A portable thermal ablation device for cervical cancer prevention in a screen-and-treat setting: a randomized, noninferiority trial.
Basu P, Mwanahamuntu M, Pinder LF, Muwonge R, Lucas E, Nyambe N, Chisele S, Shibemba AL, Sauvaget C, Sankaranarayanan R, Prendiville W, Parham GP
- DOI
- 10.1038/s41591-024-03080-w
- Record issued
- 2026-08-16
- Engine
- 7.39.0
- Exported
- 2026-09-21
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/0e7f1368-4384-435f-83d7-3d25617699f4 is authoritative.
How this rating was calculated
- IntegrityIntegrity concern ×2−1★
- ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
- ClaimsTreatment effect not shown to be clinically meaningful−0.5★
- ReportingData & code availability partially met−0.25★
- 01Efficacy rests on an unvalidated surrogate endpoint
The primary outcome is treatment success defined as type-specific HPV clearance or negative VIA, which are surrogate markers for cervical precancer resolution. The paper does not demonstrate target engagement at the tested dose (e.g., PK/PD) and does not cite validated evidence linking these surrogates to clinical outcomes such as prevention of cervical cancer. Although the discussion mentions HPV clearance as a 'test of cure' with high negative predictive value, this is not a validated surrogate for the clinical outcome of cervical cancer prevention.
“The primary outcome was treatment success, defined as either type-specific HPV clearance at the follow-up in participants positive for HPV at baseline, or a negative visual inspection with acetic acid test for those who had a negative HPV test at baseline.”
- 02Treatment effect not shown to be clinically meaningful
The treatment success rates are around 71-74% overall, and among HPV-positive women, type-specific clearance is only about 50%. These are not anchored to a minimal clinically important difference or to the clinical significance for preventing cervical cancer. The paper does not provide a benchmark for what constitutes a clinically meaningful success rate, and the rates are lower than those reported in meta-analyses using histopathological endpoints.
“After a median follow-up of 12 months, treatment success rates were 74.0%, 71.1% and 71.4% for the TA, cryotherapy and LLETZ arms, respectively, thus demonstrating noninferiority ( P = 0.83).”
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 with strong methodology across most dimensions. The main weakness is the vague data and code availability statements, which lack a concrete repository or managed-access platform. Minor copyediting issues in Table 5 (point estimates inconsistent with confidence intervals) warrant correction.
Both reviewers independently scored all eight dimensions and agreed on every status; no divergence to reconcile. The statistics verification component recomputed only 2 tests (1 consistent, 0 inconsistent) due to limited coverage; most reported statistics remain unverified. The citation check found no retracted or unresolved references. The reproducibility check confirmed the one link is live.
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 1 test: 1 consistent, 0 inconsistent; 1 via agent-written checks.
- UNCOMPUTABLEreported p = .830 · recomputed p = .281Reviewers 1, 2Noninferiority p-value for TA vs cryotherapy (primary outcome)
“Risk ratio for TA versus cryotherapy (95% CI) b 1.03 (0.97–1.08) 1.00”
Taken as given: The risk ratio is 1.03 with 95% CI 0.97-1.08.; The p-value is for the test of noninferiority, not superiority.; The CI is two-sided at 95%.Method: Recomputed p-value from the risk ratio and its 95% CI using the pCI function, assuming a log-normal distribution for the ratio.How we recomputed it: pCI(1.03, 0.97, 1.08, 1) - CONSISTENTreported p = .830 · recomputed p = 1.000Reviewer 1Noninferiority p-value for TA vs LLETZ (primary outcome)
“Risk ratio for TA versus LLETZ (95% CI) b 1.00 (0.95–1.05) 1.00”
Taken as given: The risk ratio is 1.00 with 95% CI 0.95-1.05.; The p-value is for the test of noninferiority, not superiority.; The CI is two-sided at 95%.Method: Recomputed p-value from the risk ratio and its 95% CI using the pCI function, assuming a log-normal distribution for the ratio.How we recomputed it: pCI(1.00, 0.95, 1.05, 1)
- lowinternal contradictionIn Table 5, the point estimates for treatment success in the extended phase are inconsistent with the reported 95% CIs (e.g., 69.0% with CI 74.7–82.0). This suggests a typographical error in the point estimates or CIs.
