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

Pulmonary Arterial Hypertension Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00578786
• Other study ID #: AMB-320/321-E
• Secondary ID: ARIES-E
• Status: Completed
• Phase: Phase 3
• First received: December 19, 2007
• Last updated: January 14, 2013
• Start date: February 2004
• Est. completion date: March 2010

Study information

• Verified date: January 2013
• Source: Gilead Sciences
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 383
• Est. completion date: March 2010
• Est. primary completion date: March 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Hypertension
• Pulmonary Arterial Hypertension

Intervention

Drug:
• ambrisentan
2.5, 5.0 or 10.0 mg ambrisentan po, qd, long-term

Locations

Country	Name	City	State
Argentina	Hospital Britanico-Buenos Aires	Ciudad Autonoma de Buenos Aires	Buenos Aires
Argentina	Instituto del Corazon Denton A. Cooley	Ciudad Autonoma de Buenos Aires	Buenos Aires
Argentina	Sanatorio Otamendi	Ciudad Autonoma de Buenos Aires	Buenos Aires
Argentina	UAI Hosp. Universitario	Ciudad Autonoma de Buenos Aires	Buenos Aires
Argentina	Hospital Italiano de Cordoba	Cordoba
Argentina	Hospital Privado Centro Medico de Cordoba	Cordoba
Argentina	Sanatorio Allende	Cordoba
Argentina	Instituto de Cardiologia J.F. Cabral	Corrientes
Argentina	HIGA Hospital Interzonal General de Agudos Oscar Allende	Mar del Plata	Buenos Aires
Argentina	Clinica Independencia Munro	Munro	Buenos Aires
Argentina	Hospital Italiano de Rosario	Rosario	Sante Fe
Brazil	Hospital Madre Teresa	Belo Horizonte
Brazil	Hospital Universitario Clementino Fraga Filho	Ilha do Fundao	Rio de Janeiro
Brazil	Complexo Hospitalar Sanata Casa de Porto Alegre	Porto Alegre
Brazil	Hospital San Lucas de Pontificia Universidade Catolica	Porto Alegre
Brazil	Hospital das Clinicas da FMUSP	Sao Paulo
Brazil	Universidade do Estado de Sao Paulo - UNIFESP	Sao Paulo
Chile	Hospital Clinico Universidad Catolica	Santiago	Santiago de Chile
Chile	Hospital San Juan de Dios	Santiago	Santiago de Chile
Chile	Instituto Nacional del Torax	Santiago	Santiago de Chile
Mexico	Instituto Nacional de Cardiologia Ignacio Chavez	Mexico, DF	DF
Mexico	Unidad De Investigacion Clinica en Medicina	Monterrey, Nuevo Leon	Nuevo Leon

Sponsors (1)

Lead Sponsor	Collaborator
Gilead Sciences

Countries where clinical trial is conducted

Argentina,  Brazil,  Chile,  Mexico, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Frequently Reported (15% or More Overall) Adverse Events by Severity	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).	Baseline to Week 295	Yes
Primary	Serum Aminotransferases Relative to the Upper Limit of the Normal Range (ULN)	The number of participants with serum alanine aminotransferase (ALT) and serum aspartate aminotransferase (AST) falling into the following categories: >3.0 and	Baseline to Week 295	Yes
Secondary	Baseline Exercise Capacity as Measured by the 6-Minute Walk Distance Test	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.).	Baseline	No
Secondary	Change From Baseline to Week 24 in Exercise Capacity as Measured by the 6-Minute Walk Distance Test	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.	Baseline to Week 24	No
Secondary	Change From Baseline to Week 48 (Year 1) in Exercise Capacity as Measured by the 6-Minute Walk Distance Test	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.	Baseline to Week 48	No
Secondary	Change From Baseline to Year 2 in Exercise Capacity as Measured by the 6-Minute Walk Distance Test	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.	Baseline to Year 2	No
Secondary	Change From Baseline to Year 3 in Exercise Capacity as Measured by the 6-Minute Walk Distance Test	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 to Year 3	No
Secondary	Baseline Borg Dyspnea Index	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	No
Secondary	Change From Baseline to Year 1 in Borg Dyspnea Index	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.	Baseline to Year 1	No
Secondary	Change From Baseline to Year 2 in Borg Dyspnea Index	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 to Year 2	No
Secondary	Change From Baseline to Year 3 in Borg Dyspnea Index	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 to Year 3	No
Secondary	Baseline World Health Organization (WHO) Functional Class	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	No
Secondary	Change From Baseline to Year 1 in World Health Organization (WHO) Functional Class	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 to Year 1	No
Secondary	Change From Baseline to Year 2 in World Health Organization (WHO) Functional Class	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 to Year 2	No
Secondary	Change From Baseline to Year 3 in World Health Organization (WHO) Functional Class	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 to Year 3	No
Secondary	Baseline SF-36 Health Survey Scales for the Combined Ambrisentan Group	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.	Baseline	No
Secondary	Change From Baseline to Week 12 in SF-36 Health Survey Scales for the Combined Ambrisentan Group	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.	Baseline to Week 12	No
Secondary	Change From Baseline to Week 24 in SF-36 Health Survey Scales for the Combined Ambrisentan Group	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.	Baseline to Week 24	No
Secondary	Change From Baseline to Week 36 in SF-36 Health Survey Scales for the Combined Ambrisentan Group	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.	Baseline to Week 36	No
Secondary	Percentage of Participants With No Clinical Worsening of PAH	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.	Baseline to Year 3	No
Secondary	Percentage of Participants With Failure-Free Treatment Status	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.	Baseline to Year 4	No
Secondary	Long-term Survival	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.	Baseline to Year 4	No