Back to resultsRiociguat Clinical Effects Studied in Patients With Insufficient Treatment Response to Phosphodiesterase-5 Inhibitor (RESPITE)
Primary Purpose
Hypertension, Pulmonary
Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Riociguat (Adempas, BAY63-2521)
Sponsored by
About this trial
This is an interventional treatment trial for Hypertension, Pulmonary
Eligibility Criteria
Inclusion Criteria:
- Male or female patients (18 -75 years of age) with idiopathic, familial, drug/toxin induced and associated PAH due to congenital heart disease (Group I / Dana Point Classification of PH) demonstrating insufficient response to treatment with PDE-5i for at least 3 months
- Patients with and without endothelin receptor antagonist (ERA) therapy
- World Health Organization Functional Class (WHO FC) III at screening
- 6-minute walking distance (6MWD) of 165-440 m
- Cardiac index <3.0 L/min/m*2.
Exclusion Criteria:
- All types of PH except subtypes of Dana Point Group I specified in the inclusion criteria
- Evidence of clinically significant restrictive or obstructive parenchymal lung diseases
- Diffusing capacity of the lung for carbon monoxide (DLCO) <30% predicted
- History or active state of serious hemoptysis / pulmonary hemorrhage including those managed by bronchial artery embolization
- Patients unable to perform a valid 6MWD test
- Pregnant women (i.e. positive pregnancy test or other signs of pregnancy), or breast feeding women, or women with childbearing potential not using a combination of 2 effective methods of birth control, for example a combination of condoms with a safe and highly effective contraception method (prescription oral contraceptives, contraceptive injections, contraceptive patch, intrauterine device) or a double barrier method is used throughout the study.
Sites / Locations
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Riociguat
Arm Description
Subjects received riociguat film coated immediate-release (IR) tablet 3 times a day (tid) with or without food at a starting dose of 1.0 milligram (mg) and increased by 0.5 mg increments at 2-weekly intervals to a maximum of 2.5 mg tid, until Week 8 (titration phase). An optimal dose was determined based on systolic blood pressure (SBP) and well-being. Thereafter, riociguat continued at the optimal individual dose until Week 24 (Main phase). Dose reductions or stop of study medication for safety reasons were allowed at any time. Increases or re-increases in 0.5 mg steps (maximum dose 2.5 mg) were possible at the investigator's discretion weighing the benefit with potential risks implied. Subjects were offered participation in EDSP and received riociguat 2.5 mg film coated IR tablet 3 tid with or without food for 18 months or until reimbursement.
Outcomes
Primary Outcome Measures
Change from baseline in 6 Minute Walking Distance (6MWD)
6MWD test was used to measure the subjects functional exercise capacity. Subjects were instructed to walk alone, not run, from one end to the other end of the walking course, at their own pace, while attempting to cover as much ground as possible in 6 minutes. No "warm-up" period was performed before the test. Investigators have not walked with the subjects. This was an encouraged test (the person conducting the test encouraged subjects to walk farther or faster by using only standardized phrases).
Secondary Outcome Measures
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT02007629
Brief Title
Riociguat Clinical Effects Studied in Patients With Insufficient Treatment Response to Phosphodiesterase-5 Inhibitor
Acronym
RESPITE
Official Title
An Open-label, International, Multicenter, Single-arm, Uncontrolled, Phase IIIb Study of Riociguat in Patients With Pulmonary Arterial Hypertension (PAH) Who Demonstrate an Insufficient Response to Treatment With Phosphodiesterase-5 Inhibitors (PDE-5i)
Study Type
Interventional
2. Study Status
Record Verification Date
December 2018
Overall Recruitment Status
Completed
Study Start Date
February 18, 2014 (undefined)
Primary Completion Date
December 29, 2016 (Actual)
Study Completion Date
December 29, 2016 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Bayer
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
BAY63-2521 Riociguat leads to the relaxation of smooth muscle cells in pulmonary arteria and may also inhibit abnormal remodeling of lung blood vessels. In patients with pulmonary arterial hypertension Riociguat showed to reduce the pulmonary blood pressure and improved the right heart function without unacceptable side effects. Here dose of Riociguat will be adjusted over 8 weeks then a Maintenance Phase of 16 weeks follows. Patients with Pulmonary Arterial Hypertension treated with stable doses of Phosphodiesterase Type-5 Inhibitors (Eg Sildenafil, Tadalafil) not appropriately responding to therapy will be included. Based on previous evidence and on the different modes of action an improvement of exercise capacity, heart function and quality of life may be expected if PDE5i treatment is transitioned to riociguat.
Where Riociguat is pending market approval or reimbursement once the treatment phase is completed drug can be made available for another 18 months (Extended Drug Supply Phase - EDSP) under study conditions. Patients may also transition at the end of the maintenance period or any time during the EDSP to any program that is intended to provide riociguat until drug approval/reimbursement, e.g. a long-term extension study, compassionate use or named patient program. Study termination is also possible at any time.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hypertension, Pulmonary
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
61 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Riociguat
Arm Type
Experimental
Arm Description
Subjects received riociguat film coated immediate-release (IR) tablet 3 times a day (tid) with or without food at a starting dose of 1.0 milligram (mg) and increased by 0.5 mg increments at 2-weekly intervals to a maximum of 2.5 mg tid, until Week 8 (titration phase). An optimal dose was determined based on systolic blood pressure (SBP) and well-being. Thereafter, riociguat continued at the optimal individual dose until Week 24 (Main phase). Dose reductions or stop of study medication for safety reasons were allowed at any time. Increases or re-increases in 0.5 mg steps (maximum dose 2.5 mg) were possible at the investigator's discretion weighing the benefit with potential risks implied. Subjects were offered participation in EDSP and received riociguat 2.5 mg film coated IR tablet 3 tid with or without food for 18 months or until reimbursement.
Intervention Type
Drug
Intervention Name(s)
Riociguat (Adempas, BAY63-2521)
Intervention Description
Riociguat / BAY63-2521 film-coated tablets will be used in this study at a dosage of either 0.5, 1.0, 1.5, 2.0, and 2.5 mg. 3 times daily
Primary Outcome Measure Information:
Title
Change from baseline in 6 Minute Walking Distance (6MWD)
Description
6MWD test was used to measure the subjects functional exercise capacity. Subjects were instructed to walk alone, not run, from one end to the other end of the walking course, at their own pace, while attempting to cover as much ground as possible in 6 minutes. No "warm-up" period was performed before the test. Investigators have not walked with the subjects. This was an encouraged test (the person conducting the test encouraged subjects to walk farther or faster by using only standardized phrases).
Time Frame
Baseline, Week 12 and Week 24
Other Pre-specified Outcome Measures:
Title
Change From Baseline in Cardiac Index
Description
The cardiac output was measured by using the thermodilution methodology and a respective electronic device. The cardiac index was assessed by dividing the cardiac output by the person's BSA.
Time Frame
Baseline, Week 24
Title
Change From Pre-treatment in N-Terminal Pro-Brain Natriuretic Peptide (NTproBNP)
Description
NT-proBNP cardiac biomarker was used to detect, diagnose, and evaluate the severity of heart failure. A higher level of the marker was indicative of heart failure.
Time Frame
Baseline, Week 12 and Week 24
Title
Change From Baseline in World Health Organization Functional Class (WHO FC)
Description
WHO FC assessment of PAH ranged from functional class I (subjects with PH but without resulting limitation of physical activity); class II (subjects with PH resulting in slight limitation of physical activity); class III (subjects with PH resulting in marked limitation of physical activity); class IV (subjects with PH with inability to carry out any physical activity without symptoms); and class V death. Changes to a lower WHO FC resemble improvement; changes to a higher functional class resemble deterioration of PAH.
Time Frame
Baseline, Week 12 and Week 24
Title
Percentage of Subjects With Clinical Worsening
Description
Clinical worsening was defined as death (all-cause mortality); atrial septostomy; lung transplantation; non-planned PAH-related hospitalisation; start of new PAH treatment (ERA, inhaled or oral prostanoid) or modification of pre-existing treatment, initiation of intravenous or subcutaneous prostanoids; persistent decrease of greater than (>) 15% from baseline or >30% from last measurement in 6MWD; persistent worsening of WHO FC; or appearance or worsening of signs/symptoms of right heart failure not responding to optimised oral diuretic therapy. All identified and suspected clinical worsening events were confirmed by independent central adjudication.
Time Frame
Baseline to Week 24
Title
Change From Baseline in European Quality of life (Qol)-Group (EQ)-5D Questionnaire
Description
EQ-5D was a standardized instrument which was used to measure the health outcome. The EQ-5D was a selfreport questionnaire and needed to be completed by the subject. After the subject filled in the questionnaire, the questionnaire was transferred into the electronic case report form (eCRF). EQ-5D was calculated by two types of questionnaires Part A (descriptive health profile) and Part B (visual analogue scale). Part A, EQ-5D comprised 5-item questionnaires to measure own health profile status (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Each measure has three levels (1. no problems, 2. some problems, 3. extreme problems). In Part B, visual analogue rating scale to measure how good or bad a health state was. Scale was drawn by using thermometer-like scale, on which the best state imagine was marked as 100 and worst state imagine was marked as 0.
Time Frame
Baseline, Week 12 and Week 24
Title
Change from pre-treatment of 6MWD
Time Frame
Baseline, Week 12 and Week 24
Title
Percentage of Subjects Without Clinical Worsening who Achieve at Least WHO FC II and an Improvement in 6 MWD of Greater Than or Equal to (>=) 30 meters
Description
Percentage of subjects without clinical worsening who achieve at least who FC II and an improvement in 6 MWD of >= 30 meters were reported.
Time Frame
Baseline, Week 12 and Week 24
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Male or female patients (18 -75 years of age) with idiopathic, familial, drug/toxin induced and associated PAH due to congenital heart disease (Group I / Dana Point Classification of PH) demonstrating insufficient response to treatment with PDE-5i for at least 3 months
Patients with and without endothelin receptor antagonist (ERA) therapy
World Health Organization Functional Class (WHO FC) III at screening
6-minute walking distance (6MWD) of 165-440 m
Cardiac index <3.0 L/min/m*2.
Exclusion Criteria:
All types of PH except subtypes of Dana Point Group I specified in the inclusion criteria
Evidence of clinically significant restrictive or obstructive parenchymal lung diseases
Diffusing capacity of the lung for carbon monoxide (DLCO) <30% predicted
History or active state of serious hemoptysis / pulmonary hemorrhage including those managed by bronchial artery embolization
Patients unable to perform a valid 6MWD test
Pregnant women (i.e. positive pregnancy test or other signs of pregnancy), or breast feeding women, or women with childbearing potential not using a combination of 2 effective methods of birth control, for example a combination of condoms with a safe and highly effective contraception method (prescription oral contraceptives, contraceptive injections, contraceptive patch, intrauterine device) or a double barrier method is used throughout the study.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Bayer Study Director
Organizational Affiliation
Bayer
Official's Role
Study Director
Facility Information:
City
La Jolla
State/Province
California
ZIP/Postal Code
92093
Country
United States
City
Sacramento
State/Province
California
ZIP/Postal Code
95817
Country
United States
City
Iowa City
State/Province
Iowa
ZIP/Postal Code
52242-1089
Country
United States
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02111
Country
United States
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15212
Country
United States
City
Providence
State/Province
Rhode Island
ZIP/Postal Code
02903
Country
United States
City
Bruxelles - Brussel
ZIP/Postal Code
1070
Country
Belgium
City
Leuven
ZIP/Postal Code
3000
Country
Belgium
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H3T 1E2
Country
Canada
City
Praha 2
ZIP/Postal Code
12808
Country
Czechia
City
GRENOBLE Cedex 09
ZIP/Postal Code
38043
Country
France
City
Le Kremlin Bicetre Cedex
ZIP/Postal Code
94275
Country
France
City
Marseille
ZIP/Postal Code
13005
Country
France
City
Heidelberg
State/Province
Baden-Württemberg
ZIP/Postal Code
69126
Country
Germany
City
Regensburg
State/Province
Bayern
ZIP/Postal Code
93053
Country
Germany
City
Hannover
State/Province
Niedersachsen
ZIP/Postal Code
30625
Country
Germany
City
Köln
State/Province
Nordrhein-Westfalen
ZIP/Postal Code
50924
Country
Germany
City
Dresden
State/Province
Sachsen
ZIP/Postal Code
01307
Country
Germany
City
Leipzig
State/Province
Sachsen
ZIP/Postal Code
04103
Country
Germany
City
Roma
State/Province
Lazio
ZIP/Postal Code
00161
Country
Italy
City
Pavia
State/Province
Lombardia
ZIP/Postal Code
27100
Country
Italy
City
Zürich
ZIP/Postal Code
8091
Country
Switzerland
City
Newcastle Upon Tyne
State/Province
Tyne And Wear
ZIP/Postal Code
NE7 7DN
Country
United Kingdom
City
Clydebank
State/Province
West Dunbartonshire
ZIP/Postal Code
G81 4DY
Country
United Kingdom
City
London
ZIP/Postal Code
NW3 2QG
Country
United Kingdom
City
London
ZIP/Postal Code
SW3 6NP
Country
United Kingdom
12. IPD Sharing Statement
Citations:
PubMed Identifier
27887774
Citation
Hoeper MM, Klinger JR, Benza RL, Simonneau G, Langleben D, Naeije R, Corris PA. Rationale and study design of RESPITE: An open-label, phase 3b study of riociguat in patients with pulmonary arterial hypertension who demonstrate an insufficient response to treatment with phosphodiesterase-5 inhibitors. Respir Med. 2017 Jan;122 Suppl 1:S18-S22. doi: 10.1016/j.rmed.2016.11.001. Epub 2016 Nov 5.
Results Reference
result
PubMed Identifier
28889107
Citation
Hoeper MM, Simonneau G, Corris PA, Ghofrani HA, Klinger JR, Langleben D, Naeije R, Jansa P, Rosenkranz S, Scelsi L, Grunig E, Vizza CD, Chang M, Colorado P, Meier C, Busse D, Benza RL. RESPITE: switching to riociguat in pulmonary arterial hypertension patients with inadequate response to phosphodiesterase-5 inhibitors. Eur Respir J. 2017 Sep 9;50(3):1602425. doi: 10.1183/13993003.02425-2016. Print 2017 Sep.
Results Reference
result
Links:
URL
http://www.clinicaltrialsregister.eu/
Description
Click here to find information about studies related to Bayer Healthcare products conducted in Europe.
Learn more about this trial
Riociguat Clinical Effects Studied in Patients With Insufficient Treatment Response to Phosphodiesterase-5 Inhibitor
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