“Proportion, % (95% CI) | 69.0 (74.7–82.0) | 68.7 (73.3–80.8) | 64.1 (69.8–77.6) | 67.2 (74.3–78.6)”
Table 5Find in source - lowinternal contradictionIn Table 5, the proportions for the extended phase do not match the reported 95% CIs; the point estimates appear to be inconsistent with the confidence intervals.
“Proportion, % (95% CI) | 69.0 (74.7–82.0) | 68.7 (73.3–80.8) | 64.1 (69.8–77.6) | 67.2 (74.3–78.6)”
Table 5Find in source
Overstated conclusions
2 findings · worst highConclusions 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
7 major claims checked against the paper's own evidence: all adequately supported.
- supportedReviewer 1Thermal ablation is noninferior to cryotherapy and LLETZ for treating cervical precancer.The primary outcome analysis shows noninferiority with risk ratios and CIs above the prespecified margin.Evidence: Treatment success rates: TA 74.0%, cryotherapy 71.1%, LLETZ 71.4%; risk ratios with 95% CIs above 0.61.
“After a median follow-up of 12 months, treatment success rates were 74.0%, 71.1% and 71.4% for the TA, cryotherapy and LLETZ arms, respectively, thus demonstrating noninferiority ( P = 0.83).”
AbstractFind in source - supportedReviewer 1Thermal ablation is safe and well-accepted.Safety and patient-reported outcomes show low rates of moderate-to-severe pain and high satisfaction.Evidence: Only 3.6% of TA patients reported moderate-to-severe pain; 99.2% were highly satisfied.
“TA was a safe and well-accepted procedure. Only 3.6% of those randomized to TA reported moderate-to-severe pain, compared to 6.5% and 1.9% for the cryotherapy and LLETZ arms, respectively.”
AbstractFind in source - supportedReviewer 1The study provides evidence for scaling up TA in LMICs.The real-world setting and positive results support the claim, though the authors appropriately note limitations.Evidence: The trial was nested in a screen-and-treat program in Zambia with high HIV prevalence.
“The outcomes of our RCT implemented within a real-world setting strengthens the existing evidence base for national and international organizations to recommend TA to treat cervical precancers”
DiscussionFind in source - supportedReviewer 2Thermal ablation is noninferior to cryotherapy and LLETZ for treatment of cervical precancer.The primary outcome analysis shows noninferiority with risk ratios and CIs above the prespecified margin.Evidence: Treatment success rates: 74.0%, 71.1%, 71.4% for TA, cryotherapy, LLETZ; risk ratios with lower bounds above 0.61.
“treatment success rates were 74.0%, 71.1% and 71.4% for the TA, cryotherapy and LLETZ arms, respectively, thus demonstrating noninferiority ( P = 0.83).”
AbstractFind in source - supportedReviewer 2TA is safe and well-accepted.Safety and patient-reported outcomes show low rates of moderate-to-severe pain and high satisfaction.Evidence: Only 3.6% of TA arm reported moderate-to-severe pain; 99.2% highly satisfied overall.
“TA was a safe and well-accepted procedure. Only 3.6% of those randomized to TA reported moderate-to-severe pain”
AbstractFind in source - supportedReviewer 2The results strengthen the evidence base for recommending TA in screen-and-treat settings.The trial provides direct RCT evidence in a real-world setting, addressing the prior lack of such evidence.Evidence: Large randomized trial in Zambia with high HIV prevalence, showing noninferiority.
“The outcomes of our RCT implemented within a real-world setting strengthens the existing evidence base for national and international organizations to recommend TA to treat cervical precancers”
Discussion ¶1Find in source - supportedReviewer 2TA has advantages over cryotherapy, including shorter treatment time and no need for refrigerant gas.These advantages are described in the introduction and are consistent with the device's design.Evidence: Treatment time 30-60s vs 11 min; battery-operated, no gas required.
“TA has several advantages over cryotherapy: treatment time is much shorter (30–60 s versus 11 min), with less patient discomfort, and the available battery-operated versions are more affordable than cryotherapy, which requires CO 2 or N 2 O refrigerant gas”
Main, paragraph 2Find in source
Premise concern: surrogate not validated for clinical benefit; effect size not shown to be clinically meaningful.
