Primary: to assess the efficacy of ambrisentan 5mg after treatment period of 16 weeks, in subjects with inoperable CTEPH. Secondary: safety and tolerability.
ID
Source
Brief title
Condition
- Pulmonary vascular disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Change from baseline in 6 min walk test measured at week 16.
Secondary outcome
Adverse events, PVR, WHO functional class, Borg CR10 scale, clinical worsening
of CTEPH, other haemodynamics, NT-proBNP, SF-36 questionnaire.
Background summary
Chronic thromboembolic pulmonary hypertension (CTEPH) is a life-threatening
condition characterized by thrombus organization, stenosis of pulmonary artery,
and subsequent vascular remodeling in small unobstructed vessels, resulting in
increased pulmonary vascular resistance, progressive pulmonary hypertension
(PH) and right heart failure. CTEPH is associated with considerable morbidity
and mortality.
The preferred treatment for CTEPH is surgical disobliteration of the arteries
by pulmonary endarterectomy. The perioperative mortality is 5 to 10%. There are
significant improvements in hemodynamics. However for some patients surgery is
not an option. Management of these patients was previously supportive.
Disease-modifying therapies used in other forms of pulmonary arterial
hypertension have been utilized. There are no licensed treatments for CTEPH.
Ambrisentan is a selective endotheline receptor antagonist licensed for the
treatment of WHO FC II and III PH. Given that the histopathologic changes seen
in CTEPH, the evidence that endotheline-1 levels are raised, and the clinical
evidence (mainly uncontrolled) that a number of licensed PH treatments show
efficacy in CTEPH, it is hypothesised that ambrisentan may provide benefit to
patients with inoperable CTEPH.
Study objective
Primary: to assess the efficacy of ambrisentan 5mg after treatment period of 16
weeks, in subjects with inoperable CTEPH.
Secondary: safety and tolerability.
Study design
Phase III, randomised, double-blind placebo controlled parallel group study.
Randomization (1:1) to
* ambrisentan 5 mg daily
* placebo.
160 subjects.
16 weeks of therapy. Following the End of Study visit all subjects will have
the option of entering a long-term Open Label Extension (AMB116457) at the end
of the Double-Blind treatment phase, until product is licensed and commercially
available for CTEPH.
Independent Data Monitoring Committee.
Intervention
Treatment with ambrisentan or placebo.
Study burden and risks
Risk: Adverse effects of study medication.
Burden: 7 visits in 24 weeks.
Blood draws every visit (5-10 ml/occasion). Optional pharmacogenetic research
(6 ml blood). Urine test 3x. Pregnancy test every visit.
Physical examination 3x, ECG 2x, 6 minute walk test every visit,
echocardiography 1x, right heart catheterization 2x, oximetry every visit,
SF-36 questionnaire 2x.
Huis ter Heideweg 62
Zeist 3705 LZ
NL
Huis ter Heideweg 62
Zeist 3705 LZ
NL
Listed location countries
Age
Inclusion criteria
* Age 18-80 year.
* Inoperable CTEPH (see protocol page 19 for details).
* mPAP > 25 mmHg, PVR > 400 dynes.sec/cm5 and PCWP or LVEDP < 15 mmHg.
* Distance during 6 minutes walk test 150-475 meters.
* WHO class II or III.
* SaO2 at least 92% (pulse oximetry).
* Anticoagulation for a minimum of 3 months.
* Females of childbearing potential: 2 reliable methods of contraception.
Exclusion criteria
* Previous PAH therapy (PDE5i, ERA, prostanoid (more than 7 days)) in the last 12 weeks.
* Any previous ERA treatment discontinued due to tolerance issues other than those associated with liver function abnormalities.
* Previous endarteriectomy or balloon pulmonary angioplasty.
* Intravenous inotropes in the last 2 weeks.
* Calcium Channel Blockers or statins with a dose change in the last 4 weeks.
* Enrolled in an exercise training program for cardiopulmonary rehabilitation in the last 12 weeks or plans to enrol during the first 16 weeks of the study (see protocol page 21 for details).
* BP > 180/110 mmHg or < 90/50 mmHg.
* Acute MI within the last 90 days.
* Clinically significant aortic or mitral valve disease; pericardial constriction; restrictive or congestive cardiomyopathy; life-threatening cardiac arrhythmias; significant left ventricular dysfunction; left ventricular outflow obstruction; symptomatic coronary artery disease; autonomic hypotension; fluid depletion.
* FEV1<70% of predicted.
* MBI *35.
* General exclusion criteria, see protocol page 22.
* Pregnancy or breastfeeding
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 | EUCTR2012-001646-18-NL |
| CCMO | NL45327.029.13 |
| Other | www.clinicaltrials.gov; registratienummer n.n.b. |