Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

15-strain live biotherapeutic product or same donor fecal microbiota transplant for recurrent Clostridioides difficile infection: a randomized phase 1b trial.

Name: Kaimen Rigor review — 15-strain live biotherapeutic product or same donor fecal microbiota transplant for recurrent Clostridioides difficile infection: a randomized phase 1b trial.
Item: 15-strain live biotherapeutic product or same donor fecal microbiota transplant for recurrent Clostridioides difficile infection: a randomized phase 1b trial.
Rating: 59
Author: Alpha1

Bethlehem L, Bartu L, Marke G, Mar P, Feldman S, Eggers J, Ruprecht C, Britton GJ, Aggarwala V, Bongers G, Li Z, Yang N, Hohmann EL, Mogno I, Faith JJ, Grinspan A

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Kaimen Rigor review — 2.5★ (Weak), 0 critical, 6 high issues for “15-strain live biotherapeutic product or same donor fecal microbiota transplant for recurrent Clostridioides difficile infection: a randomized phase 1b trial.”

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This rigor review was examined and confirmed by Alpha1 Editorial · August 15, 2026

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15-strain live biotherapeutic product or same donor fecal microbiota transplant for recurrent Clostridioides difficile infection: a randomized phase 1b trial.

Bethlehem L, Bartu L, Marke G, Mar P, Feldman S, Eggers J, Ruprecht C, Britton GJ, Aggarwala V, Bongers G, Li Z, Yang N, Hohmann EL, Mogno I, Faith JJ, Grinspan A

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DOI

10.1038/s41591-026-04442-2

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Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

15-strain live biotherapeutic product or same donor fecal microbiota transplant for recurrent Clostridioides difficile infection: a randomized phase 1b trial.

Bethlehem L, Bartu L, Marke G, Mar P, Feldman S, Eggers J, Ruprecht C, Britton GJ, Aggarwala V, Bongers G, Li Z, Yang N, Hohmann EL, Mogno I, Faith JJ, Grinspan A

Paper source

15-strain live biotherapeutic product or same donor fecal microbiota transplant for recurrent Clostridioides difficile infection: a randomized phase 1b trial.

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Alpha1 Editorial

This rigor review was examined and confirmed by Alpha1 Editorial · August 15, 2026

Kaimen Rigor review

Kaimen Rigor reviewed

2.5 / 5

Weak — serious problems found

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

IntegrityIntegrity concern ×2−1★
ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
ClaimsTreatment effect not shown to be clinically meaningful−0.5★
ReportingStudy design partially met−0.25★
ReportingStatistical analysis partially met−0.25★

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

Biggest issues

01Efficacy rests on an unvalidated surrogate endpoint
highOverreachreviewer-assessedFull detail
The primary efficacy claim is prevention of recurrent C. difficile infection (rCDI) at 8 weeks, which is a clinical outcome. However, the trial is a phase 1b with small sample size (N=18) and the primary endpoint is safety, not efficacy. The efficacy outcome is recurrence of CDI, which is a clinical event, but the trial is not powered for efficacy and the claim of 'similar efficacy' is based on a small number of events. The surrogate issue arises because the paper also emphasizes engraftment of bacterial strains as a secondary outcome and uses it to support the efficacy claim, but engraftment is a surrogate for clinical benefit. The paper does not provide validated evidence linking engraftment to prevention of rCDI recurrence, and target engagement at the tested dose is not established in terms of a dose-response for clinical outcome. The efficacy claim rests on a small clinical trial with a surrogate (engraftment) used to infer efficacy.
“For secondary outcomes of efficacy and engraftment, recurrent Clostridioides difficile infection was prevented eight weeks after dosing in seven out of nine LBP patients, similar to eight out of nine FMT patients.”
Find in source
02Treatment effect not shown to be clinically meaningful
highOverreachreviewer-assessedFull detail
The reported effect size for the primary efficacy outcome is the prevention of rCDI recurrence at 8 weeks: 7/9 (78%) for LBP and 8/9 (89%) for FMT. This is a small sample size and the difference between groups is not statistically tested. The effect size is not anchored to a minimal clinically important difference, and the small number of events (3 recurrences total) makes the effect size imprecise. The paper does not provide a confidence interval for the difference or a statistical comparison. The effect size is presented as 'similar' but without formal statistical support or clinical meaningfulness anchor.
“recurrent Clostridioides difficile infection was prevented eight weeks after dosing in seven out of nine LBP patients, similar to eight out of nine FMT patients.”
Find in source

Findings by category

101ArithmeticNumerical inconsistencies 302OverreachOverstated conclusions 03AuthenticityNone found 204DisclosureReporting gaps 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 phase 1b RCT comparing a defined 15-strain LBP (MTC01) with FMT from the same donor is methodologically sound in its premise, ethics, resource description, data/code availability, and reporting transparency. The main weaknesses are the open-label design, small feasibility-based sample size (18 total, not the planned 15/group), and some statistical reporting gaps (threshold p-values, unverified assumptions, post-hoc analyses).

