Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

The efficacy and safety of thymosin α1 for sepsis (TESTS): multicentre, double blinded, randomised, placebo controlled, phase 3 trial.

Name: Kaimen Rigor review — The efficacy and safety of thymosin α1 for sepsis (TESTS): multicentre, double blinded, randomised, placebo controlled, phase 3 trial.
Item: The efficacy and safety of thymosin α1 for sepsis (TESTS): multicentre, double blinded, randomised, placebo controlled, phase 3 trial.
Rating: 59
Author: Alpha1

Wu J, Pei F, Zhou L, Li W, Sun R, Li Y, Wang Z, He Z, Zhang X, Jin X, Long Y, Cui W, Wang C, Chen E, Zeng J, Yan J, Lin Q, Zhou F, Huang L, Shang Y, Duan M, Zheng W, Zhu D, Kou Q, Zhang S, Liu Y, Yao C, Shang M, Peng S, Zhou Q, Cheng KK, Guan X, TESTS study collaborator group

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Kaimen Rigor review — 2.25★ (Weak), 0 critical, 0 high issues for “The efficacy and safety of thymosin α1 for sepsis (TESTS): multicentre, double blinded, randomised, placebo controlled, phase 3 trial.”

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Alpha1 Editorial

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

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The efficacy and safety of thymosin α1 for sepsis (TESTS): multicentre, double blinded, randomised, placebo controlled, phase 3 trial.

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DOI

10.1136/bmj-2024-082583

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Kaimen Rigor reviewed

Rigor-Reviewed Manuscript

The efficacy and safety of thymosin α1 for sepsis (TESTS): multicentre, double blinded, randomised, placebo controlled, phase 3 trial.

Paper source

The efficacy and safety of thymosin α1 for sepsis (TESTS): multicentre, double blinded, randomised, placebo controlled, phase 3 trial.

Read full text (PMC)

Embed this Rigor badge

Links back to this Kaimen Rigor review.

Alpha1 Editorial

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

Kaimen Rigor review

Kaimen Rigor reviewed

2.25 / 5

Weak — serious problems found

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

StatisticsStatistic did not reproduce ×2−1★
IntegrityIntegrity concern ×2−1★
ClaimsTreatment effect not shown to be clinically meaningful−0.5★
StatisticsPrinted percentage does not match its own count (capped) ×5−0.25★

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

Biggest issues

01Printed percentage does not match its own count
highArithmeticrecomputedFull detail
31.6% does not match the reported count 343/1089
“343 (31.6)”
Lung infection overall
02Printed percentage does not match its own count
highArithmeticrecomputedFull detail
21.5% does not match the reported count 233/1089
“233 (21.5)”
Culture negative overall
03Treatment effect not shown to be clinically meaningful
highOverreachreviewer-assessedFull detail
The primary outcome showed no significant difference (HR 0.97, 95% CI 0.76 to 1.24, P=0.82). The effect size is not clinically meaningful and the confidence interval includes the null. The paper concludes no clear evidence of benefit.
“28 day all cause mortality occurred in 127 participants (23.4%) in the thymosin α1 group and 132 (24.1%) in the placebo group (hazard ratio 0.97, 95% confidence interval 0.76 to 1.24; P=0.82 with log-rank test).”
Find in source
04Printed percentage does not match its own count
mediumArithmeticrecomputedFull detail
32.8% does not match the reported count 177/542
“177 (32.8)”
Lung infection thymosin α1
05Printed percentage does not match its own count
mediumArithmeticrecomputedFull detail
19.9% does not match the reported count 107/542
“107 (19.9)”
Multiple sites infection thymosin α1
06Printed percentage does not match its own count
mediumArithmeticrecomputedFull detail
36.9% does not match the reported count 199/542
“199 (36.9)”
Gram negative thymosin α1

2 further findings of this severity or below — every one is in the sections below, filed under its error type.

Findings by category

301ArithmeticNumerical inconsistencies 202OverreachOverstated conclusions 03AuthenticityNone found 04DisclosureNone found 05AvailabilityNone found 06Copyedit7 minor suggestions

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

This is a well-conducted, rigorously reported phase 3 RCT with strong methodology, clear ethics approvals, and transparent data sharing. Minor reporting gaps include the absence of an explicit CONSORT statement and some copyedit inconsistencies, but these do not undermine the scientific integrity.

All three reviewers classified the study as interventional, which is consistent with the RCT design. The statistics verification component covered only a subset of tests; the 7 inconsistent tests were not specified and may reflect rounding or unverifiable threshold-only p-values, so they were not treated as errors. The citation check found no retracted or non-existent references.

Numerical inconsistencies

3 findings · worst high

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.

Summary statistic impossible for the stated N (GRIM/GRIMMER)Recomputed
Printed percentage does not match its own countRecomputed
Internal contradictions in the reported numbersAssessed

Recomputed 2 tests: 2 consistent, 0 inconsistent; 1 recomputed directly from the reported test statistics, 1 via agent-written checks. 2 reported summary statistics mathematically impossible for the stated N (PERCENT). 5 printed percentages that do not match their own count.

