Combination Treatment with Verinurad and Allopurinol in CKD: A Randomized Placebo and Active Controlled Trial

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

doi:10.1681/ASN.0000000000000326

Combination Treatment with Verinurad and Allopurinol in CKD: A Randomized Placebo and Active Controlled Trial

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

Barzilai University Medical Center

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

Abstract

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.MethodsIn 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.ResultsBetween 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.ConclusionsVerinurad 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.

Original language	English
Pages (from-to)	594-606
Number of pages	13
Journal	Journal of the American Society of Nephrology
Volume	35
Issue number	5
DOIs	https://doi.org/10.1681/ASN.0000000000000326
State	Published - 1 May 2024

Keywords

Albuminuria
Chronic Kidney Disease
Kidney Dysfunction
Randomized Controlled Trials

ASJC Scopus subject areas

General Medicine

Access to Document

10.1681/ASN.0000000000000326

Cite this

Heerspink, H. J. L., Stack, A. G., Terkeltaub, R., Jongs, N., Inker, L. A., Bjursell, M., Maklad, N., Perl, S., Eklund, O., Rikte, T., Sjöström, C. D., Perkovic, V., Chmelickova, H., Lukac, M., Bucek, P., Drasnar, T., Dussol, B., Guerrot, D., Legrand, E., ... Durham, W. (2024). Combination Treatment with Verinurad and Allopurinol in CKD: A Randomized Placebo and Active Controlled Trial. Journal of the American Society of Nephrology, 35(5), 594-606. https://doi.org/10.1681/ASN.0000000000000326

@article{b25baf854051480eb5ecd28796c4a2a4,

title = "Combination Treatment with Verinurad and Allopurinol in CKD: A Randomized Placebo and Active Controlled Trial",

abstract = "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.MethodsIn 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.ResultsBetween 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.ConclusionsVerinurad 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.",

keywords = "Albuminuria, Chronic Kidney Disease, Kidney Dysfunction, Randomized Controlled Trials",

author = "Heerspink, {Hiddo J.L.} and Stack, {Austin G.} and Robert Terkeltaub and Niels Jongs and Inker, {Lesley A.} and Magnus Bjursell and Noha Maklad and Shira Perl and Olof Eklund and Tord Rikte and Sj{\"o}str{\"o}m, {C. David} and Vlado Perkovic and Hana Chmelickova and Martin Lukac and Petr Bucek and Tomas Drasnar and Bertrand Dussol and Dominique Guerrot and Eric Legrand and Boffa, {Jean Jacques} and Halimi, {Jean Michel} and Philippe Zaoui and Annamaria Letoha and Csaba Hajdu and Denes Pall and Eva Peterfai and Gy{\"o}ngyi Cs{\'e}csei and Katalin Bezzegh and Laszlo Deak and Laszlo Konyves and Marianna Zsom and Peter Danos and Sandor Vangel and Szilard Vasas and Tamas Oroszlan and Zsolt Zilahi and Adi Leiba and Alon Grossman and Avshalom Leibowitz and Baruch Itzhak and Deeb Daoud and Evgeny Farber and Faiad Adawi and Nakhoul, {Farid M.} and Gil Chernin and Irina Kenis and Julio Wainstein and Lior Zeller and Mazen Elias and Shaul Atar and Victor Frajewicki and Yoram Yagil and Armaly, {Zaher A.} and Ciro Esposito and Francesca Viazzi and Giovanni Gambaro and Piermarco Piatti and Bonadonna, {Riccardo C.} and {Arias Delgadillo}, {Cristhian Ronaldt} and Flores, {Fernando Jimenez} and {Aguilera Real}, {Manuel Enrique} and Pedro Fajardo-Campos and {Violante Ortiz}, {Rafael Margarito} and {Luna Ceballos}, {Rosa Isela} and Sergio Duran-Barragan and Danuta Zytkiewicz-Jaruga and Ewa Krzyzagorska and Ewa Skokowska and Katarzyna Klodawska and Robert Mordaka and Stanislaw Mazur and Teresa Stasinska and Wladyslaw Sulowicz and Ciprian Constantin and Doru Negru and Paveliu, {Fraga Silvia} and Negrisanu, {Gabriela Doina} and Iosif Szilagyi and Busegeanu, {Mihaela Magdalena G.} and Pena, {Mihai Cosmin} and Avram, {Rodica Ioana} and Ardelean, {Silvia Luminita} and Adriana Ilavska and Andrej Dzupina and Aniko Oroszova and Eva Kolesarova and Ida Obetkova and Iveta Smatanova and Jana Babikova and Peter Fulop and Radovan Haffner and Rayner, {Brian L.} and Kruger, {Dawid Stephanus} and Urbach, {Dorothea Vera} and Essack Mitha and {Vally Mahomed Latiff}, {Gulam Hoosain} and Hemant Makan and {Du Plessis}, Hermanus and Jurgens, {Jaco Cornelius} and Jeevren Reddy and Trokis, {Julien S.} and Kirsten McHarry and Distiller, {Lawrence Allen} and Leila Mayet and Burgess, {Lesley Jean} and {Van Zyl}, {Louis Johan} and Joshi, {Mukesh P.} and Sebastian, {Peter John} and {Du Toit}, {Samantha Maria} and Blignaut, {Suzanne C.} and Serrano, {Antonio Galan} and Cristobal Morales and Esteban Poch and Mosquera, {Eva Marquez} and Castro, {Fernando Cereto} and {Gonzalez Martinez}, {Francisco Javier} and Perez-Contreras, {Francisco Javier} and Gema Fernandez-Fresnedo and {Garcia Mendez}, {Isabel Fuencisla} and Perez, {Jonay Pantoja} and Martinez, {Jordi Calabia} and {Gorriz Teruel}, {Jose Luis} and {Nieto Iglesias}, {Luis Javier} and Manuel Munoz-Torres and {Munar Vila}, {Maria Antonia} and {Arenas Jimenez}, {Maria Dolores} and Dominguez-Lopez, {Marta E.} and Val, {Miguel Hueso} and Terrades, {Natalia Ramos} and Olmo, {Rafael Santamaria} and {Malek Marin}, {Tamara Gelen} and Arif, {Ahmed A.} and Lee, {Benjamin J.} and Mehta, {Bhasker R.} and Baker, {Bruce H.} and Jere, {Charles S.} and Bains, {David G.} and Stricklin, {David G.} and Deanna Cheung and Diego Echeverri and Edgard Vera and Heurich, {Eva Maria} and Sterba, {Gary A.} and Hernandez, {German T.} and Paez, {Henry E.} and Acosta, {Idalia A.} and Intekhab Ahmed and Issac Sachmechi and Madu, {Ivy Joan E.} and Obhrai, {Jagdeep Singh} and Hammoud, {Jamal A.} and Tumlin, {James A.} and James Cain and Jaynier Moya-Hechevarria and Connaire, {Jeffrey J.} and Jehad Haggiagi and Odren, {Jennifer A.} and Bellucci-Jackson, {Jennifer M.} and Jieshi Yan and Parker, {John C.} and Tolins, {Jonathan P.} and Gomez-Cortes, {Jose D.} and Cardona, {Jose F.} and Mandry, {Jose M.} and Olivero, {Juan Jorge} and Hendon, {Kendra S.} and Kianoosh Kaveh and Kooienga, {Laura A.} and Bermudez, {Lidia R.} and Rich, {Lisa M.} and Marina Gold and Marisela Gonzalez and Schaefer, {Matthew E.} and Michelle Welch and Moustafa, {Moustafa A.} and Murtaza Mussaji and Pergola, {Pablo E.} and Piangwarin Phaosawasdi and Silva, {Ricardo A.} and Ricardo Presas and Lynn, {Robert I.} and Kronfli, {Saeed J.} and Ventrapragada, {Sailaja V.} and Niranjan, {Sankar N.} and Sayed Husain and Scott Satko and Jabbour, {Serge A.} and Rovner, {Sergio F.} and Gouge, {Steven F.} and Joshi, {Sudhir S.} and {Ramachandran Subramanian}, {Varagur Bala} and Wendy Lane and Wesley Calhoun and William Durham",

year = "2024",

month = may,

day = "1",

doi = "10.1681/ASN.0000000000000326",

language = "English",

volume = "35",

pages = "594--606",

journal = "Journal of the American Society of Nephrology",

issn = "1046-6673",

publisher = "American Society of Nephrology",

number = "5",

}

Heerspink, HJL, Stack, AG, Terkeltaub, R, Jongs, N, Inker, LA, Bjursell, M, Maklad, N, Perl, S, Eklund, O, Rikte, T, Sjöström, CD, Perkovic, V, Chmelickova, H, Lukac, M, Bucek, P, Drasnar, T, Dussol, B, Guerrot, D, Legrand, E, Boffa, JJ, Halimi, JM, Zaoui, P, Letoha, A, Hajdu, C, Pall, D, Peterfai, E, Csécsei, G, Bezzegh, K, Deak, L, Konyves, L, Zsom, M, Danos, P, Vangel, S, Vasas, S, Oroszlan, T, Zilahi, Z, Leiba, A, Grossman, A, Leibowitz, A, Itzhak, B, Daoud, D, Farber, E, Adawi, F, Nakhoul, FM, Chernin, G, Kenis, I, Wainstein, J, Zeller, L, Elias, M, Atar, S, Frajewicki, V, Yagil, Y, Armaly, ZA, Esposito, C, Viazzi, F, Gambaro, G, Piatti, P, Bonadonna, RC, Arias Delgadillo, CR, Flores, FJ, Aguilera Real, ME, Fajardo-Campos, P, Violante Ortiz, RM, Luna Ceballos, RI, Duran-Barragan, S, Zytkiewicz-Jaruga, D, Krzyzagorska, E, Skokowska, E, Klodawska, K, Mordaka, R, Mazur, S, Stasinska, T, Sulowicz, W, Constantin, C, Negru, D, Paveliu, FS, Negrisanu, GD, Szilagyi, I, Busegeanu, MMG, Pena, MC, Avram, RI, Ardelean, SL, Ilavska, A, Dzupina, A, Oroszova, A, Kolesarova, E, Obetkova, I, Smatanova, I, Babikova, J, Fulop, P, Haffner, R, Rayner, BL, Kruger, DS, Urbach, DV, Mitha, E, Vally Mahomed Latiff, GH, Makan, H, Du Plessis, H, Jurgens, JC, Reddy, J, Trokis, JS, McHarry, K, Distiller, LA, Mayet, L, Burgess, LJ, Van Zyl, LJ, Joshi, MP, Sebastian, PJ, Du Toit, SM, Blignaut, SC, Serrano, AG, Morales, C, Poch, E, Mosquera, EM, Castro, FC, Gonzalez Martinez, FJ, Perez-Contreras, FJ, Fernandez-Fresnedo, G, Garcia Mendez, IF, Perez, JP, Martinez, JC, Gorriz Teruel, JL, Nieto Iglesias, LJ, Munoz-Torres, M, Munar Vila, MA, Arenas Jimenez, MD, Dominguez-Lopez, ME, Val, MH, Terrades, NR, Olmo, RS, Malek Marin, TG, Arif, AA, Lee, BJ, Mehta, BR, Baker, BH, Jere, CS, Bains, DG, Stricklin, DG, Cheung, D, Echeverri, D, Vera, E, Heurich, EM, Sterba, GA, Hernandez, GT, Paez, HE, Acosta, IA, Ahmed, I, Sachmechi, I, Madu, IJE, Obhrai, JS, Hammoud, JA, Tumlin, JA, Cain, J, Moya-Hechevarria, J, Connaire, JJ, Haggiagi, J, Odren, JA, Bellucci-Jackson, JM, Yan, J, Parker, JC, Tolins, JP, Gomez-Cortes, JD, Cardona, JF, Mandry, JM, Olivero, JJ, Hendon, KS, Kaveh, K, Kooienga, LA, Bermudez, LR, Rich, LM, Gold, M, Gonzalez, M, Schaefer, ME, Welch, M, Moustafa, MA, Mussaji, M, Pergola, PE, Phaosawasdi, P, Silva, RA, Presas, R, Lynn, RI, Kronfli, SJ, Ventrapragada, SV, Niranjan, SN, Husain, S, Satko, S, Jabbour, SA, Rovner, SF, Gouge, SF, Joshi, SS, Ramachandran Subramanian, VB, Lane, W, Calhoun, W & Durham, W 2024, 'Combination Treatment with Verinurad and Allopurinol in CKD: A Randomized Placebo and Active Controlled Trial', Journal of the American Society of Nephrology, vol. 35, no. 5, pp. 594-606. https://doi.org/10.1681/ASN.0000000000000326

TY - JOUR

T1 - Combination Treatment with Verinurad and Allopurinol in CKD

T2 - A Randomized Placebo and Active Controlled Trial

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 - Frajewicki, Victor

AU - Yagil, Yoram

AU - Armaly, Zaher A.

AU - Esposito, Ciro

AU - Viazzi, Francesca

AU - Gambaro, Giovanni

AU - Piatti, Piermarco

AU - Bonadonna, Riccardo C.

AU - Arias Delgadillo, Cristhian Ronaldt

AU - Flores, Fernando Jimenez

AU - Aguilera Real, Manuel Enrique

AU - Fajardo-Campos, Pedro

AU - Violante Ortiz, Rafael Margarito

AU - Luna Ceballos, Rosa Isela

AU - Duran-Barragan, Sergio

AU - Zytkiewicz-Jaruga, Danuta

AU - Krzyzagorska, Ewa

AU - Skokowska, Ewa

AU - Klodawska, Katarzyna

AU - Mordaka, Robert

AU - Mazur, Stanislaw

AU - Stasinska, Teresa

AU - Sulowicz, Wladyslaw

AU - Constantin, Ciprian

AU - Negru, Doru

AU - Paveliu, Fraga Silvia

AU - Negrisanu, Gabriela Doina

AU - Szilagyi, Iosif

AU - Busegeanu, Mihaela Magdalena G.

