CD40 ligand antagonist dazodalibep in Sjögren's disease: a randomized, double-blinded, placebo-controlled, phase 2 trial.
St Clair EW, Baer AN, Ng WF, Noaiseh G, Baldini C, Tarrant TK, Papas A, Devauchelle-Pensec V, Wang L, Xu W, Pham TH, Sikora K, Rees WA, Alevizos I
- DOI
- 10.1038/s41591-024-03009-3
- Record issued
- 2026-08-16
- Engine
- 7.39.0
- Exported
- 2026-09-21
Prepared by Alpha1. This document is confidential: it is intended for the recipient it was shared with and must not be redistributed. The live record at alpha1science.com/verify/7355c93a-5932-4e1a-866a-71d7dbbfe6f2 is authoritative.
How this rating was calculated
- IntegrityIntegrity concern ×2−1★
- StatisticsStatistic did not reproduce−0.5★
- ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
- The numeric-impossibility checks (GRIM/GRIMMER/DEBIT/SPRITE) did not run: 12 reported means were read, and their group size is not stated where the values are printed (this source has no machine-readable table structure). These checks need the count the mean was averaged over, so none was performed.
- 01Printed percentage does not match its own count
65.3% does not match the reported count 32/48
“32 (65.3)”
Population 2 DAZ-PBO stage II ≥1 AE - 02Efficacy rests on an unvalidated surrogate endpoint
The primary endpoints are ESSDAI and ESSPRI, which are disease activity indices and patient-reported symptom scores, respectively. These are surrogate endpoints for clinical benefit in Sjögren's disease. The paper does not provide evidence linking changes in these indices to hard clinical outcomes such as mortality or irreversible organ damage, nor does it demonstrate target engagement at the tested dose (e.g., PK/PD data) beyond biomarker changes (CXCL13, RF).
“The primary endpoint for population 1 (n = 74) was the change from baseline in the European League Against Rheumatism Sjögren’s Syndrome Disease Activity Index at day 169. The primary endpoint for population 2 (n = 109) was the change from baseline in the…”
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-designed and transparently reported phase 2 randomized controlled trial. The paper demonstrates strong scientific premise, rigorous methodology, and comprehensive reporting across all eight dimensions. Minor copyediting issues and a few reporting gaps (e.g., explicit CONSORT statement, missing data handling) do not undermine the overall integrity.
Both reviewers independently scored all eight dimensions and agreed on every status, indicating high sampling stability. The study is an interventional clinical trial; all non-applicable sub-criteria (e.g., animal housing, cell line authentication) were excluded. The statistics verification component checked only a subset of tests (3), and one inconsistency was noted but not detailed; this is a caveat for the statistical analysis pass.
Numerical inconsistencies
2 findings · worst highValues 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
- Internal contradictions in the reported numbersAssessed
Recomputed 2 tests: 2 consistent, 0 inconsistent; 2 via agent-written checks. 1 reported summary statistic mathematically impossible for the stated N (PERCENT).
- PERCENT65.3% does not match the reported count 32/48
“32 (65.3)”
Population 2 DAZ-PBO stage II ≥1 AE
- CONSISTENTreported p = .017 · recomputed p = .017Reviewers 1, 2Primary endpoint population 1: ESSDAI LS mean difference
“yielding an LS mean difference of −2.2 ± 0.9 ( P = 0.0167).”
Taken as given: The LS mean difference is -2.2 and its standard error is 0.9.; The test statistic is approximately t = -2.2/0.9 = -2.444.; The degrees of freedom are approximately 72 (total N - 2).Method: Two-tailed t-test using the t-distribution with df=72.How we recomputed it: 2*(1-tCdf(2.2/0.9, 72)) - CONSISTENTreported p < .001 · recomputed p = <.001Reviewers 1, 2Primary endpoint population 2: ESSPRI LS mean difference
“yielding an LS mean difference of −1.3 ± 0.3 ( P = 0.0002).”
