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Riociguat Clinical Effects Studied in Patients With Insufficient Treatment Response to Phosphodiesterase-5 Inhibitor (RESPITE)

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ClinicalTrials.gov Identifier: NCT02007629
Recruitment Status : Completed
First Posted : December 11, 2013
Last Update Posted : February 21, 2019
Sponsor:
Information provided by (Responsible Party):
Bayer

Tracking Information
First Submitted Date  ICMJE December 6, 2013
First Posted Date  ICMJE December 11, 2013
Last Update Posted Date February 21, 2019
Study Start Date  ICMJE February 18, 2014
Actual Primary Completion Date December 29, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 20, 2019)
Change from baseline in 6 Minute Walking Distance (6MWD) [ Time Frame: Baseline, Week 12 and Week 24 ]
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).
Original Primary Outcome Measures  ICMJE
 (submitted: December 6, 2013)
Change from baseline in 6 minute walking distance [ Time Frame: Baseline and 24 weeks ]
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE
 (submitted: December 6, 2013)
  • Change in cardiac index [ Time Frame: Baseline and 24 weeks ]
  • Change in N-terminal pro-brain natriuretic peptide [ Time Frame: Baseline and 12 weeks,Baseline and 24 weeks ]
  • Change in World Health Organization functional class [ Time Frame: Baseline and 12 weeks,Baseline and 24 weeks ]
  • Proportion of patients with clinical worsening [ Time Frame: Baseline and 12 weeks,Baseline and 24 weeks ]
  • Change in quality of life (Qol) (EuroQol questionnaire) [ Time Frame: Baseline and 12 weeks, Baseline and 24 weeks ]
  • Change in quality of life (Living with pulmonary hypertension questionnaire) [ Time Frame: Baseline and 12 weeks, Baseline and 24 weeks ]
Current Other Pre-specified Outcome Measures
 (submitted: February 20, 2019)
  • Change From Baseline in Cardiac Index [ Time Frame: Baseline, Week 24 ]
    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.
  • Change From Pre-treatment in N-Terminal Pro-Brain Natriuretic Peptide (NTproBNP) [ Time Frame: Baseline, Week 12 and Week 24 ]
    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.
  • Change From Baseline in World Health Organization Functional Class (WHO FC) [ Time Frame: Baseline, Week 12 and Week 24 ]
    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.
  • Percentage of Subjects With Clinical Worsening [ Time Frame: Baseline to Week 24 ]
    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.
  • Change From Baseline in European Quality of life (Qol)-Group (EQ)-5D Questionnaire [ Time Frame: Baseline, Week 12 and Week 24 ]
    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.
  • Change from pre-treatment of 6MWD [ Time Frame: Baseline, Week 12 and Week 24 ]
  • 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 [ Time Frame: Baseline, Week 12 and Week 24 ]
    Percentage of subjects without clinical worsening who achieve at least who FC II and an improvement in 6 MWD of >= 30 meters were reported.
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Riociguat Clinical Effects Studied in Patients With Insufficient Treatment Response to Phosphodiesterase-5 Inhibitor
Official Title  ICMJE 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)
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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Hypertension, Pulmonary
Intervention  ICMJE Drug: Riociguat (Adempas, BAY63-2521)
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
Study Arms  ICMJE Experimental: Riociguat
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: Drug: Riociguat (Adempas, BAY63-2521)
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 4, 2016)
61
Original Estimated Enrollment  ICMJE
 (submitted: December 6, 2013)
70
Actual Study Completion Date  ICMJE December 29, 2016
Actual Primary Completion Date December 29, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Belgium,   Canada,   Czechia,   France,   Germany,   Italy,   Switzerland,   United Kingdom,   United States
Removed Location Countries Czech Republic
 
Administrative Information
NCT Number  ICMJE NCT02007629
Other Study ID Numbers  ICMJE 16719
2013-001759-10 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Bayer
Study Sponsor  ICMJE Bayer
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Bayer Study Director Bayer
PRS Account Bayer
Verification Date December 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP