Per-treatment post-hoc analysis of clinical trial outcomes with Tolvaptan in autosomal dominant polycystic kidney disease

Mallett, Andrew J., Perrone, Ronald D., Rangan, Gopala, Hawley, Carmel, El-Damanawi, Ragada, Hiemstra, Thomas F., Townsend Arellano, Carolina, Lee, Jennifer, and Torres, Vicente E. (2021) Per-treatment post-hoc analysis of clinical trial outcomes with Tolvaptan in autosomal dominant polycystic kidney disease. Kidney International Reports. (In Press)

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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 versus 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 versus placebo of 0.98 mL/min/1.73 m2/year) 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.

Item ID: 66017
Item Type: Article (Research - C1)
ISSN: 2468-0249
Keywords: autosomal dominant polycystic kidney disease, clinical trial, tolvaptan, chronic kidney disease, persistence, treatment effect
Copyright Information: © 2021 Published by Elsevier Inc. on behalf of the International Society of Nephrology. This article is available under the Creative Commons CC-BY-NC-ND license and permits non-commercial use of the work as published, without adaptation or alteration provided the work is fully attributed.
Funders: Otsuka Pharmaceutical Development & Commercialization, Inc.
Date Deposited: 17 Feb 2021 23:29
FoR Codes: 32 BIOMEDICAL AND CLINICAL SCIENCES > 3202 Clinical sciences > 320214 Nephrology and urology @ 50%
32 BIOMEDICAL AND CLINICAL SCIENCES > 3202 Clinical sciences > 320213 Medical genetics (excl. cancer genetics) @ 50%
SEO Codes: 20 HEALTH > 2001 Clinical health > 200105 Treatment of human diseases and conditions @ 100%
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