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

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

To demonstrate the effectiveness of riociguat as replacement of phosphodiesterase-5 inhibitors (PDE-5i) therapy in pulmonary arterial hypertension (PAH) patients

Study Overview

• Status: Completed
• Conditions: Pulmonary Arterial Hypertension
• Intervention / Treatment: Drug: Riociguat (Adempas, BAY63-2521); Drug: Sildenafil; Drug: Tadalafil

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
• Enrollment (Actual): 225
• Phase: Phase 4

Contacts and Locations

Study Locations

• Austria
  • Graz, Austria, 8036
• Belgium
  • Leuven, Belgium, 3000
• Brazil
  • Sao Paulo, Brazil, 05403-000
  • Sao Paulo, Brazil, 04023-061
  • Minas Gerais
    • Belo Horizonte, Minas Gerais, Brazil, 30130-100
    • Belo Horizonte, Minas Gerais, Brazil, 30441-070
  • Rio Grande Do Sul
    • Porto Alegre, Rio Grande Do Sul, Brazil, 90050-170
  • Santa Catarina
    • Blumenal, Santa Catarina, Brazil, 89030-101
• Canada
  • Quebec
    • Montreal, Quebec, Canada, H3T 1E2
• Czechia
  • Praha 2, Czechia, 12808
  • Praha 4, Czechia, 140 21
• Denmark
  • Aarhus N, Denmark, 8200
• France
  • Le Kremlin-Bicêtre, France, 94270
  • Rouen, France, 76031
• Germany
  • Berlin, Germany, 14050
  • Gießen, Germany, 35390
  • Hamburg, Germany, 20246
  • Baden-Württemberg
    • Heidelberg, Baden-Württemberg, Germany, 69126
  • Bayern
    • München, Bayern, Germany, 81377
    • München, Bayern, Germany, 80639
    • Würzburg, Bayern, Germany, 97074
  • Niedersachsen
    • Hannover, Niedersachsen, Germany, 30625
  • Nordrhein-Westfalen
    • Köln, Nordrhein-Westfalen, Germany, 50937
  • Saarland
    • Homburg, Saarland, Germany, 66421
  • Sachsen
    • Dresden, Sachsen, Germany, 01307
    • Leipzig, Sachsen, Germany, 04103
  • Schleswig-Holstein
    • Lübeck, Schleswig-Holstein, Germany, 23538
• Greece
  • Chaidari, Greece, 124 62
  • Thessaloniki, Greece, 546 36
  • Thessaloniki, Greece, 57010
• Italy
  • Campania
    • Napoli, Campania, Italy, 80131
  • Lazio
    • Roma, Lazio, Italy, 00161
  • Lombardia
    • Pavia, Lombardia, Italy, 27100
  • Sicilia
    • Palermo, Sicilia, Italy, 90127
• Japan
  • Aichi
    • Nagoya, Aichi, Japan, 467-8602
  • Miyagi
    • Sendai, Miyagi, Japan, 980-8574
  • Tokyo
    • Bunkyo-ku, Tokyo, Japan, 113-8655
• Korea, Republic of
  • Seoul, Korea, Republic of, 138-736
  • Seoul, Korea, Republic of, 110-744
  • Seoul, Korea, Republic of, 135-710
  • Seoul, Korea, Republic of, 03722
• Mexico
  • Mexico D.F., Mexico, 14080
  • Sinaloa
    • Culiacan, Sinaloa, Mexico, 80020
• Netherlands
  • Amsterdam, Netherlands, 1081 HV
  • Nijmegen, Netherlands, 6500HB
• Poland
  • Wroclaw, Poland, 51-124
• Portugal
  • Coimbra, Portugal, 3000-075
  • Lisboa, Portugal, 1649-035
  • Lisboa
    • Almada, Lisboa, Portugal, 2801-951
• Spain
  • Barcelona, Spain, 08036
  • Barcelona, Spain, 08035
  • Toledo, Spain, 45004
  • Las Palmas
    • Las Palmas de Gran Canaria, Las Palmas, Spain, 35020
• Taiwan
  • Kaoshiung, Taiwan, 81346
  • Tainan, Taiwan, 704
  • Taipei, Taiwan, 10016
• Turkey
  • Ankara, Turkey, 06100
  • Istanbul, Turkey, 34-300
  • Istanbul, Turkey, 34093
  • Izmir, Turkey, 34098
• United Kingdom
  • London, United Kingdom, NW3 2QG
  • London, United Kingdom, SW3 6NP
  • Sheffield, United Kingdom, S10 2JF
  • West Dunbartonshire
    • Clydebank, West Dunbartonshire, United Kingdom, G81 4DY
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85012
    • Tucson, Arizona, United States, 85724
  • California
    • Sacramento, California, United States, 95817
  • Florida
    • Orlando, Florida, United States, 32803
    • Weston, Florida, United States, 33331
  • Kansas
    • Kansas City, Kansas, United States, 66103
  • Kentucky
    • Louisville, Kentucky, United States, 40202
  • Michigan
    • Detroit, Michigan, United States, 48202
    • Troy, Michigan, United States, 48085
  • New Jersey
    • Newark, New Jersey, United States, 07112
  • New York
    • Mineola, New York, United States, 11501
    • New York, New York, United States, 10003
    • Rochester, New York, United States, 14623
  • Ohio
    • Cleveland, Ohio, United States, 44195
  • Tennessee
    • Nashville, Tennessee, United States, 37232
  • Texas
    • Dallas, Texas, United States, 75390
  • Virginia
    • Richmond, Virginia, United States, 23225

