsFind in source

Table 1Find in source

Participants are described as healthy adults 18-55 years who are DENV/ZIKV seronegative, and Table 1 provides age, sex, race, ethnicity, and site. Since both sexes were enrolled, sex_justified is not applicable. Weight is not reported, making age_weight_health only partially adequate. Demographics are otherwise well characterized.

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthINADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 85% conf

Sex, age, health status, and race/ethnicity are reported in Table 1 and text; body weight is not reported, so age/weight/health reporting is incomplete.

Evidence

“We enrolled healthy individuals 18–55 years of age, who were confirmed to be seronegative to DENV and Zika virus (ZIKV) prior to enrollment”

MethodsFind in source

“Mean age (SD), years | 30.0 (7.29) | 29.5 (4.59) | 36.0 (10.68) | 34.5 (9.08) | 33.6 (8.64) | 32.6 (8.35)”

Table 1Find in source

“Female sex, n (%) | 4 (50.0) | 4 (66.7) | 5 (83.3) | 7 (63.6) | 16 (69.6) | 20 (64.5)”

Table 1Find in source

PASSReviewer 2· 75% conf

Sex, age, health status, and demographics (race/ethnicity) are reported; weight is not reported, which is a minor omission for an adult CHIM trial.

Evidence

“Female sex, n (%) | 4 (50.0) | 4 (66.7) | 5 (83.3) | 7 (63.6) | 16 (69.6) | 20 (64.5)”

Table 1Find in source

“We enrolled healthy individuals 18–55 years of age, who were confirmed to be seronegative to DENV and Zika virus (ZIKV) prior to enrollment”

MethodsFind in source

PASSReviewer 3· 75% conf

Sex, age, health status, race, and ethnicity are reported in Table 1; weight is not reported.

Evidence

“Female sex, n (%) | 4 (50.0) | 4 (66.7) | 5 (83.3) | 7 (63.6) | 16 (69.6) | 20 (64.5)”

Table 1Find in source

“Mean age (SD), years | 30.0 (7.29) | 29.5 (4.59) | 36.0 (10.68) | 34.5 (9.08) | 33.6 (8.64) | 32.6 (8.35)”

Table 1Find in source

“We enrolled healthy individuals 18–55 years of age”

MethodsFind in source

Human subjects research: the protocol was reviewed and approved by Independent Ethics Committees at each site, written informed consent was obtained from each participant, and compliance with Good Clinical Practice and the Declaration of Helsinki is stated. All three applicable criteria are adequately addressed.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 90% conf

Informed consent and regulatory compliance (GCP, Declaration of Helsinki) are stated, but the approving ethics bodies are not named and no approval numbers are given.

Evidence

paraphrase[Methods, Study oversight]

“The study protocol (available with the full text of this article at NEJM.org) was reviewed and approved by Independent Ethics Committees at each site and written informed consent was obtained from each participant.”

“The study is conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki.”

MethodsFind in source

PASSReviewer 2· 90% conf

Ethics committee approval, written informed consent, and GCP/Declaration of Helsinki compliance are all stated.

Evidence

paraphrase[Methods, Study oversight]

“The study is conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki.”

MethodsFind in source

PASSReviewer 3· 90% conf

Ethics approval by Independent Ethics Committees at each site, written informed consent, and compliance with GCP and the Declaration of Helsinki are all stated.

Evidence

paraphrase[Methods, Study oversight]

“The study is conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki.”

MethodsFind in source

Mosnodenvir is identified as 10 mg, 50 mg, and 100 mg oral capsules with full loading/maintenance dose regimens, satisfying the investigational-product identification criterion. Statistical and PK software are identified with versions (SAS 9.04, R 4.2.0, Phoenix). The study does not use cell lines, antibodies, or laboratory animals, so those criteria are genuinely not applicable.

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

The investigational product (mosnodenvir capsule strengths and dose regimens) and analysis software are identified; wet-lab reagents, cell lines, antibodies, and organisms are not applicable.

Evidence

“Mosnodenvir was supplied as 10 mg, 50 mg, and 100 mg oral capsules and administered under fasted conditions.”

MethodsFind in source

“Pharmacokinetic parameters, including maximum plasma concentration (C max ), time to C max (t max ), average concentration (C avg ), terminal elimination half-life (t ½ ) and area under the plasma concentration-time curve (AUC), were determined using the validated software Phoenix (Certara, Princeton, NJ, USA).”

