Randomized, double-blind, placebo-controlled, multi-centre, multi-national study to evaluate the efficacy and safety of oral BAY 63-2521 (1 mg, 1.5 mg, 2 mg, or 2.5 mg tid) in patients with Chronic Thromboembolic Pulmonary Hypertension (CTEPH). - CHEST-1 Study

• Register: EUCTR
• Last refreshed on: 28 February 2019
• Main ID: EUCTR2007-000072-16-SK
• Date of registration: 10/09/2009
• Prospective Registration: Yes
• Primary sponsor: Bayer HealthCare AG
• Public title: Randomized, double-blind, placebo-controlled, multi-centre, multi-national study to evaluate the efficacy and safety of oral BAY 63-2521 (1 mg, 1.5 mg, 2 mg, or 2.5 mg tid) in patients with Chronic Thromboembolic Pulmonary Hypertension (CTEPH). - CHEST-1 Study
• Scientific title: Randomized, double-blind, placebo-controlled, multi-centre, multi-national study to evaluate the efficacy and safety of oral BAY 63-2521 (1 mg, 1.5 mg, 2 mg, or 2.5 mg tid) in patients with Chronic Thromboembolic Pulmonary Hypertension (CTEPH). - CHEST-1 Study
• Date of first enrolment: 23/11/2009
• Target sample size: 270
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2007-000072-16
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Austria, Belgium, Czech Republic, Denmark, France, Germany, Ireland, Italy, Netherlands, Portugal, Slovakia, Spain, United Kingdom

Key inclusion & exclusion criteria

Inclusion criteria:
• 18 to 75 years of age at Visit 1.
The lower age limit may be higher if legally requested in the participating countries.
• Male and female patients with CTEPH and a 6MWD Test between 150 m and 450 m either defined as:
o Inoperable, with pulmonary vascular resistance >480 dyn*sec*cm-5 measured at least 90 days after start of full anticoagulation and mean pulmonary artery pressure >25 mmHg
The inoperability of CTEPH patients, considered as ineligible for Pulmonary Endarterectomy (PEA) by the investigators, needs to be confirmed by an experienced surgeon before randomization.
From the study perspective, a surgeon is regarded as “experienced”, if she/he performed more than 20 PEAs in 2008 (will be documented by a declaration; see appendix 10.14.1).
Investigators who cooperate with an experienced surgeon, forward their screening cases to the respective surgeon for the study related inoperability assessment. Investigators, who do not cooperate with an experienced surgeon, forward their screening cases to a surgical adjudication committee composed of experienced surgeons nominated by the sponsor (for further details refer to Section 10.14, and the operability assessment manual).

or
o with persisting or recurrent PH after Pulmonary Endarterectomy (Patients must have a PVR >480 dyn*sec*cm-5 measured at least 180 days after surgery)
For patients with persisting or recurrent PH after PEA no study related operability assessment must be performed (Note: patients with evidence for recurrent thromboembolism are excluded from the trial / see Section 4.2.3 “Cardiovascular Exclusions”).
Note: With respect to the verification of the inclusion criteria, PAPmean and PVR are considered as calculated parameters. For the respective calculations refer to sections 4.6.4 and 10.5.
• Unspecific treatments which may also be used for the treatment of pulmonary hypertension such as oral anticoagulants, diuretics, digitalis, calcium channel blockers or oxygen supplementation are permitted. However, treatment with anticoagulants must have been started at least 90 days before Visit 1 and treatment with diuretics needs to be stable for at least 30 days before Visit 1.
• Patients with supplemental long-term oxygen therapy can be included, if the amount of supplemental oxygen and the delivery method was stable for at least 90 day before Visit 1.
• Right-heart catheterization results for the definite diagnosis of PH must not be older than 6 weeks at Visit 1 (will be considered as baseline values), must have been measured after at least 90 days of full anticoagulation, and must have been measured in collaboration with the participating center under standardized conditions (refer to the study specific Right Heart Catheterization Manual). If the respective measurements have not been performed in context with the patient’s regular diagnostic work up, they have to be performed as a part of the study during the Pre-Treatment Phase (after the patient signed the informed consent) or at Visit 1 before randomization.
• Women without childbearing potential defined as postmenopausal women (= permanent absence of monthly periods for more than 2 years), women with bilateral tubal ligation, women with bilateral ovarectomy, and women with hysterectom
Exclusion criteria:
Patient’s participating in another clinical trial during the study or within 30 days before Visit 1.
• Pregnant women (i.e. positive serum ß-human-chorionic-gonadotropin test or other signs of pregnancy), or breast feeding women, or women with childbearing potential not using a combination of condoms and a safe and highly effective contraception method (hormonal contraception with implants or combined oral contraceptives, certain IUDs).
• 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.
• Patient’s with substance abuse (e.g. alcohol or drug abuse) within the previous 180 days before Visit 1.
• Patients with underlying medical disorders with an anticipated life expectancy below 2 years (eg active cancer disease with localized and/or metastasized tumor mass).
• Patients with a history of severe allergies or multiple drug allergies.
• Patients with hypersensitivity to the investigational drug or any of the excipients.
• Patients unable to perform a valid 6MWD Test (eg patients with a severe peripheral artery occlusive disease). Note: Patients, who require walking aids, may be included, if in the opinion of the investigator the walking distance is not impaired.
• Patients with a relative difference (ie absolute difference/mean) of more than 15% between the eligibility- and the baseline 6MWD test.

Medication/Treatment Exclusions:
Patients who are screened for possible participation in the study must not been 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.
The following specific medications are not allowed:
Pre-Treatment within the last 90 days before Visit 1:
• Endothelin Receptor Antagonists
• Prostacycline analogues.
• Specific (eg Sildenafil or Tadalafil) or unspecific Phosphodiesterase Inhibitors (eg Dipyridamole, Theophylline).
• NO donors (eg Nitrates).

Pulmonary Disease Exclusions:
• All types of pulmonary hypertension except subtypes 4.1 and 4.2 of the Venice Clinical Classification of Pulmonary Hypertension.
• Moderate to severe obstructive lung disease (Forced Expiratory Volume < 60% predicted).
The predicted Forced Expiratory Volume (FEV) is a calculated value. For the calculation refer to section 10.4
• Severe restrictive lung disease (Total Lung Capacity <70% predicted).
The predicted Total Lung Capacity (TCL) is a calculated value. For the calculation refer to section 10.4
• Severe congenital abnormalities of the lungs, thorax, and diaphragm.

Exclusions related to abnormalities in blood gases (capillary or arterial at rest):
• SaO2 < 88% despite supplemental oxygen therapy.
• PaO2 < 55 mmHg despite supplemental oxygen therapy.
• PaCO2 > 45 mmHg.

Cardiovascular Exclusions:
• Uncontrolled arterial hypertension (Systolic blood pressure >180 mmHg and /or diastolic blood pressure >110 mmHg).
• Systoli

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

Health Condition(s) or Problem(s) studied

Chronic Thromboembolic Pulmonary Hypertension

Intervention(s)

Product Name: BAY 63-2521 tablets 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: BAY 63-2521
Other descriptive name: Methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo [3,4-b]pyridine-3-yl]-5-pyrimidinyl(methyl)carb
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

Product Name: BAY 63-2521 tablets 1 mg
Product Code: BAY 63-2521
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: riociguat
CAS Number: 625115-55-1
Current Sponsor code: BAY 63-2521
Other descriptive name: Methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo [3,4-b]pyridine-3-yl]-5-pyrimidinyl(methyl)carb
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 1-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Product Name: BAY 63-2521 tablets 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: BAY 63-2521
Other descriptive name: Methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo [3,4-b]pyridine-3-yl]-5-pyrimidinyl(methyl)carb
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 1.5-
Pha

Primary Outcome(s)

Main Objective: To assess the efficacy and safety of oral BAY 63-2521 in patients with inoperable Chronic Thromboembolic Pulmonary Hypertension (CTEPH) or recurrent or persisting pulmonary hypertension after surgical treatment. The optimized dose reached after individual dose titration (starting with 1 mg tid and if tolerated up-titrated after two weeks up to 1.5 mg or 2 mg or 2.5 mg tid) will be compared with placebo.

Primary end point(s): The primary endpoint is change from baseline in 6 Minute Walking Distance (6MWD) after 16 weeks.

Secondary Objective:

Secondary ID(s)

BAY 63-2521/11348

2007-000072-16-DE

Ethics review

Status: Approved
Approval date:
Contact:

Results

• Results available: Yes
• Date Posted: 05/11/2014
• Date Completed: 27/06/2012
• URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2007-000072-16/results