Safety objective:• To evaluate the long-term safety and tolerability of macitentan 10 mg in subjects withinoperable CTEPH.Efficacy objectives:• To evaluate the long term effects of macitentan 10 mg on exercise capacity andfunctional class (FC).
ID
Source
Brief title
Condition
- Pulmonary vascular disorders
- Embolism and thrombosis
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Exploratory efficacy endpoints
- Change from baseline to each scheduled time point in exercise capacity, as
measured by the 6-minute walk distance (6MWD)
- Change from baseline to each scheduled time point in Borg dyspnea index
collected at the end of the 6-minute walk test (6MWT)
- Proportion of subjects with worsening of WHO FC from baseline to each
scheduled time point.
Safety and tolerability endpoints
- 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 [as detailed in Appendix
4] upto 30 days after study drug discontinuation.
- Change in vital signs (BP [i.e., DBP and SBP],
Secondary outcome
Exploratory efficacy endpoints
- Change from baseline to each scheduled time point in exercise capacity, as
measured by the 6-minute walk distance (6MWD)
- Change from baseline to each scheduled time point in Borg dyspnea index
collected at the end of the 6-minute walk test (6MWT)
- Proportion of subjects with worsening of WHO FC from baseline to each
scheduled time point.
Safety and tolerability endpoints
- 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 [as detailed in Appendix
4] upto 30 days after study drug discontinuation.
- Change in vital signs (BP [i.e., DBP and SBP],
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
Safety objective:
• To evaluate the long-term safety and tolerability of macitentan 10 mg in
subjects with
inoperable CTEPH.
Efficacy objectives:
• To evaluate the long term effects of macitentan 10 mg on exercise capacity and
functional class (FC).
Study design
This study is a multi-center, single-arm, open-label (OL), Phase 2 extension
study to
assess the long-term safety, tolerability and efficacy of macitentan in
subjects with
inoperable CTEPH.
The study will be conducted in approximately 60 centers in approximately 15
countries.
Up to 78 subjects (males or females) from the DB AC 055E201 / MERIT-1 study
will be
enrolled in this OL study. Subjects will be rolled over from the AC-055E201 /
MERIT-1
study to this OL study without knowledge of their previous study drug
(macitentan 10 mg
or placebo).
Subjects who complete the 24 weeks of the DB MERIT-1 study as scheduled can be
enrolled in the MERIT-2 OL extension study.
Intervention
Study drug include macitentan in the dosage of 10mg
Study burden and risks
Assessments performed at enrollment are:
Physical examination (including vital signs), Determination of the WHO
functional class, 6 minute walk test, borg dyspnea index evaluation and
complete laboratory tests (for which blood is drawn from the patient). Note
that visit 5/ week 24 of the MERIT-1 study can be performed on the same day as
visit 1 of the MERIt-2 study. Then tests are not to be repeated.
Physical examination (including vital signs), and complete laboratory test are
repeated at each regular visit. 6MWT/borg dyspnea index/determination WHO
functional class are repeated at visit 3,4,5 and at the end of treatment visit
(month 24).
In between the visits the patients has to come back to the hospital/local lab
for a monthly laboratory test. This is done to monitor the liver
aminotransferases and hemoglobulin. If the patient lives far away from the
hospital monthly bloodsampling can possibly be done at a local laboratory close
to the patient*s home. When the subject is of child bearing potential a serum
pregnancy test is part of the complete laboratory tests as well as the monthly
laboratory tests.
Adverse events of macitentan are listed in the Investigator*s Brochure.
The conduct of this trial can be justified as 10-50% of the CTEPH patients are
non-operable. (pulmonary endarterectormy 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. Obviously the long term effects (efficacy, safety
and tolerability) are important to be known.
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Listed location countries
Age
Inclusion criteria
Subject with CTEPH having completed the double-blind (DB) AC-055E201 / MERIT-1 study as scheduled (i.e., who remained in the DB study up to Week 24).
Exclusion criteria
- Permanent discontinuation of DB study treatment due to an hepatic adverse event or liver aminotransferase abnormalities.
- Any known factor (e.g., drug or substance abuse) or disease (e.g., unstable psychiatric illness) that, in the opinion of the investigator, may interfere with treatment compliance or interpretation of the results, or that may influence the ability to comply with any of the study requirements.
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 | EUCTR2013-003457-25-NL |
| CCMO | NL47490.029.14 |