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Riociguat; 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.	Drug: Riociguat (Adempas, 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).
Active Comparator: PDE-5i; 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.	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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Satisfactory Clinical Response at Week 24	The treatment is assessed as efficient (participants with satisfactory clinical response) 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	At Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in 6 Minute Walking Distance (6MWD) With Last Observation Carried Forward From Baseline to 24 Weeks	Six-minute walk distance (6MWD) was conducted to test the physical limitations of the participant by assessing the participant's exercise capacity. The distance walked by the participant in 6 minutes was measured.	From baseline and up to 24 weeks
Change in N-terminal Pro-Brain Natriuretic Peptide (NT-proBNP) With Last Observation Carried Forward at Week 24	N-terminal pro-brain natriuretic peptide (NT-proBNP) levels in the blood are used for screening, diagnosis of acute congestive heart failure (CHF) and may be useful to establish prognosis in heart failure.	From baseline and up to 24 weeks
Change in World Health Organization Functional Class (WHO FC) With Last Observation Carried Forward From Baseline to Week 24	The participant's functional class was determined by using the WHO classification. Possible classes range from I (patients with pulmonary hypertension (PH) but without resulting limitation of physical activity) to IV (patients with PH with inability to carry out any physical activity without symptoms).	From baseline and up to 24 weeks
Number of Participants With Adjudicated Clinical Worsening at Week 24	Clinical worsening was defined as death of any cause, hospitalization due to worsening pulmonary arterial hypertension (PAH) (adjudicated) or disease progression (adjudicated).	Up to 24 weeks

Collaborators and Investigators

• Sponsor: Bayer

Publications and helpful links

General Publications

• Hoeper MM, Al-Hiti H, Benza RL, Chang SA, Corris PA, Gibbs JSR, Grunig E, Jansa P, Klinger JR, Langleben D, McLaughlin VV, Meyer GMB, Ota-Arakaki J, Peacock AJ, Pulido T, Rosenkranz S, Vizza CD, Vonk-Noordegraaf A, White RJ, Chang M, Kleinjung F, Meier C, Paraschin K, Ghofrani HA, Simonneau G; REPLACE investigators. Switching to riociguat versus maintenance therapy with phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension (REPLACE): a multicentre, open-label, randomised controlled trial. Lancet Respir Med. 2021 Jun;9(6):573-584. doi: 10.1016/S2213-2600(20)30532-4. Epub 2021 Mar 24.

Helpful Links

• Click here to find information about studies related to Bayer Healthcare products conducted in Europe
• Click here to find results for studies related to Bayer products.

Study record dates

Study Major Dates

• Study Start (Actual): January 11, 2017
• Primary Completion (Actual): January 29, 2020
• Study Completion (Actual): March 3, 2020

Study Registration Dates

• First Submitted: August 26, 2016
• First Submitted That Met QC Criteria: September 1, 2016
• First Posted (Estimate): September 8, 2016

Study Record Updates

• Last Update Posted (Actual): February 26, 2021
• Last Update Submitted That Met QC Criteria: February 3, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension, Pulmonary; Hypertension; Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Urological Agents; Enzyme Inhibitors; Phosphodiesterase Inhibitors; Phosphodiesterase 5 Inhibitors; Enzyme Activators; Sildenafil Citrate; Tadalafil; Riociguat
• Other Study ID Numbers: 18588; 2016-001067-36 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated device product: No