Anti-CD38 monoclonal antibody CM313 for primary immune thrombocytopenia: multicentre, randomised, placebo controlled, phase 2 trial.
Chen Y, Xu Y, Dai J, Sun T, Li H, Hua Z, Zhou Z, Zhou H, Yan Z, Zhao X, Xue F, Liu W, Liu X, Fu R, Wang W, Chi Y, Dong H, Ju M, Dai X, Gu W, Pei X, Yang R, Zhang L
- DOI
- 10.1136/bmj-2025-084314
- Record issued
- 2026-08-15
- 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/2232d714-701e-41d0-a6dc-14f5010fa55e is authoritative.
How this rating was calculated
- IntegrityIntegrity concern−0.5★
- ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
- ClaimsTreatment effect not shown to be clinically meaningful−0.5★
- ReportingData & code availability partially met−0.25★
- No data or code availability links were detected to verify.
- 01Efficacy rests on an unvalidated surrogate endpoint
The primary efficacy endpoint is the overall response rate based on platelet counts (≥30×10^9/L with doubling from baseline and no bleeding), which is a surrogate biomarker for clinical benefit (bleeding risk). The paper does not provide evidence linking this platelet count threshold to validated clinical outcomes such as reduced major bleeding or mortality, nor does it demonstrate target engagement at the tested dose (e.g., PK/PD data showing CD38 receptor occupancy).
“The primary outcome was overall response rate (at least two consecutive platelet counts ≥30×10 9 /L, a minimum doubling from baseline, and no bleeding) at week 8.”
- 02Treatment effect not shown to be clinically meaningful
The primary effect is a platelet count increase to ≥30×10^9/L, which is a small fraction of the normal platelet count (150-400×10^9/L). The paper does not anchor this threshold to a minimal clinically important difference or demonstrate that it translates to meaningful reduction in bleeding events or other patient-important outcomes. Although the response rate difference is statistically significant, the clinical meaningfulness of the surrogate threshold is not established.
“At week 8, the overall response rate was higher in the CM313 group (83%; 25/30) compared with placebo group (20%; 3/15): difference 63.3% (95% confidence interval 33.7% to 81.3%; P<0.001).”
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 and well-reported phase 2 randomised controlled trial of CM313 in immune thrombocytopenia. The main methodological strengths are rigorous design, clear reporting of ethics, demographics, and statistical methods. The primary weakness is the vague data availability statement, which lacks a concrete access mechanism.
Both reviewers independently scored all eight dimensions and agreed on every status; no divergence required reconciliation. The statistics verification recomputed 4 reported tests consistently, but this covers only a subset of all reported statistics; the paper's statistics should not be considered fully verified beyond those checks. The citation check found no retracted or unresolved references.
Numerical inconsistencies
1 finding · worst lowValues that contradict each other or are impossible for the stated sample: recomputed p-values and test statistics, GRIM/GRIMMER checks on summary numbers, percentages against their own counts, totals against their parts, and estimates against their own confidence intervals.
- Internal contradictions in the reported numbersAssessed
Recomputed 4 tests: 4 consistent, 0 inconsistent; 4 via agent-written checks.
- CONSISTENTreported p < .001 · recomputed p = <.001Reviewers 1, 2Primary outcome: overall response rate at week 8 (CM313 vs placebo) using Fisher's exact test.
“At week 8, the overall response rate was higher in the CM313 group (83%; 25/30) compared with placebo group (20%; 3/15): difference 63.3% (95% confidence interval 33.7% to 81.3%; P<0.001).”
Taken as given: The numbers 25/30 and 3/15 are the event counts and group totals for the primary outcome.; Fisher's exact test was used for group comparisons as stated in the methods.; The p-value is two-tailed.Method: Fisher's exact test on the 2x2 table (25,5,3,12) using the pFisher2x2 function with midP=0.How we recomputed it: pFisher2x2(25,5,3,12,0) - CONSISTENTreported p < .001 · recomputed p = <.001Reviewer 1Complete response rate within eight weeks (CM313 vs placebo) using Fisher's exact test.
“The complete response rate within eight weeks was also higher in the CM313 group (73%; 22/30) compared with placebo group (7%; 1/15), with a difference of 66.7% (95% CI 38.8% to 82.0%; P<0.001).”
Taken as given: The numbers 22/30 and 1/15 are the event counts and group totals for complete response.; Fisher's exact test was used for group comparisons.; The p-value is two-tailed.Method: Fisher's exact test on the 2x2 table (22,8,1,14) using the pFisher2x2 function with midP=0.How we recomputed it: pFisher2x2(22,8,1,14,0) - CONSISTENTreported p < .001 · recomputed p = <.001Reviewer 1Proportion of patients achieving two consecutive platelet counts ≥50×10^9/L within eight weeks (CM313 vs placebo) using Fisher's exact test.
