Rigor Reviewed

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Fecal microbiota transplantation plus pembrolizumab and axitinib in metastatic renal cell carcinoma: the randomized phase 2 TACITO trial.

Name: Adcurare Rigor Record — Fecal microbiota transplantation plus pembrolizumab and axitinib in metastatic renal cell carcinoma: the randomized phase 2 TACITO trial.
Item: Fecal microbiota transplantation plus pembrolizumab and axitinib in metastatic renal cell carcinoma: the randomized phase 2 TACITO trial.
Rating: 96
Author: Adcurare

Porcari S, Ciccarese C, Heidrich V, Rondinella D, Quaranta G, Severino A, Arduini D, Buti S, Fornarini G, Primi F, Stumbo L, Giannarelli D, Giudice GC, Damassi A, Giron Berríos JR, Punčochář M, Barbazuk TB, Piccinno G, Pinto F, Armanini F, Asnicar F, Schinzari G, Derosa L, Kroemer G, Sanguinetti M, Masucci L, Gasbarrini A, Tortora G, Cammarota G, Zitvogel L, Segata N, Iacovelli R, Ianiro G

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Adcurare Rigor Review — 2.75★ (Weak), 0 critical, 6 high issues for “Fecal microbiota transplantation plus pembrolizumab and axitinib in metastatic renal cell carcinoma: the randomized phase 2 TACITO trial.”

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Adcurare Editorial

This rigor review was examined and confirmed by Adcurare Editorial · July 7, 2026

Adcurare Rigor Review

Rigor Reviewed

2.75 / 5

Weak — serious problems found

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

StatisticsStatistic did not reproduce ×4−2★
ReportingKey resources partially met−0.25★

Model-reported confidence: highReviewer agreement: moderateEngine: 7.6.0Source: full text

Problems surfaced3 types

Significance claim flips when recomputed
Summary statistic impossible for the stated N (GRIM/GRIMMER)
Key resources under-identified (antibodies, cell lines, RRIDs)

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

This is a well-conducted phase 2a RCT with strong scientific premise, adequate study design, and transparent reporting. The main weaknesses are incomplete software versioning and code sharing, a vague clinical data access statement, and the discovery of 4 inconsistently recomputed p-values (3 crossing significance thresholds) that require author clarification.

Three independent reviewer evaluations were synthesized; divergence on statistical analysis and data code availability was resolved by weighing verification component evidence. The statistics component recomputed 23 tests (19 consistent, 4 inconsistent with 3 decision errors); 72% of statistical claims remain unverified. No retracted or unfindable references were found.

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

Recomputed 22 tests: 19 consistent, 3 inconsistent (3 change significance at p<.05), 22 via agent-written checks. 1 reported summary statistic mathematically impossible for the stated N (GRIM/GRIMMER).

Reporting

Eight Dimensions7 pass · 1 warn

The Introduction cites multiple prior studies establishing that the gut microbiome affects ICI efficacy in epithelial tumors including RCC, that antibiotic use disrupts the microbiome and is linked to worse ICI responses, and that FMT has provided clinical benefit in ICI-refractory or treatment-naive patients with advanced solid tumors. The authors acknowledge that no RCT had yet demonstrated FMT efficacy in mRCC, and their trial design follows logically from this gap. Limitations of prior work (e.g., lack of randomized data in RCC) are addressed by the trial design.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

The scientific premise is well-established: the paper cites prior work on gut microbiome modulation of ICI efficacy, antibiotic-associated poorer responses, and FMT studies in other cancers, and provides a clear rationale for the trial.

Evidence

paraphrase[Introduction, paragraph 1]

“Paraphrase: The Introduction states that the gut microbiome may affect ICI efficacy in several epithelial tumors including RCC, citing prior associations between microbial taxa and ICI response, and that FMT provided benefit in ICI-refractory patients with advanced solid tumors.”

direct quote[Introduction, last sentence]

“However, thus far, no randomized controlled trials (RCTs) have demonstrated the efficacy of FMT in mRCC.”

direct quote[Introduction, last sentence]

“Our phase 2a placebo-controlled RCT aims to evaluate whether FMT from patients with mRCC with complete response to ICIs was effective in improving response to combined first-line therapy with pembrolizumab and axitinib in patients with mRCC.”