MethodsFind in source

“Analyses were performed with SAS 9.04 (SAS Institute Inc., Cary, NC, USA). Graphs were created in R version 4.2.0”

Statistical analysisFind in source

PASSReviewer 2· 80% conf

The investigational product (mosnodenvir) is identified with formulation and dose/regimen, and analysis software is named with versions; bench-resource criteria are n/a.

Evidence

“Mosnodenvir was supplied as 10 mg, 50 mg, and 100 mg oral capsules and administered under fasted conditions.”

MethodsFind in source

“Analyses were performed with SAS 9.04 (SAS Institute Inc., Cary, NC, USA). Graphs were created in R version 4.2.0”

Statistical analysisFind in source

PASSReviewer 3· 80% conf

The investigational product (mosnodenvir) is identified with formulation and dose regimens, and analysis software is named with versions.

Evidence

“Mosnodenvir was supplied as 10 mg, 50 mg, and 100 mg oral capsules and administered under fasted conditions.”

MethodsFind in source

“Analyses were performed with SAS 9.04 (SAS Institute Inc., Cary, NC, USA). Graphs were created in R version 4.2.0”

Statistical analysisFind in source

Tobit ANOVA and exact Wilcoxon rank sum tests are named, with software identified and individual data points displayed. The reported p=0.001 for the Wilcoxon test is exact, but the primary Tobit result is only 'p<0.001,' which is imprecise. No point estimate or 95% CI for the high-dose versus placebo difference in log10 AUC is provided, leaving effect_sizes_ci not reported. The invalid table percentage '8.79.1' is a copyediting issue, not a statistical impossibility.

Sub-criteria

tests namedADEQUATE

exact p valuesINADEQUATE

effect sizes ciNOT REPORTED

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedADEQUATE

mathematical plausibilityPASS

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 80% conf

Tests and software are named, individual data are shown, and no arithmetic impossibilities were found; however, the primary p-value is reported only as p<0.001 and no effect-size estimate with confidence interval is reported for the primary comparison.

Evidence

paraphrase[Results, Primary endpoint analysis]

“A Tobit analysis of variance showed a statistically significant reduction on the log 10 AUC D1-D29 VL in the high-dose mosnodenvir arm versus the placebo arm (2-sided p<0.001).”

“The statistically significant result was also seen by the exact Wilcoxon rank sum test (2-sided p=0.001).”

ResultsFind in source

“Solid black dots represent the individual log10 AUCD1-D29 (viral load) values.”

Figure 2Find in source

PASSReviewer 2· 75% conf

Tests are named, software identified, data shown with individual points and per-group n, and p-values are exact; the main gap is the absence of an effect estimate with confidence interval for the primary comparison.

Evidence

“A Tobit analysis of variance showed a statistically significant reduction on the log 10 AUC D1-D29 VL in the high-dose mosnodenvir arm versus the placebo arm (2-sided p<0.001)”

ResultsFind in source

“Solid black dots represent the individual log10 AUCD1-D29 (viral load) values.”

Figure 2Find in source

WARNReviewer 3· 75% conf

Tests are named, software identified, and data presented with individual points, but the primary p-value is printed only as a threshold and the primary effect size lacks a confidence interval.

Evidence

“A Tobit analysis of variance showed a statistically significant reduction on the log 10 AUC D1-D29 VL in the high-dose mosnodenvir arm versus the placebo arm (2-sided p<0.001)”

ResultsFind in source

“The statistically significant result was also seen by the exact Wilcoxon rank sum test (2-sided p=0.001).”

ResultsFind in source

“Solid black dots represent the individual log10 AUCD1-D29 (viral load) values.”

Figure 2Find in source

The paper mentions a protocol available at NEJM.org and ClinicalTrials.gov registration, but these are not data-availability mechanisms. There is no statement about access to individual participant data, no managed-access platform or data-access committee, and no deposit of viral sequencing data or analysis code. Because the trial generated human subject data and sequencing data, the data_availability_statement and related criteria are applicable and are not addressed.

Sub-criteria

code sharingNOT REPORTED

accession numbersNOT REPORTED

repository depositNOT REPORTED

data availability statementNOT REPORTED

Per reviewer (3) — the votes behind the verdict

FAILReviewer 1· 90% conf

No data availability statement, repository deposit, accession numbers, or code-sharing mechanism is reported in the manuscript.