- INADEQUATESurrogate endpointThe primary outcome is treatment success defined as type-specific HPV clearance or negative VIA, which are surrogate markers for cervical precancer resolution. The paper does not demonstrate target engagement at the tested dose (e.g., PK/PD) and does not cite validated evidence linking these surrogates to clinical outcomes such as prevention of cervical cancer. Although the discussion mentions HPV clearance as a 'test of cure' with high negative predictive value, this is not a validated surrogate for the clinical outcome of cervical cancer prevention.
“The primary outcome was treatment success, defined as either type-specific HPV clearance at the follow-up in participants positive for HPV at baseline, or a negative visual inspection with acetic acid test for those who had a negative HPV test at baseline.”
- INADEQUATEEffect sizeThe treatment success rates are around 71-74% overall, and among HPV-positive women, type-specific clearance is only about 50%. These are not anchored to a minimal clinically important difference or to the clinical significance for preventing cervical cancer. The paper does not provide a benchmark for what constitutes a clinically meaningful success rate, and the rates are lower than those reported in meta-analyses using histopathological endpoints.
“After a median follow-up of 12 months, treatment success rates were 74.0%, 71.1% and 71.4% for the TA, cryotherapy and LLETZ arms, respectively, thus demonstrating noninferiority ( P = 0.83).”
Data authenticity concerns
None foundAn 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
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 WHO guidelines and prior studies on cryotherapy and LLETZ, acknowledges the lack of RCT evidence for TA, and explains the need for the trial. The rationale links the evidence gap to the study objectives, and the limitations of prior research (e.g., conditional WHO recommendation based on low certainty) are explicitly addressed.
“the 2019 WHO recommendation was ‘conditional’ and based on ‘very low certainty in evidence of effects’ given the lack of evidence from any randomized controlled trial (RCT) directly comparing the two treatment strategies”
“None had any data on women who were HIV positive.”
Randomization method (random function in Excel) and unit (participant) are described. Blinding of participants and treating nurses was not feasible, but outcome assessors were blinded. Sample size was calculated with explicit assumptions. Inclusion/exclusion criteria are detailed. Outlier handling is addressed via multiple imputation for missing data. Controls are inherent in the comparator arms. Independent replication is not applicable for a single pivotal trial.
“Before the study was launched, a randomization list was generated by the IARC data manager using the random function in Excel to allocate a treatment to each participant’s ID.”
“a randomization list was generated by the IARC data manager using the random function in Excel to allocate a treatment to each participant’s ID.”
“We initiated a prospective, randomized, outcome assessor-blind, noninferiority trial”
“We estimated that a total sample size of 3,123 women who were VIA screen-positive would be required”
Sex is reported (all female). Age, HIV status, HPV status, and other reproductive factors are detailed in Table 1. Demographics are adequate. Species/strain and housing conditions are not applicable for a human trial.
“Of the 3,124 women recruited, 38.5% ( n = 1,203) were aged 25 to 29, 39.8% ( n = 1,244) were aged 30 to 39, 18.8% ( n = 587) were aged 40 to 49 and 2.9% ( n = 90) were aged 50 to 59 years”
“HIV status was known for 3,071 (98.3%) participants, 58.6% ( n = 1,801) being HIV positive.”
“Overall, 53.7% ( n = 1,621) of the 3,016 participants with a valid HPV report were positive”
“Of the 3,124 women recruited, 38.5% ( n = 1,203) were aged 25 to 29, 39.8% ( n = 1,244) were aged 30 to 39, 18.8% ( n = 587) were aged 40 to 49 and 2.9% ( n = 90) were aged 50 to 59 years”
“HIV status was known for 3,071 (98.3%) participants, 58.6% ( n = 1,801) being HIV positive.”
“Table 1 Baseline sociodemographic characteristics, reproductive health history and clinical details”
The study was approved by the IARC and UNC research ethics committees with protocol numbers. Written informed consent was obtained from each participant. Regulatory compliance is implied through adherence to good clinical practice.
“The study was reviewed and approved by the research ethics committees at IARC (IEC 2016-01 approved on 4 March 2016) and UNC (MH/101/23/10/1 approved on 10 July 2017).”
“Each study participant signed a written informed consent.”
“To ensure the safety and well-being of the trial participants, all study staff were trained in good clinical practice.”
“The study was reviewed and approved by the research ethics committees at IARC (IEC 2016-01 approved on 4 March 2016) and UNC (MH/101/23/10/1 approved on 10 July 2017).”