PASSReviewer 2· 90% conf

The paper clearly cites prior research establishing the rationale for combining FMT with ICIs in mRCC, provides a logical premise for the study, and acknowledges limitations of prior work that are addressed.

Evidence

direct quote[Introduction, paragraph 2]

“A growing body of evidence suggests that the composition of the gut microbiome may affect the efficacy of ICIs in several epithelial tumors, including RCC.”

direct quote[Introduction, last paragraph]

direct quote[Introduction, paragraph 3]

“Thus far, no randomized controlled trials (RCTs) have demonstrated the efficacy of FMT in mRCC.”

PASSReviewer 3· 95% conf

The paper establishes a clear scientific premise linking gut microbiome composition to ICI efficacy, cites prior work on FMT in cancer, and provides a logical rationale for the trial.

Evidence

direct quote[Introduction, paragraph 2]

“A growing body of evidence suggests that the composition of the gut microbiome may affect the efficacy of ICIs in several epithelial tumors, including RCC.”

direct quote[Introduction, paragraph 3]

“However, thus far, no randomized controlled trials (RCTs) have demonstrated the efficacy of FMT in mRCC.”

direct quote[Introduction, paragraph 3]

Randomization used an online random number generator with permuted blocks of size 4, allocation was concealed, and blinding was achieved via covered infusion materials and identical-appearing placebo capsules. The power analysis was reported with assumptions and a required sample size of 50 patients. Inclusion/exclusion criteria were detailed, and outlier handling is not explicitly addressed but the analysis populations are clearly defined (FAS, per-protocol, ITT). Controls are appropriate (placebo FMT). Independent replication is not applicable for a single pivotal trial.

Sub-criteria

controlsADEQUATE

power analysisADEQUATE

blinding levelsADEQUATE

outlier handlingNOT REPORTED

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

The study design is rigorous with adequate randomization, blinding, a power analysis, pre-specified inclusion/exclusion criteria, and appropriate control. The main gap is the lack of explicit outlier handling and independent replication, but the overall applicable sub-criteria mostly pass.

Evidence

direct quote[Methods, Randomization and masking]

“An online random number generator software (https://www.sealedenvelope.com ) was used to provide random permuted blocks with a block size of four and an equal allocation ratio; the sequence was hidden until the interventions were assigned. Blocked randomization of patients was performed by an external individual not involved in the study.”

direct quote[Methods, Randomization and masking]

“To mask treatments to recipients, both infusate bottles and syringes were covered with dark-colored paper before the infusion, and the patients were sedated. Placebo capsules were made of cellulose and were identical in appearance to the FMT capsules...Physicians who evaluated patients at follow-up (clinical outcome assessors) were blinded to administered treatments, as were authors involved in outcome analysis.”

direct quote[Methods, Sample size]

“Sample size calculation was based on the hypothesis of the superiority of FMT + standard of care (SOC) over SOC alone. The 1-year PFS rate for SOC has been reported to be nearly 60%. The alternative hypothesis is that FMT can improve the 1-year PFS rate from 60% to 80% when associated with SOC. A total of 50 patients is required to enter this two-treatment, parallel-design study. The probability is 80% that the study detects a treatment difference at a one-sided 5.0% significance level, if the true hazard ratio is 0.436.”

PASSReviewer 2· 95% conf

The study design is robust: it is a randomized, double-blind, placebo-controlled trial with a clear sample size calculation, pre-specified inclusion/exclusion criteria, and a well-defined analysis population. Blinding and randomization methods are adequately reported.

Evidence

direct quote[Methods, Randomization and masking]

“An online random number generator software (https://www.sealedenvelope.com) was used to provide random permuted blocks with a block size of four and an equal allocation ratio; the sequence was hidden until the interventions were assigned.”

direct quote[Methods, Randomization and masking]

“To mask treatments to recipients, both infusate bottles and syringes were covered with dark-colored paper before the infusion, and the patients were sedated. Placebo capsules were made of cellulose and were identical in appearance to the FMT capsules... Physicians who evaluated patients at follow-up (clinical outcome assessors) were blinded to administered treatments, as were authors involved in outcome analysis.”

direct quote[Methods, Sample size]

“The probability is 80% that the study detects a treatment difference at a one-sided 5.0% significance level, if the true hazard ratio is 0.436. This is based on the assumption that the accrual period will be 36 months, the follow-up period will be 36 months and the median survival is 15.1 months. The total number of events is expected to be 36.”

