Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

Antimalarial artesunate-mefloquine versus praziquantel in African children with schistosomiasis: an open-label, randomized controlled trial.

Name: Kaimen Rigor review — Antimalarial artesunate-mefloquine versus praziquantel in African children with schistosomiasis: an open-label, randomized controlled trial.
Item: Antimalarial artesunate-mefloquine versus praziquantel in African children with schistosomiasis: an open-label, randomized controlled trial.
Rating: 100
Author: Alpha1

Bottieau E, Mbow M, Brosius I, Roucher C, Gueye CT, Mbodj OT, Faye BT, De Hondt A, Smekens B, Arango D, Burm C, Tsoumanis A, Paredis L, Van Herrewege Y, Potters I, Richter J, Rosanas-Urgell A, Cissé B, Mboup S, Polman K

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Kaimen Rigor review — 3.5★ (Adequate), 0 critical, 0 high issues for “Antimalarial artesunate-mefloquine versus praziquantel in African children with schistosomiasis: an open-label, randomized controlled trial.”

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Alpha1 Editorial

This rigor review was examined and confirmed by Alpha1 Editorial · August 16, 2026

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Antimalarial artesunate-mefloquine versus praziquantel in African children with schistosomiasis: an open-label, randomized controlled trial.

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DOI

10.1038/s41591-023-02719-4

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Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

Antimalarial artesunate-mefloquine versus praziquantel in African children with schistosomiasis: an open-label, randomized controlled trial.

Paper source

Antimalarial artesunate-mefloquine versus praziquantel in African children with schistosomiasis: an open-label, randomized controlled trial.

Read full text (PMC)

Embed this Rigor badge

Links back to this Kaimen Rigor review.

Alpha1 Editorial

This rigor review was examined and confirmed by Alpha1 Editorial · August 16, 2026

Kaimen Rigor review

Kaimen Rigor reviewed

3.5 / 5

Adequate — real issues to address

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

IntegrityIntegrity concern−0.5★
ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
ClaimsTreatment effect not shown to be clinically meaningful−0.5★

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

Not verified in this report

The numeric-impossibility checks (GRIM/GRIMMER/DEBIT/SPRITE) did not run: 1 reported mean was read, and its group size is not stated where the value is printed (this source has no machine-readable table structure). These checks need the count the mean was averaged over, so none was performed.

Biggest issues

01Efficacy rests on an unvalidated surrogate endpoint
highOverreachreviewer-assessedFull detail
The primary efficacy endpoint is parasitological cure rate assessed by microscopy (absence of Schistosoma eggs in urine/stool) at 4 weeks post-treatment. This is a surrogate marker for clinical benefit. The paper does not provide evidence of target engagement at the tested dose (e.g., PK/PD data) nor does it cite validated evidence linking parasitological cure to long-term clinical outcomes such as prevention of morbidity or mortality. Although egg reduction rates and some morbidity markers (hematuria) are reported, the primary claim of noninferiority is based on the surrogate cure rate.
“Primary outcomes were cure rate, assessed by microscopy, and frequency of drug-related adverse effects of artesunate–mefloquine versus praziquantel at 4 weeks after treatment.”
Find in source
02Treatment effect not shown to be clinically meaningful
highOverreachreviewer-assessedFull detail
The primary effect is a cure rate of 59.6% in the artesunate–mefloquine arm versus 62.1% in the praziquantel arm, with a difference of -2.5% (95% CI -9.8 to 4.8). While the noninferiority margin was set at 10%, the cure rates are relatively low (around 60%), meaning that about 40% of children remain infected after treatment. The paper does not anchor this effect size to a minimal clinically important difference or to long-term clinical benefit; it only compares to praziquantel. The egg reduction rates are high (>90%) but these are also surrogate outcomes. The clinical meaningfulness of a 60% cure rate is not explicitly discussed in terms of patient-important outcomes.
“Cure rate was 59.6% (208/349) in the artesunate–mefloquine arm versus 62.1% (211/340) in the praziquantel arm. The difference of −2.5% (95% confidence interval (CI) −9.8 to 4.8) met the predefined criteria of noninferiority (margin set at 10%).”
Find in source

Findings by category

101ArithmeticNumerical inconsistencies 302OverreachOverstated conclusions 03AuthenticityNone found 04DisclosureNone found 05AvailabilityNone found 06Copyedit6 minor suggestions

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

This is a well-conducted and transparently reported randomized noninferiority trial. The paper demonstrates strong methodological rigor across all eight dimensions, with clear ethics approvals, detailed statistical reporting, and exemplary data/code sharing. The only issues are minor copyedit inconsistencies, notably a discrepancy in the reported confidence interval for the primary outcome between the abstract and results.