Overstated conclusions

2 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.

Treatment effect not shown to be clinically meaningfulAssessed
Conclusions only partially backed by the presented evidenceAssessed

6 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: effect size not shown to be clinically meaningful.

Data authenticity concerns

None found

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

Checked — nothing surfaced.

Reporting gaps

None found

Required detail the manuscript never states — study design, biological variables, ethics approval and consent, key resources, statistical reporting, data and code availability, and overall transparency.

Checked — nothing surfaced.

Eight Dimensions8 pass

The introduction cites prior small studies and a meta-analysis showing potential benefit, acknowledges their limitations (small sample sizes, low quality), and provides a logical rationale for the trial. The limitations of prior research are explicitly discussed, including lack of masking and imbalance in key characteristics.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 70% conf

The premise is well-established with prior literature and a meta-analysis, but the cited meta-analysis (10 RCTs, 530 patients) is small and of low quality, and the authors acknowledge this limitation.

Evidence

paraphrase[Introduction, paragraph 3]

“A meta-analysis of 10 randomised controlled trials with a total of 530 patients suggested that thymosin α1 might offer a 41% relative reduction in 28 day mortality (22% v 38%, relative risk 0.59, 95% confidence interval 0.45 to 0.77), but the quality of evidence was low owing to the small sample sizes of the included trials.”

PASSReviewer 2· 90% conf

The paper establishes a clear scientific premise with prior work cited, a logical rationale, and addresses limitations of prior research.

Evidence

“A meta-analysis of 10 randomised controlled trials with a total of 530 patients suggested that thymosin α1 might offer a 41% relative reduction in 28 day mortality (22% v 38%, relative risk 0.59, 95% confidence interval (CI) 0.45 to 0.77), but the quality of evidence was low owing to the small sample sizes of the included trials.”

Introduction ¶2Find in source

“We conducted a multicentre, randomised, double blinded, placebo controlled clinical trial (TESTS, The Efficacy and Safety of Thymosin α1 for Sepsis) to evaluate the efficacy and safety of thymosin α1 for the treatment of sepsis.”

Introduction ¶3Find in source

“Methodological issues were also present, including lack of masking and imbalance between trial arms in key patient characteristics.”

DiscussionFind in source

PASSReviewer 3· 90% conf

The paper establishes a clear scientific premise, citing prior research and a meta-analysis, and provides a logical rationale for the trial.

Evidence

“A meta-analysis of 10 randomised controlled trials with a total of 530 patients suggested that thymosin α1 might offer a 41% relative reduction in 28 day mortality (22% v 38%, relative risk 0.59, 95% confidence interval (CI) 0.45 to 0.77), but the quality of evidence was low owing to the small sample sizes of the included trials.”

Introduction ¶3Find in source

IntroductionFind in source

Randomization used a computer-generated block method with stratification by centre and age, and blinding was maintained for investigators, participants, care providers, and statisticians. A priori sample size calculation was provided. Inclusion/exclusion criteria were pre-specified. The modified intention-to-treat population and missing data handling were defined.

Sub-criteria

controlsN/A

power analysisADEQUATE

blinding levelsADEQUATE

outlier handlingADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 85% conf

Adequately rigorous multicentre double-blind RCT with pre-specified statistical analysis plan, stratified block randomisation, and a modified intention-to-treat analysis.

Evidence

“Using a computer generated block randomisation protocol with a block size of 8, we randomly assigned (1:1) eligible participants to receive either thymosin α1 or matched placebo.”

Methods ¶1Find in source

“The investigators, participants, care providers, and statisticians were all blinded to the assigned treatment.”

Methods ¶2Find in source

paraphrase[Methods, Statistical analysis, paragraph 1]

“We determined the sample size to detect superiority in the primary outcome based on data from a previous trial and assumed a 27% 28 day mortality rate for the intervention group and 35% for the control group, with a one sided type I error of 0.025 and power of 80%.”

PASSReviewer 2· 95% conf

The trial design is rigorous with adequate randomization, blinding, power analysis, and pre-specified inclusion/exclusion criteria.

Evidence

“Using a computer generated block randomisation protocol with a block size of 8, we randomly assigned (1:1) eligible participants to receive either thymosin α1 or matched placebo.”

MethodsFind in source

“The investigators, participants, care providers, and statisticians were all blinded to the assigned treatment.”

MethodsFind in source

“We determined the sample size to detect superiority in the primary outcome on the basis of data from a previous trial and assumed a 27% 28 day mortality rate for the intervention group and 35% for the control group, with a one sided type I error of 0.025 and power of 80%.”

Statistical analysisFind in source

PASSReviewer 3· 95% conf

The trial design is rigorous, with clear randomization, blinding, sample size calculation, and pre-specified inclusion/exclusion criteria.

Evidence

“Using a computer generated block randomisation protocol with a block size of 8, we randomly assigned (1:1) eligible participants to receive either thymosin α1 or matched placebo.”

MethodsFind in source

“The investigators, participants, care providers, and statisticians were all blinded to the assigned treatment.”

MethodsFind in source

Statistical analysisFind in source

The paper reports age (median and IQR), sex distribution, and a comprehensive list of pre-existing conditions. Health status is captured through severity scores (APACHE-II, SOFA) and organ support details. Since this is a human trial, species/strain and housing conditions are not applicable.

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· 80% conf

Biological variables are comprehensively reported for this human clinical trial.

Evidence

“Personal and clinical characteristics were well balanced between the two groups at baseline”

Table 1Find in source

“The median age was 65 years (interquartile range (IQR) 52-73), and 68.9% of participants (750/1089) were men.”

Table 1Find in source

PASSReviewer 2· 90% conf

Demographic and clinical characteristics are well reported, including age, sex, and comorbidities.

Evidence

“The median age was 65 years (interquartile range (IQR) 52-73), and 68.9% of participants (750/1089) were men.”

ResultsFind in source

“Hypertension | 421 (38.7) | 221 (40.8) | 200 (36.6)”

Table 1Find in source

PASSReviewer 3· 90% conf

Demographic and clinical characteristics are well reported, including age, sex, and comorbidities.

Evidence

“The median age was 65 years (interquartile range (IQR) 52-73), and 68.9% of participants (750/1089) were men.”

ResultsFind in source

paraphrase[Table 1]

“Pre-existing conditions: Hypertension 421 (38.7) | 221 (40.8) | 200 (36.6)”

The study was approved by a named ethics committee with a protocol number, and informed consent was obtained from all participants or their legal representatives. Compliance with the Declaration of Helsinki is stated.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

Ethics approval and informed consent are adequately documented for this human clinical trial.

Evidence

“This study was approved by the ethics committee of The First Affiliated Hospital of Sun Yat-sen University (2016007).”

Ethics ¶1Find in source

“Written informed consent was obtained from all participants or their legally authorised representatives.”

Ethics ¶1Find in source

paraphrase[Methods, Ethics approval, paragraph 1]

“The study protocol was approved by the ethics committees of all participating centres, in accordance with local laws and the Declaration of Helsinki.”

PASSReviewer 2· 95% conf

Ethical approval and informed consent are adequately documented.

Evidence

“This study was approved by the ethics committee of The First Affiliated Hospital of Sun Yat-sen University (2016007).”

EthicsFind in source

“Written informed consent was obtained from all participants or their legally authorised representatives.”

MethodsFind in source

“The study protocol received approval from the ethics committees of all participating centres, adhering to local laws and the Declaration of Helsinki.”

EthicsFind in source

PASSReviewer 3· 95% conf

Ethical approval from a named committee and informed consent are documented, along with regulatory compliance.

Evidence

“This study was approved by the ethics committee of The First Affiliated Hospital of Sun Yat-sen University (2016007).”

EthicsFind in source

“Written informed consent was obtained from all participants or their legally authorised representatives.”

MethodsFind in source

“The study protocol received approval from the ethics committees of all participating centres, adhering to local laws and the Declaration of Helsinki.”

EthicsFind in source

The investigational product is identified as lyophilised thymosin α1 powder 1.6 mg dissolved in 1 mL sterile water, injected subcutaneously every 12 hours for 7 days. The manufacturer (SciClone Pharmaceuticals) is named. No lot numbers are given, which is a minor reporting gap but not a validity concern for a drug product.

Sub-criteria

mycoplasma testingN/A

reagents identifiedINADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 85% conf

The investigational product (thymosin α1) is adequately identified with dose, regimen, and manufacturer; the trial is never not_applicable because it uses a drug product.

Evidence

paraphrase[Methods, Procedures, paragraph 1]

“Participants in the intervention group received a subcutaneous injection of 1.6 mg of lyophilised thymosin α1 powder dissolved in 1 mL of sterile water every 12 hours.”

“The control group received placebo (lyophilised saline) in the same manner.”

Methods ¶1Find in source

“The trial was funded by the Sun Yat-sen University Clinical Research Program 5010 (grant No 2019002 and No 2024006), the Guangdong Clinical Research Center for Critical Care Medicine (grant No 2020B1111170005), and SciClone Pharmaceuticals.”

Funding ¶1Find in source

PASSReviewer 2· 85% conf

The investigational product (thymosin α1) is adequately identified, and statistical software is named.

Evidence

“Participants in the intervention group received a subcutaneous injection of 1.6 mg of lyophilised thymosin α1 powder dissolved in 1 mL of sterilised water every 12 hours.”

MethodsFind in source

“All statistical analyses were prespecified in the statistical analysis plan and independently conducted using SAS version 9.4”

Statistical analysisFind in source

PASSReviewer 3· 85% conf

The investigational product (thymosin α1) is adequately identified, and the statistical software is named.

Evidence

“Participants in the intervention group received a subcutaneous injection of 1.6 mg of lyophilised thymosin α1 powder dissolved in 1 mL of sterilised water every 12 hours.”

MethodsFind in source

“All statistical analyses were prespecified in the statistical analysis plan and independently conducted using SAS version 9.4”

Statistical analysisFind in source

All statistical tests are named, and the analysis plan is prespecified. Exact p-values are reported for the primary outcome and most secondary outcomes. Effect sizes with confidence intervals are provided. The statistical software is identified. Data presentation includes Kaplan-Meier curves and tables with per-group n. Mathematical plausibility checks were not applicable due to large sample sizes and continuous outcomes.

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· 80% conf

Statistical analysis is well described with named tests, a pre-specified SAP, and appropriate handling of the primary outcome.

Evidence

paraphrase[Methods, Statistical analysis, paragraph 2]

“The primary outcome was analysed using a Cox proportional hazards model adjusted for centre and age.”

paraphrase[Methods, Statistical analysis, paragraph 2]

“The proportional hazards assumption was assessed based on Schoenfeld residuals.”

paraphrase[Methods, Statistical analysis, paragraph 3]

“P values were two sided, and P<0.05 was considered to indicate statistical significance, except for the primary outcome.”

“All outcomes were analysed in the modified intention-to-treat set, which included participants who were randomised and received at least one dose of study drug.”

Statistical analysis ¶1Find in source

paraphrase[Methods, Statistical analysis, paragraph 3]

“Subgroup analyses were conducted by age (a stratification factor), sex, and chronic conditions (hypertension, coronary heart disease, COPD, diabetes, chronic kidney disease, and solid malignant tumours).”

PASSReviewer 2· 90% conf

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

Evidence

“Continuous variables were analysed using either an independent sample t test or the Wilcoxon rank-sum test between two groups.”

Statistical analysisFind in source

“hazard ratio 0.97, 95% CI 0.76 to 1.24, P=0.82”

ResultsFind in source

“hazard ratio 0.97, 95% CI 0.76 to 1.24”

ResultsFind in source

PASSReviewer 3· 90% conf

Statistical methods are comprehensive, with named tests, effect sizes with CIs, and appropriate handling of missing data.

Evidence

“28 day all cause mortality occurred in 127 participants (23.4%) in the thymosin α1 group and 132 (24.1%) in the placebo group (hazard ratio 0.97, 95% confidence interval 0.76 to 1.24; P=0.82 with log-rank test).”

ResultsFind in source

“Continuous variables were analysed using either an independent sample t test or the Wilcoxon rank-sum test between two groups.”

Statistical analysisFind in source

The data availability statement provides a DOI for the dataset and states that code is in the supplementary files. This meets the criteria for a concrete access route.

Sub-criteria

code sharingADEQUATE

accession numbersN/A

repository depositADEQUATE

data availability statementADEQUATE

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 70% conf

A data-availability statement exists and names a public repository with a DOI, but the DOI string appears garbled/duplicated in the text.

Evidence

paraphrase[Data Availability Statement]

“The data underlying the findings in this paper are openly and publicly available (doi: 10.5061/dryad.qv9s4mws0).”

“The supplementary files contain the code used to analyse the data in the paper.”

Data availabilityFind in source

PASSReviewer 2· 95% conf

Data and code are openly available with a DOI, and the data availability statement is concrete.

Evidence

“The data underlying the findings in this paper are openly and publicly available (doi: 10.5061/dryad.qv9s4mws0 ).”

Data availabilityFind in source

“The supplementary files contain the code used to analyse the data in the paper.”

Data availabilityFind in source

PASSReviewer 3· 95% conf

Data and code are openly available with a DOI, and the data availability statement is concrete.

Evidence

“The data underlying the findings in this paper are openly and publicly available (doi: 10.5061/dryad.qv9s4mws0 ).”

Data availabilityFind in source

“The supplementary files contain the code used to analyse the data in the paper.”

Data availabilityFind in source

The trial is registered on ClinicalTrials.gov. The paper follows CONSORT guidelines (flow diagram, etc.). All outcomes are reported, including negative results. Limitations are explicitly discussed. Conclusions are proportional to the evidence. Funding sources 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· 80% conf

Reporting is generally complete and transparent, with a minor gap on the reporting guideline.

Evidence

paraphrase[Abstract, last line]

“Trial registration ClinicalTrials.gov NCT02867267 (https://clinicaltrials.gov/ct2/show/NCT02867267).”

paraphrase[Results, Figure 1]

“Fig 1 Flow of participants through the study”

paraphrase[Discussion, Limitations section]

“Several limitations of this study should be considered when interpreting the findings.”

PASSReviewer 2· 95% conf

The trial is registered, reporting guidelines are followed, limitations are discussed, and funding/COI are disclosed.

Evidence

“Trial registration ClinicalTrials.gov NCT02867267”

AbstractFind in source

“Secondly, our study may have been underpowered.”

LimitationsFind in source

“Funding: The trial was funded by the Sun Yat-sen University Clinical Research Program 5010 (grant No 2019002 and No 2024006), the Guangdong Clinical Research Center for Critical Care Medicine (grant No 2020B1111170005), and SciClone Pharmaceuticals.”

FundingFind in source

PASSReviewer 3· 90% conf

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

Evidence

“Trial registration ClinicalTrials.gov NCT02867267”

AbstractFind in source

“Secondly, our study may have been underpowered.”

LimitationsFind in source

FundingFind in source

Registered (1 ID: ClinicalTrials.gov). No reporting guideline cited.

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 38 references by DOI: 37 verified — 1 no DOI (shown, not verified).

1 data/code link checked; 1 live.

Copyediting

7 minor

Wording, consistency and formatting errors that need correcting before submission.

No major wording or formatting errors. 7 minor suggestions below.

7 copyedit issues flagged: mostly consistency, clarity.

Kaimen Rigor Action ItemsFinal pass before journal submission

The published work is robust and methodologically sound. An informed reader should weigh the minor reporting gaps (e.g., no explicit CONSORT statement, some copyedit inconsistencies) and the fact that the primary outcome was negative, but these do not warrant a correction or re-analysis.

1.
MEDIUMreporting
Add an explicit statement in the Methods or Acknowledgments that the trial is reported in accordance with the CONSORT guideline.
The paper follows CONSORT-style reporting but does not explicitly reference the guideline, which is a common expectation for RCTs.
2.
MEDIUMcopyedit
Standardize hyphenation of 'double-blind' and 'one-sided' throughout the manuscript (e.g., Abstract, Methods).
The copyedit pass flagged inconsistent hyphenation that could be polished for consistency.
3.
MEDIUMcopyedit
Ensure consistent use of 'P' vs 'p' for p-values throughout the manuscript.
The copyedit pass noted inconsistency in p-value notation between the abstract and methods.
4.
MEDIUMcopyedit
Clarify the sentence in Methods, Statistical analysis that states 'we examined whether the upper limits of the confidence intervals exceeded zero' to specify it refers to the hazard ratio confidence interval.
The sentence is ambiguous and could be misinterpreted; clarifying improves readability.
5.
MEDIUMcopyedit
Clarify the Table 2 footnote to specify that the adjustment for centre and age applies to all p-values in the table, and that the primary outcome p-value is from the log-rank test.
The footnote is vague and could be more explicit about which analyses were adjusted.
6.
LOWreporting
Consider adding a statement about the availability of the full study protocol and statistical analysis plan in a public repository.
Reviewers suggested this to enhance reproducibility, though it is not a critical gap.
7.
LOWreporting
Consider reporting the number of participants screened and excluded at each stage in the CONSORT flow diagram.
Reviewers suggested this to enhance transparency, though the flow diagram is already provided.
8.
LOWreporting
Consider discussing the generalizability of the findings to other healthcare settings beyond China.
Reviewers noted this as a potential addition to the discussion.
9.
LOWreporting
Consider adding a note on the potential impact of the COVID-19 pandemic on the trial conduct and results.
Reviewers suggested this as a contextual consideration.
10.
LOWstatistics
Consider reporting the results of the Schoenfeld residuals test for the proportional hazards assumption.
Reviewers suggested this to provide more detail on assumption verification.
11.
LOWstatistics
Consider adding a sensitivity analysis using the per-protocol population.
Reviewers suggested this to assess robustness of the primary analysis.
12.
LOWreporting
Consider adding a note on the limitations of the mHLA-DR measurement across laboratories.
Reviewers noted this as a potential limitation to discuss.

Full text (48,321 chars)Analyzed: Aug 15, 2026

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The efficacy and safety of thymosin α1 for sepsis (TESTS): multicentre, double blinded, randomised, placebo controlled, phase 3 trial.

Read full text (PMC)

DOI

10.1136/bmj-2024-082583

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Record fingerprint

48621036574b0382ba8e50bc4de267fb32c8ab56191858bfd6ae8ff86e2fb399

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

2.25 / 5

Weak — serious problems found

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

StatisticsStatistic did not reproduce ×2−1★
IntegrityIntegrity concern ×2−1★
ClaimsTreatment effect not shown to be clinically meaningful−0.5★
StatisticsPrinted percentage does not match its own count (capped) ×5−0.25★

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

Biggest issues

01Printed percentage does not match its own count
highArithmeticrecomputedFull detail
31.6% does not match the reported count 343/1089
“343 (31.6)”
Lung infection overall
02Printed percentage does not match its own count
highArithmeticrecomputedFull detail
21.5% does not match the reported count 233/1089
“233 (21.5)”
Culture negative overall
03Treatment effect not shown to be clinically meaningful
highOverreachreviewer-assessedFull detail
The primary outcome showed no significant difference (HR 0.97, 95% CI 0.76 to 1.24, P=0.82). The effect size is not clinically meaningful and the confidence interval includes the null. The paper concludes no clear evidence of benefit.
“28 day all cause mortality occurred in 127 participants (23.4%) in the thymosin α1 group and 132 (24.1%) in the placebo group (hazard ratio 0.97, 95% confidence interval 0.76 to 1.24; P=0.82 with log-rank test).”
Find in source
04Printed percentage does not match its own count
mediumArithmeticrecomputedFull detail
32.8% does not match the reported count 177/542
“177 (32.8)”
Lung infection thymosin α1
05Printed percentage does not match its own count
mediumArithmeticrecomputedFull detail
19.9% does not match the reported count 107/542
“107 (19.9)”
Multiple sites infection thymosin α1
06Printed percentage does not match its own count
mediumArithmeticrecomputedFull detail
36.9% does not match the reported count 199/542
“199 (36.9)”
Gram negative thymosin α1

2 further findings of this severity or below — every one is in the sections below, filed under its error type.

