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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT02891850




Registration number
NCT02891850
Ethics application status
Date submitted
26/08/2016
Date registered
8/09/2016
Date last updated
3/07/2019

Titles & IDs
Public title
Riociguat rEplacing PDE-5i Therapy evaLuated Against Continued PDE-5i thErapy
Scientific 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
Secondary ID [1] 0 0
2016-001067-36
Secondary ID [2] 0 0
18588
Universal Trial Number (UTN)
Trial acronym
REPLACE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Pulmonary Arterial Hypertension 0 0
Condition category
Condition code
Cardiovascular 0 0 0 0
Hypertension
Respiratory 0 0 0 0
Other respiratory disorders / diseases
Human Genetics and Inherited Disorders 0 0 0 0
Other human genetics and inherited disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Adempas (Riociguat, BAY63-2521)
Treatment: Drugs - Sildenafil
Treatment: Drugs - Tadalafil

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.

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.


Treatment: Drugs: 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).

Treatment: Drugs: 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.

Treatment: Drugs: 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 code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Efficacy (Y/N) - 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
Timepoint [1] 0 0
at Week 24
Secondary outcome [1] 0 0
Change in 6 Minute Walking Distance (6MWD) from baseline to 24 weeks
Timepoint [1] 0 0
Baseline and Week 24
Secondary outcome [2] 0 0
Change in N-terminal pro-brain natriuretic peptide (NT-proBNP) from baseline to 24 weeks
Timepoint [2] 0 0
Baseline and Week 24
Secondary outcome [3] 0 0
Change in World Health Organization Functional Class (WHO FC) from baseline to 24 weeks
Timepoint [3] 0 0
Baseline and Week 24
Secondary outcome [4] 0 0
Change in clinical worsening from baseline to 24 weeks - 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.
Timepoint [4] 0 0
Baseline and Week 24

Eligibility
Key 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.
Minimum age
18 Years
Maximum age
75 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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 design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD
Recruitment hospital [1] 0 0
- Camperdown
Recruitment hospital [2] 0 0
- Chermside
Recruitment postcode(s) [1] 0 0
2050 - Camperdown
Recruitment postcode(s) [2] 0 0
4032 - Chermside
Recruitment outside Australia
Country [1] 0 0
United States of America
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Arizona
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California
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Connecticut
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Illinois
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Kansas
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Kentucky
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Massachusetts
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Michigan
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Missouri
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New Jersey
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New York
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North Carolina
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Ohio
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Wisconsin
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Austria
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Graz
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Austria
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Innsbruck
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Austria
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Wien
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Belgium
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Bruxelles - Brussel
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Belgium
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Leuven
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Santa Catarina
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Rio de Janeiro
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Sao Paulo
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Alberta
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British Columbia
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Ontario
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Canada
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Quebec
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Czechia
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Praha 2
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Czechia
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Praha 4
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Denmark
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Aarhus N
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France
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Besancon
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France
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GRENOBLE Cedex 09
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France
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France
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France
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Rouen
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Germany
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Bayern
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Germany
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Cambridgeshire
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West Dunbartonshire
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London
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United Kingdom
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Sheffield

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Bayer
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
To demonstrate the effectiveness of riociguat as replacement of phosphodiesterase-5
inhibitors (PDE-5i) therapy in pulmonary arterial hypertension (PAH) patients
Trial website
https://clinicaltrials.gov/show/NCT02891850
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Bayer Study Director
Address 0 0
Bayer
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Bayer Clinical Trials Contact
Address 0 0
Country 0 0
Phone 0 0
(+) 1-888-8422937
Fax 0 0
Email 0 0
clinical-trials-contact@bayer.com
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT02891850