Placebo-controlled, multi-center study to evaluate catheter derived tests of Riociguat (BAY 63-2521) as well as safety and blood samples in patients with pulmonary hypertension associated with left heart failure.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Bayer AG

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

Trial duration

29 Apr 2010 → 24 Jul 2025

Decision date (initial)

2024-03-26

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Bayer AG, D-51368, Leverkusen, Germany

External identifiers

EU CT number

2023-507001-34-00

EudraCT number

2009-015878-35

ClinicalTrials.gov

NCT01065454

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy

The primary objective of this study is to assess the hemodynamic profile of Riociguat in patients with symptomatic pulmonary hypertension associated with left ventricular systolic dysfunction (PH-sLVD).

Secondary objectives 1

1. The secondary objectives of this study are to assess safety, tolerability and pharmacokinetic profile of Riociguat in patients with symptomatic pulmonary hypertension associated with left ventricular systolic dysfunction (PH-sLVD), and to explore doses and potential endpoints for phase III

Conditions and MedDRA coding

Patients symptomatic with pulmonary hypertension associated with left ventricular systolic dysfunction (PH-sLVD)

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. 18 to 80 years of age at the time of informed consent (The lower age limit may be higher if legally required in participating countries.)
2. Male and female subjects with symptomatic PH-sLVD (group 2 / 2.1 of Dana Point Classification and World Health Organization [WHO] class II-IV) due to ischemic heart disease or dilated cardiomyopathy (DCM). Transplant candidates can be included. (Other groups of pulmonary hypertension, especially CTEPH, must have been ruled out according to accepted diagnostic procedures and guidelines, see section 5.1.2 Exclusion criteria.) PH-sLVD is defined as: - LVEF ≤ 40%, diagnosed by echocardiography, radionuclide ventriculography or left heart catheter (LHC) exam within 30 days before randomization, or in the baseline echocardiography (Note: the definition of PH-sLVD was changed in amendment 3 see section 13.2.1.2) - PAPmean ≥ 25 mmHg at rest, measured by right heart catheter (RHC)
3. Subjects must be pre treated and individually maximally titrated with optimized CHF therapy according to European Society of Cardiology (ESC) (9), American College of Cardiology/American Heart Association (ACC/AHA) (10) or Japanese Circulation Society (11) guidelines with angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), beta blockers and mineralocorticoid receptor (MR) antagonists as clinically indicated. The dose regimen must have been stable for > 30 days prior to randomization. Diuretic therapy must have been stable for ≥ 1 week before performing baseline RHC.
4. RHC results for the definite diagnosis of PH not older than 1 week at Visit 1. RHC must have been performed in the participating centre under standardized conditions (refer to the study specific right heart catheterization manual).
5. Left heart catheter results available any time prior to randomization to judge if left-heart disease is caused by ischemic heart disease or dilated cardiomyopathy
6. A negative stress test must have been performed < 1 year prior to randomization according to guidelines (stress electrocardiography [ECG], stress echocardiography, stress scintigraphy) to exclude overt or silent ischemia.
7. Women are eligible if not of childbearing potential, defined as: - postmenopausal women (i.e. last menstrual bleeding at least 2 years before randomization) - women with bilateral tubal ligation - women with bilateral ovariectomy - women with hysterectomy or, if of childbearing potential, women are eligible if - a serological pregnancy test is negative at the pre-study visit, and - the woman uses a combination of condoms and a safe and highly effective contraception method (hormonal contraception with implants or combined oral contraceptives, certain intrauterine devices) for the duration of the study.
8. Subject is able to understand and follow instructions and is able to participate in the study for the entire period
9. Written informed consent.

