Rationale, design, demographics and baseline characteristics of the randomized, controlled, Phase 2b SAPPHIRE study of verinurad plus allopurinol in patients with chronic kidney disease and hyperuricaemia

Abstract

Background: Verinurad is a human uric acid (UA) transporter (URAT1) inhibitor known to decrease serum UA (sUA) levels and that may reduce albuminuria. In a Phase 2a study (NCT03118739), treatment with verinurad + febuxostat lowered urine albumin-to-creatinine ratio (UACR) at 12 weeks by 39% (90% confidence interval 4-62%) among patients with Type 2 diabetes mellitus, hyperuricaemia and albuminuria. The Phase 2b, randomized, placebo-controlled Study of verinurAd and alloPurinol in Patients with cHronic kIdney disease and hyperuRicaEmia (SAPPHIRE; NCT03990363) will examine the effect of verinurad + allopurinol on albuminuria and estimated glomerular filtration rate (eGFR) slope among patients with chronic kidney disease (CKD) and hyperuricaemia.

Methods: Adults (≥18 years of age) with CKD, eGFR ≥25 mL/min/1.73 m2, UACR 30-5000 mg/g and sUA ≥6.0 mg/dL will be enrolled. Approximately 725 patients will be randomized 1:1:1:1:1 to 12, 7.5 or 3 mg verinurad + allopurinol, allopurinol or placebo. An 8-week dose-titration period will precede a 12-month treatment period; verinurad dose will be increased to 24 mg at Month 9 in a subset of patients in the 3 mg verinurad + allopurinol arm. The primary efficacy endpoint the is change from baseline in UACR at 6 months. Secondary efficacy endpoints include changes in UACR, eGFR and sUA from baseline at 6 and 12 months.

Conclusions: This study will assess the combined clinical effect of verinurad + allopurinol on kidney function in patients with CKD, hyperuricaemia and albuminuria, and whether this combination confers renoprotection beyond standard-of-care.

Keywords: URAT1 inhibitor; chronic kidney disease; hyperuricaemia; randomized controlled clinical trial; verinurad.

Conflict of interest statement

H.J.L.H. is a consultant for AbbVie, AstraZeneca, Boehringer Ingelheim, Chinook Therapeutics, CSL Pharma, Gilead, Janssen, Merck, Mundi Pharma, Mitsubishi Tanabe, Novo Nordisk and Travere Pharma. He has received research support from AbbVie, AstraZeneca, Boehringer Ingelheim and Janssen. T.A.G. has performed statistical consultations with Janssen Pharmaceuticals, DURECT Corporation, Pfizer Inc., AstraZeneca and CSL Pharma. L.A.I. has received funding from National Institutes of Health, National Kidney Foundation, Retrophin, Omeros, Dialysis Clinics, Inc., and Reata Pharmaceuticals for research and contracts to Tufts Medical Center; and consulting agreements with Tricida and Goldfinch Bio. A.G.S. has received grants from the Health Research Board, Enterprise Ireland, Midwest Kidney Disease Research and Education Foundation, Menarini and Vifor; and has served on Steering Committees, Advisory Boards and consulted for AstraZeneca, Astellas Pharma Inc., Grünenthal, Medscape and Menarini. R.T. has consulted for AstraZeneca, Selecta Biosciences, SOBI and Horizon Therapeutics; and currently holds a research grant from AstraZeneca. M.B., S.P., T.R. and F.E. are employees and stockholders of AstraZeneca. V.P. has served on Steering Committees, Advisory Boards or given scientific presentations supported by supported by AbbVie, Amgen, Astellas, AstraZeneca, Bayer, Baxter, Bristol Myers Squibb, Boehringer Ingelheim, Chinook Therapeutics, Dimerix, DURECT Corporation, Eli Lilly and Company, Gilead, GlaxoSmithKline, Janssen, Merck, Metavant, Mitsubishi Tanabe, Mundipharma, Novartis, Novo Nordisk, Pfizer, PharmaLink, Relypsa, Retrophin, Sanofi, Servier, Vifor Pharma, Vitae Pharmaceuticals, UptoDate and Tricida. The results presented in this article have not been published previously in whole or part, except in abstract format.

© The Author(s) 2021. Published by Oxford University Press on behalf of ERA-EDTA.

Figures

Graphical Abstract

FIGURE 1

SAPPHIRE study design. aOccurrence ≥3 months before randomization of eGFR <60 mL/min/1.73 m2, UACR ≥30 mg/g and/or ≥1 other marker(s) of kidney damage. bPatients unable to tolerate the dosage may be down-titrated only by reversing the assigned steps within the treatment group.

FIGURE 2

Countries participating in SAPPHIRE.

FIGURE 3

LSM percentage change from baseline in UACR at Weeks 12 and 24 in the CITRINE study. Error bars are 95% CIs. Results are based on a mixed-effects model for repeated measures. Baseline mean (SD) UACR was 459.1 (824.7) mg/g for verinurad plus febuxostat and 411.6 (547.8) mg/g for placebo. LSM, least-squares mean.