Evidence

paraphrase[Methods, Study oversight]

“The study protocol (available with the full text of this article at NEJM.org) was reviewed and approved by Independent Ethics Committees at each site”

absence[Entire manuscript]

No data-sharing statement is present.

FAILReviewer 2· 80% conf

No data availability statement is present; the paper only notes that the protocol is available at NEJM.org, which does not constitute a data-access route.

Evidence

paraphrase[Methods, Study oversight]

“The study protocol (available with the full text of this article at NEJM.org) was reviewed and approved by Independent Ethics Committees at each site”

absence[Full text (search for data availability)]

No statement of where or how study data can be accessed.

FAILReviewer 3· 85% conf

No data-availability statement is provided; the protocol is available at NEJM.org but no patient-level or study data access route is described.

Evidence

paraphrase[Methods, Study oversight]

“The study protocol (available with the full text of this article at NEJM.org)”

paraphrase[Methods, Study oversight]

“Data were gathered by the study site investigators and analyzed at Johnson & Johnson in collaboration with the NIH; no statement of data availability or access mechanism is provided.”

ClinicalTrials.gov registration (NCT05048875) is provided, methods are detailed with reference to a full protocol, and the Discussion explicitly notes CHIM limitations and the need for larger field studies. Funding and disclosure forms are stated. A CONSORT or other reporting guideline checklist is not mentioned, which is a minor transparency gap but does not undermine the manuscript's overall completeness.

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineNOT REPORTED

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 85% conf

Methods are sufficiently detailed, the trial is registered, outcomes appear consistently reported, limitations are discussed, conclusions are proportionate, and funding/COI are disclosed; no reporting checklist (e.g., CONSORT) is referenced.

Evidence

“ClinicalTrials.gov (https://ClinicalTrials.gov) number, NCT05048875 (https://clinicaltrials.gov/ct2/show/NCT05048875)”

MethodsFind in source

“Findings from those studies must be confirmed in larger safety and efficacy studies in the target population since CHIM studies do not reflect field conditions.”

Discussion ¶5Find in source

“This study was funded in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health (NIH) and Johnson & Johnson.”

FundingFind in source

PASSReviewer 2· 85% conf

Methods are detailed, the trial is registered (NCT05048875), outcomes are reported including negatives, limitations are discussed, conclusions are proportional, and funding/COI are disclosed; only a reporting-guideline (CONSORT) reference is missing.

Evidence

“ClinicalTrials.gov (https://ClinicalTrials.gov) number, NCT05048875 (https://clinicaltrials.gov/ct2/show/NCT05048875)”

MethodsFind in source

FundingFind in source

PASSReviewer 3· 85% conf

Trial registration, methods, funding/COI, limitations, and proportional conclusions are all reported; only a CONSORT-style reporting-guideline reference is missing.

Evidence

“ClinicalTrials.gov (https://ClinicalTrials.gov) number, NCT05048875”

MethodsFind in source

“Findings from those studies must be confirmed in larger safety and efficacy studies in the target population since CHIM studies do not reflect field conditions.”

DiscussionFind in source

FundingFind in source

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

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 38 references by DOI: 2 verified — 36 no DOI (shown, not verified).

4 data/code links checked; 3 live.

Copyediting

1 finding · worst low

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

Wording or formatting errors that need correctingAssessed

9 copyedit issues flagged (1 major): mostly consistency, other, typo.

Full text (33,563 chars)Analyzed: Aug 10, 2026

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Daily Mosnodenvir as Dengue Prophylaxis in a Controlled Human Infection Model.

Read full text (PMC)

DOI

10.1056/NEJMoa2500179

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Record fingerprint

f6f3a1362d676554f05a7949bd62215419ee5c3717e5492d0a03331a8ec2bebb

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

1.25 / 5

Critical — serious problems across many checks

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

IntegrityIntegrity concern ×4−2★
ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
ClaimsTreatment effect not shown to be clinically meaningful−0.5★
ReportingData & code availability not met−0.5★
ReportingStatistical analysis partially met−0.25★

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

Not verified in this report

Statistics were not checked: no recomputable values were found in this text — no test statistic reported with its degrees of freedom, no effect estimate printed with both a 95% CI and a p-value, and no percentage printed with both its count and its denominator.

