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Tolvaptan for Children and Adolescents with Autosomal Dominant Polycystic Kidney Disease: Randomized Controlled Trial
Djalila Mekahli1,2, Lisa M Guay-Woodford3, Melissa A Cadnapaphornchai4
1PKD Research Group, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
Insights
Tolvaptan shows promise in treating children with autosomal dominant polycystic kidney disease (ADPKD), demonstrating pharmacodynamic activity and manageable side effects. This offers a potential treatment option to slow kidney disease progression in pediatric patients.
Area of Science:
- Pediatric Nephrology
- Pharmacology
- Genetics
Background:
- Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder characterized by kidney cyst formation.
- Tolvaptan is approved for adults with ADPKD to slow kidney volume expansion and function decline.
- Limited data exist on tolvaptan's efficacy and safety in pediatric ADPKD patients, necessitating evaluation before irreversible kidney damage occurs.
Purpose of the Study:
- To evaluate the safety and efficacy of tolvaptan in children and adolescents diagnosed with ADPKD.
- To assess tolvaptan's pharmacodynamic effects, including inhibition of antidiuretic hormone activity.
- To monitor adverse events, tolerability, and quality of life in pediatric ADPKD patients treated with tolvaptan.
Main Methods:
- A 1-year, randomized, double-blind, placebo-controlled trial involving pediatric patients (aged 4-17 years) with ADPKD and eGFR ≥60 ml/min per 1.73 m2.
- Participants were divided into two groups based on age (12-17 years and 4-11 years) and received either tolvaptan or placebo, with dosages titrated by body weight and tolerability.
- Coprimary endpoints included changes in spot urine osmolality and specific gravity at week 1; key secondary endpoint was change in height-adjusted total kidney volume (htTKV) at 12 months.
Main Results:
- Tolvaptan demonstrated significant pharmacodynamic activity, evidenced by greater reductions in urine osmolality and specific gravity compared to placebo at week 1.
- In the older age group (12-17 years), the increase in height-adjusted total kidney volume (htTKV) over 12 months was 2.6% with tolvaptan versus 5.8% with placebo (P>0.05).
- Aquaretic adverse events were more frequent with tolvaptan (65%) than placebo (16%), but generally manageable, with few discontinuations (4 vs 3) and no cases of elevated transaminases or drug-induced liver injury.
Conclusions:
- Tolvaptan exhibits pharmacodynamic activity in pediatric patients with ADPKD, indicating potential to inhibit ADH activity.
- The aquaretic effects associated with tolvaptan were manageable and led to few treatment discontinuations.
- These findings support further investigation into tolvaptan as a treatment option for slowing disease progression in children and adolescents with ADPKD.
Background:
Tolvaptan 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.
Methods:
This 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.
Results:
Among 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.
Conclusions:
Tolvaptan exhibited pharmacodynamic activity in pediatric ADPKD. Aquaretic effects were manageable, with few discontinuations.
Clinical Trial Registry Name And Registration Number:
Safety, Pharmacokinetics, Tolerability and Efficacy of Tolvaptan in Children and Adolescents With ADPKD (Autosomal Dominant Polycystic Kidney Disease) NCT02964273.
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