A study to find out whether some PAH patients may benefit by replacing their current phosphodiesterase-5 inhibitors (PDE-5i) with or without endothelin receptor antagonist (ERA), with Riociguat

• Register: EUCTR
• Last refreshed on: 25 May 2020
• Main ID: EUCTR2016-001067-36-DK
• Date of registration: 23/12/2016
• Prospective Registration: Yes
• Primary sponsor: Bayer AG
• Public title: A study to find out whether some PAH patients may benefit by replacing their current phosphodiesterase-5 inhibitors (PDE-5i) with or without endothelin receptor antagonist (ERA), with Riociguat
• Scientific title: A prospective, randomized, international, multicenter, double-arm, controlled, open-label study of Riociguat in patients with pulmonary arterial hypertension (PAH) who are on a stable dose of phosphodiesterase-5 inhibitors (PDE-5i) with or without endothelin receptor antagonist (ERA), but not at treatment goal - Riociguat rEplacing PDE-5i therapy evaLuated Against Continued PDE-5i thErapy
• Date of first enrolment: 15/03/2017
• Target sample size: 218
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-001067-36
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: yes; Single blind: no; Double blind: no; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: yes; Placebo: no; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): yes

Countries of recruitment

Australia, Austria, Belgium, Brazil, Canada, Czech Republic, Denmark, France, Germany, Greece, Italy, Japan, Korea, Republic of, Mexico, Netherlands, New Zealand, Poland, Portugal, Spain, Switzerland, Taiwan, Turkey, United Kingdom, United States

Contacts

• Name: Bayer Clinical Trials Contact
• Affiliation: Bayer AG

• Name: Bayer Clinical Trials Contact
• Affiliation: Bayer AG

Key inclusion & exclusion criteria

Inclusion criteria:
1. Male and female patients aged 18 to 75 years.
2. Patients with symptomatic PAH with a pulmonary vascular resistance (PVR) > 400 dyn*sec*cm-5, mean pulmonary artery pressure = 25 mmHg, and pulmonary capillary wedge pressure (PCWP) = 15 mmHg as assessed by the most recent right heart catheterization (RHC) from medical history prior to screening to confirm the diagnosis. Alternatively, PCWP can be replaced by left ventricular end-diastolic pressure (= 15
mmHg).
PAH of the following types:
a. Idiopathic
b. Hereditary
c. Drug and toxin induced PAH
d. Associated with PAH due to:
- Connective tissue disease (CTD)
- Congenital heart disease, but only if the patient underwent surgical repair more than one year before enrolment
- Portal hypertension with liver cirrhosis (Note: patients with clinical relevant hepatic dysfunction are excluded; see exclusions related to disorders in organ function)
3. Patients who are on stable doses of a PDE-5i and ERA combination therapy or on stable PDE-5i monotherapy 6 weeks prior to and at randomization but not at treatment goal (tadalafil 20 to 40 mg once daily or sildenafil at least 60 mg daily dose).
4. WHO FC III at screening and at randomization.
5. 6MWD test between 165 m and 440 m at screening and at randomization.
6. Stable dose of diuretics, if used, for at least 30 days prior to and at randomization.
7. Patients who are able to understand and follow instructions and who are able to participate in the study for the entire study.
8. Women of childbearing potential must agree to use adequate contraception when sexually active. Adequate contraception is defined as any combination of at least 2 effective methods of birth control, of which at least 1 is a physical barrier (e.g. condom with hormonal contraception like implants or combined oral contraceptives, condom
with intrauterine devices). This applies beginning with signing of the informed consent form until 30 (+5) days after the last administration of study drug.
9. Patients must have given their written informed consent to participate in the study after having received adequate previous information and prior to any study-specific procedures.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 164
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 54

