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Completed

NCT Number: NCT02310672

REPAIR: Right vEntricular Remodeling in Pulmonary ArterIal hypeRtension

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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Key information

Conditions

Pulmonary Arterial Hypertension Hypertension, Pulmonary Lung Diseases Respiratory Tract Diseases

Age range

18 year–64 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 4

Primary location

The Prince Charles Hospital, Chermside, Queensland, Australia

Loading trial locations.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Signed informed consent prior to any study-mandated procedure
  • Symptomatic pulmonary arterial hypertension (PAH)
  • World Health Organization (WHO) Functional Class (FC) I to III
  • 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
  • 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-minute walk distance (6MWD) ≥ 150 m during screening
  • For patients treated with oral diuretics, treatment dose must have been stable at least 1 month prior to RHC during the screening period
  • 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
  • For patients treated with beta blockers, treatment dose must have been stable at least 1 month prior to the RHC during the screening period
  • Men or women ≥18 and < 65 years
  • 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

  • Body weight < 40 kg
  • 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.
  • Pregnancy, breastfeeding or intention to become pregnant during the study
  • Recently started (< 8 weeks prior to informed consent signature) or planned cardio-pulmonary rehabilitation program
  • Known concomitant life-threatening disease with a life expectancy < 12 months
  • Any condition likely to affect protocol or treatment compliance
  • Hospitalization for PAH within 3 months prior to informed consent signature
  • Left atrial volume indexed for body surface area ≥ 43mL/m2 by echocardiography or cardiac MRI
  • Valvular disease grade 2 or higher
  • History of pulmonary embolism or deep vein thrombosis
  • Documented moderate to severe chronic obstructive pulmonary disease
  • Documented moderate to severe restrictive lung disease
  • 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
  • Diabetes mellitus
  • Moderate to severe renal insufficiency (calculated creatinine clearance < 60 mL/min/1.73 m2)
  • Cancer
  • Systolic blood pressure < 90 mmHg
  • 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.
  • Hemoglobin < 100g/L
  • AST and/or alanine aminotransferase (ALT) > 3× ULN
  • Need for dialysis
  • Responders to acute vasoreactivity test based on medical history
  • Prior use of endothelin receptor antagonists (ERAs), stimulators of soluble guanylate cyclase or prostacyclin or prostacyclin analogues
  • 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)
  • 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)
  • Treatment with another investigational drug (planned, or taken within the 3 months prior to study treatment initiation).
  • 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)
  • Claustrophobia
  • Permanent cardiac pacemaker, automatic internal cardioverter
  • Metallic implant (e.g., defibrillator, neurostimulator, hearing aid, permanent use of infusion device)
  • Atrial fibrillation, multiple premature ventricular or atrial contractions, or any other condition that would interfere with proper cardiac gating during MRI.
  • For patients enrolling in the metabolism sub-study only: glucose intolerance
  • For patients enrolling in the biopsy sub-study only: PAH etiology belonging to Nice classification 1.4.4: PAH associated with congenital heart diseases

Treatment and study plan

Macitentan

Drug

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

Other names: ACT-064992

Primary outcomes

  1. Change From Baseline in Right Ventricular Stroke Volume (RVSV) to Week 26

    Time frame: Baseline and 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.

  2. Ratio of Week 26 to Baseline Pulmonary Vascular Resistance (PVR)

    Time frame: Baseline and Week 26

    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.

Secondary outcomes

  1. Change From Baseline in Right Ventricular End Diastolic Volume (RVEDV) to Week 26

    Time frame: Baseline to Week 26

    Change from baseline to Week 26 in RVEDV assessed by cardiac MRI was reported.

  2. Change From Baseline in Right Ventricular End Systolic Volume (RVESV) to Week 26

    Time frame: Baseline to Week 26

    Change from baseline to Week 26 in RVESV assessed by cardiac MRI was reported.

  3. Change From Baseline in Right Ventricular Ejection Fraction (RVEF) to Week 26 (% Blood Volume)

    Time frame: Baseline to Week 26

    Change from baseline to Week 26 in RVEF based on pulmonary artery flow assessed by cardiac MRI was reported.

  4. Change From Baseline in Right Ventricle (RV) Mass to Week 26

    Time frame: Baseline to Week 26

    Change from baseline to Week 26 in RV mass assessed by cardiac MRI was reported.

  5. Change From Baseline in Six-minutes Walk Distance (6MWD) to Week 26

    Time frame: Baseline 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.

  6. Change From Baseline in World Health Organization Functional Class (WHO FC) to Week 26

    Time frame: Baseline 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).

Sponsors and collaborators

Lead sponsor

Actelion

Industry

Registry information

Official study 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

Acronym: REPAIR

Important dates

Study start
2015
Primary completion
2019
Study completion
2019
First posted
Dec 8, 2014
Registry last updated
Mar 30, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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