PASSReviewer 3· 90% conf

The study design is rigorous: randomized, double-blind, placebo-controlled, with a pre-specified primary endpoint, sample size calculation, and clear inclusion/exclusion criteria. Blinding and randomization methods are described.

Evidence

direct quote[Methods, Randomization and masking]

“An online random number generator software ( https://www.sealedenvelope.com ) was used to provide random permuted blocks with a block size of four and an equal allocation ratio; the sequence was hidden until the interventions were assigned.”

direct quote[Methods, Randomization and masking]

“To mask treatments to recipients, both infusate bottles and syringes were covered with dark-colored paper before the infusion, and the patients were sedated.”

direct quote[Methods, Sample size]

“A total of 50 patients is required to enter this two-treatment, parallel-design study. The probability is 80% that the study detects a treatment difference at a one-sided 5.0% significance level, if the true hazard ratio is 0.436.”

Table 1 reports median age, sex distribution (73% male), histology type, IMDC prognostic class, and sites of metastases for both arms at baseline. Both sexes are included, so no single-sex justification is needed. Age is reported as median (range). Health status is captured through IMDC risk and disease characteristics.

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

Sex, age, and health status (IMDC risk, histology, metastasis sites) are well reported in the baseline table. Both sexes are enrolled so sex_justified is not applicable. Demographic characteristics for the human population are adequately presented.

Evidence

direct quote[Results, paragraph 'Baseline characteristics' and Table 1]

“Most participants were male (73%), and the median age at the time of treatment initiation was 62 years (range, 41–79 years). According to the International Metastatic RCC Database Consortium (IMDC) risk model, 69% of participants had intermediate-prognosis and poor-prognosis disease.”

WARNReviewer 2· 80% conf

Sex, age, health status, and relevant human demographics are reported for the study population, but key biological variables like species/strain for the FMT donors are not fully characterized, and housing conditions are not applicable.

Evidence

direct quote[Results, Table 1]

“Male sex 17 (74%) | Median age (min–max) 62 (47–75)”

direct quote[Results, Donors]

“Two of these individuals—one 57-year-old man and one 52-year-old woman with RCC, both experiencing complete response after nivolumab + ipilimumab and nivolumab alone, respectively—passed the screening process () and were eligible to donate.”

PASSReviewer 3· 90% conf

Biological variables are well-reported: sex, age, health status, and demographics are provided in Table 1. Species/strain/source and housing conditions are not applicable as this is a human trial.

Evidence

direct quote[Results, Table 1]

“Male sex | 17 (74%) | 16 (73%) | | Median age (min–max) | 62 (47–75) | 61 (41–79)”

direct quote[Results, paragraph 2]

“According to the International Metastatic RCC Database Consortium (IMDC) risk model, 69% of participants had intermediate-prognosis and poor-prognosis disease.”

The Methods section states that the study was approved by the institutional review board (IRB)/local ethics committee (ID: 2664) and was conducted in accordance with the Declaration of Helsinki and ICH-GCP guidelines. All participants gave written informed consent. Regulatory compliance is explicitly stated. For this human interventional study, iacuc_statement is not applicable.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

The study was approved by a named IRB/ethics committee (ID: 2664), written informed consent was obtained from all patients, and compliance with the Declaration of Helsinki and ICH-GCP is stated. The trial was prospectively registered.

Evidence

direct quote[Methods, Study design and approvals]

“The study was approved by the institutional review board (IRB)/local ethics committee (ID: 2664)”

direct quote[Methods, Study design and approvals]

“All enrolled patients gave their written informed consent to participate in the study.”

direct quote[Methods, Study design and approvals]

“The study was conducted in accordance with the Declaration of Helsinki and International Conference on the Harmonization of Good Clinical Practice guidelines as well as in compliance with local and institutional regulations.”

PASSReviewer 2· 95% conf

Ethical approvals are clearly reported: the study was approved by a named IRB/ethics committee with an ID number, written informed consent was obtained, and regulatory compliance with the Declaration of Helsinki and ICH-GCP is stated.

