Clinical trial NCT02891850: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Pulmonary Arterial Hypertension
Lead sponsor: Bayer
Sponsor class: INDUSTRY
First posted: 2016-09-08
Enrollment: 225
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Number of Participants With Satisfactory Clinical Response at Week 24
timeFrame: At Week 24
Secondary outcomes:
measure: Change in 6 Minute Walking Distance (6MWD) With Last Observation Carried Forward From Baseline to 24 Weeks
timeFrame: From baseline and up to 24 weeks
measure: Change in N-terminal Pro-Brain Natriuretic Peptide (NT-proBNP) With Last Observation Carried Forward at Week 24
timeFrame: From baseline and up to 24 weeks
measure: Change in World Health Organization Functional Class (WHO FC) With Last Observation Carried Forward From Baseline to Week 24
timeFrame: From baseline and up to 24 weeks
measure: Number of Participants With Adjudicated Clinical Worsening at Week 24
timeFrame: Up to 24 weeks
Other outcomes:
Locations:
city: Phoenix
country: United States
state: Arizona
city: Tucson
country: United States
state: Arizona
city: Sacramento
country: United States
state: California
city: Orlando
country: United States
state: Florida
city: Weston
country: United States
state: Florida
city: Kansas City
country: United States
state: Kansas
city: Louisville
country: United States
state: Kentucky
city: Detroit
country: United States
state: Michigan
city: Troy
country: United States
state: Michigan
city: Newark
country: United States
state: New Jersey
city: Mineola
country: United States
state: New York
city: New York
country: United States
state: New York
city: Rochester
country: United States
state: New York
city: Cleveland
country: United States
state: Ohio
city: Nashville
country: United States
state: Tennessee
city: Dallas
country: United States
state: Texas
city: Richmond
country: United States
state: Virginia
city: Graz
country: Austria
city: Leuven
country: Belgium
city: Belo Horizonte
country: Brazil
state: Minas Gerais
city: Belo Horizonte
country: Brazil
state: Minas Gerais
city: Porto Alegre
country: Brazil
state: Rio Grande Do Sul
city: Blumenal
country: Brazil
state: Santa Catarina
city: Sao Paulo
country: Brazil
city: Sao Paulo
country: Brazil
city: Montreal
country: Canada
state: Quebec
city: Praha 2
country: Czechia
city: Praha 4
country: Czechia
city: Aarhus N
country: Denmark
city: Le Kremlin-Bicêtre
country: France
city: Rouen
country: France
city: Heidelberg
country: Germany
state: Baden-Württemberg
city: München
country: Germany
state: Bayern
city: München
country: Germany
state: Bayern
city: Würzburg
country: Germany
state: Bayern
city: Hannover
country: Germany
state: Niedersachsen
city: Köln
country: Germany
state: Nordrhein-Westfalen
city: Homburg
country: Germany
state: Saarland
city: Dresden
country: Germany
state: Sachsen
city: Leipzig
country: Germany
state: Sachsen
city: Lübeck
country: Germany
state: Schleswig-Holstein
city: Berlin
country: Germany
city: Gießen
country: Germany
city: Hamburg
country: Germany
city: Chaidari
country: Greece
city: Thessaloniki
country: Greece
city: Thessaloniki
country: Greece
city: Napoli
country: Italy
state: Campania
city: Roma
country: Italy
state: Lazio
city: Pavia
country: Italy
state: Lombardia
city: Palermo
country: Italy
state: Sicilia
city: Nagoya
country: Japan
state: Aichi
city: Sendai
country: Japan
state: Miyagi
city: Bunkyo-ku
country: Japan
state: Tokyo
city: Seoul
country: Korea, Republic of
city: Seoul
country: Korea, Republic of
city: Seoul
country: Korea, Republic of
city: Seoul
country: Korea, Republic of
city: Culiacan
country: Mexico
state: Sinaloa
city: Mexico D.F.
country: Mexico
city: Amsterdam
country: Netherlands
city: Nijmegen
country: Netherlands
city: Wroclaw
country: Poland
city: Almada
country: Portugal
state: Lisboa
city: Coimbra
country: Portugal
city: Lisboa
country: Portugal
city: Las Palmas de Gran Canaria
country: Spain
state: Las Palmas
city: Barcelona
country: Spain
city: Barcelona
country: Spain
city: Toledo
country: Spain
city: Kaoshiung
country: Taiwan
city: Tainan
country: Taiwan
city: Taipei
country: Taiwan
city: Ankara
country: Turkey
city: Istanbul
country: Turkey
city: Istanbul
country: Turkey
city: Izmir
country: Turkey
city: Clydebank
country: United Kingdom
state: West Dunbartonshire
city: London
country: United Kingdom
city: London
country: United Kingdom
city: Sheffield
country: United Kingdom
Study officials:
affiliation: Bayer
name: Bayer Study Director
role: STUDY_DIRECTOR
References:
citation: 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.