Both reviewers classified the study as interventional (RCT), and I adopt that. The statistics verification covered only 2 tests (1 consistent, 0 inconsistent) due to limited reporting of test statistics/df; most model-based estimates remain unverified. The citation check found no retracted or unresolved references. The integrity check flagged two low-severity internal contradictions (arm order, AE relatedness) that do not change the overall assessment.

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 1 test: 1 consistent, 0 inconsistent; 1 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

8 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

2 findings · worst high

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.

Statistical reporting gaps (tests, assumptions, effect sizes)Assessed
Study-design details incomplete (controls, blinding, power)Assessed

Eight Dimensions6 pass · 2 warn

The introduction cites prior FMT and LBP trials, acknowledges limitations of undefined fecal products, and justifies the need for defined LBPs. The hypothesis that strains with high engraftment frequencies will improve LBP efficacy is logically derived from prior observations. The paper also addresses limitations of prior research by directly comparing the same strains in FMT and LBP forms.

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, citing prior work on FMT and LBPs, and provides a logical rationale for the study.

Evidence

paraphrase[Introduction, paragraph 1]

“The recent approvals of two stool-derived therapeutics, live-jslm (Rebyota) and live-brpk (Vowst) ... mark a key milestone in the development of live microbial therapeutics. However, the undefined composition of these products also highlights our limited understanding of what is necessary and sufficient for success.”

paraphrase[Results, Manufacturing of LBP MTC01]

“Given prior observations that higher engraftment of FMT and LBP donor strains is predictive of relapse prevention in rCDI trials of microbial therapeutics, we hypothesized that an LBP comprised of strains with high FMT engraftment frequencies would facilitate high LBP engraftment and protection from relapse.”

“These shared donor-derived FMT and donor-isolated LBP drug products allowed us to compare the safety, efficacy, and engraftment of the same strains manufactured in vitro with the full spectrum donor sourced FMT fecal slurry at two matched doses.”

Introduction ¶3Find in source

PASSReviewer 2· 90% conf

The paper establishes a clear scientific premise with extensive prior work and a logical rationale for comparing LBP and FMT.

Evidence

paraphrase[Introduction, paragraph 1]

“The recent approvals of two stool-derived therapeutics, live-jslm (Rebyota) and live-brpk (Vowst) ... mark a key milestone ... However, the undefined composition of these products also highlights our limited understanding of what is necessary and sufficient for success.”

“We developed a novel cost- and space-efficient platform for manufacturing human-grade LBPs for clinical trials.”

Introduction ¶3Find in source

“fecal-based drugs have little to no overlap in strain composition across the varied donors used in their production – , and therefore the efficacy and safety of such products represent an average across many microbial compositions resulting in uncertainty for individual product batches.”

Introduction ¶2Find in source

Randomization method (block randomization) and unit (individual participant) are reported. The trial is open-label, which is stated but not justified. A power analysis is mentioned but not detailed (no effect size, alpha, or power). Inclusion/exclusion criteria are pre-specified. Outlier handling is not explicitly addressed. Controls are inherent (FMT comparator). Independent replication is not applicable for a single trial.

Sub-criteria

controlsADEQUATE

power analysisINADEQUATE

blinding levelsINADEQUATE

outlier handlingNOT REPORTED

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (2) — the votes behind the verdict

WARNReviewer 1· 85% conf

The trial is randomized and includes a power analysis, but lacks blinding (open-label) and has a small sample size with no formal sample size calculation.

Evidence

“In this open label trial, patients were block randomized (fixed block size = 4) without stratification to receive either high dose FMT, low dose FMT, high dose MTC01, or low dose MTC01.”

MethodsFind in source

“The study was open label with no concealment of the randomization from the clinical team.”

MethodsFind in source

“An original sample size of 15 subjects per group was selected based off feasibility of manufacturing and the size of prior exploratory studies to assess safety and microbiome engraftment in rCDI.”

MethodsFind in source

WARNReviewer 2· 85% conf

The trial is randomized and includes a power analysis, but blinding is absent (open-label) and the sample size is small with no formal justification for the final number.

Evidence

“In this open label trial, patients were block randomized (fixed block size = 4) without stratification to receive either high dose FMT, low dose FMT, high dose MTC01, or low dose MTC01.”

MethodsFind in source

“The study was open label with no concealment of the randomization from the clinical team.”

MethodsFind in source

Sex is reported (15 females, 3 males) and justified by higher incidence in females. Age (median 59.5) and health status (comorbidities listed) are reported. Demographics include race/ethnicity (Hispanic/not-Hispanic). Species/strain and housing conditions are not applicable.

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedADEQUATE

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Sex, age, and health status are reported; demographics are provided. Species/strain and housing are not applicable for a human trial.

Evidence

paraphrase[Results, Phase-1b clinical trial]

“The median patient age was 59.5 with 15 females and 3 males. The higher enrolment of female participants reflects the higher incidence of rCDI in females.”

“hispanic | 2 (40%) | 0 (0%) | 1 (20%) | 0 (0%)”

Table 2Find in source

PASSReviewer 2· 90% conf

Sex, age, and health status are reported; demographics are provided. Species/strain and housing are not applicable for a human trial.

Evidence

paraphrase[Results, Phase-1b clinical trial]

“The median patient age was 59.5 with 15 females and 3 males ... The higher enrolment of female participants reflects the higher incidence of rCDI in females”

paraphrase[Table 2]

“Table 2. Baseline characteristics and secondary outcome of recurrence at week 8 ... hispanic ... not-hispanic ... male ... female”

The paper states IRB approval (Icahn School of Medicine IRB, STUDY-23-00563) and that all participants provided written informed consent. Regulatory compliance is implied through IND submission and FDA interactions.

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 approval from a named IRB and informed consent are documented.

Evidence

“Ethical approval was obtained from the (Icahn School of Medicine IRB, STUDY-23-00563), and all participants provided written informed consent prior to enrolment.”

EthicsFind in source

paraphrase[Online Methods, Trial design and ethics approval]

“Patients were consented at Mount Sinai Hospital under IRB STUDY-23–00563.”

PASSReviewer 2· 95% conf

Ethical approval from a named IRB and informed consent are documented.

Evidence

“Patients were consented at Mount Sinai Hospital under IRB STUDY-23–00563”

EthicsFind in source

“all participants provided written informed consent prior to enrolment.”

EthicsFind in source

MTC01 strains are identified by species and source; manufacturing details are extensive. FMT is described with donor and processing. Software (Strainer, Metaphlan4, R packages) is named with versions. Antibodies, cell lines, and mycoplasma testing are not applicable.

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedADEQUATE

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 (MTC01 and FMT) are thoroughly described, and software tools are identified.

Evidence

paraphrase[Results, Manufacturing of LBP MTC01]

“Drug candidate “Microbiome Translational Center drug 01” (MTC01) is composed of 15 obligate anaerobe bacterial strains isolated from a single FMT donor (D283).”

paraphrase[Online Methods, Statistical analyses]

“Linear mixed effects models, using the lme4 R package, were used to assess differences in engraftment.”

PASSReviewer 2· 85% conf

The investigational products (MTC01 and FMT) are thoroughly described, and software tools are identified.

Evidence

“Drug candidate “Microbiome Translational Center drug 01” (MTC01) is composed of 15 obligate anaerobe bacterial strains isolated from a single FMT donor (D283)”

ResultsFind in source

“Linear mixed effects models, using the lme4 R package”

Statistical analysisFind in source

Tests (linear mixed effects, Wilcoxon) are named. Assumptions are not explicitly verified. Exact p-values are sometimes given (e.g., p=0.004) but also thresholds (p<1.0×10−8). Effect sizes with CIs are reported. Software is identified. Data presentation includes individual data points in figures. Mathematical plausibility checks were not possible for most statistics.

Sub-criteria

tests namedADEQUATE

exact p valuesINADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedNOT REPORTED

mathematical plausibilityN/A

Per reviewer (2) — the votes behind the verdict

WARNReviewer 1· 80% conf

Statistical tests are named and effect sizes with CIs are reported, but p-values are often reported as thresholds and some analyses are post-hoc.

