Effect of methylcobalamin on capecitabine induced hand-foot syndrome in patients with HER2 negative early breast cancer: multicentre, double blind, randomised, placebo controlled, phase 3 trial.
Xia Y, Zhu Y, Ling L, Xu F, Yang Y, Ye J, Tan W, Chen Z, Liu Q, Wei W, Zhang J, Zhang A, Zhang L, Song E, Gong C
- DOI
- 10.1136/bmj-2025-084290
- 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/c8f148c8-99fc-4fd5-956f-df86bb1f9f0d 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★
- 01Efficacy rests on an unvalidated surrogate endpoint
The primary endpoint is the incidence of grade ≥2 hand-foot syndrome, a clinical toxicity grading scale (NCI-CTCAE v5.0), which is a surrogate for clinically meaningful outcomes such as quality of life and treatment adherence. The paper does not demonstrate target engagement of methylcobalamin at the tested dose (no PK/PD or dose-exposure data) and does not cite validated evidence linking the reduction in grade ≥2 hand-foot syndrome to improved long-term clinical outcomes (e.g., survival or quality of life). The secondary endpoints of quality of life showed no significant treatment effect in the primary analysis, and survival outcomes were not significantly different.
“The primary endpoint was the incidence of grade ≥2 hand-foot syndrome occurring for the first time during capecitabine treatment in the intention-to-treat analysis.”
- 02Treatment effect not shown to be clinically meaningful
The primary effect is a reduction in grade ≥2 hand-foot syndrome from 29.1% to 14.5% (risk difference −14.5%). While this is statistically significant, the clinical meaningfulness is not explicitly anchored to a minimal clinically important difference or a validated threshold. The paper does not provide a clear anchor for what constitutes a clinically meaningful reduction in hand-foot syndrome incidence, and the secondary outcomes (quality of life, dose modifications) were not significantly improved in the primary analysis.
“Grade ≥2 hand-foot syndrome occurred in 17 (14.5%) of 117 patients in the methylcobalamin group and 34 (29.1%) of 117 patients in the placebo group (risk difference −14.5%, 95% confidence interval −24.9% to −4.1%; one sided P value=0.003).”
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, rigorously reported phase 3 randomised controlled trial. The methodology is sound across all eight dimensions, with clear randomisation, blinding, sample size justification, ethics approval, data/code availability, and transparent reporting. The only issues are minor copyedit-level inconsistencies in reported percentages that do not undermine the statistical conclusions.
Both reviewers classified the study as interventional, and this was adopted. The evaluation covered the full text, including methods, results, and supplementary materials. Non-applicable criteria (e.g., animal housing, cell line authentication) were excluded. The statistics verification recomputed only 4 tests (those with test statistics/df or effect estimates with CIs); the remaining analyses were not machine-verified and should not be assumed correct beyond what was checked.
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 4 tests: 4 consistent, 0 inconsistent; 1 recomputed directly from the reported test statistics, 3 via agent-written checks.
- CONSISTENTreported p = .007 · recomputed p = .005Recomputed risk ratio 0.47 (95% CI 0.28–0.81), reported p=0.007
“risk ratio 0.47, 95% confidence interval 0.28 to 0.81; P=0.007”
Taken as given: 0.28–0.81 is a two-sided 95% confidence interval for the risk ratio of 0.47, not a range, an IQR, or a different interval level; the risk ratio is a RATIO measure, so the interval is symmetric on the log scale; p=0.007 is the p for THIS estimate, not for another comparison in the same sentenceMethod: back the two-tailed p out of the log-scale CI width and compare it against the printed pHow we recomputed it: pCI(0.47, 0.28, 0.81, 1) - CONSISTENTreported p = .003 · recomputed p = .004Reviewers 1, 2Primary endpoint: Cochran-Mantel-Haenszel one-sided p-value for grade ≥2 HFS
“The incidence of grade ≥2 hand-foot syndrome was lower in the methylcobalamin group (17 of 117, 14.5%) than the placebo group (34 of 117, 29.1%; unadjusted risk difference −14.5%, 95% confidence interval −24.9% to −4.1%; Cochran-Mantel-Haensel one sided P value=0.003; ).”