“Similarly, the proportion of patients achieving two consecutive platelet counts ≥50×10 9 /L within eight weeks was higher in the CM313 group (90%; 27/30) compared with placebo group (33%; 5/15), with a difference of 56.7% (95% CI 28.0% to 77.5%; P<0.001).”
Taken as given: The numbers 27/30 and 5/15 are the event counts and group totals for this outcome.; Fisher's exact test was used for group comparisons.; The p-value is two-tailed.Method: Fisher's exact test on the 2x2 table (27,3,5,10) using the pFisher2x2 function with midP=0.How we recomputed it: pFisher2x2(27,3,5,10,0) - CONSISTENTreported p < .001 · recomputed p = <.001Reviewer 2Secondary outcome: complete response rate within 8 weeks (CM313 vs placebo) using Fisher's exact test.
“The complete response rate within eight weeks was also higher in the CM313 group (73%; 22/30) compared with placebo group (7%; 1/15), with a difference of 66.7% (95% CI 38.8% to 82.0%; P<0.001).”
Taken as given: The numbers 22/30 and 1/15 are the event counts and group totals for complete response.; The test used is Fisher's exact test (two-tailed).Method: Fisher's exact test on the 2x2 table (22,8,1,14).How we recomputed it: pFisher2x2(22, 8, 1, 14, 0)
- lowinternal contradictionThe abstract reports 'median cumulative response duration for platelet counts ≥50×10 9 /L was 18 weeks in the CM313 group versus three weeks in the placebo group (P=0.004)', while Table 2 reports 'Median (95% CI) cumulative duration of PLT count ≥50×10 9 /L at ≤24 weeks (weeks) | 18.0 (10.0 to NR) | 3.0 (2.0 to NR) | - | 0.004'. The values are consistent, but the abstract says 'response duration' while the table says 'duration of PLT count ≥50×10 9 /L', which may be a minor terminology inconsistency.
“The median cumulative response duration for platelet counts ≥50×10 9 /L was 18 weeks in the CM313 group versus three weeks in the placebo group (P=0.004).”
Table 2Find 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
- Treatment effect not shown to be clinically meaningfulAssessed
4 major claims checked against the paper's own evidence: all adequately supported.
- supportedReviewers 1, 2CM313 showed a favourable safety profile and encouraging efficacy in adults with persistent or chronic primary immune thrombocytopenia.The primary endpoint and secondary outcomes show statistically significant improvements in platelet counts, and safety data show manageable adverse events.Evidence: Primary outcome: 83% vs 20% overall response rate (P<0.001); safety: most TEAEs grade 1-2, no deaths.
“CM313 showed a favourable safety profile and encouraging efficacy in adults with persistent or chronic primary immune thrombocytopenia, characterised by rapid increase in platelet count, sustained platelet responses, and manageable adverse events.”
ConclusionFind in source - supportedReviewers 1, 2CM313 rapidly increased platelet counts within three days.The paper reports a statistically significant difference in mean platelet count by day 3 (P=0.01).Evidence: As early as day 3, the mean platelet count was higher in the CM313 group than in the placebo group (P=0.01).
As early as day 3, the mean platelet count was higher in the CM313 group than in the placebo group (P=0.01).
Resultsreviewer’s wording - supportedReviewers 1, 2CM313 reduced bleeding episodes and the requirement for rescue treatment.The paper reports lower bleeding rates and fewer rescue treatments in the CM313 group compared to placebo.Evidence: Bleeding decreased from 37% to 10% in CM313 group vs increased in placebo; rescue drugs required in 10% vs 53% within first eight weeks.
The proportion of patients in the CM313 group with bleeding decreased from 37% (11/30) at baseline to 10% (3/30) at week 8 and remained at 13% (4/30) at week 24, without requiring rescue treatment.
Resultsreviewer’s wording - supportedReviewers 1, 2CM313 treatment induced a pronounced and sustained reduction in peripheral blood antibody-secreting cells and serum immunoglobulins.The paper reports significant declines in these immune parameters in the CM313 group compared to placebo.Evidence: Antibody secreting cells and serum immunoglobulin levels exhibited a pronounced decline in the CM313 group compared with placebo group, with levels maintained consistently up to week 24.
After treatment, CD19+B cell counts remained stable (see supplementary fig S4A), whereas antibody secreting cells and serum immunoglobulin levels exhibited a pronounced decline in the CM313 group compared with placebo group, with levels maintained consistently up to week 24.
