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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/study/NCT02310672
Registration number
NCT02310672
Ethics application status
Date submitted
4/12/2014
Date registered
8/12/2014
Date last updated
24/09/2020
Titles & IDs
Public title
REPAIR: Right vEntricular Remodeling in Pulmonary ArterIal hypeRtension
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Scientific title
A Prospective, Multicenter, Single-arm, Open-label, Phase 4 Study to Evaluate the Effects of Macitentan on Right vEntricular Remodeling in Pulmonary ArterIal hypeRtension Assessed by Cardiac Magnetic Resonance Imaging
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Secondary ID [1]
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AC-055-403
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Universal Trial Number (UTN)
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Trial acronym
REPAIR
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Pulmonary Arterial Hypertension
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Condition category
Condition code
Respiratory
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Other respiratory disorders / diseases
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Human Genetics and Inherited Disorders
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Other human genetics and inherited disorders
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Cardiovascular
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Hypertension
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Cardiovascular
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Other cardiovascular diseases
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - Macitentan
Experimental: Macitentan - All patients take open-label macitentan 10mg o.d.
Treatment: Drugs: Macitentan
All patients take open-label macitentan 10mg o.d.
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Change From Baseline in Right Ventricular Stroke Volume (RVSV) to Week 26
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Assessment method [1]
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Change from baseline in RVSV assessed by cardiac magnetic resonance imaging (MRI) from pulmonary artery flow was reported at Week 26. Primary analysis were based on interim results as pre-planned and the primary outcome measures data table reported is finalized as is.
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Timepoint [1]
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Baseline and Week 26
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Primary outcome [2]
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Ratio of Week 26 to Baseline Pulmonary Vascular Resistance (PVR)
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Assessment method [2]
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Ratio of Week 26 to baseline PVR as assessed by RHC was reported. PVR represents the resistance against which the right ventricle needs to pump. PVR is determined by right heart catheterization (RHC). PVR was calculated as 80\*(Mean pulmonary arterial pressure \[mPAP\] -\[Pulmonary capillary wedge pressure {PCWP} or Left ventricular end diastolic pressure {LVEDP} if PCWP not available/cardiac output \[CO\]). Primary analysis were based on interim results as pre-planned and the primary outcome measures data table reported is finalized as is.
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Timepoint [2]
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Baseline and Week 26
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Secondary outcome [1]
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Change From Baseline in Right Ventricular End Diastolic Volume (RVEDV) to Week 26
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Assessment method [1]
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Change from baseline to Week 26 in RVEDV assessed by cardiac MRI was reported.
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Timepoint [1]
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Baseline to Week 26
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Secondary outcome [2]
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Change From Baseline in Right Ventricular End Systolic Volume (RVESV) to Week 26
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Assessment method [2]
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Change from baseline to Week 26 in RVESV assessed by cardiac MRI was reported.
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Timepoint [2]
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Baseline to Week 26
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Secondary outcome [3]
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Change From Baseline in Right Ventricular Ejection Fraction (RVEF) to Week 26 (% Blood Volume)
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Assessment method [3]
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Change from baseline to Week 26 in RVEF based on pulmonary artery flow assessed by cardiac MRI was reported.
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Timepoint [3]
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Baseline to Week 26
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Secondary outcome [4]
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Change From Baseline in Right Ventricle (RV) Mass to Week 26
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Assessment method [4]
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Change from baseline to Week 26 in RV mass assessed by cardiac MRI was reported.
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Timepoint [4]
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Baseline to Week 26
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Secondary outcome [5]
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Change From Baseline in Six-minutes Walk Distance (6MWD) to Week 26
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Assessment method [5]
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6MWD is a non-encouraged test performed in a 30 meter (m) long flat corridor, where the participant is instructed to walk as far as possible, back and forth around two cones, with the permission to slow down, rest, or stop if needed. This test is used to assess exercise capacity. The test was performed about 30 minutes after study drug administration. Any increase in the walk distance was considered improvement from baseline.
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Timepoint [5]
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Baseline to Week 26
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Secondary outcome [6]
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Change From Baseline in World Health Organization Functional Class (WHO FC) to Week 26
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Assessment method [6]
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WHO FC is a classification which reflects disease severity based on symptoms. WHO Functional Classification of pulmonary hypertension comprises of Class I (participants with pulmonary hypertension but without resulting limitation of physical activity), II (participants with pulmonary hypertension resulting in slight limitation of physical activity), III (participants with pulmonary hypertension resulting in marked limitation of physical activity) and IV (participants with pulmonary hypertension with inability to carry out any physical activity without symptoms). Changes from baseline to Week 26 included: improvement (change from a higher to a lower FC), worsening (change from a lower to a higher FC) or unchanged/stable (same FC at baseline and at the post-baseline time point).
