Study of Add-on Ambrisentan Therapy to Background Phosphodiesterase Type-5 Inhibitor (PDE5i) Therapy in Pulmonary Arterial Hypertension (ATHENA-1) (ATHENA-1)

This study has been completed.

Sponsor:

Information provided by (Responsible Party):

Gilead Sciences

ClinicalTrials.gov Identifier:

NCT00617305

First received: February 6, 2008

Last updated: June 22, 2012

Last verified: June 2012

History of Changes

Results First Received: May 11, 2012

Study Type:	Interventional
Study Design:	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double Blind (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Condition:	Pulmonary Arterial Hypertension
Interventions:	Drug: Ambrisentan Drug: Placebo Drug: Sildenafil Drug: Tadalafil

Participant Flow

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Baseline Characteristics

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Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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Reporting Groups

	Description
Ambrisentan Only	Patients were assigned ambrisentan at open-label enrollment or randomization, and received at least one dose of ambrisentan plus an approved phosphodiesterase type-5 (PDE-5) inhibitor (PDE-5i)
Placebo/Ambrisentan	Patients were assigned placebo at randomization and received at least one dose of placebo plus an approved PDE-5i; patients also received at least one dose of open-label ambrisentan plus an approved PDE-5i
Placebo Only	Patients were assigned placebo at randomization and received at least one dose of placebo plus an approved PDE-5i
Total	Total of all reporting groups

Baseline Measures

	Ambrisentan Only	Placebo/Ambrisentan	Placebo Only	Total
Overall Participants Analyzed [Units: Participants]	33	4	1	38

Age [Units: Participants]
<=18 years	0	0	0	0
Between 18 and 65 years	29	4	1	34
>=65 years	4	0	0	4

Age [Units: Years] Mean (Standard Deviation)	48.2 (13.72)	43.5 (14.89)	49.0 (0)	47.8 (13.52)

Gender [Units: Participants]
Female	26	2	0	28
Male	7	2	1	10

Ethnicity (NIH/OMB) [Units: Participants]
Hispanic or Latino	8	0	0	8
Not Hispanic or Latino	25	4	1	30
Unknown or Not Reported	0	0	0	0

Race/Ethnicity, Customized [Units: Participants]
Asian	2	0	0	2
Black or African American	2	0	0	2
Hispanic	1	0	0	1
More than one race	1	0	0	1
White	27	4	1	32

Region of Enrollment [Units: Participants]
United States	33	4	1	38

Outcome Measures

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1. Primary:

Change From Baseline in Pulmonary Vascular Resistance (PVR), Last Observation Carried Forward (LOCF) [ Time Frame: Baseline to Week 24 ]

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2. Secondary:

Change From Baseline in Mean Pulmonary Artery Pressure (mPAP) (LOCF) [ Time Frame: Baseline to Week 24 ]

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3. Secondary:

Change From Baseline in Mean Right Atrial Pressure (mRAP) (LOCF) [ Time Frame: Baseline to Week 24 ]

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4. Secondary:

Change From Baseline in Cardiac Output (LOCF) [ Time Frame: Baseline to Week 24 ]

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5. Secondary:

Change From Baseline in Six Minute Walk Distance (6MWD) Measured at Weeks 4, 12, 24, 36 and 48 (LOCF) [ Time Frame: Baseline to Week 48 ]

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6. Secondary:

Change in Dyspnea Index Measured at Weeks 4, 12, 24, 36 and 48 (LOCF) [ Time Frame: Baseline to Week 48 ]

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7. Secondary:

Change From Baseline in the Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) Quality of Life (QOL) Survey Overall Score Measured at Weeks 12, 24, 36 and 48 (LOCF) [ Time Frame: Baseline to Week 48 ]

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8. Secondary:

Change From Baseline in World Health Organization (WHO) Functional Class (LOCF) Measured at Weeks 4, 12, 24, 36 and 48. [ Time Frame: Baseline to Week 48 ]

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9. Secondary:

Change From Baseline in Log-transformed N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) Measured at Weeks 4, 12, 24, 36 and 48 (LOCF) [ Time Frame: Baseline to Week 48 ]

Show Outcome Measure 9

10. Secondary:

Time to Clinical Worsening of PAH, Evaluated at Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and After Week 48 [ Time Frame: Baseline to Week 48+ ]

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11. Secondary:

Overall Survival, Evaluated at Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and After Week 48 [ Time Frame: Baseline to Week 48+ ]

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Serious Adverse Events

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Other Adverse Events

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Time Frame	Adverse events (AEs) and serious adverse events (SAEs) were reported through Week 48.
Additional Description	AEs/SAEs were analyzed for patients who: received ambrisentan but not placebo ("Ambrisentan Only"); received ambrisentan and did or did not receive placebo ("Any Ambrisentan"); received placebo and did or did not receive ambrisentan ("Any Placebo"). Safety analysis was not done for the "Ambrisentan/Placebo" or "Placebo Only" groups.