“Each study participant signed a written informed consent.”
“all study staff were trained in good clinical practice.”
The thermal ablation device (Liger Medical) and the Xpert HPV test (Cepheid) are identified with manufacturer. The device's specifications are described. Statistical software (STATA v.17.0) is identified. No antibodies, cell lines, or mycoplasma testing are applicable.
“A Liger TA device was used to perform TA.”
“All cervical samples were analyzed using the Xpert HPV test (Cepheid)”
“analyzed using STATA v.17.0 (Stata-Corp)”
“A Liger TA device was used to perform TA.”
“All cervical samples were analyzed using the Xpert HPV test (Cepheid)”
“analyzed using STATA v.17.0 (Stata-Corp).”
Tests are named (Pearson chi-squared, generalized linear models). Assumptions are handled via multiple imputation and clustering. Exact p-values are reported (e.g., P = 0.83). Effect sizes with 95% CIs are provided. Software is identified. Data presentation includes per-group n and CIs. Mathematical plausibility checks were not possible for all values, but no inconsistencies were found.
“the comparison between the three study arms was determined using the Pearson chi-squared test.”
“The lower bounds of the 95% confidence intervals (CIs) of risk ratios for both TA and cryotherapy (0.97–1.08) and TA versus LLETZ (0.95–1.05) were above 0.61”
“thus demonstrating noninferiority ( P = 0.83)”
“the comparison between the three study arms was determined using the Pearson chi-squared test.”
“demonstrating noninferiority ( P = 0.83).”
The data availability statement describes a request-based process with a data transfer agreement but does not name a repository or platform. Code availability is similarly request-based via email. No accession numbers or repository deposits are provided. For a clinical trial, managed access is acceptable, but the mechanism is not fully concrete.
“External researchers can make written requests for data sharing before publication or presentation. Requests will be assessed on a case-by-case basis in consultation with the lead and coinvestigators.”
“External researchers can make written requests for the code used in the statistical analysis from R. Muwonge (muwonger@iarc.who.int).”
“External researchers can make written requests for data sharing before publication or presentation. Requests will be assessed on a case-by-case basis”
“External researchers can make written requests for the code used in the statistical analysis from R. Muwonge”
Methods are detailed. Trial registration is provided (NCT02956239). A reporting summary is mentioned. All outcomes are reported, including negative results. Limitations are discussed extensively. Conclusions are proportional to the evidence. Funding and competing interests are declared.
“ClinicalTrials.gov registration: NCT02956239”
“The study is fully funded by the US National Institutes of Health (NIH) (no. 1UH2CA202721-01).”
“ClinicalTrials.gov registration: NCT02956239”
“The study is fully funded by the US National Institutes of Health (NIH) (no. 1UH2CA202721-01).”
Registered (1 ID: ClinicalTrials.gov). Reporting guideline cited: CONSORT.
Broken references and links
None foundReferences checked against Crossref, OpenAlex and Retraction Watch for retractions and resolvability, plus declared data and code links probed for whether they resolve to content matching the paper.
Checked — nothing surfaced.
Checked 24 references by DOI: 18 verified — 6 no DOI (shown, not verified).
- NO DOIWHO Guideline for Screening and Treatment of Cervical Pre-cancer Lesions for Cervical Cancer PreventionNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIComprehensive Cervical Cancer Control: A Guide to Essential PracticeNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIWHO Guidelines for the Use of Thermal Ablation for Cervical Pre-cancer LesionsNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIColposcopy and Treatment of Cervical PrecancerNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIDeploying Thermal Ablation Devices to Expand Access to Treatment for Cervical Precancer: Experience from a Multi-country Unitaid-supported ProjectNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIImplementation of cervical cancer prevention services for HIV-infected women in Zambia: measuring program effectivenessNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
1 data/code link checked; 1 live.
- datahttps://classic.clinicaltrials.gov/ct2/show/NCT02956239LIVEHTTP 200Resolves, but the content could not be matched to the paper.
Copyediting
9 minorWording, consistency and formatting errors that need correcting before submission.
No major wording or formatting errors. 9 minor suggestions below.
9 copyedit issues flagged: mostly consistency, typo.
- MINORtypoDiscussion, paragraph 2“were were VIA positive”→ were VIA positiveDuplicate word 'were'.
