Rigor Reviewed

Rigor-Reviewed Manuscript

Oral Nirmatrelvir-Ritonavir for Covid-19 in Higher-Risk Outpatients.

Name: Adcurare Rigor Record — Oral Nirmatrelvir-Ritonavir for Covid-19 in Higher-Risk Outpatients.
Item: Oral Nirmatrelvir-Ritonavir for Covid-19 in Higher-Risk Outpatients.
Rating: 79
Author: Adcurare

Butler CC, Pinto AD, Harris V, Holmes J, Rahman NM, Cureton L, Hayward G, Richards DB, Lowe DM, Standing JF, Breuer J, Hood K, Png ME, Petrou S, Dorward J, Patel MG, Thomas NPB, Evans P, Hart ND, Jani BD, Hosseini B, Murthy S, McBrien K, Condon A, McDonald EG, Daley P, Greiver M, da Costa BR, Selby P, Jüni P, Lee TC, Shi H, Detry MA, Saunders CT, Fitzgerald M, Berry NS, Saville BR, Khoo SH, Nguyen-Van-Tam JS, Hobbs FDR, Yu LM, Little P, PANORAMIC Trial and CanTreatCOVID Trial Collaborative Groups

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Adcurare Rigor Review — 4★ (Strong), 0 critical, 7 high issues for “Oral Nirmatrelvir-Ritonavir for Covid-19 in Higher-Risk Outpatients.”

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Adcurare Editorial

This rigor review was examined and confirmed by Adcurare Editorial · July 6, 2026

Adcurare Rigor Review

Rigor Reviewed

4 / 5

Strong — minor issues to address

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

IntegrityIntegrity concern−0.5★
ReportingData & code availability not met−0.5★

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

Not verified in this report

No reported statistical tests were found to recompute.

Problems surfaced2 types

Data and code not shared
Internal contradictions in the reported numbers

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

This manuscript reports two well-conducted pragmatic RCTs with strong scientific premise, clear registration, and proportional conclusions. However, the absence of a data availability statement, missing outlier handling specification, no explicit reporting guideline reference, and an unexplained gap in the CanTreatCOVID participant flow are notable deficits that should be addressed before submission.

Three independent rigor evaluations were synthesized. The study is an interventional clinical trial. Dimensions with no applicable sub-criteria (e.g., cell lines, housing conditions) were marked 'not applicable'. The statistics verification component checked no tests due to limited reporting of test statistics with degrees of freedom; this does not indicate errors. The citation check found no retracted or non-existent references. The integrity check noted an imbalance in missing data for sex in CanTreatCOVID that may warrant discussion.

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

1 integrity concern flagged (0 high).

Reporting

Eight Dimensions7 pass · 1 fail

Prior work (EPIC-HR, EPIC-SR) is cited with explicit discussion of their strengths and limitations. The rationale for evaluating nirmatrelvir-ritonavir in vaccinated populations is clearly stated. Limitations of prior observational studies (residual confounding, immortal time bias) are acknowledged.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

The paper clearly establishes the scientific foundation by citing key prior trials, acknowledging their limitations, and providing a logical rationale for the study.

Evidence

direct quote[Introduction, paragraphs 2-3]

“that reduced COVID-19 related hospitalization and death over 28 days in high-risk unvaccinated patients in the Evaluation of Protease Inhibition for COVID-19 in High-Risk (EPIC-HR) trial”

direct quote[Introduction, paragraph 3]

“Observational studies following licensure have been and are being conducted, but all have issues with residual confounding, confounding by indication, and immortal time bias.”

direct quote[Introduction, paragraph 4]

“Since the EPIC-HR and EPIC-SR studies many more people have been multiply vaccinated and infected naturally so it is unclear whether nirmatrelvir-ritonavir still benefits those at higher risk.”

PASSReviewer 2· 95% conf

The paper clearly establishes its scientific foundation by citing the EPIC-HR and EPIC-SR trials, acknowledging their limitations, and providing a logical rationale for studying nirmatrelvir-ritonavir in vaccinated populations.

Evidence

direct quote[Introduction]

“Nirmatrelvir-ritonavir – that reduced COVID-19 related hospitalization and death over 28 days in high-risk unvaccinated patients in the Evaluation of Protease Inhibition for COVID-19 in High-Risk (EPIC-HR) trial”

direct quote[Introduction]

“Observational studies following licensure have been and are being conducted, but all have issues with residual confounding, confounding by indication, and immortal time bias.”

direct quote[Introduction]

“Since the EPIC-HR and EPIC-SR studies many more people have been multiply vaccinated and infected naturally so it is unclear whether nirmatrelvir-ritonavir still benefits those at higher risk.”

PASSReviewer 3· 95% conf

The scientific premise is well established. The paper cites prior key trials (EPIC-HR, EPIC-SR) and acknowledges their limitations and the gap in evidence for vaccinated populations, providing a clear rationale for the current study.

Evidence

direct quote[Introduction, paragraph 1-2]

“Observational studies following licensure have been and are being conducted, but all have issues with residual confounding, confounding by indication, and immortal time bias.”

direct quote[Introduction, paragraph 2]

“Since the EPIC-HR and EPIC-SR studies many more people have been multiply vaccinated and infected naturally so it is unclear whether nirmatrelvir-ritonavir still benefits those at higher risk.”

Randomization was performed using secure web-based systems with stratification. Open-label design is stated with a pragmatic rationale. A priori sample size calculations are reported and revised based on observed event rates. Inclusion and exclusion criteria are clearly defined. Missing data handling and sensitivity analyses are described.

Sub-criteria

controlsN/A

power analysisADEQUATE

blinding levelsADEQUATE

outlier handlingADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 98% conf

The study design components are well described, including randomization methods, open-label rationale, sample size calculations, eligibility criteria, and missing data handling.

Evidence

direct quote[Methods, Randomization and Masking]

“A secure, web-based system (Spinnaker; version custom built for the PANORAMIC trial; Spiral Software, Wellington, New Zealand) was used for randomization, stratified by age (<50 years vs ≥50 years) and vaccination status (yes vs no).”

direct quote[Discussion, paragraph 3]

“we conducted an open-label trial, suited to answering pragmatic questions of the effectiveness during routine clinical care because placebos are generally not used in routine care.”

direct quote[Methods, Statistical Analysis]

“With a control event rate of 1.3%, a relative risk of 0.23 (corresponding to an event rate of 0.3% in the intervention arm and which is smaller than the 88% relative risk reduction reported in the EPIC-HR trial), 1438 participants per group would be required to achieve 80% power at a two-sided 5% significance level.”

PASSReviewer 2· 90% conf

The trials are randomized with web-based allocation, stratification, clear eligibility criteria, pre-specified ITT analysis, and sample size calculations. The open-label design is stated with rationale.

Evidence

direct quote[Methods, Randomization and Masking]

direct quote[Methods, Statistical Analysis]

“However, the sample size in PANORAMIC was revised in conjunction with the trial steering committee in April 2023 due lower than anticipated event rate. With a control event rate of 1.3%, a relative risk of 0.23 ... 1438 participants per group would be required to achieve 80% power at a two-sided 5% significance level.”

direct quote[Methods, Statistical Analysis]

“The primary analysis population was defined as all eligible participants who were randomly assigned and analyzed according to allocation.”

WARNReviewer 3· 85% conf

The study design has notable strengths including concealed randomization and a large sample, but is limited by an open-label design (no placebo) with no blinding, and no pre-specified plan for handling outliers.

Evidence

direct quote[Methods, Randomization and Masking]

direct quote[Discussion, paragraph 4]

“we conducted an open-label trial, suited to answering pragmatic questions of the effectiveness during routine clinical care because placebos are generally not used in routine care.”

absence[Methods, Statistical Analysis]

Outlier handling not reported

Age, sex, ethnicity, socioeconomic status, and comorbidities are presented for both trials. Vaccination status is reported. Wellness score is provided for PANORAMIC. Weight is not reported but is not a key variable for this outpatient study.

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedADEQUATE

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

Key biological variables (age, sex, comorbidities, demographics) are reported in Table 1.

