Eight Years of Canadian Real-World Assessment of Tolvaptan in Patients With Autosomal Dominant Polycystic Kidney Disease: The C-MAJOR Registry.

Background: Tolvaptan is the only approved treatment in Canada for slowing the progression of kidney enlargement and kidney function decline in people with autosomal dominant polycystic kidney disease (ADPKD). The Canadian Medical Assessment of Jinarc® Outcome Registry (C-MAJOR) registry evaluating long-term clinical outcomes of tolvaptan use was initiated in 2015, as per Health Canada requirements. Objective: To describe the study design and methodology of the C-MAJOR registry, and present baseline patient and disease characteristics, time to and reasons for treatment and study discontinuation, time to kidney replacement therapy (KRT), and the long-term safety with tolvaptan. Design: C-MAJOR is an ongoing, observational, non-interventional, multicenter registry study. Setting: Multicenter study at 24 polycystic kidney disease (PKD) clinics and centers across Canada. Participants: People with ADPKD treated with tolvaptan. Measurements: The primary study objective was to assess the impact of tolvaptan on health-related quality of life (HRQoL) using patient-reported outcome measures. Secondary study outcomes included time to KRT; mortality rate, and time to and cause of death; markers of kidney function; treatment adherence; time to and reasons for treatment/study discontinuation; and incidence of adverse events. This analysis focused on summarizing baseline demographic, clinical, treatment, and safety data collected between 2015 and December 2023. Methods: Outcomes were summarized descriptively or using the Kaplan-Meier method for time-to-event data. Results: Among 470 people with ADPKD enrolled and analyzed in C-MAJOR, the mean age at diagnosis and at tolvaptan initiation was 29.8 years and 44.4 years, respectively. Patients had a mean baseline total kidney volume of 2010.8 mL. Most patients (67%) had mild to moderate kidney dysfunction (chronic kidney disease [CKD] category G1-3a) and were at high risk of disease progression (Mayo class 1C-E) at baseline, with hypertension (85%) and hepatic cysts (72%) being common manifestations. Mean baseline patient-reported outcome scores were indicative of minimally impacted HRQoL, with mean ADPKD-Impact Scale scores of 1.6, 2.0, and 2.0 for the physical, fatigue, and emotional scales, respectively, and ADPKD Pain and Discomfort Scale scores of 1.8, 2.0, 1.4, and 2.1 for the Overall Pain and Discomfort, Dull Pain, Sharp Pain, and Discomfort severity scales, among others. Treatment and study discontinuation occurred in 29 and 27% of patients, respectively, with a mean time to discontinuation of 70.5 and 62.1 months. Adverse events were the primary reason for treatment (46%) and study (15%) discontinuations. During follow-up, 8% of patients progressed to KRT with a mean time to KRT of 82.5 months. Adverse events were reported in 93% of patients; most common adverse events (~25% each) were polyuria, nocturia and fatigue. Limitations: Recruitment from specialized PKD centers may limit generalizability, and patient-reported outcome analyses were limited to the subgroup enrolled prospectively (~40%) who completed assessments (<25%). Conclusions: This first report of 8-year follow-up data from the C-MAJOR registry confirms that most people with ADPKD treated with tolvaptan in Canada are in early CKD category of disease and at risk of rapid progression, with minimally impacted HRQoL at baseline. Registration number: NCT02925221.