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Riociguat rEplacing PDE-5i Therapy evaLuated Against Continued PDE-5i thErapy (REPLACE)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02891850
Recruitment Status : Completed
First Posted : September 8, 2016
Last Update Posted : March 31, 2020
Sponsor:
Information provided by (Responsible Party):
Bayer

Tracking Information
First Submitted Date  ICMJE August 26, 2016
First Posted Date  ICMJE September 8, 2016
Last Update Posted Date March 31, 2020
Actual Study Start Date  ICMJE January 11, 2017
Actual Primary Completion Date January 29, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 1, 2016)
Efficacy (Y/N) [ Time Frame: at Week 24 ]
The treatment is assessed efficient in case at least 2 out of the following 3 criteria were fulfilled
  • 6 Minute Walking Distance increase by ≥ 10% or ≥ 30 m from baseline to Week 24
  • World Health Organization Functional Class (WHO FC) I or II at Week 24
  • N-terminal pro-brain natriuretic peptide (NT-proBNP) reduction ≥ 30% from baseline to Week 24 (NT-proBNP ratio Week 24/baseline ≤ 0.7)
and in absence of the defined criteria of clinical worsening
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 30, 2016)
  • Change in 6 Minute Walking Distance (6MWD) from baseline to 24 weeks [ Time Frame: Baseline and Week 24 ]
  • Change in N-terminal pro-brain natriuretic peptide (NT-proBNP) from baseline to 24 weeks [ Time Frame: Baseline and Week 24 ]
  • Change in World Health Organization Functional Class (WHO FC) from baseline to 24 weeks [ Time Frame: Baseline and Week 24 ]
  • Change in clinical worsening from baseline to 24 weeks [ Time Frame: Baseline and Week 24 ]
    Clinical Worsening:
    • Death of any cause.
    • Hospitalization due to worsening PAH (adjudicated):
    • Non-elective hospitalization due to PAH, or
    • Initiation of intravenous/subcutaneous prostanoid therapy.
    • Disease progression (adjudicated):
    • 6MWD decrease ≥ 15% from baseline (2 measurements on 2 separate days), and
    • Worsening in WHO FC. OR
    • 6MWD decrease ≥ 15% (2 measurements on 2 separate days), and
    • Need of new PAH-targeted medication or decompensated right sided heart failure.
Original Secondary Outcome Measures  ICMJE
 (submitted: September 1, 2016)
  • Change in 6 Minute Walking Distance (6MWD) from baseline to 24 weeks [ Time Frame: Baseline and Week 24 ]
  • Change in N-terminal pro-brain natriuretic peptide (NT-proBNP) from baseline to 24 weeks [ Time Frame: Baseline and Week 24 ]
  • Change in World Health Organization Functional Class (WHO FC) from baseline to 24 weeks [ Time Frame: Baseline and Week 24 ]
  • Change in clinical worsening from baseline to 24 weeks [ Time Frame: Baseline and Week 24 ]
    Clinical Worsening:
    • Death of any cause
    • Hospitalization due to worsening PAH (adjudicated):
    • Non-elective hospitalization due to PAH, or
    • Initiation of intravenous/subcutaneous prostanoid therapy.
    • Disease progression (adjudicated):
    • 6MWD decrease ≥ 15% from baseline (2 measurements on 2 separate days), and
    • Worsening in WHO FC. OR
    • 6MWD decrease ≥ 15% (2 measurements on 2 separate days), and
    • Need of new PAH-targeted medication or decompensated right sided heart failure.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Riociguat rEplacing PDE-5i Therapy evaLuated Against Continued PDE-5i thErapy
Official Title  ICMJE 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
Brief Summary To demonstrate the effectiveness of riociguat as replacement of phosphodiesterase-5 inhibitors (PDE-5i) therapy in pulmonary arterial hypertension (PAH) patients
Detailed Description

Data from a previous single arm study (RESPITE) indicate that transition from PDE5i to riociguat may be feasible, safe and beneficial in patients not adequately responding to PDE5i.