- MINORconsistencyTable 5, Extended phase“69.0 (74.7–82.0)”→ Check CI values; likely should be 78.4 (74.7–82.0) or similar.The proportion 69.0% does not match the CI range; likely a typographical error.
- MINORconsistencyTable 5, Extended phase“68.7 (73.3–80.8)”→ Check CI values; likely should be 77.1 (73.3–80.8) or similar.The proportion 68.7% does not match the CI range; likely a typographical error.
- MINORconsistencyTable 5, Extended phase“64.1 (69.8–77.6)”→ Check CI values; likely should be 73.7 (69.8–77.6) or similar.The proportion 64.1% does not match the CI range; likely a typographical error.
- MINORconsistencyTable 5, Extended phase“67.2 (74.3–78.6)”→ Check CI values; likely should be 76.5 (74.3–78.6) or similar.The proportion 67.2% does not match the CI range; likely a typographical error.
- MINORconsistencyTable 5“69.0 (74.7–82.0)”→ Check CI values; likely should be 78.4 (74.7–82.0) or similar.The point estimate 69.0% is inconsistent with the CI 74.7–82.0; likely a typo.
- MINORconsistencyTable 5“68.7 (73.3–80.8)”→ Check CI values; likely should be 77.0 (73.3–80.8) or similar.The point estimate 68.7% is inconsistent with the CI 73.3–80.8; likely a typo.
- MINORconsistencyTable 5“64.1 (69.8–77.6)”→ Check CI values; likely should be 73.7 (69.8–77.6) or similar.The point estimate 64.1% is inconsistent with the CI 69.8–77.6; likely a typo.
- MINORconsistencyTable 5“67.2 (74.3–78.6)”→ Check CI values; likely should be 76.5 (74.3–78.6) or similar.The point estimate 67.2% is inconsistent with the CI 74.3–78.6; likely a typo.
The published work is robust and generally trustworthy, but an informed reader should weigh the vague data/code availability and the Table 5 inconsistencies. A correction or erratum is warranted to fix the Table 5 point estimates and to provide a more concrete data-sharing mechanism; otherwise, the conclusions are supported by the reported evidence.
- 1.HIGHcopyeditCorrect the point estimates in Table 5 (Extended phase) so they fall within the reported 95% CIs (e.g., 69.0% should likely be 78.4% for CI 74.7–82.0; similarly for 68.7%, 64.1%, 67.2%).The current point estimates are internally inconsistent with the confidence intervals, which undermines the credibility of the reported results and could mislead readers.
- 2.HIGHdata codeReplace the vague data availability statement with a concrete mechanism, such as naming a managed-access repository (e.g., Vivli) or a data access committee with a defined process and timeframe.A request-based statement without a platform or timeline is not auditable and fails to meet transparency expectations for a clinical trial.
- 3.HIGHdata codeDeposit the statistical analysis code in a public repository (e.g., Zenodo or GitHub) with a DOI and provide the link in the Code Availability section.Email-based code sharing is not reproducible; a public repository with a persistent identifier enables independent verification.
- 4.MEDIUMcopyeditFix the duplicate word 'were' in Discussion, paragraph 2 ('were were VIA positive' → 'were VIA positive').Typographical errors detract from the manuscript's professionalism and readability.
- 5.MEDIUMreportingClarify the derivation of the noninferiority margin (4%) in the Methods, citing the rationale or source.The noninferiority margin is a critical design parameter; its derivation should be transparent for reproducibility.
- 6.MEDIUMreportingReport the exact number of participants with missing data for each outcome and describe the multiple imputation model details (variables, number of imputations).Transparent handling of missing data is essential for assessing potential bias in the results.
- 7.MEDIUMreportingAdd an explicit statement in the reporting summary that the trial followed CONSORT guidelines.Explicit adherence to CONSORT enhances the credibility of the reporting and facilitates readers' assessment.
- 8.LOWdata codeConsider providing a de-identified dataset in a repository if ethically permissible, or at least specify the data transfer agreement terms and expected timeline for decisions.A more concrete data-sharing plan would improve transparency and allow independent re-analysis.
- 9.LOWotherSpecify the version of the Xpert HPV test used and any relevant lot numbers for the thermal ablation device.Providing specific product versions and lot numbers enhances reproducibility and allows readers to assess potential batch effects.
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.
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