Efficacy and safety of sparsentan versus irbesartan in patients with IgA nephropathy (PROTECT): 2-year results from a randomised, active-controlled, phase 3 trial

Authors: Brad H. Rovin, Jonathan Barratt, Hiddo J.L. Heerspink, Charles E. Alpers, Stewart Bieler, Dong-Wan Chae, Ulysses Diva, Jürgen Floege, Loreto Gesualdo, Jula K. Inrig, Donald E. Kohan, Radko Komers, Laura Kooienga, Richard Lafayette, Bart Maes, Robert Małecki, Alex Mercer, Irene L. Noronha, Se Won Oh, Chen Au Peh, Manuel Praga, Priscila Preciado, Jai Radhakrishnan, Michelle N. Rheault, William E. Rote, Sydney Tang, Vladimı́r Tesař, Howard Trachtman, Hernán Trimarchi, James A. Tumlin, Muh Geot Wong, Vlado Perkovic, Isabella Abbasciano, Catarina Abrantes, Simone Accarino, Sharon G. Adler, Annika Adoberg, Rouzbeh Afsari, Syeda B. Ahmad, Jafar Ahmed, Wooin Ahn, Bamidele Ajayi, Dariusz Aksamit, Saif Al‐Chalabi, É. Alamartine, Bassam Alchi, Mohammad Ali, Roberta Aliotta, Salem Almaani, Catarina Almeida, Edgar Almeida, Francisco de la Prada Álvarez, Patrícia Marques‐Alves, Francesca Annese, Gerald B. Appel, Gerald Appel, Maria Arena, Marta Calvo Arevalo, Dariush Arfaania, Carlos Arias, Emma Calatayud Aristoy, Eglė Ašakienė, Sarah Ashley, Ali Assefi, Alba Atenza, Asta Auerbach, Hanna Augustyniak‐Bartosik, Hanna Augustyniak-Bartosik, Jonathan Ayling-Smith, Isabelle Ayoub, Isabelle Ayoub, Rocco Baccaro, Asha Bailey, Bruce Baker, Saravanan Balamuthusamy, José Ballarín, Rui Barata, Jerko Barbić, Dunja Barisic, Jonathan Barratt, José C. Barreto, Clara Barrios, Mirco Belingheri, Anna Benesova, Ana Ávila Bernabéu, Wanja Bernhardt, Shamik Bhadra, Luigi Biancone, Anne Blanchard, Elena Boaglio, Davide Bolignano, Andrew S. Bomback, Gustavo Andres Useche Bonilla, M Bordoli, Bhadran Bose, Neil Boudville, Donald Brandon, Donald Brandon, Karen Brown, C Broyet, Thomas Bucknall, Alexandre Buffet, Inga Arūnė Bumblytė, Manuel Burdese, Natalia Allende Burgos, Natalia Allende Burgos, Laure Burguet, Stéphane Burtey, Martin Busch, Figen Cakiroglu, Victoria Campbell, Pietro A. Canetta, Flavia Capaccio, Juan Carbonell, Filipa Cardoso, Clara García Carro, Robert J. Carroll, Pierre‐Louis Carron, Nazareno Carullo, Matthias Cassia, Dawn J. Caster, Belén Vizcaíno Castillo, Davide Catucci, Andrea Cavalli, Dong-Wan Chae, Aron Chakera, Doris Chan, Gary C.W. Chan, Anthony Ting Pong Chan, Lai Wan Chan, Jae Hyun Chang, Ming-Shan Chang, Fiona A. Chapman, Chaim Charytan, Asghar Chaudhry, Melissa S Cheetham, Cheng‐Hsu Chen, Hsin-Yu Chen, Chien‐Liang Chen, Hung‐Yuan Chen, Hung‐Chun Chen, Leïla Chénine, Siu Fai Cheung, Chee Kay Cheung, Chee Kay Cheung, Hsien‐Fu Chiu, Yen‐Ling Chiu, Yi‐Wen Chiu, Ian Chiu, Hoon Young Choi, Kang‐Ju Chou, Paramit Chowdhury, Pradip Chowdhury, Constantina Chrysochou, Chukwuma Chukwu, Ka Yeong Chun, Wookyung Chung, Dominik Cieniawski, Guillaume Claisse, Philip A. Clayton, Catalina Martín Cleary, Nisha Clement, Toby Coates, C Cogno, Loredana Colla, Michael Collins, Marco Colucci, Christian Combe, Nicolino Comi, Roderick Comunale, Gabriel Contreras, Bruce A. Cooper, Gaia Coppock, Ana Cortesão Costa, Stefano Costanzi, Mario Cozzolino, Susan Crail, Liliana Cunha, Elizabeth Curry, Tiane Dai, Erica Daina, Sam Daneshvari, Indranil