Evidence

direct quote[Table 1]

“Sex*, n(%) | Female | 1182 (68.1%) | 1223 (69.2%) | 237 (66.2%) | 231 (64.5%)”

direct quote[Table 1]

“Age, mean(SD) [min,max] | 54.7 (12.1) [18 to 96] | 54.8 (11.7) [18 to 93] | 54.7 (13.6) [19 to 88] | 55.0 (13.5) [18 to 89]”

direct quote[Table 1]

“Ethnicity category, n(%) | White | 1647 (94.9%) | 1661 (93.9%) | 290 (81%) | 272 (76%)”

PASSReviewer 2· 95% conf

Sex, age, health comorbidities, and demographics are comprehensively reported in Table 1 for both trials.

Evidence

direct quote[Results, Table 1]

“Sex*, n(%) Female | 1182 (68.1%) | 1223 (69.2%) | 237 (66.2%) | 231 (64.5%)”

direct quote[Results, Table 1]

“Age, mean(SD) [min,max] | 54.7 (12.1) [18 to 96] | 54.8 (11.7) [18 to 93] | 54.7 (13.6) [19 to 88] | 55.0 (13.5) [18 to 89]”

direct quote[Results, Table 1]

“Comorbidity, n(%) | 1127 (64.9%) | 1185 (67.0%) | 173 (48.3%) | 160 (44.7%)”

PASSReviewer 3· 70% conf

Sex and age (as a continuous variable) are well reported, but health status and comorbidities are reported, though the paper is limited regarding age-weight-health reporting for individual participants. As a human trial, species/strain/housing are not applicable.

Evidence

direct quote[Table 1]

“Age, mean(SD) [min,max] | 54.7 (12.1) [18 to 96] ... Sex*, n(%) | Female | 1182 (68.1%)”

direct quote[Table 1]

“Comorbidity, n(%) | 1127 (64.9%) ... Wellness score, mean(SD) ... | 4.7 (1.7)”

direct quote[Table 1]

“Ethnicity category, n(%) | White | 1647 (94.9%)”

The PANORAMIC trial was approved by the South Central-Berkshire Research Ethics Committee of the Health Research Authority. CanTreatCOVID was approved by Health Canada and ethics boards in participating provinces. Written informed consent was obtained from all participants.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 98% conf

Ethical approval from named committees and informed consent are clearly stated.

Evidence

direct quote[Methods, Objectives, Patients and Oversight]

“The UK Medicines and Healthcare products Regulatory Agency and the South Central-Berkshire Research Ethics Committee of the Health Research Authority approved the PANORAMIC trial protocol. The CanTreatCOVID trial was approved by Health Canada and research ethics boards in the participating provinces across Canada.”

direct quote[Methods, Objectives, Patients and Oversight]

“Written informed consent was obtained from all participants or a legal representative.”

WARNReviewer 2· 85% conf

Ethics approval from named bodies and informed consent are reported, but a statement of compliance with a recognized ethical framework (e.g., Declaration of Helsinki) is not explicitly provided.

Evidence

direct quote[Methods, Objectives, Patients and Oversight]

“The UK Medicines and Healthcare products Regulatory Agency and the South Central-Berkshire Research Ethics Committee of the Health Research Authority approved the PANORAMIC trial protocol.”

direct quote[Methods, Objectives, Patients and Oversight]

“Written informed consent was obtained from all participants or a legal representative.”

absence[Methods, Objectives, Patients and Oversight]

No explicit statement of compliance with an ethical framework.

PASSReviewer 3· 95% conf

Ethical approvals are comprehensively reported with named bodies for both trials, informed consent is documented, and regulatory compliance is stated.

Evidence

direct quote[Methods, Objectives, Patients and Oversight]

“The UK Medicines and Healthcare products Regulatory Agency and the South Central-Berkshire Research Ethics Committee of the Health Research Authority approved the PANORAMIC trial protocol.”

direct quote[Methods, Objectives, Patients and Oversight]

“Written informed consent was obtained from all participants or a legal representative.”

direct quote[Methods, Objectives, Patients and Oversight]

“The CanTreatCOVID trial was approved by Health Canada and research ethics boards in the participating provinces across Canada.”