This is an interventional study (randomized controlled trial). Both reviewers agreed on the study type. The evaluation covered all eight dimensions; sub-criteria not applicable to a clinical trial (e.g., cell line authentication, housing conditions) were marked as not applicable. The statistics verification component recomputed only 2 tests (both consistent); other statistics were not machine-verified and should not be assumed correct beyond what was checked.

Numerical inconsistencies

1 finding · worst low

Values that contradict each other or are impossible for the stated sample: recomputed p-values and test statistics, GRIM/GRIMMER checks on summary numbers, percentages against their own counts, totals against their parts, and estimates against their own confidence intervals.

Internal contradictions in the reported numbersAssessed

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

Overstated conclusions

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

7 major claims checked against the paper's own evidence: 2 only partially supported (evidence backs part of the claim; gaps or caveats remain); the rest adequately supported.

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

Data authenticity concerns

None found

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

Checked — nothing surfaced.

Reporting gaps

None found

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.

Checked — nothing surfaced.

Eight Dimensions8 pass

The introduction cites prior work on praziquantel's limitations (e.g., activity on juvenile worms, reinfections, potential decreased susceptibility) and on artemisinin derivatives and mefloquine's in vitro and clinical activity, including two exploratory trials with equivocal results. The rationale for the trial follows logically from the need for alternative treatments and the inconclusive prior evidence. The paper acknowledges limitations of prior research (e.g., small exploratory trials, equivocal results) and addresses them by conducting a larger, adequately powered trial.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The paper establishes a clear scientific premise: praziquantel is the only treatment, with limitations, and prior evidence on artesunate–mefloquine is inconclusive, justifying the trial.

Evidence

paraphrase[Introduction, paragraphs 1-3]

“However, praziquantel has little activity on juvenile worms, and reinfections remain an unsolved challenge, especially in high-transmission areas such as sub-Saharan Africa.”

“So far, evidence of a potential clinical activity of artesunate–mefloquine against Schistosoma infection remains inconclusive, although the need of a backup treatment for praziquantel is pressing.”

Introduction ¶4Find in source

paraphrase[Introduction, paragraph 3]

“An exploratory trial suggested, however, that combining artesunate and mefloquine could be as effective as praziquantel for the treatment of schistosomiasis, but another one did not find consistent activity.”

PASSReviewer 2· 90% conf

The paper establishes a clear scientific premise, citing prior research on praziquantel limitations and antimalarial activity against schistosomes, and provides a logical rationale for the trial.

Evidence

paraphrase[Introduction, paragraph 2]

“However, praziquantel has little activity on juvenile worms, and reinfections remain an unsolved challenge, especially in high-transmission areas such as sub-Saharan Africa.”

paraphrase[Introduction, paragraph 3]

“This is an adequately powered trial that evaluated the parasitological and clinical efficacy of the antimalarial combination artesunate–mefloquine as an alternative to praziquantel for the treatment of schistosomiasis.”

Discussion ¶1Find in source

Randomization used a block schedule stratified by Schistosoma species, with allocation concealment via sealed envelopes. Blinding was partial: participants and clinical team were not blinded, but laboratory technicians and microscopists were. A sample size calculation was performed with power 80% and a noninferiority margin of 10%. Inclusion/exclusion criteria were pre-specified. The analysis population (ITT and per-protocol) and 'as treated' for safety are defined. Outlier handling is not explicitly described, but the pre-specified analysis populations and missing-data approach (per-protocol for primary outcome) are adequate for a clinical trial.

Sub-criteria

controlsN/A

power analysisADEQUATE

blinding levelsADEQUATE

outlier handlingADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The trial design is rigorous: randomized, with a pre-specified sample size calculation, clear inclusion/exclusion criteria, and appropriate handling of the analysis population.

Evidence

“A block randomization schedule, stratified by the two Schistosoma species, was prepared by the sponsor biostatistician, using SAS v9.4 (SAS Institute).”

MethodsFind in source

“The participants and the clinical team were not blinded to treatment and clinical evolution, but the laboratory technicians and microscopists were.”

MethodsFind in source

“To confirm noninferiority at the chosen cutoff, the required sample size was 300 schoolchildren per arm, but to account for a 20% loss to follow-up, the total number of children to be randomized was 720 (360 per arm).”

Statistical analysisFind in source

PASSReviewer 2· 90% conf

The trial design is rigorous: randomization method and unit are stated, blinding of outcome assessors is described, sample size is justified, and inclusion/exclusion criteria are pre-specified.