Biggest issues

01Efficacy rests on an unvalidated surrogate endpoint
highOverreachreviewer-assessedFull detail
Primary efficacy endpoint is DENV-3 RNA viral load AUC, a surrogate outcome. No validated evidence linking this surrogate to clinical benefit is provided, and target engagement at the tested dose is not demonstrated.
“The primary objective was to assess the antiviral activity of mosnodenvir versus placebo in terms of reduction of DENV-3 RNA by evaluating the area under the DENV-3 RNA viral load (VL) concentration-time curves from immediately before inoculation (D1) until…”
Find in source
02Treatment effect not shown to be clinically meaningful
highOverreachreviewer-assessedFull detail
The reported effect is reduction in viral RNA AUC, with 60% of high-dose participants having undetectable RNA vs 0% in placebo. The magnitude is not anchored to a minimal clinically important difference or clinical benefit.
“The proportion of participants without signs of DENV-3 infection was 0% (0/6), 17% (1/6), 60% (6/10) in low-, medium-, high-dose regimens, respectively, versus 0% (0/7) in the placebo arm.”
Find in source
03Data and code not shared
highDisclosurereviewer-assessedFull detail
No data availability statement, repository deposit, accession numbers, or code-sharing mechanism is reported in the manuscript.

Findings by category

101ArithmeticNumerical inconsistencies 302OverreachOverstated conclusions 103AuthenticityData authenticity concerns 204DisclosureReporting gaps 05AvailabilityNone found 106CopyeditCopyediting

Numerical inconsistencies

1 finding · worst low

Internal contradictions in the reported numbersAssessed

Overstated conclusions

3 findings · worst high

Efficacy rests on an unvalidated surrogate endpointAssessed
Treatment effect not shown to be clinically meaningfulAssessed
Conclusions only partially backed by the presented evidenceAssessed

12 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

1 finding · worst low

Methods and results do not matchAssessed

4 integrity concerns flagged (0 high).

Reporting gaps

2 findings · worst high

Data and code not sharedAssessed
Statistical reporting gaps (tests, assumptions, effect sizes)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

Evidence

“Licensed dengue treatments are currently unavailable and management consists of supportive measures, such as antipyretics and volume repletion.”

Introduction ¶1Find in source

paraphrase[Introduction, paragraph 3]

“Mosnodenvir is an oral, pan-serotype dengue small-molecule antiviral, that blocks viral replication by inhibiting de novo DENV nonstructural protein 3 (NS3)-NS4B interaction.”

“Findings from those studies must be confirmed in larger safety and efficacy studies in the target population since CHIM studies do not reflect field conditions.”

Discussion ¶5Find in source

PASSReviewer 2· 90% conf

Evidence

Introduction ¶1Find in source

“Findings from those studies must be confirmed in larger safety and efficacy studies in the target population since CHIM studies do not reflect field conditions.”

DiscussionFind in source

PASSReviewer 3· 90% conf

The premise is firmly grounded in prior literature on dengue burden, vaccine limitations, and mosnodenvir's mechanism and preclinical efficacy, with a clear rationale for prophylaxis.

Evidence

IntroductionFind in source

“Findings from those studies must be confirmed in larger safety and efficacy studies in the target population since CHIM studies do not reflect field conditions.”

DiscussionFind in source

Sub-criteria

controlsN/A

power analysisADEQUATE

blinding levelsADEQUATE

outlier handlingADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodINADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 85% conf

Evidence

“In this phase 2a, double-blind study, healthy adults were randomized to receive once daily oral mosnodenvir at different dose levels or placebo for 26 days”

AbstractFind in source

MethodsFind in source

Table 1Find in source

PASSReviewer 2· 80% conf

Evidence

paraphrase[Methods, Study procedures]

“the power to detect a relevant reduction of ≥ 30% on log 10 AUC D1-D29 (VL) at the 2-sided 10% significance level was calculated to be more than 85%”

MethodsFind in source

PASSReviewer 3· 80% conf

Core clinical trial design elements are well reported: double-blind, placebo-controlled, with sample-size simulation, inclusion/exclusion criteria, and a pre-specified missing-data rule.

Evidence

“This is a phase 2a, randomized, double-blind, placebo-controlled human infection model (CHIM) study”

MethodsFind in source

Table 1Find in source

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthINADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 85% conf

Sex, age, health status, and race/ethnicity are reported in Table 1 and text; body weight is not reported, so age/weight/health reporting is incomplete.

Evidence

“We enrolled healthy individuals 18–55 years of age, who were confirmed to be seronegative to DENV and Zika virus (ZIKV) prior to enrollment”

MethodsFind in source

“Mean age (SD), years | 30.0 (7.29) | 29.5 (4.59) | 36.0 (10.68) | 34.5 (9.08) | 33.6 (8.64) | 32.6 (8.35)”

Table 1Find in source

“Female sex, n (%) | 4 (50.0) | 4 (66.7) | 5 (83.3) | 7 (63.6) | 16 (69.6) | 20 (64.5)”

Table 1Find in source

PASSReviewer 2· 75% conf

Sex, age, health status, and demographics (race/ethnicity) are reported; weight is not reported, which is a minor omission for an adult CHIM trial.

Evidence

“Female sex, n (%) | 4 (50.0) | 4 (66.7) | 5 (83.3) | 7 (63.6) | 16 (69.6) | 20 (64.5)”

Table 1Find in source

“We enrolled healthy individuals 18–55 years of age, who were confirmed to be seronegative to DENV and Zika virus (ZIKV) prior to enrollment”

MethodsFind in source

PASSReviewer 3· 75% conf

Sex, age, health status, race, and ethnicity are reported in Table 1; weight is not reported.

Evidence

“Female sex, n (%) | 4 (50.0) | 4 (66.7) | 5 (83.3) | 7 (63.6) | 16 (69.6) | 20 (64.5)”

Table 1Find in source

“Mean age (SD), years | 30.0 (7.29) | 29.5 (4.59) | 36.0 (10.68) | 34.5 (9.08) | 33.6 (8.64) | 32.6 (8.35)”

Table 1Find in source

“We enrolled healthy individuals 18–55 years of age”

MethodsFind in source

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 90% conf

Informed consent and regulatory compliance (GCP, Declaration of Helsinki) are stated, but the approving ethics bodies are not named and no approval numbers are given.

Evidence

paraphrase[Methods, Study oversight]

“The study is conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki.”

MethodsFind in source

PASSReviewer 2· 90% conf

Ethics committee approval, written informed consent, and GCP/Declaration of Helsinki compliance are all stated.

Evidence

paraphrase[Methods, Study oversight]

“The study is conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki.”

MethodsFind in source

PASSReviewer 3· 90% conf

Ethics approval by Independent Ethics Committees at each site, written informed consent, and compliance with GCP and the Declaration of Helsinki are all stated.

Evidence

paraphrase[Methods, Study oversight]

“The study is conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki.”

MethodsFind in source

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

The investigational product (mosnodenvir capsule strengths and dose regimens) and analysis software are identified; wet-lab reagents, cell lines, antibodies, and organisms are not applicable.

Evidence

“Mosnodenvir was supplied as 10 mg, 50 mg, and 100 mg oral capsules and administered under fasted conditions.”

MethodsFind in source

“Analyses were performed with SAS 9.04 (SAS Institute Inc., Cary, NC, USA). Graphs were created in R version 4.2.0”

Statistical analysisFind in source

PASSReviewer 2· 80% conf

The investigational product (mosnodenvir) is identified with formulation and dose/regimen, and analysis software is named with versions; bench-resource criteria are n/a.

Evidence

“Mosnodenvir was supplied as 10 mg, 50 mg, and 100 mg oral capsules and administered under fasted conditions.”

MethodsFind in source

“Analyses were performed with SAS 9.04 (SAS Institute Inc., Cary, NC, USA). Graphs were created in R version 4.2.0”

Statistical analysisFind in source

PASSReviewer 3· 80% conf

The investigational product (mosnodenvir) is identified with formulation and dose regimens, and analysis software is named with versions.

Evidence

“Mosnodenvir was supplied as 10 mg, 50 mg, and 100 mg oral capsules and administered under fasted conditions.”

MethodsFind in source

“Analyses were performed with SAS 9.04 (SAS Institute Inc., Cary, NC, USA). Graphs were created in R version 4.2.0”

Statistical analysisFind in source

Sub-criteria

tests namedADEQUATE

exact p valuesINADEQUATE

effect sizes ciNOT REPORTED

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedADEQUATE

mathematical plausibilityPASS

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 80% conf

Evidence

paraphrase[Results, Primary endpoint analysis]

“A Tobit analysis of variance showed a statistically significant reduction on the log 10 AUC D1-D29 VL in the high-dose mosnodenvir arm versus the placebo arm (2-sided p<0.001).”

