TY - JOUR
T1 - Combination Treatment with Verinurad and Allopurinol in CKD
T2 - A Randomized Placebo and Active Controlled Trial
AU - SAPPHIRE Investigators
AU - Heerspink, Hiddo J.L.
AU - Stack, Austin G.
AU - Terkeltaub, Robert
AU - Jongs, Niels
AU - Inker, Lesley A.
AU - Bjursell, Magnus
AU - Maklad, Noha
AU - Perl, Shira
AU - Eklund, Olof
AU - Rikte, Tord
AU - Sjöström, C. David
AU - Perkovic, Vlado
AU - Chmelickova, Hana
AU - Lukac, Martin
AU - Bucek, Petr
AU - Drasnar, Tomas
AU - Dussol, Bertrand
AU - Guerrot, Dominique
AU - Legrand, Eric
AU - Boffa, Jean Jacques
AU - Halimi, Jean Michel
AU - Zaoui, Philippe
AU - Letoha, Annamaria
AU - Hajdu, Csaba
AU - Pall, Denes
AU - Peterfai, Eva
AU - Csécsei, Gyöngyi
AU - Bezzegh, Katalin
AU - Deak, Laszlo
AU - Konyves, Laszlo
AU - Zsom, Marianna
AU - Danos, Peter
AU - Vangel, Sandor
AU - Vasas, Szilard
AU - Oroszlan, Tamas
AU - Zilahi, Zsolt
AU - Leiba, Adi
AU - Grossman, Alon
AU - Leibowitz, Avshalom
AU - Itzhak, Baruch
AU - Daoud, Deeb
AU - Farber, Evgeny
AU - Adawi, Faiad
AU - Nakhoul, Farid M.
AU - Chernin, Gil
AU - Kenis, Irina
AU - Wainstein, Julio
AU - Zeller, Lior
AU - Elias, Mazen
AU - Atar, Shaul
AU - Calhoun, W. J.
AU - Durham, William
N1 - Publisher Copyright:
© 2024 Wolters Kluwer Health. All rights reserved.
PY - 2024/5
Y1 - 2024/5
N2 - Background: Hyperuricemia is associated with elevated risks of cardiovascular and chronic kidney disease (CKD). Since inhibition of urate transporter 1 has been suggested to be potentially nephroprotective, we performed a phase 2b study to assess albuminuria-lowering effects of the urate transporter 1 inhibitor verinurad combined with the xanthine oxidase inhibitor allopurinol in patients with CKD and hyperuricemia.Methods: In this randomized placebo and active controlled trial, we enrolled participants with serum urate concentrations ≥6.0 mg/dl, eGFR ≥25 ml/min per 1.73 m2, and a urinary albumin-creatinine ratio (UACR) 30-5000 mg/g to one of five treatment arms: placebo, placebo+allopurinol 300 mg/day, verinurad 3 mg+allopurinol 300 mg/day, verinurad 7.5 mg+allopurinol 300 mg/day, or verinurad 12 mg+allopurinol 300 mg/day in a 1:1:1:1:1 ratio. The primary end point was the change in UACR from baseline to 34 weeks. Secondary end points were changes from baseline in UACR at week 60 and changes in serum urate and eGFR at weeks 34 and 60.Results: Between August 2019 and November 2021, 861 adults with CKD (mean age 65 years, 33.0% female, mean eGFR 48 ml/min per 1.73 m2, median UACR 217 mg/g) were enrolled. At 34 weeks, the geometric mean percentage change in UACR from baseline did not differ among treatment groups (16.7%, 95% confidence interval [CI],-0.6 to 37.1 in the 3 mg group, 15.0% [95% CI,-1.85 to 34.6] in the 7.5 mg group, 14.0% [95% CI,-3.4 to 34.4] in the 12 mg group versus 9.9% [95% CI,-6.6 to 29.4] in the allopurinol group, and 37.3% [95% CI, 16.6 to 61.8] in the placebo group). UACR and eGFR change from baseline did not differ among treatment groups after 60 weeks. Verinurad/allopurinol combination dose-dependently reduced serum urate concentrations compared with placebo. The proportion of patients with adverse events and serious adverse events was balanced among treatment groups.Conclusions: Verinurad in combination with allopurinol did not decrease UACR or eGFR decline, but further reduced serum urate compared with allopurinol alone or placebo.Clinical Trial registry name and registration number: SAPPHIRE Trial registration number, NCT03990363.
AB - Background: Hyperuricemia is associated with elevated risks of cardiovascular and chronic kidney disease (CKD). Since inhibition of urate transporter 1 has been suggested to be potentially nephroprotective, we performed a phase 2b study to assess albuminuria-lowering effects of the urate transporter 1 inhibitor verinurad combined with the xanthine oxidase inhibitor allopurinol in patients with CKD and hyperuricemia.Methods: In this randomized placebo and active controlled trial, we enrolled participants with serum urate concentrations ≥6.0 mg/dl, eGFR ≥25 ml/min per 1.73 m2, and a urinary albumin-creatinine ratio (UACR) 30-5000 mg/g to one of five treatment arms: placebo, placebo+allopurinol 300 mg/day, verinurad 3 mg+allopurinol 300 mg/day, verinurad 7.5 mg+allopurinol 300 mg/day, or verinurad 12 mg+allopurinol 300 mg/day in a 1:1:1:1:1 ratio. The primary end point was the change in UACR from baseline to 34 weeks. Secondary end points were changes from baseline in UACR at week 60 and changes in serum urate and eGFR at weeks 34 and 60.Results: Between August 2019 and November 2021, 861 adults with CKD (mean age 65 years, 33.0% female, mean eGFR 48 ml/min per 1.73 m2, median UACR 217 mg/g) were enrolled. At 34 weeks, the geometric mean percentage change in UACR from baseline did not differ among treatment groups (16.7%, 95% confidence interval [CI],-0.6 to 37.1 in the 3 mg group, 15.0% [95% CI,-1.85 to 34.6] in the 7.5 mg group, 14.0% [95% CI,-3.4 to 34.4] in the 12 mg group versus 9.9% [95% CI,-6.6 to 29.4] in the allopurinol group, and 37.3% [95% CI, 16.6 to 61.8] in the placebo group). UACR and eGFR change from baseline did not differ among treatment groups after 60 weeks. Verinurad/allopurinol combination dose-dependently reduced serum urate concentrations compared with placebo. The proportion of patients with adverse events and serious adverse events was balanced among treatment groups.Conclusions: Verinurad in combination with allopurinol did not decrease UACR or eGFR decline, but further reduced serum urate compared with allopurinol alone or placebo.Clinical Trial registry name and registration number: SAPPHIRE Trial registration number, NCT03990363.
KW - Albuminuria
KW - Chronic Kidney Disease
KW - Kidney Dysfunction
KW - Randomized Controlled Trials
UR - http://www.scopus.com/inward/record.url?scp=85192028768&partnerID=8YFLogxK
U2 - 10.1681/ASN.0000000000000326
DO - 10.1681/ASN.0000000000000326
M3 - Article
C2 - 38564654
AN - SCOPUS:85192028768
SN - 1046-6673
VL - 35
SP - 594
EP - 606
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
IS - 5
ER -