REPAIR: Right vEntricular Remodeling in Pulmonary ArterIal hypeRtension

Conditions

Pulmonary Arterial Hypertension

Keywords

Pulmonary Arterial Hypertension

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.

Vallerie V. McLaughlin, Olivier Sitbon, Kelly Chin, Nazzareno Galiè, Marius M. Hoeper et al. (14 authors)

European Journal of Heart Failure2024-07-0514 citations

10.1002/ejhf.3319

Effect of Macitentan in Pulmonary Arterial Hypertension and the Relationship Between Echocardiography and cMRI Variables: REPAIR Echocardiography Sub-study Results.

Torbicki A, Channick R, Galiè N, Kiely DG, Moceri P, Peacock A, Swift AJ, Tawakol A, Vonk Noordegraaf A, Flores D, Martin N, Rosenkranz S.

2024-01-28

10.1007/s40119-023-00345-2

Comparison of cardiac magnetic resonance imaging, functional and haemodynamic variables in pulmonary arterial hypertension: insights from REPAIR

David G. Kiely, Richard N. Channick, Dayana Flores, Nazzareno Galiè, Gwen MacDonald et al. (13 authors)

ERJ Open Research2024-01-01

10.1183/23120541.00547-2023

The REPAIR Study

Anton Vonk Noordegraaf, Richard N. Channick, Emmanuelle Cottreel, David G. Kiely, J. Tim Marcus et al. (13 authors)

JACC. Cardiovascular imaging2021-11-1751 citations

10.1016/j.jcmg.2021.07.027

S93 REPAIR: long-term effects of macitentan on the right ventricle (RV) in pulmonary arterial hypertension (PAH)

DG Kiely, Emmanuelle Cottreel, Nazzareno Galiè, JT Marcus, A. Peacock et al. (12 authors)

2021-01-21

10.1136/thorax-2020-btsabstracts.98

Effect of macitentan on left ventricular (LV) function in pulmonary arterial hypertension (PAH): results from REPAIR

Stephan Rosenkranz, Richard N. Channick, Emmanuelle Cottreel, Nazzareno Galiè, DG Kiely et al. (12 authors)

European Heart Journal2020-11-01

10.1093/ehjci/ehaa946.2296

REPAIR: long-term effects of macitentan on the right ventricle (RV) in pulmonary arterial hypertension (PAH)

David G. Kiely, Emmanuelle Cottreel, Nazzareno Galiè, J. Tim Marcus, Andrew J. Peacock et al. (12 authors)

2020-09-07

10.1183/13993003.congress-2020.3971

P116 Effects of macitentan on right ventricular remodeling in pulmonary arterial hypertension – results from the REPAIR study interim analysis

DG Kiely, Stephan Rosenkranz, Nazzareno Galiè, Richard N. Channick, Emmanuelle Cottreel et al. (10 authors)

2019-11-121 citations

10.1136/thorax-2019-btsabstracts2019.259

Interventions

DRUGMacitentan

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

Study design

Allocation

NA

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 64 Years

Healthy volunteers

No

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

Design outcomes

Primary

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

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

Countries

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

Participant flow

Pre-assignment details

Total 112 participants were screened out of them 89 participants were enrolled in the study and of which 87 participants received study medication. Two participants who did not receive study treatment were wrongly classified as enrolled by the sites.

Participants by arm

Arm	Count
Macitentan 10 mg Participants received macitentan 10 milligrams (mg) tablets once daily until the premature discontinuation of study drug or end of treatment (EOT) on the day of the last dose of study drug at Week 52.	87
Total	87

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Death	1
Overall Study	Lost to Follow-up	1
Overall Study	Sponsor's decision	12
Overall Study	Withdrawal by Subject	1

Baseline characteristics

Characteristic	Macitentan 10 mg
Age, Continuous	45.9 years STANDARD_DEVIATION 14.48
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	72 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	14 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	0 Participants
Race/Ethnicity, Customized Asian	26 Participants
Race/Ethnicity, Customized Black or African American	1 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	0 Participants
Race/Ethnicity, Customized Other	0 Participants
Race/Ethnicity, Customized Unknown or Not Reported	14 Participants
Race/Ethnicity, Customized White	46 Participants
Region of Enrollment FRANCE	14 Participants
Region of Enrollment GERMANY	12 Participants
Region of Enrollment Hong Kong	7 Participants
Region of Enrollment ISRAEL	2 Participants
Region of Enrollment ITALY	3 Participants
Region of Enrollment MALAYSIA	8 Participants
Region of Enrollment NETHERLANDS	12 Participants
Region of Enrollment RUSSIAN FEDERATION	11 Participants
Region of Enrollment SINGAPORE	9 Participants
Region of Enrollment UNITED KINGDOM	3 Participants
Region of Enrollment UNITED STATES	6 Participants
Sex: Female, Male Female	70 Participants
Sex: Female, Male Male	17 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	1 / 87
other Total, other adverse events	57 / 87
serious Total, serious adverse events	15 / 87

Outcome results

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.

Time frame: Baseline and Week 26

Population: The Modified full analysis set (mFAS) included of all screened participants who received at least one dose of study drug and who had a baseline as well as a post-baseline measurement taken between 16 weeks and 30 weeks of treatment.

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Macitanten 10 mg	Change From Baseline in Right Ventricular Stroke Volume (RVSV) to Week 26	15.17 milliliters (mL)	Standard Error 2.75

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.

Time frame: Baseline and Week 26

Population: mFAS included of all screened participants who received at least one dose of study drug and who had a baseline as well as a post-baseline measurement taken between 16 weeks and 30 weeks of treatment.

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Macitanten 10 mg	Ratio of Week 26 to Baseline Pulmonary Vascular Resistance (PVR)	0.63 Ratio	Geometric Coefficient of Variation 0.11

Secondary