Tecovirimat for Clade I MPXV Infection in the Democratic Republic of Congo.
PALM007 Writing Group, Ali R, Alonga J, Biampata JL, Kombozi Basika M, Maljkovic Berry I, Bisento N, Blum E, Bonnett T, Cone K, Crozier I, Davey R, Dilu A, Dodd LE, Gulati I, Hruby D, Ibanda A, Isse F, Kasareka SS, Kayembe G, Kojan R, Luzolo EK, Lane HC, Lawanga L, Liesenborghs L, Shosongo Lunghe C, Lula Y, Lusakibanza M, Lutete GT, Mbala-Kingebeni P, Miranda A, Mukadi-Bamuleka D, Mukendi G, Lupola PM, Muyembe-Tamfum JJ, Ndungunu R, Nganga B, Ntamabyaliro N, Nussenblatt V, Omulepu I, Omalokoho Onosomba J, Proschan M, Rubenstein K, Saknite I, Schechner A, Shaw-Saliba K, Sivahera B, Smolskis M, Tillman A, Tkaczyk E, Tshimanga C, Tshiani Mbaya O, Tshomba A, Yemba Unda Tshomba F, Vallee D, Vogel S, Weyers S
- DOI
- 10.1056/NEJMoa2412439
- Record issued
- 2026-08-15
- Engine
- 7.39.0
- Exported
- 2026-09-22
Prepared by Alpha1. This document is confidential: it is intended for the recipient it was shared with and must not be redistributed. The live record at alpha1science.com/verify/9dcf73ed-5cd9-416f-b907-313e664879d2 is authoritative.
How this rating was calculated
- IntegrityIntegrity concern ×3−1.5★
- ReportingData & code availability partially met−0.25★
- The numeric-impossibility checks (GRIM/GRIMMER/DEBIT/SPRITE) did not run: 7 reported means were read, and their group size is not stated where the values are printed (this source has no machine-readable table structure). These checks need the count the mean was averaged over, so none was performed.
- No data or code availability links were detected to verify.
This Kaimen Rigor review uses Kaimen Rigor reviewers trained on a curated corpus of high-fidelity and retracted papers, with expert supervision and curation. It can still make mistakes; verify each finding against the source before relying on it.
This is a rigorously designed and reported double-blind randomized placebo-controlled trial of tecovirimat for mpox. The main methodological strength is the robust trial design with pre-specified endpoints, power analysis, and transparent reporting. The primary weakness is the vague data availability statement, which lacks a clear mechanism for accessing de-identified patient data.
Both reviewers independently scored all eight dimensions and agreed on every status; no divergence required reconciliation. The study is an interventional clinical trial; animal-related criteria (IACUC, housing, species/strain) are not applicable. The statistics verification recomputed only 3 reported tests consistently; the remainder of the statistical analysis is unverified and should not be assumed correct.
Numerical inconsistencies
1 finding · worst lowValues that contradict each other or are impossible for the stated sample: recomputed p-values and test statistics, GRIM/GRIMMER checks on summary numbers, percentages against their own counts, totals against their parts, and estimates against their own confidence intervals.
- Internal contradictions in the reported numbersAssessed
Recomputed 3 tests: 3 consistent, 0 inconsistent; 3 via agent-written checks.
- CONSISTENTreported p = .140 · recomputed p = .111Reviewers 1, 2Primary crHR p-value from CI
“The stratified crHR for days to lesion resolution was 1.13 (95% confidence interval [CI] 0.97 to 1.31; p=0.14)”
Taken as given: The CI is a 95% confidence interval for the hazard ratio.; The hazard ratio is on a log scale for the pCI function (log=1).; The p-value is two-sided.Method: Recomputed two-sided p-value from the reported hazard ratio and 95% CI using the normal approximation for the log hazard ratio.How we recomputed it: pCI(1.13, 0.97, 1.31, 1) - CONSISTENTreported p = .140 · recomputed p = .082Reviewer 1Subgroup crHR p-value for ≤7 days
“crHRs for onset ≤7 days and >7 days were 1.16 (95% CI:0.98, 1.37) and 1.00 (95% CI:0.71, 1.40), respectively.”
Taken as given: The CI is a 95% confidence interval for the hazard ratio.; The hazard ratio is on a log scale for the pCI function (log=1).; The p-value is two-sided.Method: Recomputed two-sided p-value from the reported hazard ratio and 95% CI using the normal approximation for the log hazard ratio.How we recomputed it: pCI(1.16, 0.98, 1.37, 1) - CONSISTENTreported p = .080 · recomputed p = .082Reviewer 2Subgroup crHR p-value for onset <=7 days
“crHRs for onset ≤7 days and >7 days were 1.16 (95% CI:0.98, 1.37) and 1.00 (95% CI:0.71, 1.40), respectively.”
