Phase 3 trial of tolvaptan in pediatric autosomal dominant polycystic kidney disease (adpkd): two years of data from an open-label extension

Abstract Background and Aims The 1-year, randomized, placebo-controlled phase (Phase A) of a 2-part trial of tolvaptan in children/adolescents with ADPKD (NCT02964273) demonstrated acceptable safety/tolerability and evidence of vasopressin V2 receptor antagonism. A 2-year, open-label extension (Phase B) evaluated longer-term outcomes. Method By entry criteria, participants at Phase A baseline were aged 4-17 years, had a diagnosis of ADPKD, estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2, and body weight ≥20 kg. Participants in the tolvaptan and placebo arms who completed Phase A could enter Phase B to receive open-label tolvaptan for 24 months. Dosing was based on body weight and tolerability, with tolvaptan re-initiated in participants who had received tolvaptan in Phase A to preserve the blind until Phase A completion. Phase B post-baseline study visits occurred at Week 1, Months 1, 6, 12, 18, and 24. Laboratory assessments to monitor safety were performed monthly, with more frequent liver function testing if any indication of liver injury was detected. eGFR and height-adjusted total kidney volume (htTKV) were calculated using the mixed model repeated measures method with model terms treatment, visit, treatment by visit, and baseline by visit interaction. To exclude the acute hemodynamic effect of tolvaptan, change in eGFR after week 1 of treatment is shown. Results Of 83 Phase A completers, 81 (42 prior tolvaptan, 39 prior placebo) enrolled in Phase B; 33/42 (78.6%) prior tolvaptan and 30/39 (76.9%) prior placebo participants completed the Phase B Month 24 visit on tolvaptan. The average daily tolvaptan dose was 41.1 mg in the prior tolvaptan group (mean [SD] age 14.3 [3.2] years) and 38.0 mg in the prior placebo group (13.9 [2.9] years). Adherence determined by returned drug was ≥90% in 32/42 (76.2%) participants in the prior tolvaptan group and 28/39 (71.8%) in prior placebo. In Phase A, eGFR increased in the tolvaptan group and decreased in the placebo group (significant difference at Month 6), with significant benefit maintained at most assessment visits in Phase B for the prior tolvaptan group compared to the prior placebo group (Figure 1A). Growth in htTKV on MRI (participants ages 12-17) was slowest during the first year of tolvaptan treatment, as shown by the slope of htTKV during Phase A in the tolvaptan group and during year 1 of Phase B in the prior placebo group (Figure 1B), with growth rates higher thereafter, although sample sizes did not permit meaningful statistical comparison of the changes. Scores on pediatric health-related quality of life assessment instruments, including the PedsQL Generic Core Scale and the PedsQL Multidimensional Fatigue Scale, remained stable during both phases and indicated low health-related quality of life burden and high functioning. The most common adverse events in Phase B (>15% participants overall; prior tolvaptan and prior placebo, respectively) were headache (36%, 44%), nasopharyngitis (26%, 33%), rhinitis (26%, 10%), oropharyngeal pain (21%, 18%), pyrexia (19%, 18%), cough (17%, 21%), abdominal pain (12%, 31%), polyuria (5%, 33%). Eleven participants overall experienced elevated liver enzymes by investigator report (no prespecified enzyme levels were required to report an event): 6 recovered without intervention, treatment was interrupted in 4, and in 1 tolvaptan was withdrawn for a reason other than the hepatic event. No participant met predefined laboratory criteria for serious drug-induced liver injury in either phase. There were no notable differences between prior tolvaptan and prior placebo in Tanner staging progression or change from baseline in growth percentile in Phase B. Conclusion Consistent with adult data in the TEMPO 3:4 and TEMPO 4:4 trials, children and adolescents who received tolvaptan during a randomized trial exhibited eGFR benefit relative to those who received placebo, a difference that was preserved during a 2-year, open-label extension. As in adults, kidney volume growth was higher after 1 year of treatment. Tolvaptan exhibited acceptable safety and good tolerability, with few discontinuations and a low quality of life burden.