Exclusion criteria 28

1. PH in groups other than group 2.1 according to Dana Point classification (2). In particular, CTEPH must have been ruled out according to accepted diagnostic procedures and guidelines.
2. Cardiac decompensation, either with hospitalization or visit to the emergency department, ≤ 30 days prior to randomization
3. Resynchronization therapy initiated ≤ 90 days prior to randomization
4. Need of intravenous (IV) diuretics ≤ 30 days prior to randomization
5. Treatment with IV inotropes or IV vasodilators ≤ 30 days prior to randomization
6. Chronic treatment with endothelin receptor antagonists (ERAs), phosphodiesterase type 5 (PDE5) inhibitors or prostanoids ≤ 30 days prior to randomization, or with nitrates ≤ 7 days prior to randomization (PDE5 inhibitors ≤ 7 days prior to randomization if indicated for erectile dysfunction)
7. Subjects who medically require treatment with drugs that are not in line with the in or exclusion criteria of this study or that are prohibited concomitant medications (see section 6.9) for this study
8. Bronchial asthma or chronic obstructive pulmonary disease (COPD) with forced expiratory volume in one second (FEV1) < 60% of predicted
9. Restrictive lung disease with total lung capacity (TLC) < 60% of predicted
10. Subjects on O2 therapy
11. Severe congenital abnormalities of the lungs, thorax or diaphragm
12. Clinically relevant hepatic dysfunction indicated by either: - aspartate aminotransferase (AST) ≥ 3 times the upper limit of normal (ULN) - Child Pugh stage B and C in cirrhotic patients.
13. Severe renal impairment (glomerular filtration rate [GFR] < 30 mL/min calculated by Modification of Diet in Renal Disease [MDRD] formula)
14. Uncontrolled arterial hypertension (systolic blood pressure [SBP] > 180 mmHg or diastolic blood pressure [DBP] > 110 mmHg)
15. SBP < 100 mmHg at baseline or clinical signs or symptoms of hypotension (Note: limit changed and additional text added in amendment 3 see section 13.2.1.3)
16. Myocardial disease other than ischemic or dilatative, such as infiltrative myocardial disease (i.e. amyloidosis, hypertrophic cardiomyopathy)
17. Severe aortic or mitral stenosis, or any such stenosis with indication for surgery
18. Coronary artery disease with angina of Canadian Cardiovascular Society (CCS) class III or IV or requiring nitrates, unstable angina, or acute myocardial infarction less than 90 days prior to randomization
19. Reperfusion procedure (percutaneous coronary intervention [PCI] or coronary artery bypass graft [CABG]) less than 90 days prior to randomization, or less than 3 weeks in case of a negative stress test after PCI
20. Stroke with persistent neurological deficit or known hemodynamically relevant symptomatic carotid artery stenosis
21. Subjects positive for human immunodeficiency virus (HIV)
22. Resting heart rate (HR) while awake of < 50 beats per minute (BPM) or > 105 BPM (in case of atrial fibrillation > 110 BPM)
23. Investigational treatment in another clinical trial during the preceding 30 days
24. Subjects with a medical disorder, condition, or history thereof that in the opinion of the investigator would impair the subject's ability to participate or complete the 4 month main study
25. Subjects with underlying medical disorders with an anticipated life expectancy below 2 years not due to cardiac conditions (e.g. active cancer disease with localized and/or metastasized tumor mass)
26. Subjects with a history of multiple drug allergies
27. Subjects with hypersensitivity to the investigational drug or any of the excipients
28. Previous assignment to treatment during this study.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Change from baseline to week 16 in Pulmonary artery mean pressure (PAPmean) at rest

Secondary endpoints 12

1. Change from baseline in venous oxygen saturation (SvO2) measured by RHC
2. Change from baseline in pulmonary vascular resistance (PVR), systemic vascular resistance (SVR), transpulmonary pressure gradient (TPG) and pulmonary capillary wedge pressure (PCWP), all measured by right heart catheter (RHC).
3. Change from baseline in tricuspid annular plane systolic excursion (TAPSE), systolic pulmonary arterial pressure (PAPsyst) and left ventricular ejection fraction (LVEF), ratio of mitral peak velocity of early filling to mitral peak velocity of late filling (E/A), ratio of mitral velocity of early filling to early diastolic velocity of the mitral annulus (E/E'), E wave deceleration time all measured by echocardiography
4. Change from baseline in WHO class
5. Change from baseline in 6-minute walking distance (6MWD) and in Borg CR 10 scale, measured at the end of the 6MWD test
6. Change from baseline in quality of life (QoL) scores: EQ-5D questionnaire (EQ-5D), Minnesota Living with Heart Failure Questionnaire (MLHF)
7. Change from baseline in cardiac biomarkers N-terminal pro-brain natriuretic peptide (NT-pro BNP) and troponin T
8. Change from baseline in exploratory biomarkers asymmetric dimethyl arginine (ADMA) and osteopontin (section 14.10)
9. Events of special interest considered for the calculation of the combined endpoint "time to clinical worsening" (see section 7.3.8)
10. Events of special safety interest (see section 7.5.1.6)
11. All-cause mortality
12. Composite endpoint as defined by: time to death from cardiovascular causes or first hospitalization for a cardiovascular event, including heart failure, acute myocardial infarction, stroke or ventricular arrhythmia.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Bayer AG

Sponsor organisation

Bayer AG

Address

Kaiser-Wilhelm-Allee 1, Wiesdorf Wiesdorf

City

Leverkusen

Postcode

51373

Country

Germany

Scientific contact point

Organisation

Bayer AG

Contact name

Therapeutic Area Head

Public contact point

Organisation

Bayer AG

Contact name

Therapeutic Area Head

Third parties 1

Locations

3 EU/EEA countries · 3 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 26 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications