A Long Term Study of Ambrisentan in Pulmonary Arterial Hypertension Subjects Having Completed AMB-320 (NCT00423748) or AMB-321 (NCT00423202)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Gilead Sciences
ClinicalTrials.gov Identifier:
NCT00578786
First received: December 19, 2007
Last updated: January 14, 2013
Last verified: January 2013
  Purpose

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.


Condition Intervention Phase
Pulmonary Arterial Hypertension
Drug: ambrisentan
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Long Term Study of Ambrisentan in Pulmonary Arterial Hypertension Subjects Having Completed AMB-320 (NCT00423748) or AMB-321 (NCT00423202)

Resource links provided by NLM:


Further study details as provided by Gilead Sciences:

Primary Outcome Measures:
  • Frequently Reported (15% or More Overall) Adverse Events by Severity [ Time Frame: Baseline to Week 295 ] [ Designated as safety issue: Yes ]
    The primary endpoint of this study is the incidence and severity of adverse events associated with long-term exposure to AMB in participants with PAH. The most frequently occurring adverse events (occurring in 15% or more of the participants in the combined group) are presented, by severity, that began after entering this extension study. Adverse events that were serious are included. Adverse events are coded according to the Medical Dictionary for Regulatory Activities (MedDRA) Version 6.1 and are presented by MedDRA preferred term. Severity was graded as follows: mild (AE did not interfere with routine activities; subject may have experienced slight discomfort), moderate (AE interfered with routine activities; subject may have experienced significant discomfort), and severe (AE made it impossible to perform routine activities; subject may have experienced intolerable discomfort or pain).

  • Serum Aminotransferases Relative to the Upper Limit of the Normal Range (ULN) [ Time Frame: Baseline to Week 295 ] [ Designated as safety issue: Yes ]
    The number of participants with serum alanine aminotransferase (ALT) and serum aspartate aminotransferase (AST) falling into the following categories: >3.0 and </= 5.0 x ULN, >5.0 and </= 8.0 x ULN, and >8.0 x ULN. Includes the highest value per participant across all visits as well as values from early termination visits.


Secondary Outcome Measures:
  • Baseline Exercise Capacity as Measured by the 6-Minute Walk Distance Test [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    The 6-minute walk distance (6MWD) test was conducted according to the American Thoracic Society guidelines (ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002; 166(1):111-117.).

  • Change From Baseline to Week 24 in Exercise Capacity as Measured by the 6-Minute Walk Distance Test [ Time Frame: Baseline to Week 24 ] [ Designated as safety issue: No ]
    The 6-minute walk distance (6MWD) test was conducted according to the American Thoracic Society guidelines (ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002; 166(1):111-117.). Missing values were imputed using LOCF method based on post-baseline observations. Baseline (BL) values from the screening/randomization visit of the 2 prior studies defined the BL of this long-term analysis for those receiving ambrisentan in the prior studies. The Screening/Randomization Visit of the present study was the BL for subjects receiving placebo in the prior studies.

  • Change From Baseline to Week 48 (Year 1) in Exercise Capacity as Measured by the 6-Minute Walk Distance Test [ Time Frame: Baseline to Week 48 ] [ Designated as safety issue: No ]
    The 6-minute walk distance (6MWD) test was conducted according to the American Thoracic Society guidelines (ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002; 166(1):111-117.). The last-observation-carried-forward (LOCF) imputation method was used. Baseline (BL) values from the screening/randomization visit of the 2 prior studies defined the BL of this long-term analysis for those receiving AMB in the prior studies. The Screening/Randomization Visit of the present study was the BL for subjects receiving placebo in the prior studies.

  • Change From Baseline to Year 2 in Exercise Capacity as Measured by the 6-Minute Walk Distance Test [ Time Frame: Baseline to Year 2 ] [ Designated as safety issue: No ]
    The 6-minute walk distance (6MWD) test was conducted according to the American Thoracic Society guidelines (ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002; 166(1):111-117.). The last-observation-carried-forward (LOCF) imputation method was used. Baseline (BL) values from the screening/randomization visit of the 2 prior studies defined the BL of this long-term analysis for those receiving AMB in the prior studies. The Screening/Randomization Visit of the present study was the BL for subjects receiving placebo in the prior studies.

  • Change From Baseline to Year 3 in Exercise Capacity as Measured by the 6-Minute Walk Distance Test [ Time Frame: Baseline to Year 3 ] [ Designated as safety issue: No ]
    Thoracic Society guidelines (ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002; 166(1):111-117.). The last-observation-carried-forward (LOCF) imputation method was used. Baseline (BL) values from the screening/randomization visit of the 2 prior studies defined the BL of this long-term analysis for those receiving AMB in the prior studies. The Screening/Randomization Visit of the present study was the BL for subjects receiving placebo in the prior studies.

  • Baseline Borg Dyspnea Index [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    Borg Dyspnea Index is a measure of perceived shortness of breath: 0 units on a scale (none) to 10 units on a scale (maximum breathlessness).

  • Change From Baseline to Year 1 in Borg Dyspnea Index [ Time Frame: Baseline to Year 1 ] [ Designated as safety issue: No ]
    Borg Dyspnea Index is a measure of perceived shortness of breath: 0 units on a scale (none) to 10 units on a scale (maximum breathlessness). Baseline (BL) values from the screening/randomization visit of the 2 prior studies defined the BL of this long-term analysis for those receiving ambrisentan in the prior studies. The Screening/Randomization Visit of the present study was the BL for subjects receiving placebo in the prior studies.

  • Change From Baseline to Year 2 in Borg Dyspnea Index [ Time Frame: Baseline to Year 2 ] [ Designated as safety issue: No ]
    Borg Dyspnea Index is a measure of perceived shortness of breath: 0 units on a scale (none) to 10 units on a scale (maximum breathlessness). Baseline (BL) values from the screening/randomization visit of the 2 prior studies defined the BL of this long-term analysis for those receiving AMB in the prior studies. The Screening/Randomization Visit of the present study was the BL for subjects receiving placebo in the prior studies.

  • Change From Baseline to Year 3 in Borg Dyspnea Index [ Time Frame: Baseline to Year 3 ] [ Designated as safety issue: No ]
    Borg Dyspnea Index is a measure of perceived shortness of breath: 0 units on a scale (none) to 10 units on a scale (maximum breathlessness). Baseline (BL) values from the screening/randomization visit of the 2 prior studies defined the BL of this long-term analysis for those receiving AMB in the prior studies. The Screening/Randomization Visit of the present study was the BL for subjects receiving placebo in the prior studies.

  • Baseline World Health Organization (WHO) Functional Class [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    WHO Classes: I) pulmonary hypertension (PH); ordinary physical activity not limited or causes increased dyspnea, fatigue, chest pain, or presyncope. II) PH; ordinary physical activity mildly limited and causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. III) PH; physical activity markedly limited and less than ordinary physical activity causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. IV) PH; physical activity causes symptoms; signs of right heart failure; dyspnea/fatigue possible at rest.

  • Change From Baseline to Year 1 in World Health Organization (WHO) Functional Class [ Time Frame: Baseline to Year 1 ] [ Designated as safety issue: No ]
    WHO Classes: I) pulmonary hypertension (PH); ordinary physical activity not limited or causes increased dyspnea, fatigue, chest pain, or presyncope. II) PH; ordinary physical activity mildly limited and causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. III) PH; physical activity markedly limited and less than ordinary physical activity causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. IV) PH; physical activity causes symptoms; signs of right heart failure; dyspnea/fatigue possible at rest.

  • Change From Baseline to Year 2 in World Health Organization (WHO) Functional Class [ Time Frame: Baseline to Year 2 ] [ Designated as safety issue: No ]
    WHO Classes: I) pulmonary hypertension (PH); ordinary physical activity not limited or causes increased dyspnea, fatigue, chest pain, or presyncope. II) PH; ordinary physical activity mildly limited and causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. III) PH; physical activity markedly limited and less than ordinary physical activity causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. IV) PH; physical activity causes symptoms; signs of right heart failure; dyspnea/fatigue possible at rest.