REPLACE is a randomized controlled study to confirm the potential clinical benefit of transition from PDE5i to riociguat. Satisfactory clinical response in patients who are on a stable dose of phosphodiesterase-5inhibitors (PDE-5i) with or without endothelin receptor antagonist (ERA), but not at treatment goal will be compared between one group of patients randomized to maintain current treatment and another group where the PDE5i is replaced by riociguat.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Pulmonary Arterial Hypertension
Intervention  ICMJE
  • Drug: Adempas (Riociguat, BAY63-2521)
    Film-coated tablets will be used in this study at a dosage of 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg. Tablets will be administered orally.The starting dose is 1 mg TID; the intervals between drug intakes should be 6 to 8 hours. The dosage should be increased by 0.5 mg increments in 2 week intervals to 1.5 mg, 2.0 mg, and 2.5 mg TID (maximal total daily dose).
  • Drug: Sildenafil
    Patients randomized to the control arm will continue to receive stable doses of tadalafil (daily dose 20 to 40 mg) or sildenafil (daily dose at least 60 mg) as well as other supportive treatments at the discretion of the investigator.
  • Drug: Tadalafil
    Patients randomized to the control arm will continue to receive stable doses of tadalafil (daily dose 20 to 40 mg) or sildenafil (daily dose at least 60 mg) as well as other supportive treatments at the discretion of the investigator.
Study Arms  ICMJE
  • Experimental: BAY63-2521
    PDE5i treatment will be stopped and riociguat treatment initiated following a defined washout period with a starting dose of 1 mg riociguat TID followed by an 8 weeks dose adjustment phase according to the approved riociguat dose adjustment scheme.
    Intervention: Drug: Adempas (Riociguat, BAY63-2521)
  • Active Comparator: Sildenafil or Tadalafil
    Patients will continue to receive PDE5i treatment as well as other standard of care treatments at the discretion of the investigator up to Week 24. Patients in the experimental and active comparator treatment arms follow the same visit schedule.
    Interventions:
    • Drug: Sildenafil
    • Drug: Tadalafil
Publications * Not Provided

*   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: March 30, 2020)
225
Original Estimated Enrollment  ICMJE
 (submitted: September 1, 2016)
218
Actual Study Completion Date  ICMJE March 3, 2020
Actual Primary Completion Date January 29, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Male and female patients aged 18 to 75 years.
  • 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:

    • Idiopathic
    • Hereditary
    • Drug and toxin induced PAH
    • 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)
  • 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).
  • WHO FC III at screening and at randomization.
  • 6MWD test between 165 m and 440 m at screening and at randomization.
  • Stable dose of diuretics, if used, for at least 30 days prior to and at randomization.
  • Patients who are able to understand and follow instructions and who are able to participate in the study for the entire study.
  • 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.
  • 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.

Exclusion Criteria:

  • Participation in another interventional clinical study within 30 days prior to screening.
  • All types of PH (including PH-IIP) except subtypes of Dana Point Group I specified in the inclusion criteria.
  • Previous treatment with riociguat.
  • 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 2 effective contraception methods (as laid out in inclusion criterion) throughout the study.
  • 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.
  • Relevant obstructive and restrictive or other lung diseases.
  • Patients with underlying medical disorders with an anticipated life expectancy below 2 years (e.g., active cancer disease with localized and/or metastasized tumor mass).
  • Cardiovascular exclusion criteria like left ventricular disease, coronary heart disease or stroke within previous 3 months.
  • Patients with hypersensitivity to the investigational drug or any of the excipients.
  • Patients unable to perform a valid 6MWD test (e.g., orthopedic disease, peripheral artery occlusive disease, which affects the patient's ability to walk). 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 variance of more than 15% between the screening and the randomization (i.e., baseline) 6MWD test.
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 Austria,   Belgium,   Brazil,   Canada,   Czechia,   Denmark,   France,   Germany,   Greece,   Italy,   Japan,   Korea, Republic of,   Mexico,   Netherlands,   Poland,   Portugal,   Spain,   Taiwan,   Turkey,   United Kingdom,   United States
Removed Location Countries Australia,   Switzerland
 
Administrative Information
NCT Number  ICMJE NCT02891850
Other Study ID Numbers  ICMJE 18588
2016-001067-36 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
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 March 2020

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