The primary objective of the study is to evaluate the effect of macitentan on right ventricular and hemodynamic properties in patients with symptomatic PAH.Secondary objectivesTo evaluate the safety and tolerability of macitentan in patients with…
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Brief title
Condition
- Pulmonary vascular disorders
Synonym
Research involving
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Intervention
Outcome measures
Primary outcome
The study has two primary efficacy endpoints:
• Change from baseline to Week 26 in Right Ventricular (RV) Stroke Volume
(RVSV) assessed by cardiac MRI from pulmonary artery flow.
• Ratio of Week 26 to baseline PVR assessed by RHC.
RVSV is determined by the IAC. Assessors are blinded to the patient identity
and to the date of image acquisition.
Secondary outcome
In the same way as the primary endpoints, secondary endpoints are assessed at
26 weeks. They consist in characteristics of the right ventricle and pulmonary
vasculature, and in widely accepted tools to assess PAH progression:
Change from baseline to Week 26 in:
• RV End Diastolic Volume (RVEDV)
• RV End Systolic Volume (RVESV)
• RV Ejection Fraction (RVEF)
• RV mass
• 6MWD
• WHO FC
MRI variables and variables determined from pressure-volume relationship will
be assessed by the IAC.
Background summary
The most serious chronic disorder of the pulmonary circulation is pulmonary
arterial hypertension (PAH), a syndrome of diverse etiology and pathogenesis
characterized by a progressive increase in pulmonary arterial pressure (PAP)
and in pulmonary vascular resistance (PVR) potentially leading to right heart
failure and death [Benza 2010, Kylhammar 2014, Oudiz 2013].
PAH is associated with structural changes in both pulmonary vasculature and
right ventricle. The changes in vascular structure involve three combined
elements: vasoconstriction, vascular-wall remodeling, and thrombosis in situ
[Humbert 2004]. The changes in the right ventricle mainly consist of
hypertrophy, dilation, altered contractility and septal bowing [Rich 2012,
Franco 2012, Vonk-Noordegraaf 2011]. Collectively these changes of the right
ventricle are termed remodeling.
Currently, there is no cure for PAH. However, recent advances in the
understanding of the pathogenic factors leading to the pulmonary vascular
disease have led to the development of new therapies targeting specific
pathways (prostacyclin pathway, endothelin pathway, and nitric oxide pathway)
[Galiè 2013] that are believed to play important pathogenic roles.
Several agents are currently approved for the treatment of PAH in the United
States, Europe, and Australia. Intravenous (i.v.) prostacyclin (epoprostenol),
prostanoid analogues, i.e., treprostinil (i.v., subcutaneous [s.c.], inhaled
and oral), and iloprost (i.v. and inhaled), dual endothelin receptor
antagonists (ERAs; bosentan and macitentan), a selective ERA (ambrisentan),
phosphodiesterase type 5 (PDE-5) inhibitors (sildenafil and tadalafil), and
more recently, a stimulator of soluble guanylate cyclase (riociguat).
Vasodilators, such as calcium channel blockers, are effective only in a
minority of patients who have an acute response to vasodilator testing [Rich
1992, Sitbon 2005].
Despite these achievements, PAH remains a serious life-threatening condition
[Galiè 2013, Benza 2010], and new compounds continue to be explored.
Macitentan is approved in the US, Europe, Australia, Canada, Israel, Mexico,
and Switzerland for the treatment of PAH.
Effectiveness was established in a long-term study in PAH patients with
predominantly WHO Functional Class (FC) II-III symptoms treated for an average
of 2 years [Pulido 2013]. Patients were treated with macitentan monotherapy or
in combination with PDE-5 inhibitors or inhaled prostanoids.
The trial demonstrated that macitentan 10 mg reduces the risk of morbidity/
mortality in patients with symptomatic PAH (a risk reduction of 45%).
The placebo-corrected mean change in 6-minute walk distance (6MWD) from
baseline to Month 6 showed an increase of 22.0 m with macitentan 10 mg versus
placebo. A hemodynamic sub-study showed a reduction of PVR from baseline to
Month 6 of 36.5% with macitentan 10 mg.
The purpose of the study is to further extend the knowledge of macitentan by
assessing the effects of macitentan on the cardiac muscle, and specifically on
the right ventricle.
Study objective
The primary objective of the study is to evaluate the effect of macitentan on
right ventricular and hemodynamic properties in patients with symptomatic PAH.
Secondary objectives
To evaluate the safety and tolerability of macitentan in patients with
symptomatic PAH.
Study design
This is a prospective, multi-center, 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.
One hundred patients will be enrolled in approximately 50 sites in
approximately 12 countries in Asia, Australia, Europe, and North America.
Enrollment will be competitive across participating sites.
The study consists of the following time points and periods:
Screening commences from signature of the Informed Consent Form (ICF) and ends
with study treatment initiation (up to 28 days after informed consent
signature).
Baseline: baseline values are those collected during screening or at Treatment
Initiation Visit (Day 1) before initiation of study treatment.
Treatment Period starts with the 1st dose of study drug (Day 1 of study) and
ends with EOT on the day of the last dose of study drug. EOT visit for
premature discontinued patients must be organized as soon as possible and no
later thatn 7 days after decision to end study treatment.
The Safety follow-up period starts immediately after the last dose of study
drug and ends 30 to 37 days after EOT, with End of Study (EOS) Visit. For
patients who withdraw their consent, the investigator will seek agreement to
conduct the safety follow-up.