  • Change From Baseline to Year 3 in World Health Organization (WHO) Functional Class [ Time Frame: Baseline to Year 3 ] [ Designated as safety issue: No ]
    WHO Classes: I) pulmonary hypertension (PH); ordinary physical activity not limited or causes increased dyspnea, fatigue, chest pain, or presyncope. II) PH; ordinary physical activity mildly limited and causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. III) PH; physical activity markedly limited and less than ordinary physical activity causes increased dyspnea, fatigue, chest pain, or presyncope; comfortable at rest. IV) PH; physical activity causes symptoms; signs of right heart failure; dyspnea/fatigue possible at rest.

  • Baseline SF-36 Health Survey Scales for the Combined Ambrisentan Group [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    The 8 scales of the SF-36 Health Survey measured included physical functioning, role physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health, and the summary measures included physical health and mental health. Scores for each scale are transformed and the transformed scores range from 0 (worst health) to 100 (best health). The scores are then standardized with the 1998 General United States (US) population mean and standard deviation (SD). Finally, the scores are transformed to the norm-based scoring with a mean of 50 and SD of 10.

  • Change From Baseline to Week 12 in SF-36 Health Survey Scales for the Combined Ambrisentan Group [ Time Frame: Baseline to Week 12 ] [ Designated as safety issue: No ]
    The 8 scales of the SF-36 Health Survey measured included physical functioning, role physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health, and the summary measures included physical health and mental health. Scores for each scale are transformed and the transformed scores range from 0 (worst health) to 100 (best health). The scores are then standardized with the 1998 General US population mean and SD. Finally, the scores are transformed to the norm-based scoring with a mean of 50 and SD of 10.

  • Change From Baseline to Week 24 in SF-36 Health Survey Scales for the Combined Ambrisentan Group [ Time Frame: Baseline to Week 24 ] [ Designated as safety issue: No ]
    The 8 scales of the SF-36 Health Survey measured included physical functioning, role physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health, and the summary measures included physical health and mental health. Scores for each scale are transformed and the transformed scores range from 0 (worst health) to 100 (best health). The scores are then standardized with the 1998 General US population mean and SD. Finally, the scores are transformed to the norm-based scoring with a mean of 50 and SD of 10.

  • Change From Baseline to Week 36 in SF-36 Health Survey Scales for the Combined Ambrisentan Group [ Time Frame: Baseline to Week 36 ] [ Designated as safety issue: No ]
    The 8 scales of the SF-36 Health Survey measured included physical functioning, role physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health, and the summary measures included physical health and mental health. Scores for each scale are transformed and the transformed scores range from 0 (worst health) to 100 (best health). The scores are then standardized with the 1998 General US population mean and SD. Finally, the scores are transformed to the norm-based scoring with a mean of 50 and SD of 10.

  • Percentage of Participants With No Clinical Worsening of PAH [ Time Frame: Baseline to Year 3 ] [ Designated as safety issue: No ]
    Clinical worsening of PAH was defined as the time from randomization to ambrisentan therapy to the first occurrence of death, lung transplantation, hospitalization for PAH, atrial septostomy, addition of approved prostanoid therapy, study withdrawal due to the addition of other clinically approved PAH therapeutics, or study withdrawal due to 2 or more early escape criteria (for subjects randomized to AMB in NCT00423748 or NCT00423202). Results are presented as the Kaplan-Meier estimate (% probability) of not having clinical worsening after a given time.

  • Percentage of Participants With Failure-Free Treatment Status [ Time Frame: Baseline to Year 4 ] [ Designated as safety issue: No ]
    Treatment failure was defined as the time from randomization to ambrisentan therapy to the first occurrence of death, lung transplantation, addition of approved prostanoid therapy, study withdrawal due to the addition of other clinically approved PAH therapeutics, or study withdrawal due to 2 or more early escape criteria (for subjects randomized to ambrisentan in NCT00423748 or NCT00423202). Results are presented as the Kaplan-Meier estimate (% probability) of not having treatment failure after a given time.