Exclusion criteria:
1.Participation in another interventional clinical study within 30 days prior to screening.
2.Previous randomization to treatment during this study (no rerandomization).
3.Previous treatment with riociguat.
4.Pregnant women, or breast feeding women, or women with childbearing potential not using a combination of 2 effective contraception methods throughout the study.
5.Patients with a medical disorder, condition, or history of such that would impair the patient's ability to participate or complete this study, in the opinion of the investigator.
6.Patients with substance abuse within the previous 3 months prior to and at randomization.
7.Patients with underlying medical disorders with an anticipated life expectancy below 2 years.
8.Patients with a history of severe allergies or multiple drug allergies.
9.Patients with hypersensitivity to the investigational drug or any of the excipients.
10.Patients unable to perform a valid 6MWD test.
11.Participation at a supportive physical training program, defined as a structured exercise and rehabilitation program supervised by a physician and/or a physiotherapist within 12 weeks prior to screening.
Participants enrolled in an exercise program for pulmonary rehabilitation > 12 weeks prior to screening may enter the study if they agree to maintain their current level of rehabilitation during the screening and the 24 weeks of the study.
12.Excluded medication/treatment:
a.Patients who are screened for possible participation in the study must not be withdrawn from treatments which are medically required. If such treatments are not in-line with the entry criteria of this study, the patient must not be enrolled. Concomitant use with riociguat of the following specific medications for treatment of PAH is not allowed at any time during the study:
• PDE-5i must not be co-administered with riociguat
• Non-specific PDE-inhibitors
• NO donors
b.Prostacyclin analogues (PCA) and prostacyclin-receptor agonists (PRA) by any administration route within 30 days prior to and at randomization (except for vasoreactivity testing).
13.Exclusion criteria related to pulmonary disease:
a.All types of PH (including PH-IIP) except subtypes of Dana Point Group
I specified in the inclusion criteria.
b.Evidence of clinically significant restrictive or obstructive parenchymal lung diseases in the judgment of the investigator
c.Severe congenital abnormalities of the lungs, thorax, and diaphragm.
d.Severe restrictive lung disease (total lung capacity [TLC] < 60%).
e.Moderate obstructive lung disease (forced expiratory volume in one second/forced vital capacity [FEV1/FVC] < 50%).
f.Confirmed obstructive sleep apnea
g.Severe diffusion impairment (diffusing capacity of the lung for carbon
monoxide < 30% predicted).
h.History or active state of serious hemoptysis/pulmonary hemorrhage including those managed by bronchial artery embolization
14.Exclusion criterion related to hypoxia (pulse oximeter at rest):
a. Peripheral capillary oxygen saturation (SpO2) < 88% despite supplemental oxygen therapy (<= 4 L/min) at rest.
15.Cardiovascular exclusion criteria:
a.Uncontrolled arterial hypertension (SBP > 180 mmHg and/or diastolic BP > 110 mmHg).
b.SBP < 95 mmHg prior to and at randomization.
c.Resting heart rate in the awake patient < 50 bpm or > 105 bpm.
d.Permanent atrial fibrillation and new onset of atrial fibrillation within the last 3 months prior to screening.
e.Left ventricular systolic dysfunction by echocardiography (left ventri

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Cardiovascular Diseases [C14]

Pulmonary Arterial Hypertension (PAH)
MedDRA version: 20.0 Level: PT Classification code 10064911 Term: Pulmonary arterial hypertension System Organ Class: 10038738 - Respiratory, thoracic and mediastinal disorders

Intervention(s)

Trade Name: Adempas
Product Name: Adempas® 0.5 mg film-coated tablets
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Riociguat
CAS Number: 625115-55-1
Current Sponsor code: BAY63-2521
Other descriptive name: RIOCIGUAT
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 0.5-

Trade Name: Adempas
Product Name: Adempas® 1.0 mg film-coated tablets
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Riociguat
CAS Number: 625115-55-1
Current Sponsor code: BAY63-2521
Other descriptive name: RIOCIGUAT
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 1.0-

Trade Name: Adempas
Product Name: Adempas® 1.5 mg film-coated tablets
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Riociguat
CAS Number: 625115-55-1
Current Sponsor code: BAY63-2521
Other descriptive name: RIOCIGUAT
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 1.5-

Trade Name: Adempas
Product Name: Adempas® 2.0 mg film-coated tablets
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Riociguat
CAS Number: 625115-55-1
Current Sponsor code: BAY63-2521
Other descriptive name: RIOCIGUAT
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 2.0-

Trade Name: Adempas
Product Name: Adempas® 2.5 mg film-coated tablets
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Riociguat
CAS Number: 625115-55-1
Current Sponsor code: BAY63-2521
Other descriptive name: RIOCIGUAT
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 2.5-

Trade Name: Adcirca
Product Name: ADCIRCA 20 mg film-coated tablets
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: TADALAFIL
CAS Number: 171596-29-5
Concentration unit: mg mil

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: 24 Weeks

Main Objective: To assess the proportion of patients in each treatment arm with a satisfactory clinical response as defined by a composite primary
endpoint at Week 24.

Primary end point(s): The primary efficacy endpoint ‘satisfactory clinical response’ is defined as the composite endpoint comprising the following components (independent central adjudication):
2 of 3 must be fulfilled
- 6MWD increase by = 10% or = 30 m from baseline to Week 24
- WHO FC I or II at Week 24
- NT-proBNP reduction = 30% from baseline to Week 24 (NT-proBNP ratio Week 24/baseline = 0.7), AND
- No clinical worsening (for definition, see protocol)

Secondary Objective: To demonstrate safety and clinical effect at Week 24 indicated by change in 6-minute walking distance (6MWD), N-terminal pro-brain natriuretic peptide (NT-proBNP), World Health Organization Functional Class (WHO FC) and clinical worsening from baseline in each treatment arm.

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: 24 Weeks

Secondary end point(s): - Change from baseline in 6MWD (blinded assessment)
- Change from baseline in NT-proBNP
- Change from baseline in WHO FC (blinded assessment)
- Clinical worsening

Secondary ID(s)

18588

2016-001067-36-ES

Source(s) of Monetary Support

Bayer AG

Ethics review

Status: Approved
Approval date: 15/03/2017
Contact: