REPAIR: Right vEntricular Remodeling in Pulmonary ArterIal hypeRtension

NCT ID: NCT02310672

Last Updated: 2025-03-30

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 89 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-06-01
• Study Completion Date: 2019-09-10

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.

Conditions

Pulmonary Arterial Hypertension

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Macitentan

All patients take open-label macitentan 10mg o.d.

Group Type: EXPERIMENTAL

Macitentan

Intervention Type: DRUG

All patients take open-label macitentan 10mg o.d.

Interventions

Macitentan

All patients take open-label macitentan 10mg o.d.

Intervention Type: DRUG

Other Intervention Names

ACT-064992

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 64 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Actelion

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Loïc Perchenet

Role: STUDY_DIRECTOR

Actelion

Locations

Massachussetts General Hospital

Boston, Massachusetts, United States

University of Minnesota

Minneapolis, Minnesota, United States

Washington University School of Medicine

St Louis, Missouri, United States

Rudgers New Jersey Medical School

New Brunswick, New Jersey, United States

Cornell University

New York, New York, United States

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, United States

University of Texas Southwestern Medical

Dallas, Texas, United States

St. Luke's Medical Center

Milwaukee, Wisconsin, United States

The Prince Charles Hospital

Chermside, Queensland, Australia

Hopital Gabriel Montpied

Clermont-Ferrand, , France

Hôpital Michallon

La Tronche, , France

"CHRU de Lille - Hôpital Albert Calmette "

Lille, , France

Hopital de Brabois

Nancy, , France

Hôpital Laennec

Nantes, , France

Hôpital Pasteur

Nice, , France

Hôpital Européen Georges-Pompidou

Paris, , France

Medizinische Klinik und Poliklinik II Universitätsklinik Bonn

Bonn, , Germany

Universitätsklinikum Köln Herzzentrum / Klinik III für Innere Medizin

Cologne, , Germany

Thoraxklinik am Universitätsklinikum Heidelberg

Heidelberg, , Germany

Universitätsmedizin der Johannes Gutenberg-Universität Mainz Centrum für Thrombose und Hämostase

Mainz, , Germany

Grantham Hospital, Cardiac Medical Unit

Hong Kong, , Hong Kong

Queen Mary Hospital

Hong Kong, , Hong Kong

United Christian Hospital

Hong Kong, , Hong Kong

Pulmonology institute, Soroka Medical Center

Beersheba, , Israel

Shaare Zedek Medical Center

Jerusalem, , Israel

Policlinico Sant'Orsola-Malpighi

Bologna, , Italy

Fondazione IRCCS Policlinico San Matteo Ambulatorio Scompenso Cardiaco e Trapianti

Pavia, , Italy

Hospital Pulau Pinang

George Town, , Malaysia

Institut Jantung Negara (National Heart Institute)

Kuala Lumpur, , Malaysia

VU University Medical Center (VUMC)

Amsterdam, , Netherlands

Maastricht UMC+

Maastricht, , Netherlands

St. Antonius Ziekenhuis

Nieuwegein, , Netherlands

Radboud UMC

Nijmegen, , Netherlands

Erasmus University medical Center

Rotterdam, , Netherlands

Russian Cardiology Scientific and Production Complex

Moscow, , Russia

Almazov Federal North-West Medical Research Centre of Department of Health

Saint Petersburg, , Russia

National University Hospital - The Heart Institute - Cardiac Department

Singapore, , Singapore

National Heart Centre (NHC) Singapore

Singapore, , Singapore

Golden Jubilee National Hospital

Glasgow, , United Kingdom

The Royal Free Hospital

London, , United Kingdom

"Sheffield Teaching Hospitals NHS Foundation Trust Royal Hallamshire Hospital"

Sheffield, , United Kingdom

Countries

United States; Australia; France; Germany; Hong Kong; Israel; Italy; Malaysia; Netherlands; Russia; Singapore; United Kingdom

References

Kiely DG, Channick R, Flores D, Galie N, MacDonald G, Marcus JT, Mitchell L, Peacock A, Rosenkranz S, Tawakol A, Torbicki A, Vonk Noordegraaf A, Swift AJ. Comparison of cardiac magnetic resonance imaging, functional and haemodynamic variables in pulmonary arterial hypertension: insights from REPAIR. ERJ Open Res. 2024 Feb 12;10(1):00547-2023. doi: 10.1183/23120541.00547-2023. eCollection 2024 Jan.

Reference Type: DERIVED

PMID: 38348238 (View on PubMed)

Torbicki A, Channick R, Galie N, Kiely DG, Moceri P, Peacock A, Swift AJ, Tawakol A, Vonk Noordegraaf A, Flores D, Martin N, Rosenkranz S. Effect of Macitentan in Pulmonary Arterial Hypertension and the Relationship Between Echocardiography and cMRI Variables: REPAIR Echocardiography Sub-study Results. Cardiol Ther. 2024 Mar;13(1):173-190. doi: 10.1007/s40119-023-00345-2. Epub 2024 Jan 28.

Reference Type: DERIVED

PMID: 38281309 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 34801462 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

AC-055-403

Identifier Type: -

Identifier Source: org_study_id