“The statistically significant result was also seen by the exact Wilcoxon rank sum test (2-sided p=0.001).”

ResultsFind in source

“Solid black dots represent the individual log10 AUCD1-D29 (viral load) values.”

Figure 2Find in source

PASSReviewer 2· 75% conf

Evidence

“A Tobit analysis of variance showed a statistically significant reduction on the log 10 AUC D1-D29 VL in the high-dose mosnodenvir arm versus the placebo arm (2-sided p<0.001)”

ResultsFind in source

“Solid black dots represent the individual log10 AUCD1-D29 (viral load) values.”

Figure 2Find in source

WARNReviewer 3· 75% conf

Tests are named, software identified, and data presented with individual points, but the primary p-value is printed only as a threshold and the primary effect size lacks a confidence interval.

Evidence

“A Tobit analysis of variance showed a statistically significant reduction on the log 10 AUC D1-D29 VL in the high-dose mosnodenvir arm versus the placebo arm (2-sided p<0.001)”

ResultsFind in source

“The statistically significant result was also seen by the exact Wilcoxon rank sum test (2-sided p=0.001).”

ResultsFind in source

“Solid black dots represent the individual log10 AUCD1-D29 (viral load) values.”

Figure 2Find in source

Sub-criteria

code sharingNOT REPORTED

accession numbersNOT REPORTED

repository depositNOT REPORTED

data availability statementNOT REPORTED

Per reviewer (3) — the votes behind the verdict

FAILReviewer 1· 90% conf

No data availability statement, repository deposit, accession numbers, or code-sharing mechanism is reported in the manuscript.

Evidence

paraphrase[Methods, Study oversight]

“The study protocol (available with the full text of this article at NEJM.org) was reviewed and approved by Independent Ethics Committees at each site”

absence[Entire manuscript]

No data-sharing statement is present.

FAILReviewer 2· 80% conf

No data availability statement is present; the paper only notes that the protocol is available at NEJM.org, which does not constitute a data-access route.

Evidence

paraphrase[Methods, Study oversight]

“The study protocol (available with the full text of this article at NEJM.org) was reviewed and approved by Independent Ethics Committees at each site”

absence[Full text (search for data availability)]

No statement of where or how study data can be accessed.

FAILReviewer 3· 85% conf

No data-availability statement is provided; the protocol is available at NEJM.org but no patient-level or study data access route is described.

Evidence

paraphrase[Methods, Study oversight]

“The study protocol (available with the full text of this article at NEJM.org)”

paraphrase[Methods, Study oversight]

“Data were gathered by the study site investigators and analyzed at Johnson & Johnson in collaboration with the NIH; no statement of data availability or access mechanism is provided.”

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineNOT REPORTED

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 85% conf

Evidence

“ClinicalTrials.gov (https://ClinicalTrials.gov) number, NCT05048875 (https://clinicaltrials.gov/ct2/show/NCT05048875)”

MethodsFind in source

“Findings from those studies must be confirmed in larger safety and efficacy studies in the target population since CHIM studies do not reflect field conditions.”

Discussion ¶5Find in source

FundingFind in source

PASSReviewer 2· 85% conf

Evidence

“ClinicalTrials.gov (https://ClinicalTrials.gov) number, NCT05048875 (https://clinicaltrials.gov/ct2/show/NCT05048875)”

MethodsFind in source

FundingFind in source

PASSReviewer 3· 85% conf

Trial registration, methods, funding/COI, limitations, and proportional conclusions are all reported; only a CONSORT-style reporting-guideline reference is missing.

Evidence

“ClinicalTrials.gov (https://ClinicalTrials.gov) number, NCT05048875”

MethodsFind in source

“Findings from those studies must be confirmed in larger safety and efficacy studies in the target population since CHIM studies do not reflect field conditions.”

DiscussionFind in source

FundingFind in source

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

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 38 references by DOI: 2 verified — 36 no DOI (shown, not verified).

4 data/code links checked; 3 live.

Copyediting

1 finding · worst low

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

Wording or formatting errors that need correctingAssessed

9 copyedit issues flagged (1 major): mostly consistency, other, typo.

Full text (33,563 chars)Analyzed: Aug 10, 2026