Resultsreviewer’s wording
Premise concern: surrogate not validated for clinical benefit; effect size not shown to be clinically meaningful.
- INADEQUATESurrogate endpointThe primary efficacy endpoint is the overall response rate based on platelet counts (≥30×10^9/L with doubling from baseline and no bleeding), which is a surrogate biomarker for clinical benefit (bleeding risk). The paper does not provide evidence linking this platelet count threshold to validated clinical outcomes such as reduced major bleeding or mortality, nor does it demonstrate target engagement at the tested dose (e.g., PK/PD data showing CD38 receptor occupancy).
“The primary outcome was overall response rate (at least two consecutive platelet counts ≥30×10 9 /L, a minimum doubling from baseline, and no bleeding) at week 8.”
- INADEQUATEEffect sizeThe primary effect is a platelet count increase to ≥30×10^9/L, which is a small fraction of the normal platelet count (150-400×10^9/L). The paper does not anchor this threshold to a minimal clinically important difference or demonstrate that it translates to meaningful reduction in bleeding events or other patient-important outcomes. Although the response rate difference is statistically significant, the clinical meaningfulness of the surrogate threshold is not established.
“At week 8, the overall response rate was higher in the CM313 group (83%; 25/30) compared with placebo group (20%; 3/15): difference 63.3% (95% confidence interval 33.7% to 81.3%; P<0.001).”
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
1 finding · worst mediumRequired detail the manuscript never states — study design, biological variables, ethics approval and consent, key resources, statistical reporting, data and code availability, and overall transparency.
- Data/code availability incompleteAssessed
The introduction cites prior work on ITP pathophysiology, current treatments, and the rationale for targeting CD38, including previous studies of anti-CD38 antibodies and a prior phase 1/2 trial of CM313. The premise is well-supported and the hypothesis follows logically. Limitations of prior research are acknowledged, such as the heterogeneity of ITP and the need for new treatments.
“Preliminary results from our previous single arm phase 1/2 trial highlighted the promising efficacy and tolerable safety profile of CM313 in patients with previously treated immune thrombocytopenia.”
“CD38, a type II glycoprotein abundantly expressed on antibody-producing plasmablasts and plasma cells, represents a promising therapeutic target in autoimmune diseases.”
“Despite these advancements, the heterogeneity of immune thrombocytopenia and the persistence of therapeutic refractoriness in certain patients underscore the urgent need for innovative and effective treatment strategies.”
“Preliminary results from our previous single arm phase 1/2 trial highlighted the promising efficacy and tolerable safety profile of CM313 in patients with previously treated immune thrombocytopenia.”
“CD38, a type II glycoprotein abundantly expressed on antibody-producing plasmablasts and plasma cells, represents a promising therapeutic target in autoimmune diseases.”
“However, the indirect method used in both of our studies for detecting platelet glycoprotein autoantibodies has notable limitations in sensitivity and diversity, which urgently require technical updates.”
Randomisation was performed using SAS with a block size of three, and blinding was maintained with visually indistinguishable treatments and an independent data collection team. A power analysis was conducted to determine the sample size. Inclusion/exclusion criteria were described in supplementary table S1 and summarised in the text. The analysis population (full analysis set) and handling of missing data (e.g., rescue treatment as non-response) were pre-specified. The trial is a human RCT, so replicate_distinction, controls, and independent_replication are not applicable.
“Using SAS software, a statistician applied a block size of three to generate the randomisation list for patients.”
“To maintain blinding, both CM313 and placebo were visually indistinguishable.”
“Assuming a response rate of 70% for CM313 at week 8 and a spontaneous remission rate of 18% for placebo, we required a sample size of 39 participants (allocated 2:1) to provide a power of 80% to detect a difference between groups at a two sided α level of 0.05.”
“Using SAS software, a statistician applied a block size of three to generate the randomisation list for patients.”
“To maintain blinding, both CM313 and placebo were visually indistinguishable.”
“Assuming a response rate of 70% for CM313 at week 8 and a spontaneous remission rate of 18% for placebo, we required a sample size of 39 participants (allocated 2:1) to provide a power of 80% to detect a difference between groups at a two sided α level of 0.05.”
Sex is reported for both groups (60% female in CM313, 73% in placebo). Age is reported as median with IQR. Demographics include BMI, duration of ITP, baseline platelet counts, and previous treatments. Since both sexes are enrolled, sex_justified is not applicable. Species/strain and housing conditions are not applicable for a human trial.
