To characterize safety, tolerability, pharmacodynamic effects, and pharmacokinetics of the oral sGC stimulator BAY 1021189 in addition to standard therapy for heart failure with reduced EF (HFrEF) over 12 weeks in patients with worsening chronic…
Source
Brief title
Condition
- Heart failures
Synonym
Research involving
Sponsors and support
Intervention
No registrations found.
Outcome measures
Primary outcome
Change from baseline to week 12 in log-transformed NT-proBNP
Secondary outcome
* ECHO parameters
* Change in composite endpoint
* Change in health-related QOL
* Change in vital signs (blood pressure and heart rate)
* Nr of participants with adverse events
Background summary
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).
Study objective
To characterize safety, tolerability, pharmacodynamic effects, and
pharmacokinetics of the oral sGC stimulator BAY 1021189 in addition to standard
therapy for heart failure with reduced EF (HFrEF) over 12 weeks in patients
with worsening chronic HFrEF in 4 dose arms and to find the optimal target dose
Study design
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 reduced ejection fraction
(HFrEF) suffering from worsening signs and symptoms of HF.
Intervention
12 weeks treatment with study medication
Study burden and risks
* 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
Energieweg 1
Mijdrecht 3641 RT
NL
Energieweg 1
Mijdrecht 3641 RT
NL
Listed location countries
Age
Inclusion criteria
1. Written informed consent signed before any study-specific procedure ;2. Ability to understand and follow study-related instructions;3. Worsening chronic heart failure requiring hospitalization (or IV diuretic treatment for HF without hospitalization) with initiation of study treatment after clinical stabilization:;Diagnostic methods:;- History of chronic HF: NYHA class II-IV *30 days before hospitalization (or before IV diuretic treatment for HF without hospitalization);- Worsening HF at hospitalization (or at the time of IV diuretic treatment for HF without hospitalization);- NT-proBNP *1000 or BNP *300 pg/mL in sinus rhythm, or NT-proBNP *1600 or BNP *500 pg/mL in A. fib. in local routine labs, and;- Symptoms and signs of congestion (clinical or radiographic signs in routine chest x-ray demonstrating pleural effusion, pulmonary congestion (redistribution, interstitial or alveolar edema), or cardiomegaly;- Clinical stabilization defined by;- no IV vasodilator for >24h and no IV diuretic for >12h before randomization and;- SBP *110 and <160, and resting HR *50 and <100 bpm at randomization;- LVEF <45% by echocardiography at randomization;4. Ability to understand and follow study-related instructions;5. Men or confirmed postmenopausal women or women without childbearing potential based on surgical treatment such as bilateral tubal ligation, bilateral ovarectomy, or hysterectomy. Men enrolled in this study must agree to use adequate barrier birth control measures during the treatment period of the study.
Exclusion criteria
1. Legal lower age limitations for adults (country specific);2. IV inotropes at any time after hospitalization;3. Concurrent of anticipated nitrate use (all routes, incl. prn) for the treatment of ischemic heart disease or HF, including:;- subjects tolerant of and treated with isosorbide dinitrate/hydralazine therapy for chronic HFrEF according to guideline recommendations;- subjects requiring nitrates as anti-anginal therapy in addition or alternatively to beta-blockers;4. Cardiac comorbidity (either of the following):;- Specific HF etiologies, including: ;- Hypertrophic cardiomyopathy with LV outflow tract obstruction; or;- Pericardial disease, such as constrictive pericarditis; or;- Infiltrative or inflammatory myocardial disease such as acute myocarditis, amyloidosis, sarcoidosis; or;- Valvular heart disease: (severe aortic or mitral regurgitation, moderate or severe aortic stenosis, any mitral stenosis requiring surgical repair, active endocarditis);- Acute coronary syndrome, including unstable angina, NSTEMI or STEMI, or CABG within 60 days prior to randomization, or indication for PCI or CABG;- Significant cardiac ischemia in a stress test within a year of enrollment without revascularization since ;- Symptomatic carotid stenosis, or transient ischemic attack or stroke within 30 days prior to randomization;- New initiation of cardiac resynchronization therapy within 60 days prior to randomization;- Listing for heart transplantation and/or anticipated/implanted ventricular assist device;- Complex congenital heart disease;5. Non-cardiac comorbidity, indicated by either of the following at the time of randomization;- Glomerular filtration rate <30 ml/min/1.73 m2 calculated by Modification of Diet in Renal Disease [MDRD] formula;- Hepatic insufficiency classified as Child-Pugh B or C;- Morbid obesity with a BMI >40 kg/m² ;- Malignancy or other non-cardiac condition limiting life expectancy to <1 year, per physician judgment;- Severe pulmonary disease with either requirement of continuous home oxygen or recent bronchial artery embolization for massive hemoptysis;- Subjects with allergies, intolerance or hypersensitivity to investigational drug or any of the excipients;- Medical condition or history thereof that in the opinion of the investigator would impair the ability to complete the planned study procedures;6. Concomitant Treatment with a PDE5 inhibitor or sGC stimulator;7. Participation in another clinical study or treatment with another investigational product *30 days prior to randomization
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
Register | ID |
---|---|
Other | Een beschrijving van dit onderzoek zal vermeld worden op websites: www.clinicaltrials.gov en op www.ccmo.nl. Identificatie nummer op dit moment nog onbekend. |
EudraCT | EUCTR2013-002287-11-NL |
CCMO | NL45849.060.13 |