A randomized parallel-group, placebo-controlled, double-blind, multi-center dose finding phase II trial exploring the pharmacodynamic effects, safety and tolerability, and pharmacokinetics of four dose regimens of the oral sGC stimulator BAY 1021189 over 12 weeks in patients with worsening heart failure and preserved ejection fraction.

HF is associated with a wide spectrum of left ventricular (LV) functional
abnormalities, ranging from patients with normal LV size and preserved ejection
fraction (EF) to those with severe dilatation and/or markedly reduced EF (Hunt
SA et al., J Am Coll Cardiol 53:e1*e90). It is important to differentiate those
with HFrEF from those with HFpEF because these represent groups with different
underlying pathophysiological, haemodynamic, and neurohormonal abnormalities
and distinctly different clinical characteristics, varying risks for adverse
outcomes, and dissimilar efficacy of existing therapies.
The nitric oxide (NO)*soluble guanylate cyclase (sGC)*cyclic guanosine
monophosphate (cGMP) pathway is a relevant mechanism in HF that remains
unaffected by neurohumoral antagonists. cGMP deficiency causes two important
pathophysiologies in HF: Myocardial and endothelial dysfunction. Restoration of
sufficient sGC*cGMP signaling appears to be an important pathophysiological
target in HF. Previous attempts to increase cGMP remain limited.
A novel class of sGC stimulators directly stimulates the NO receptor sGC with a
dual mode of action. They sensitize sGC to endogenous NO by stabilizing the
NO-sGC binding and also directly stimulate sGC via a different binding site,
independently of NO. The 3 times daily administered oral sGC stimulator BAY
63-2521 (riociguat) is currently developed in PH, including patients with HF
and secondary PH. In the Phase IIb LEPHT study (IMP14308, NCT01065454) in
patients with systolic HF and secondary PH, riociguat was well tolerated in
these patients, and improved cardiac index, pulmonary vascular resistance
(PVR), systemic vascular resistance (SVR), and quality of life in addition to
standard HF treatment over 16 weeks without significantly changing systemic
blood pressure or mPAP as primary endpoint (Circulation. 2012; 126: 2776-2799).

To characterize safety, tolerability, pharmacodynamic effects, and
pharmacokinetics of the oral sGC stimulator BAY 1021189 in addition to standard
diuretic and comorbidity treatment over 12 weeks in patients with worsening
chronic heart failure with preserved EF (HFpEF) in 4 dose arms and to find the
optimal target dose

Randomized parallel-group, placebo-controlled, multi-center dose finding phase
II trial exploring the pharmacodynamic effects, safety and tolerability, and
pharmacokinetics of four dose regimens of the oral sGC stimulator BAY 1021189
over 12 weeks in patients with heart failure and preserved ejection fraction
(HFpEF) suffering from worsening signs and symptoms of Heart Failure (HF) -
SOluble Guanylate Cyclase stimulatoR in heArT failurE patientS with PRESERVED
EF (SOCRATES-PRESERVED)

12 weeks treatment with study medication

* As with any drug, side effects may occur with the study drug (see ABR section
E9)
* Up to five study visits in 90 days
* Blood samples at every visit
* Physical examination at every visit
* ECG at every visit
* QOL questionnaire (KCCQ, EQ-5D-3L) at 4 visits
* ECHO cardiography at 2 visits