Rationale and design of the SOluble guanylate Cyclase stimulatoR in heArT failurE Studies (SOCRATES)
Burkert Pieske, Javed Butler, Gerasimos Filippatos, Carolyn Lam, Aldo Pietro Maggioni, Piotr Ponikowski, Sanjiv Shah, Scott Solomon, Elisabeth Kraigher-Krainer, Eliana Tibana Samano, Andrea Viviana Scalise, Katharina Müller, Lothar Roessig, Mihai Gheorghiade, SOCRATES Investigators and Coordinators, Gerasimos Filippatos, Piotr Ponikowski, Greg Fonarow, John Atherton, Nathan Dwyer, David Kaye, Anne Keogh, Burkert Pieske, Thomas Stefenelli, Uta Hoppe, Deddo Mörtl, Diana Bonderman, Elena Kinova, Katerina Vitlianova, Chavdar Shalganov, Valentina Mincheva, Ivan Kamburov, Anne-Catherine Pouleur, Geert Vervoort, Harry Striekwold, Christiaan Vrints, Michel De Ceuninck, Jean Leroy, Yves Vandekerckhove, Hans Vandekerckhove, Marc Delforge, Serge Lepage, Gordon Moe, Sebastien Bergeron, Sherryn Roth, Milan Gupta, Jiri Knot, Eva Krcova, Jan Belohlavek, Radovan Stancik, Jan Vojacek, Vojtech Melenovsky, Pavel Trestik, Jens Refsgaard, Niels Bruun, Peter Johansen, Peter Søgaard, Søren Mellemkjssr, Albert-Alain Hagege, François Picard, Jacques Mansourati, Pascal De Groote, Yannick Neuder, Fabrice Bauer, Michel Galinier, Alain Cohen-Solal, Michael Böhm, Harald Lapp, Stephan Rosenkranz, Stephan Felix, Dirk Westermann, Carolin Sonne, Jörg Stypmann, Ebrahim Noori, Zoltan Jarai, Elod Papp, Imre Varju, Robert Kirschner, Amos Katz, Tuvia Ben Gal, Sorel Goland, Avraham Shotan, Ofer Havakuk, Yoav Turgeman, Michael Eldar, Zvi Vered, Tanya Weitsman, Marco Metra, Piergiuseppe Agostoni, Giorgio Morando, Laura Scelsi, Giuseppe De Angelis, Carlo Campana, Alessandro Capucci, Fabrizio Oliva, Masahiro Yagi, Yukihiko Momiyama, Kazuki Fukui, Harukazu Iseki, Masayoshi Aijoka, Satoru Sakagami, Takahiko Aoyama, Haruhiko Onaka, Yoshinori Yasaka, Shinobu Hosokawa, Hiroyuki Fujinaga, Hironori Ueda, Yasuhiro Morikami, Tatsuya Nunohiro, Kazuo Usuda, Tokuhisa Uejima, Takamasa Iwasawa, Toru Kataoka, Shinichiro Sakota, Akira Yamada, Henk Swart, Dirk Jan Lok, Robert Wim Breedveld, Remco Nijmeijer, Bernard Cost, Wouter Kok, Janina Stepinska, Joanna Szachniewicz, Jadwiga Nessler, Jaroslaw Drozdz, Stefan Grajek, Barbara Engel, Katarzyna Mizia-Stec, Wlodzimierz Musial, Robert Gil, Tadeusz Zechowicz, David Sim, Daniel Yeo, Hean Yee Ong, Raymond Wong, Jae-Joong Kim, Eun-Seok Jeon, Seok-Min Kang, Luis Almenar Bonet, Marta Cobo Marcos, Nicolás Manito, Fernando Cereto Castro, Jordi Bruguera Cortada, Francisco González Vilchez, Maria Casares, Vincente Climent Payá, Manuel Gómez Bueno, Josep Comín Colet, Ole Hansen, Jens Olson, Emil Pantev, Laila Hübbert, Ola Hallén, Stella Cizinsky, Peter Rickenbacher, Otmar Pfister, Philippe Meyer, Tiziano Moccetti, Frank Enseleit, Fu-tien Chiang, Chern-En Chiang, Chi-Tai Kuo, Wen-Ter Lai, Raymond Benza, Vinay Mehta, Sonjoy Laskar, Antoine Hage, David Pham, Dianne Zwicke, Garrie Haas, Veronica Franco, Yelena Selektor, Daniel Lenihan, James Maher, KellyAnn Light-McGroary, Claire Hunter, Sanjiv Shah, Jalal Ghali, Anthony Alfieri, Steven Goldsmith, Michael Zile, Douglas Chapman, Frank Smart, David Markham, Cristina Tita, Frank McGrew, Joshua Larned, Robert Long, Diana Gorog, David Sprigings, Justin Cooke, Burkert Pieske, Javed Butler, Gerasimos Filippatos, Carolyn Lam, Aldo Pietro Maggioni, Piotr Ponikowski, Sanjiv Shah, Scott Solomon, Elisabeth Kraigher-Krainer, Eliana Tibana Samano, Andrea Viviana Scalise, Katharina Müller, Lothar Roessig, Mihai Gheorghiade, SOCRATES Investigators and Coordinators, Gerasimos Filippatos, Piotr Ponikowski, Greg Fonarow, John Atherton, Nathan Dwyer, David Kaye, Anne Keogh, Burkert Pieske, Thomas Stefenelli, Uta Hoppe, Deddo Mörtl, Diana Bonderman, Elena Kinova, Katerina Vitlianova, Chavdar Shalganov, Valentina Mincheva, Ivan Kamburov, Anne-Catherine Pouleur, Geert Vervoort, Harry Striekwold, Christiaan Vrints, Michel De Ceuninck, Jean Leroy, Yves Vandekerckhove, Hans Vandekerckhove, Marc Delforge, Serge Lepage, Gordon Moe, Sebastien Bergeron, Sherryn Roth, Milan Gupta, Jiri Knot, Eva Krcova, Jan Belohlavek, Radovan Stancik, Jan Vojacek, Vojtech Melenovsky, Pavel Trestik, Jens Refsgaard, Niels Bruun, Peter Johansen, Peter Søgaard, Søren Mellemkjssr, Albert-Alain Hagege, François Picard, Jacques Mansourati, Pascal De Groote, Yannick Neuder, Fabrice Bauer, Michel Galinier, Alain Cohen-Solal, Michael Böhm, Harald Lapp, Stephan Rosenkranz, Stephan Felix, Dirk Westermann, Carolin Sonne, Jörg Stypmann, Ebrahim Noori, Zoltan Jarai, Elod Papp, Imre Varju, Robert Kirschner, Amos Katz, Tuvia Ben Gal, Sorel Goland, Avraham Shotan, Ofer Havakuk, Yoav Turgeman, Michael Eldar, Zvi Vered, Tanya Weitsman, Marco Metra, Piergiuseppe Agostoni, Giorgio Morando, Laura Scelsi, Giuseppe De Angelis, Carlo Campana, Alessandro Capucci, Fabrizio Oliva, Masahiro Yagi, Yukihiko Momiyama, Kazuki Fukui, Harukazu Iseki, Masayoshi Aijoka, Satoru Sakagami, Takahiko Aoyama, Haruhiko Onaka, Yoshinori Yasaka, Shinobu Hosokawa, Hiroyuki Fujinaga, Hironori Ueda, Yasuhiro Morikami, Tatsuya Nunohiro, Kazuo Usuda, Tokuhisa Uejima, Takamasa Iwasawa, Toru Kataoka, Shinichiro Sakota, Akira Yamada, Henk Swart, Dirk Jan Lok, Robert Wim Breedveld, Remco Nijmeijer, Bernard Cost, Wouter Kok, Janina Stepinska, Joanna Szachniewicz, Jadwiga Nessler, Jaroslaw Drozdz, Stefan Grajek, Barbara Engel, Katarzyna Mizia-Stec, Wlodzimierz Musial, Robert Gil, Tadeusz Zechowicz, David Sim, Daniel Yeo, Hean Yee Ong, Raymond Wong, Jae-Joong Kim, Eun-Seok Jeon, Seok-Min Kang, Luis Almenar Bonet, Marta Cobo Marcos, Nicolás Manito, Fernando Cereto Castro, Jordi Bruguera Cortada, Francisco González Vilchez, Maria Casares, Vincente Climent Payá, Manuel Gómez Bueno, Josep Comín Colet, Ole Hansen, Jens Olson, Emil Pantev, Laila Hübbert, Ola Hallén, Stella Cizinsky, Peter Rickenbacher, Otmar Pfister, Philippe Meyer, Tiziano Moccetti, Frank Enseleit, Fu-tien Chiang, Chern-En Chiang, Chi-Tai Kuo, Wen-Ter Lai, Raymond Benza, Vinay Mehta, Sonjoy Laskar, Antoine Hage, David Pham, Dianne Zwicke, Garrie Haas, Veronica Franco, Yelena Selektor, Daniel Lenihan, James Maher, KellyAnn Light-McGroary, Claire Hunter, Sanjiv Shah, Jalal Ghali, Anthony Alfieri, Steven Goldsmith, Michael Zile, Douglas Chapman, Frank Smart, David Markham, Cristina Tita, Frank McGrew, Joshua Larned, Robert Long, Diana Gorog, David Sprigings, Justin Cooke
Abstract
Aims: The clinical outcomes for patients with worsening chronic heart failure (WCHF) remain exceedingly poor despite contemporary evidence-based therapies, and effective therapies are urgently needed. Accumulating evidence supports augmentation of cyclic guanosine monophosphate (cGMP) signalling as a potential therapeutic strategy for HF with reduced or preserved ejection fraction (HFrEF and HFpEF, respectively). Direct soluble guanylate cyclase (sGC) stimulators target reduced cGMP generation due to insufficient sGC stimulation and represent a promising method for cGMP enhancement.
Methods: The phase II SOluble guanylate Cyclase stimulatoR in heArT failurE Study (SOCRATES) programme consists of two randomized, parallel-group, placebo-controlled, double-blind, multicentre studies, SOCRATES-REDUCED (in patients with LVEF <45%) and SOCRATES-PRESERVED (in those with LVEF ≥ 45%), that will explore the pharmacodynamic effects, safety and tolerability, and pharmacokinetics of four dose regimens of the once-daily oral sGC stimulator vericiguat (BAY 1021189) over 12 weeks compared with placebo. These studies will enrol patients stabilized during hospitalization for HF at the time of discharge or within 4 weeks thereafter. The primary endpoint in SOCRATES-REDUCED is change in NT-proBNP at 12 weeks. The primary endpoints in SOCRATES-PRESERVED are change in NT-proBNP and left atrial volume at 12 weeks.
Perspectives: SOCRATES will be the first programme to enrol specifically both inpatients and outpatients with WCHF and patients with reduced or preserved ejection fraction. Results will inform the benefits of pursuing subsequent event-driven clinical outcome trials with sGC stimulators in this patient population.
Keywords: Left atrial volume; Natriuretic peptides; Preserved ejection fraction; Reduced ejection fraction; Soluble guanylate cyclase; Worsening chronic heart failure.
© 2014 The Authors. European Journal of Heart Failure © 2014 European Society of Cardiology.
Source: PubMed