Evidence

paraphrase[Online Methods, Statistical analyses]

“Linear mixed effects models, using the lme4 R package, were used to assess differences in engraftment.”

paraphrase[Results, Engraftment]

“High dose MTC01 had the highest overall number of the 15 strains colonized even when compared with high dose FMT (β = 3.9, 95%CI [1.8,6.0], p=0.004).”

paraphrase[Results, Engraftment]

“we detect MTC01 strains far more often in recipients after dosing than prior to dosing (p<1.0×10−8 for all groups; linear mixed effects model)”

WARNReviewer 2· 80% conf

Statistical tests are named and effect sizes with CIs are reported, but p-values are often reported as thresholds and some analyses are post-hoc.

Evidence

“High dose MTC01 had the highest overall number of the 15 strains colonized even when compared with high dose FMT (β = 3.9, 95%CI [1.8,6.0], p=0.004; ).”

ResultsFind in source

paraphrase[Results, Engraftment]

“we detect MTC01 strains far more often in recipients after dosing than prior to dosing (p<1.0×10−8 for all groups; linear mixed effects model)”

Data availability statement names a repository (PRJNA1322507) for metagenomic data and mentions supplementary materials. Code is available on GitHub. Individual clinical metadata are in supplementary tables. Managed access is not needed as data are not identifiable.

Sub-criteria

code sharingADEQUATE

accession numbersADEQUATE

repository depositADEQUATE

data availability statementADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Data availability statement is concrete, with metagenomic data deposited and code shared on GitHub.

Evidence

paraphrase[Data availability]

“Metagenomic sequencing data are available at PRJNA1322507 (https://www.ncbi.nlm.nih.gov/bioproject/PRJNA1322507).”

“Custom code used for strain tracking is available at GitHub ( https://github.com/jeremiahfaith/strainer2 ).”

Data availabilityFind in source

PASSReviewer 2· 90% conf

Data availability statement is concrete, with metagenomic data deposited and code shared on GitHub.

Evidence

“Metagenomic sequencing data are available at PRJNA1322507 (https://www.ncbi.nlm.nih.gov/bioproject/PRJNA1322507)”

Data availabilityFind in source

“Custom code used for strain tracking is available at GitHub ( https://github.com/jeremiahfaith/strainer2 ).”

Data availabilityFind in source

Trial registration (NCT05911997) is provided. Methods are comprehensive. CONSORT checklist is mentioned. All outcomes are reported. Limitations are discussed (manufacturing time, endoscopic delivery). Conclusions are proportional. Funding and competing interests are stated.

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

The trial is registered, methods are detailed, limitations are discussed, and funding/COI are disclosed.

Evidence

“ClinicalTrials.gov (http://ClinicalTrials.gov) identifier: NCT05911997”

AbstractFind in source

“A key limitation to the manufacturing process used here is the time restriction of only manufacturing two strains per week, which could be prohibitive to produce very large consortia.”

Discussion ¶2Find in source

paraphrase[Acknowledgements and Competing interests]

“The trial was funded by NIH award DK130337 [JJF] ... Competing interests: J.J.F. is on the scientific advisory board of Vedanta Biosciences...”

PASSReviewer 2· 85% conf

The trial is registered, methods are detailed, limitations are discussed, and funding/COI are disclosed.

Evidence

“ClinicalTrials.gov (http://ClinicalTrials.gov) identifier: NCT05911997”

AbstractFind in source

“A key limitation to the manufacturing process used here is the time restriction of only manufacturing two strains per week”

Discussion ¶2Find in source

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 70 references by DOI: 65 verified — 5 no DOI (shown, not verified).

2 data/code links checked; 2 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 typo, consistency, clarity.

Kaimen Rigor Action ItemsFinal pass before journal submission

The published work is robust in its core design, ethics, and data sharing, but an informed reader should weigh the open-label design, the small feasibility-based sample size, and the threshold-only p-values when interpreting efficacy claims. The minor internal inconsistencies (arm order, AE relatedness) and the species-name typo are cosmetic and do not warrant an erratum, but the lack of a formal power analysis and assumption checks are worth noting in any independent re-analysis.