“with female patients comprising 18 (60%) and 11 (73%) participants, respectively.”
“Median age was 38.5 years (interquartile range (IQR) 29.0-52.0) in the CM313 group and 45.0 (25.0-52.0) years in the placebo group”
“Median (IQR) body mass index | 26.1 (23.4-28.6) | 24.6 (21.7-27.8) | 26.0 (23.0-27.8)”
“Median (IQR) age (years) | 38.5 (29.0-52.0) | 45.0 (25.0-52.0) | 41.0 (29.0-52.0)”
“Baseline platelet counts were low, with mean values of 8×10 9 /L in the CM313 group and 15×10 9 /L in the placebo group.”
The trial protocol received approval from the ethics committees of the Institute of Hematology and Blood Diseases Hospital (IIT2023068-EC-1), and all patients provided written informed consent. The study was conducted in accordance with the Declaration of Helsinki. These satisfy the requirements for human research.
“The trial protocol received approval from the ethics committees of the Institute of Hematology and Blood Diseases Hospital (IIT2023068-EC-1)”
“All patients provided written informed consent.”
“and was conducted in strict accordance with the principles of the Declaration of Helsinki.”
“The trial protocol received approval from the ethics committees of the Institute of Hematology and Blood Diseases Hospital (IIT2023068-EC-1) and was conducted in strict accordance with the principles of the Declaration of Helsinki.”
“All patients provided written informed consent.”
CM313 is identified as a humanised anti-CD38 monoclonal antibody, and the placebo composition is described. The manufacturer (Keymed Biosciences) is acknowledged. Statistical software (SAS 9.4, PASS 2022) is identified. No other biological/chemical resources are used, so other sub-criteria are not applicable.
“CM313, a humanised anti-CD38 monoclonal antibody, is distinguished by a unique complementarity-determining region sequence that differentiates it from daratumumab.”
“The placebo contained the same excipient components as CM313 (histidine, histidine hydrochloride, arginine hydrochloride, and polysorbate 80) but without the active component.”
“Statistical analyses were conducted using SAS version 9.4.”
“CM313 or matching placebo was administered intravenously at a dose of 16 mg/kg weekly for eight weeks. The placebo contained the same excipient components as CM313 (histidine, histidine hydrochloride, arginine hydrochloride, and polysorbate 80) but without the active component.”
“Statistical analyses were conducted using SAS version 9.4.”
Statistical tests are named (Fisher's exact test, Miettinen-Nurminen method, mixed effects model, Kaplan-Meier). Assumptions are handled by design (e.g., mixed model for repeated measures). Exact p-values are reported (e.g., P<0.001). Effect sizes with 95% CIs are reported. Software is identified. Data presentation includes per-group n and appropriate figures. Mathematical plausibility checks were not performed due to lack of raw data, but no obvious inconsistencies were found.
“Fisher’s exact test was used for group comparisons and the Miettinen-Nurminen method was used to calculate 95% CIs for differences between groups.”
“difference 63.3% (95% confidence interval 33.7% to 81.3%; P<0.001)”
“difference 63.3% (95% confidence interval 33.7% to 81.3%; P<0.001)”
“Fisher’s exact test was used for group comparisons and the Miettinen-Nurminen method was used to calculate 95% CIs for differences between groups.”
The data availability statement is incomplete in the provided text (cut off). It likely says 'available on reasonable request' but no platform or conditions are given. No repository deposit or accession numbers are provided. No custom code is mentioned, so code_sharing is not applicable.
“The code used to analyse”
“The code used to analyse”
The trial is registered (NCT06199089). Limitations are discussed in a dedicated section. Conclusions are proportional to the evidence. Funding sources and competing interests are declared. Reporting guidelines are not explicitly mentioned, but the paper follows standard clinical trial reporting.
“Trial registration ClinicalTrials.gov NCT06199089 .”
“This study has several limitations, including a small sample size, a limited follow-up period, and the lack of patient health related quality of life measurements.”
“Funding: This study received support from the Chinese Academy of Medical Sciences innovation fund for medical sciences (2024-I2M-C&T-B-085 CYF, 2024-I2M-C&T-B-086 ST, 2022-I2M-2-003 ZL, 2023-I2M-2-007 ZL)”
“Trial registration ClinicalTrials.gov NCT06199089 .”
“This study has several limitations, including a small sample size, a limited follow-up period, and the lack of patient health related quality of life measurements.”
Registered (2 IDs: ClinicalTrials.gov). No reporting guideline cited.
Broken references and links
None found · partly checkedReferences 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.
Nothing surfaced — but not everything feeding this category ran (missing: data/code link verification), so read this as a partial clean bill.