Taken as given: The 17 and 34 are the event counts in the methylcobalamin and placebo groups, respectively.; The 117 and 117 are the group totals.; The Cochran-Mantel-Haenszel test is approximated by a chi-square test on the 2x2 table.; The one-sided p-value is half of the two-sided p-value.Method: Computed two-sided Pearson chi-square p-value from cell counts and halved it to approximate the one-sided p-value.How we recomputed it: pChi2x2(17,100,34,83)/2 - CONSISTENTreported p = .140 · recomputed p = .139Reviewers 1, 2Secondary endpoint: Pearson chi-square p-value for hand-foot syndrome related reduction or discontinuation
“The rate of reduction or discontinuation of capecitabine treatment because of hand-foot syndrome was 7.7% (9 of 117) in the methylcobalamin group and 13.7% (16 of 117) in the placebo group (risk difference −6.0%, 95% confidence interval −13.9% to 1.9%).”
Taken as given: The 9 and 16 are the event counts in the methylcobalamin and placebo groups, respectively.; The 117 and 117 are the group totals.; The p-value is from Pearson's chi-square test as stated in Table 2 footnote.Method: Computed two-sided Pearson chi-square p-value from cell counts.How we recomputed it: pChi2x2(9,108,16,101) - CONSISTENTreported p = .360 · recomputed p = .358Reviewers 1, 2Secondary endpoint: Pearson chi-square p-value for any grade hand-foot syndrome
“In the post hoc analysis, hand-foot syndrome of any grade occurred in 60 and 67 patients in the methylcobalamin and placebo groups, respectively (risk difference −6.0%, 95% confidence interval −18.7% to 6.8%; ).”
Taken as given: The 60 and 67 are the event counts in the methylcobalamin and placebo groups, respectively.; The 117 and 117 are the group totals.; The p-value is from Pearson's chi-square test as stated in Table 2 footnote.Method: Computed two-sided Pearson chi-square p-value from cell counts.How we recomputed it: pChi2x2(60,57,67,50)
- lowinternal contradictionIn Table 2, the 'Reduction' row shows 21 (17.9) for all patients, but the subgroup rows (25% and 50%) sum to 13+8=21, which is consistent. However, the percentages for the subgroups (5.6% and 3.4%) sum to 9.0%, not 17.9%. This is likely due to rounding or a different denominator, but it is worth noting.
“Reduction | 21 (17.9) | 8 (6.8) | 13 (11.1) | −4.3 (−11.6 to 3.0) | 0.25‡”
Table 2Find in source - lowinternal contradictionIn the Results section, the text states 'two patients (6.8%) in the methylcobalamin group and three (11.1%) in the placebo group reduced capecitabine owing to other adverse events', but 2/117 is 1.7% and 3/117 is 2.6%. This appears to be a typographical error in the percentages.
“Additionally, two patients (6.8%) in the methylcobalamin group and three (11.1%) in the placebo group reduced capecitabine owing to other adverse events”
ResultsFind in source
Overstated conclusions
3 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
- Conclusions only partially backed by the presented evidenceAssessed
4 major claims checked against the paper's own evidence: 1 only partially supported (evidence backs part of the claim; gaps or caveats remain); the rest adequately supported.
- partialReviewers 1, 2Methylcobalamin has the potential to reduce the rate of dose modification of capecitabine.The reduction in dose modification was not statistically significant, so the claim is partially supported.Evidence: Hand-foot syndrome related reduction/discontinuation: 9/117 (7.7%) vs 16/117 (13.7%), risk difference −6.0%, 95% CI −13.9% to 1.9%, P=0.14.
“Additionally, we found that oral methylcobalamin had the potential to reduce the rate of dose modification of capecitabine.”
Discussion ¶1Find in source - supportedReviewers 1, 2Oral methylcobalamin significantly lowered the severity of hand-foot syndrome by reducing the incidence of grade ≥2 symptoms.The primary endpoint result directly supports this claim with a statistically significant difference.Evidence: Primary endpoint: 17/117 (14.5%) vs 34/117 (29.1%), risk difference −14.5%, 95% CI −24.9% to −4.1%, one-sided P=0.003.