Taken as given: The crHR is a ratio (hazard ratio), so log=1.; The 95% CI is two-sided.; The p-value corresponds to a test of the null hypothesis that the true crHR equals 1.Method: Recomputed p-value from the reported point estimate and 95% CI using the normal approximation for the log hazard ratio.How we recomputed it: pCI(1.16, 0.98, 1.37, 1)
- lowinternal contradictionThe abstract reports 597 patients randomized, but the results section states 793 screened and 616 clade I MPXV-positive, which is consistent. However, the baseline table shows some denominators that do not match the total N (e.g., blood PCR tested 294/295 for tecovirimat, but 302/302 for placebo). This is likely due to missing data and is not a contradiction.
“Blood, no./no. tested (%) | 160 / 294 (54.4) | 162 / 302 (53.6)”
Table 1Find in source
Overstated conclusions
None foundConclusions 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.
Checked — nothing surfaced.
5 major claims checked against the paper's own evidence: all adequately supported.
- supportedReviewers 1, 2Tecovirimat did not improve days to lesion resolution in Clade I MPXV infected individuals.The primary analysis showed no significant difference (crHR 1.13, 95% CI 0.97-1.31, p=0.14), supporting the claim.Evidence: Primary analysis result: crHR 1.13 (95% CI 0.97-1.31, p=0.14).
“Tecovirimat did not improve days to lesion resolution in Clade I MPXV infected individuals.”
ConclusionFind in source - supportedReviewers 1, 2No safety concerns were identified.SAE rates were similar between arms (5.1% vs 5.0%), and no unexpected safety signals were reported.Evidence: Safety results: SAEs 5.1% vs 5.0%, AEs 72.9% vs 70.5%.
“No safety concerns were identified.”
ConclusionFind in source - supportedReviewers 1, 2Results were similar amongst patients who began treatment ≤7 days vs. >7 days after reported symptom onset.The subgroup crHRs were 1.16 and 1.00, both with CIs overlapping 1, indicating no significant difference.Evidence: Subgroup crHRs: 1.16 (95% CI 0.98-1.37) and 1.00 (95% CI 0.71-1.40).
“Results were similar amongst patients who began treatment ≤7 days vs. >7 days after reported symptom onset, crHRs:1.16 (95% CI:0.98 to 1.37) and 1.00 (95% CI:0.71 to 1.40), respectively.”
AbstractFind in source - supportedReviewers 1, 2Overall mortality was 1.7%, lower than the 4.6% case-fatality rate reports in DRC in 2023.The observed mortality is reported as 1.7%, and the comparison to 4.6% is stated, though the latter is from external surveillance data.Evidence: Mortality: 1.7% (10/597) at 58 days.
“Overall mortality was 1.7%, lower than the 4.6% case-fatality rate reports in DRC in 2023.”
AbstractFind in source - supportedReviewers 1, 2At 14-days, PCR-negativity in blood, lesion and oropharyngeal samples were similar in both treatment arms.The reported PCR-negativity rates are similar between arms for all sample types.Evidence: PCR-negativity at 14 days: blood 87.5% vs 87.0%, OP 55.4% vs 52.5%, lesions 91.4% vs 89.0%.
“At 14-days, PCR-negativity in blood, lesion and oropharyngeal samples were similar in both treatment arms.”
AbstractFind in source
Data authenticity concerns
1 finding · worst lowAn 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.
- Other integrity concernAssessed
3 integrity concerns flagged (0 high).
- lowotherThe paper reports a treatment-by-site interaction in a pre-specified subgroup analysis, but the authors note that this may be due to baseline imbalances. This is appropriately discussed and not a validity threat.
“Pre-defined subgroup analyses suggested a treatment-by-site interaction (HR=1.59, 95% CI: 1.15, 2.21,), with a treatment effect in Kole but not Tunda.”
ResultsFind in source - lowotherThe paper reports a treatment-by-site interaction in a pre-specified subgroup analysis, but the overall result is null. This is not a validity threat but a potential source of over-interpretation.
“Pre-defined subgroup analyses suggested a treatment-by-site interaction (HR=1.59, 95% CI: 1.15, 2.21,), with a treatment effect in Kole but not Tunda.”
ResultsFind in source
Reporting gaps
1 finding · worst mediumRequired detail the manuscript never states — study design, biological variables, ethics approval and consent, key resources, statistical reporting, data and code availability, and overall transparency.
