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.

Center for Translational Research Children's National Research Institute Washington DC

Cerevel Therapeutics Cambridge Massachusetts

Department of Nephrology Kidney Transplantation and Arterial Hypertension Children's Memorial Health Institute Warsaw Poland

Department of Pediatric Nephrology University Hospital of Leuven Leuven Belgium

Department of Pediatrics 2nd Faculty of Medicine Charles University and Motol University Hospital Prague Czech Republic

Department of Pediatrics Dr von Hauner Children's Hospital LMU Munich Munich Germany

Division of Pediatric Nephrology Department of Pediatrics Emory University School of Medicine and Children's Healthcare of Atlanta Atlanta Georgia

Division of Pediatric Nephrology University Children's Hospital Heidelberg Heidelberg Germany

Otsuka Pharmaceutical Development and Commercialization Princeton New Jersey

Otsuka Pharmaceutical Development and Commercialization Rockville Maryland

PKD Research Group Department of Cellular and Molecular Medicine KU Leuven Leuven Belgium

Rocky Mountain Pediatric Kidney Center Rocky Mountain Hospital for Children at Presbyterian St Luke's Medical Center Denver Colorado

Clin J Am Soc Nephrol. 2023 Jan 1;18(1):11-13. doi: 10.2215/CJN.0000000000000028. PubMed

Zobrazit více v PubMed

De Rechter S Bockenhauer D Guay-Woodford LM, et al. . ADPedKD Consortium. ADPedKD: A global online platform on the management of children with ADPKD. Kidney Int Rep. 2019;4:1271-1284. doi:10.1016/j.ekir.2019.05.015 PubMed DOI PMC

Gimpel C Bergmann C Bockenhauer D, et al. . International consensus statement on the diagnosis and management of autosomal dominant polycystic kidney disease in children and young people. Nat Rev Nephrol. 2019;15:713-726. doi:10.1038/s41581-019-0155-2 PubMed DOI PMC

Grantham JJ, Cook LT, Wetzel LH, Cadnapaphornchai MA, Bae KT. Evidence of extraordinary growth in the progressive enlargement of renal cysts. Clin J Am Soc Nephrol. 2010;5:889-896. doi:10.2215/cjn.00550110 PubMed DOI PMC

Seeman T Dusek J Vondrák K, et al. . Renal concentrating capacity is linked to blood pressure in children with autosomal dominant polycystic kidney disease. Physiol Res. 2004;53:629-634. PubMed

Seeman T, Pohl M, John U. Proteinuria in children with autosomal dominant polycystic kidney disease. Minerva Pediatr. 2018;70:413-417. doi:10.23736/s0026-4946.16.04404-2 PubMed DOI

Marlais M, Rajalingam S, Gu H, Savis A, Sinha MD, Winyard PJ. Central blood pressure and measures of early vascular disease in children with ADPKD. Pediatr Nephrol. 2019;34:1791-1797. doi:10.1007/s00467-019-04287-7 PubMed DOI PMC

Massella L Mekahli D Paripović D, et al. . Prevalence of hypertension in children with early-stage ADPKD. Clin J Am Soc Nephrol. 2018;13:874-883. doi:10.2215/cjn.11401017 PubMed DOI PMC

Nowak KL, Cadnapaphornchai MA, Chonchol MB, Schrier RW, Gitomer B. Long-term outcomes in patients with very-early onset autosomal dominant polycystic kidney disease. Am J Nephrol. 2016;44:171-178. doi:10.1159/000448695 PubMed DOI PMC

Nowak KL, Farmer H, Cadnapaphornchai MA, Gitomer B, Chonchol M. Vascular dysfunction in children and young adults with autosomal dominant polycystic kidney disease. Nephrol Dial Transplant. 2017;32:342-347. doi:10.1093/ndt/gfw013 PubMed DOI PMC

Gimpel C, Bergmann C, Mekahli D. The wind of change in the management of autosomal dominant polycystic kidney disease in childhood. Pediatr Nephrol. 2022;372:473-487. doi:10.1007/s00467-021-04974-4 PubMed DOI PMC

De Rechter S, Breysem L, Mekahli D. Is autosomal dominant polycystic kidney disease becoming a pediatric disorder? Front Pediatr. 2017;5:272. doi:10.3389/fped.2017.00272 PubMed DOI PMC

Torres VE Chapman AB Devuyst O, et al. .; for the TEMPO 3:4 Trial Investigators. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 2012;367:2407-2418. doi:10.1056/nejmoa1205511 PubMed DOI PMC

Torres VE Chapman AB Devuyst O, et al. .; for the REPRISE Trial Investigators. Tolvaptan in later-stage autosomal dominant polycystic kidney disease. N Engl J Med. 2017;377:1930-1942. doi:10.1056/nejmoa1710030 PubMed DOI

Raina R, Chakraborty R, DeCoy ME, Kline T. Autosomal-dominant polycystic kidney disease: tolvaptan use in adolescents and young adults with rapid progression. Pediatr Res. 2021;89:894-899. doi:10.1038/s41390-020-0942-2 PubMed DOI

Gansevoort RT Arici M Benzing T, et al. . Recommendations for the use of tolvaptan in autosomal dominant polycystic kidney disease: a position statement on behalf of the ERA-EDTA Working Groups on Inherited Kidney Disorders and European Renal Best Practice. Nephrol Dial Transplant. 2016;31:337-348. doi:10.1093/ndt/gfv456 PubMed DOI PMC

