Clazakizumab in Chronic Active Antibody-Mediated Kidney Transplant Rejection: Results of the IMAGINE Phase 3 Study
Bibliographic record
Abstract
Background: Chronic active antibody-mediated rejection (caAMR) is a common cause of graft loss after kidney transplant with no approved therapies. Clazakizumab, a high-affinity, humanized monoclonal antibody that binds IL-6, decreased donor-specific antibody (DSA) production and microvascular inflammation and stabilized eGFR in a phase 2 study in kidney transplant recipients (KTRs) with caAMR. Methods: IMAGINE (NCT03744910; start date: Oct 2019), a global (66 sites) double-blind phase 3 study, aimed to recruit ~350 KTRs with caAMR determined by kidney biopsy based on Banff 2015 criteria. KTRs were randomized 1:1 to clazakizumab (12.5 mg SC q4w) or placebo. Primary endpoint was time to all-cause graft loss (return to dialysis, graft nephrectomy, re-transplantation, eGFR <15 mL/min/1.73m2, death from any cause or sustained 40% reduction in eGFR). 1-yr eGFR was accepted as a reasonably likely surrogate endpoint (RLSE) for accelerated approval by the FDA. Temporary dose reduction was allowed at investigator discretion. This interim analysis (IA) was conducted when ~100 KTRs completed 1 yr of study participation. Results: At the time of the IA, 194 KTRs had been enrolled, and 115 were followed for 52 weeks for eGFR change from baseline. The analysis indicated that the study was unlikely to meet the primary efficacy outcome (time to composite all-cause allograft loss or irreversible loss of allograft function), and the data and safety monitoring board recommended to stop the study. No gastrointestinal perforations or other safety concerns were noted. Conclusion: Despite encouraging phase 2 results, the data from the IMAGINE IA did not support continuation. Nonetheless, this was the largest placebo-controlled study in KTRs with caAMR and was first transplant study for which the FDA accepted a 1-yr eGFR slope as a RLSE. No safety concerns were noted. Detailed primary analyses will be presented after the database has been unblinded prior to ASN Kidney Week. Funding: Commercial Support - CSL Behring
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.004 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.002 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".