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Timepoint [6]
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Baseline to Week 26
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Eligibility
Key inclusion criteria
1. Signed informed consent prior to any study-mandated procedure
2. Symptomatic pulmonary arterial hypertension (PAH)
3. World Health Organization (WHO) Functional Class (FC) I to III
4. PAH etiology belonging to one of the following groups according to Nice classification:
* Idiopathic PAH
* Heritable PAH
* Drug- and toxin-induced PAH
* PAH associated with congenital heart diseases: only simple (atrial septal defect, ventricular septal defect, patent ductus arteriosus) congenital systemic to pulmonary shunts at least 2 year post surgical repair
5. Hemodynamic diagnosis of PAH confirmed by right heart catheterization (RHC) during screening showing:
• mean pulmonary arterial pressure (mPAP) = 25 mmHg and
* PCWP (pulmonary capillary wedge pressure) or left ventricular end diastolic pressure (LVEDP) = 12 mmHg and pulmonary vascular resistance (PVR) = 4 Wood Units (WU) (320 dyn.sec.cm-5) or
* 12 mmHg = PCWP or LVEDP = 15 mmHg and PVR = 6WU (480 dyn.sec.cm-5)
6. 6-minute walk distance (6MWD) = 150 m during screening
7. For patients treated with oral diuretics, treatment dose must have been stable at least 1 month prior to RHC during the screening period
8. For patients treated with phosphodiesterase type-5 (PDE-5) inhibitors, treatment dose must have been stable at least 3 months prior to RHC during the screening period
9. For patients treated with beta blockers, treatment dose must have been stable at least 1 month prior to the RHC during the screening period
10. Men or women =18 and < 65 years
11. Women of childbearing potential (defined in protocol) must:
* Have a negative serum pregnancy test during screening and a negative urine pregnancy test on Day 1, and
* Agree to use reliable methods of contraception (defined in protocol) from screening up to 30 days after study treatment discontinuation, and
* Agree to perform monthly pregnancy tests up to 30 days after study treatment discontinuation
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Minimum age
18
Years
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Maximum age
64
Years
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
1. Body weight < 40 kg
2. Body mass index (BMI) > 35kg/m2. For patients with 30kg/m2 < BMI < 35kg/m2, an eligibility form will be submitted to a Steering Committee member who will reserve the right to exclude the patient.
3. Pregnancy, breastfeeding or intention to become pregnant during the study
4. Recently started (< 8 weeks prior to informed consent signature) or planned cardio-pulmonary rehabilitation program
5. Known concomitant life-threatening disease with a life expectancy < 12 months
6. Any condition likely to affect protocol or treatment compliance
7. Hospitalization for PAH within 3 months prior to informed consent signature
8. Left atrial volume indexed for body surface area = 43mL/m2 by echocardiography or cardiac MRI
9. Valvular disease grade 2 or higher
10. History of pulmonary embolism or deep vein thrombosis
11. Documented moderate to severe chronic obstructive pulmonary disease
12. Documented moderate to severe restrictive lung disease
13. Historical evidence of significant coronary artery disease established by:
* History of myocardial infarction or
* More than 50% stenosis in a coronary artery (by percutaneous coronary intervention or angiography) or
* Elevation of the ST segment on electrocardiogram or
* History of coronary artery bypass grafting or
* Stable angina
14. Diabetes mellitus
15. Moderate to severe renal insufficiency (calculated creatinine clearance < 60 mL/min/1.73 m2)
16. Cancer
17. Systolic blood pressure < 90 mmHg
18. Severe hepatic impairment (with or without cirrhosis) according to National Cancer Institute organ dysfunction working group criteria, defined as total bilirubin > 3 × upper limit of the normal range (ULN) accompanied by an aspartate aminotransferase (AST) elevation > ULN at Screening.
19. Hemoglobin < 100g/L
20. AST and/or alanine aminotransferase (ALT) > 3× ULN
21. Need for dialysis
22. Responders to acute vasoreactivity test based on medical history
23. Prior use of endothelin receptor antagonists (ERAs), stimulators of soluble guanylate cyclase or prostacyclin or prostacyclin analogues
24. Treatment with strong inducers of cytochrome P450 isozyme 3A4 (CYP3A4) within 4 weeks prior to study treatment initiation (e.g., carbamazepine, rifampicin, rifabutin, phenytoin and St. John's Wort)
25. Treatment with strong inhibitors of CYP3A4 within 4 weeks prior to study treatment initiation (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir, and saquinavir)
26. Treatment with another investigational drug (planned, or taken within the 3 months prior to study treatment initiation).