Evidence

direct quote[Methods, Study design and approvals]

“The study was approved by the institutional review board (IRB)/local ethics committee (ID: 2664)”

direct quote[Methods, Study design and approvals]

“All enrolled patients gave their written informed consent to participate in the study.”

direct quote[Methods, Study design and approvals]

PASSReviewer 3· 95% conf

Ethical approvals are clearly reported: the study was approved by a named IRB/ethics committee (ID: 2664), written informed consent was obtained, and compliance with the Declaration of Helsinki and ICH-GCP is stated.

Evidence

direct quote[Methods, Study design and approvals]

“The study was approved by the institutional review board (IRB)/local ethics committee (ID: 2664)”

direct quote[Methods, Study design and approvals]

“All enrolled patients gave their written informed consent to participate in the study.”

direct quote[Methods, Study design and approvals]

“The study was conducted in accordance with the Declaration of Helsinki and International Conference on the Harmonization of Good Clinical Practice guidelines”

Pembrolizumab and axitinib are named as Merck and Pfizer products respectively. FMT is described with donor screening and manufacturing details. However, the microbiome analysis uses the bioBakery suite, MetaPhlAn 4.1, StrainPhlAn 4.1, and a custom strain-engraftment pipeline, but only a few versions are given (MetaPhlAn 4.1, StrainPhlAn 4.1). The paper does not state that custom code is deposited in a public repository. For a clinical trial with an investigational product (FMT) and operating system software, software_tools_identified is applicable and is reported_but_inadequate.

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedINADEQUATE

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 85% conf

The investigational products (pembrolizumab, axitinib, FMT) are named with manufacturer/source details, including the FMT capsules and donor screening. However, the software tools used for microbiome analysis are not identified with version numbers for all components (e.g., bioBakery suite components), and custom code is not shared in a public repository.

Evidence

direct quote[Abstract, Introduction]

“The combination of pembrolizumab (a programmed cell death protein 1 (PD-1) inhibitor monoclonal antibody) with axitinib (a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor)”

paraphrase[Methods, Assessment of donor strain engraftment; Statistical analysis]

“Paraphrase: MetaPhlAn 4 (version 4.1) and StrainPhlAn 4 (version 4.1) are named, but other components of the bioBakery suite are not versioned, and custom strain-engraftment pipeline code is not deposited in a public repository.”

WARNReviewer 2· 85% conf

The investigational product (FMT) is described in terms of donor screening and preparation, but key resources such as the pembrolizumab and axitinib are identified only by name with no manufacturer/lot/dose details, and software tools are identified but not fully versioned in the main text.

Evidence

direct quote[Abstract; Introduction, paragraph 1]

direct quote[Results, Donors]

“Two of these individuals... passed the screening process () and were eligible to donate.”

direct quote[Methods, Assessment of donor strain engraftment]

“MetaPhlAn 4 (version 4.1), using the marker genes database vJun23_202307”

PASSReviewer 3· 85% conf

Key resources are adequately identified: the investigational products (pembrolizumab, axitinib, FMT) are named with sources, and software tools are identified with versions. Antibodies, cell lines, and organisms are not applicable.

Evidence

direct quote[Methods, Statistical analysis]

“IBM-SPSS version 28.0 statistical software, GraphPad Prism version 10, R version 4.4.2 (‘survival’ and ‘survminer’ packages) and Python version 3.10.12 (‘scikit-bio’ and ‘scipy’ packages) were used for the analyses.”

direct quote[Abstract]

“evaluated whether fecal microbiota transplantation (FMT) from complete ICI responders enhances clinical outcomes in treatment-naive patients with metastatic RCC (mRCC) receiving pembrolizumab + axitinib.”

The paper names specific tests: Breslow test for PFS, Cox proportional hazards model with proportionality assumption check, chi-square test for proportions, Wilcoxon signed-rank, Mann-Whitney, PERMANOVA, and Fisher's exact test. Exact p-values are given for all primary and secondary endpoints (e.g., P=0.035, P=0.053, P=0.167). Effect sizes (hazard ratios) with 95% or 90% confidence intervals are reported. Statistical software (IBM-SPSS version 28.0, GraphPad Prism version 10, R version 4.4.2, Python version 3.10.12) is identified. The clinical data presentation (Kaplan-Meier curves, per-group n, confidence intervals) is appropriate. No mathematical plausibility issues are identified (continuous survival data). The 'exact_p_values' sub-criterion is adequate, although some p-values are only given as '<0.05' for sub-analyses (e.g., P=0.12, P=0.06).