Taken as given: The LS mean difference is -1.3 and its standard error is 0.3.; The test statistic is approximately t = -1.3/0.3 = -4.333.; The degrees of freedom are approximately 107 (total N - 2).Method: Two-tailed t-test using the t-distribution with df=107.How we recomputed it: 2*(1-tCdf(1.27/0.3, 107))
- lowinternal contradictionIn the safety section for Stage II, the text states 'One participant in the PBO–DAZ group discontinued the study due to an AE (rash) compared with none in the PBO–DAZ group.' This appears to be a typographical error; the comparison should be with the DAZ–PBO group.
“One participant in the PBO–DAZ group discontinued the study due to an AE (rash) compared with none in the PBO–DAZ group.”
ResultsFind in source - lowinternal contradictionIn Table 3, the column headers for Stage II are repeated, and the layout may be confusing, but no numerical inconsistency is apparent.
“Stage II + follow-up | | Population 1 | Population 2 | Population 1 | Population 2 |”
Table 3Find in source
Overstated conclusions
2 findings · worst highConclusions that reach past what the paper's own results support — including a significance claim that no longer holds when the statistic is recomputed, and efficacy resting on an unvalidated surrogate endpoint.
- Efficacy rests on an unvalidated surrogate endpointAssessed
- Conclusions only partially backed by the presented evidenceAssessed
7 major claims checked against the paper's own evidence: 3 only partially supported (evidence backs part of the claim; gaps or caveats remain); the rest adequately supported.
- partialReviewer 1The efficacy of DAZ implies an important role for the CD40/CD40 ligand pathway in SjD pathogenesis.The clinical efficacy supports the pathway's importance, but this is an inference from a single trial and not directly tested.Evidence: Clinical efficacy and biomarker changes (CXCL13, RF).
“In summary, DAZ appears to be a potential new therapy for SjD and its efficacy implies an important role for the CD40/CD40 ligand pathway in its pathogenesis.”
AbstractFind in source - partialReviewer 2DAZ appears to be a potential new therapy for SjD.The claim is supported by positive phase 2 results but requires larger confirmatory trials.Evidence: Primary endpoints met in both populations; however, the study is phase 2 with small sample sizes.
“In summary, DAZ appears to be a potential new therapy for SjD and its efficacy implies an important role for the CD40/CD40 ligand pathway in its pathogenesis.”
AbstractFind in source - partialReviewer 2The efficacy implies an important role for the CD40/CD40 ligand pathway in SjD pathogenesis.The efficacy of DAZ supports the pathway's role, but direct mechanistic evidence is limited.Evidence: Biomarker reductions (CXCL13, RF) support pathway engagement, but not direct proof of pathogenesis.
“its efficacy implies an important role for the CD40/CD40 ligand pathway in its pathogenesis.”
AbstractFind in source - supportedReviewers 1, 2DAZ significantly improved systemic disease activity in population 1.The primary endpoint was met with statistical significance (P=0.0167), supporting the claim.Evidence: Primary endpoint ESSDAI change from baseline: DAZ -6.3 vs PBO -4.1, P=0.0167.
“The primary endpoints (least squares mean ± standard error) were achieved with statistical significance for both population 1 (DAZ, −6.3 ± 0.6; PBO, −4.1 ± 0.6; P = 0.0167)”
AbstractFind in source - supportedReviewers 1, 2DAZ significantly improved symptoms in population 2.The primary endpoint was met with statistical significance (P=0.0002), supporting the claim.Evidence: Primary endpoint ESSPRI change from baseline: DAZ -1.8 vs PBO -0.5, P=0.0002.
“and population 2 (DAZ, −1.8 ± 0.2; PBO, −0.5 ± 0.2; P = 0.0002).”
AbstractFind in source - supportedReviewers 1, 2DAZ was generally safe and well tolerated.The safety data show no major safety signals, though there was an imbalance in COVID-19 infections and a few SAEs considered related.Evidence: Safety results in Table 3 and text.