“Oral methylcobalamin significantly lowered the severity of hand-foot syndrome by reducing the incidence of grade ≥2 symptoms without unexpected safety concerns”
ConclusionFind in source - supportedReviewers 1, 2Methylcobalamin is safe with no unexpected safety concerns.Safety data show similar adverse event rates between groups and no serious adverse events, supporting the claim.Evidence: Overall adverse events: 88 (75.2%) vs 95 (81.2%); grade ≥3: 12 (10.3%) vs 18 (15.4%); no serious adverse events.
“No patient experienced serious adverse events, and no deaths caused by adverse events were reported.”
ResultsFind in source - supportedReviewers 1, 2The findings support the use of methylcobalamin to prevent capecitabine associated severe hand-foot syndrome.The primary endpoint and safety data support this conclusion.Evidence: Primary endpoint result and safety profile.
“The findings support the use of methylcobalamin to prevent capecitabine associated severe hand-foot syndrome in this patient population.”
ConclusionFind in source
Premise concern: surrogate not validated for clinical benefit; effect size not shown to be clinically meaningful.
- INADEQUATESurrogate endpointThe primary endpoint is the incidence of grade ≥2 hand-foot syndrome, a clinical toxicity grading scale (NCI-CTCAE v5.0), which is a surrogate for clinically meaningful outcomes such as quality of life and treatment adherence. The paper does not demonstrate target engagement of methylcobalamin at the tested dose (no PK/PD or dose-exposure data) and does not cite validated evidence linking the reduction in grade ≥2 hand-foot syndrome to improved long-term clinical outcomes (e.g., survival or quality of life). The secondary endpoints of quality of life showed no significant treatment effect in the primary analysis, and survival outcomes were not significantly different.
“The primary endpoint was the incidence of grade ≥2 hand-foot syndrome occurring for the first time during capecitabine treatment in the intention-to-treat analysis.”
- INADEQUATEEffect sizeThe primary effect is a reduction in grade ≥2 hand-foot syndrome from 29.1% to 14.5% (risk difference −14.5%). While this is statistically significant, the clinical meaningfulness is not explicitly anchored to a minimal clinically important difference or a validated threshold. The paper does not provide a clear anchor for what constitutes a clinically meaningful reduction in hand-foot syndrome incidence, and the secondary outcomes (quality of life, dose modifications) were not significantly improved in the primary analysis.
“Grade ≥2 hand-foot syndrome occurred in 17 (14.5%) of 117 patients in the methylcobalamin group and 34 (29.1%) of 117 patients in the placebo group (risk difference −14.5%, 95% confidence interval −24.9% to −4.1%; one sided P value=0.003).”
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
None foundRequired 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.
The paper cites prior studies on hand-foot syndrome prevention (pyridoxine, celecoxib, urea cream) and notes their limitations (ineffectiveness, safety concerns, uncertainty). It also cites mechanistic evidence linking small fibre neuropathy to hand-foot syndrome and methylcobalamin's neuroprotective effects, forming a logical hypothesis. The limitations of prior research are addressed by designing a randomised, double-blind, placebo-controlled trial.
“Unfortunately, pyridoxine did not significantly reduce the risk of hand-foot syndrome, and the effect of urea based cream in preventing grade 2 or 3 disease remains uncertain. Although celecoxib has been reported as effective in preventing hand-foot syndrome, its long term use is limited because of safety concerns about cardiovascular events”
“Methylcobalamin (vitamin B12) has been found to promote neurite outgrowth and neuronal survival by enhancing Erk 1/2 and Akt activities through the methylation cycle in vitro and in vivo, alleviating neuropathic pain and dysesthesia”
“We hypothesised that methylcobalamin might decrease the risk of hand-foot syndrome among patients with HER2 negative early breast cancer receiving adjuvant capecitabine treatment.”
“Unfortunately, pyridoxine did not significantly reduce the risk of hand-foot syndrome, and the effect of urea based cream in preventing grade 2 or 3 disease remains uncertain.”