Frequency Threshold

Threshold above which other adverse events are reported	5%

Reporting Groups

	Description
Ambrisentan Only	Patients were assigned ambrisentan at open-label enrollment or randomization, and received at least one dose of ambrisentan plus an approved phosphodiesterase type-5 (PDE-5) inhibitor (PDE-5i)
Any Ambrisentan	Patients were assigned either ambrisentan or placebo at enrollment or randomization and received at least one dose of ambrisentan plus an approved PDE-5i
Any Placebo	Patients were assigned placebo at randomization and received at least one dose of placebo plus an approved PDE-5i

Other Adverse Events

	Ambrisentan Only	Any Ambrisentan	Any Placebo
Total, Other (not including serious) Adverse Events
# participants affected / at risk	32/33 (96.97%)	36/37 (97.30%)	4/5 (80.00%)
Blood and lymphatic system disorders
Anaemia ^* 1
# participants affected / at risk	3/33 (9.09%)	3/37 (8.11%)	0/5 (0.00%)
Cardiac disorders
Tachycardia ^* 1
# participants affected / at risk	2/33 (6.06%)	3/37 (8.11%)	0/5 (0.00%)
Ear and labyrinth disorders
Deafness neurosensory ^* 1
# participants affected / at risk	1/33 (3.03%)	2/37 (5.41%)	0/5 (0.00%)
Gastrointestinal disorders
Abdominal pain ^* 1
# participants affected / at risk	3/33 (9.09%)	3/37 (8.11%)	1/5 (20.00%)
Gastrooesophageal reflux disease ^* 1
# participants affected / at risk	3/33 (9.09%)	3/37 (8.11%)	0/5 (0.00%)
Constipation ^* 1
# participants affected / at risk	2/33 (6.06%)	2/37 (5.41%)	1/5 (20.00%)
Abdominal discomfort ^* 1
# participants affected / at risk	2/33 (6.06%)	2/37 (5.41%)	0/5 (0.00%)
Diarrhoea ^* 1
# participants affected / at risk	2/33 (6.06%)	2/37 (5.41%)	0/5 (0.00%)
Haemorrhoids ^* 1
# participants affected / at risk	2/33 (6.06%)	2/37 (5.41%)	0/5 (0.00%)
Nausea ^* 1
# participants affected / at risk	2/33 (6.06%)	2/37 (5.41%)	0/5 (0.00%)
Toothache ^* 1
# participants affected / at risk	2/33 (6.06%)	2/37 (5.41%)	0/5 (0.00%)
General disorders
Oedema peripheral ^* 1
# participants affected / at risk	7/33 (21.21%)	7/37 (18.92%)	0/5 (0.00%)
Fatigue ^* 1
# participants affected / at risk	5/33 (15.15%)	5/37 (13.51%)	1/5 (20.00%)
Chest pain ^* 1
# participants affected / at risk	2/33 (6.06%)	2/37 (5.41%)	0/5 (0.00%)
Infections and infestations
Upper respiratory tract infection ^* 1
# participants affected / at risk	8/33 (24.24%)	8/37 (21.62%)	0/5 (0.00%)
Urinary tract infection ^* 1
# participants affected / at risk	5/33 (15.15%)	5/37 (13.51%)	0/5 (0.00%)
Nasopharyngitis ^* 1
# participants affected / at risk	3/33 (9.09%)	4/37 (10.81%)	1/5 (20.00%)
Lower respiratory tract infection ^* 1
# participants affected / at risk	3/33 (9.09%)	3/37 (8.11%)	0/5 (0.00%)
Sinusitis ^* 1
# participants affected / at risk	2/33 (6.06%)	3/37 (8.11%)	0/5 (0.00%)
Cellulitis ^* 1
# participants affected / at risk	2/33 (6.06%)	2/37 (5.41%)	0/5 (0.00%)
Viral infection ^* 1
# participants affected / at risk	2/33 (6.06%)	2/37 (5.41%)	0/5 (0.00%)
Bronchitis ^* 1
# participants affected / at risk	1/33 (3.03%)	2/37 (5.41%)	0/5 (0.00%)
Investigations
Brain natriuretic peptide increased ^* 1
# participants affected / at risk	3/33 (9.09%)	3/37 (8.11%)	0/5 (0.00%)
Blood uric acid increased ^* 1
# participants affected / at risk	2/33 (6.06%)	2/37 (5.41%)	0/5 (0.00%)
Protein total increased ^* 1
