Vicente E Torres1, Arlene B Chapman1, Olivier Devuyst1, Ron T Gansevoort1, Ronald D Perrone1, Gary Koch1, John Ouyang1, Robert D McQuade1, Jaime D Blais1, Frank S Czerwiec1, Olga Sergeyeva1. 1. From the Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN (V.E.T.); the Section of Nephrology, University of Chicago, Chicago (A.B.C.); the Institute of Physiology, University of Zurich, Zurich, Switzerland (O.D.); the Division of Nephrology, Université Catholique de Louvain Medical School, Brussels (O.D.); the Division of Nephrology, University Medical Center Groningen, Groningen, the Netherlands (R.T.G.); the Division of Nephrology, Department of Medicine, Tufts Medical Center, Boston (R.D.P.); the Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill (G.K.); and Otsuka Pharmaceutical Development and Commercialization, Rockville, MD (J.O., R.D.M., J.D.B., F.S.C., O.S.).
Abstract
BACKGROUND: In a previous trial involving patients with early autosomal dominant polycystic kidney disease (ADPKD; estimated creatinine clearance, ≥60 ml per minute), the vasopressin V2-receptor antagonist tolvaptan slowed the growth in total kidney volume and the decline in the estimated glomerular filtration rate (GFR) but also caused more elevations in aminotransferase and bilirubin levels. The efficacy and safety of tolvaptan in patients with later-stage ADPKD are unknown. METHODS: We conducted a phase 3, randomized withdrawal, multicenter, placebo-controlled, double-blind trial. After an 8-week prerandomization period that included sequential placebo and tolvaptan run-in phases, during which each patient's ability to take tolvaptan without dose-limiting side effects was assessed, 1370 patients with ADPKD who were either 18 to 55 years of age with an estimated GFR of 25 to 65 ml per minute per 1.73 m2 of body-surface area or 56 to 65 years of age with an estimated GFR of 25 to 44 ml per minute per 1.73 m2 were randomly assigned in a 1:1 ratio to receive tolvaptan or placebo for 12 months. The primary end point was the change in the estimated GFR from baseline to follow-up, with adjustment for the exact duration that each patient participated (interpolated to 1 year). Safety assessments were conducted monthly. RESULTS: The change from baseline in the estimated GFR was -2.34 ml per minute per 1.73 m2 (95% confidence interval [CI], -2.81 to -1.87) in the tolvaptan group, as compared with -3.61 ml per minute per 1.73 m2 (95% CI, -4.08 to -3.14) in the placebo group (difference, 1.27 ml per minute per 1.73 m2; 95% CI, 0.86 to 1.68; P<0.001). Elevations in the alanine aminotransferase level (to >3 times the upper limit of the normal range) occurred in 38 of 681 patients (5.6%) in the tolvaptan group and in 8 of 685 (1.2%) in the placebo group. Elevations in the aminotransferase level were reversible after stopping tolvaptan. No elevations in the bilirubin level of more than twice the upper limit of the normal range were detected. CONCLUSIONS:Tolvaptan resulted in a slower decline than placebo in the estimated GFR over a 1-year period in patients with later-stage ADPKD. (Funded by Otsuka Pharmaceuticals and Otsuka Pharmaceutical Development and Commercialization; REPRISE ClinicalTrials.gov number, NCT02160145 .).
RCT Entities:
BACKGROUND: In a previous trial involving patients with early autosomal dominant polycystic kidney disease (ADPKD; estimated creatinine clearance, ≥60 ml per minute), the vasopressin V2-receptor antagonist tolvaptan slowed the growth in total kidney volume and the decline in the estimated glomerular filtration rate (GFR) but also caused more elevations in aminotransferase and bilirubin levels. The efficacy and safety of tolvaptan in patients with later-stage ADPKD are unknown. METHODS: We conducted a phase 3, randomized withdrawal, multicenter, placebo-controlled, double-blind trial. After an 8-week prerandomization period that included sequential placebo and tolvaptan run-in phases, during which each patient's ability to take tolvaptan without dose-limiting side effects was assessed, 1370 patients with ADPKD who were either 18 to 55 years of age with an estimated GFR of 25 to 65 ml per minute per 1.73 m2 of body-surface area or 56 to 65 years of age with an estimated GFR of 25 to 44 ml per minute per 1.73 m2 were randomly assigned in a 1:1 ratio to receive tolvaptan or placebo for 12 months. The primary end point was the change in the estimated GFR from baseline to follow-up, with adjustment for the exact duration that each patient participated (interpolated to 1 year). Safety assessments were conducted monthly. RESULTS: The change from baseline in the estimated GFR was -2.34 ml per minute per 1.73 m2 (95% confidence interval [CI], -2.81 to -1.87) in the tolvaptan group, as compared with -3.61 ml per minute per 1.73 m2 (95% CI, -4.08 to -3.14) in the placebo group (difference, 1.27 ml per minute per 1.73 m2; 95% CI, 0.86 to 1.68; P<0.001). Elevations in the alanine aminotransferase level (to >3 times the upper limit of the normal range) occurred in 38 of 681 patients (5.6%) in the tolvaptan group and in 8 of 685 (1.2%) in the placebo group. Elevations in the aminotransferase level were reversible after stopping tolvaptan. No elevations in the bilirubin level of more than twice the upper limit of the normal range were detected. CONCLUSIONS:Tolvaptan resulted in a slower decline than placebo in the estimated GFR over a 1-year period in patients with later-stage ADPKD. (Funded by Otsuka Pharmaceuticals and Otsuka Pharmaceutical Development and Commercialization; REPRISE ClinicalTrials.gov number, NCT02160145 .).
Authors: Matteo Bargagli; Nasser A Dhayat; Manuel Anderegg; Mariam Semmo; Uyen Huynh-Do; Bruno Vogt; Pietro Manuel Ferraro; Daniel G Fuster Journal: Clin J Am Soc Nephrol Date: 2020-06-11 Impact factor: 8.237
Authors: Sebastian Strubl; Jacob A Torres; Alison K Spindt; Hannah Pellegrini; Max C Liebau; Thomas Weimbs Journal: Cell Signal Date: 2020-04-20 Impact factor: 4.315
Authors: James J Beaudoin; Jacqueline Bezençon; Yanguang Cao; Katsuhiko Mizuno; Sharin E Roth; William J Brock; Kim L R Brouwer Journal: Drug Metab Dispos Date: 2018-11-30 Impact factor: 3.922
Authors: Rory J Olson; Katharina Hopp; Harrison Wells; Jessica M Smith; Jessica Furtado; Megan M Constans; Diana L Escobar; Aron M Geurts; Vicente E Torres; Peter C Harris Journal: J Am Soc Nephrol Date: 2019-08-19 Impact factor: 10.121
Authors: Irina M Sanchis; Shehbaz Shukoor; Maria V Irazabal; Charles D Madsen; Fouad T Chebib; Marie C Hogan; Ziad El-Zoghby; Peter C Harris; John Huston; Robert D Brown; Vicente E Torres Journal: Clin J Am Soc Nephrol Date: 2019-07-30 Impact factor: 8.237
Authors: Salim S Hayek; Douglas P Landsittel; Changli Wei; Martin Zeier; Alan S L Yu; Vicente E Torres; Sharin Roth; Christina S Pao; Jochen Reiser Journal: J Am Soc Nephrol Date: 2019-06-06 Impact factor: 10.121
Authors: Susan E Shoaf; John Ouyang; Olga Sergeyeva; Alvin Estilo; Hui Li; Deborah Leung Journal: Clin J Am Soc Nephrol Date: 2020-04-02 Impact factor: 8.237