“Methylcobalamin (vitamin B12) has been found to promote neurite outgrowth and neuronal survival by enhancing Erk 1/2 and Akt activities through the methylation cycle in vitro and in vivo, alleviating neuropathic pain and dysesthesia”
“We hypothesised that methylcobalamin might decrease the risk of hand-foot syndrome among patients with HER2 negative early breast cancer receiving adjuvant capecitabine treatment.”
Randomisation used a computer-generated code with stratification and block size, and allocation concealment via sealed envelopes. Blinding of participants, investigators, and site staff is stated. Sample size calculation is provided with assumptions. Inclusion/exclusion criteria are described, and the analysis populations (ITT, per-protocol, safety) are defined. Outlier handling is addressed through the per-protocol definition and missing data approach.
“The participants, investigators, and site staff were masked to treatment allocation.”
“The participants, investigators, and site staff were masked to treatment allocation.”
The study reports age, menopausal status, TNM stage, hormone receptor status, and previous chemotherapy. Sex is reported (all female) and justified by the disease context. Age and health status (ECOG) are reported. Demographics are adequately described in Table 1.
“Eligible participants were women aged 18-75 years with an ECOG (Eastern Cooperative Oncology Group) score of 0 or 1 and centrally pathologically confirmed HER2 negative early breast cancer.”
“The median age of the 234 patients at randomisation was 50 years (interquartile range 41-59), and 53.0% were premenopausal.”
“The median age of the 234 patients at randomisation was 50 years (interquartile range 41-59), and 53.0% were premenopausal.”
The paper states ethics approval was obtained from the ethics committee of each hospital and all participants gave written informed consent. It also states compliance with the Declaration of Helsinki. This satisfies the requirements for human research.
“Ethics approval was obtained from the ethics committee of each hospital and all participants gave written informed consent.”
“The study was conducted in accordance with the Declaration of Helsinki.”
“Ethics approval was obtained from the ethics committee of each hospital and all participants gave written informed consent.”
“The study was conducted in accordance with the Declaration of Helsinki.”
The trial uses methylcobalamin and placebo; the dose, regimen, and physical properties are described. The placebo supplier is acknowledged. Statistical software (R studio version 4.2.2) is identified. No other key biological/chemical resources are used.
“Patients were given 0.5 mg of methylcobalamin orally three times daily (a dosage used in neuropathy) or a placebo to be taken for a maximum of 24 weeks. The physical properties of the methylcobalamin and placebo treatment, such as appearance, size, colour, dosage form, weight, taste, and odour, were the same.”
“All statistical analyses were performed using R studio software (version 4.2.2).”
“Patients were given 0.5 mg of methylcobalamin orally three times daily (a dosage used in neuropathy) or a placebo to be taken for a maximum of 24 weeks.”
“The support provided by Yangtze River Pharmaceutical Group for supplying the placebo used in this study is appreciated.”
“All statistical analyses were performed using R studio software (version 4.2.2).”
The primary analysis uses Cochran-Mantel-Haenszel test with one-sided p-value, and risk differences with 95% CIs are reported. Secondary analyses use appropriate tests (chi-square, Wilcoxon, log-rank, mixed models). Exact p-values are given (e.g., 0.003). Software is identified. Data presentation includes per-group n and percentages. Mathematical plausibility checks are not applicable due to large N and continuous outcomes.
“The incidence of grade ≥2 hand-foot syndrome was lower in the methylcobalamin group (17 of 117, 14.5%) than the placebo group (34 of 117, 29.1%; unadjusted risk difference −14.5%, 95% confidence interval −24.9% to −4.1%; Cochran-Mantel-Haensel one sided P value=0.003; ).”
“All statistical analyses were performed using R studio software (version 4.2.2).”
“The incidence of grade ≥2 hand-foot syndrome was lower in the methylcobalamin group (17 of 117, 14.5%) than the placebo group (34 of 117, 29.1%; unadjusted risk difference −14.5%, 95% confidence interval −24.9% to −4.1%; Cochran-Mantel-Haensel one sided P value=0.003; ).”
“The difference between the groups (P value) was evaluated using the Cochran-Mantel-Haensel test, adjusting for the stratification factors (hormone receptor status and study centre).”
