Supplementary Appendix
This appendix has been provided by the authors to give readers additional information about their work.
Supplement to: Bakris GL, Agarwal R, Anker SD, et al. Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. N Engl J Med. DOI: 10.1056/NEJMoa2025845
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Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes
Supplementary Appendix
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Contents FIDELIO-DKD committees .................................................................................................... 4
Executive committee ......................................................................................................... 4
National lead investigators ................................................................................................ 4
Clinical event committee ................................................................................................... 4
Cardiovascular clinical event adjudication committee ................................................... 5
Renal clinical event adjudication committee .................................................................. 5
Neurological clinical event adjudication committee ....................................................... 5
Independent data monitoring committee ........................................................................... 5
Sponsor study team .......................................................................................................... 5
Participating countries and investigators .............................................................................. 7
Inclusion and exclusion criteria ........................................................................................... 14
Inclusion criteria .............................................................................................................. 14
Exclusion criteria ............................................................................................................. 14
Outcome definitions ............................................................................................................ 16
Kidney outcome events ................................................................................................... 16
Kidney failure ............................................................................................................... 16
Sustained decrease (≥40%/≥57%) in estimated glomerular filtration rate ................... 16
Cardiovascular endpoint events ...................................................................................... 17
Acute myocardial infarction ......................................................................................... 17
Stroke .......................................................................................................................... 18
Hospitalization due to heart failure .............................................................................. 18
Causes of death .............................................................................................................. 19
Cardiovascular death ................................................................................................... 19
Renal death ................................................................................................................. 21
Non-cardiovascular and non-renal death .................................................................... 21
Additional methods ............................................................................................................. 22
Estimation of glomerular filtration rate for Black / African American patients: ................. 22
Serum potassium monitoring and management of hyperkalemia ................................... 22
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Statistical analyses .......................................................................................................... 23
Mean dosing of study drug .......................................................................................... 23
Subgroup analyses of the primary outcome ................................................................ 23
Number needed to treat estimation ............................................................................. 23
Change in urine albumin-to-creatinine ratio and estimated glomerular filtration rate
over time ...................................................................................................................... 23
Estimated glomerular filtration rate slope analyses ..................................................... 23
Critical Good Clinical Practice violations ............................................................................ 24
Tipping point analysis of primary efficacy endpoint ............................................................ 25
Supplementary figures ........................................................................................................ 26
Figure S1. Study design of FIDELIO-DKD ...................................................................... 26
Figure S2. Consort diagram ............................................................................................ 28
Figure S3. Primary composite renal outcome according to key prespecified subgroups 29
Figure S4. Secondary outcomes ..................................................................................... 30
Figure S5. Tipping point analysis for the primary efficacy outcome ................................ 32
Figure S6. Effects of finerenone and placebo on eGFR ................................................. 33
Figure S7. Mean systolic blood pressure over time ........................................................ 34
Figure S8. Mean HbA1C over time ................................................................................. 35
Figure S9. Mean body weight over time .......................................................................... 36
Supplementary tables ......................................................................................................... 37
Table S1. Baseline patient demographics, clinical characteristics and medications ....... 37
Table S2. Dosing of renin–angiotensin system inhibitors* .............................................. 41
Table S3. Concomitant medications initiated after start of study drug ............................ 43
Table S4. Sensitivity analysis – efficacy outcomes in the on-treatment analysis ............ 44
Table S5. Tipping point analysis for the primary efficacy outcome ................................. 45
Table S6. Summary of treatment-emergent adverse events by body system or organ
class ................................................................................................................................ 47
Reference ........................................................................................................................... 48
4
FIDELIO-DKD committees
Executive committee
Role: The executive committee contributed to development and amendments to the Study Protocol and Statistical Analysis Plan, supervised trial conduct, provided scientific guidance
and analyzed and interpreted the data
Members: George L. Bakris; Gerasimos Filippatos; Rajiv Agarwal; Stefan D. Anker; Luis M. Ruilope; Bertram Pitt
National lead investigators
Augusto Vallejos (Argentina), Richard MacIsaac (Australia), Guntram Schernthaner (Austria),
Pieter Gillard (Belgium), Maria Eugenia F. Canziani (Brazil), Theodora Temelkova-
Kurktschiev (Bulgaria), Ellen Burgess and Sheldon Tobe (Canada), Fernando González
(Chile), Zhi-Hong Liu (China), Andrés Ángelo Cadena Bonfanti and Carlos Francisco
Jaramillo (Colombia), Martin Prazny (Czech Republic), Peter Rossing (Denmark), Jorma
Strand (Finland), Michel Marre (France), Roland Schmieder and Christoph Wanner
(Germany), Pantelis A. Sarafidis (Greece), Juliana Chan (Hong Kong), László Rosivall
(Hungary), Joseph Eustace (Ireland), Ehud Grossman and Yoram Yagil (Israel), Giuseppe
Remuzzi (Italy), Daisuke Koya and Takashi Wada (Japan), Magdalena Madero Rovalo
(Mexico), Ron Gansevoort and Adriaan Kooy (Netherlands), Trine Finnes (Norway), Froilan
De Leon (Philippines), Janusz Gumprecht (Poland), Fernando Teixeira e Costa (Portugal),
Alexander Dreval (Russia), Anantharaman Vathsala (Singapore), Aslam Amod (South
Africa), Sin Gon Kim and Byung Wan Lee (South Korea), Julio Pascual Santos (Spain),
Bengt-Olov Tengmark (Sweden), Michel Burnier (Switzerland), Chien-Te Lee (Taiwan), Sukit
Yamwong (Thailand), Ramazan Sari (Turkey), Kieran McCafferty (United Kingdom), Borys
Mankovsky (Ukraine), Sharon Adler, Linda Fried, Robert Toto and Mark Williams (United
States), Tran Quang Khanh (Vietnam).
Clinical event committee
Role: The clinical event committee (CEC), blinded to study treatment assignment, adjudicated all events that could potentially fulfill the criteria for the primary, secondary or
other endpoints during the study, including; kidney failure, ≥40% decrease in estimated
glomerular filtration rate (eGFR) from baseline (confirmed by ≥1 additional standardized
measurement ≥4 weeks after initial measurement), ≥57% decrease in eGFR from baseline
(confirmed by ≥1 additional standardized measurement ≥4 weeks after initial measurement),
eGFR
5
infarction, non-fatal stroke, hospitalization for heart failure, other CV hospitalization and new
onset atrial fibrillation or atrial flutter. The CEC also adjudicated all hospitalizations and
deaths in the study.
Members: Rajiv Agarwal (chair); Stefan Anker; Phyllis August; Andrew Coats; Hans Diener; Wolfram Döhner; Barry Greenberg; Stephan von Haehling; James Januzzi; Alan Jardine;
Carlos Kase; Sankar Navaneethan; Lauren Phillips; Piotr Ponikowski; Pantelis Sarafidis; Titte
Srinivas; Turgut Tatlisumak; John Teerlink
Cardiovascular clinical event adjudication committee
Stefan Anker (chair); Andrew Coats; Wolfram Döhner; Barry Greenberg; Stephan von
Haehling; James Januzzi; Piotr Ponikowski; John Teerlink
Renal clinical event adjudication committee
Rajiv Agarwal (chair); Phyllis August; Alan Jardine; Sankar Navaneethan; Titte Srinivas;
Pantelis Sarafidis
Neurological clinical event adjudication committee
Wolfram Döhner (chair); Hans Diener; Carlos Kase; Lauren Phillips; Turgut Tatlisumak;
Independent data monitoring committee
Role: The data monitoring committee provided ongoing safety monitoring during the conduct of the study and conducted one formal interim analysis when 2/3 of the required total number
of primary efficacy endpoint events had been observed
Members: Murray Epstein (co-chair); Aldo Maggioni (co-chair); Glenn Chertow; Gerald DiBona; Tim Friede (statistician); Jose Lopez-Sendon; Jean Rouleau
Sponsor study team
Study coordinators: Stefania Collamati (Italy), Laurence West, Angela May, Lydia Christopher, Michelle King, Nicki Beakhouse (UK), Anna Lindroth, Malin Hussell (Sweden),
Cecilia Fedorov (Canada), GoUne You (South Korea), Dirk Alta (the Netherlands);
Statisticians: Patrick Schloemer, Christoph Tasto and Nicole Mentenich (Germany) Data managers: Jeannette Gerstner, Jacobus Buytendach (Germany), Martin Gregory (UK) Statistical analysts: Yosia Hadisusanto, Cosima Klein, Aziz Tuemer (Germany), Konrad Zywno (Poland)
Study physicians: Luke Roberts (UK), Andrea Lage, Anna Carolina Ferreira (Brazil), Giovanni Palombo (UK), Meike Brinker (Germany)
Safety physician: Andrea Horvat-Broecker (Germany)
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Clinical leads: Amer Joseph, Christina Nowack (Germany)
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Participating countries and investigators Argentina: Diego Aizenberg, Inés Bartolacci, Diego Besada, Julio Bittar, Mariano Chahin, Alicia Elbert, Elizabeth Gelersztein, Alberto Liberman, Laura Maffei, Federico Pérez Manghi,
Hugo Sanabria, Augusto Vallejos, Gloria Viñes, Alfredo Wassermann
Australia: Walter Abhayaratna, Shamasunder Acharya, Elif Ekinci, Darren Lee, Richard MacIsaac, Peak Mann Mah, Craig Nelson, David Packham, Alexia Pape, Simon Roger,
Hugo Stephenson, Michael Suranyi, Gary Wittert, Elizabeth Vale
Austria: Martin Clodi, Christoph Ebenbichler, Evelyn Fliesser-Görzer, Ursula Hanusch, Michael Krebs, Karl Lhotta, Bernhard Ludvik, Gert Mayer, Peter Neudorfer, Bernhard
Paulweber, Rudolf Prager, Wolfgang Preiß, Friedrich Prischl, Gerit-Holger Schernthaner,
Harald Sourij, Martin Wiesholzer
Belgium: Peter Doubel, Wendy Engelen, Pieter Gillard, Jean-Michel Hougardy, Jean-Marie Krzesinski, Bart Maes, Marijn Speeckaert, Koen Stas, Luc van Gaal, Hilde Vanbelleghem
Brazil: Daniela Antunes, Roberto Botelho, Claudia Brito, Luis Canani, Maria Eugenia Canziani, Maria Cerqueira, Rogerio de Paula, Freddy Eliaschewitz, Carlos Eduardo
Figueiredo, Adriana Forti, Miguel Hissa, Maurilo Leite Jr, Emerson Lima, Irene Noronha,
Bruno Paolino, Nathalia Paschoalin, Raphael Paschoalin, Roberto Pecoits Filho, Marcio
Pereira, Evandro Portes, Dalton Precoma, Rosangela Rea, Miguel Riella, Joao Eduardo
Salles, Eduardo Vasconcellos, Sergio Vencio
Bulgaria: Emiliya Apostolova, Radostina Boshnyashka, Ghassan Farah, Dimitar Georgiev, Valentina Gushterova, Neli Klyuchkova, Mariya Lucheva, Petya Manova, Dotska Minkova,
Boyan Nonchev, Mariyana Pichmanova, Zhulieta Prakova, Rangel Rangelov, Rosen
Rashkov, Pavel Stanchev, Bilyana Stoyanovska-Elencheva, Zhivko Tagarev, Theodora
Temelkova-Kurktschieva, Svetla Vasileva, Mariana Yoncheva-Mihaylova
Canada: Paul Barre, Brian Carlson, James Conway, Serge Cournoyer, Richard Dumas, Sameh Fikry, Richard Goluch, Pavel Hamet, Randolph Hart, Sam Henein, Joanne Liutkus,
Francois Madore, Valdemar Martinho, Giuseppe Mazza, Philip McFarlane, Dennis O’ Keefe,
Sean Peterson, Daniel Schwartz, Daniel Shu, Andrew Steele, Guy Tellier, Karthik
Tennankore, Sheldon Tobe, George Tsoukas, Richard Tytus, Louise Vitou, Michael Walsh,
Stanley Weisnagel, Igor Wilderman, Jean-Francois Yale
Chile: Jorge Cobos, Juan Godoy, Fernando González, Sergio Lobos, Juan Carlos Palma, Juan Carlos Prieto, Eliana Reyes, Carmen Romero, Victor Saavedra, Mario Vega
China: Ruifang Bu, Hanqing Cai, Nan Chen, Qinkai Chen, Dejun Chen, Jinluo Cheng, Youping Dong, Junwu Dong, Tianjun Guan, Chuanming Hao, Wen Huang, Fangfang Jiang,
Minxiang Lei, Ling Li, Zhonghe Li, Xuemei Li, Jingmei Li, Yan Li, Xinling Liang, Bo Liang,
Fang Liu, Yinghong Liu, Yuantao Liu, Zhihong Liu, Gang Long, Guoyuan Lu, Weiping Lu,
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Yibing Lu, Ping Luo, Jianhua Ma, Zhaohui Mo, Jianying Niu, Ai Peng, Jiansong Shen, Feixia
Shen, Bingyin Shi, Qing Su, Zhuxing Sun, Shuifu Tang, Nanwei Tong, Hao Wang, Xinjun
Wang, Lihua Wang, Guixia Wang, Jianqin Wang, Yangang Wang, Li Wang, Jiali Wei,
Tianfeng Wu, Chaoqing Wu, Changying Xing, Fei Xiong, Xudong Xu, Ning Xu, Tiekun Yan,
Jinkui Yang, Aiping Yin, Longyi Zeng, Hao Zhang, Yanlin Zhang, Ying Zhang, Wenjing Zhao,
Zhiquan Zhao, Hongguang Zheng, Ling Zhong, Dalong Zhu, Yongze Zhuang
Colombia: Clara Arango, Sandra Barrera, Nelly Beltrán López, Diego Benitez, Guillermo Blanco, Andrés Cadena, Julian Coronel, Carlos Cure, Carlos Durán, Alexander González,
Gustavo Guzmán, Eric Hernández, Jaime Ibarra, Carlos Jaramillo, Nicolás Jaramillo, William
Kattah, Dora Molina, Gregorio Sánchez, Mónica Terront, Freddy Trujillo, Miguel Urina,
Ruben Vargas, Iván Villegas, Hernán Yupanqui
Czech Republic: Dino Alferi, Michal Brada, Jiri Brezina, Petr Bucek, Tomas Edelsberger, Drahomira Gulakova, Jitka Hasalova Zapletalova, Olga Hola, Lucie Hornova, Jana Houdova,
Helena Hrmova, David Karasek, Sarka Kopecka, Richard Kovar, Eva Krcova, Jiri Kuchar,
Vlasta Kutejova, Hana Lubanda, Ivo Matyasek, Magdalena Mokrejsova, Libor Okenka,
Martin Prazny, Jiri Pumprla, Pavel Tomanek
Denmark: Jesper Bech, Jens Faber, Gunnar Gislason, Jørgen Hangaard, Grzegorz Jaroslaw Pacyk, Claus Juhl, Thure Krarup, Morten Lindhardt, Sten Madsbad, Joan Nielsen,
Ulrik Pedersen-Bjergaard, Per Poulsen, Ole Rasmussen, Peter Rossing, Karoline
Schousboe
Finland: Mikko Honkasalo, Mikko Honkasalo, Kari Humaloja, Kristiina Kananen, Ilkka Kantola, Arvo Koistinen, Pirkko Korsoff, Jorma Lahtela, Sakari Nieminen, Tuomo Nieminen,
Karita Sadeharju, Jorma Strand, Sakari Sulosaari
France: Bertrand Cariou, François Chantrel, Sylvaine Clavel, Christian Combe, Jean-Pierre Fauvel, Karim Gallouj, Didier Gouet, Bruno Guerci, Dominique Guerrot, Maryvonne
Hourmant, Alexandre Klein, Christophe Mariat, Michel Marre, Rafik Mesbah, Yannick Le
Meur, Arnaud Monier, Olivier Moranne, Pierre Serusclat, Benoit Vendrely, Bruno Verges,
Philippe Zaoui
Germany: Christoph Axthelm, Andreas Bergmann, Andreas L. Birkenfeld, Hermann Braun, Klaus Busch, Christel Contzen, Stefan Degenhardt, Karl Derwahl, Thomas Giebel, Andreas
Hagenow, Hermann Haller, Christoph Hasslacher, Thomas Horacek, Wolfgang Jungmair,
Christof Kloos, Thorsten Koch, Thilo Krüger, Anja Mühlfeld, Joachim Müller, Andreas
Pfützner, Frank Pistrosch, Ludger Rose, Lars Rump, Volker Schettler, Ingolf Schiefke, Heike
Schlichthaar, Bernd Schröppel, Thomas Schürholz, Helena Sigal, Lutz Stemler, Georg
Strack, Heidrun Täschner, Nicole Toursarkissian, Diethelm Tschöpe, Achim Ulmer, Markus
van der Giet, Christoph Wanner, Bernhard R. Winkelmann
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Greece: Ioannis Boletis, Erifili Hatziagelaki, Ioannis Ioannidis, Theodora Kounadi, Ioanna Makriniotou, Dorothea Papadopoulou, Aikaterini Papagianni, Ploumis Passadakis, Ioannis
Stefanidis
Hong Kong: Tai Pang Ip, Paul Lee, On Yan Andrea Luk, Angela Wang, Vincent Yeung Hungary: Dora Bajcsi, Peter Danos, Eleonora Harcsa, Szilvia Kazup, Katalin Keltai, Robert Kirschner, Julianna Kiss, Laszlo Kovacs, Beata Lamboy, Botond Literati-Nagy, Margit
Mileder, Laszlo Nagy, Ebrahim Noori, Gabor Nyirati, Gizella Petro, Karoly Schneider, Albert
Szocs, Szilard Vasas, Krisztina Wudi, Zsolt Zilahi, Marianna Zsom
Ireland: Joe Eustace, John Holian, Donal Reddan, Yvonne O’ Meara Israel: Rosane Abramof Ness, Faiad Adawi, Zaher Armaly, Shaul Atar, Sydney Ben Chetrit, Noa Berar Yanay, Gil Chernin, Mahmud Darawsha, Shai Efrati, Mazen Elias, Evgeny Farber,
Mariela Glandt, Ehud Grossman, Majdi Halabi, Khaled Khazim, Idit Liberty, Ofri Mosenzon,
Assy Nimer, Doron Schwartz, Julio Wainstein, Yoram Yagil, Robert Zukermann
Italy: Angelo Avogaro, Giovanni Giorgio Battaglia, Enzo Bonora, Carlo Antonio Bossi, Paolo Calabrò, Franco Luigi Cavalot, Roberto Cimino, Mario Gennaro Cozzolino, Enrico Fiaccadori,
Paolo Fiorina, Carlo Bruno Giorda, Maria Cristina Gregorini, Gaetano La Manna, Davide
Carlo Maggi, Antonello Pani, Norberto Perico, PierMarco Piatti, Antonio Pisani, Paola
Ponzani, Gennaro Santorelli, Domenico Santoro, Giancarlo Tonolo, Roberto Trevisan, Anna
Maria Veronelli
Japan: Hideo Araki, Osamu Ebisui, Naruhiro Fujita, Ryuichi Furuya, Yoshiyuki Hamamoto, Masahiro Hatazaki, Terumasa Hayashi, Takayuki Higashi, Yoshihide Hirohata, Shuji
Horinouchi, Masayuki Inagaki, Masao Ishii, Tamayo Ishiko, Hideaki Jinnouchi, Hidetoshi
Kanai, Daisuke Kanda, Hideo Kanehara, Masayuki Kashima, Kiyoe Kato, Takeshi Katsuki,
Katsunori Kawamitsu, Satsuki Kawasaki, Fumi Kikuchi, Hidetoshi Kikuchi, Kunihisa
Kobayashi, Junko Koide, Miyuki Kubota, Yoshiro Kusano, Hajime Maeda, Sunao
Matsubayashi, Kazunari Matsumoto, Yasuto Matsuo, Naoki Matsuoka, Hiroaki Miyaoka,
Satoshi Murao, Mikihiro Nakayama, Jun Nakazawa, Takashi Nomiyama, Masayuki Noritake,
Takayuki Ogiwara, Hiroshi Ohashi, Hideki Okamoto, Takeshi Osonoi, Nobuhiro Sasaki, Taiji
Sekigami, Taro Shibasaki, Hirotaka Shibata, Junji Shinoda, Hiroshi Sobajima, Kazuya
Sugitatsu, Toshiyuki Sugiura, Toru Sugiyama, Daisuke Suzuki, Hiroyuki Suzuki, Masaaki
Suzuki, Asami Takeda, Asami Tanaka, Seiichi Tanaka, Izumi Tsunematsu, Makoto Ujihara,
Daishiro Yamada, Masayo Yamada, Kazuo Yamagata, Ken Yamakawa, Fumiko Yamakawa,
Yoshimitsu Yamasaki, Yuko Yambe, Taihei Yanagida, Hidekatsu Yanai, Tetsuyuki Yasuda
Lithuania: Dovile Kriauciuniene, Jurate Lasiene, Antanas Navickas, Lina Radzeviciene, Egle Urbanaviciene, Gediminas Urbonas, Audrone Velaviciene
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Malaysia: Rohana Abd Ghani, Nor Azizah Aziz, Li Yuan Lee, Chek Loong Loh, Norhaliza Mohd Ali, Nurain Mohd Noor, Nik Nur Fatnoon Nik Ahmad, Jeyakantha Ratnasingam, Wan
Hasnul Halimi Bin Wan Hasan, Wan Mohd Izani Wan Mohamed
Mexico: Sandro Avila Pardo, Miriam Bastidas Adrian, Alfredo Chew Wong, Jorge Escobedo de la Peña, Guillermo Fanghänel Salmón, Guillermo González Gálvez, Ramiro Gutiérrez
Ochoa, Saúl Irizar Santana, Magdalena Madero Rovalo, Gustavo Méndez Machado, Luis
Nevarez Ruiz, Denisse Ramos Ibarra, Gabriel Ramos López, Leobardo Sauque Reyna,
Gustavo Solache Ortiz, Rafael Valdez Ortiz, Juan Villagordoa Mesa
Netherlands: R.C. Bakker, J.N.M. Barendregt, A.H. Boonstra, Willem Bos, C.B. Brouwer, M. van Buren, Ron Gansevoort, Adriaan Kooy, Marielle Krekels, Ruud J.M. van Leendert, Louis
A.G. Lieverse, P.T. Luik, E. Lars Penne, Peter Smak Gregoor, Liffert Vogt
New Zealand: John Baker, Veronica Crawford, Rick Cutfield, Peter Dunn, Jeremy Krebs, Kingsley Nirmalaraj, Russell Scott, Nine Smuts
Norway: Erik Eriksen, Trine Finnes, Hans Høivik, Thomas Karlsson, Peter Scott Munk, Maria Radtke, Knut Risberg, Jan Rocke, Leidulv Solnør, Aud-Eldrid Stenehjem, Anne-Beathe
Tafjord
Philippines: Glenda Pamugas, Araceli Panelo, Ronald Perez, Maribel Tanque, Louie Tirador, Michael Villa
Poland: Patrycja Butrymowicz, Kazimierz Ciechanowski, Grazyna Cieslik, Edward Franek, Janusz Gumprecht, Michal Hoffmann, Jolanta Krzykowska, Ilona Kurnatowska, Katarzyna
Landa, Adam Madrzejewski, Katarzyna Madziarska, Stanislaw Mazur, Piotr Napora, Michal
Nowicki, Anna Ocicka-Kozakiewicz, Barbara Rewerska, Teresa Rusicka, Jan Ruxer, Ewa
Skokowska, Andrzej Stankiewicz, Tomasz Stompor, Agnieszka Tiuryn-Petrulewicz,
Katarzyna Wasilewska, Bogna Wierusz-Wysocka, Renata Wnetrzak-Michalska
Portugal: Edgar Almeida, Rosa Ballesteros, Carlos Barreto, Idalina Beirao, Rita Birne, Cesar Esteves, Jose Guia, Susana Heitor, Olinda Marques, Pedro Melo, Fernando Nolasco, Amalia
Pereira, Cristina Roque, Francisco Rosario, Gil Silva, Ana Silva, Fernando Teixeira e Costa,
Ana Vila Lobos
Puerto Rico: Gregorio Cortes-Maisonet, Amaury Roman-Miranda Romania: Adrian Albota, Cornelia Bala, Hortensia Barbonta, Elena Caceaune, Doina Catrinoui, Ciprian Constantin, Adriana Dumitrescu, Nicoleta Mindrescu, Cristina Mistode,
Gabriela Negrisanu, Adriana Onaca, Silvia Paveliu, Ella Pintilei, Lavinia Pop, Amorin Popa,
Alexandrina Popescu, Gabriela Radulian, Iosif Szilagyi, Liana Turcu, Georgeta Vacaru,
Adrian Vlad
