Eight Years of Canadian Real-World Assessment of Tolvaptan in ADPKD: C-MAJOR Study and Safety Monitoring and Distribution Program
Bibliographic record
Abstract
Background: Tolvaptan is approved in Canada for slowing renal function decline and kidney enlargement in patient with ADPKD. As required by Health Canada, a patient registry study evaluating long-term clinical outcomes (C-MAJOR) and a hepatic safety monitoring and distribution program (HSMDP) to mitigate risk of liver injury were implemented. The aim of this interim analysis is to describe patient characteristics at tolvaptan initiation from the C-MAJOR study and to report on liver transaminase elevation rates and treatment persistence through the HSMDP. Methods: C-MAJOR is a non-interventional, observational, multi-centre study of ADPKD patients treated with tolvaptan. HSMDP ensures tolvaptan is dispensed under controlled liver function monitoring. Results: As of February 2023, 469 patients were enrolled in C-MAJOR. At baseline, 51% were female, with a mean (SD) age of 45 (12) years, BP 129 (13)/83 (10) mmHg and eGFR 64 (28) mL/min/1.73 m2. Overall, 68% were in early CKD stages 1, 2 and 3a. Total kidney volume was 1963 (1538) mL, 80% had a family history of ADPKD, 38% had a family history of early end-stage kidney disease, and 91% were at high risk of disease progression (Mayo Imaging Class 1C-D-E). The most common clinical manifestations were hypertension (84%), hepatic cysts (71%) and kidney pain (24%). From the HSMDP, 82 (3.4%) of the 2418 patients who initiated tolvaptan reported an elevation of transaminases (>3x ULN), with 11 (0.45%) meeting guidelines for permanent discontinuation. No cases of drug-induced liver injury were reported. Occurrence of ALT/AST levels greater than 3x ULN were seen up to 81 months post tolvaptan initiation and of these, 32% of the episodes occurred following the first 18 months of treatment. Treatment persistence rates at 12, 24 and 36 months were 84%, 77% and 72%, respectively. Conclusions: This analysis provides Canadian real-world evidence that most ADPKD patients treated with tolvaptan are at high-risk of disease progression and threeyear treatment persistence is similar to phase III study data. The HSMDP in Canada has been effective at avoiding the incidence of drug-induced liver injury associated with tolvaptan. Funding: Commercial Support - Otsuka Canada
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
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 teacher head, 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".