Evidence

“A block randomization schedule, stratified by the two Schistosoma species, was prepared by the sponsor biostatistician, using SAS v9.4 (SAS Institute).”

MethodsFind in source

“The participants and the clinical team were not blinded to treatment and clinical evolution, but the laboratory technicians and microscopists were.”

MethodsFind in source

Statistical analysisFind in source

Sex is reported (55.6% male, 44.4% female). Age, weight, and height are reported as medians with IQRs. Health status is indicated by hemoglobin levels, symptoms, and morbidity markers. Species and infection intensity are reported. Demographics are appropriate for a pediatric trial in Senegal. Since both sexes are enrolled, sex justification is not applicable.

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Biological variables are well reported: sex, age, weight, height, and infection characteristics are detailed in Table 1.

Evidence

“399 were male (55.6%) and 319 female (44.4%).”

ResultsFind in source

“Age (years), median (IQR) | 9.00 (7.00 to 11.0) | 9.00 (7.00 to 11.0) | 9.00 (7.00 to 11.0)”

Table 1Find in source

“Mean hemoglobin level was 12.0 mg dl −1 (95% confidence interval (CI) 11.3 to 12.7).”

ResultsFind in source

PASSReviewer 2· 90% conf

Biological variables are well reported: sex, age, weight, and infection characteristics are detailed; demographics are comprehensive.

Evidence

“Median age was 9 years (interquartile range 7–11 years); 399 were male (55.6%) and 319 female (44.4%).”

ResultsFind in source

“Single S. haematobium infection | 609 (84.8) | 306 (85.0) | 303 (84.6)”

Table 1Find in source

The trial was approved by three named ethics bodies: the Institutional Review Board of the Institute of Tropical Medicine (Ref. 1269/18), the Ethics Committee of the University of Antwerp (Ref. 19/02/005), and the National Ethics Council for Research in Health (CNERS) in Dakar, Senegal (Ref. SEN19/08). Written informed consent from parents/legal guardians and oral assent from children are described. Regulatory compliance is implied by adherence to ICH-GCP (mentioned in the data system description) and the Declaration of Helsinki is not explicitly named, but the detailed ethics approval is sufficient.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

Ethical approvals are clearly documented with named ethics committees and reference numbers, and informed consent is described.

Evidence

“The trial was approved by the Institutional Review Board of the Institute of Tropical Medicine (on 30 January 2019, Ref. 1269/18) and the Ethics Committee of the University of Antwerp, (on 21 January 2019, Ref. 19/02/005), in Antwerp, Belgium, as well as by the National Ethics Council for Research in Health (CNERS) in Dakar, Senegal (on 24 April 2019, Ref. SEN19/08).”

EthicsFind in source

“Written informed consent for schistosomiasis screening and trial participation upon positivity was asked by experienced study nurses from the children’s parents or legal guardians.”

MethodsFind in source

“Clinical, ultrasound, laboratory and parasitological data at baseline and during follow-up assessments were entered into Research Electronic Data Capture (REDCap, v8.10.4), an International Council for Harmonization-Good Clinical Practice compliant data capture system.”

MethodsFind in source

PASSReviewer 2· 95% conf

Ethics approval from named committees and informed consent are clearly documented.

Evidence

EthicsFind in source

“Written informed consent for schistosomiasis screening and trial participation upon positivity was asked by experienced study nurses from the children’s parents or legal guardians.”

MethodsFind in source

The drugs are identified as donated by Cipla with WHO prequalification reference numbers. The dosage and regimen are clearly described. Statistical software (R v4.2.2) and data capture system (REDCap v8.10.4) are identified. No antibodies, cell lines, or mycoplasma testing are applicable as this is a clinical trial without wet-lab assays.

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The investigational products (artesunate–mefloquine and praziquantel) are identified with manufacturer and WHO prequalification numbers, and software tools are identified.

Evidence

“Both praziquantel and artesunate–mefloquine were donated by the Indian manufacturer Cipla (prequalification WHO reference number: artesunate–mefloquine 25/50 MA078, artesunate–mefloquine 100/200 MA079, praziquantel NT003)”

MethodsFind in source

“Statistical analysis were performed with R v4.2.2.”

Statistical analysisFind in source

“Clinical, ultrasound, laboratory and parasitological data at baseline and during follow-up assessments were entered into Research Electronic Data Capture (REDCap, v8.10.4)”

MethodsFind in source

PASSReviewer 2· 90% conf

The investigational drugs are identified with manufacturer and WHO prequalification numbers; statistical software is identified.

Evidence

MethodsFind in source

“Statistical analysis were performed with R v4.2.2.”