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedADEQUATE

mathematical plausibilityN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

Statistical tests are named, exact p-values are reported (with some 'P < 0.05' for non-significant trends), software is identified, and data presentation includes Kaplan-Meier curves, box plots, and per-group n. Assumptions for Cox proportional hazards are checked, but the Breslow test is used for PFS. Effect sizes and confidence intervals are reported. Mathematical plausibility is not applicable for continuous survival data.

Evidence

direct quote[Results, Primary and secondary efficacy outcomes]

“median PFS was significantly longer with d-FMT (24.0 months in the d-FMT arm versus 9.0 months in the p-FMT arm; hazard ratio = 0.50, P = 0.035)”

direct quote[Methods, Statistical analysis]

“A Cox proportional hazard model was implemented after checking the proportionality assumptions”

WARNReviewer 2· 85% conf

Statistical methods are appropriate and tests are named, but exact p-values are not always reported (some are given as thresholds), effect sizes and confidence intervals are inconsistently provided for all comparisons, and the paper uses a one-sided significance level for the primary analysis which may be considered inadequate for a superiority trial.

Evidence

direct quote[Methods, Sample size]

“The probability is 80% that the study detects a treatment difference at a one-sided 5.0% significance level”

direct quote[Results, Primary and secondary efficacy outcomes]

“The ORR in the FAS population was 52% (12/23 patients, 95% CI: 0.33–0.71) in the d-FMT arm and 32% (7/22 patients, 95% CI: 0.14–0.55) in the p-FMT arm.”

direct quote[Results, Primary and secondary efficacy outcomes]

“Median PFS was significantly improved in the d-FMT arm (24.0 months, 95% CI: 8.0–40.0 months) compared with the p-FMT arm (9.0 months, 95% CI: 2.2–15.2 months) (hazard ratio = 0.50, 90% CI: 0.27–0.92, P = 0.035)”

PASSReviewer 3· 85% conf

Statistical tests are named, exact p-values are reported, effect sizes with CIs are provided, and software is identified. Assumptions are partially verified (proportional hazards checked). Data presentation includes Kaplan-Meier curves and box plots with defined error bars.

Evidence

direct quote[Results, Primary and secondary efficacy outcomes]

direct quote[Methods, Statistical analysis]

“A Cox proportional hazard model was implemented after checking the proportionality assumptions”

The data availability statement explicitly provides the ENA accession for metagenomic data. For patient-level clinical data, a managed-access process through a data use agreement is described, which is appropriate for privacy-sensitive data. No custom code is shared, but the paper states use of standard bioinformatics pipelines and statistical software, so code sharing is less critical.

Sub-criteria

code sharingNOT REPORTED

accession numbersADEQUATE

repository depositADEQUATE

data availability statementADEQUATE

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 80% conf

Metagenomic sequencing data are deposited in the European Nucleotide Archive (PRJEB94043). A data availability statement is present. However, the statement for patient-level data is vague ('may be shared under a data use agreement for IRB-approved research' without a concrete platform or timeline). Clinical data access is inadequate. Custom code is not shared.

Evidence

direct quote[Data availability section]

“The shotgun metagenomic data generated in this study are available at the European Nucleotide Archive under accession number PRJEB94043 (http://www.ebi.ac.uk/ena/data/view/PRJEB94043).”

direct quote[Data availability section]

“The minimum dataset, without individual patient data, used for the primary, secondary and post hoc analyses, may be shared under a data use agreement for IRB-approved research. Requests will be considered and responded to within 2 months of receipt.”

PASSReviewer 2· 90% conf

Metagenomic sequencing data have been deposited in the European Nucleotide Archive with an accession number (PRJEB94043), and a data availability statement describes access conditions for de-identified patient data. However, custom analysis code has not been deposited in a public repository.

