REPAIR: Right vEntricular Remodeling in Pulmonary ArterIal hypeRtension (REPAIR)

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

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.

Study Overview

• Status: Completed
• Conditions: Pulmonary Arterial Hypertension
• Intervention / Treatment: Drug: Macitentan

• Study Type: Interventional
• Enrollment (Actual): 89
• Phase: Phase 4

Contacts and Locations

Study Locations

• Australia
  • Queensland
    • Chermside, Queensland, Australia, 4032
      • The Prince Charles Hospital
• France
  • Clermont-Ferrand, France, 63003
    • Hôpital Gabriel Montpied
  • La Tronche, France, 38700
    • Hôpital Michallon
  • Lille Cedex, France, 59037
    • "CHRU de Lille - Hôpital Albert Calmette "
  • Nancy, France, 54511
    • Hôpital de Brabois
  • Nantes Cedex 01, France, 44093
    • Hopital Laennec
  • Nice, France, 06002
    • Hopital PASTEUR
  • Paris, France, 75015
    • Hopital Europeen Georges-Pompidou
• Germany
  • Bonn, Germany, 53105
    • Medizinische Klinik und Poliklinik II Universitätsklinik Bonn
  • Heidelberg, Germany, 69126
    • Thoraxklinik am Universitatsklinikum Heidelberg
  • Köln, Germany, 50924
    • Universitätsklinikum Köln Herzzentrum / Klinik III für Innere Medizin
  • Mainz, Germany, 55131
    • Universitätsmedizin der Johannes Gutenberg-Universität Mainz Centrum für Thrombose und Hämostase
• Hong Kong
  • Hong Kong, Hong Kong, 999077
    • Queen Mary Hospital
  • Hong Kong, Hong Kong, 999077
    • Grantham Hospital, Cardiac Medical Unit
  • Hong Kong, Hong Kong, 999077
    • United Christian Hospital
• Israel
  • Beer-Sheva, Israel, 84101
    • Pulmonology institute, Soroka Medical Center
  • Jerusalem, Israel, 9103102
    • Shaare Zedek Medical Center
• Italy
  • Bologna, Italy, 40138
    • Policlinico Sant'Orsola-Malpighi
  • Pavia, Italy, 27100
    • Fondazione IRCCS Policlinico San Matteo Ambulatorio Scompenso Cardiaco e Trapianti
• Malaysia
  • George Town, Malaysia, 10990
    • Hospital Pulau Pinang
  • Kuala Lumpur, Malaysia, 50400
    • Institut Jantung Negara (National Heart Institute)
• Netherlands
  • Amsterdam, Netherlands, 1081 HV
    • VU University Medical Center (VUMC)
  • Maastricht, Netherlands, 6229
    • Maastricht UMC+
  • Nieuwegein, Netherlands, 3435 CM
    • St. Antonius Ziekenhuis
  • Nijmegen, Netherlands, 6525 GA
    • Radboud UMC
  • Rotterdam, Netherlands, 3000 CA
    • Erasmus University Medical Center
• Russian Federation
  • Moscow, Russian Federation, 121552
    • Russian Cardiology Scientific and Production Complex
  • Saint Petersburg, Russian Federation, 197341
    • Almazov Federal North-West Medical Research Centre of Department of Health
• Singapore
  • Singapore, Singapore, 169609
    • National Heart Centre (NHC) Singapore
  • Singapore, Singapore, 119228
    • National University Hospital - The Heart Institute - Cardiac Department
• United Kingdom
  • Glasgow, United Kingdom, G81 4DY
    • Golden Jubilee National Hospital
  • London, United Kingdom, NW3 2QG
    • The Royal Free Hospital
  • Sheffield, United Kingdom, S10 2JF
    • "Sheffield Teaching Hospitals NHS Foundation Trust Royal Hallamshire Hospital"
• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachussetts General Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University Of Minnesota
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New Jersey
    • New Brunswick, New Jersey, United States, 08901
      • Rudgers New Jersey Medical School
  • New York
    • New York, New York, United States, 10065
      • Cornell University
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Medical Center
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53215
      • St. Luke's Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 64 years (Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Macitentan; All patients take open-label macitentan 10mg o.d.	Drug: Macitentan; All patients take open-label macitentan 10mg o.d.; Other Names: ACT-064992

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Right Ventricular Stroke Volume (RVSV) to Week 26	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.	Baseline and Week 26
Ratio of Week 26 to Baseline Pulmonary Vascular Resistance (PVR)	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.	Baseline and Week 26

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Right Ventricular End Diastolic Volume (RVEDV) to Week 26	Change from baseline to Week 26 in RVEDV assessed by cardiac MRI was reported.	Baseline to Week 26
Change From Baseline in Right Ventricular End Systolic Volume (RVESV) to Week 26	Change from baseline to Week 26 in RVESV assessed by cardiac MRI was reported.	Baseline to Week 26
Change From Baseline in Right Ventricular Ejection Fraction (RVEF) to Week 26 (% Blood Volume)	Change from baseline to Week 26 in RVEF based on pulmonary artery flow assessed by cardiac MRI was reported.	Baseline to Week 26
Change From Baseline in Right Ventricle (RV) Mass to Week 26	Change from baseline to Week 26 in RV mass assessed by cardiac MRI was reported.	Baseline to Week 26
Change From Baseline in Six-minutes Walk Distance (6MWD) to Week 26	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.	Baseline to Week 26
Change From Baseline in World Health Organization Functional Class (WHO FC) to Week 26	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).	Baseline to Week 26

Collaborators and Investigators

• Sponsor: Actelion
• Investigators: Study Director: Loïc Perchenet, Actelion

Publications and helpful links

General 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.

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2015
• Primary Completion (Actual): September 10, 2019
• Study Completion (Actual): September 10, 2019

Study Registration Dates

• First Submitted: December 4, 2014
• First Submitted That Met QC Criteria: December 5, 2014
• First Posted (Estimated): December 8, 2014

Study Record Updates

• Last Update Posted (Actual): March 30, 2025
• Last Update Submitted That Met QC Criteria: March 28, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: Pulmonary Arterial Hypertension
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Pathological Conditions, Anatomical; Respiratory Tract Diseases; Lung Diseases; Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Hypertension; Familial Primary Pulmonary Hypertension; Ventricular Remodeling; Molecular Mechanisms of Pharmacological Action; Endothelin A Receptor Antagonists; Endothelin Receptor Antagonists; Endothelin B Receptor Antagonists; Macitentan
• Other Study ID Numbers: AC-055-403