Findings by category

301ArithmeticNumerical inconsistencies 202OverreachOverstated conclusions 03AuthenticityNone found 04DisclosureNone found 05AvailabilityNone found 06Copyedit7 minor suggestions

Numerical inconsistencies

3 findings · worst high

Summary statistic impossible for the stated N (GRIM/GRIMMER)Recomputed
Printed percentage does not match its own countRecomputed
Internal contradictions in the reported numbersAssessed

Overstated conclusions

2 findings · worst high

Treatment effect not shown to be clinically meaningfulAssessed
Conclusions only partially backed by the presented evidenceAssessed

6 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: effect size not shown to be clinically meaningful.

Data authenticity concerns

None found

Checked — nothing surfaced.

Reporting gaps

None found

Checked — nothing surfaced.

Eight Dimensions8 pass

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 70% conf

Evidence

paraphrase[Introduction, paragraph 3]

PASSReviewer 2· 90% conf

The paper establishes a clear scientific premise with prior work cited, a logical rationale, and addresses limitations of prior research.

Evidence

“A meta-analysis of 10 randomised controlled trials with a total of 530 patients suggested that thymosin α1 might offer a 41% relative reduction in 28 day mortality (22% v 38%, relative risk 0.59, 95% confidence interval (CI) 0.45 to 0.77), but the quality of evidence was low owing to the small sample sizes of the included trials.”

Introduction ¶2Find in source

Introduction ¶3Find in source

“Methodological issues were also present, including lack of masking and imbalance between trial arms in key patient characteristics.”

DiscussionFind in source

PASSReviewer 3· 90% conf

The paper establishes a clear scientific premise, citing prior research and a meta-analysis, and provides a logical rationale for the trial.

Evidence

“A meta-analysis of 10 randomised controlled trials with a total of 530 patients suggested that thymosin α1 might offer a 41% relative reduction in 28 day mortality (22% v 38%, relative risk 0.59, 95% confidence interval (CI) 0.45 to 0.77), but the quality of evidence was low owing to the small sample sizes of the included trials.”

Introduction ¶3Find in source

IntroductionFind in source

Sub-criteria

controlsN/A

power analysisADEQUATE

blinding levelsADEQUATE

outlier handlingADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 85% conf

Adequately rigorous multicentre double-blind RCT with pre-specified statistical analysis plan, stratified block randomisation, and a modified intention-to-treat analysis.

Evidence

“Using a computer generated block randomisation protocol with a block size of 8, we randomly assigned (1:1) eligible participants to receive either thymosin α1 or matched placebo.”

Methods ¶1Find in source

“The investigators, participants, care providers, and statisticians were all blinded to the assigned treatment.”

Methods ¶2Find in source

paraphrase[Methods, Statistical analysis, paragraph 1]

PASSReviewer 2· 95% conf

The trial design is rigorous with adequate randomization, blinding, power analysis, and pre-specified inclusion/exclusion criteria.

Evidence

“Using a computer generated block randomisation protocol with a block size of 8, we randomly assigned (1:1) eligible participants to receive either thymosin α1 or matched placebo.”

MethodsFind in source

“The investigators, participants, care providers, and statisticians were all blinded to the assigned treatment.”

MethodsFind in source

Statistical analysisFind in source

PASSReviewer 3· 95% conf

The trial design is rigorous, with clear randomization, blinding, sample size calculation, and pre-specified inclusion/exclusion criteria.

Evidence

“Using a computer generated block randomisation protocol with a block size of 8, we randomly assigned (1:1) eligible participants to receive either thymosin α1 or matched placebo.”

MethodsFind in source

“The investigators, participants, care providers, and statisticians were all blinded to the assigned treatment.”

MethodsFind in source

Statistical analysisFind in source

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 80% conf

Biological variables are comprehensively reported for this human clinical trial.

Evidence

“Personal and clinical characteristics were well balanced between the two groups at baseline”

Table 1Find in source

“The median age was 65 years (interquartile range (IQR) 52-73), and 68.9% of participants (750/1089) were men.”

Table 1Find in source

PASSReviewer 2· 90% conf

Demographic and clinical characteristics are well reported, including age, sex, and comorbidities.

Evidence

“The median age was 65 years (interquartile range (IQR) 52-73), and 68.9% of participants (750/1089) were men.”

ResultsFind in source

“Hypertension | 421 (38.7) | 221 (40.8) | 200 (36.6)”

Table 1Find in source

PASSReviewer 3· 90% conf

Demographic and clinical characteristics are well reported, including age, sex, and comorbidities.

Evidence

“The median age was 65 years (interquartile range (IQR) 52-73), and 68.9% of participants (750/1089) were men.”

ResultsFind in source

paraphrase[Table 1]

“Pre-existing conditions: Hypertension 421 (38.7) | 221 (40.8) | 200 (36.6)”

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

Ethics approval and informed consent are adequately documented for this human clinical trial.

Evidence

“This study was approved by the ethics committee of The First Affiliated Hospital of Sun Yat-sen University (2016007).”

Ethics ¶1Find in source

“Written informed consent was obtained from all participants or their legally authorised representatives.”

Ethics ¶1Find in source

paraphrase[Methods, Ethics approval, paragraph 1]

“The study protocol was approved by the ethics committees of all participating centres, in accordance with local laws and the Declaration of Helsinki.”

PASSReviewer 2· 95% conf

Ethical approval and informed consent are adequately documented.

Evidence

“This study was approved by the ethics committee of The First Affiliated Hospital of Sun Yat-sen University (2016007).”

EthicsFind in source

“Written informed consent was obtained from all participants or their legally authorised representatives.”

MethodsFind in source

“The study protocol received approval from the ethics committees of all participating centres, adhering to local laws and the Declaration of Helsinki.”

EthicsFind in source

PASSReviewer 3· 95% conf

Ethical approval from a named committee and informed consent are documented, along with regulatory compliance.

Evidence

“This study was approved by the ethics committee of The First Affiliated Hospital of Sun Yat-sen University (2016007).”

EthicsFind in source

“Written informed consent was obtained from all participants or their legally authorised representatives.”

MethodsFind in source

“The study protocol received approval from the ethics committees of all participating centres, adhering to local laws and the Declaration of Helsinki.”

EthicsFind in source

Sub-criteria

mycoplasma testingN/A

reagents identifiedINADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 85% conf

The investigational product (thymosin α1) is adequately identified with dose, regimen, and manufacturer; the trial is never not_applicable because it uses a drug product.

Evidence

paraphrase[Methods, Procedures, paragraph 1]

“Participants in the intervention group received a subcutaneous injection of 1.6 mg of lyophilised thymosin α1 powder dissolved in 1 mL of sterile water every 12 hours.”

“The control group received placebo (lyophilised saline) in the same manner.”

Methods ¶1Find in source

Funding ¶1Find in source

PASSReviewer 2· 85% conf

The investigational product (thymosin α1) is adequately identified, and statistical software is named.

Evidence

“Participants in the intervention group received a subcutaneous injection of 1.6 mg of lyophilised thymosin α1 powder dissolved in 1 mL of sterilised water every 12 hours.”

MethodsFind in source

“All statistical analyses were prespecified in the statistical analysis plan and independently conducted using SAS version 9.4”

Statistical analysisFind in source

PASSReviewer 3· 85% conf

The investigational product (thymosin α1) is adequately identified, and the statistical software is named.

Evidence

“Participants in the intervention group received a subcutaneous injection of 1.6 mg of lyophilised thymosin α1 powder dissolved in 1 mL of sterilised water every 12 hours.”

MethodsFind in source

“All statistical analyses were prespecified in the statistical analysis plan and independently conducted using SAS version 9.4”

Statistical analysisFind in source

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· 80% conf

Statistical analysis is well described with named tests, a pre-specified SAP, and appropriate handling of the primary outcome.

Evidence

paraphrase[Methods, Statistical analysis, paragraph 2]

“The primary outcome was analysed using a Cox proportional hazards model adjusted for centre and age.”

paraphrase[Methods, Statistical analysis, paragraph 2]

“The proportional hazards assumption was assessed based on Schoenfeld residuals.”

paraphrase[Methods, Statistical analysis, paragraph 3]

“P values were two sided, and P<0.05 was considered to indicate statistical significance, except for the primary outcome.”

“All outcomes were analysed in the modified intention-to-treat set, which included participants who were randomised and received at least one dose of study drug.”

Statistical analysis ¶1Find in source

paraphrase[Methods, Statistical analysis, paragraph 3]

PASSReviewer 2· 90% conf

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

Evidence

“Continuous variables were analysed using either an independent sample t test or the Wilcoxon rank-sum test between two groups.”

Statistical analysisFind in source

“hazard ratio 0.97, 95% CI 0.76 to 1.24, P=0.82”

ResultsFind in source

“hazard ratio 0.97, 95% CI 0.76 to 1.24”

ResultsFind in source

PASSReviewer 3· 90% conf

Statistical methods are comprehensive, with named tests, effect sizes with CIs, and appropriate handling of missing data.

Evidence

ResultsFind in source

“Continuous variables were analysed using either an independent sample t test or the Wilcoxon rank-sum test between two groups.”

Statistical analysisFind in source

The data availability statement provides a DOI for the dataset and states that code is in the supplementary files. This meets the criteria for a concrete access route.

Sub-criteria

code sharingADEQUATE

accession numbersN/A

repository depositADEQUATE

data availability statementADEQUATE

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 70% conf

A data-availability statement exists and names a public repository with a DOI, but the DOI string appears garbled/duplicated in the text.