“DAZ was generally safe and well tolerated.”
AbstractFind in source - supportedReviewer 1DAZ reduced CXCL13 and RF levels.Biomarker results show significant reductions in CXCL13 and RF in both populations.Evidence: CXCL13 and RF biomarker results.
“DAZ rapidly reduced CXCL13 levels during stage I, and levels remained suppressed below baseline values through to day 169.”
ResultsFind in source
Premise concern: surrogate not validated for clinical benefit.
- INADEQUATESurrogate endpointThe primary endpoints are ESSDAI and ESSPRI, which are disease activity indices and patient-reported symptom scores, respectively. These are surrogate endpoints for clinical benefit in Sjögren's disease. The paper does not provide evidence linking changes in these indices to hard clinical outcomes such as mortality or irreversible organ damage, nor does it demonstrate target engagement at the tested dose (e.g., PK/PD data) beyond biomarker changes (CXCL13, RF).
“The primary endpoint for population 1 (n = 74) was the change from baseline in the European League Against Rheumatism Sjögren’s Syndrome Disease Activity Index at day 169. The primary endpoint for population 2 (n = 109) was the change from baseline in the European League Against Rheumatism Sjögren’s Syndrome Patient Reported Index at day 169.”
- ADEQUATEEffect sizeThe effect sizes are explicitly anchored to minimal clinically important differences (MCID). For population 1, the ESSDAI improvement of -6.3 exceeds the three-point MCID. For population 2, the ESSPRI improvement of -1.8 exceeds the one-point MCID. These are statistically significant and clinically meaningful.
“In participants in population 1 with moderate-to-high systemic disease activity, improvement in the change from baseline in ESSDAI total score at day 169 of −6.3 ± 0.6 surpassed the three-point reduction in ESSDAI that has been defined as minimal clinically important improvement. Moreover, in population 2, the subgroup with a high symptom burden, the improvement in change from baseline in ESSPRI total score at day 169 of −1.8 ± 0.2 also surpassed the one-point reduction in ESSPRI considered to be minimal clinically important improvement.”
Data authenticity concerns
None foundAn adversarial read for patterns associated with data that may not be genuine: results that look too clean, implausibly large effects, duplicated data or images, and methods that do not match the results reported.
Checked — nothing surfaced.
Reporting gaps
None foundRequired detail the manuscript never states — study design, biological variables, ethics approval and consent, key resources, statistical reporting, data and code availability, and overall transparency.
Checked — nothing surfaced.
The introduction cites prior work on the CD40/CD40L pathway's role in SjD, including upregulation in salivary glands and elevated soluble CD40L in sera. It also acknowledges the failure of first-generation anti-CD40L mAbs due to thromboembolic complications and explains how DAZ's Tn3 scaffold avoids this. The rationale for testing DAZ in two distinct populations is clearly linked to the unmet need and the pathway's importance.
“To circumvent this problem, DAZ antigen-binding sites were engineered into a Tn3 scaffold, a non-mAb platform, which lacked an Fc region.”
“the latter group has largely been excluded from recent clinical trials”
“To circumvent this problem, DAZ antigen-binding sites were engineered into a Tn3 scaffold, a non-mAb platform, which lacked an Fc region.”
Randomization was 1:1, stratified by baseline ESSDAI (population 1) or ESSPRI (population 2) scores. Blinding was maintained by using an unblinded pharmacy staff to prepare and cover IV bags, and a separate unblinded monitor. Power analysis was provided for both populations with effect sizes, alpha (0.10), and power (80%). Inclusion/exclusion criteria are detailed. Outlier handling is addressed via the full analysis set and handling of rescue therapy. Controls are the placebo group. Independent replication is not applicable for a single pivotal trial.
“Randomization was stratified by ESSDAI score at screening (below 10 points versus 10 or above) for population 1, and by ESSPRI score at screening (under 7.5 points versus 7.5 or above) for population 2.”
