학술논문
Combination Treatment with Verinurad and Allopurinol in CKD: A Randomized Placebo and Active Controlled Trial
Document Type
Academic Journal
Author
Heerspink, Hiddo J.L.; Stack, Austin G.; Terkeltaub, Robert; Jongs, Niels; Inker, Lesley A.; Bjursell, Magnus; Maklad, Noha; Perl, Shira; Eklund, Olof; Rikte, Tord; Sjöström, C. David; Perkovic, Vlado; Chmelickova, Hana; Lukac, Martin; Bucek, Petr; Drasnar, Tomas; Dussol, Bertrand; Guerrot, Dominique; Legrand, Eric; Boffa, Jean-Jacques; Halimi, Jean-Michel; Zaoui, Philippe; Letoha, Annamaria; Hajdu, Csaba; Pall, Denes; Peterfai, Eva; Csécsei, Gyöngyi; Bezzegh, Katalin; Deak, Laszlo; Konyves, Laszlo; Zsom, Marianna; Danos, Peter; Vangel, Sandor; Vasas, Szilard; Oroszlan, Tamas; Zilahi, Zsolt; Leiba, Adi; Grossman, Alon; Leibowitz, Avshalom; Itzhak, Baruch; Daoud, Deeb; Farber, Evgeny; Adawi, Faiad; Nakhoul, Farid M.; Chernin, Gil; Kenis, Irina; Wainstein, Julio; Zeller, Lior; Elias, Mazen; Atar, Shaul; Frajewicki, Victor; Yagil, Yoram; Armaly, Zaher A.; Esposito, Ciro; Viazzi, Francesca; Gambaro, Giovanni; Piatti, Piermarco; Bonadonna, Riccardo C.; Arias Delgadillo, Cristhian Ronaldt; Flores, Fernando Jimenez; Aguilera Real, Manuel Enrique; Fajardo-Campos, Pedro; Violante Ortiz, Rafael Margarito; Luna Ceballos, Rosa Isela; Duran-Barragan, Sergio; Zytkiewicz-Jaruga, Danuta; Krzyzagorska, Ewa; Skokowska, Ewa; Klodawska, Katarzyna; Mordaka, Robert; Mazur, Stanislaw; Stasinska, Teresa; Sulowicz, Wladyslaw; Constantin, Ciprian; Negru, Doru; Paveliu, Fraga-Silvia; Negrisanu, Gabriela Doina; Szilagyi, Iosif; Busegeanu, Mihaela Magdalena G.; Pena, Mihai Cosmin; Avram, Rodica Ioana; Ardelean, Silvia Luminita; Ilavska, Adriana; Dzupina, Andrej; Oroszova, Aniko; Kolesarova, Eva; Obetkova, Ida; Smatanova, Iveta; Babikova, Jana; Fulop, Peter; Haffner, Radovan; Rayner, Brian L.; Kruger, Dawid Stephanus; Urbach, Dorothea Vera; Mitha, Essack; Vally Mahomed Latiff, Gulam Hoosain; Makan, Hemant; du Plessis, Hermanus; Jurgens, Jaco Cornelius; Reddy, Jeevren; Trokis, Julien S.; McHarry, Kirsten; Distiller, Lawrence Allen; Mayet, Leila; Burgess, Lesley Jean; Van Zyl, Louis Johan; Joshi, Mukesh P.; Sebastian, Peter John; Du Toit, Samantha Maria; Blignaut, Suzanne C.; Serrano, Antonio Galan; Morales, Cristobal; Poch, Esteban; Mosquera, Eva Marquez; Castro, Fernando Cereto; Gonzalez Martinez, Francisco Javier; Perez- Contreras, Francisco Javier; Fernandez-Fresnedo, Gema; Garcia Mendez, Isabel Fuencisla; Perez, Jonay Pantoja; Martinez, Jordi Calabia; Gorriz Teruel, Jose Luis; Nieto Iglesias, Luis Javier; Munoz-Torres, Manuel; Munar Vila, Maria Antonia; Arenas Jimenez, Maria Dolores; Dominguez-Lopez, Marta E.; Val, Miguel Hueso; Terrades, Natalia Ramos; Olmo, Rafael Santamaria; Malek Marin, Tamara Gelen; Arif, Ahmed A.; Lee, Benjamin J.; Mehta, Bhasker R.; Baker, Bruce H.; Jere, Charles S.; Bains, David G.; Stricklin, David G.; Cheung, Deanna; Echeverri, Diego; Vera, Edgard; Heurich, Eva-Maria; Sterba, Gary A.; Hernandez, German T.; Paez, Henry E.; Acosta, Idalia A.; Ahmed, Intekhab; Sachmechi, Issac; Madu, Ivy-Joan E.; Obhrai, Jagdeep Singh; Hammoud, Jamal A.; Tumlin, James A.; Cain, James; Moya-Hechevarria, Jaynier; Connaire, Jeffrey J.; Haggiagi, Jehad; Odren, Jennifer A.; Bellucci-Jackson, Jennifer M.; Yan, Jieshi; Parker, John C.; Tolins, Jonathan P.; Gomez-Cortes, Jose D.; Cardona, Jose F.; Mandry, Jose M.; Olivero, Juan Jorge; Hendon, Kendra S.; Kaveh, Kianoosh; Kooienga, Laura A.; Bermudez, Lidia R.; Rich, Lisa M.; Gold, Marina; Gonzalez, Marisela; Schaefer, Matthew E.; Welch, Michelle; Moustafa, Moustafa A.; Mussaji, Murtaza; Pergola, Pablo E.; Phaosawasdi, Piangwarin; Silva, Ricardo A.; Presas, Ricardo; Lynn, Robert I.; Kronfli, Saeed J.; Ventrapragada, Sailaja V.; Niranjan, Sankar N.; Husain, Sayed; Satko, Scott; Jabbour, Serge A.; Rovner, Sergio F.; Gouge, Steven F.; Joshi, Sudhir S.; Ramachandran Subramanian, Varagur Bala; Lane, Wendy; Calhoun, Wesley; Durham, William
Source
Journal of the American Society of Nephrology. Feb 20, 2024
Subject
Language
English
ISSN
1046-6673
Abstract
KEY POINTS: 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 m, 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 m, 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.