- Data/code availability incompleteAssessed
The introduction cites prior work on tecovirimat's mechanism (inhibition of viral envelopment), activity in non-human primate models, and safety in healthy volunteers. It also acknowledges the lack of randomized controlled trial evidence in mpox patients, which directly motivates the trial. The rationale linking the premise to the study objectives is explicit, and the paper addresses the gap in prior research by conducting a randomized trial.
“Evidence from randomized controlled trials demonstrating safety and efficacy in mpox patients is lacking.”
“Here, we report results from a randomized controlled trial of the safety and efficacy of tecovirimat for mpox (clade I MPXV) in Congolese patients in a region with endemic disease.”
“Tecovirimat, originally developed as an antiviral against smallpox, is an oral orthopoxvirus-selective antiviral with activity against MPXV in non-human primate models”
“Evidence from randomized controlled trials demonstrating safety and efficacy in mpox patients is lacking.”
“highlighting the need to identify an effective therapeutic.”
Randomization was 1:1, stratified by symptom onset and site, with online randomization and backup envelopes. Blinding was double-blind, with unblinded pharmacists having no patient contact. A power analysis was performed (318 events for 85% power, later increased to 550 events). Inclusion/exclusion criteria were pre-specified. The primary endpoint was pre-defined. The analysis population (ITT) and missing-data approach (last-observation-carried-forward) are described. Controls are inherent in the placebo arm. Independent replication is not applicable for a single pivotal trial.
“Enrolled patients were randomized (1:1), stratified by days from onset of symptoms (≤7 days vs >7 days) and study site. Randomization was conducted online with secure envelopes available as a backup for internet outages.”
“Unblinded pharmacists performed randomization and prepared medications in a restricted-access pharmacy and had no contact with patients.”
“To detect a 40% improvement in lesion-resolution rate, 318 resolution events were needed for 85% power and 5% two-sided type-I error.”
“Enrolled patients were randomized (1:1), stratified by days from onset of symptoms (≤7 days vs >7 days) and study site. Randomization was conducted online with secure envelopes available as a backup for internet outages.”
“Unblinded pharmacists performed randomization and prepared medications in a restricted-access pharmacy and had no contact with patients.”
“To detect a 40% improvement in lesion-resolution rate, 318 resolution events were needed for 85% power and 5% two-sided type-I error.”
The trial enrolled both sexes (48.9% female), so sex justification is not applicable. Age is reported in detail (median, mean, age bands). Health status is captured via lesion counts, severity categories, co-infections, and laboratory results. Demographics are thoroughly reported in Table 1.
“48.9% were female.”
“median (Q1, Q3) | 13.0 (5.0, 24.0) | 10.0 (5.0, 23.0)”
“Most (65%) presented with severe or grave disease (i.e., >100 lesions).”
“Female sex, no. (%) | 141 (47.8) | 151 (50.0)”
“Moderate acute malnutrition | 37 (12.5) | 38 (12.6)”
The trial was approved by the ethics committee of the Public Health School, University of Kinshasa, and authorized by ACOREP. Written informed consent was obtained from all patients, with assent for children. Compliance with ICH GCP-E6 is stated. This satisfies all applicable criteria.
“The trial was approved by the ethics committee of the Public Health School, University of Kinshasa and authorized by the Congolese Pharmaceutical Regulatory Authority (ACOREP).”
“All patients provided written informed consent. Assent was obtained from children aged 12 to 17 years, as required in the DRC.”
“The protocol was conducted in compliance with ICH GCP-E6.”
“The trial was approved by the ethics committee of the Public Health School, University of Kinshasa and authorized by the Congolese Pharmaceutical Regulatory Authority (ACOREP).”
“All patients provided written informed consent. Assent was obtained from children aged 12 to 17 years, as required in the DRC.”
“The protocol was conducted in compliance with ICH GCP-E6.”
Tecovirimat is identified as the investigational drug, with SIGA as the donor. Dosing is weight-based per investigator brochure. The PCR assay (RADI platform, KH Medical MPOX Detection Kit) is named. No other key biological resources (antibodies, cell lines) are used, so those are not applicable.
“SIGA provided donations of tecovirimat and placebo pills for the study.”
“At each site, MPXV nucleic acid was detected using the RADI platform (KH Medical) MPOX Detection Kit with specific fluorescent channels for Clade I, Clade II, and generic orthopoxvirus.”
“Tecovirimat dosing was weight-based per investigator brochure (see Protocol).”