# participants affected / at risk	2/33 (6.06%)	2/37 (5.41%)	0/5 (0.00%)
Urine leukocyte esterase positive ^* 1
# participants affected / at risk	2/33 (6.06%)	2/37 (5.41%)	0/5 (0.00%)
Blood creatinine increased ^* 1
# participants affected / at risk	1/33 (3.03%)	1/37 (2.70%)	1/5 (20.00%)
Metabolism and nutrition disorders
Fluid overload ^* 1
# participants affected / at risk	5/33 (15.15%)	7/37 (18.92%)	1/5 (20.00%)
Hypokalaemia ^* 1
# participants affected / at risk	3/33 (9.09%)	3/37 (8.11%)	1/5 (20.00%)
Fluid retention ^* 1
# participants affected / at risk	3/33 (9.09%)	3/37 (8.11%)	0/5 (0.00%)
Musculoskeletal and connective tissue disorders
Arthralgia ^* 1
# participants affected / at risk	2/33 (6.06%)	2/37 (5.41%)	0/5 (0.00%)
Musculoskeletal pain ^* 1
# participants affected / at risk	2/33 (6.06%)	2/37 (5.41%)	0/5 (0.00%)
Pain in extremity ^* 1
# participants affected / at risk	2/33 (6.06%)	2/37 (5.41%)	0/5 (0.00%)
Nervous system disorders
Headache ^* 1
# participants affected / at risk	7/33 (21.21%)	7/37 (18.92%)	1/5 (20.00%)
Dizziness ^* 1
# participants affected / at risk	5/33 (15.15%)	5/37 (13.51%)	1/5 (20.00%)
Carpal tunnel syndrome ^* 1
# participants affected / at risk	2/33 (6.06%)	2/37 (5.41%)	0/5 (0.00%)
Psychiatric disorders
Anxiety ^* 1
# participants affected / at risk	2/33 (6.06%)	2/37 (5.41%)	0/5 (0.00%)
Depression ^* 1
# participants affected / at risk	1/33 (3.03%)	1/37 (2.70%)	1/5 (20.00%)
Respiratory, thoracic and mediastinal disorders
Nasal congestion ^* 1
# participants affected / at risk	10/33 (30.30%)	10/37 (27.03%)	0/5 (0.00%)
Dyspnoea ^* 1
# participants affected / at risk	4/33 (12.12%)	4/37 (10.81%)	0/5 (0.00%)
Epistaxis ^* 1
# participants affected / at risk	4/33 (12.12%)	4/37 (10.81%)	0/5 (0.00%)
Oropharyngeal pain ^* 1
# participants affected / at risk	2/33 (6.06%)	2/37 (5.41%)	0/5 (0.00%)
Pulmonary arterial hypertension ^* 1
# participants affected / at risk	2/33 (6.06%)	2/37 (5.41%)	0/5 (0.00%)

*	Events were collected by non-systematic assessment
1	Term from vocabulary, MedDRA 14.0

Limitations and Caveats

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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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More Information

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Certain Agreements:

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.

Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed.

Restriction Description:

After conclusion of the study and without prior written approval from Gilead, investigators in this study may communicate, orally present, or publish in scientific journals or other media only after the following conditions have been met:

The results of the study in their entirety have been publicly disclosed by or with the consent of Gilead in an abstract, manuscript, or presentation form; or
The study has been completed at all study sites for at least 2 years

Results Point of Contact:

Name/Title: Ellen Shen, PhD, Senior Manager, Regulatory Affairs
Organization: Gilead Sciences
phone: +1 (650) 522-5278
e-mail: Ellen.Shen@gilead.com

Responsible Party:	Gilead Sciences
ClinicalTrials.gov Identifier:	NCT00617305 History of Changes
Other Study ID Numbers:	GS-US-300-0117
Study First Received:	February 6, 2008
Results First Received:	May 11, 2012
Last Updated:	June 22, 2012

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