“All statistical analyses were performed using R studio software (version 4.2.2).”
The data availability statement provides a concrete route: raw database openly available via Dryad with a DOI, and code in supplementary appendix 3. This meets the criteria for data and code sharing.
“The raw database underlying the study is openly and publicly available ( https://doi.org/10.5061/dryad.gmsbcc31k ).”
“The code used to analyse the data in the paper can be found in supplementary appendix 3.”
“The raw database underlying the study is openly and publicly available ( https://doi.org/10.5061/dryad.gmsbcc31k ).”
“The code used to analyse the data in the paper can be found in supplementary appendix 3.”
Trial registration number is provided (NCT05165069). Methods are detailed enough for replication. A CONSORT diagram is included. All pre-specified outcomes are reported, including negative results. Limitations are explicitly discussed. Conclusions are proportional to the evidence. Funding and competing interests are disclosed.
“Trial registration ClinicalTrials.gov NCT05165069 (https://clinicaltrials.gov/ct2/show/NCT05165069) .”
“Our trial only included Chinese participants. Considering there are known differences in the pharmacokinetic profile of capecitabine for Asians and non-Asians, caution is required when generalising our findings to patients from other geographical regions and different racial or ethnic backgrounds.”
“Trial registration ClinicalTrials.gov NCT05165069 (https://clinicaltrials.gov/ct2/show/NCT05165069) .”
“Our trial only included Chinese participants. Considering there are known differences in the pharmacokinetic profile of capecitabine for Asians and non-Asians, caution is required when generalising our findings to patients from other geographical regions and different racial or ethnic backgrounds.”
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 37 references by DOI: 35 verified — 2 no DOI (shown, not verified).
- NO DOIThe hand-foot syndrome—a frequent secondary manifestation in antineoplastic chemotherapyNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIEffect of celecoxib on capecitabine-induced hand-foot syndrome and antitumor activityNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
1 data/code link checked; 1 live.
- dataDryadLIVEHTTP 200https://doi.org/10.5061/dryad.gmsbcc31kResolves to Dryad (data repository).
Copyediting
8 minorWording, consistency and formatting errors that need correcting before submission.
No major wording or formatting errors. 8 minor suggestions below.
8 copyedit issues flagged: mostly consistency, clarity, typo.
- MINORconsistencyAbstract, Results“The rate of reduction or discontinuation of capecitabine treatment because of hand-foot syndrome was 7.7% (9 of 117) in the methylcobalamin group and 13.7% (16 of 117) in the placebo group”→ Ensure the percentages match the fractions (7.7% of 117 is 9.009, 13.7% of 117 is 16.029). Consider using exact counts or rounding consistently.Minor rounding discrepancy in percentages.
- MINORconsistencyResults, Secondary endpoints“Eight patients (6.8%) in the methylcobalamin group and 13 (11.1%) in the placebo group reduced capecitabine because of hand-foot syndrome”→ Check that the percentages match the counts (6.8% of 117 is 7.956, 11.1% of 117 is 12.987). Consider using exact counts or rounding consistently.Minor rounding discrepancy in percentages.
- MINORconsistencyResults, Secondary endpoints“Additionally, two patients (6.8%) in the methylcobalamin group and three (11.1%) in the placebo group reduced capecitabine owing to other adverse events”→ The percentages appear to be incorrect: 2/117 is 1.7% and 3/117 is 2.6%. Please verify and correct.Likely typographical error in percentages.
- MINORclarityMethods, Statistical analysis“Unless specified, a two sided P value <0.05 was considered statistically significant.”→ Clarify that the primary endpoint used a one-sided test, while other analyses used two-sided tests, to avoid confusion.Ambiguity in significance threshold.
- MINORconsistencyTable 2“Reduction | 21 (17.9) | 8 (6.8) | 13 (11.1)”→ Check the percentage for the 'Reduction' row: 8/117 is 6.8% and 13/117 is 11.1%, but the total 21/117 is 17.9%. The percentages for the subgroups (25% and 50%) sum to 8.5% (5.1+3.4) not 6.8%. Please verify the counts.Potential inconsistency in subgroup counts.
