Rationale and design of the SOluble guanylate Cyclase stimulatoR in heArT failurE Studies (SOCRATES).

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.

• Authors: 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
• Journal: European journal of heart failure (Eur J Heart Fail) Vol. 16 Issue 9 Pg. 1026-38 (Sep 2014) ISSN: 1879-0844 [Electronic] England
• PMID: 25056511 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 The Authors. European Journal of Heart Failure © 2014 European Society of Cardiology.

Chemical References

• Peptide Fragments
• Protein Precursors
• Receptors, Cytoplasmic and Nuclear
• pro-brain natriuretic peptide (1-76)
• Natriuretic Peptide, Brain
• Guanylate Cyclase
• Soluble Guanylyl Cyclase

Topics

• Administration, Oral
• Aged
• Double-Blind Method
• Female
• Guanylate Cyclase (administration & dosage, pharmacokinetics)
• Heart Failure (blood, drug therapy, physiopathology)
• Humans
• Male
• Natriuretic Peptide, Brain (blood)
• Peptide Fragments (blood)
• Prognosis
• Protein Precursors
• Receptors, Cytoplasmic and Nuclear (administration & dosage, pharmacokinetics)
• Soluble Guanylyl Cyclase
• Stroke Volume (physiology)
• Treatment Outcome