Nirmatrelvir-ritonavir is described with dose, regimen, and source (provided by UK Department of Health and Public Health Agency of Canada). Statistical software (STATA v18.0, R v4.2.1) is specified. No cell lines, antibodies, or mycoplasma testing are relevant for this clinical trial.

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· 92% conf

The investigational product is fully identified, and software tools are described with versions.

Evidence

direct quote[Methods, Procedures]

“nirmatrelvir at a dosage of 300 mg (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet) orally twice daily for 5 days.”

direct quote[Methods, Statistical Analysis]

“All analyses were performed in STATA (version 18.0) and R (version 4.2.1).”

PASSReviewer 2· 90% conf

The investigational product (nirmatrelvir-ritonavir) is described with dose, regimen, and source; statistical software is identified with versions.

Evidence

direct quote[Methods, Procedures]

“nirmatrelvir at a dosage of 300 mg (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet) orally twice daily for 5 days”

direct quote[Funding]

“with the first trial therapeutic, nirmatrelvir/ritonavir (Paxlovid), provided by the Public Health Agency of Canada.”

direct quote[Methods, Statistical Analysis]

“All analyses were performed in STATA (version 18.0) and R (version 4.2.1).”

PASSReviewer 3· 75% conf

The investigational drug nirmatrelvir-ritonavir is adequately identified with dosing regimen. Software tools are identified. Other biological resources are not applicable for this type of study.

Evidence

direct quote[Abstract]

“nirmatrelvir-ritonavir (300mg/100mg BID x 5 days)”

direct quote[Methods, Statistical Analysis]

“All analyses were performed in STATA (version 18.0) and R (version 4.2.1).”

direct quote[Methods, Randomization and Masking]

“A secure, web-based system (Spinnaker; version custom built for the PANORAMIC trial; Spiral Software, Wellington, New Zealand)”

Primary analysis used Bayesian logistic regression with weakly informative priors. Tests are named. Sensitivity analyses for missing data and crossovers are reported. Effect estimates are presented with 95% Bayesian credible intervals. No mathematical implausibilities were detected.

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedADEQUATE

mathematical plausibilityN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 93% conf

Statistical methods are appropriately described with Bayesian models, sensitivity analyses, and software identified.

Evidence

direct quote[Methods, Statistical Analysis]

“Effect of treatment (and corresponding 95% Bayesian credible intervals (BCIs)) on the primary outcome was estimated using a Bayesian logistic regression model with weakly informative Cauchy priors, adjusting for comorbidity, age, and vaccination status.”

direct quote[Methods, Statistical Analysis]

“multiple imputation was carried out to assess the impact of missing data in CanTreatCOVID. Tipping point analysis was carried out as a post-hoc sensitivity analysis.”

direct quote[Methods, Statistical Analysis]

“All analyses were performed in STATA (version 18.0) and R (version 4.2.1).”

PASSReviewer 2· 85% conf

Statistical tests are named (Bayesian logistic regression), software is identified, effect sizes with credible intervals are reported, and data presentation includes counts and percentages. No p-values are reported (Bayesian analysis).

Evidence

direct quote[Methods, Statistical Analysis]

direct quote[Results, Primary Outcome]

“PANORAMIC: adjusted-odds ratio [OR], 1.18; 95% Bayesian credible interval [BCI], 0.55 to 2.62; probability of superiority 0.334”

direct quote[Methods, Statistical Analysis]

“All analyses were performed in STATA (version 18.0) and R (version 4.2.1).”

WARNReviewer 3· 95% conf

Statistical tests are named, software is identified, and data presentation follows trial standards. However, exact p-values are mostly absent (only Bayesian credible intervals reported), and effect sizes with confidence intervals are partially reported (primary outcome). The mathematical plausibility is not independently verifiable due to complex modeling and relatively rare events, thus not flagged.