Russia: Mikhail Antsiferov, Mikhail Arkhipov, Andrey Babkin, Olga Barbarash, Vitaliy Baranov, Elena Chernyavskaya, Arkadiy Demko, Alexander Dreval, Anton Edin, Polina
Ermakova, Valentin Fadeev, Albert Galyavich, Leyla Gaysina, Ivan Gordeev, Irina Ipatko,
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Marina Kalashnikova, Yuriy Khalimov, Vadim Klimontov, Zhanna Kobalava, Elena
Kosmacheva, Natalya Koziolova, Lyudmila Kvitkova Sergey Levashov, Roman Libis,
Vyacheslav Marasaev, Natalia Malykh, Vladimir Martynenko, Sofya Malyutina, Imad Merai,
Ashot Mkrtumyan, Galina Nechaeva, Nina Petunina, Shamil Palyutin, Leonid Pimenov, Elena
Rechkova, Tatyana Rodionova, Oksana Rymar, Ruslan Sardinov, Olga Semenova,
Alexander Sherenkov, Oleg Solovev, Elena Smolyarchuk, Leonid Strongin, Olga Ukhanova,
Nadezhda Verlan, Natalya Vorokhobina, Davyd Yakhontov, Sergey Yakushin, Elena
Zakharova, Alsu Zalevskaya, Olga Zanozina, Elena Zhdanova, Larisa Zhukova, Tatyana
Zykova
Singapore: Chee Fang Sum, Sufi Muhummad Suhail, Ru San Tan, Anantharaman Vathsala, Edmund Wong
Slovakia: Jana Babikova, Ingrid Buganova, Andrej Dzupina, Zuzana Ochodnicka, Dalibor Sosovec, Denisa Spodniakova
South Africa: Fayzal Ahmed, Aslam Amod, Sindeep Bhana, Larry Distiller, Dirkie Jansen van Rensburg, Mukesh Joshi, Shaifali Joshi, Deepak Lakha, Essack Mitha, Gracjan
Podgorski, Naresh Ranjith, Brian Rayner, Paul Rheeder, Mohamed Sarvan, Mary Seeber,
Heidi Siebert, Mohammed Tayob, Julien Trokis, Dorothea Urbach, Louis van Zyl
South Korea: Bum-Soon Choi, Moon Gi Choi, ChoonHee Chung, YouCheol Hwang, ChongHwa Kim, InJoo Kim, JaeHyeon Kim, SinGon Kim, SungGyun Kim, Tae Hee Kim,
WooJe Lee, ByungWan Lee, Kang Wook Lee, Kook-Hwan Oh, Ji Eun Oh, Yun Kyu Oh,
Dong-Jin Oh, Junbeom Park, Seok Joon Shin, Su-Ah Sung, Jae Myung Yu
Spain: Irene Agraz, Francisco Javier Ampudia, Hanane Bouarich, Francesca Calero, Cristina Castro, Secundino Cigarrán Guldris, Josep Cruzado Garrit, Fernando de Álvaro,
Josep Galcerán, Olga González Albarrán, Julio Hernández Jaras, Meritxell Ibernón,
Francisco Martínez Deben, Mª Dolores Martínez Esteban, José María Pascual Izuel, Judith
Martins, Juan Mediavilla, Alfredo Michán, Julio Pascual Santos, Esteban Poch, Manuel
Polaina Rusillo, Carlos Sánchez Juan, Rafael Santamaría Olmo, José Julián Segura de la
Morena, Alfonso Soto, Maribel Troya
Sweden: Annette Bruchfeld, Dan Curiac, Ken Eliasson, Malin Frank, Gregor Guron, Olof Hellberg, Margareta Hellgren, Hans Larnefeldt, Carl-Johan Lindholm, Magnus Löndahl, Erik
Rein-Hedin, Inga Soveri, Jonas Spaak, Bengt-Olov Tengmark
Switzerland: Daniel Ackermann, Stefan Bilz, Michel Burnier, Christian Forster, Stefan Kalbermatter, Andreas Kistler, Antoinette Pechère-Bertschi, Bernd Schultes
Taiwan: Chiz-Tzung Chang, Cheng-Chieh Hung, Ju-Ying Jiang, Chien-Te Lee, Shuei-Liong Lin, Der-Cherng Tarng, Shih-Te Tu, Mai-Szu Wu, Ming-Ju Wu
Thailand: Chaicharn Deerochanawong, Chagriya Kitiyakara, Vuddhidej Ophascharoensuk, Chatlert Pongchaiyakul, Bancha Satirapoj
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Turkey: Necmi Eren, Ibrahim Gul, Okan Gulel, Ismail Kocyigit, Abdulbaki Kumbasar, Idris Sahin, Ramazan Sari, Burak Sayin, Talat Tavli, Sedat Ustundag, Yavuz Yenicerioglu
Ukraine: Iryna Bondarets, Volodymyr Botsyurko, Viktoriia Chernikova, Oleksandra Donets, Ivan Fushtey, Mariia Grachova, Anna Isayeva, Dmytro Kogut, Julia Komisarenko, Nonna
Kravchun, Kateryna Malyar, Borys Mankovsky, Liliya Martynyuk, Vitaliy Maslyanko, Halyna
Myshanych, Larysa Pererva, Nataliia Pertseva, Oleksandr Serhiyenko, Ivan Smirnov, Liubov
Sokolova, Vasyl Stryzhak, Maryna Vlasenko
United Kingdom: Ahmad AbouSaleh, Jonathan Barratt, Cuong Dang, Hassan Kahal, Adam Kirk, Anne Kilvert, Sui Phi Kon, Kieran McCafferty, Dipesh Patel, Sam Rice, Arutchelvam
Vijayaraman, Yuk-ki Wong, Martin Gibson, Mona Wahba, Reza Zaidi
United States: Idalia Acosta, Atoya Adams, Sharon Adler, Dilawar Ajani, Slamat Ali, Radica Alicic, Amer Al-Karadsheh, Sreedhara Alla, D. Allison, Nabil Andrawis, Ahmed Arif, Ahmed
Awad, Masoud Azizad, Michael Bahrami, Shweta Bansal, Steven Barag, Ahmad Barakzoy,
Mark Barney, Joshua Barzilay, Khalid Bashir, Jose Bautista, Srinivasan Beddhu, Diogo Belo,
Sabrina Benjamin, Ramin Berenji, Anuj Bhargava, Jose Birriel, Stephen Brietzke, Frank
Brosius, Osvaldo Brusco, Anna Burgner, Robert Busch, Rafael Canadas, Maria Caramori,
Jose Cardona, Christopher Case, Humberto Cruz, Ramprasad Dandillaya, Dalia Dawoud,
Zia Din, Bradley Dixon, Ankur Doshi, James Drakakis, Mahfouz El Shahawy, Ashraf El-
Meanawy, Mohammed El-Shahawy, John Evans, George Fadda, Umar Farooq, Roland
Fernando, Raymond Fink, Brian First, David Fitz-Patrick, John Flack, Patrick Fluck, Leon
Fogelfeld, Vivian Fonseca, Juan Frias, Claude Galphin, Luis Garcia-Mayol, Gary Goldstein,
Edgar Gonzalez, Francisco Gonzalez-Abreu, Ashwini Gore, David Grant, Violet Habwe,
Maxine Hamilton, Jamal Hammoud, Stuart Handelsman, Israel Hartman, Glenn Heigerick,
Andrew Henry, German Hernandez, Carlos Hernandez-Cassis, Carlos Herrera, Joachim
Hertel, Wenyu Huang, Rogelio Iglesias, Ali Iranmanesh, Timothy Jackson, Mahendra Jain,
Kenneth Jamerson, Karen Johnson, Eric Judd, Joshua Kaplan, Zeid Kayali, Bobby Khan,
Muhammad Khan, Sourabh Kharait, M. Sue Kirkman, Nelson Kopyt, Wayne Kotzker, Csaba
Kovesdy, Camil Kreit, Arvind Krishna, Saeed Kronfli, Keung Lee, Derek LeJeune, Brenda
Lemus, Carlos Leon-Forero, Douglas Linfert, Henry Lora, Alexander Lurie, Geetha
Maddukuri, Alexander Magno, Louis Maletz, Sreedhar Mandayam, Mariana Markell, Ronald
Mayfield, Caroline Mbogua, Dierdre McMullen, Carl Meisner, Stephen Minton, Bharat
Mocherla, Rajesh Mohandas, Manuel Montero, Moustafa Moustafa, Salil Nadkarni, Samer
Nakhle, Jesus Navarro, Nilda Neyra, Romanita Nica, Philip Nicol, Paul Norwood, Visal
Numrungroad, Richard O’ Donovan, A. Odugbesan, Jorge Paoli-Bruno, Samir Parikh,
Rakesh Patel, Aldo Peixoto, Pablo Pergola, Alan Perlman, Karlton Pettis, Roberto Pisoni,
Mirela Ponduchi, Jorge Posada, Sharma Prabhakar, Jai Radhakrishnan, Mahboob Rahman,
Rupesh Raina, Anjay Rastogi, Efrain Reisin, Marc Rendell, David Robertson, Michael Rocco,
13
Hugo Romeu, Sylvia Rosas, Jack Rosenfeld, Dennis Ross, Jeffrey Rothman, Lance
Rudolph, Yusuf Ruhullah, Gary Ruoff, Jeffrey Ryu, Mandeep Sahani, Ramin Sam, Garfield
Samuels, William Sanchez, Vladimir Santos, Scott Satko, Sanjeev Saxena, David Scott,
Gilberto Seco, Melvin Seek, Harvey Serota, Tariq Shafi, Nauman Shahid, Michael Shanik,
Santosh Sharma, Arjun Sinha, James Smelser, Mark Smith, Kyaw Soe, Richard Solomon,
Eugene Soroka, Joseph Soufer, Bruce Spinowitz, Leslie Spry, Rosa Suarez, Bala
Subramanian, Harold Szerlip, Aparna Tamirisa, Stephen Thomson, Tuan-Huy Tran, Richard
Treger, Gretel Trullenque, Thomas Turk, Guillermo Umpierrez, Daniel Urbach, Martin
Valdes, Shujauddin Valika, Damaris Vega, Peter Weissman, Adam Whaley-Connell,
Jonathan Winston, Jonathan Wise, Alan Wynne, Steven Zeig
Vietnam: Phuong Chu, Lam Van Hoang, Tran Khanh, Nguyen Thi Phi Nga, Pham Nguyen Son, Lan Phuong Tran.
14
Inclusion and exclusion criteria
Inclusion criteria
1. Male or female patient aged ≥18 years
2. Patient with type 2 diabetes (T2D) as defined by the American Diabetes Association in
the 2010 Standards of Medical Care in Diabetes
3. Patient with a diagnosis of chronic kidney disease (CKD) based on meeting persistent
albuminuria (≥2 out of 3 morning void samples taken on consecutive days assessed by
the central laboratory) and estimated glomerular filtration rate (eGFR – calculated by the
central laboratory using the Chronic Kidney Disease Epidemiology Collaboration formula
with adjustment for race in Black/African American patients1) criteria at the run-in and
screening visits – specifically, either:
i. Persistent moderately elevated (‘high’) albuminuria (defined as urine albumin-to-
creatinine ratio [UACR] ≥30–
15
• Glycated hemoglobin >12% at the run-in visit or the screening visit
• Uncontrolled arterial hypertension with mean sitting systolic blood pressure (SBP)
≥170 mmHg or mean sitting diastolic blood pressure (DBP) ≥110 mmHg at the run-in
visit or mean sitting SBP ≥160 mmHg or mean sitting DBP ≥100 mmHg at the
screening visit
• A mean SBP
16
Outcome definitions
Kidney outcome events
Kidney failure
Kidney failure was defined as end-stage kidney disease (ESKD) or a sustained estimated
glomerular filtration rate (eGFR)
17
had to be collected ≥4 weeks after the initial eGFR measurement showing a decrease in
eGFR by ≥40%/≥57%. The baseline eGFR value was the eGFR from visit 1 (unless this
value was missing, in which case the last value measured prior to randomization was used
as the baseline value). The date of onset of sustained decrease in eGFR (≥40%/≥57%)
compared with baseline was the date of the initial sample exceeding the threshold.
Cardiovascular endpoint events
Acute myocardial infarction
Acute myocardial infarction (MI) was defined based on detection of rise and/or fall in cardiac
biomarkers (preferably cardiac troponin [cTn]) with at ≥1 value above the 99th percentile of
the upper reference limit [URL] or ≥1 value exceeding the local reference limit for non-highly
sensitive methods), together with evidence of myocardial ischemia, including ≥1 of the
following:
• Symptoms of ischemia (e.g., discomfort in the chest, upper extremity, mandibular or
epigastric region lasting >20 minutes that was usually diffuse and may have been
accompanied by diaphoresis, nausea, or syncope. Atypical symptoms of ischemia
included palpitation or cardiac arrest)
• Electrocardiogram (ECG) changes indicative of new ischemia (new ST-T changes or
new left bundle branch block [LBBB])
• Development of pathological Q waves in the ECG
• Imaging evidence of new loss of viable myocardium or new regional wall motion
abnormality
• Identification of an intracoronary thrombus by angiography
Percutaneous coronary intervention (PCI)-related MI was arbitrarily defined by elevation of
cTn values (>5 x 99th percentile URL) in patients with normal baseline values (≤99th
percentile URL) or a rise of cTn values >20% if the baseline values were elevated and were
stable or falling. In addition, either (i) symptoms suggestive of myocardial ischemia, or (ii)
new ischemic ECG changes, or (iii) angiographic findings consistent with a procedural
complication, or (iv) imaging demonstration of new loss of viable myocardium or new regional
wall motion abnormality, were required.
Coronary artery bypass grafting (CABG)-related MI was arbitrarily defined by elevation of
cardiac biomarker values (>10 x 99th percentile URL) in patients with normal baseline cTn
values (≤99th percentile URL). In addition, either (i) new pathological Q waves or new LBBB,
or (ii) angiographic documented new graft or new native coronary artery occlusion, or (iii)
18
imaging evidence of new loss of viable myocardium or new regional wall motion abnormality,
were required.
Stroke
Stroke was defined as an acute episode of focal or global neurological dysfunction caused by
brain, spinal cord, or retinal vascular injury as a result of hemorrhage or infarction, with
symptom duration of ≥24 hours. Episodes lasting
19
ii. Laboratory evidence of new or worsening HF, including the following, if
obtained within 24 hours of presentation:
- Increased B-type natriuretic peptide (BNP) / N-terminal pro-BNP (NT-pro
BNP) or mid-regional pro-atrial natriuretic peptide (MP-proANP)
concentrations consistent with decompensation of HF. In patients who
had chronically elevated natriuretic peptides, levels had to be significantly
increased relative to baseline
- Radiological evidence of pulmonary congestion
- Non-invasive or invasive diagnostic evidence of clinically significant
elevated left- or right-sided ventricular filling pressure or low cardiac
output
• The patient received initiation or intensification of HF-specific treatment, including ≥1
of the following:
i. Intravenous diuretic, inotrope, or vasodilator therapy
ii. Mechanical or surgical intervention, including:
- Mechanical circulatory support (e.g., intra–aortic balloon pump, ventricular
assist device)
- Mechanical fluid removal (e.g., ultrafiltration, hemofiltration, dialysis)
Causes of death
Causes of death were classified into three categories – cardiovascular (CV) death, renal
death or non-CV and non-renal death.
Cardiovascular death
Events that were classified as CV death included the following: (1) death due to acute MI; (2)
sudden cardiac death; (3) undetermined death; (4) death due to HF; (5) death due to stroke;
(6) death due to CV procedures; or (7) death due to other CV causes.
(1) Death due to acute myocardial infarction Death due to acute MI referred to a death by any CV mechanism (e.g. arrhythmia, sudden
death, HF, stroke, pulmonary embolus, peripheral artery disease) within 30 days after an MI
and related to the immediate consequences of the MI, such as progressive HF or recalcitrant
arrhythmia. Death which resulted from a procedure to treat a MI (including PCI and CABG),
or to treat a complication resulting from MI was also considered death due to acute MI.
Any death that resulted from an elective coronary procedure to treat myocardial ischemia
(i.e., chronic stable angina) or any death due to an MI that occurs as a direct consequence of
a CV investigation/procedure/operation was considered as a death due to a CV procedure.
20
(2) Sudden cardiac death Sudden cardiac death referred to any death that occurred unexpectedly, not following an
acute MI, (i.e., not within 30 days of an acute MI) and included the following deaths:
• Death witnessed and instantaneous without new or worsening symptoms
• Death witnessed within 1 hour of the onset of new or worsening cardiac symptoms,
unless the symptoms suggest acute MI
• Death witnessed and attributed to an identified arrhythmia (e.g., captured on an
electrocardiographic [ECG] recording, witnessed on a monitor, or unwitnessed but
found on implantable cardioverter-defibrillator review)
• Death after unsuccessful resuscitation from cardiac arrest
• Death after successful resuscitation from cardiac arrest and without identification of a
specific etiology
• Unwitnessed death in a patient seen alive and clinically stable ≤24 hours prior to
being found dead without any evidence supporting a specific non-CV cause of death
(3) Undetermined death Any death occurring in a patient NOT observed alive within 24 hours of death and without
any other likely cause of death, was recorded as undetermined. All patients who died of
undetermined causes were considered by default as CV death because of the patient
population and competing causes of death.
(4) Death due to heart failure Death due to HF or cardiogenic shock referred to a death associated with clinically
worsening symptoms and/or signs of HF without evidence of another cause which did NOT
occur following an acute MI. Deaths due to HF could have various etiologies, including single
or recurrent MIs (late effect, i.e., >30 days), ischemic or non-ischemic cardiomyopathy,
hypertension, or valvular disease. Sudden deaths occurring during an admission for
worsening HF, as well as death from progressive HF or cardiogenic shock, following
implantation of a mechanical assist device were also classified as death due to HF if there
was no evidence of acute MI or stroke in the previous 30 days.
(5) Death due to stroke Any death that occurred within 30 days after a stroke was classified as death due to stroke,
whether a direct consequence of the stroke or a complication of the stroke.
21
(6) Death due to cardiovascular procedures Any death occurring within 30 days of a CV procedure (as a result of complications of the CV
procedure) was classified as death due to CV procedures.
(7) Death due to other cardiovascular causes Any CV death that was not included in the above categories was classified as CV death due
to other causes (e.g. CV hemorrhage, pulmonary embolism or peripheral arterial
disease). Non-stroke intracranial hemorrhage, non-procedural or non-traumatic vascular
rupture (e.g. aortic rupture) or hemorrhage causing cardiac tamponade were considered CV
hemorrhages. Any other bleeding was considered as non-CV.
Renal death
Events were classified as renal death if: (1) the patient died; (2) RRT had not been initiated
despite being clinically indicated; and (3) there was no other likely cause of death. If a patient
was initially denied RRT for a specific reason (e.g. metastatic cancer, shock or sepsis) then
another more proximal cause of death was identified.
Non-cardiovascular and non-renal death
Events were classified as non-CV and non-renal deaths if they were not thought to be due to
a CV or renal cause. Non-CV and non-renal deaths were categorized as infection,
malignancy or specific other causes
22
Additional methods
Estimation of glomerular filtration rate for Black/African American patients:
The CKD-EPI equation used for calculation of estimated glomerular filtration rate (eGFR) in
FIDELIO-DKD incorporates an adjustment factor for Black/African American patients
compared to patients of other races.1 This leads to a higher eGFR for Black/African American
patients when compared to non-Black patients at a given level of serum creatinine. The
FIDELIO-DKD trial leadership acknowledges that many institutions have recently started to
remove this adjustment. For the purposes of the FIDELIO-DKD analysis, because the
proportion of randomized Black/African American patients was small and balanced between
treatment groups, no additional analysis without the adjustment factor was performed.
Serum potassium monitoring and management of hyperkalemia
Assessment of serum potassium was scheduled for all study visits, and was performed at
both local and central laboratories. In previous studies, falsely elevated serum potassium
values have been observed in centrally analyzed samples, because of sample handling and
extended transport time to the central laboratory. Therefore, dose adjustments of study drug
were based on local laboratory results, and were as follows:
• First sample:
- Serum potassium ≤4.8 mEq/L: if on 10 mg once-daily (od) dose of study drug,
uptitrate to 20 mg od. If on 20 mg od, continue on same dose
- Serum potassium 4.9–5.5 mEq/L: continue on same dose of study drug
- Serum potassium >5.5 mEq/L: withhold study drug and recheck potassium within
72 hours
• Second and subsequent samples:
- Serum potassium ≤5.0 mEq/L: re-start study drug at 10 mg od dose
- Serum potassium >5.0 mEq/L: continue to withhold study drug and monitor serum
potassium. Only restart study drug (at the 10 mg od dose) once serum potassium
is ≤5.0 mEq/L
Further management of hyperkalemia, e.g. use of potassium-lowering agents, was at the
investigator’s discretion, based on standard local guidelines. Permanent discontinuation of
study drug was recommended if a patient experienced a recurrent hyperkalemia event soon
after a previous hyperkalemia event with interruption of study drug, if there was no
explanation for the recurring hyperkalemia event other than intake of study drug.
23
Patients maintained their usual diet throughout the study and were not given any specific
advice on dietary potassium restrictions. Use of potassium supplements was permitted
during the study – investigators were advised to closely monitor potassium levels, to adjust
potassium supplement dosing based on potassium values, and to discontinue potassium
supplements once potassium was within the normal range. Potassium-lowering agents were
also permitted during the study.
Statistical analyses
Mean dosing of study drug
Mean dose of study drug was the mean dose from randomization until last intake of study
drug, including interruptions (where dose imputed was 0 mg).
Subgroup analyses of the primary outcome
For subgroup analyses, hazard ratios were derived from stratified Cox proportional hazards
models, including treatment subgroup and a subgroup by treatment interaction term as fixed
effects.
Number needed to treat estimation
The number needed to treat to prevent one event during 3 years was calculated as the
reciprocal of the Kaplan–Meier estimates for the between-group difference in the cumulative
incidence probability at 3 years.
Change in urine albumin-to-creatinine ratio and estimated glomerular filtration rate
over time
The secondary efficacy outcome of change in UACR from baseline to month 4 was tested
with an analysis of covariance (ANCOVA) model adjusting for treatment group, stratification
factors and baseline value. Changes in UACR and eGFR over time were analyzed with
mixed models, assuming an unstructured covariance matrix and adjusting for treatment
group, stratification factors, visit, interaction between treatment group and visit, baseline
value and interaction between baseline value and visit.
Estimated glomerular filtration rate slope analyses
The annualized change in eGFR from month 4 to the permanent discontinuation or end of
study visit was evaluated by means of an ANCOVA model including baseline eGFR,
treatment group and the stratification factors as covariates. All available eGFR
measurements were included in the analyses, irrespective of discontinuation of study
treatment.
24
Critical Good Clinical Practice violations A total of 60 patients were prospectively excluded from all analyses in the study due to
critical Good Clinical Practice violations. This affected one site in the US that was
subsequently closed during the conduct of the trial leading to the exclusion of 29 patients. In
addition, during trial conduct it was detected that several patients were randomized
simultaneously at multiple trial sites in the same locality in Florida, USA. This led to the
exclusion of a total of 31 patient IDs.
25
Tipping point analysis of primary efficacy endpoint The potential impact of missing data was investigated by means of a tipping point analysis.
The tipping point shows how much higher the hazard rate of the last timepoint with complete
information on the primary endpoint would need to be for subjects in the finerenone arm
without complete endpoint follow-up (as indicated by the inflation factor) so that statistical
significance is lost. Further details on the tipping point analysis can be found in the Statistical
Analysis Plan.
With an inflation factor of 0, the hazard ratio (HR) was 0.83 (96.72% confidence interval [CI]
0.73–0.94). The tipping point was reached using an inflation factor of 80% because the upper
limit of the multiple imputation HR was above 1.0 (HR=0.89, 96.72% CI 0.78–1.01) (see
Table S5 and Figure S4).
This confirms a robust outcome, because the treatment difference is still significant for an
inflation factor of 70%, where the mean number of imputed events in the finerenone arm of
95.5 clearly exceeds the mean number of imputed events in the placebo arm of 69.6.
