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

• ClinicalTrials.gov Identifier: NCT02891850
• Recruitment Status: Completed
• First Posted: September 8, 2016
• Last Update Posted: March 31, 2020
• Sponsor: Bayer
• Information provided by (Responsible Party): Bayer

Tracking Information

• First Submitted Date: August 26, 2016
• First Posted Date: September 8, 2016
• Last Update Posted Date: March 31, 2020
• Actual Study Start Date: January 11, 2017
• Actual Primary Completion Date: January 29, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (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: Same as current

Current Secondary Outcome Measures (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 (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: Riociguat rEplacing PDE-5i Therapy evaLuated Against Continued PDE-5i thErapy
• Official Title: 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: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Pulmonary Arterial Hypertension

Intervention

• 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

• 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

Recruitment Information

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

Eligibility Criteria

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

• Sexes Eligible for Study: All

• Ages: 18 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: 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: NCT02891850
• Other Study ID Numbers: 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: Not Provided
• Responsible Party: Bayer
• Study Sponsor: Bayer
• Collaborators: Not Provided

Investigators

• Study Director: Bayer Study Director; Bayer

• PRS Account: Bayer
• Verification Date: March 2020