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The NOCTURNE Randomized Trial Comparing 2 Tolvaptan Formulations.

ABSTRACT: Introduction: Tolvaptan, a treatment for autosomal dominant polycystic kidney disease (ADPKD), inhibits vasopressin V2 receptor signaling, which causes aquaretic adverse events (AAEs). The short-term efficacy and tolerability of a once-daily, modified-release (MR) formulation was assessed relative to the twice-daily, immediate-release (IR) formulation.

Methods: This Phase 2 multicenter, randomized (1:1:1:1), placebo-controlled, double-blind, placebo-masked, parallel-group study (NCT01451827) compared tolvaptan MR 50 mg once daily or tolvaptan MR 80 mg once daily with tolvaptan IR 60/30 mg daily split dose and placebo over 8 weeks in 177 subjects. The primary endpoint was percent change from baseline in total kidney volume (TKV) at week 3. Other endpoints included tolerability, assessed by adverse events and quality of life (QOL) measures.

Results: Mean percentage decreases in TKV at week 3 were observed for the pooled group of all (MR+IR) tolvaptan-treated subjects (-2.07%), tolvaptan MR 80 mg (-2.55%), and tolvaptan MR 50 mg (-2.46%) versus placebo (0.09%; P < 0.02 for each comparison with placebo), whereas the decrease with tolvaptan IR 60/30 mg (-1.17%; P = 0.24) did not reach significance. All tolvaptan regimens were associated with AAEs, but scores on ADPKD-specific and generic patient-reported outcome assessments showed little impact based on dosage on overall health-related QOL versus placebo.

Conclusion: Tolvaptan MR and tolvaptan IR demonstrated similar short-term efficacy, tolerability, and safety, with low impact on multiple measures of QOL. Conclusions regarding long-term efficacy are limited by the short duration of follow-up.

SUBMITTER: Perrone RD

PROVIDER: S-EPMC7271939 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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The NOCTURNE Randomized Trial Comparing 2 Tolvaptan Formulations.

Perrone Ronald D RD Chapman Arlene B AB Oberdhan Dorothee D Czerwiec Frank S FS Sergeyeva Olga O Ouyang John J Shoaf Susan E SE

Kidney international reports 20200427 6

<h4>Introduction</h4>Tolvaptan, a treatment for autosomal dominant polycystic kidney disease (ADPKD), inhibits vasopressin V2 receptor signaling, which causes aquaretic adverse events (AAEs). The short-term efficacy and tolerability of a once-daily, modified-release (MR) formulation was assessed relative to the twice-daily, immediate-release (IR) formulation.<h4>Methods</h4>This Phase 2 multicenter, randomized (1:1:1:1), placebo-controlled, double-blind, placebo-masked, parallel-group study (NCT ...[more]

PMID: 32518862

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Project description:BackgroundTolvaptan slows expansion of kidney volume and kidney function decline in adults with autosomal dominant polycystic kidney disease (ADPKD). Progression during childhood could be treated before irreversible kidney damage occurs, but trial data are lacking. We evaluated the safety and efficacy of tolvaptan in children/adolescents with ADPKD.MethodsThis was the 1-year, randomized, double-blind, portion of a phase 3b, two-part trial being conducted at 20 academic pediatric nephrology centers. Key eligibility criteria were ADPKD and eGFR ≥60 ml/min per 1.73 m2. Participants aged 12-17 years were the target group (group 1, enrollment goal n≥60); participants aged 4-11 years could additionally enroll (group 2, anticipated enrollment approximately 40). Treatments were tolvaptan or placebo titrated by body weight and tolerability. Coprimary end points, change from baseline in spot urine osmolality and specific gravity at week 1, assessed inhibition of antidiuretic hormone activity. The key secondary end point was change in height-adjusted total kidney volume (htTKV) to month 12 in group 1. Additional end points were safety/tolerability and quality of life. Statistical comparisons were exploratory and post hoc.ResultsAmong the 91 randomized (group 1, n=66; group 2, n=25), least squares (LS) mean reduction (±SEM) in spot urine osmolality at week 1 was greater with tolvaptan (-390 [28] mOsm/kg) than placebo (-90 [29] mOsm/kg; P<0.001), as was LS mean reduction in specific gravity (-0.009 [0.001] versus -0.002 [0.001]; P<0.001). In group 1, the 12-month htTKV increase was 2.6% with tolvaptan and 5.8% with placebo (P>0.05). For tolvaptan and placebo, respectively, 65% and 16% of subjects experienced aquaretic adverse events, and 2% and 0% experienced hypernatremia. There were no elevated transaminases or drug-induced liver injuries. Four participants discontinued tolvaptan, and three discontinued placebo. Quality-of-life assessments remained stable.ConclusionsTolvaptan exhibited pharmacodynamic activity in pediatric ADPKD. Aquaretic effects were manageable, with few discontinuations.Clinical trial registry name and registration numberSafety, Pharmacokinetics, Tolerability and Efficacy of Tolvaptan in Children and Adolescents With ADPKD (Autosomal Dominant Polycystic Kidney Disease) NCT02964273.

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The NOCTURNE Randomized Trial Comparing 2 Tolvaptan Formulations.

Publications

The NOCTURNE Randomized Trial Comparing 2 Tolvaptan Formulations.

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