Dasgupta, Louise DaSilva, Robert M. Davidson, Aine Maire De Bhailis, V. de Précigout, Marc Decupere, Yahsou Delmas, Francesca Deodato, Neeraj Dhaun, Ajay Dhaygude, Ranjit Dhelaria, Federica Di Maio, María Ángeles Goicoechea Diezhandino, Živka Dika, M. Dinic, Ian Dittmer, Mirela Dobre, Gabriel Doctor, Gabriele Donati, Peter Doubel, Nicole Douthit, Nicole Douthit, Yelena Drexler, Martin Drinković, Martin Drinkovic, Caroline Dudreuilh, Clément Dumond, Ivan Durlen, Bertrand Dussol, Montserrat M. Díaz Encarnación, Zoltán Endre, Jorge Enrique, Yusuf Eqbal, Jonathan Erlich, Vittoria Esposito, Ciro Esposito, Faisal Fakih, Hua‐Chang Fang, Ana Farinha, Aaron Fearday, Joana Felgueiras, Joana de Sousa Soares Felgueiras, Elzbieta Felicjanczuk, Sara Fernandes, Adriana Fernandes, José Luño Fernández, Víctor Fernández, Mangalee Fernando, Ana Figueiredo, Éric Firre, Jürgen Floege, Oliver Floßmann, Lauren Floyd, Nuno Moreira Fonseca, José Nuno Fonseca, Celine Foote, Suzanne Forbes, Ángel Blasco Forcén, Alessia Fornoni, David Fouassier, Ian Fraser, Samuel Fung, Mónica Furlano, Teresa Furtado, Rajdeep Gadh, Roxane Gaïsset, M. W. Gallagher, Joana Gameiro, Muralikrishna Gangadharan, Fabiola Alonso García, Olga Gracia García, Gunjan Garg, Cyril Garrouste, Archana Gautam, Abdallah Sassine Geara, Colin Geddes, Lana Gellineo, Michael J. Germain, Loreto Gesualdo, Farid Ghalli, Francesco Giaroni, Harold Giles, Alastair Gillies, Ana Vilar Gimeno, Annette Girardet, Jeffrey Glaze, Tze Liang Goh, Mário Góis, Christopher Goldsmith, Elena Gomá-Garcés, Ana Marta Gomes, Luis Pedro Falcao Goncalves, Sara Gonçalves, Julita Gontarek-Kacprzak, Carlos González, Arun Gopu, Nayan Gowda, Nicholas A. Gray, Barbara Greco, Heather Green, Clarisse Grèze, Siân Griffin, Secundino Cigarrán, Úrsula Verdalles Guzmán, Jeffrey T. Ha, Amanda K. Hall, Patrick Hamilton, Seung Hyeok Han, Robert Haws, Ashik Hayat, Lauren Heath, Sven Heinrichs, Andrew Henderson, Amy Henderson, Elizabeth Hendren, Anne-Elisabeth Heng, Salia Virxinia Pol Heres, Johann Konstantin Herfurth, Evangelina Merida Herrero, Tzung‐Yo Ho, Jonathan J. Hogan, Bernd Hohenstein, Peter Hollett, Ivica Horvatić, Bang‐Gee Hsu, Chia‐Tien Hsu, Chih‐Yang Hsu, Shih‐Ping Hsu, Chien‐Wei Huang, Amy Hudson, Chi‐Chih Hung, Shang‐Jyh Hwang, Daw‐Yang Hwang, Young Youl Hyun, Madis Ilmoja, Georgina Irish, Radu Jacob, Sadia Jahan, Arunima Jain, Sofie Jamar, Anna Jander, Hye Ryoun Jang, Catherine Janko, Meg Jardine, Piotr Jaśkowskí, Guillaume Jeantet, Bojan Jelaković, Junseok Jeon, Jong Cheol Jeong, Shilpanjali Jesudason, Arksarapuk Jittirat, Sang‐Kyung Jo, Rachel Jones, Narae Joo, Sofía Jorge, Bruce A. Julian, JiYong Jung, JiYong Jung, Jigar Kadakia, Fahameedah Kamal, Durga Kanigicherla, Sandra Karanović, Alexandre Karras, Theodoros Kasimatis, Mohamad Kassem, Siddhartha Kattamanchi, Christopher Keller, Christopher Keller, Christiane Kettner, Kassem Khalil, Dana Kim, Se Joong Kim, Yeong Hoon Kim, Yunmi Kim, Hyung Wook Kim, Sunggyun Kim, Jwa-Kyung Kim, Aejin Kim, Myung-Gyu Kim, Cassandra Kimber, Cassandra Kimber, Annegret Koch, Annegret Koch, Külli Kõlvald, Sui Phi Kon, Laura Kooienga, Sradha Kotwal, Magdalena Krajewska, Karolína Krátká, Anoushka Krishnan, Rathika Krishnasamy, Thilo Krueger, Ivan Kruljac, Simone Kulka, Ulrich Kunzendorf, Mei‐Chuan Kuo, Hung‐Tien Kuo, Sheng Kuo, Lorraine Pui Yuen Kwan, Norbert Kwella, Bogna Kwella, Kay Kyaw, Aurore Labat, Richard Lafayette, Mark Lagatta, Chi Kwan Darwin Lam, Mark Lambie, Camille Lanaret, Farah Latif, Margo Laute, Wai Ping Law, Sarah Lawman, Mercedes Salgueira Lazo, Hajeong Lee, Moon‐Hyoung Lee, Kyu‐Beck Lee, Hyungseok Lee, Jung Eun Lee, Hyun Hee Lee, Po‐Tsang Lee, Liisi Leis, Wim Lemahieu, Janson Leung, Li Yan, Davina Ngoi Wah Lie, Davina Ngoi Wah Lie, Kadri Lilienthal, Wai H. Lim, Monica Limardo, Marine Livrozet, Selena Longhi, Daniela Lopes, José António Lopes, Nathan Lorde, Grant Luxton, Mingyao Ma, Machaiah Madhrira, Phillip Madonia, Bart Maes, Kumaradevan Mahadevan, Amar Mahdi, Eamon Mahdi, Nicolas Maillard, Dita Maixnerová, Karolina Majstorović Barać, Robert Małecki, Thomas Malfait, Silvia Malvica, Sreedhar Mandayam, Paul W. Manley, Nick Mansfield, Carmelita Marcantoni, Christophe Mariat, Tamara Malek Marin, Lida María Rodas Marín, Patrick B. Mark, Joana Marques, Eduardo Gutiérrez Martínez, Stacy Martinez, Catherine Masset, Ingrid Masson, Amanda Mather, Thida Maung Myint, Valentin Mayet, Kieran McCafferty, Ellen T. McCarthy, Stephen McDonald, Kerri McGreal, Kellyn McMahon, Andrew McNally, Emily P. McQuarrie, Allyson Medina, Gert Meeus, Kshama Mehta, Elder Mendoza, Maria Do Mar Menezes, Jerry Meng, Piergiorgio Messa, Ana Messias, Przemysław Miarka, Marius Miglinas, Ivana Mikačić, Ashraf Mikhail, Martina Milicevic, Raffi Minasian, Marcus J. Moeller, Hesham Mohey, Javad Najjar Mojarrab, Maggie Ming Yee Mok, Eduardo Parra Moncasi, Martial Moonen, Wenceslao Adrian Aguilera Morales, Eduardo Verde Moreno, Antolina Moreno, Adam Morris, D.-A. Moutzouris, Mercedes González Moya, Simon Mucha, Michela Musolino, Pietro Napodano, Ana Natário, Lavinia Negrea, Bradley Nelson, Brendon L. Neuen, Britt B. Newsome, Jack Kit‐Chung Ng, Thu Nguyen, Viet Nguyen, C. Nicolò, Martin Nitschke, Euan Noble, Euan Noble, Fernando Nolasco, Emma O’Lone, Adriana Sierra Ochoa, Kook‐Hwan Oh, Se Won Oh, Pedro Okoh, Sara Ombelet, Michelle M. O’Shaughnessy, Shih‐Hsiang Ou, David Packham, Aparna Padiyar, Mei‐Fen Pai, Irene Agraz Pamplona, Szu‐Yu Pan, Bhavna Pandya, Federica Papadia, Clara Pardinhas, Nishita Parikh, Samir M. Parikh, Hyeong Cheon Park, Jung Tak Park, Lúcia Parreira, Patrizia Passerini, Ramachandra Patak, Margret Patecki, Rajan Patel, Jusmin Patel, Meera Patel Suthar, Gemma Patella, Gemma Patella, Draško Pavlović, William G. Paxton, Chen Au Peh, Yonatan Peleg, Josep Miquel Blasco Pelicano, Yu‐Sen Peng, Manuel Pereira de Vicente, Jonay Pantoja Perez, Erika Pérez, Ana Pérez de José, María Vanessa Pérez-Gómez, María Vanessa Pérez Gómez, Usha Peri, Norberto Perico, Carole Philipponnet, Elaine Phua, Julia Piel, Unnikrishnan Pillai, Helen Pilmore, Djuro Plavljanic, Mercedes Velo Plaza, Carol A. Pollock, Arvind Ponnusamy, Serena Ponti, T. D. Powell, Nishigandha Pradhan, Raúl Fernández Prado, Ingrid Prkačin, Rishi Pruthi, Dan Pugh, Sarah Quinn, Luís F. Quintana, Luis F Quintana, Kannaiyan S Rabindranath, Luc Radermacher, Jai Radhakrishnan, Omar Ragy, Ritesh Raichoudhury, Mário Raimundo, Paolo Randone, Mona Razavian, Helmut Reichel, Marina Reis, Giuseppe Remuzzi, Annie Reynolds, Anna Ricchiuto, Ivon Maritza Bobadilla Rico, Claire Rigothier, Angus Ritchie, Maria Antonieta Azancot Rivero, Dana V. Rizk, Han Ro, Alfred Rodriguez, Eva Rodriguez Garcia, Simon D. Roger, Simon Roger, Mai Rosenberg, Stéphane Roueff, Brad H. Rovin, Sarah Roxburgh, Mario Ruiz, Helena Marco Rusiñol, Ivan Rychlík, Helena Marco Rusinol, Tania Salehi, María Dolores Sánchez de la Nieta, Silja K. Sanden, Lina Santockiene, Patricia Valerio Santos, Iara Da Silva Santos, Mari Sargsyan, Iara Da Silva Santos, Sebahat Şat, Franziska Sarnow, Ana Šavuk, Matthew Sayer, Georg Schlieper, Mandy Schlosser, Hans Schmidt-Guertler, Olivier P. Schockaert, Kevin Schulte, Lisa Schulz, Haresh Selvaskandan, David Semple, Shaundeep Sen, Elviira Seppet, Antonio Galán Serrano, Jean‐Emmanuel Serre, Ángel Sevillano, Sapna Shah, Yvonne Shen, Brittany Sheridan, Kai-Hsiang Shu, Brittany Sheridan, Sónia Silva, Arnold Silva, Smeeta Sinha, Amanda Siriwardana, Zvonimir Sitaš, Carmen Sivo, Peter Sizeland, Cathylee Sly, Priscilla Smith, Brian Snow, Elsa Sofia Quadrado Soares, Andrea Solazzo, Elena Gutiérrez Solís, Laurence Solomon, Young Song, Laurence Solomon, Bruce Spinowitz, Elizabeth Stallworthy, Eleni Stamellou, Małgorzata Stańczyk, Stefanie Stangenberg, Marija Stanković, Asta Stankuvienė, Emma Diletta Stea, Tomasz Stompór, Joshua Storrar, James Sullivan, Władysław Sułowicz, James Sullivan, Cheuk‐Chun Szeto, E. Alba Tamarit, Eddie Tan, May Tan, Sydney Tang, Hon Tang, Catarina Teixeira, Kadri Telling, Natàlia Ramos, Vladimı́r Tesař, Didem Tez, Éric Thervet, Damien Thibaudin, Mark Thomas, Nikhil Thyagarajan, Marcin Tkaczyk, Massimo Torreggiani, Matias Trillini, Shang‐Feng Tsai, Wan‐Chuan Tsai, Jer‐Chia Tsai, Po‐Yu Tseng, James A. Tumlin, Kuei‐Ting Tung, Angus Turnbull, Suneel Udani, Jana Uhlinova, Suneel Udani, Federica Urciuolo, An Vanacker, Bert Vandewiele, Álvaro Vaz, Kristi Veermae, Liesbeth Viaene, Alvita Vickienė, Sara Viganò, María Antonia Munar Vila, Eswari Vilayur, Caridad Martinez Villanueva, Cristina Medrano Villarroya, Alejandro Soria Villen, Veronica Viramontes, Caterina Vita, Dunja Vujčić, Mona Wahba, Susan Wan, Chih‐Hsien Wang, Xavier Warling, Gerald P Waters, Jane Waugh, Lea Weiland, Stefan M. Weiner, Thomas Weinreich, Stephan Christian Werth, Olivia Wickens, Stephan Christian Werth, Olivia Wickens, Lisa Willcocks, Allister Williams, Agata Winiarska, Nikolaus Wirtz, Lothar Wolf, Günter Wolf, Muh Geot Wong, Yick Hei Wong, Sze Ho Sunny Wong, Biruh Workeneh, Ming‐Ju Wu, Hon‐Yen Wu, Roger Wyndham, Jihyun Yang, Ju‐Yeh Yang, Chii Yeap, Ka Fai Yim, Kenneth Yong, Tae‐Hyun Yoo, Songuk Yoon, Tung‐Min Yu, Tak Tai Andrew Yue, Michel Zakari, Urtė Žakauskienė, Philippe Zaoui, Justyna Zbrzeźniak, Dorota Zielińska, Carlotta Federica Zizzi, Dorota Zielińska, Carlotta Federica Zizzi - The Lancet 2023 cited by 267

