Clinical trial NCT00578786: A Long Term Study of Ambrisentan in Pulmonary Arterial Hypertension Subjects Having Completed AMB-320 (NCT00423748) or AMB-321 (NCT00423202)
Official title: A Long Term Study of Ambrisentan in Pulmonary Arterial Hypertension Subjects Having Completed AMB-320 (NCT00423748) or AMB-321 (NCT00423202)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Pulmonary Arterial Hypertension
Lead sponsor: Gilead Sciences
Sponsor class: INDUSTRY
First posted: 2007-12-21
Enrollment: 383
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: AMB-320/321-E was designed to provide long-term, controlled monitoring of pulmonary arterial hypertension (PAH) patients treated with ambrisentan (AMB) in order to properly define the adverse event profile associated with this endothelin receptor antagonist (ERA), including the incidence and severity of elevated serum liver function tests (LFTs). In addition, this study continued the efficacy assessments of the previous studies, examined long-term AMB treatment success, and compared long-term survival of subjects treated with AMB to the NIH registry of patients with PAH.

Detailed description: AMB-320 (ARIES-1; NCT00423748) and AMB-321 (ARIES-2; NCT00423202) were 12-week, Phase 3, randomized, double-blind, placebo-controlled, multicenter, efficacy studies of AMB in subjects with PAH. The objectives of these studies were to determine the effect of three doses of AMB (2.5, 5.0, and 10.0 mg) on exercise capacity, as well as several clinical measures of PAH. The current study (NCT00578786) was unblinded (by design) prior to completion. The ARIES studies were identical except for the dose groups assessed and the geographic locations where the studies were conducted. Both studies evaluated placebo and 5.0-mg AMB dose groups; however, AMB-320 (NCT00423748) also examined an AMB dose of 10.0 mg, while AMB-321 (NCT00423202) included an AMB dose of 2.5 mg. AMB-320/321-E was an optional study for subjects who had participated in AMB-320 (NCT00423748) or AMB-321 (NCT00423202) that allowed continued long-term treatment with AMB.

Eligibility criteria: Inclusion Criteria:

1. Subject must have completed Week 12 of AMB-320 (NCT00423748) or AMB-321 (NCT00423202) or must have received placebo during AMB-320 (NCT00423748) or AMB-321 (NCT00423202) and met two or more early escape criteria;
2. Subject must be competent to understand the information given in the Institutional Review Board (IRB) or Independent Ethics Committee (IEC) approved informed consent form and must sign the form prior to the initiation of any study procedures.
3. Female subject of childbearing potential must agree to use two reliable methods of contraception until study completion and for at least four weeks following their final study visit. Reliable methods include: birth control pills/implants/injections, intrauterine devices (IUDs), spermicide, diaphragms, or condoms.

Exclusion Criteria:

* Subjects must have met the exclusion criteria of the AMB-320 (NCT00423748) and AMB-321 (NCT00423202)studies. In addition, a subject who meets any one of the following criteria is ineligible for participation in the study:

  1. Subject receiving bosentan, sildenafil, or iv inotropes at any time within four weeks prior to the AMB-320/321-E Screening/Randomization Visit;
  2. Subject receiving chronic prostanoid therapy (epoprostenol, treprostinil, iloprost, beraprost, or any other investigational prostacyclin derivative) within four weeks prior to the AMB-320/321-E Screening/RandomizationVisit;
  3. Female subject who is pregnant or breastfeeding;
  4. Subject with cardiovascular, liver, renal, hematologic, gastrointestinal, immunologic, endocrine, metabolic, or central nervous system disease that, in the opinion of the Investigator, may adversely affect the safety of the subject and/or efficacy of the study drug or severely limit the lifespan of the subject;
  5. Subject who has demonstrated noncompliance with previous medical regimens;
  6. Subject who has a recent history of abusing alcohol or illicit drugs;
  7. Subject who has participated in a clinical study involving another investigational drug or device at any time within four weeks prior to the AMB-320/321-E Screening/Randomization Visit.

Primary outcomes:
measure: Frequently Reported (15% or More Overall) Adverse Events by Severity
timeFrame: Baseline to Week 295
measure: Serum Aminotransferases Relative to the Upper Limit of the Normal Range (ULN)
timeFrame: Baseline to Week 295
Secondary outcomes:
measure: Baseline Exercise Capacity as Measured by the 6-Minute Walk Distance Test
timeFrame: Baseline
measure: Change From Baseline to Week 24 in Exercise Capacity as Measured by the 6-Minute Walk Distance Test
timeFrame: Baseline to Week 24
measure: Change From Baseline to Week 48 (Year 1) in Exercise Capacity as Measured by the 6-Minute Walk Distance Test
timeFrame: Baseline to Week 48
measure: Change From Baseline to Year 2 in Exercise Capacity as Measured by the 6-Minute Walk Distance Test
timeFrame: Baseline to Year 2
measure: Change From Baseline to Year 3 in Exercise Capacity as Measured by the 6-Minute Walk Distance Test
timeFrame: Baseline to Year 3
measure: Baseline Borg Dyspnea Index
timeFrame: Baseline
measure: Change From Baseline to Year 1 in Borg Dyspnea Index
timeFrame: Baseline to Year 1
measure: Change From Baseline to Year 2 in Borg Dyspnea Index
timeFrame: Baseline to Year 2
measure: Change From Baseline to Year 3 in Borg Dyspnea Index
timeFrame: Baseline to Year 3
measure: Baseline World Health Organization (WHO) Functional Class
timeFrame: Baseline
measure: Change From Baseline to Year 1 in World Health Organization (WHO) Functional Class
timeFrame: Baseline to Year 1
measure: Change From Baseline to Year 2 in World Health Organization (WHO) Functional Class
timeFrame: Baseline to Year 2
measure: Change From Baseline to Year 3 in World Health Organization (WHO) Functional Class
timeFrame: Baseline to Year 3
measure: Baseline SF-36 Health Survey Scales for the Combined Ambrisentan Group
timeFrame: Baseline
measure: Change From Baseline to Week 12 in SF-36 Health Survey Scales for the Combined Ambrisentan Group
timeFrame: Baseline to Week 12
measure: Change From Baseline to Week 24 in SF-36 Health Survey Scales for the Combined Ambrisentan Group
timeFrame: Baseline to Week 24
measure: Change From Baseline to Week 36 in SF-36 Health Survey Scales for the Combined Ambrisentan Group
timeFrame: Baseline to Week 36
measure: Percentage of Participants With No Clinical Worsening of PAH
timeFrame: Baseline to Year 3
measure: Percentage of Participants With Failure-Free Treatment Status
timeFrame: Baseline to Year 4
measure: Long-term Survival
timeFrame: Baseline to Year 4
Other outcomes:
Locations:
city: Ciudad Autonoma de Buenos Aires
country: Argentina
facility: Sanatorio Otamendi
state: Buenos Aires
city: Ciudad Autonoma de Buenos Aires
country: Argentina
facility: Hospital Britanico-Buenos Aires
state: Buenos Aires
city: Ciudad Autonoma de Buenos Aires
country: Argentina
facility: Instituto del Corazon Denton A. Cooley
state: Buenos Aires
city: Ciudad Autonoma de Buenos Aires
country: Argentina
facility: UAI Hosp. Universitario
state: Buenos Aires
city: Mar del Plata
country: Argentina
facility: HIGA Hospital Interzonal General de Agudos Oscar Allende
state: Buenos Aires
city: Munro
country: Argentina
facility: Clinica Independencia Munro
state: Buenos Aires
city: Rosario
country: Argentina
facility: Hospital Italiano de Rosario
state: Sante Fe
city: Cordoba
country: Argentina
facility: Sanatorio Allende
city: Cordoba
country: Argentina
facility: Hospital Italiano de Cordoba
city: Cordoba
country: Argentina
facility: Hospital Privado Centro Medico de Cordoba
city: Corrientes
country: Argentina
facility: Instituto de Cardiologia J.F. Cabral
city: Ilha do Fundao
country: Brazil
facility: Hospital Universitario Clementino Fraga Filho
state: Rio de Janeiro
city: Belo Horizonte
country: Brazil
facility: Hospital Madre Teresa
city: Porto Alegre
country: Brazil
facility: Hospital San Lucas de Pontificia Universidade Catolica
city: Porto Alegre
country: Brazil
facility: Complexo Hospitalar Sanata Casa de Porto Alegre
city: Sao Paulo
country: Brazil
facility: Universidade do Estado de Sao Paulo - UNIFESP
city: Sao Paulo
country: Brazil
facility: Hospital das Clinicas da FMUSP
city: Santiago
country: Chile
facility: Hospital San Juan de Dios
state: Santiago de Chile
city: Santiago
country: Chile
facility: Hospital Clinico Universidad Catolica
state: Santiago de Chile
city: Santiago
country: Chile
facility: Instituto Nacional del Torax
state: Santiago de Chile
city: Mexico, DF
country: Mexico
facility: Instituto Nacional de Cardiologia Ignacio Chavez
state: DF
city: Monterrey, Nuevo Leon
country: Mexico
facility: Unidad De Investigacion Clinica en Medicina
state: Nuevo Leon
Study officials:
affiliation: Gilead Sciences
name: Chris Dufton, PhD
role: STUDY_CHAIR
References:
citation: Oudiz RJ, Galie N, Olschewski H, Torres F, Frost A, Ghofrani HA, Badesch DB, McGoon MD, McLaughlin VV, Roecker EB, Harrison BC, Despain D, Dufton C, Rubin LJ; ARIES Study Group. Long-term ambrisentan therapy for the treatment of pulmonary arterial hypertension. J Am Coll Cardiol. 2009 Nov 17;54(21):1971-81. doi: 10.1016/j.jacc.2009.07.033.