@article{88bbe2bd39c94e6f8c83b3795ef105f0,
title = "Per-Treatment Post Hoc Analysis of Clinical Trial Outcomes With Tolvaptan in ADPKD",
abstract = "Introduction: In pivotal trials of patients with autosomal dominant polycystic kidney disease at risk of rapid progression, tolvaptan slowed estimated glomerular filtration rate (eGFR) decline in early-to-moderate (TEMPO 3:4 [NCT00428948]) and moderate- to late-stage (REPRISE [NCT02160145]) chronic kidney disease (CKD). Discontinuation was less frequent in REPRISE (15.0%) than TEMPO 3:4 (23.0%), given that in REPRISE, only subjects who tolerated tolvaptan 60/30 mg daily initiated the double-blind phase. We evaluated whether the greater treatment effect in REPRISE was attributable to different completion rates. Methods: We conducted post hoc analyses of TEMPO 3:4 and REPRISE completers, defined as subjects who took trial drug to the end of the treatment period in TEMPO 3:4 (3 years) or REPRISE (1 year). Efficacy (rate of change in eGFR for tolvaptan vs. placebo) was analyzed as in each trial. Subjects from TEMPO 3:4 and REPRISE were also matched by propensity score for age, gender, and baseline eGFR to explore potential additional determinants of treatment effect. Results: The annualized tolvaptan treatment effect in TEMPO 3:4 completers (difference vs. placebo of 0.98 ml/min per 1.73 m2/y) and REPRISE completers (difference of 1.23) was similar to that of the respective total trial populations (TEMPO 3:4: 0.94; REPRISE: 1.27). The treatment effect of tolvaptan was also similar between matched subjects. Conclusion: Greater treatment completion rate did not drive greater treatment effect in REPRISE. The more advanced CKD of REPRISE subjects may be more relevant. More rapid decline in kidney function in later-stage CKD enabled the effects of tolvaptan to be more easily discerned.",
keywords = "autosomal dominant polycystic kidney disease, chronic kidney disease, clinical trial, persistence, tolvaptan, treatment effect",
author = "Mallett, {Andrew J.} and Perrone, {Ronald D.} and Gopala Rangan and Carmel Hawley and Ragada El-Damanawi and Hiemstra, {Thomas F.} and Arellano, {Carolina Townsend} and Jennifer Lee and Torres, {Vicente E.}",
note = "Funding Information: AJM reports being a Medical Advisory Board member for Otsuka; and receiving grants from Sanofi-Genzyme, PKD Australia, Queensland Health, and NHMRC for studies outside the submitted work. RDP reports grants from Otsuka and Otsuka Steering Committee Membership during the conduct of the study; grants from Department of Defense, grants from Sanofi-Genzyme, personal fees from Sanofi-Genzyme, Palladio Biosciences, and Reata, grants from Kadmon, grants from Reata, other from UpToDate, outside the submitted work. GR is a member of the Scientific Advisory Board of PKD Australia; received grants from the National Health and Medical Research Council of Australia; investigator-initiated grants from PKD Australia, Danone Nutricia (manufacturer of bottled water), Otsuka Australia, and been a member of an Advisory Board for Sanofi-Genzyme. CH reports receiving personal fees from GlaxoSmithKline, Johnson & Johnson, and Otsuka; and grants from Baxter Healthcare, Fresenius Medical Care, PKD Australia, Queensland Health, and NHMRC Australia for studies outside the submitted work. TFH reports having received research funding from AstraZeneca and GlaxoSmithKline, and having served as an advisor to AstraZeneca and Vifor Pharma. JL is an employee of Otsuka. VET reports grants and/or other fees from Acceleron Pharma Inc., Blueprint Medicines, Mironid, Otsuka Pharmaceuticals, Palladio Biosciences, Sanofi Genzyme, Regulus Therapeutics, and Vertex Pharmaceuticals, all outside the submitted work. All the other authors declared no competing interests. Funding Information: This analysis was funded by Otsuka Pharmaceutical Development & Commercialization , Inc. (Rockville, MD, USA). Editorial services in preparation of the manuscript, also funded by Otsuka , were provided by BioScience Communications, Inc (New York, NY, USA). Publisher Copyright: {\textcopyright} 2021 International Society of Nephrology",
year = "2021",
doi = "10.1016/j.ekir.2021.01.014",
language = "English (US)",
journal = "Kidney International Reports",
issn = "2468-0249",
publisher = "Elsevier Inc.",
}