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

NCT02891850 | Completed Phase 4 Results

• 2 other identifiers: 185882016-001067-36
• Study Type: interventional
• Target: 225
• Locations: 21 countries
• Sites: 81

Brief Summary

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

Conditions

Pulmonary Arterial Hypertension

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (4)

• Change in 6 Minute Walking Distance (6MWD) With Last Observation Carried Forward From Baseline to 24 Weeks

  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

  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

  From baseline and up to 24 weeks

• Number of Participants With Adjudicated Clinical Worsening at Week 24

  Up to 24 weeks

Study Arms (2)

Riociguat

EXPERIMENTAL

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)

PDE-5i

ACTIVE COMPARATOR

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; Drug: Tadalafil

Interventions

Riociguat (Adempas, BAY63-2521) 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).

Riociguat

Sildenafil 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.

PDE-5i

Tadalafil 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.

PDE-5i

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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.
• MWD 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.

You may not qualify if:

• Participation in another interventional clinical study within 30 days prior to screening.
• Previous treatment with riociguat.
• 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).
• 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.

Sponsors & Collaborators

• Bayer: lead

Study Sites (81)

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Phoenix, Arizona, 85012, United States

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Tucson, Arizona, 85724, United States

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Sacramento, California, 95817, United States

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Orlando, Florida, 32803, United States

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Weston, Florida, 33331, United States

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Kansas City, Kansas, 66103, United States

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Louisville, Kentucky, 40202, United States

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Detroit, Michigan, 48202, United States

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Troy, Michigan, 48085, United States

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Newark, New Jersey, 07112, United States

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Mineola, New York, 11501, United States

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New York, New York, 10003, United States

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Rochester, New York, 14623, United States

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Cleveland, Ohio, 44195, United States

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Nashville, Tennessee, 37232, United States

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Dallas, Texas, 75390, United States

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Richmond, Virginia, 23225, United States

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Graz, 8036, Austria

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Leuven, 3000, Belgium

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Belo Horizonte, Minas Gerais, 30130-100, Brazil

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Belo Horizonte, Minas Gerais, 30441-070, Brazil

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Porto Alegre, Rio Grande do Sul, 90050-170, Brazil

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Blumenal, Santa Catarina, 89030-101, Brazil

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São Paulo, 04023-061, Brazil

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São Paulo, 05403-000, Brazil

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Montreal, Quebec, H3T 1E2, Canada

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Prague, 12808, Czechia

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Prague, 140 21, Czechia

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Aarhus N, 8200, Denmark

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Le Kremlin-Bicêtre, 94270, France

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Rouen, 76031, France

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Heidelberg, Baden-Wurttemberg, 69126, Germany

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München, Bavaria, 80639, Germany

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München, Bavaria, 81377, Germany

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Würzburg, Bavaria, 97074, Germany

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Hanover, Lower Saxony, 30625, Germany

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Cologne, North Rhine-Westphalia, 50937, Germany

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Homburg, Saarland, 66421, Germany

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Dresden, Saxony, 01307, Germany

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Leipzig, Saxony, 04103, Germany

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Lübeck, Schleswig-Holstein, 23538, Germany

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Berlin, 14050, Germany

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Giessen, 35390, Germany

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Hamburg, 20246, Germany

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Chaïdári, 124 62, Greece

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Thessaloniki, 546 36, Greece

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Thessaloniki, 57010, Greece

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Napoli, Campania, 80131, Italy

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Rome, Lazio, 00161, Italy

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Pavia, Lombardy, 27100, Italy

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Palermo, Sicily, 90127, Italy

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Nagoya, Aichi-ken, 467-8602, Japan

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Sendai, Miyagi, 980-8574, Japan

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Bunkyo-ku, Tokyo, 113-8655, Japan

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Culiacán, Sinaloa, 80020, Mexico

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Mexico City, 14080, Mexico

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Amsterdam, 1081 HV, Netherlands

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Nijmegen, 6500HB, Netherlands

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Wroclaw, 51-124, Poland

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Almada, Lisbon District, 2801-951, Portugal

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Coimbra, 3000-075, Portugal

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Lisbon, 1649-035, Portugal

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Seoul, 03722, South Korea

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Seoul, 110-744, South Korea

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Seoul, 135-710, South Korea

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Seoul, 138-736, South Korea

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Las Palmas de Gran Canaria, Las Palmas, 35020, Spain

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Barcelona, 08035, Spain

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Barcelona, 08036, Spain

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Toledo, 45004, Spain

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Kaoshiung, 81346, Taiwan

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Tainan, 704, Taiwan

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Taipei, 10016, Taiwan

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Ankara, 06100, Turkey (Türkiye)

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Istanbul, 34-300, Turkey (Türkiye)

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Istanbul, 34093, Turkey (Türkiye)

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Izmir, 34098, Turkey (Türkiye)

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Clydebank, West Dunbartonshire, G81 4DY, United Kingdom

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London, NW3 2QG, United Kingdom

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London, SW3 6NP, United Kingdom

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Sheffield, S10 2JF, United Kingdom

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Related Publications (1)

• 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.

  PMID: 33773120 DERIVED

Related Links

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

MeSH Terms

Conditions

Pulmonary Arterial Hypertension

Interventions

riociguat; Sildenafil Citrate; Tadalafil

Condition Hierarchy (Ancestors)

Hypertension, Pulmonary; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Carbolines; Pyridines; Indole Alkaloids; Indoles; Heterocyclic Compounds, 3-Ring

Results Point of Contact

• Title: Therapeutic Area Head
• Organization: Bayer

clinical-trials-contact@bayer.com

(+) 1-888-8422937

Study Officials

• Bayer Study Director

  Bayer

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 26, 2016
• First Posted: September 8, 2016
• Study Start: January 11, 2017
• Primary Completion: January 29, 2020
• Study Completion: March 3, 2020
• Last Updated: February 26, 2021
• Results First Posted: January 22, 2021

Record last verified: 2021-01

Locations

NL (2); GR (3); DE (13); FR (2); JP (3); AU (1); IT (4); CA (1); BE (1); TU (4); ES (4); TW (3); GB (4); DK (1); PL (1); KR (4); ME (2); PT (3); BR (6); CZ (2); US (17)