Riociguat rEplacing PDE-5i Therapy evaLuated Against Continued PDE-5i thErapy

NCT ID: NCT02891850

Last Updated: 2021-02-26

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 225 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-01-11
• Study Completion Date: 2020-03-03

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.

Conditions

Pulmonary Arterial Hypertension

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Riociguat (Adempas, BAY63-2521)

Intervention Type: DRUG

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).

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.

Group Type: ACTIVE_COMPARATOR

Sildenafil

Intervention Type: DRUG

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.

Tadalafil

Intervention Type: DRUG

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.

Interventions

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).

Intervention Type: 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.

Intervention Type: 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.

Intervention Type: DRUG

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.

• 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).

Exclusion Criteria

• Participation in another interventional clinical study within 30 days prior to screening.
• 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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Bayer

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Bayer Study Director

Role: STUDY_DIRECTOR

Bayer

Locations

Phoenix, Arizona, United States

Tucson, Arizona, United States

Sacramento, California, United States

Orlando, Florida, United States

Weston, Florida, United States

Kansas City, Kansas, United States

Louisville, Kentucky, United States

Detroit, Michigan, United States

Troy, Michigan, United States

Newark, New Jersey, United States

Mineola, New York, United States

New York, New York, United States

Rochester, New York, United States

Cleveland, Ohio, United States

Nashville, Tennessee, United States

Dallas, Texas, United States

Richmond, Virginia, United States

Graz, , Austria

Leuven, , Belgium

Belo Horizonte, Minas Gerais, Brazil

Belo Horizonte, Minas Gerais, Brazil

Porto Alegre, Rio Grande do Sul, Brazil

Blumenal, Santa Catarina, Brazil

São Paulo, , Brazil

São Paulo, , Brazil

Montreal, Quebec, Canada

Prague, , Czechia

Prague, , Czechia

Aarhus N, , Denmark

Le Kremlin-Bicêtre, , France

Rouen, , France

Heidelberg, Baden-Wurttemberg, Germany

München, Bavaria, Germany

München, Bavaria, Germany

Würzburg, Bavaria, Germany

Hanover, Lower Saxony, Germany

Cologne, North Rhine-Westphalia, Germany

Homburg, Saarland, Germany

Dresden, Saxony, Germany

Leipzig, Saxony, Germany

Lübeck, Schleswig-Holstein, Germany

Berlin, , Germany

Giessen, , Germany

Hamburg, , Germany

Chaïdári, , Greece

Thessaloniki, , Greece

Thessaloniki, , Greece

Napoli, Campania, Italy

Rome, Lazio, Italy

Pavia, Lombardy, Italy

Palermo, Sicily, Italy

Nagoya, Aichi-ken, Japan

Sendai, Miyagi, Japan

Bunkyo-ku, Tokyo, Japan

Culiacán, Sinaloa, Mexico

Mexico City, , Mexico

Amsterdam, , Netherlands

Nijmegen, , Netherlands

Wroclaw, , Poland

Almada, Lisbon District, Portugal

Coimbra, , Portugal

Lisbon, , Portugal

Seoul, , South Korea

Seoul, , South Korea

Seoul, , South Korea

Seoul, , South Korea

Las Palmas de Gran Canaria, Las Palmas, Spain

Barcelona, , Spain

Barcelona, , Spain

Toledo, , Spain

Kaoshiung, , Taiwan

Tainan City, , Taiwan

Taipei, , Taiwan

Ankara, , Turkey (Türkiye)

Istanbul, , Turkey (Türkiye)

Istanbul, , Turkey (Türkiye)

Izmir, , Turkey (Türkiye)

Clydebank, West Dunbartonshire, United Kingdom

London, , United Kingdom

London, , United Kingdom

Sheffield, , United Kingdom

Countries

United States; Austria; Belgium; Brazil; Canada; Czechia; Denmark; France; Germany; Greece; Italy; Japan; Mexico; Netherlands; Poland; Portugal; South Korea; Spain; Taiwan; Turkey (Türkiye); United Kingdom

References

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.

Reference Type: DERIVED

PMID: 33773120 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

http://clinicaltrials.bayer.com/

Click here to find results for studies related to Bayer products.

http://www.clinicaltrialsregister.eu/

Click here to find information about studies related to Bayer Healthcare products conducted in Europe

Other Identifiers

2016-001067-36

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

18588

Identifier Type: -

Identifier Source: org_study_id