Clinical trial NCT02310672: REPAIR: Right vEntricular Remodeling in Pulmonary ArterIal hypeRtension
Official 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Pulmonary Arterial Hypertension
Keywords: Pulmonary Arterial Hypertension
Lead sponsor: Actelion
Sponsor class: INDUSTRY
First posted: 2014-12-08
Enrollment: 89
Sex: ALL
Minimum age (years): 18
Maximum age (years): 64
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

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

Primary outcomes:
measure: Change From Baseline in Right Ventricular Stroke Volume (RVSV) to Week 26
timeFrame: Baseline and Week 26
measure: Ratio of Week 26 to Baseline Pulmonary Vascular Resistance (PVR)
timeFrame: Baseline and Week 26
Secondary outcomes:
measure: Change From Baseline in Right Ventricular End Diastolic Volume (RVEDV) to Week 26
timeFrame: Baseline to Week 26
measure: Change From Baseline in Right Ventricular End Systolic Volume (RVESV) to Week 26
timeFrame: Baseline to Week 26
measure: Change From Baseline in Right Ventricular Ejection Fraction (RVEF) to Week 26 (% Blood Volume)
timeFrame: Baseline to Week 26
measure: Change From Baseline in Right Ventricle (RV) Mass to Week 26
timeFrame: Baseline to Week 26
measure: Change From Baseline in Six-minutes Walk Distance (6MWD) to Week 26
timeFrame: Baseline to Week 26
measure: Change From Baseline in World Health Organization Functional Class (WHO FC) to Week 26
timeFrame: Baseline to Week 26
Other outcomes:
Locations:
city: Boston
country: United States
facility: Massachussetts General Hospital
state: Massachusetts
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: New Brunswick
country: United States
facility: Rudgers New Jersey Medical School
state: New Jersey
city: New York
country: United States
facility: Cornell University
state: New York
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Dallas
country: United States
facility: University of Texas Southwestern Medical
state: Texas
city: Milwaukee
country: United States
facility: St. Luke's Medical Center
state: Wisconsin
city: Chermside
country: Australia
facility: The Prince Charles Hospital
state: Queensland
city: Clermont-Ferrand
country: France
facility: Hopital Gabriel Montpied
city: La Tronche
country: France
facility: Hôpital Michallon
city: Lille Cedex
country: France
facility: "CHRU de Lille - Hôpital Albert Calmette "
city: Nancy
country: France
facility: Hopital de Brabois
city: Nantes Cedex 01
country: France
facility: Hôpital Laennec
city: Nice
country: France
facility: Hôpital Pasteur
city: Paris
country: France
facility: Hôpital Européen Georges-Pompidou
city: Bonn
country: Germany
facility: Medizinische Klinik und Poliklinik II Universitätsklinik Bonn
city: Heidelberg
country: Germany
facility: Thoraxklinik am Universitätsklinikum Heidelberg
city: Köln
country: Germany
facility: Universitätsklinikum Köln Herzzentrum / Klinik III für Innere Medizin
city: Mainz
country: Germany
facility: Universitätsmedizin der Johannes Gutenberg-Universität Mainz Centrum für Thrombose und Hämostase
city: Hong Kong
country: Hong Kong
facility: Grantham Hospital, Cardiac Medical Unit
city: Hong Kong
country: Hong Kong
facility: Queen Mary Hospital
city: Hong Kong
country: Hong Kong
facility: United Christian Hospital
city: Beer-Sheva
country: Israel
facility: Pulmonology institute, Soroka Medical Center
city: Jerusalem
country: Israel
facility: Shaare Zedek Medical Center
city: Bologna
country: Italy
facility: Policlinico Sant'Orsola-Malpighi
city: Pavia
country: Italy
facility: Fondazione IRCCS Policlinico San Matteo Ambulatorio Scompenso Cardiaco e Trapianti
city: George Town
country: Malaysia
facility: Hospital Pulau Pinang
city: Kuala Lumpur
country: Malaysia
facility: Institut Jantung Negara (National Heart Institute)
city: Amsterdam
country: Netherlands
facility: VU University Medical Center (VUMC)
city: Maastricht
country: Netherlands
facility: Maastricht UMC+
city: Nieuwegein
country: Netherlands
facility: St. Antonius Ziekenhuis
city: Nijmegen
country: Netherlands
facility: Radboud UMC
city: Rotterdam
country: Netherlands
facility: Erasmus University medical Center
city: Moscow
country: Russian Federation
facility: Russian Cardiology Scientific and Production Complex
city: Saint Petersburg
country: Russian Federation
facility: Almazov Federal North-West Medical Research Centre of Department of Health
city: Singapore
country: Singapore
facility: National University Hospital - The Heart Institute - Cardiac Department
city: Singapore
country: Singapore
facility: National Heart Centre (NHC) Singapore
city: Glasgow
country: United Kingdom
facility: Golden Jubilee National Hospital
city: London
country: United Kingdom
facility: The Royal Free Hospital
city: Sheffield
country: United Kingdom
facility: "Sheffield Teaching Hospitals NHS Foundation Trust Royal Hallamshire Hospital"
Study officials:
affiliation: Actelion
name: Loïc Perchenet
role: STUDY_DIRECTOR
References:
citation: 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.