“a local unblinded pharmacy staff member had the responsibility of allocating, dispensing and preparing the study medication, and covering the IV bags.”
“The planned sample size of 72 participants in population 1 (36 in the DAZ group and 36 in the PBO group) provided 80% power to detect a difference in mean change from baseline to day 169 in ESSDAI of 3.0 (assumed s.d. = 5) between the DAZ and PBO groups at a two-sided alpha level of 0.10 using a two-sample t -test.”
“Randomization was stratified by ESSDAI score at screening (below 10 points versus 10 or above) for population 1, and by ESSPRI score at screening (under 7.5 points versus 7.5 or above) for population 2.”
“To maintain blinding of the participants, investigators, site staff, sponsor, contract research organization and staff, a local unblinded pharmacy staff member had the responsibility of allocating, dispensing and preparing the study medication, and covering the IV bags.”
“The planned sample size of 72 participants in population 1 (36 in the DAZ group and 36 in the PBO group) provided 80% power to detect a difference in mean change from baseline to day 169 in ESSDAI of 3.0 (assumed s.d. = 5) between the DAZ and PBO groups at a two-sided alpha level of 0.10 using a two-sample t -test.”
Sex is reported for all groups, with the majority female. Age, weight, and health status (disease activity scores) are reported. Demographics include race and ethnicity. Species/strain and housing conditions are not applicable as this is a human trial.
“Age, years, mean (s.d.) | 48.8 (12.1) | 51.7 (9.6) | 49.0 (12.6) | 50.9 (11.7)”
“At baseline, participants in population 1 had an ESSDAI total score (mean ± s.d.) of 10.7 ± 4.3 and an ESSPRI total score (mean ± s.d.) of 6.6 ± 1.7.”
“Age, years, mean (s.d.) | 48.8 (12.1) | 51.7 (9.6) | 49.0 (12.6) | 50.9 (11.7)”
“Female | 38 (100) | 35 (97.2) | 50 (90.9) | 53 (98.1)”
The Methods state that the study was approved by the IRB/IEC and conducted in accordance with the Declaration of Helsinki and ICH-GCP. Written informed consent was obtained from all participants. The approval is not named specifically, but the statement is adequate for a clinical trial.
“This study was approved by the Institutional Review Board/Independent Ethics Committee and conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki and are consistent with both the International Council for Harmonisation/Good Clinical Practice and applicable regulatory requirements”
“All participants that participated in this study provided written informed consent.”
DAZ is described as a nonantibody fusion protein, and the dose (1,500 mg IV) and regimen are specified. The placebo is saline. Statistical analysis used SAS v.9.4. Antibodies, cell lines, mycoplasma, and organisms are not applicable as this is a clinical trial without wet-lab assays.
“Eligible participants were randomized 1:1 to receive three doses of either IV DAZ 1,500 mg or PBO every 2 weeks, then four additional doses every 4 weeks (stage I).”
“Data analysis was performed using SAS v.9.4.”
“Eligible participants were randomized 1:1 to receive three doses of either IV DAZ 1,500 mg or PBO every 2 weeks, then four additional doses every 4 weeks (stage I).”
“Data analysis was performed using SAS v.9.4.”
Tests are named (MMRM, logistic regression, two-sided t-test). Assumptions are handled by the pre-specified models. Exact p-values are reported (e.g., P = 0.0167). Effect sizes with 90% CIs are reported. Data presentation includes per-group n and LS means with SE. Mathematical plausibility checks were not performed due to continuous outcomes and model-based estimates.
“yielding an LS mean difference of −2.2 ± 0.9 ( P = 0.0167).”
“LS mean difference (90% CI); P value | −2.2 (−3.6, −0.7); 0.0167”
“The primary endpoint for each population was analyzed using the mixed-effect model for repeated measures (MMRM) approach.”
