REPAIR: Right vEntricular Remodeling in Pulmonary ArterIal hypeRtension

Pulmonary Arterial Hypertension Clinical Trial

— REPAIR  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02310672
• Other study ID #: AC-055-403
• Status: Completed
• Phase: Phase 4
• Start date: June 1, 2015
• Est. completion date: September 10, 2019

Study information

• Verified date: September 2020
• Source: Actelion
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 89
• Est. completion date: September 10, 2019
• Est. primary completion date: September 10, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 64 Years

Eligibility

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

Related Conditions & MeSH terms

• Familial Primary Pulmonary Hypertension
• Hypertension
• Pulmonary Arterial Hypertension
• Ventricular Remodeling

Intervention

Drug:
• Macitentan
All patients take open-label macitentan 10mg o.d.

Locations

Country	Name	City	State
Australia	The Prince Charles Hospital	Chermside	Queensland
France	Hopital Gabriel Montpied	Clermont-Ferrand
France	Hôpital Michallon	La Tronche
France	"CHRU de Lille - Hôpital Albert Calmette "	Lille Cedex
France	Hopital de Brabois	Nancy
France	Hôpital Laennec	Nantes Cedex 01
France	Hôpital Pasteur	Nice
France	Hôpital Européen Georges-Pompidou	Paris
Germany	Medizinische Klinik und Poliklinik II Universitätsklinik Bonn	Bonn
Germany	Thoraxklinik am Universitätsklinikum Heidelberg	Heidelberg
Germany	Universitätsklinikum Köln Herzzentrum / Klinik III für Innere Medizin	Köln
Germany	Universitätsmedizin der Johannes Gutenberg-Universität Mainz Centrum für Thrombose und Hämostase	Mainz
Hong Kong	Grantham Hospital, Cardiac Medical Unit	Hong Kong
Hong Kong	Queen Mary Hospital	Hong Kong
Hong Kong	United Christian Hospital	Hong Kong
Israel	Pulmonology institute, Soroka Medical Center	Beer-Sheva
Israel	Shaare Zedek Medical Center	Jerusalem
Italy	Policlinico Sant'Orsola-Malpighi	Bologna
Italy	Fondazione IRCCS Policlinico San Matteo Ambulatorio Scompenso Cardiaco e Trapianti	Pavia
Malaysia	Hospital Pulau Pinang	George Town
Malaysia	Institut Jantung Negara (National Heart Institute)	Kuala Lumpur
Netherlands	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
Russian Federation	Russian Cardiology Scientific and Production Complex	Moscow
Russian Federation	Almazov Federal North-West Medical Research Centre of Department of Health	Saint Petersburg
Singapore	National Heart Centre (NHC) Singapore	Singapore
Singapore	National University Hospital - The Heart Institute - Cardiac Department	Singapore
United Kingdom	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 States	Massachussetts General Hospital	Boston	Massachusetts
United States	University of Texas Southwestern Medical	Dallas	Texas
United States	St. Luke's Medical Center	Milwaukee	Wisconsin
United States	University of Minnesota	Minneapolis	Minnesota
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	Washington University School of Medicine	Saint Louis	Missouri

Sponsors (1)

Lead Sponsor	Collaborator
Actelion

Countries where clinical trial is conducted

United States,  Australia,  France,  Germany,  Hong Kong,  Israel,  Italy,  Malaysia,  Netherlands,  Russian Federation,  Singapore,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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