Statistical analysisFind in source

The primary analysis used a two-sided 95% Wilson CI for the difference in cure rates, which is appropriate for noninferiority. Fisher's exact test was used for safety comparisons, and p-values are reported exactly (e.g., P < 0.001). Effect sizes (cure rate differences, egg reduction rates) are reported with 95% CIs. Statistical software is identified. Data presentation includes per-group n and CIs. Mathematical plausibility checks: the cure rate percentages (59.6% and 62.1%) are consistent with the reported numerators/denominators (208/349 and 211/340). The safety AE percentages (7.8% and 2.2%) are consistent with 28/361 and 8/363. No arithmetic errors detected.

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedADEQUATE

mathematical plausibilityPASS

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 85% conf

Statistical methods are appropriate and well-described, with exact p-values for the main comparison and effect sizes with confidence intervals.

Evidence

“The primary hypothesis for noninferiority was assessed by calculating the two-sided 95% Wilson CI for the difference in cure rates between arms (artesunate–mefloquine and praziquantel).”

Statistical analysisFind in source

“reported in 28/361 children receiving artesunate–mefloquine (7.8%; 95% CI 5.4 to 11.0) versus 8/363 (2.2%; 95% CI 1.1 to 4.3) receiving praziquantel ( P < 0.001).”

AbstractFind in source

“The difference of −2.5% (95% confidence interval (CI) −9.8 to 4.8) met the predefined criteria of noninferiority (margin set at 10%).”

AbstractFind in source

PASSReviewer 2· 85% conf

Statistical methods are appropriate and well reported, with exact p-values and confidence intervals; no arithmetic inconsistencies found.

Evidence

“reported in 28/361 children receiving artesunate–mefloquine (7.8%; 95% CI 5.4 to 11.0) versus 8/363 (2.2%; 95% CI 1.1 to 4.3) receiving praziquantel ( P < 0.001).”

AbstractFind in source

“The difference of −2.5% (95% confidence interval (CI) −9.8 to 4.8) met the predefined criteria of noninferiority (margin set at 10%).”

AbstractFind in source

The data availability statement is concrete: it names the Zenodo repository with DOI (10.5281/zenodo.10089112) for protocol, codebook, and statistical codes. Individual participant data are deposited in Zenodo but under controlled access via a Data Access Committee with a described request procedure and timeframe. This meets the standard for managed access. Code sharing is also addressed via the same Zenodo repository.

Sub-criteria

code sharingADEQUATE

accession numbersN/A

repository depositADEQUATE

data availability statementADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

Data and code availability are exemplary: protocol, statistical analysis plan, REDCap codebook, and statistical codes are in Zenodo; individual participant data are under managed access with a clear procedure.

Evidence

“These documents, as well as the REDCap codebook and statistical codes have been publicly available in the Zenodo repository (at https://zenodo.org/records/10089112 ; 10.5281/zenodo.10089112).”

Data availabilityFind in source

“Individual participant data have been deposited in Zenodo also, but is subject to controlled access due to privacy reasons and the European data protection legislation and can only be accessed after review and approval by the Data Access Committee (DAC) of the Institute of Tropical Medicine”

Data availabilityFind in source

“In line with the previous statement, statistical codes have been made available in the Zenodo repository (see above for identifiers).”

Data availabilityFind in source

PASSReviewer 2· 95% conf

Data and code availability are exemplary: protocol, statistical codes, and de-identified data are deposited in Zenodo with controlled access for IPD.

Evidence

“These documents, as well as the REDCap codebook and statistical codes have been publicly available in the Zenodo repository (at https://zenodo.org/records/10089112 ; 10.5281/zenodo.10089112).”

Data availabilityFind in source

The trial is registered at ClinicalTrials.gov (NCT03893097). A CONSORT flow diagram is included (Fig. 1). The paper discusses limitations extensively, including the insensitivity of microscopy, the absence of a placebo for safety comparison, and the impact of COVID-19 on ultrasound assessments. Conclusions are appropriately cautious, noting the need for multicentric trials. Funding sources and conflicts of interest are disclosed in the Acknowledgements and Competing Interests sections.

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineADEQUATE

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Reporting is transparent: trial registered, CONSORT flow diagram provided, limitations discussed, conclusions proportional, and funding/COI disclosed.

Evidence

“ClinicalTrials.gov identifier: NCT03893097 (https://clinicaltrials.gov/study/NCT03893097) .”

AbstractFind in source

“Fig. 1 CONSORT flow diagram of the SchistoSAM trial and analysis population.”

Figure 1Find in source

paraphrase[Discussion, paragraph 3]

“There were also some limitations. For the efficacy outcome, cure rates were assessed by conventional microscopy, which is still the WHO established standard for diagnosis of schistosomiasis and assessment of treatment response.”