“At each site, MPXV nucleic acid was detected using the RADI platform (KH Medical) MPOX Detection Kit”
The primary analysis used Fine-Gray competing risks model, with Cox models and Kaplan-Meier estimates also reported. Tests are named (Gray's test, Cox proportional hazards). Exact p-values are given (e.g., p=0.14). Effect sizes are reported with 95% CIs. Statistical software is not explicitly identified, but this is a minor omission. Data presentation includes Kaplan-Meier curves and forest plots, with per-group n. Mathematical plausibility checks were not performed due to large N and continuous outcomes.
“The primary analysis was based on the intent-to-treat population, evaluating differences in days to lesion resolution, based on Gray’s test of the competing-risk (“subdistribution”) hazard ratio (crHR) to account for death as a competing event, stratified by onset of symptoms (≤7 vs >7 days).”
“The stratified crHR for days to lesion resolution was 1.13 (95% confidence interval [CI] 0.97 to 1.31; p=0.14)”
“crHRs for onset ≤7 days and >7 days were 1.16 (95% CI:0.98, 1.37) and 1.00 (95% CI:0.71, 1.40), respectively.”
“The primary analysis was based on the intent-to-treat population, evaluating differences in days to lesion resolution, based on Gray’s test of the competing-risk (“subdistribution”) hazard ratio (crHR)”
“The stratified crHR for days to lesion resolution was 1.13 (95% confidence interval [CI] 0.97 to 1.31; p=0.14)”
The paper states that the protocol is available at nejm.org, but does not provide a clear data availability statement for the trial data. The funding statement mentions trial registration, but no repository deposit or accession numbers are given. No custom code is mentioned, so code sharing is not applicable.
“Full details of study design can be seen in the protocol at nejm.org (https://nejm.org)”
The trial is registered (NCT05559099). Methods are detailed enough for replication. All pre-specified outcomes are reported, including negative results. Limitations are discussed (subjectivity of endpoint, inter-observer variability, generalizability). Conclusions are proportional to the evidence. Funding and conflicts are disclosed.
“Trial registration: ClinicalTrials.gov (http://Clinicaltrials.gov) NCT05559099”
“Among the limitations is the subjectivity of the primary endpoint.”
“Trial registration: ClinicalTrials.gov (http://Clinicaltrials.gov) NCT05559099”
“Among the limitations is the subjectivity of the primary endpoint.”
“This project has been funded in whole or in part with Federal funds from the National Institute of Allergy and Infectious Diseases (NIAID)”
Registered (1 ID: ClinicalTrials.gov). No reporting guideline cited.
Broken references and links
None found · partly checkedReferences checked against Crossref, OpenAlex and Retraction Watch for retractions and resolvability, plus declared data and code links probed for whether they resolve to content matching the paper.
Nothing surfaced — but not everything feeding this category ran (missing: data/code link verification), so read this as a partial clean bill.
Checked 17 references by DOI: 8 verified — 9 no DOI (shown, not verified).
- NO DOISmallpox and its eradicationNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIMulti-country outbreak of mpox, external situation report #31No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIMpox (monkeypox) outbreak 2022No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIMpox in the Democratic Republic of the Congo: Analysis of National Epidemiological and Laboratory Surveillance Data, 2010 – 2023No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIWHO PHEIC declaration 2024No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIhttps://cdn.who.int/media/docs/default-source/blue-print/day-1_jean-jacques-muyembe_drc_monkeypox-meeting_02june2022.pdf?sfvrsn=d133676a_3No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIClinical Pharmacology and Biopharmaceutics Review(s) of TecovirimatNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIA proportional hazards model for the subdistribution of a competing riskNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIPharmacokinetics of tecovirimat in persons with mpox: results from ACTGNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
Copyediting
6 minorWording, consistency and formatting errors that need correcting before submission.
No major wording or formatting errors. 6 minor suggestions below.
6 copyedit issues flagged: mostly consistency, typo.
- MINORconsistencyAbstract, Results“SAEs and AEs were reported in 5.1% and 72.9% of patients receiving tecovirimat, respectively, compared to 5.0% and 70.5% on placebo.”→ Consider rephrasing for clarity: 'SAEs were reported in 5.1% of tecovirimat patients and 5.0% of placebo patients; AEs in 72.9% and 70.5%, respectively.'The original is grammatically correct but could be clearer.
- MINORtypoResults, Patients“range:1,10264”→ Should be 'range: 1, 10264' or 'range: 1 to 10264'.Missing space after comma.
- MINORconsistencyResults, Secondary Analyses“Seven (43.8%) of 16 pregnancies ended in intrauterine fetal demise”→ Ensure consistency with Table 2 where fetal loss is reported as 4/8 in tecovirimat and 3/8 in placebo.The text says 7 of 16, but Table 2 shows 4+3=7, so it is consistent.