  • Long-term Survival [ Time Frame: Baseline to Year 4 ] [ Designated as safety issue: No ]
    Long-term survival was defined as the time from initiation of active treatment to death. Results are presented as the Kaplan-Meier estimate (% probability) of survival after a given time.


Enrollment: 383
Study Start Date: February 2004
Study Completion Date: March 2010
Primary Completion Date: March 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Ambrisentan
2.5, 5 or 10 mg ambrisentan
Drug: ambrisentan
2.5, 5.0 or 10.0 mg ambrisentan po, qd, long-term
Other Name: Letairis(TM)

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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00578786

Locations
Argentina
Hospital Britanico-Buenos Aires
Ciudad Autonoma de Buenos Aires, Buenos Aires, Argentina, C1280AEB
UAI Hosp. Universitario
Ciudad Autonoma de Buenos Aires, Buenos Aires, Argentina, C1437BZL
Sanatorio Otamendi
Ciudad Autonoma de Buenos Aires, Buenos Aires, Argentina, C1115AAB
Instituto del Corazon Denton A. Cooley
Ciudad Autonoma de Buenos Aires, Buenos Aires, Argentina, C1416A
HIGA Hospital Interzonal General de Agudos Oscar Allende
Mar del Plata, Buenos Aires, Argentina, 07600
Clinica Independencia Munro
Munro, Buenos Aires, Argentina, 01605
Hospital Italiano de Rosario
Rosario, Sante Fe, Argentina, 02000
Hospital Privado Centro Medico de Cordoba
Cordoba, Argentina, X5016KEH
Hospital Italiano de Cordoba
Cordoba, Argentina, X5004 FJE
Sanatorio Allende
Cordoba, Argentina, X5000JHQ
Instituto de Cardiologia J.F. Cabral
Corrientes, Argentina, W3400AMZ
Brazil
Hospital Universitario Clementino Fraga Filho
Ilha do Fundao, Rio de Janeiro, Brazil, 21941-590
Hospital Madre Teresa
Belo Horizonte, Brazil, 30380-090
Complexo Hospitalar Sanata Casa de Porto Alegre
Porto Alegre, Brazil, 92020-090
Hospital San Lucas de Pontificia Universidade Catolica
Porto Alegre, Brazil, 90610-000
Hospital das Clinicas da FMUSP
Sao Paulo, Brazil, 05403-000
Universidade do Estado de Sao Paulo - UNIFESP
Sao Paulo, Brazil, 04023-062
Chile
Hospital Clinico Universidad Catolica
Santiago, Santiago de Chile, Chile, CP 8350488
Hospital San Juan de Dios
Santiago, Santiago de Chile, Chile, CP 8330024
Instituto Nacional del Torax
Santiago, Santiago de Chile, Chile, CP7500691
Mexico
Instituto Nacional de Cardiologia Ignacio Chavez
Mexico, DF, DF, Mexico, 14080
Unidad De Investigacion Clinica en Medicina
Monterrey, Nuevo Leon, Nuevo Leon, Mexico, 64718
Sponsors and Collaborators
Gilead Sciences
Investigators
Study Chair: Chris Dufton, PhD Gilead Sciences
  More Information

No publications provided

Responsible Party: Gilead Sciences
ClinicalTrials.gov Identifier: NCT00578786     History of Changes
Other Study ID Numbers: AMB-320/321-E, ARIES-E
Study First Received: December 19, 2007
Results First Received: April 12, 2012
Last Updated: January 14, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Hypertension, Pulmonary
Hypertension
Lung Diseases
Respiratory Tract Diseases
Vascular Diseases
Cardiovascular Diseases

ClinicalTrials.gov processed this record on August 21, 2014