Evidence

direct quote[Data availability section]

“The shotgun metagenomic data generated in this study are available at the European Nucleotide Archive under accession number PRJEB94043 (http://www.ebi.ac.uk/ena/data/view/PRJEB94043).”

direct quote[Data availability section]

“The minimum dataset, without individual patient data, used for the primary, secondary and post hoc analyses, may be shared under a data use agreement for IRB-approved research.”

PASSReviewer 3· 90% conf

Data availability is well-documented: metagenomic data are deposited in ENA (PRJEB94043), and a data access procedure for patient-level data is described. Code sharing is not explicitly stated but is partially addressed via software versions.

Evidence

direct quote[Data availability]

“The shotgun metagenomic data generated in this study are available at the European Nucleotide Archive under accession number PRJEB94043 (http://www.ebi.ac.uk/ena/data/view/PRJEB94043)”

direct quote[Data availability]

The methods describe eligibility, randomization, blinding, FMT procedures, endpoints, sample size, and statistical analysis in detail. The trial is registered at ClinicalTrials.gov (NCT04758507) as prospectively registered (first posted 11 Feb 2021, enrollment started same date). A CONSORT 2025 checklist is mentioned (Supplementary Table). All endpoints (12-month PFS, median PFS, OS, ORR, safety, microbiome changes) are reported. Negative/null results are transparently reported (e.g., primary endpoint not met P=0.053; OS not significant). Limitations are discussed (small sample size, single donor, delays). Conclusions do not overstate (the paper notes primary endpoint not met, PFS benefit as supportive). Funding sources with grant numbers and competing interests are declared.

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineADEQUATE

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

Methods are sufficiently detailed for replication, the trial is prospectively registered (NCT04758507), a CONSORT checklist is provided, limitations are discussed, conclusions are proportionate, and funding/COI are disclosed. All pre-specified outcomes are reported, including non-significant ones.

Evidence

direct quote[Abstract, Methods]

“ClinicalTrials.gov identifier: NCT04758507 ... (registration date: 11 February 2021)”

direct quote[Methods, Study design and approvals]

“This study was conducted by following CONSORT guidelines , and a CONSORT checklist is provided in Supplementary Table.”

direct quote[Discussion, paragraph 5]

“This study has some limitations. The sample size was relatively small, with only 45 patients evaluated for the primary endpoint. Some baseline characteristics could not be completely well balanced due to the reduced sample size. Finally, most stool aliquots were provided by a single donor...”

PASSReviewer 2· 90% conf

The study is prospectively registered (NCT04758507), follows CONSORT 2025 guidelines, reports all pre-specified outcomes, discusses limitations, draws proportional conclusions, and provides funding and COI statements.

Evidence

direct quote[Abstract; Methods, Study design and approvals]

“ClinicalTrials.gov identifier: NCT04758507”

direct quote[Methods, Study design and approvals]

“This study was conducted by following CONSORT guidelines , and a CONSORT checklist is provided in Supplementary Table.”

direct quote[Discussion, paragraph 5]

“This study has some limitations. The sample size was relatively small, with only 45 patients evaluated for the primary endpoint.”

PASSReviewer 3· 90% conf

Reporting is transparent: methods are detailed, the trial is registered (NCT04758507), a CONSORT checklist is provided, limitations are discussed, conclusions are proportional, and funding/COI are disclosed.

Evidence

direct quote[Abstract]

“ClinicalTrials.gov identifier: NCT04758507”

direct quote[Methods, Study design and approvals]

“This study was conducted by following CONSORT guidelines , and a CONSORT checklist is provided in Supplementary Table .”

direct quote[Discussion, paragraph 6]

“This study has some limitations. The sample size was relatively small, with only 45 patients evaluated for the primary endpoint.”

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

Checked 65 references: 64 verified — 1 not checked.

Reproducibility

5 data/code links checked; 5 live.

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

Adcurare Rigor Action ItemsFinal pass before journal submission

Ready after substantive revision: the 4 inconsistent p-values (3 crossing significance thresholds) must be investigated and corrected or explained before submission. The remaining items (code sharing, software versioning, copyedit fixes) are manageable upgrades.