EOS for a patient is the end of safety follow-up, or date of death, or date of
consent withdrawal, or date of last contact for patients lost to follow-up.
Sub-studies
As part of this protocol, three sub-studies will be conducted in selected
centers. Each selected center will participate in one or more sub-studies. In
these centers, all patients eligible for the main study will be offered to
participate in these sub-studies.
1. Metabolism sub-study (selected US sites only).
2. Biopsy sub-study.
3. Echo sub-study.
For an individual patient, treatment duration will be up to 371 days. Patient
participation in the study will be approximately 14 months. Once the study
treatment is finished, patients will receive local standard medical care.
Intervention
The study treatment is macitentan 10 mg, for once daily oral administration.
The dose and regimen are in accordance with product labeling.
Study burden and risks
Burden: patients need to visit the site per protocol. They undergo cardiac
MRIs, right heart catheterizations and blood draws. Patients in the Echo
sub-study undergo echocardiographies in addition. Female patients of
childbearing potential need to follow strict contraception rules and to perform
monthly pregnancy tests.
Risks: macitentan may be associated with headache, abnormal liver function,
anemia, fluid retention, low blood pressure, inflammation of the throat and
nasal passages, inflammation of the airways, influenza, urinary tract
infection, hypersensitivity reactions, pulmonary edema in patients with
pulmonary veno-occlusive disease.
There is a slight risk of pain or bruising and infection when blood is drawn.
Right heart catheterization may be associated with side effects. Minor local
side effects include bruising or hematoma, swelling and infection. Side effects
that are seen rarely include heart rhythm abnormalities, low blood pressure,
bleeding, general infection, collapsed lung, or clotting of the blood,
sometimes followed by an obstruction of an artery. Complications can sometimes,
although rarely, be fatal.
Benefits: There is no guarantee that patients will benefit directly from this
research.
Gewerbestrasse 16
Allschwil 4123
CH
Gewerbestrasse 16
Allschwil 4123
CH
Listed location countries
Age
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:
1.1 Idiopathic PAH
1.2 Heritable PAH
1.3 Drug- and toxin-induced PAH
1.4.1 PAH associated with connective tissue disease
1.4.4 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) performed between Day -28 and Day 1 (inclusion RHC; RHC data obtained at study site within this time frame, prior to obtaining signed informed consent, are acceptable) showing:
• mPAP >= 25 mmHg and
o PCWP or LVEDP <= 12 mmHg and PVR >= 4 Wood Units (WU) (320 dyn.sec.cm-5) or
o 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 loop diuretics, treatment dose must be stable since at least 1 month prior to the inclusion RHC.
8.For patients treated with PDE-5 inhibitors, treatment dose must be stable since at least 3 months prior to the inclusion RHC (initiation of PDE-5 inhibitors during screening is allowed after all screening assessments have been performed).
9.For patients treated with beta blockers, treatment dose must be stable since at least 1 month prior to the inclusion RHC.
10.Men or women >=18 and < 75 years. For patients aged >= 65 and < 75 years, an eligibility form will be submitted to a Steering Committee member who will reserve the right to exclude the patient.
11.Women of childbearing potential must:
a. Have a negative serum pregnancy test during screening and a negative urine pregnancy test on Day 1, and
b. Agree to use reliable methods of contraception from screening up to 30 days after study treatment discontinuation, and
c. 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 (except for diagnosis of PAH) within 3 months prior to informed consent signature
8.Left atrial volume indexed for body surface area (BSA) >= 43mL/m2 by echocardiography or cardiac MRI
9.Moderate to severe left-heart valvular disease
10.History of pulmonary embolism or deep vein thrombosis
11.Presence of one or more of the following signs of relevant lung disease at any time up to screening:
o Diffusing capacity of the lung for carbon monoxide (DLCO) < 40% of predicted (eligible only if no or mild interstitial lung disease on computed tomography).
o FVC < 60% of predicted.
o Forced expiratory volume in one second (FEV1) < 60% of predicted.
12. Moderate to severe restrictive lung disease (i.e., total lung capacity < 60% of predicted value) at any time prior to enrollment.
13.Historical evidence of significant coronary artery disease established by:
o History of myocardial infarction or
o More than 50% stenosis in a coronary artery (by percutaneous coronary intervention or angiography) or
o Elevation of the ST segment on electrocardiogram or
o History of coronary artery bypass grafting or
o Stable angina
14. Known uncontrolled diabetes mellitus (in the opinion of the investigator)
15. Severe renal insufficiency (calculated creatinine clearance < 30 mL/min)
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 × ULN accompanied by an AST elevation > ULN at Screening.
19.Hemoglobin < 100g/L
20.Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 3 times the upper limit of the normal range
21.Need for dialysis
22.Responders to acute vasoreactivity test based on medical history
23.Prior use of endothelin receptor antagonists, stimulators of soluble guanylate cyclase or prostacyclin or prostacyclin analogs
24.Treatment with strong inducers of 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 endothelin receptor antagonist 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.MRI-incompatible 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 (PVCs/PACs), or any other condition that would interfere with proper cardiac gating during magnetic resonance imaging (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 or 1.4.1: PAH
associated with connective tissue disease.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2014-004066-20-NL |
| ClinicalTrials.gov | NCT02310672 |
| CCMO | NL51561.029.14 |