Checked 40 references by DOI: 39 verified — 1 no DOI (shown, not verified).
- NO DOISafety, tolerability, and efficacy of mezagitamab (TAK-079) in chronic or persistent primary immune thrombocytopenia: Interim results from a phase 2, randomized, double-blind, placebo-controlled studyNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
Copyediting
6 minorWording, consistency and formatting errors that need correcting before submission.
No major wording or formatting errors. 6 minor suggestions below.
6 copyedit issues flagged: mostly consistency, typo, clarity.
- MINORconsistencyAbstract, Results“The median cumulative response duration for platelet counts ≥50×10 9 /L was 18 weeks in the CM313 group versus three weeks in the placebo group (P=0.004).”→ Ensure consistent use of 'three' vs '3' in text.Minor style inconsistency.
- MINORtypoResults, Efficacy“By day 5, 87% (26/30) of patients in the CM313 group achieved platelet counts ≥50×10 9 /L compared with 40% (6/15) in the placebo group (P=0.004) ().”→ Remove extra parentheses.Extra parentheses in text.
- MINORclarityDiscussion, Comparison with other studies“This may explain why only two patients in our study had a history of splenectomy.”→ Clarify the link between splenectomy risks and the low number.Could be clearer.
- MINORtypoAbstract, Results“Treatment emergent adverse events occurred in 87% (26/30) of patients in the CM313 group and 80% (12/15) in the placebo group”→ Consider hyphenating 'Treatment-emergent' for consistency.Minor style issue.
- MINORconsistencyTable 2, footnote“Overall response was defined as complete or partial response.”→ Ensure consistent use of 'overall response' vs 'overall response rate'.Minor terminology consistency.
- MINORclarityResults, Efficacy“By day 5, 87% (26/30) of patients in the CM313 group achieved platelet counts ≥50×10 9 /L compared with 40% (6/15) in the placebo group (P=0.004)”→ Clarify that this is a secondary outcome.Minor clarity improvement.
The published work is robust and well-reported, with only minor reporting gaps. An informed reader should weigh the vague data availability statement and the lack of explicit CONSORT adherence as minor limitations, but neither undermines the core findings. No erratum appears warranted based on the checks performed.
- 1.HIGHdata codeComplete the data availability statement in the Data availability section to specify a concrete access route, e.g., 'De-identified participant data will be shared upon reasonable request to the corresponding author after approval by the ethics committee and with a data sharing agreement.'The current statement is cut off and vague, which is a reporting gap that reviewers and readers will notice.
- 2.HIGHdata codeDeposit de-identified individual patient data in a controlled-access repository (e.g., Vivli) and provide an accession or DOI in the data availability statement.This would comply with data-sharing norms for clinical trials and enhance reproducibility.
- 3.MEDIUMreportingExplicitly state adherence to the CONSORT reporting guideline in the Methods or a separate section, and consider submitting a CONSORT checklist.This is a standard expectation for randomised trials and would strengthen reporting transparency.
- 4.MEDIUMdata codeShare the statistical analysis code (e.g., SAS code) in a public repository like GitHub or Zenodo with a DOI.Sharing code enhances reproducibility and is increasingly expected for clinical trials.
- 5.MEDIUMreportingProvide a link to the full trial protocol or statistical analysis plan in the supplementary materials.This would allow readers to verify pre-specified analyses and outcomes.
- 6.LOWcopyeditIn the Abstract Results, change 'three weeks' to '3 weeks' for consistent numeric style.Minor style inconsistency flagged by copyedit.
- 7.LOWcopyeditIn Results Efficacy, remove the extra parentheses after '(P=0.004) ()'.Typo flagged by copyedit.
- 8.LOWcopyeditIn the Discussion, clarify the link between splenectomy risks and the low number of patients with a history of splenectomy.Clarity improvement flagged by copyedit.
- 9.LOWcopyeditIn the Abstract Results, hyphenate 'Treatment-emergent' for consistency.Minor style issue flagged by copyedit.
- 10.LOWcopyeditIn Table 2 footnote, ensure consistent use of 'overall response' vs 'overall response rate'.Minor terminology consistency flagged by copyedit.
- 11.LOWcopyeditIn Results Efficacy, clarify that the day 5 platelet count outcome is a secondary outcome.Minor clarity improvement flagged by copyedit.
- 12.LOWreportingIn the Abstract and Table 2, align terminology for the duration outcome: use 'duration of platelet count ≥50×10 9 /L' consistently instead of 'response duration'.The integrity check noted a minor terminology inconsistency that could confuse readers.
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.