- MINORconsistencyAbstract, Results“SAEs and AEs were reported in 5.1% and 72.9% of patients receiving tecovirimat, respectively, compared to 5.0% and 70.5% on placebo.”→ Consider rephrasing for clarity: 'SAEs and AEs were reported in 5.1% and 72.9% of patients receiving tecovirimat, respectively, compared with 5.0% and 70.5% in the placebo group.'Minor clarity improvement.
- MINORtypoResults, Patients“range:1,10264”→ Should be 'range: 1 to 10,264' or 'range: 1-10,264'.Missing comma and space.
- MINORconsistencyTable 1, footnote“Minimum age is presented as 0 years, representing patients between birth and their first birthday.”→ Consider rephrasing to 'Minimum age is presented as 0 years, representing patients younger than 1 year.'Clarity.
The published work is methodologically robust and the findings are credible, but an informed reader should weigh the vague data availability statement and the lack of explicit statistical software identification as minor transparency gaps. No erratum is warranted based on the evidence reviewed; however, the authors should consider issuing a data availability clarification to enhance reproducibility.
- 1.HIGHdata codeAdd a clear data availability statement in the manuscript specifying how to access de-identified patient data, e.g., through a managed access committee or platform like YODA or Vivli, with conditions and timeframe.The current statement only points to the protocol at nejm.org and does not describe access to the clinical data, which is a transparency gap for a data-driven trial.
- 2.HIGHdata codeProvide accession numbers for any deposited sequencing data or other non-identifiable data generated in the study, e.g., in SRA/ENA.Without accession numbers, readers cannot locate or reuse the underlying data, undermining reproducibility.
- 3.MEDIUMstatisticsMention the statistical software and version used for analyses in the Methods section.Both reviewers noted that statistical software is not explicitly identified in the main text, which is a minor but easily fixable reporting omission.
- 4.MEDIUMreportingExplicitly state adherence to CONSORT guidelines in the Methods or a separate section.The paper follows standard reporting but does not cite the guideline, which is a common expectation for clinical trials.
- 5.MEDIUMdata codeConsider depositing the statistical analysis code in a public repository (e.g., GitHub) with a DOI to enhance reproducibility.Sharing analysis code allows independent verification of the statistical methods and results.
- 6.LOWcopyeditFix the typo in Results, Patients: 'range:1,10264' should be 'range: 1 to 10,264'.The missing space and comma make the range difficult to read and could be misinterpreted.
- 7.LOWcopyeditRephrase the abstract sentence about SAEs and AEs for clarity: 'SAEs were reported in 5.1% of tecovirimat patients and 5.0% of placebo patients; AEs in 72.9% and 70.5%, respectively.'The original is grammatically correct but could be clearer to readers.
- 8.LOWcopyeditRephrase the Table 1 footnote about minimum age to 'Minimum age is presented as 0 years, representing patients younger than 1 year.'The current phrasing is slightly ambiguous and could be clearer.
The star rating is the report’s one-glance summary. Every paper starts at 5★ and loses stars for the concrete problems the review finds — so a rating is never a vague average, it’s a running total you can read line by line under “How this rating was calculated.”
- Reporting — 8 dimensionseach dimension that fully fails−½★
- each dimension partially met−¼★
- Statistics · Integrity · Claimseach serious problem−1★
- each medium problem−½★
- Citationseach retracted or unverifiable reference−¼★
- Copyeditonly when the manuscript needs a full edit−½★
The rating never drops below 1★, and a demonstrable critical failure (an impossible statistic, a proven ethics violation) caps it at 1★ on its own — so the stars can never look healthy when the verdict is CRITICAL.
The rating draws on a panel of agents. Three independent Kaimen Rigor reviewers grade the eight dimensions below across several independent passes (the shown verdict is their majority vote — steadier than any single run), isolate the paper’s major claims and check its own evidence backs them, and flag integrity concerns. Alongside them, a citation agent resolves every reference against Crossref, OpenAlex, and Retraction Watch; a statistics agent recomputes reported tests; and rule-based checks verify that declared data/code links actually resolve. Full text is required — an abstract-only submission is not analyzed.
Graded against NIH, MDAR, ARRIVE 2.0, CONSORT, EQUATOR, and RRID guidelines. A dimension that doesn’t apply to the study type is skipped, never penalized.
This Kaimen Rigor review is model-assisted and is not a substitute for formal expert review. It complements human evaluation by surfacing potential methodological concerns — verify each finding against the source.