Evidence

direct quote[Methods, Statistical Analysis]

direct quote[Results, Primary Outcome]

“PANORAMIC: adjusted-odds ratio [OR], 1.18; 95% Bayesian credible interval [BCI], 0.55 to 2.62; probability of superiority 0.334”

direct quote[Results, Primary Outcome]

“CanTreatCOVID: adjusted-OR, 0.48; 95% BCI, 0.08 to 2.23; probability of superiority 0.830”

The paper lacks a data availability statement mentioning where raw data can be accessed. No repository deposit or code repository is described. While trial registration numbers are given, these do not constitute data availability. For a clinical trial, a data-sharing plan is expected.

Sub-criteria

code sharingNOT REPORTED

accession numbersN/A

repository depositNOT REPORTED

data availability statementNOT REPORTED

Per reviewer (3) — the votes behind the verdict

FAILReviewer 1· 85% conf

No data availability statement or code sharing is provided in the manuscript text.

Evidence

absence[Entire manuscript]

No data availability statement found in the manuscript.

absence[Entire manuscript]

No code repository mentioned.

FAILReviewer 2· 80% conf

No explicit data availability statement is present; no code sharing is mentioned.

Evidence

absence[Throughout paper]

No data availability statement found.

direct quote[Methods, Statistical Analysis]

“Full details and results are available at NEJM.Org (https://www.nejm.org/)”

WARNReviewer 3· 75% conf

The paper provides data availability statements and links to protocols, but no raw data or code are publicly deposited, and the statements are somewhat vague regarding detailed access procedures.

Evidence

direct quote[Methods, Statistical Analysis]

“Full details and results are available at NEJM.Org (https://www.nejm.org/) .”

absence[Entire paper]

No repository deposit mentioned

Both trials are registered with numbers. Primary and secondary outcomes are fully reported. Limitations (open-label, low event rate) are discussed. Conclusions are proportional. Funding sources and conflict of interest disclosures are provided. No CONSORT checklist is explicitly referenced, but reporting quality is high.

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineINADEQUATE

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 93% conf

The manuscript is well-structured and transparent, with trial registration, outcomes reporting, limitations discussion, and funding disclosure.

Evidence

direct quote[Abstract and end of Introduction]

“EudraCT Number 2021-005748-31 (PANORAMIC); ClinicalTrials.gov (https://clinicaltrials.gov/) number NCT05614349 (CanTreatCOVID).”

direct quote[Discussion, paragraph 4]

“open label design does not allow estimation of the contribution of either placebo or nocebo effects”

direct quote[Funding section]

“Funding NIHR135366”

PASSReviewer 2· 90% conf

Methods are detailed, trial registration numbers are provided, all primary and secondary outcomes are reported, limitations are discussed, conclusions are proportional, and funding/COI are stated.

Evidence

direct quote[Abstract, Conclusions]

“EudraCT Number 2021-005748-31 (PANORAMIC); ClinicalTrials.gov (https://clinicaltrials.gov/) number NCT05614349 (CanTreatCOVID)”

direct quote[Discussion]

“We found no evidence that early treatment with nirmatrelvir-ritonavir reduced the low incidence of hospitalization and/or death in either study”

direct quote[Funding]

“Funding PANORMIC was supported by a grant (NIHR135366) from the National Institute of Health and Care Research. ... Disclosure forms provided by the authors are available with the full text of this article at NEJM.org”

WARNReviewer 3· 85% conf

Methods are generally complete for replication, and conclusions are proportional. Limitations are well discussed. However, trial registration is only mentioned for one trial partially, and no reporting checklist (CONSORT) is mentioned. The primary outcome is reported.

Evidence

direct quote[Abstract, Conclusions]

“EudraCT Number 2021-005748-31 (PANORAMIC); ClinicalTrials.gov (https://clinicaltrials.gov/) number NCT05614349 (CanTreatCOVID).”

absence[Entire paper]

Reporting guideline not mentioned

direct quote[Funding and Disclosure forms]

“Disclosure forms provided by the authors are available with the full text of this article at NEJM.org (https://www.nejm.org/) .”

6 copyedit issues flagged: mostly grammar, clarity, consistency.

Checked 26 references: 21 verified — 5 not checked.

Reproducibility

2 data/code links checked; 1 live.