26
Supplementary figures
Figure S1. Study design of FIDELIO-DKD
*The purpose of the mandatory run-in period was to allow for optimization of participant standard of care medical therapies. This included ensuring that a
patient was pretreated with a maximally tolerated labelled dose of either an ACEi or an ARB (preferably without dose adjustments or switching to a different
ACEi or ARB) for >4 weeks prior to the Screening visit †Two prespecified recruitment caps closed per region limited the randomization of: (1) patients with moderately elevated albuminuria and diabetic retinopathy
(to approximately 10% of all randomized patients); and (2) patients with severely elevated albuminuria and an eGFR 60–
27
‡Randomization was stratified by region (North America, Latin America, Europe, Asia or Other), eGFR category at screening visit (25–
28
Figure S2. Consort diagram
*The patient was considered as having completed the study if there was a contact with the patient after the end of study notification or if the
patient died
FAS, full analysis set; GCP, Good Clinical Practice
29
Figure S3. Primary composite renal outcome according to key prespecified subgroups
BMI, body mass index; CI, confidence interval; CV, cardiovascular; eGFR, estimated
glomerular filtration rate; GLP-1RA, glucagon like peptide-1 receptor agonist; HbA1c,
glycated hemoglobin; SBP, systolic blood pressure; SGLT-2, sodium glucose co-transporter-
2; UACR, urine albumin-to-creatinine ratio
30
Figure S4. Secondary outcomes
31
Panel A shows the key secondary outcome of time to first onset of cardiovascular death, non-fatal MI, non-fatal stroke, or hospitalization for
heart failure. Panel B shows the secondary outcome of death from any cause. Panel C shows hospitalization for any cause. Panel D shows time
to a sustained ≥57% decrease in eGFR from baseline
CI, confidence interval; eGFR, estimated glomerular filtration rate; MI, myocardial infarction
32
Figure S5. Tipping point analysis for the primary efficacy outcome
CI, confidence interval; HR, hazard ratio
33
Figure S6. Effects of finerenone and placebo on eGFR
Shown are the change from the baseline level in eGFR in the full-analysis set. Data are
least-squares mean ± 95% CI
CI, confidence interval; eGFR, estimated glomerular filtration rate; EoS, end of study; LS,
least-squares; PD, permanent discontinuation
34
Figure S7. Mean systolic blood pressure over time
Effects of finerenone and placebo on systolic blood pressure in the safety analysis set. Data
are mean ± standard deviation.
SBP, systolic blood pressure
35
Figure S8. Mean HbA1C over time
Effects of finerenone and placebo on HbA1c in the safety analysis set. Data are mean ±
standard deviation.
HbA1c, glycated hemoglobin
36
Figure S9. Mean body weight over time
Mean bodyweight over time in the safety analysis set. Data are mean ± standard deviation
37
Supplementary tables
Table S1. Baseline patient demographics, clinical characteristics and medications
Characteristic Finerenone (10 mg od or 20 mg od)
(N=2833)
Placebo (N=2841)
All patients (N=5674)
Age – no. (%) 65.4 (8.9) 65.7 (9.2) 65.6 ± 9.1
Male sex — no. (%) 1953 (68.9) 2030 (71.5) 3983 (70.2)
Race or ethnic group — no. (%)
White
Black/African American
Asian
Other
1777 (62.7)
140 (4.9)
717 (25.3)
199 (7.0)
1815 (63.9)
124 (4.4)
723 (25.4)
179 (6.3)
3592 (63.3)
264 (4.7)
1440 (25.4)
378 (6.7)
Geographic region — no. (%)
Europe
North America
Latin America
Asia
Other
1182 (41.7)
467 (16.5)
295 (10.4)
790 (27.9)
99 (3.5)
1176 (41.4)
477 (16.8)
298 (10.5)
789 (27.8)
101 (3.6)
2358 (41.6)
944 (16.6)
593 (10.5)
1579 (27.8)
200 (3.5)
Duration of diabetes duration — years 16.6 ± 8.8 16.6 ± 8.8 16.6 ± 8.8
HbA1c — % 7.7 ± 1.3 7.7 ± 1.4 7.7 ± 1.3
Body mass index — kg/m2 31.1 ± 6.0 31.1 ± 6.0 31.1 ± 6.0
38
Systolic blood pressure — mmHg 138.1 ± 14.3 138.0 ± 14.4 138.0 ± 14.4
Diastolic blood pressure — mmHg 75.8 ± 9.7 75.8 ± 9.7 75.8 ± 9.7
Smoking history — no. (%)
Never smoked
Former smoker
Current smoker
1375 (48.5)
1044 (36.9)
414 (14.6)
1371 (48.3)
1078 (37.9)
392 (13.8)
2746 (48.4)
2122 (37.4)
806 (14.2)
eGFR — mL/min/1.73 m2 44.4 ± 12.5 44.3 ± 12.6 44.3 ± 12.6
eGFR, mL/min/1.73 m2 — no. (%)
≥60
45 to
39
Coronary artery disease
Myocardial infarction
Peripheral arterial occlusive disease
Ischemic stroke
842 (29.7)
378 (13.3)
470 (16.6)
329 (11.6)
860 (30.3)
388 (13.7)
453 (15.9)
360 (12.7)
1702 (30.0)
766 (13.5)
923 (16.3)
689 (12.1)
Heart failure — no. (%) 195 (6.9) 241 (8.5) 436 (7.7)
Baseline medications Angiotensin-converting enzyme inhibitors — no. (%)* 950 (33.5) 992 (34.9) 1942 (34.2)
Angiotensin receptor blockers — no. (%)* 1879 (66.3) 1846 (65.0) 3725 (65.7)
β-blockers — no. (%) 1462 (51.6) 1506 (53.0) 2968 (52.3)
α-blocking agents — no. (%) 693 (24.5) 715 (25.2) 1408 (24.8) Calcium antagonists — no. (%) 1773 (62.6) 1812 (63.8) 3585 (63.2) Diuretics — no. (%)
Loop diuretics
Thiazide diuretics
1577 (55.7)
786 (27.7)
700 (24.7)
1637 (57.6)
833 (29.3)
655 (23.1)
3214 (56.6)
1619 (28.5)
1355 (23.9)
Statins — no. (%) 2105 (74.3) 2110 (74.3) 4215 (74.3)
Platelet aggregation inhibitors† — no. (%) 1633 (57.6) 1595 (56.1) 3228 (56.9) Potassium-lowering agents — no. (%)‡ 70 (2.5) 66 (2.3) 136 (2.4)
Glucose-lowering therapies — no. (%)
Insulin
Metformin
Sulfonylurea
Alpha-glucosidase inhibitor
DPP-4 inhibitors
2747 (97.0)
1843 (65.1)
1251 (44.2)
654 (23.1)
163 (5.8)
764 (27.0)
2777 (97.7)
1794 (63.1)
1239 (43.6)
673 (23.7)
161 (5.7)
758 (26.7)
5524 (97.4)
3637 (64.1)
2490 (43.9)
1327 (23.4)
324 (5.7)
1522 (26.8)
40
GLP-1 receptor agonists
SGLT-2 inhibitors
189 (6.7)
124 (4.4)
205 (7.2)
135 (4.8)
394 (6.9)
259 (4.6)
*14 patients were not treated with either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker at baseline; 7 patients
received treatment with both an angiotensin-converting enzyme inhibitor and an angiotensin receptor blocker
†Excluding heparins
‡Includes sodium polystyrene sulfonate, calcium polystyrene sulfonate, and potassium-binding agents
DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; od, once daily; SGLT-2, sodium-glucose co-transporter-2 inhibitor
41
Table S2. Dosing of renin–angiotensin system inhibitors*
Finerenone (N=2833)
Placebo (N=2841)
Patient on maximum tolerated dose of ACEi for >4 weeks prior to screening visit† Yes — no. (%)
No — no. (%)
927/951(97.5)
24/951 (2.5)
982/994 (98.8)
12/994 (1.2)
ACEi dosing at baseline — no. (%) 950 (33.5) 992 (34.9) Unclassified dose – 1 (0.1)
minimum and maximum label recommended dose 8 (0.8) 8 (0.8)
Patient on maximum tolerated dose of ARB for >4 weeks prior to screening visit† Yes — no. (%)
No — no. (%)
1858/1883 (98.7)
25/1883 (1.3)
1827/1848 (98.9)
21/1848 (1.1)