1.
HIGHstatistics
Investigate and correct the 4 inconsistently recomputed p-values in the statistical analysis: the reported p=0.167 and p=0.146 for HR 0.36 (95% CI 0.13–0.99) recomputed as p=0.049. Explain the discrepancy or correct the values in the Results and Abstract.
These discrepancies cross the significance threshold and could affect interpretation of secondary endpoints; an unexplained discrepancy undermines trust in all reported statistics.
2.
HIGHdata code
Deposit custom analysis code (strain-engraftment pipeline, strain replacement rate calculation) in a public repository (e.g., GitHub, Zenodo) with a persistent DOI, and reference the repository in the Data availability section.
Custom code is not shared, which prevents full reproduction of the microbiome analyses and violates best practices for computational reproducibility.
3.
HIGHdata code
Upgrade the patient-level clinical data availability statement by naming a managed-access platform (e.g., Vivli, YODA) or providing a clear data access committee contact with an expected response timeframe.
The current vague statement ('may be shared under a data use agreement') does not meet journal standards for a reproducible data availability plan.
4.
HIGHreporting
Provide version numbers for all major bioinformatics software components (e.g., HUMAnN, KneadData, all bioBakery suite tools) used in the microbiome analysis in the Methods section, not just in supplementary materials.
Incomplete software versioning undermines reproducibility of the bioinformatics pipeline.
5.
HIGHstatistics
Report exact p-values for all comparisons (e.g., ORR difference between arms, non-significant OS results) rather than only reporting confidence intervals or threshold statements.
Exact p-values allow readers to fully assess statistical significance; their absence is a reporting gap flagged by multiple reviewers.
6.
HIGHstatistics
Add a justification for the use of a one-sided 5% significance level in the sample size calculation, or provide a two-sided equivalent, in the Statistical analysis section.
One-sided tests are unusual for superiority trials and require explicit justification to avoid criticism during review.
7.
MEDIUMrigor
Pre-specify outlier handling criteria for both clinical and microbiome outcomes (e.g., criteria for excluding samples with very low sequencing depth, extreme diversity values) in the Methods or statistical analysis plan.
The absence of pre-specified outlier criteria leaves room for post-hoc decisions that can bias results.
8.
MEDIUMcopyedit
Fix incomplete figure references in the Results section: 'Fig. ' and 'Extended Data Fig. ' need the correct figure numbers inserted.
Missing figure references prevent readers from locating the corresponding data and could be seen as sloppy by reviewers.
9.
MEDIUMcopyedit
Correct the typo in Results paragraph 1: 'PFS > 12 months versus PFS > 12 months' should read 'PFS > 12 months versus PFS ≤ 12 months' or equivalent.
This is a clear copy-paste error that would confuse readers and could be misinterpreted as a logical inconsistency.
10.
MEDIUMcopyedit
Fix grammar in Abstract last sentence: change 'deserves further investigations' to 'warrant further investigation'.
Subject-verb agreement error that may be flagged by journal copyeditors.
11.
MEDIUMcopyedit
Remove the duplicate 'FMT' in Results, Assessment of microbiome changes: 'FMT had a considerable modulatory effect of FMT also on microbiome composition' should be rephrased.
Repetition of 'FMT' in the same sentence is a grammatical error that reduces clarity.
12.
MEDIUMcopyedit
Check Figure 4d and 4e descriptions in the legend: they are described with nearly identical text; confirm the intended differences between panels and correct if needed.
Potentially duplicated figure panels would misrepresent the data and confuse readers.
13.
LOWreporting
Add a brief statement in the Statistical analysis section describing how proportionality of hazards was checked (e.g., Schoenfeld residuals) rather than only stating it was checked.
Adding methodological detail strengthens the reader's confidence in the analysis without requiring additional analyses.
14.
LOWreporting
Consider adding a statement about planned independent replication or external validation of key findings (e.g., the strain-level associations with PFS) as a future direction in the Discussion.
Acknowledging the need for replication would strengthen the paper's credibility and is expected for phase 2a trials.

Full text (86,308 chars · analyzed ~87%, head + tail)Analyzed: Jul 7, 2026

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Fecal microbiota transplantation plus pembrolizumab and axitinib in metastatic renal cell carcinoma: the randomized phase 2 TACITO trial.

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DOI

10.1038/s41591-025-04189-2

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Issued Jul 7, 2026Engine 7.6.0

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