- MINORconsistencyResults, Secondary endpoints“Additionally, two patients (6.8%) in the methylcobalamin group and three (11.1%) in the placebo group reduced capecitabine owing to other adverse events”→ The percentages appear to be incorrect; 2/117 is 1.7% and 3/117 is 2.6%. Please verify and correct.The percentages do not match the numerators.
- MINORtypoAbstract, Results“The rate of reduction or discontinuation of capecitabine treatment because of hand-foot syndrome was 7.7% (9 of 117) in the methylcobalamin group and 13.7% (16 of 117) in the placebo group”→ Ensure consistent use of 'hand-foot syndrome' hyphenation.Minor style consistency.
- MINORclarityMethods, Statistical analysis“Unless specified, a two sided P value <0.05 was considered statistically significant.”→ Clarify that the primary endpoint used a one-sided test, while other analyses used two-sided tests.Potential confusion for readers.
The published work is robust and well-reported; an informed reader should weigh the minor percentage inconsistencies flagged by the copyedit pass as reporting errors that do not affect the primary conclusions. No erratum is strictly required, but correcting the percentage typos would improve accuracy. The trial's single-country (Chinese) population and one-sided primary test are noted limitations that readers should consider when generalising.
- 1.HIGHcopyeditIn the Results section (Secondary endpoints), correct the percentages for 'two patients (6.8%)' and 'three (11.1%)' to the correct values (1.7% and 2.6%, respectively) for the methylcobalamin and placebo groups.The current percentages are arithmetically inconsistent with the numerators (2/117 and 3/117), which could mislead readers and undermine trust in the reported data.
- 2.HIGHcopyeditIn the Abstract and Results, verify and correct the percentages for 'reduction or discontinuation' (7.7% for 9/117 and 13.7% for 16/117) to ensure they match the exact fractions or are rounded consistently.Minor rounding discrepancies in key outcome percentages can be flagged by careful readers and detract from the paper's precision.
- 3.MEDIUMcopyeditIn Table 2, verify the subgroup percentages for the 'Reduction' row (25% and 50% reductions) to ensure they sum correctly to the total (17.9%) and match the counts.The integrity check noted that the subgroup percentages (5.6% and 3.4%) sum to 9.0%, not 17.9%, indicating a potential inconsistency in the table.
- 4.MEDIUMreportingIn the Methods (Statistical analysis), clarify that the primary endpoint used a one-sided test (alpha=0.025) while secondary analyses used two-sided tests (alpha=0.05), to avoid ambiguity.The current statement 'Unless specified, a two sided P value <0.05 was considered statistically significant' could confuse readers about the primary analysis's significance threshold.
- 5.MEDIUMreportingAdd an explicit statement in the Methods or Acknowledgments that the trial was reported according to the CONSORT guideline, in addition to including the CONSORT diagram.Explicitly naming the reporting guideline strengthens transparency and aligns with journal expectations for randomised trials.
- 6.MEDIUMethicsIn the Ethics section, consider naming the specific ethics committees (or providing a reference to the approval documents) to fully satisfy the 'named ethics body' criterion.While the current statement is adequate, naming the committees would enhance transparency and reproducibility.
- 7.MEDIUMdata codeIn the Data Availability statement, consider also depositing the analysis code in a version-controlled public repository (e.g., GitHub) with a DOI, in addition to the supplementary appendix.A version-controlled repository improves code accessibility and long-term reproducibility beyond a static supplementary file.
- 8.LOWstatisticsIn the Methods (Statistical analysis), clarify the handling of missing data for quality-of-life questionnaires (e.g., imputation methods) to strengthen the assumptions_verified criterion.Explicitly describing missing data handling would improve the completeness of the statistical methods.
- 9.LOWreportingIn the Discussion, consider adding a note on the generalisability of the findings beyond Chinese women, given the single-country setting.While limitations already mention this, a more explicit discussion of generalisability would be helpful for readers.
- 10.LOWreportingIn the Methods (Randomisation and masking), provide more detail on the randomisation code generation and envelope preparation to further reassure allocation concealment.Additional detail would strengthen confidence in the allocation concealment process.
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.