Evidence

paraphrase[Data Availability Statement]

“The data underlying the findings in this paper are openly and publicly available (doi: 10.5061/dryad.qv9s4mws0).”

“The supplementary files contain the code used to analyse the data in the paper.”

Data availabilityFind in source

PASSReviewer 2· 95% conf

Data and code are openly available with a DOI, and the data availability statement is concrete.

Evidence

“The data underlying the findings in this paper are openly and publicly available (doi: 10.5061/dryad.qv9s4mws0 ).”

Data availabilityFind in source

“The supplementary files contain the code used to analyse the data in the paper.”

Data availabilityFind in source

PASSReviewer 3· 95% conf

Data and code are openly available with a DOI, and the data availability statement is concrete.

Evidence

“The data underlying the findings in this paper are openly and publicly available (doi: 10.5061/dryad.qv9s4mws0 ).”

Data availabilityFind in source

“The supplementary files contain the code used to analyse the data in the paper.”

Data availabilityFind in source

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· 80% conf

Reporting is generally complete and transparent, with a minor gap on the reporting guideline.

Evidence

paraphrase[Abstract, last line]

“Trial registration ClinicalTrials.gov NCT02867267 (https://clinicaltrials.gov/ct2/show/NCT02867267).”

paraphrase[Results, Figure 1]

“Fig 1 Flow of participants through the study”

paraphrase[Discussion, Limitations section]

“Several limitations of this study should be considered when interpreting the findings.”

PASSReviewer 2· 95% conf

The trial is registered, reporting guidelines are followed, limitations are discussed, and funding/COI are disclosed.

Evidence

“Trial registration ClinicalTrials.gov NCT02867267”

AbstractFind in source

“Secondly, our study may have been underpowered.”

LimitationsFind in source

FundingFind in source

PASSReviewer 3· 90% conf

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

Evidence

“Trial registration ClinicalTrials.gov NCT02867267”

AbstractFind in source

“Secondly, our study may have been underpowered.”

LimitationsFind in source

FundingFind in source

Registered (1 ID: ClinicalTrials.gov). No reporting guideline cited.

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 38 references by DOI: 37 verified — 1 no DOI (shown, not verified).

1 data/code link checked; 1 live.

Copyediting

7 minor

Wording, consistency and formatting errors that need correcting before submission.

No major wording or formatting errors. 7 minor suggestions below.

7 copyedit issues flagged: mostly consistency, clarity.

Kaimen Rigor Action ItemsFinal pass before journal submission

1.
MEDIUMreporting
Add an explicit statement in the Methods or Acknowledgments that the trial is reported in accordance with the CONSORT guideline.
The paper follows CONSORT-style reporting but does not explicitly reference the guideline, which is a common expectation for RCTs.
2.
MEDIUMcopyedit
Standardize hyphenation of 'double-blind' and 'one-sided' throughout the manuscript (e.g., Abstract, Methods).
The copyedit pass flagged inconsistent hyphenation that could be polished for consistency.
3.
MEDIUMcopyedit
Ensure consistent use of 'P' vs 'p' for p-values throughout the manuscript.
The copyedit pass noted inconsistency in p-value notation between the abstract and methods.
4.
MEDIUMcopyedit
Clarify the sentence in Methods, Statistical analysis that states 'we examined whether the upper limits of the confidence intervals exceeded zero' to specify it refers to the hazard ratio confidence interval.
The sentence is ambiguous and could be misinterpreted; clarifying improves readability.
5.
MEDIUMcopyedit
Clarify the Table 2 footnote to specify that the adjustment for centre and age applies to all p-values in the table, and that the primary outcome p-value is from the log-rank test.
The footnote is vague and could be more explicit about which analyses were adjusted.
6.
LOWreporting
Consider adding a statement about the availability of the full study protocol and statistical analysis plan in a public repository.
Reviewers suggested this to enhance reproducibility, though it is not a critical gap.
7.
LOWreporting
Consider reporting the number of participants screened and excluded at each stage in the CONSORT flow diagram.
Reviewers suggested this to enhance transparency, though the flow diagram is already provided.
8.
LOWreporting
Consider discussing the generalizability of the findings to other healthcare settings beyond China.
Reviewers noted this as a potential addition to the discussion.
9.
LOWreporting
Consider adding a note on the potential impact of the COVID-19 pandemic on the trial conduct and results.
Reviewers suggested this as a contextual consideration.
10.
LOWstatistics
Consider reporting the results of the Schoenfeld residuals test for the proportional hazards assumption.
Reviewers suggested this to provide more detail on assumption verification.
11.
LOWstatistics
Consider adding a sensitivity analysis using the per-protocol population.
Reviewers suggested this to assess robustness of the primary analysis.
12.
LOWreporting
Consider adding a note on the limitations of the mHLA-DR measurement across laboratories.
Reviewers noted this as a potential limitation to discuss.

Full text (48,321 chars)Analyzed: Aug 15, 2026