ESPN 53rd Annual Meeting

ESPN 2021


 
Randomized, Placebo-controlled, Phase 3b Trial of Tolvaptan in the Treatment of Children and Adolescents with Autosomal Dominant Polycystic Kidney Disease (ADPKD): 1-Year Data
DJALILA MEKAHLI 1 LISA GUAY-WOODFORD 2 MELISSA A. CADNAPAPHORNCHAI 3 LARRY A. GREENBAUM 4 MIECZYSLAW LITWIN 5 TOMAS SEEMAN 6 ANN DANDURAND 7 LILY SHI 8 KIMBERLY SIKES 8 SUSAN E. SHOAF 9 FRANZ SCHAEFER 10

1- DEPARTMENT OF PEDIATRIC NEPHROLOGY, UNIVERSITY HOSPITALS LEUVEN AND PKD RESEARCH GROUP, DEPARTMENT OF DEVELOPMENT AND REGENERATION, KU LEUVEN, LEUVEN, BELGIUM
2- CENTER FOR TRANSLATIONAL SCIENCE, CHILDRENS NATIONAL HEALTH SYSTEM, WASHINGTON, DC, USA
3- ROCKY MOUNTAIN PEDIATRIC KIDNEY CENTER, ROCKY MOUNTAIN HOSPITAL FOR CHILDREN AT PRESBYTERIAN/ST. LUKE’S MEDICAL CENTER, DENVER, CO, USA
4- DEPARTMENT OF PEDIATRICS, DIVISION OF PEDIATRIC NEPHROLOGY, EMORY UNIVERSITY SCHOOL OF MEDICINE AND CHILDRENS HEALTHCARE OF ATLANTA, ATLANTA, GA, USA
5- DEPARTMENT OF NEPHROLOGY, KIDNEY TRANSPLANTATION AND ARTERIAL HYPERTENSION, CHILDRENS MEMORIAL HEALTH INSTITUTE, WARSAW, POLAND
6- DEPARTMENT OF PAEDIATRICS, 2ND FACULTY OF MEDICINE, CHARLES UNIVERSITY AND MOTOL UNIVERSITY HOSPITAL, PRAGUE, CZECH REPUBLIC
7- OTSUKA PHARMACEUTICAL DEVELOPMENT & COMMERCIALIZATION, PRINCETON, NJ, USA (PREVIOUSLY AFFILIATED WITH OTSUKA AT THE TIME THE RESEARCH WAS CONDUCTED)
8- OTSUKA PHARMACEUTICAL DEVELOPMENT & COMMERCIALIZATION, ROCKVILLE, MD, USA
9- OTSUKA PHARMACEUTICAL DEVELOPMENT & COMMERCIALIZATION, PRINCETON, NJ, USA
10- DIVISION OF PEDIATRIC NEPHROLOGY, CENTER FOR PEDIATRICS AND ADOLESCENT MEDICINE, HEIDELBERG, GERMANY
 
Abstract:

Objectives

To evaluate the vasopressin V2 receptor antagonist tolvaptan for pharmacodynamic activity and preliminary efficacy and safety in children/adolescents with early manifesting ADPKD.

 

Methods

Phase 3b, 2-part trial (EudraCT 2016-000187-42). Phase A (reported here) was a 1-year (y), randomized, double-blind, placebo-controlled, multicenter trial; Phase B is an ongoing, 2-y, open-label extension. Eligibility criteria: ADPKD (renal cysts with family history and/or genetic diagnosis), eGFR ≥60 mL/min/1.73m2, body weight ≥20 kg. The target population was age 12-17y; subjects 4-11y could also enter if eligible. Tolvaptan/placebo were titrated based on body weight and tolerability. Co-primary endpoints: changes from baseline in spot urine osmolality (Uosm) and specific gravity (SG) at Week 1. Additional endpoints: 12-month changes in height-adjusted total kidney volume (htTKV) and eGFR, safety/tolerability. Statistical comparisons were exploratory and post hoc.

Results

Of 91 subjects enrolled (66 age 12-17y; 25 age <12y), 48 were randomized to tolvaptan and 43 to placebo. Mean reduction (±SD) from baseline to Week 1 (tolvaptan vs placebo): 386 (284) vs 93 (332) mOsm/kg for Uosm (P<.001) and 0.009 (0.007) vs 0.002 (0.008) for urine SG (P<.001). In subjects 12-17y, mean %htTKV increase from baseline to Month 12 was 2.3% (8.8) for tolvaptan and 6.1% (7.5) for placebo (P=.14). Mean eGFR change from Day 7 to Month 12 (all subjects) was 2.7 (10.7) mL/min/1.73m2 for tolvaptan, -3.2 (10.9) mL/min/1.73m2 for placebo (P=.10). Most frequent adverse events over 12 months (tolvaptan/placebo): polyuria (25.0/2.3%), elevated serum creatinine (18.8/4.7%), pollakiuria (18.8/0.0%), cough (14.6/11.6%), and nocturia (14.6/4.7%). No elevated transaminases or drug-induced liver injury. Serious adverse events in 1 tolvaptan (viral pericarditis) and 6 placebo, none treatment-related. One discontinuation due to pollakiuria (tolvaptan), 1 due to dizziness (placebo).

Conclusions

Tolvaptan exhibited evidence of V2 receptor antagonism in pediatric ADPKD patients. Results suggestive of slowed TKV growth and eGFR decline warrant further investigation.