PASSReviewer 2· 90% conf

Reporting is transparent: trial registered, CONSORT flow diagram, limitations discussed, conclusions proportional, funding and COI disclosed.

Evidence

“ClinicalTrials.gov identifier: NCT03893097 (https://clinicaltrials.gov/study/NCT03893097) .”

AbstractFind in source

paraphrase[Discussion, paragraph 3]

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

Broken references and links

None found

References checked against Crossref, OpenAlex and Retraction Watch for retractions and resolvability, plus declared data and code links probed for whether they resolve to content matching the paper.

Checked — nothing surfaced.

Checked 50 references by DOI: 46 verified — 4 no DOI (shown, not verified).

3 data/code links checked; 3 live.

Copyediting

6 minor

Wording, 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, clarity.

Kaimen Rigor Action ItemsFinal pass before journal submission

The published work is robust and well-reported; an informed reader should weigh the minor CI inconsistency and the open-label design as limitations, but neither undermines the conclusions. No erratum is warranted for the CI discrepancy, though the authors may consider a correction for consistency. The data and code availability are exemplary, supporting independent re-analysis.

1.
MEDIUMcopyedit
Reconcile the cure rate difference confidence interval between the Abstract (−9.8 to 4.8) and the Results section (−9.7 to 4.8) so they match exactly.
The internal inconsistency in the primary outcome CI could confuse readers and undermine trust in the reported precision.
2.
MEDIUMcopyedit
In Methods, Statistical analysis, change 'Statistical analysis were performed' to 'Statistical analyses were performed'.
Corrects a subject-verb agreement error.
3.
MEDIUMcopyedit
In Table 2 footnote, correct 'Fischer’s exact test' to 'Fisher's exact test'.
Corrects a misspelling of the test name.
4.
MEDIUMcopyedit
In Methods, Statistical analysis, remove the redundant phrase 'co-endemic areas co-endemic settings' and keep a single clear phrase.
Eliminates a clarity issue in the justification of the noninferiority margin.
5.
LOWreporting
In Methods, Ethics approval, explicitly state adherence to the Declaration of Helsinki or ICH-GCP guidelines.
Strengthens the regulatory compliance reporting, though the current ethics approvals are already detailed.
6.
LOWstatistics
In Methods, Statistical analysis, describe how missing data (e.g., participants lost to follow-up) were handled in the intention-to-treat analysis.
Clarifies the handling of missing data beyond the per-protocol primary analysis, improving transparency.
7.
LOWreporting
In Methods, add a statement on whether any data monitoring committee interim analyses were pre-specified and how they were handled.
Addresses a common reviewer question about trial oversight.
8.
LOWreporting
In the Discussion, discuss the generalizability of the findings to other Schistosoma species and settings, as the trial was predominantly S. haematobium.
Helps readers understand the applicability of the results beyond the study population.
9.
LOWdata code
In the Data Availability statement, specify the exact conditions for data access (e.g., proposal requirements) in more detail.
Enhances the managed access description, though the current statement is already adequate.
10.
LOWstatistics
In the Results, report the exact p-value for the Fisher's exact test comparing AE rates instead of only 'P < 0.001'.
Provides more precise statistical reporting.
11.
LOWreporting
In Methods, explicitly state whether the study followed the CONSORT extension for noninferiority trials.
Clarifies adherence to the appropriate reporting guideline.
12.
LOWreporting
In Results, report the number of participants with missing data for each outcome.
Improves transparency about completeness of outcome data.
13.
LOWreporting
In Methods, report the intra-observer variability of the microscopists.
Provides additional quality assurance information for the primary outcome assessment.
14.
LOWreporting
In the Discussion, add a note on the generalizability of the findings to other epidemiological settings.
Addresses external validity considerations.
15.
LOWreporting
In Results, report the exact number of children who received each dose of artesunate–mefloquine.
Provides complete dosing information.

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Antimalarial artesunate-mefloquine versus praziquantel in African children with schistosomiasis: an open-label, randomized controlled trial.

Read full text (PMC)

DOI

10.1038/s41591-023-02719-4

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  <img src="https://alpha1science.com/verify/79fd7fd5-433c-4bd9-b181-fa05763131f5/badge" alt="Kaimen Rigor review — 3.5★ (Adequate), 0 critical, 0 high issues for “Antimalarial artesunate-mefloquine versus praziquantel in African children with schistosomiasis: an open-label, randomized controlled trial.”" width="440" height="104" style="max-width:100%;height:auto" />
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Record fingerprint

25a0466292d66b2a359615f3dc2d7777a7175593a7c728990d7a693ac77013f8

Verify via API

Issued Aug 16, 2026Engine 7.39.0

Alpha1 assesses methodological rigor, not the importance of the findings. See how we calibrate →

Kaimen Rigor review

Kaimen Rigor reviewed

3.5 / 5

Adequate — real issues to address

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

IntegrityIntegrity concern−0.5★
ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
ClaimsTreatment effect not shown to be clinically meaningful−0.5★

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

Not verified in this report

The numeric-impossibility checks (GRIM/GRIMMER/DEBIT/SPRITE) did not run: 1 reported mean was read, and its group size is not stated where the value is printed (this source has no machine-readable table structure). These checks need the count the mean was averaged over, so none was performed.

Biggest issues

01Efficacy rests on an unvalidated surrogate endpoint
highOverreachreviewer-assessedFull detail
The primary efficacy endpoint is parasitological cure rate assessed by microscopy (absence of Schistosoma eggs in urine/stool) at 4 weeks post-treatment. This is a surrogate marker for clinical benefit. The paper does not provide evidence of target engagement at the tested dose (e.g., PK/PD data) nor does it cite validated evidence linking parasitological cure to long-term clinical outcomes such as prevention of morbidity or mortality. Although egg reduction rates and some morbidity markers (hematuria) are reported, the primary claim of noninferiority is based on the surrogate cure rate.
“Primary outcomes were cure rate, assessed by microscopy, and frequency of drug-related adverse effects of artesunate–mefloquine versus praziquantel at 4 weeks after treatment.”
Find in source
02Treatment effect not shown to be clinically meaningful
highOverreachreviewer-assessedFull detail
The primary effect is a cure rate of 59.6% in the artesunate–mefloquine arm versus 62.1% in the praziquantel arm, with a difference of -2.5% (95% CI -9.8 to 4.8). While the noninferiority margin was set at 10%, the cure rates are relatively low (around 60%), meaning that about 40% of children remain infected after treatment. The paper does not anchor this effect size to a minimal clinically important difference or to long-term clinical benefit; it only compares to praziquantel. The egg reduction rates are high (>90%) but these are also surrogate outcomes. The clinical meaningfulness of a 60% cure rate is not explicitly discussed in terms of patient-important outcomes.
“Cure rate was 59.6% (208/349) in the artesunate–mefloquine arm versus 62.1% (211/340) in the praziquantel arm. The difference of −2.5% (95% confidence interval (CI) −9.8 to 4.8) met the predefined criteria of noninferiority (margin set at 10%).”
Find in source

Findings by category

101ArithmeticNumerical inconsistencies 302OverreachOverstated conclusions 03AuthenticityNone found 04DisclosureNone found 05AvailabilityNone found 06Copyedit6 minor suggestions

Numerical inconsistencies

1 finding · worst low

Internal contradictions in the reported numbersAssessed

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

Overstated conclusions

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

7 major claims checked against the paper's own evidence: 2 only partially supported (evidence backs part of the claim; gaps or caveats remain); the rest adequately supported.

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

Data authenticity concerns

None found

Checked — nothing surfaced.

Reporting gaps

None found

Checked — nothing surfaced.

Eight Dimensions8 pass

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The paper establishes a clear scientific premise: praziquantel is the only treatment, with limitations, and prior evidence on artesunate–mefloquine is inconclusive, justifying the trial.

Evidence

paraphrase[Introduction, paragraphs 1-3]

“However, praziquantel has little activity on juvenile worms, and reinfections remain an unsolved challenge, especially in high-transmission areas such as sub-Saharan Africa.”

Introduction ¶4Find in source

paraphrase[Introduction, paragraph 3]

PASSReviewer 2· 90% conf

The paper establishes a clear scientific premise, citing prior research on praziquantel limitations and antimalarial activity against schistosomes, and provides a logical rationale for the trial.

Evidence

paraphrase[Introduction, paragraph 2]

“However, praziquantel has little activity on juvenile worms, and reinfections remain an unsolved challenge, especially in high-transmission areas such as sub-Saharan Africa.”

paraphrase[Introduction, paragraph 3]

Discussion ¶1Find in source

Sub-criteria

controlsN/A

power analysisADEQUATE

blinding levelsADEQUATE

outlier handlingADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The trial design is rigorous: randomized, with a pre-specified sample size calculation, clear inclusion/exclusion criteria, and appropriate handling of the analysis population.

Evidence

“A block randomization schedule, stratified by the two Schistosoma species, was prepared by the sponsor biostatistician, using SAS v9.4 (SAS Institute).”

MethodsFind in source

“The participants and the clinical team were not blinded to treatment and clinical evolution, but the laboratory technicians and microscopists were.”

MethodsFind in source

Statistical analysisFind in source

PASSReviewer 2· 90% conf

The trial design is rigorous: randomization method and unit are stated, blinding of outcome assessors is described, sample size is justified, and inclusion/exclusion criteria are pre-specified.

Evidence

“A block randomization schedule, stratified by the two Schistosoma species, was prepared by the sponsor biostatistician, using SAS v9.4 (SAS Institute).”

MethodsFind in source

“The participants and the clinical team were not blinded to treatment and clinical evolution, but the laboratory technicians and microscopists were.”

MethodsFind in source

Statistical analysisFind in source

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Biological variables are well reported: sex, age, weight, height, and infection characteristics are detailed in Table 1.

Evidence

“399 were male (55.6%) and 319 female (44.4%).”

ResultsFind in source

“Age (years), median (IQR) | 9.00 (7.00 to 11.0) | 9.00 (7.00 to 11.0) | 9.00 (7.00 to 11.0)”

Table 1Find in source

“Mean hemoglobin level was 12.0 mg dl −1 (95% confidence interval (CI) 11.3 to 12.7).”

ResultsFind in source

PASSReviewer 2· 90% conf

Biological variables are well reported: sex, age, weight, and infection characteristics are detailed; demographics are comprehensive.

Evidence

“Median age was 9 years (interquartile range 7–11 years); 399 were male (55.6%) and 319 female (44.4%).”

ResultsFind in source

“Single S. haematobium infection | 609 (84.8) | 306 (85.0) | 303 (84.6)”

Table 1Find in source

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

Ethical approvals are clearly documented with named ethics committees and reference numbers, and informed consent is described.

Evidence

EthicsFind in source

“Written informed consent for schistosomiasis screening and trial participation upon positivity was asked by experienced study nurses from the children’s parents or legal guardians.”

MethodsFind in source

PASSReviewer 2· 95% conf

Ethics approval from named committees and informed consent are clearly documented.

Evidence

EthicsFind in source

“Written informed consent for schistosomiasis screening and trial participation upon positivity was asked by experienced study nurses from the children’s parents or legal guardians.”

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 (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The investigational products (artesunate–mefloquine and praziquantel) are identified with manufacturer and WHO prequalification numbers, and software tools are identified.

Evidence

MethodsFind in source

“Statistical analysis were performed with R v4.2.2.”

Statistical analysisFind in source

“Clinical, ultrasound, laboratory and parasitological data at baseline and during follow-up assessments were entered into Research Electronic Data Capture (REDCap, v8.10.4)”

MethodsFind in source

PASSReviewer 2· 90% conf

The investigational drugs are identified with manufacturer and WHO prequalification numbers; statistical software is identified.

Evidence

MethodsFind in source

“Statistical analysis were performed with R v4.2.2.”

Statistical analysisFind in source

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedADEQUATE

mathematical plausibilityPASS

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 85% conf

Statistical methods are appropriate and well-described, with exact p-values for the main comparison and effect sizes with confidence intervals.

Evidence

“The primary hypothesis for noninferiority was assessed by calculating the two-sided 95% Wilson CI for the difference in cure rates between arms (artesunate–mefloquine and praziquantel).”

Statistical analysisFind in source

“reported in 28/361 children receiving artesunate–mefloquine (7.8%; 95% CI 5.4 to 11.0) versus 8/363 (2.2%; 95% CI 1.1 to 4.3) receiving praziquantel ( P < 0.001).”

AbstractFind in source

“The difference of −2.5% (95% confidence interval (CI) −9.8 to 4.8) met the predefined criteria of noninferiority (margin set at 10%).”

AbstractFind in source

PASSReviewer 2· 85% conf

Statistical methods are appropriate and well reported, with exact p-values and confidence intervals; no arithmetic inconsistencies found.

Evidence

“reported in 28/361 children receiving artesunate–mefloquine (7.8%; 95% CI 5.4 to 11.0) versus 8/363 (2.2%; 95% CI 1.1 to 4.3) receiving praziquantel ( P < 0.001).”

AbstractFind in source

“The difference of −2.5% (95% confidence interval (CI) −9.8 to 4.8) met the predefined criteria of noninferiority (margin set at 10%).”

AbstractFind in source

Sub-criteria

code sharingADEQUATE

accession numbersN/A

repository depositADEQUATE

data availability statementADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

Evidence

“These documents, as well as the REDCap codebook and statistical codes have been publicly available in the Zenodo repository (at https://zenodo.org/records/10089112 ; 10.5281/zenodo.10089112).”