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

Adcurare Rigor Action ItemsFinal pass before journal submission

The paper requires moderate revision before submission: the most critical gap is the missing data availability statement (which can trigger outright return). The open-label design and low event rate are inherent limitations adequately discussed, but the missing outlier handling, missing CONSORT reference, and the unexplained participant flow gap are fixable reporting issues. The copyedit issues (duplicated phrases, missing preposition, inconsistent dash style) are minor. With these addressed, the paper is ready for submission to a high-impact clinical journal.

1.
HIGHdata code
Add a data availability statement specifying where de-identified individual participant data can be accessed (e.g., via a managed-access platform such as Vivli or YODA, or on reasonable request with conditions). Place in the Methods section after the Statistical Analysis subsection.
Most clinical journals require a data availability statement; its absence is a common reason for editorial return.
2.
HIGHdata code
Deposit the custom analysis code (e.g., for the Bayesian logistic regression models and sensitivity analyses) in a public repository (e.g., GitHub, Zenodo) with a persistent DOI, and mention the repository in the manuscript.
Code sharing enables reproducibility of the Bayesian models and is increasingly expected for clinical trial publications.
3.
HIGHreporting
Explain the gap in the CanTreatCOVID participant flow: 1997 screened minus 880 ineligible leaves 1117 eligible, but only 721 were randomized. Provide the reasons (e.g., declined, not approached) and add this to the Results section or the CONSORT diagram.
An unexplained gap between eligible and randomized participants raises questions about selection that reviewers will notice.
4.
HIGHethics
Add an explicit statement of compliance with the Declaration of Helsinki or ICH-Good Clinical Practice guidelines in the Ethics section (Methods, Objectives, Patients and Oversight).
Clinical trial manuscripts routinely include this statement; its absence is a reporting gap that some reviewers flag.
5.
HIGHreporting
Explicitly state adherence to the CONSORT reporting guideline and provide the CONSORT checklist as a supplementary file. Add a sentence in the Methods or at the end of the Introduction.
CONSORT is the standard reporting guideline for RCTs; not referencing it is a gap in transparency.
6.
HIGHrigor
Pre-specify the method for handling outliers (e.g., Winsorization, sensitivity analysis excluding extreme values) in the Statistical Analysis section.
Outlier handling is part of a complete statistical analysis plan; its absence is flagged by rigorous reviewers.
7.
HIGHreporting
Discuss the imbalance in missing data for sex between arms in CanTreatCOVID (0.6% vs 7.5%) in the Limitations section, and consider an additional sensitivity analysis to assess its impact.
Differential missing data can bias estimates; acknowledging and addressing it strengthens the paper's credibility.
8.
MEDIUMcopyedit
Fix the duplicated phrase in Statistical Analysis: revise 'ensure a would ensure a reduction' to 'ensure a reduction'.
This is a clear copy-paste error that distracts from the scientific content.
9.
MEDIUMcopyedit
Fix the missing preposition in Statistical Analysis: change 'due lower than' to 'due to lower than'.
Grammatical error that should be corrected before submission.
10.
MEDIUMcopyedit
Unify dash style for drug names: consistently use an en dash (nirmatrelvir–ritonavir) throughout the manuscript.
Inconsistent hyphen/en-dash use is a minor but distracting inconsistency.
11.
MEDIUMcopyedit
Rewrite the fragmented sentence in Statistical Analysis: 'PANORAMIC assumed an event rate lower than had been observed event rate ... 5300 per arm to ensure a would ensure a reduction to 2% ...' into a clear single sentence.
The current wording is difficult to parse and may confuse readers.
12.
LOWstatistics
If a pre-specified frequentist analysis was conducted, report the exact p-values alongside the Bayesian results. Otherwise, state clearly that only Bayesian analysis was used.
Clarifying the analytic approach prevents confusion and satisfies transparency expectations.
13.
LOWreporting
Consider providing the per-protocol analysis results for the primary outcome in a supplementary table, if not already available.
Per-protocol analyses complement the ITT analysis and are expected in RCT reports.

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Oral Nirmatrelvir-Ritonavir for Covid-19 in Higher-Risk Outpatients.

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DOI

10.1056/NEJMoa2502457

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Issued Jul 6, 2026Engine 7.6.0

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