27. Hypersensitivity to any ERA or any excipients of the formulation of macitentan (lactose, magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate, polyvinyl alcohol, polysorbate, titanium dioxide, talc, xanthan gum, and lecithin soya)
28. Claustrophobia
29. Permanent cardiac pacemaker, automatic internal cardioverter
30. Metallic implant (e.g., defibrillator, neurostimulator, hearing aid, permanent use of infusion device)
31. Atrial fibrillation, multiple premature ventricular or atrial contractions, or any other condition that would interfere with proper cardiac gating during MRI.
32. For patients enrolling in the metabolism sub-study only: glucose intolerance
33. For patients enrolling in the biopsy sub-study only: PAH etiology belonging to Nice classification 1.4.4: PAH associated with congenital heart diseases
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Study design
Purpose of the study
Treatment
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Allocation to intervention
NA
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Single group
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Other design features
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Phase
Phase 4
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
1/06/2015
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
10/09/2019
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Sample size
Target
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Accrual to date
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Final
89
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Recruitment in Australia
Recruitment state(s)
QLD
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Recruitment hospital [1]
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The Prince Charles Hospital - Chermside
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Recruitment postcode(s) [1]
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4032 - Chermside
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Recruitment outside Australia
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United States of America
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Massachusetts
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United States of America
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Minnesota
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United States of America
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Missouri
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New Jersey
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United States of America
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New York
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United States of America
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Pennsylvania
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Texas
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Wisconsin
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France
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Clermont-Ferrand
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France
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La Tronche
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France
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Lille Cedex
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France
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Nancy
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France
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Nantes Cedex 01
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France
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Nice
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France
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Paris
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Germany
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Bonn
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Germany
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Heidelberg
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Germany
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Köln
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Germany
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Mainz
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Hong Kong
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Hong Kong
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Israel
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Beer-Sheva
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Israel
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Jerusalem
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Italy
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Bologna
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Italy
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Pavia
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Malaysia
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George Town
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Malaysia
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Kuala Lumpur
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Netherlands
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Amsterdam
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Netherlands
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Maastricht
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Nieuwegein
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Netherlands
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Nijmegen
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Netherlands
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Rotterdam
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Russian Federation
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Moscow
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Russian Federation
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Saint Petersburg
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Singapore
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Singapore
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United Kingdom
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Glasgow
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United Kingdom
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London
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United Kingdom
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Sheffield
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Funding & Sponsors
Primary sponsor type
Commercial sector/industry
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Name
Actelion
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Address
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Ethics approval
Ethics application status
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Summary
Brief summary
The study evaluates the effect of macitentan on right ventricular and hemodynamic properties in patients with symptomatic pulmonary arterial hypertension. Patients are treated with macitentan for 1 year. Patients undergo right heart catheterization (RHC) at baseline and Week 26. They also undergo cardiac magnetic resonance imaging (MRI) at baseline, Week 26 and Week 52. Safety is monitored throughout the study. The study has three stub-studies. Each patient can participate in no sub-study or in one sub-study. The sub-studies are: (1) metabolism sub-study (with PET-MR scans); (2) biopsy sub-study (biopsies taken during the RHC); (3) Echo sub-study.
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Trial website
https://clinicaltrials.gov/study/NCT02310672
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Trial related presentations / publications
Vonk Noordegraaf A, Channick R, Cottreel E, Kiely DG, Marcus JT, Martin N, Moiseeva O, Peacock A, Swift AJ, Tawakol A, Torbicki A, Rosenkranz S, Galie N. The REPAIR Study: Effects of Macitentan on RV Structure and Function in Pulmonary Arterial Hypertension. JACC Cardiovasc Imaging. 2022 Feb;15(2):240-253. doi: 10.1016/j.jcmg.2021.07.027. Epub 2021 Nov 17.
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Public notes
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Contacts
Principal investigator
Name
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Loïc Perchenet
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Address
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Actelion
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Contact person for public queries
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Contact person for scientific queries
No information has been provided regarding IPD availability
What supporting documents are/will be available?
No Supporting Document Provided
Type
Other Details
Attachment
Study protocol
https://cdn.clinicaltrials.gov/large-docs/72/NCT02310672/Prot_000.pdf
Statistical analysis plan
https://cdn.clinicaltrials.gov/large-docs/72/NCT02310672/SAP_001.pdf
Results publications and other study-related documents
No documents have been uploaded by study researchers.
Results are available at
https://clinicaltrials.gov/study/NCT02310672
Download to PDF