Janssens P, Weydert C, De Rechter S, Wissing KM, Liebau MC, Mekahli D. Expanding the role of vasopressin antagonism in polycystic kidney diseases: from adults to children? Pediatr Nephrol. 2018;33:395-408. doi:10.1007/s00467-017-3672-x PubMed DOI

Irazabal MV Rangel LJ Bergstralh EJ, for the CRISP Investigators . Imaging classification of autosomal dominant polycystic kidney disease: a simple model for selecting patients for clinical trials. J Am Soc Nephrol. 2015;26:160-172. doi:10.1681/asn.2013101138 PubMed DOI PMC

Cornec-Le Gall E Audrézet MP Rousseau A, et al. . The PROPKD score: a new algorithm to predict renal survival in autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 2016;27:942-951. doi:10.1681/asn.2015010016 PubMed DOI PMC

McEwan P Bennett Wilton H Ong ACM, et al. . A model to predict disease progression in patients with autosomal dominant polycystic kidney disease (ADPKD): the ADPKD Outcomes Model. BMC Nephrol. 2018;19:37. doi:10.1186/s12882-017-0804-2 PubMed DOI PMC

Chebib FT, Torres VE. Assessing risk of rapid progression in autosomal dominant polycystic kidney disease and special considerations for disease-modifying therapy. Am J Kidney Dis. 2021;78:282-292. doi:10.1053/j.ajkd.2020.12.020 PubMed DOI

Schaefer F Mekahli D Emma F, et al. . Tolvaptan use in children and adolescents with autosomal dominant polycystic kidney disease: rationale and design of a two-part, randomized, double-blind, placebo-controlled trial. Eur J Pediatr. 2019;178:1013-1021. doi:10.1007/s00431-019-03384-x PubMed DOI PMC

Schwartz G Munoz A Schneider M, et al. . New equations to estimate GFR in children with CKD. J Am Soc Nephrol. 2009;20:629-637. doi:10.1681/asn.2008030287 PubMed DOI PMC

Magistroni R, Corsi C, Martí T, Torra R. A review of the imaging techniques for measuring kidney and cyst volume in establishing autosomal dominant polycystic kidney disease progression. Am J Nephrol. 2018;48:67-78. doi:10.1159/000491022 PubMed DOI

O'Neill WC Robbin ML Bae KT, et al. . Sonographic assessment of the severity and progression of autosomal dominant polycystic kidney disease: the Consortium of Renal Imaging Studies in Polycystic Kidney Disease (CRISP). Am J Kidney Dis. 2005;46:1058-1064. doi:10.1053/j.ajkd.2005.08.026 PubMed DOI

Varni JW, Seid M, Rode CA. The PedsQL: measurement model for the pediatric quality of life inventory. Med Care. 1999;37:126-139. doi:10.1097/00005650-199902000-00003 PubMed DOI

Varni JW, Burwinkle TM, Seid M, Skarr D. The PedsQL 4.0 as a pediatric population health measure: feasibility, reliability, and validity. Ambul Pediatr. 2003;3:329-341. doi:10.1367/1539-4409(2003)003<0329:tpaapp>2.0.co;2 PubMed DOI

Varni JW, Burwinkle TM, Seid M. The PedsQL as a pediatric patient-reported outcome: reliability and validity of the PedsQL Measurement Model in 25,000 children. Expert Rev Pharmacoecon Outcomes Res. 2005;5:705-719. doi:10.1586/14737167.5.6.705 PubMed DOI

Irazabal MV Torres VE Hogan MC, et al. . Short-term effects of tolvaptan on renal function and volume in patients with autosomal dominant polycystic kidney disease. Kidney Int. 2011;80:295-301. doi:10.1038/ki.2011.119 PubMed DOI

Boertien WE Meijer E de Jong PE, et al. . Short-term renal hemodynamic effects of tolvaptan in subjects with autosomal dominant polycystic kidney disease at various stages of chronic kidney disease. Kidney Int. 2013;84:1278-1286. doi:10.1038/ki.2013.285 PubMed DOI

MedDRA MSSO. Introductory Guide for Standardised MedDRA Queries (SMQs) Version 22.1. Available at: https://admin.new.meddra.org/sites/default/files/guidance/file/000356_smq_intguide_22_1.pdf. Accessed February 3, 2021.

De Rechter S, Bammens B, Schaefer F, Liebau MC, Mekahli D. Unmet needs and challenges for follow-up and treatment of autosomal dominant polycystic kidney disease: the paediatric perspective. Clin Kidney J. 2018;11(suppl 1):i14-i26. doi:10.1093/ckj/sfy088 PubMed DOI PMC

Perrone RD Chapman AB Oberdhan D, et al. . The NOCTURNE randomized trial comparing 2 tolvaptan formulations. Kidney Int Rep. 2020;5:801-812. doi:10.1016/j.ekir.2020.03.011 PubMed DOI PMC

Mekahli D, Womack H, Dahl NK. Perspectives on drug development in early ADPKD. Clin J Am Soc Nephrol. 2022;17:1555-1558. doi:10.2215/cjn.05190422 PubMed DOI PMC

Gilbert RD, Evans H, Olalekan K, Nagra A, Haq MR, Griffiths M. Tolvaptan treatment for severe neonatal autosomal-dominant polycystic kidney disease. Pediatr Nephrol. 2017;32:893-896. doi:10.1007/s00467-017-3584-9 PubMed DOI PMC

Design of two ongoing clinical trials of tolvaptan in the treatment of pediatric patients with autosomal recessive polycystic kidney disease

Zobrazit více v PubMed

ClinicalTrials.gov
NCT02964273