1.
HIGHrigor
Add a formal a priori power analysis with effect size, alpha, and power to the Methods section, or explicitly justify the final sample size of 18 patients relative to the original 15-per-group target.
The current power analysis is feasibility-based and the final sample size deviates from the stated target, which weakens the statistical foundation for efficacy claims.
2.
HIGHrigor
Provide a rationale for the open-label design and describe any blinding measures for outcome assessors, or acknowledge the potential bias in the Discussion.
The open-label design with no concealment is a known source of bias that should be explicitly justified or mitigated.
3.
HIGHstatistics
Report exact p-values for all statistical tests instead of threshold-only values (e.g., p<1.0×10−8) in the Results section.
Threshold-only p-values reduce transparency and prevent readers from assessing the strength of evidence.
4.
HIGHstatistics
Add a statement on verification of statistical assumptions (e.g., normality, homoscedasticity) for the linear mixed effects models in the Methods.
Assumption checks are currently not reported, which is a standard expectation for model-based analyses.
5.
HIGHstatistics
Clarify how outliers were handled in the statistical analyses, or explicitly state that no outliers were excluded.
Outlier handling is not explicitly described, and readers need to know whether any data points were excluded and why.
6.
HIGHreporting
Clarify the post-hoc nature of the engraftment frequency comparison and its exploratory status in the Methods or Results.
Some analyses appear post-hoc; pre-registering or labeling them as exploratory improves transparency.
7.
MEDIUMreporting
Include a CONSORT flow diagram in the main text (currently only mentioned in supplementary).
A CONSORT flow diagram is a standard reporting element for RCTs and improves completeness.
8.
MEDIUMreporting
Add a note in Table 1 indicating whether each adverse event was considered treatment-related, to reconcile with the text stating 'no treatment-related adverse events'.
The current table lists AEs without relatedness, creating an apparent contradiction with the text.
9.
MEDIUMreporting
Standardize the order of trial arms (low dose FMT, high dose FMT, low dose MTC01, high dose MTC01) consistently across the Abstract and Results.
The arm order differs between the abstract and results, which is a minor consistency issue that could confuse readers.
10.
MEDIUMcopyedit
Fix the typo 'Bifididobacterium pseudocatenulatum' to 'Bifidobacterium pseudocatenulatum' in the Results section.
The species name is misspelled, which is a factual error in a scientific name.
11.
MEDIUMdata code
Provide exact version numbers for all software used (e.g., R version, lme4 version) in the Methods.
Exact software versions are needed for reproducibility.
12.
MEDIUMdata code
Consider depositing the full de-identified clinical dataset in a repository with managed access to enhance reproducibility.
While supplementary tables are provided, a managed-access repository would strengthen data sharing for a clinical trial.
13.
LOWcopyedit
Rephrase the abstract sentence 'recurrent Clostridioides difficile infection was prevented eight weeks after dosing in seven out of nine LBP patients' to 'prevented at eight weeks after dosing in seven of nine LBP patients' for clarity.
Minor wording improvement for readability.
14.
LOWcopyedit
Format the model formula 'number _ MTC 01 _ strains _ detected ~ baseline _ drugDose + ( 1 | patient _ id )' using readable notation (e.g., LaTeX or code block).
The current formatting is difficult to read due to spaces and underscores.

Full text (64,427 chars)Analyzed: Aug 15, 2026

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15-strain live biotherapeutic product or same donor fecal microbiota transplant for recurrent Clostridioides difficile infection: a randomized phase 1b trial.

Bethlehem L, Bartu L, Marke G, Mar P, Feldman S, Eggers J, Ruprecht C, Britton GJ, Aggarwala V, Bongers G, Li Z, Yang N, Hohmann EL, Mogno I, Faith JJ, Grinspan A

Read full text (PMC)

DOI

10.1038/s41591-026-04442-2

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Record fingerprint

2630a810c1d6b01b1853568f0b7a4d7f0834c18ea41a00e5a5804c85f34ef496

Verify via API

Issued Aug 15, 2026Engine 7.39.0

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

Kaimen Rigor review

Kaimen Rigor reviewed

2.5 / 5

Weak — serious problems found

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

IntegrityIntegrity concern ×2−1★
ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
ClaimsTreatment effect not shown to be clinically meaningful−0.5★
ReportingStudy design partially met−0.25★
ReportingStatistical analysis partially met−0.25★

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

Biggest issues

01Efficacy rests on an unvalidated surrogate endpoint
highOverreachreviewer-assessedFull detail
The primary efficacy claim is prevention of recurrent C. difficile infection (rCDI) at 8 weeks, which is a clinical outcome. However, the trial is a phase 1b with small sample size (N=18) and the primary endpoint is safety, not efficacy. The efficacy outcome is recurrence of CDI, which is a clinical event, but the trial is not powered for efficacy and the claim of 'similar efficacy' is based on a small number of events. The surrogate issue arises because the paper also emphasizes engraftment of bacterial strains as a secondary outcome and uses it to support the efficacy claim, but engraftment is a surrogate for clinical benefit. The paper does not provide validated evidence linking engraftment to prevention of rCDI recurrence, and target engagement at the tested dose is not established in terms of a dose-response for clinical outcome. The efficacy claim rests on a small clinical trial with a surrogate (engraftment) used to infer efficacy.
“For secondary outcomes of efficacy and engraftment, recurrent Clostridioides difficile infection was prevented eight weeks after dosing in seven out of nine LBP patients, similar to eight out of nine FMT patients.”
Find in source
02Treatment effect not shown to be clinically meaningful
highOverreachreviewer-assessedFull detail
The reported effect size for the primary efficacy outcome is the prevention of rCDI recurrence at 8 weeks: 7/9 (78%) for LBP and 8/9 (89%) for FMT. This is a small sample size and the difference between groups is not statistically tested. The effect size is not anchored to a minimal clinically important difference, and the small number of events (3 recurrences total) makes the effect size imprecise. The paper does not provide a confidence interval for the difference or a statistical comparison. The effect size is presented as 'similar' but without formal statistical support or clinical meaningfulness anchor.
“recurrent Clostridioides difficile infection was prevented eight weeks after dosing in seven out of nine LBP patients, similar to eight out of nine FMT patients.”
Find in source

Findings by category

101ArithmeticNumerical inconsistencies 302OverreachOverstated conclusions 03AuthenticityNone found 204DisclosureReporting gaps 05AvailabilityNone found 06Copyedit6 minor suggestions

Numerical inconsistencies

1 finding · worst low

Internal contradictions in the reported numbersAssessed

Recomputed 1 test: 1 consistent, 0 inconsistent; 1 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

8 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

2 findings · worst high

Statistical reporting gaps (tests, assumptions, effect sizes)Assessed
Study-design details incomplete (controls, blinding, power)Assessed

Eight Dimensions6 pass · 2 warn

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, citing prior work on FMT and LBPs, and provides a logical rationale for the study.

Evidence

paraphrase[Introduction, paragraph 1]

paraphrase[Results, Manufacturing of LBP MTC01]

Introduction ¶3Find in source

PASSReviewer 2· 90% conf

The paper establishes a clear scientific premise with extensive prior work and a logical rationale for comparing LBP and FMT.

Evidence

paraphrase[Introduction, paragraph 1]

“We developed a novel cost- and space-efficient platform for manufacturing human-grade LBPs for clinical trials.”

Introduction ¶3Find in source

Introduction ¶2Find in source

Sub-criteria

controlsADEQUATE

power analysisINADEQUATE

blinding levelsINADEQUATE

outlier handlingNOT REPORTED

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (2) — the votes behind the verdict

WARNReviewer 1· 85% conf

The trial is randomized and includes a power analysis, but lacks blinding (open-label) and has a small sample size with no formal sample size calculation.

Evidence

“In this open label trial, patients were block randomized (fixed block size = 4) without stratification to receive either high dose FMT, low dose FMT, high dose MTC01, or low dose MTC01.”

MethodsFind in source

“The study was open label with no concealment of the randomization from the clinical team.”

MethodsFind in source

WARNReviewer 2· 85% conf

The trial is randomized and includes a power analysis, but blinding is absent (open-label) and the sample size is small with no formal justification for the final number.

Evidence

“In this open label trial, patients were block randomized (fixed block size = 4) without stratification to receive either high dose FMT, low dose FMT, high dose MTC01, or low dose MTC01.”

MethodsFind in source

“The study was open label with no concealment of the randomization from the clinical team.”

MethodsFind in source

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedADEQUATE

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Sex, age, and health status are reported; demographics are provided. Species/strain and housing are not applicable for a human trial.

Evidence

paraphrase[Results, Phase-1b clinical trial]

“The median patient age was 59.5 with 15 females and 3 males. The higher enrolment of female participants reflects the higher incidence of rCDI in females.”

“hispanic | 2 (40%) | 0 (0%) | 1 (20%) | 0 (0%)”

Table 2Find in source

PASSReviewer 2· 90% conf

Sex, age, and health status are reported; demographics are provided. Species/strain and housing are not applicable for a human trial.

Evidence

paraphrase[Results, Phase-1b clinical trial]

“The median patient age was 59.5 with 15 females and 3 males ... The higher enrolment of female participants reflects the higher incidence of rCDI in females”

paraphrase[Table 2]

“Table 2. Baseline characteristics and secondary outcome of recurrence at week 8 ... hispanic ... not-hispanic ... male ... female”

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 approval from a named IRB and informed consent are documented.

Evidence

“Ethical approval was obtained from the (Icahn School of Medicine IRB, STUDY-23-00563), and all participants provided written informed consent prior to enrolment.”

EthicsFind in source

paraphrase[Online Methods, Trial design and ethics approval]

“Patients were consented at Mount Sinai Hospital under IRB STUDY-23–00563.”

PASSReviewer 2· 95% conf

Ethical approval from a named IRB and informed consent are documented.

Evidence

“Patients were consented at Mount Sinai Hospital under IRB STUDY-23–00563”

EthicsFind in source

“all participants provided written informed consent prior to enrolment.”

EthicsFind in source

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedADEQUATE

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 (MTC01 and FMT) are thoroughly described, and software tools are identified.

Evidence

paraphrase[Results, Manufacturing of LBP MTC01]

“Drug candidate “Microbiome Translational Center drug 01” (MTC01) is composed of 15 obligate anaerobe bacterial strains isolated from a single FMT donor (D283).”

paraphrase[Online Methods, Statistical analyses]

“Linear mixed effects models, using the lme4 R package, were used to assess differences in engraftment.”

PASSReviewer 2· 85% conf

The investigational products (MTC01 and FMT) are thoroughly described, and software tools are identified.

Evidence

“Drug candidate “Microbiome Translational Center drug 01” (MTC01) is composed of 15 obligate anaerobe bacterial strains isolated from a single FMT donor (D283)”

ResultsFind in source

“Linear mixed effects models, using the lme4 R package”

Statistical analysisFind in source

Sub-criteria

tests namedADEQUATE

exact p valuesINADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedNOT REPORTED

mathematical plausibilityN/A

Per reviewer (2) — the votes behind the verdict

WARNReviewer 1· 80% conf

Statistical tests are named and effect sizes with CIs are reported, but p-values are often reported as thresholds and some analyses are post-hoc.

Evidence

paraphrase[Online Methods, Statistical analyses]

“Linear mixed effects models, using the lme4 R package, were used to assess differences in engraftment.”

paraphrase[Results, Engraftment]

“High dose MTC01 had the highest overall number of the 15 strains colonized even when compared with high dose FMT (β = 3.9, 95%CI [1.8,6.0], p=0.004).”

paraphrase[Results, Engraftment]

“we detect MTC01 strains far more often in recipients after dosing than prior to dosing (p<1.0×10−8 for all groups; linear mixed effects model)”

WARNReviewer 2· 80% conf

Statistical tests are named and effect sizes with CIs are reported, but p-values are often reported as thresholds and some analyses are post-hoc.

Evidence

“High dose MTC01 had the highest overall number of the 15 strains colonized even when compared with high dose FMT (β = 3.9, 95%CI [1.8,6.0], p=0.004; ).”

ResultsFind in source

paraphrase[Results, Engraftment]

“we detect MTC01 strains far more often in recipients after dosing than prior to dosing (p<1.0×10−8 for all groups; linear mixed effects model)”

Sub-criteria

code sharingADEQUATE

accession numbersADEQUATE

repository depositADEQUATE

data availability statementADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Data availability statement is concrete, with metagenomic data deposited and code shared on GitHub.

Evidence

paraphrase[Data availability]

“Metagenomic sequencing data are available at PRJNA1322507 (https://www.ncbi.nlm.nih.gov/bioproject/PRJNA1322507).”

“Custom code used for strain tracking is available at GitHub ( https://github.com/jeremiahfaith/strainer2 ).”

Data availabilityFind in source

PASSReviewer 2· 90% conf

Data availability statement is concrete, with metagenomic data deposited and code shared on GitHub.

Evidence

“Metagenomic sequencing data are available at PRJNA1322507 (https://www.ncbi.nlm.nih.gov/bioproject/PRJNA1322507)”

Data availabilityFind in source

“Custom code used for strain tracking is available at GitHub ( https://github.com/jeremiahfaith/strainer2 ).”

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

The trial is registered, methods are detailed, limitations are discussed, and funding/COI are disclosed.

Evidence

“ClinicalTrials.gov (http://ClinicalTrials.gov) identifier: NCT05911997”

AbstractFind in source

“A key limitation to the manufacturing process used here is the time restriction of only manufacturing two strains per week, which could be prohibitive to produce very large consortia.”

Discussion ¶2Find in source

paraphrase[Acknowledgements and Competing interests]

“The trial was funded by NIH award DK130337 [JJF] ... Competing interests: J.J.F. is on the scientific advisory board of Vedanta Biosciences...”

PASSReviewer 2· 85% conf

The trial is registered, methods are detailed, limitations are discussed, and funding/COI are disclosed.

Evidence

“ClinicalTrials.gov (http://ClinicalTrials.gov) identifier: NCT05911997”

AbstractFind in source

“A key limitation to the manufacturing process used here is the time restriction of only manufacturing two strains per week”

Discussion ¶2Find in source

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 70 references by DOI: 65 verified — 5 no DOI (shown, not verified).

2 data/code links checked; 2 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 typo, consistency, clarity.

Kaimen Rigor Action ItemsFinal pass before journal submission

1.
HIGHrigor
Add a formal a priori power analysis with effect size, alpha, and power to the Methods section, or explicitly justify the final sample size of 18 patients relative to the original 15-per-group target.
The current power analysis is feasibility-based and the final sample size deviates from the stated target, which weakens the statistical foundation for efficacy claims.
2.
HIGHrigor
Provide a rationale for the open-label design and describe any blinding measures for outcome assessors, or acknowledge the potential bias in the Discussion.
The open-label design with no concealment is a known source of bias that should be explicitly justified or mitigated.
3.
HIGHstatistics
Report exact p-values for all statistical tests instead of threshold-only values (e.g., p<1.0×10−8) in the Results section.
Threshold-only p-values reduce transparency and prevent readers from assessing the strength of evidence.
4.
HIGHstatistics
Add a statement on verification of statistical assumptions (e.g., normality, homoscedasticity) for the linear mixed effects models in the Methods.
Assumption checks are currently not reported, which is a standard expectation for model-based analyses.
5.
HIGHstatistics
Clarify how outliers were handled in the statistical analyses, or explicitly state that no outliers were excluded.
Outlier handling is not explicitly described, and readers need to know whether any data points were excluded and why.
6.
HIGHreporting
Clarify the post-hoc nature of the engraftment frequency comparison and its exploratory status in the Methods or Results.
Some analyses appear post-hoc; pre-registering or labeling them as exploratory improves transparency.
7.
MEDIUMreporting
Include a CONSORT flow diagram in the main text (currently only mentioned in supplementary).
A CONSORT flow diagram is a standard reporting element for RCTs and improves completeness.
8.
MEDIUMreporting
Add a note in Table 1 indicating whether each adverse event was considered treatment-related, to reconcile with the text stating 'no treatment-related adverse events'.
The current table lists AEs without relatedness, creating an apparent contradiction with the text.
9.
MEDIUMreporting
Standardize the order of trial arms (low dose FMT, high dose FMT, low dose MTC01, high dose MTC01) consistently across the Abstract and Results.
The arm order differs between the abstract and results, which is a minor consistency issue that could confuse readers.
10.
MEDIUMcopyedit
Fix the typo 'Bifididobacterium pseudocatenulatum' to 'Bifidobacterium pseudocatenulatum' in the Results section.
The species name is misspelled, which is a factual error in a scientific name.
11.
MEDIUMdata code
Provide exact version numbers for all software used (e.g., R version, lme4 version) in the Methods.
Exact software versions are needed for reproducibility.
12.
MEDIUMdata code
Consider depositing the full de-identified clinical dataset in a repository with managed access to enhance reproducibility.
While supplementary tables are provided, a managed-access repository would strengthen data sharing for a clinical trial.
13.
LOWcopyedit
Rephrase the abstract sentence 'recurrent Clostridioides difficile infection was prevented eight weeks after dosing in seven out of nine LBP patients' to 'prevented at eight weeks after dosing in seven of nine LBP patients' for clarity.
Minor wording improvement for readability.
14.
LOWcopyedit
Format the model formula 'number _ MTC 01 _ strains _ detected ~ baseline _ drugDose + ( 1 | patient _ id )' using readable notation (e.g., LaTeX or code block).
The current formatting is difficult to read due to spaces and underscores.

Full text (64,427 chars)Analyzed: Aug 15, 2026