AU - Pena, Mihai Cosmin

AU - Avram, Rodica Ioana

AU - Ardelean, Silvia Luminita

AU - Ilavska, Adriana

AU - Dzupina, Andrej

AU - Oroszova, Aniko

AU - Kolesarova, Eva

AU - Obetkova, Ida

AU - Smatanova, Iveta

AU - Babikova, Jana

AU - Fulop, Peter

AU - Haffner, Radovan

AU - Rayner, Brian L.

AU - Kruger, Dawid Stephanus

AU - Urbach, Dorothea Vera

AU - Mitha, Essack

AU - Vally Mahomed Latiff, Gulam Hoosain

AU - Makan, Hemant

AU - Du Plessis, Hermanus

AU - Jurgens, Jaco Cornelius

AU - Reddy, Jeevren

AU - Trokis, Julien S.

AU - McHarry, Kirsten

AU - Distiller, Lawrence Allen

AU - Mayet, Leila

AU - Burgess, Lesley Jean

AU - Van Zyl, Louis Johan

AU - Joshi, Mukesh P.

AU - Sebastian, Peter John

AU - Du Toit, Samantha Maria

AU - Blignaut, Suzanne C.

AU - Serrano, Antonio Galan

AU - Morales, Cristobal

AU - Poch, Esteban

AU - Mosquera, Eva Marquez

AU - Castro, Fernando Cereto

AU - Gonzalez Martinez, Francisco Javier

AU - Perez-Contreras, Francisco Javier

AU - Fernandez-Fresnedo, Gema

AU - Garcia Mendez, Isabel Fuencisla

AU - Perez, Jonay Pantoja

AU - Martinez, Jordi Calabia

AU - Gorriz Teruel, Jose Luis

AU - Nieto Iglesias, Luis Javier

AU - Munoz-Torres, Manuel

AU - Munar Vila, Maria Antonia

AU - Arenas Jimenez, Maria Dolores

AU - Dominguez-Lopez, Marta E.

AU - Val, Miguel Hueso

AU - Terrades, Natalia Ramos

AU - Olmo, Rafael Santamaria

AU - Malek Marin, Tamara Gelen

AU - Arif, Ahmed A.

AU - Lee, Benjamin J.

AU - Mehta, Bhasker R.

AU - Baker, Bruce H.

AU - Jere, Charles S.

AU - Bains, David G.

AU - Stricklin, David G.

AU - Cheung, Deanna

AU - Echeverri, Diego

AU - Vera, Edgard

AU - Heurich, Eva Maria

AU - Sterba, Gary A.

AU - Hernandez, German T.

AU - Paez, Henry E.

AU - Acosta, Idalia A.

AU - Ahmed, Intekhab

AU - Sachmechi, Issac

AU - Madu, Ivy Joan E.

AU - Obhrai, Jagdeep Singh

AU - Hammoud, Jamal A.

AU - Tumlin, James A.

AU - Cain, James

AU - Moya-Hechevarria, Jaynier

AU - Connaire, Jeffrey J.

AU - Haggiagi, Jehad

AU - Odren, Jennifer A.

AU - Bellucci-Jackson, Jennifer M.

AU - Yan, Jieshi

AU - Parker, John C.

AU - Tolins, Jonathan P.

AU - Gomez-Cortes, Jose D.

AU - Cardona, Jose F.

AU - Mandry, Jose M.

AU - Olivero, Juan Jorge

AU - Hendon, Kendra S.

AU - Kaveh, Kianoosh

AU - Kooienga, Laura A.

AU - Bermudez, Lidia R.

AU - Rich, Lisa M.

AU - Gold, Marina

AU - Gonzalez, Marisela

AU - Schaefer, Matthew E.

AU - Welch, Michelle

AU - Moustafa, Moustafa A.

AU - Mussaji, Murtaza

AU - Pergola, Pablo E.

AU - Phaosawasdi, Piangwarin

AU - Silva, Ricardo A.

AU - Presas, Ricardo

AU - Lynn, Robert I.

AU - Kronfli, Saeed J.

AU - Ventrapragada, Sailaja V.

AU - Niranjan, Sankar N.

AU - Husain, Sayed

AU - Satko, Scott

AU - Jabbour, Serge A.

AU - Rovner, Sergio F.

AU - Gouge, Steven F.

AU - Joshi, Sudhir S.

AU - Ramachandran Subramanian, Varagur Bala

AU - Lane, Wendy

AU - Calhoun, Wesley

AU - Durham, William

PY - 2024/5/1

Y1 - 2024/5/1

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.MethodsIn 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.ResultsBetween 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.ConclusionsVerinurad 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.MethodsIn 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.ResultsBetween 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.ConclusionsVerinurad 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 -

Combination Treatment with Verinurad and Allopurinol in CKD: A Randomized Placebo and Active Controlled Trial

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