Background Sparsentan, a novel, non-immunosuppressive, single-molecule, dual endothelin angiotensin receptor antagonist, significantly reduced proteinuria versus irbesartan, an angiotensin II receptor blocker, at 36 weeks (primary endpoint) in patients with immunoglobulin A nephropathy in the phase 3 PROTECT trial's previously reported interim analysis. Here, we report kidney function and outcomes over 110 weeks from the double-blind final analysis. Methods PROTECT, a double-blind, randomised, active-controlled, phase 3 study, was done across 134 clinical practice sites in 18 countries throughout the Americas, Asia, and Europe. Patients aged 18 years or older with biopsy-proven primary IgA nephropathy and proteinuria of at least 1·0 g per day despite maximised renin–angiotensin system inhibition for at least 12 weeks were randomly assigned (1:1) to receive sparsentan (target dose 400 mg oral sparsentan once daily) or irbesartan (target dose 300 mg oral irbesartan once daily) based on a permuted-block randomisation method. The primary endpoint was proteinuria change between treatment groups at 36 weeks. Secondary endpoints included rate of change (slope) of the estimated glomerular filtration rate (eGFR), changes in proteinuria, a composite of kidney failure (confirmed 40% eGFR reduction, end-stage kidney disease, or all-cause mortality), and safety and tolerability up to 110 weeks from randomisation. Secondary efficacy outcomes were assessed in the full analysis set and safety was assessed in the safety set, both of which were defined as all patients who were randomly assigned and received at least one dose of randomly assigned study drug. This trial is registered with ClinicalTrials.gov, NCT03762850. Findings Between Dec 20, 2018, and May 26, 2021, 203 patients were randomly assigned to the sparsentan group and 203 to the irbesartan group. One patient from each group did not receive the study drug and was excluded from the efficacy and safety analyses (282 [70%] of 404 included patients were male and 272 [67%] were White) . Patients in the sparsentan group had a slower rate of eGFR decline than those in the irbesartan group. eGFR chronic 2-year slope (weeks 6–110) was −2·7 mL/min per 1·73 m 2 per year versus −3·8 mL/min per 1·73 m 2 per year (difference 1·1 mL/min per 1·73 m 2 per year, 95% CI 0·1 to 2·1; p=0·037); total 2-year slope (day 1–week 110) was −2·9 mL/min per 1·73 m 2 per year versus −3·9 mL/min per 1·73 m 2 per year (difference 1·0 mL/min per 1·73 m 2 per year, 95% CI −0·03 to 1·94; p=0·058). The significant reduction in proteinuria at 36 weeks with sparsentan was maintained throughout the study period; at 110 weeks, proteinuria, as determined by the change from baseline in urine protein-to-creatinine ratio, was 40% lower in the sparsentan group than in the irbesartan group (−42·8%, 95% CI −49·8 to −35·0, with sparsentan versus −4·4%, −15·8 to 8·7, with irbesartan; geometric least-squares mean ratio 0·60, 95% CI 0·50 to 0·72). The composite kidney failure endpoint was reached by 18 (9%) of 202 patients in the sparsentan group versus 26 (13%) of 202 patients in the irbesartan group (relative risk 0·7, 95% CI 0·4 to 1·2). Treatment-emergent adverse events were well balanced between sparsentan and irbesartan, with no new safety signals. Interpretation Over 110 weeks, treatment with sparsentan versus maximally titrated irbesartan in patients with IgA nephropathy resulted in significant reductions in proteinuria and preservation of kidney function. Funding Travere Therapeutics.