ARB dosing at baseline — no. (%) 1879 (66.3) 1846 (65.0) Unclassified dose 1 (
42
>maximum label recommended dose 21 (1.1) 28 (1.5)
*7 patients were treated with both an ACEi and an ARB at baseline
†As reported by the investigator at the screening visit
ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker
43
Table S3. Concomitant medications initiated after start of study drug
Medication Finerenone (N=2833)
Placebo (N=2841)
Angiotensin-converting enzyme inhibitors 428 (15.1) 430 (15.1)
Angiotensin receptor blockers 747 (26.4) 822 (28.9)
Alpha-blocking agents 806 (28.5) 881 (31.0)
β-blockers 767 (27.1) 855 (30.1)
Calcium antagonists 999 (35.3) 1178 (41.5)
Diuretics 1213 (42.8) 1290 (45.4)
Statins 833 (29.4) 862 (30.3)
Potassium-lowering agents* 307 (10.8) 184 (6.5)
Platelet aggregation inhibitors 670 (23.6) 693 (24.4)
Glucose-lowering therapies
Insulin
Metformin
Sulfonylurea
Alpha-glucosidase inhibitor
DPP-4 inhibitors
GLP-1 receptor agonists
SGLT-2 inhibitors
1792 (63.3)
1335 (47.1)
516 (18.2)
301 (10.6)
119 (4.2)
472 (16.7)
260 (9.2)
186 (6.6)
1841 (64.8)
1384 (48.7)
495 (17.4)
334 (11.8)
116 (4.1)
474 (16.7)
264 (9.3)
216 (7.6)
*Includes sodium polystyrene sulfonate, calcium polystyrene sulfonate, and potassium-
binding agents
DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; SGLT-2, sodium-glucose co-
transporter-2 inhibitor
44
Table S4. Sensitivity analysis – efficacy outcomes in the on-treatment analysis
Finerenone (N=2833)
Placebo (N=2841)
Hazard ratio (95% CI)
no. (%) Events per 100 patient
years
no. (%) Events per 100 patient
years Primary composite renal outcome 384 (13.6) 6.31 493 (17.4) 8.01 0.78 (0.68–0.89)
Kidney failure 112 (4.0) 1.78 147 (5.2) 2.31 – End-stage kidney disease 41 (1.4) 0.64 53 (1.9) 0.82 – Sustained decrease in eGFR to
45
Table S5. Tipping point analysis for the primary efficacy outcome
Inflation factor for hazard rate in finerenone group
Finerenone Placebo Multiple imputation HR: finerenone vs
placebo (96.72% CI)
Mean number of patients
with primary efficacy outcome
event
Mean number of imputed events
Mean number of events per 100 patient years
(95% simulation CI)
Mean number of patients
with primary efficacy outcome
event
Mean number of imputed events
Mean number of events per 100 patient years
(95% simulation CI)
0% 569.4 65.4 8.11
(8.11–8.12)
669.6 69.6 9.64
(9.64–9.65)
0.83
(0.73–0.94)
10% 574.4 70.4 8.19
(8.18–8.20)
669.2 69.2 9.64
(9.63–9.64)
0.84
(0.74–0.95)
20% 578.9 74.9 8.26
(8.25–8.26)
669.1 69.1 9.64
(9.63–9.64)
0.85
(0.75–0.96)
30% 583.3 79.3 8.32
(8.32–8.33)
669.1 69.1 9.64
(9.63–9.64)
0.85
(0.75–0.97)
40% 587.4 83.4 8.39
(8.38–8.39)
669.3 69.3 9.64
(9.63–9.64)
0.86
(0.76–0.98)
50% 592.1 88.1 8.46
(8.45–8.47)
668.9 68.9 9.63
(9.63–9.64)
0.87
(0.77–0.98)
60% 595.6 91.6 8.51
(8.51–8.52)
668.9 68.9 9.63
(9.63–9.64)
0.87
(0.77–0.99)
46
70% 599.5 95.5 8.57
(8.57–8.58)
669.6 69.6 9.64
(9.64–9.65)
0.88
(0.78–1.00)
80% 603.4 99.4 8.63
(8.63–8.64)
669.1 69.1 9.64 (9.63–9.64) 0.89
(0.78–1.01)
90% 607.0 103.0 8.69
(8.68–8.70)
669.2 69.2 9.64 (9.63–9.64) 0.89
(0.79–1.01)
100% 610.9 106.9 8.75
(8.74–8.76)
669.5 69.5 9.64 (9.64–9.65) 0.90
(0.79–1.02)
CI, confidence interval; HR, hazard ratio
47
Table S6. Summary of treatment-emergent adverse events by body system or organ class
Body system or organ class, no. (%) Finerenone (N=2827)
Placebo (N=2831)
Blood and lymphatic system disorders 311 (11.0) 301 (10.6)
Cardiac disorders 313 (11.1) 393 (13.9)
Congenital, familial and genetic disorders 18 (0.6) 15 (0.5)
Ear and labyrinth disorders 121 (4.3) 102 (3.6)
Endocrine disorders 83 (2.9) 103 (3.6)
Eye disorders 339 (12.0) 387(13.7)
Gastrointestinal disorders 747 (26.4) 772 (27.3)
General disorders and administration site
conditions 512 (18.1) 645 (22.8)
Hepatobiliary disorders 123 (4.4) 136 (4.8)
Immune system disorders 27 (1.0) 23 (0.8)
Infections and infestations 1227 (43.4) 1255 (44.3)
Injury, poisoning and procedural complications 455 (16.1) 467 (16.5)
Investigations 649 (23.0) 682 (24.1)
Metabolism and nutrition disorders 1045 (37.0) 958 (33.8)
Musculoskeletal and connective tissue
disorders 773 (27.3) 790 (27.9)
Neoplasms benign, malignant and unspecified
(including cysts and polyps) 206 (7.3) 198 (7.0)
Nervous system disorders 567 (20.1) 623 (22.0)
Pregnancy, puerperium and perinatal
conditions 0 1 (
48
Surgical and medical procedures 181 (6.4) 192 (6.8)
Vascular disorders 537 (19.0) 537 (19.0)
Reference 1. Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular
filtration rate. Ann Intern Med 2009;150:604-12.
FIDELIO-DKD committeesExecutive committeeNational lead investigatorsClinical event committeeCardiovascular clinical event adjudication committeeRenal clinical event adjudication committeeNeurological clinical event adjudication committee
Independent data monitoring committeeSponsor study team
Participating countries and investigatorsInclusion and exclusion criteriaInclusion criteriaExclusion criteria
Outcome definitionsKidney outcome eventsKidney failureSustained decrease (≥40%/≥57%) in estimated glomerular filtration rate
Cardiovascular endpoint eventsAcute myocardial infarctionStrokeHospitalization due to heart failure
Causes of deathCardiovascular deathRenal deathNon-cardiovascular and non-renal death
Additional methodsEstimation of glomerular filtration rate for Black/African American patients:Serum potassium monitoring and management of hyperkalemiaStatistical analysesMean dosing of study drugSubgroup analyses of the primary outcomeNumber needed to treat estimationChange in urine albumin-to-creatinine ratio and estimated glomerular filtration rate over timeEstimated glomerular filtration rate slope analyses
Critical Good Clinical Practice violationsTipping point analysis of primary efficacy endpointSupplementary figuresFigure S1. Study design of FIDELIO-DKDFigure S2. Consort diagramFigure S3. Primary composite renal outcome according to key prespecified subgroupsFigure S4. Secondary outcomesFigure S5. Tipping point analysis for the primary efficacy outcomeFigure S6. Effects of finerenone and placebo on eGFRFigure S7. Mean systolic blood pressure over timeFigure S8. Mean HbA1C over timeFigure S9. Mean body weight over time
Supplementary tablesTable S1. Baseline patient demographics, clinical characteristics and medicationsTable S2. Dosing of renin–angiotensin system inhibitors*Table S3. Concomitant medications initiated after start of study drugTable S4. Sensitivity analysis – efficacy outcomes in the on-treatment analysisTable S5. Tipping point analysis for the primary efficacy outcomeTable S6. Summary of treatment-emergent adverse events by body system or organ class
Reference
