Efficacy and safety of riociguat in patients with high blood pressure in the blood vessels of the lungs associated with interstitial pneumonias of unknown cause.

• Register: EUCTR
• Last refreshed on: 3 October 2016
• Main ID: EUCTR2010-024332-42-ES
• Date of registration: 25/04/2014
• Prospective Registration: Yes
• Primary sponsor: Bayer HealthCare AG
• Public title: Efficacy and safety of riociguat in patients with high blood pressure in the blood vessels of the lungs associated with interstitial pneumonias of unknown cause.
• Scientific title: A randomized, double-blind, placebo-controlled phase II study to investigate the efficacy and safety of riociguat (0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg TID) in patients with symptomatic pulmonary hypertension associated with idiopathic interstitial pneumonias (IIP) - RISE-IIP
• Date of first enrolment: 03/07/2014
• Target sample size: 120
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2010-024332-42
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Australia, Belgium, Canada, Denmark, France, Germany, Greece, Italy, Japan, Portugal, Spain, Switzerland, United Kingdom, United States

Contacts

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

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

Key inclusion & exclusion criteria

Inclusion criteria:
1. Men or women aged from >=18 to <=80 years
2. Diagnosed with one of the following (confirmed using a multidisciplinary approach, as per ATS/ERS/JRS/ALAT guidelines [1]):
-Major IIPs diagnosis or suspected as one of the following:
* Idiopathic pulmonary fibrosis
* Idiopathic nonspecific interstitial pneumonia
* Respiratory bronchiolitis-interstitial lung disease
* Desquamative interstitial pneumonia
* Cryptogenic organizing pneumonia
* Acute interstitial pneumonia
-Rare IIPs diagnosis by one of the following:
* Idiopathic lymphoid interstitial pneumonia
* Idiopathic pleuroparenchymal fibroelastosis
-Unclassifiable idiopathic interstitial pneumonias
3. FVC >= 45 %
4. 6MWD >= 150 m to <= 450 m (under stable O2 supplementation via nasal cannula)
5. Diagnosis of PH confirmed by right heart catheter (RHC) with mPAP >= 25 mmHg and PAWP <=15 mmHg at rest
6. Systolic blood pressure (SBP) >= 95 mmHg and no signs or symptoms of hypotension
7. WHO functional class II-IV
8. Women of childbearing potential can only be included in the study if a pregnancy test is negative. Women of childbearing potential and all non-vasectomized male participants 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 one is a physical barrier (e.g. condoms with hormonal contraception or implants or combined oral contraceptives, certain intrauterine devices). Adequate contraception is required from the signing of the informed consent form up until 6 weeks after the last study drug administration
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 96
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 24

Exclusion criteria:
1. Known significant left heart disease:
- Pulmonary venous hypertension indicated by baseline pulmonary capillary wedge pressure > 15 mmHg
- Symptomatic coronary artery disease
- Systolic left-ventricular dysfunction with an left ventricular ejection fraction (LVEF) <45%
2. Active state of hemoptysis or pulmonary hemorrhage, including those events managed by bronchial artery embolization
3. Any history of bronchial artery embolization or massive hemoptysis within 3 months prior to screening. Massive hemoptysis being defined as acute bleeding >240 mL in a
24-hour period or recurrent bleeding >100 mL/d over several days
4. History of acute lung infection or acute exacerbation prior to screening
5. Reasonable likelihood of receiving a lung transplant within the 26 week main study period
6. Pulmonary veno-occlusive disease
7. Difference > 15% between the eligibility and the baseline 6MWD test
8. Saturation of peripheral oxygen (SpO2) remains < 92 % with not more than 6 L of supplemental oxygen at rest
9. Forced expiratory volume in one second (FEV1)/FVC <0.65 after bronchodilator administration
10. CO2 > 45 mmHg
11. Other known cause of ILD including:
a. connective tissue disease
b. sarcoidosis
c. chronic hypersensitivity pneumonitis
d. significant environmental exposure likely to be the cause of the patients ILD (such as asbestos or silica exposure)
12. Extent of emphysema greater than the extent of fibrotic changes (honeycombing, reticular changes) on HRCT scan
13. Use of cytotoxic, immunosuppressive, cytokine modulating therapy initiated within and including 3 months prior to screening or if used systemically e.g. azathioprine, cyclophosphamide, corticosteroids, etanercept, tumor necrosis factor alpha (TNF alpha) inhibitors and others
14. Pirfenidone and any other drug approved specifically for IPF initiated within 3 months prior to screening
15. Any specific treatment for PAH/PH within 3 months prior to screening
16. Active smoking of tobacco of any type or quantity
17. Active participation in a Pulmonary Rehabilitation program, defined as a structured exercise and rehabilitation program supervised by a physician, respiratory therapist and/or a physiotherapist. Patients who have completed a course of Pulmonary Rehabilitation and are in the maintenance phase of the program are eligible for study enrollment
18. Concomitant use of the following medication: nitrates or NO donors (such as amyl nitrite) in any form, phosphodiesterase 5 inhibitors (such as sildenafil, tadalafil, vardenafil) and non-specific phosphodiesterase (PDE) inhibitors (theophylline, dipyridamole),
19. Severe hepatic impairment (Child Pugh C)
20. Creatinine clearance < 15 ml/min or on dialysis
21. Pregnant women (i.e. positive pregnancy test or other signs of pregnancy), or breast feeding women, or women of childbearing potential not using adequate contraception (as defined in the aforementioned inclusion criterion) and not willing to agree to 4-weekly pregnancy testing from Visit 1(first administration of study drug) onwards until 6 weeks after last study drug intake
22. Previous randomization to treatment during this study
23. Participation in another clinical study with an investigational drug or a medical device within 30 days prior to randomization (phase I-III clinical studies)
24. Active neurologic, orthopedic or musculoskeletal disorder that is likely to affect performance of the 6MWD test


