Primary objective* To evaluate the effect of macitentan 10 mg on pulmonary vascular resistance (PVR) at rest in comparison with placebo in subjects with inoperable chronic thromboembolic pulmonary hypertension (CTEPH).Secondary objectives* To…
ID
Source
Brief title
Condition
- Pulmonary vascular disorders
- Embolism and thrombosis
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Efficacy
Primary endpoint
* PVR at rest at Week 16 expressed as percent of baseline PVR at rest.
Secondary endpoints
* Change from baseline to Week 24 in exercise capacity, as measured by the 6MWD.
* Change from baseline to Week 24 in Borg dyspnea index collected at the end of
the 6MWT.
* Proportion of subjects with worsening in WHO FC from baseline to Week 24.
Additional efficacy endpoints are described in the protocol.
For the efficacy endpoints, the baseline value is the last valid assessment
obtained prior to randomization.
Tolerability and safety
* Treatment-emergent AEs up to 30 days after study drug discontinuation.
* AEs leading to premature discontinuation of study drug.
* Treatment-emergent SAEs up to 30 days after study drug discontinuation.
* Treatment-emergent marked laboratory abnormalities up to 30 days after study
drug discontinuation.
* Change in laboratory variables from baseline to all assessed timepoints
during the study.
* Change in vital signs (arterial blood pressure, heart rate) and body weight
from baseline to all assessed timepoints during the study.
Except when otherwise specified, the baseline value is the last valid
assessment obtained prior to randomization.
Pharmacokinetic/pharmacodynamic endpoints
Pharmacokinetic (PK) endpoints
* Trough concentrations of macitentan and its metabolite ACT-132577 in plasma
at Week 16 and Week 24, or at EOT in case of premature study drug
discontinuation.
Secondary outcome
Secondary endpoints
* Change from baseline to Week 24 in exercise capacity, as measured by the 6MWD.
* Change from baseline to Week 24 in Borg dyspnea index collected at the end of
the 6MWT.
* Proportion of subjects with worsening in WHO FC from baseline to Week 24.
Additional efficacy endpoints are described in the protocol.
For the efficacy endpoints, the baseline value is the last valid assessment
obtained prior to randomization.
Background summary
Chronic thromboembolic pulmonary hypertension (CTEPH), one of the leading
causes of severe pulmonary hypertension (PH), develops from the obstruction of
pulmonary artery branches following episodes of pulmonary embolism (PE) with
incomplete thrombus resolution, formation of fibrosis and remodeling of
pulmonary blood vessels. Consequently, pulmonary vascular resistance (PVR) is
increased, leading to PH and progressive right heart failure [Jenkins 2012].
CTEPH belongs to the WHO Group 4 [Simonneau 2009].
Pulmonary endarterectomy (PEA) is the gold standard treatment for CTEPH and
represents a potentially curative option in eligible patients [Jamieson 2003].
However, many patients with CTEPH are considered non-operable due to
predominantly distal thromboembolic pathology, or concomitant small-vessel
arteriopathy. Therefore, there is a high need for medical treatments for CTEPH
patients who are inoperable.
Histopathologic studies of vascular changes in CTEPH have identified vascular
lesions similar to those seen in idiopathic PAH (iPAH) [Galiè 2006]. There is
also evidence that in particular CTEPH subjects with a predominantly distal,
PAH-like arteriopathy might benefit from vasodilating pharmacotherapy.[Jaïs
2008].
As in PAH, ET-mediated vascular remodeling has been demonstrated in animal
models of CTEPH, and increased ET levels and ETB receptor expression have been
observed in CTEPH patients [Jaïs 2008].
For these reasons, ERA appears to be a potential treatment option for
inoperable CTEPH
Macitentan (ACT-064992) is an orally active, non-peptide, potent dual
endothelin (ET) ETA and ETB receptor antagonist (ERA) in clinical development.
Endothelin receptor antagonists are being developed for a variety of diseases
associated with the deleterious effects of ET, particularly in the pulmonary
and cardiovascular fields.
This study aims to investigate the effect in the CTEPH population of
macitentan, an ERA that demonstrated higher potency than bosentan in
nonclinical in vivo studies [Macitentan IB].