Data availabilityFind in source

“In line with the previous statement, statistical codes have been made available in the Zenodo repository (see above for identifiers).”

Data availabilityFind in source

PASSReviewer 2· 95% conf

Data and code availability are exemplary: protocol, statistical codes, and de-identified data are deposited in Zenodo with controlled access for IPD.

Evidence

“These documents, as well as the REDCap codebook and statistical codes have been publicly available in the Zenodo repository (at https://zenodo.org/records/10089112 ; 10.5281/zenodo.10089112).”

Data availabilityFind in source

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineADEQUATE

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Reporting is transparent: trial registered, CONSORT flow diagram provided, limitations discussed, conclusions proportional, and funding/COI disclosed.

Evidence

“ClinicalTrials.gov identifier: NCT03893097 (https://clinicaltrials.gov/study/NCT03893097) .”

AbstractFind in source

“Fig. 1 CONSORT flow diagram of the SchistoSAM trial and analysis population.”

Figure 1Find in source

paraphrase[Discussion, paragraph 3]

PASSReviewer 2· 90% conf

Reporting is transparent: trial registered, CONSORT flow diagram, limitations discussed, conclusions proportional, funding and COI disclosed.

Evidence

“ClinicalTrials.gov identifier: NCT03893097 (https://clinicaltrials.gov/study/NCT03893097) .”

AbstractFind in source

paraphrase[Discussion, paragraph 3]

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

Broken references and links

None found

References checked against Crossref, OpenAlex and Retraction Watch for retractions and resolvability, plus declared data and code links probed for whether they resolve to content matching the paper.

Checked — nothing surfaced.

Checked 50 references by DOI: 46 verified — 4 no DOI (shown, not verified).

3 data/code links checked; 3 live.

Copyediting

6 minor

Wording, 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, clarity.

Kaimen Rigor Action ItemsFinal pass before journal submission

1.
MEDIUMcopyedit
Reconcile the cure rate difference confidence interval between the Abstract (−9.8 to 4.8) and the Results section (−9.7 to 4.8) so they match exactly.
The internal inconsistency in the primary outcome CI could confuse readers and undermine trust in the reported precision.
2.
MEDIUMcopyedit
In Methods, Statistical analysis, change 'Statistical analysis were performed' to 'Statistical analyses were performed'.
Corrects a subject-verb agreement error.
3.
MEDIUMcopyedit
In Table 2 footnote, correct 'Fischer’s exact test' to 'Fisher's exact test'.
Corrects a misspelling of the test name.
4.
MEDIUMcopyedit
In Methods, Statistical analysis, remove the redundant phrase 'co-endemic areas co-endemic settings' and keep a single clear phrase.
Eliminates a clarity issue in the justification of the noninferiority margin.
5.
LOWreporting
In Methods, Ethics approval, explicitly state adherence to the Declaration of Helsinki or ICH-GCP guidelines.
Strengthens the regulatory compliance reporting, though the current ethics approvals are already detailed.
6.
LOWstatistics
In Methods, Statistical analysis, describe how missing data (e.g., participants lost to follow-up) were handled in the intention-to-treat analysis.
Clarifies the handling of missing data beyond the per-protocol primary analysis, improving transparency.
7.
LOWreporting
In Methods, add a statement on whether any data monitoring committee interim analyses were pre-specified and how they were handled.
Addresses a common reviewer question about trial oversight.
8.
LOWreporting
In the Discussion, discuss the generalizability of the findings to other Schistosoma species and settings, as the trial was predominantly S. haematobium.
Helps readers understand the applicability of the results beyond the study population.
9.
LOWdata code
In the Data Availability statement, specify the exact conditions for data access (e.g., proposal requirements) in more detail.
Enhances the managed access description, though the current statement is already adequate.
10.
LOWstatistics
In the Results, report the exact p-value for the Fisher's exact test comparing AE rates instead of only 'P < 0.001'.
Provides more precise statistical reporting.
11.
LOWreporting
In Methods, explicitly state whether the study followed the CONSORT extension for noninferiority trials.
Clarifies adherence to the appropriate reporting guideline.
12.
LOWreporting
In Results, report the number of participants with missing data for each outcome.
Improves transparency about completeness of outcome data.
13.
LOWreporting
In Methods, report the intra-observer variability of the microscopists.
Provides additional quality assurance information for the primary outcome assessment.
14.
LOWreporting
In the Discussion, add a note on the generalizability of the findings to other epidemiological settings.
Addresses external validity considerations.
15.
LOWreporting
In Results, report the exact number of children who received each dose of artesunate–mefloquine.
Provides complete dosing information.

Full text (56,021 chars)Analyzed: Aug 16, 2026