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

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Respiratory Tract Diseases [C08]

pulmonary hypertension associated with idiopathic interstitial pneumonias
MedDRA version: 16.1 Level: LLT Classification code 10037406 Term: Pulmonary hypertension secondary System Organ Class: 100000004855

Intervention(s)

Trade Name: Adempas
Product Name: BAY 63-2521 coated tablet 0.5 mg
Product Code: BAY 63-2521
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-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Trade Name: Adempas
Product Name: BAY 63-2521 coated tablet 1.0 mg
Product Code: BAY 63-2521
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-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Trade Name: Adempas
Product Name: BAY 63-2521 coated tablet 1.5 mg
Product Code: BAY 63-2521
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-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Trade Name: Adempas
Product Name: BAY 63-2521 coated tablet 2.0 mg
Product Code: BAY 63-2521
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-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Trade Name: Adempas
Product Name: BAY 63-2521 coated tablet 2.5 mg
Product Code: BAY 63-2521
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Riociguat
CAS Number: 625115-55-1
Current Sponsor

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: 26Weeks

Main Objective: To evaluate the efficacy and safety of 26-weeks of treatment with riociguat vs. placebo in patients with symptomatic PH associated with IIP

Primary end point(s): the mean change in 6 minute walking distance from baseline to week 26

Secondary Objective: Time to clinical worsening as evidenced by the first of any of the following four events:
*All-cause mortality
*Worsening of WHO functional class.
*Need for hospitalization due to worsening cardiopulmonary status, attributable to progression of disease (including but not limited to increased shortness of breath or increased leg swelling)
*15% decrease in the 6MWD test

Secondary Outcome(s)

Secondary end point(s): Time to clinical worsening as evidenced by the first of any of the following four events:
* All-cause mortality
* Need for hospitalization due to worsening cardiopulmonary status, attributable to
progression of disease (including but not limited to increased shortness of breath or
increased leg swelling)
* 15% decrease in the 6MWD test
* Worsening of WHO functional class.
Exploratory efficacy measures
* Time to disease progression as defined by >15% decrease in the 6MWD test or a 10% decrease in the FVC.
* Competing risk analysis based on 50 meter decrease in the 6MWD test, 50 meter increase in the 6MWD test or patients who remain within 50 meters of their baseline 6MWD test.
* Change in DLCO (Hbg corrected) baseline to week 26
* Change in FVC baseline to week 26
* Change in Kco from baseline to week 26
* Change in mPAP, PVR and CI baseline to week 26 (only patients with RHC at baseline and week 26)
* Change in heart rate recovery between 6MWD baseline and week 26. Heart rate recovery calculated by the difference between the heart rate at the end of the 6MWD test and after one minute of recovery.
* Change in dyspnea using the Borg scale baseline to week 26
* Change in resting partial pressure of mixed venous oxygen tension baseline to week 26 (only patients with RHC at baseline and week 26)
* Change in resting oxygen saturation using pulse oximetry (SpO2) baseline to week 26
* Change in venous oxygen saturation (SvO2 ) baseline to week 26 (only patients with RHC at baseline and week 26)
* Change in alveolar-arterial (A-a) gradient baseline to week 26
* Change in quality of life (QoL) (SGRQ) baseline to week 26
* Number of clinical worsenings baseline to week 26
* Number of hospitalizations due to disease progression baseline to week 26
* Number of hospital days between groups.
* All-cause mortality baseline to week 26
* Change in NT-proBNP baseline to weeks 18 and 26
* Change in osteopontin, chemokine CCL18, matrix metalloproteinases MMP7 and MMP9 baseline to weeks 18 and 26
* Evaluation and change in echo parameters from baseline to week 26 Endpoints for the long-term phase (week 26 to study completion)
* Change in 6MWD baseline to week 48 and every 12 weeks thereafter until study completion
* Clinical worsening events to week 48 and every 12 weeks thereafter until study completion
* Time to clinical worsening to week 48 and every 12 weeks thereafter until study completion
* Change in WHO functional class baseline to week 48 and every 12 weeks thereafter until study completion
* Change in dyspnea using the Borg scale from baseline to week 48, and 12 weeks thereafter until study completion
* Change in QoL (SGRQ) baseline to week 48 and every 12 weeks thereafter until study completion

Timepoint(s) of evaluation of this end point: 26 Weeks

Secondary ID(s)

2010-024332-42-IT

BAY63-2521/13605

Source(s) of Monetary Support

Bayer HealthCare AG