Study objective
Primary objective
* To evaluate the effect of macitentan 10 mg on pulmonary vascular resistance
(PVR) at rest in comparison with placebo in subjects with inoperable chronic
thromboembolic pulmonary hypertension (CTEPH).
Secondary objectives
* To evaluate the effects of macitentan 10 mg in comparison with placebo on:
* Exercise capacity
* Dyspnea (assessed by the Borg dyspnea index)
* WHO functional class (FC)
* To evaluate the safety and tolerability of macitentan 10 mg in this subject
population.
Study design
This study is designed as a prospective, randomized, placebo controlled,
double-blind, multi-center, parallel-group, Phase 2 study.
Subjects will receive macitentan or placebo for 24 weeks. Previous experience
with ERAs, including bosentan, has shown that a duration of 16 weeks is
sufficient to observe significant placebo-adjusted treatment effects on
hemodynamic variables [Galiè 2006]. However exercise capacity increases
gradually in this population, and does not immediately follow the hemodynamic
improvement. Therefore, a treatment duration of 24 weeks has been chosen for
this study.
In studies involving hemodynamics and exercise capacity, measurement
variability and placebo effect are of sufficient magnitude to justify the
inclusion of a placebo control group [Wright 2009]. A placebo-controlled study
is considered ethically acceptable due to the eligibility criteria restricting
enrollment to stable CTEPH subjects and the duration of treatment which is
relatively short (i.e., 24 weeks).
Intervention
Study drugs include macitentan in the dosage of 10mg or placebo
Study burden and risks
Assessments performed at screening are:
Physical examination (including vital signs, weight, height)
Right heart catheterization (if not performed within 8 weeks prior to screening
visit)
Pulmonary function test (if not performed within 1 year prior to screening
visit)
Determination of WHO functional class
Ventilation/perfusion scan (if not performed within 1 year prior to screening)
At least one of the following tests ((if not performed within 1 year prior to
screening)
- Computed Tomography Pulmonary Angiogram
- Magnetic resonance angiography
- Pulmonary Angiography
6 minute walk test, borg dyspnea index evaluation, heart rate (2 in total)
PAH-Sympact questionnaire (to be completed at home by the patient)
Complete laboratory tests (for which blood is drawn from the patient)
Physical examinations, 6mwt/borg dyspnea/HR, complete laboratory test and
determination of WHO class are repeated at each visit, RHC at visit 4,
PAH-sympact questionnaire at visit 3 and visit 4,
The EQ-5D questionnaire needs to be completed at visit 2,3,4 and 5
Blood for biomarkertest is drawn at visit 2,3,4 and 5
Blood for PK sampling is drawn at visit 4 and 5.
Adverse events of macitentan are listed in the Investigator*s Brochure. For
possible complications regarding the heart catheterization please refer to E9
of this ABR form.
The conduct of this trial can be justified as 10-50% of the CTEPH patients are
non-operable (Pulmonary endarterectomy is the standard therapy) due to
predominantly distal thromboembolic pathology, or concomitant small-vessel
arteriopathy. Therefore, there is a high need for medical treatments for CTEPH
patients who are inoperable.
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Listed location countries
Age
Inclusion criteria
- Male or female * 18 and * 80 years of age.;- Subject with CTEPH (WHO Group 4) judged as inoperable due to the localization of the obstruction being surgically inaccessible (i.e., distal disease).
Exclusion criteria
- Previous pulmonary endarterectomy.
- Recurrent thromboembolism despite sufficient oral anticoagulants.
- Symptomatic acute pulmonary embolism in the 6-month period prior to randomization.
- Known moderate-to-severe restrictive lung disease (i.e., TLC < 60% of predicted value) or obstructive lung disease (i.e., FEV1 < 70% of predicted, with FEV1/FVC < 65%) or known significant chronic lung disease diagnosed by chest imaging (e.g., interstitial lung disease, emphysema).
- Acute or chronic conditions (other than dyspnea) that limit the ability to comply with study requirements in the 3-month period prior to Screening visit or during the Screening period.
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 |
|---|---|
| Other | clinicaltrials.gov (NCT02021292)and CCMO register |
| EudraCT | EUCTR2013-002950-56-NL |
| CCMO | NL46965.029.14 |