“LS mean difference (90% CI); P value | −2.2 (−3.6, −0.7); 0.0167”
The data availability statement describes a concrete process for requesting deidentified individual patient data, including conditions and a review committee. This is reported_and_adequate for a clinical trial. Repository deposit and accession numbers are not applicable for patient-level data. Code sharing is not applicable as no bespoke code is mentioned.
“Data-sharing requests relating to data in this paper will be considered after the publication date and providing that either (1) this product and indication (or other new use) have been granted marketing authorization in both the United States and Europe or (2) clinical development discontinues and the data will not be submitted to the regulatory authorities.”
“Data-sharing requests relating to data in this paper will be considered after the publication date and providing that either (1) this product and indication (or other new use) have been granted marketing authorization in both the United States and Europe or (2) clinical development discontinues and the data will not be submitted to the regulatory authorities.”
Trial registration is provided. Methods are comprehensive. Limitations are explicitly discussed (single dose, small sample size, alpha of 0.1). Conclusions are appropriately cautious. Funding and competing interests are disclosed. A reporting guideline is not explicitly mentioned, but the paper follows CONSORT-like structure.
“ClinicalTrials.gov identifier: NCT04129164”
“There are several limitations of our phase 2 study of DAZ in SjD. Only a single DAZ dosing regimen was tested, precluding any conclusions about dose–response.”
“ClinicalTrials.gov identifier: NCT04129164”
“There are several limitations of our phase 2 study of DAZ in SjD. Only a single DAZ dosing regimen was tested, precluding any conclusions about dose–response.”
Registered (2 IDs: ClinicalTrials.gov, EudraCT). No reporting guideline cited.
Broken references and links
None foundReferences checked against Crossref, OpenAlex and Retraction Watch for retractions and resolvability, plus declared data and code links probed for whether they resolve to content matching the paper.
Checked — nothing surfaced.
Checked 39 references by DOI: 38 verified — 1 no DOI (shown, not verified).
- NO DOISystemic manifestations of primary Sjögren’s syndrome out of the ESSDAI classification: prevalence and clinical relevance in a large international, multi-ethnic cohort of patientsNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
2 data/code links checked; 2 live.
- datahttps://classic.clinicaltrials.gov/ct2/show/NCT04129164LIVEHTTP 200Resolves, but the content could not be matched to the paper.
- datahttps://wwwext.amgen.com/science/clinical-trials/clinical-data-transparency-practices/clinical-trial-data-sharing-requestLIVEHTTP 200Resolves, but the content could not be matched to the paper.
Copyediting
4 minorWording, consistency and formatting errors that need correcting before submission.
No major wording or formatting errors. 4 minor suggestions below.
4 copyedit issues flagged: mostly consistency, typo, clarity.
- MINORtypoMethods, Exclusion criteria“excluded form population 2”→ excluded from population 2Typographical error: 'form' should be 'from'.
- MINORconsistencyResults, Safety, Stage II“One participant in the PBO–DAZ group discontinued the study due to an AE (rash) compared with none in the PBO–DAZ group.”→ One participant in the PBO–DAZ group discontinued the study due to an AE (rash) compared with none in the DAZ–PBO group.The comparison group appears to be mislabeled; should be DAZ–PBO.
- MINORconsistencyTable 3“Stage II + follow-up”→ Ensure column headers are consistent with the text.The table layout is complex and may be confusing.
- MINORclarityResults, Safety“In population 2, two SAEs were reported in two participants in the DAZ–PBO group (urinary tract infection and invasive ductal breast carcinoma (both also captured as AESIs)) and one SAE was reported in the PBO–DAZ group (atrial flutter).”→ Clarify that the SAE of atrial flutter was in the PBO-DAZ group.The sentence is slightly ambiguous.
The published work is robust and well-reported. An informed reader should weigh the minor copyediting errors (e.g., mislabeled comparison group in safety section) and the lack of explicit CONSORT statement, but these do not warrant a correction. The single statistical inconsistency noted by the verification component is worth a closer look, but given the limited coverage, it is not a definitive validity threat.
- 1.HIGHcopyeditIn Results, Safety, Stage II, correct the mislabeled comparison group: change 'compared with none in the PBO–DAZ group' to 'compared with none in the DAZ–PBO group'.The current text contains an internal contradiction that could confuse readers about the safety data.
- 2.HIGHstatisticsInvestigate the one inconsistent test flagged by the statistics verification component; if it is a genuine error, issue a correction or provide clarification.An unexplained statistical inconsistency, even if minor, could undermine trust in the reported results.
- 3.MEDIUMreportingAdd an explicit statement in the Methods or Reporting Summary that the trial adheres to CONSORT guidelines.Both reviewers noted the absence of an explicit reporting guideline statement, which is a common expectation for clinical trials.
- 4.MEDIUMstatisticsIn the Statistical analysis section, clarify the handling of missing data in the MMRM analysis (e.g., state the missing-at-random assumption).Both reviewers suggested this clarification to improve transparency and reproducibility.
- 5.MEDIUMreportingProvide a link or reference to the statistical analysis plan (SAP) and protocol in the data availability section.Reviewer 2 noted that the SAP and protocol are mentioned but not linked, which limits transparency.
- 6.MEDIUMreportingConsider naming the specific IRB/ethics committee in the main text for full transparency.Reviewer 2 suggested this to strengthen the ethics reporting, though it is not a major gap.
- 7.MEDIUMreportingProvide exact p-values for all secondary endpoints in the text, not just in tables.Reviewer 1 suggested this to improve transparency and reader access to key results.
- 8.LOWcopyeditFix the typo in Methods, Exclusion criteria: change 'excluded form population 2' to 'excluded from population 2'.This is a minor typographical error that should be corrected for professionalism.
- 9.LOWcopyeditClarify the sentence in Results, Safety regarding SAEs to explicitly state that the atrial flutter was in the PBO–DAZ group.The current sentence is ambiguous and could be misread.
- 10.LOWreportingConsider adding a table of baseline characteristics for the crossover stage to show balance after switching.Reviewer 2 suggested this to enhance transparency of the crossover design.
- 11.LOWreportingReview Table 3 layout to ensure column headers are consistent and not confusing, especially for Stage II.The copyedit pass flagged the table as complex and potentially confusing.
The star rating is the report’s one-glance summary. Every paper starts at 5★ and loses stars for the concrete problems the review finds — so a rating is never a vague average, it’s a running total you can read line by line under “How this rating was calculated.”
- Reporting — 8 dimensionseach dimension that fully fails−½★
- each dimension partially met−¼★
- Statistics · Integrity · Claimseach serious problem−1★
- each medium problem−½★
- Citationseach retracted or unverifiable reference−¼★
- Copyeditonly when the manuscript needs a full edit−½★
The rating never drops below 1★, and a demonstrable critical failure (an impossible statistic, a proven ethics violation) caps it at 1★ on its own — so the stars can never look healthy when the verdict is CRITICAL.
The rating draws on a panel of agents. Three independent Kaimen Rigor reviewers grade the eight dimensions below across several independent passes (the shown verdict is their majority vote — steadier than any single run), isolate the paper’s major claims and check its own evidence backs them, and flag integrity concerns. Alongside them, a citation agent resolves every reference against Crossref, OpenAlex, and Retraction Watch; a statistics agent recomputes reported tests; and rule-based checks verify that declared data/code links actually resolve. Full text is required — an abstract-only submission is not analyzed.
Graded against NIH, MDAR, ARRIVE 2.0, CONSORT, EQUATOR, and RRID guidelines. A dimension that doesn’t apply to the study type is skipped, never penalized.
This Kaimen Rigor review is model-assisted and is not a substitute for formal expert review. It complements human evaluation by surfacing potential methodological concerns — verify each finding against the source.