Canadian Real-World Assessment of Tolvaptan in ADPKD: C-MAJOR Study and Safety Monitoring and Distribution Program
Bibliographic record
Abstract
Background: Tolvaptan is the only approved treatment in Canada for slowing renal function decline and kidney enlargement in ADPKD patients. As per Health Canada requirement, a patient registry evaluating long-term clinical outcomes (C-MAJOR study) and a hepatic safety monitoring and distribution program (HSMDP) to mitigate risk of liver injury were implemented and have been ongoing for 5 years. The aim of this interim analysis is to describe baseline characteristics of patients at initiation of tolvaptan through the C-MAJOR study and to report on treatment persistence and liver transaminases elevation rate through the HSMDP. Methods: C-MAJOR is a non-interventional, multi-centre study of ADPKD patients treated with tolvaptan. HSMDP ensures tolvaptan is dispensed under controlled liver function monitoring. Results: As of April 2020, 398 patients, 51% female, were enrolled in C-MAJOR. At baseline, mean (SD) age was 45.1 (11.5) years, BP was 129.4 (13.4)/83.1 (10.0) mmHg and eGFR was 63.6 (27.8) mL/min/1.73 m2. Total kidney volume was 1949 (1562) mL, 80.7% of patients had a family history of ADPKD and 39.4% had a family history of early end-stage renal disease. As per Mayo classification, 90.2% were at high risk of disease progression (1C-D-E). The most common ADPKD clinical manifestations were hypertension (83.2%), hepatic cysts (69.6%) and kidney pain (24.1%). Over a mean (SD) follow-up of 2.0 (1.0) years, adverse events were reported in 82.7% of patients, most common being polyuria (19.6%), fatigue (18.6%), and nocturia (15.1%). Over a mean (SD) follow-up of 23.0 (17.6) months in the HSMDP, 2.4% (39) of the 1,600 patients who received at least one shipment of tolvaptan reported an elevation of transaminases >3x ULN. There were 0.3% (5) of patients meeting the guidelines for permanent discontinuation. No cases of drug-induced liver injury were reported. Treatment discontinuation rates at 12, 24 and 36 months were 14%, 21% and 26%, respectively. Conclusions: This analysis provides Canadian real-world evidence of high-risk disease progression at tolvaptan initiation, 3-y persistence data similar to phase III study and the HSMDP showing tolvaptan was permanently discontinued in 0.3% of patients because of hepatic effects. Funding: Commercial Support - Otsuka Canada Pharmaceutical Inc.
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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 | 0.005 | 0.007 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.004 |
| Science and technology studies | 0.002 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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 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".