Trial Outcomes & Findings for The Safety Evaluation of Aminophylline and Ambrisentan When Administered Orally Alone and in Combination to Healthy Volunteers (NCT NCT01530464)

Last Updated: 2014-01-16

Results Overview

Dosing schedule: Aminophylline Alone (Single Dose of 500mg Aminophylline) Ambrisentan Alone (Single Dose of 5mg Ambrisentan) Ambrisentan and Aminophylline (Combined Single Dose of 500mg Aminophylline and 5mg Ambrisentan)

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

18 participants

Primary outcome timeframe

48 h following each dose

Results posted on

2014-01-16

Participant Flow

Recruitment started on August 1, 2011, was stopped again after delays in acquiring study drug (ambrisentan), and commenced again on February 6, 2012, until April 14, 2012. The study was conducted in the Duke Clinical Research Unit (DCRU).

The study was initiated on August 1, 2011 and stopped on August 9, 2011 after a delay in acquiring the study drug ambrisentan. None of the 24 screened subjects were randomized in this period. The trial was re-started on February 6, 2012 and completed on April 14, 2012 with the last subject being evaluated on April 30, 2012.

Participant milestones

Participant milestones
Measure	Sequence A Period 1: First intervention (Aminophylline 500mg, 24h) Period 2: Washout (24 hours) Period 3: Second intervention (Ambrisentan 5mg, 24h) Period 4: Washout (24h) Period 5: Third intervention (Aminophylline 500mg plus ambrisentan 5mg, 24h) Period 6: Washout (24h)	Sequence B Period 1: First intervention (Ambrisentan 5mg, 24h) Period 2: Washout (24 hours) Period 3: Second intervention (Aminophylline 500mg, 24h) Period 4: Washout (24h) Period 5: Third intervention (Aminophylline 500mg plus ambrisentan 5mg, 24h) Period 6: Washout (24h)
First Intervention (24h) STARTED	10	8
First Intervention (24h) COMPLETED	10	8
First Intervention (24h) NOT COMPLETED	0	0
Washout (24h) STARTED	9	8
Washout (24h) COMPLETED	9	7
Washout (24h) NOT COMPLETED	0	1
Second Intervention (24h) STARTED	10	8
Second Intervention (24h) COMPLETED	10	8
Second Intervention (24h) NOT COMPLETED	0	0
Third Intervention (24h) STARTED	9	8
Third Intervention (24h) COMPLETED	9	8
Third Intervention (24h) NOT COMPLETED	0	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Sequence A Period 1: First intervention (Aminophylline 500mg, 24h) Period 2: Washout (24 hours) Period 3: Second intervention (Ambrisentan 5mg, 24h) Period 4: Washout (24h) Period 5: Third intervention (Aminophylline 500mg plus ambrisentan 5mg, 24h) Period 6: Washout (24h)	Sequence B Period 1: First intervention (Ambrisentan 5mg, 24h) Period 2: Washout (24 hours) Period 3: Second intervention (Aminophylline 500mg, 24h) Period 4: Washout (24h) Period 5: Third intervention (Aminophylline 500mg plus ambrisentan 5mg, 24h) Period 6: Washout (24h)
Washout (24h) Withdrawal by Subject	0	1

Baseline Characteristics

The Safety Evaluation of Aminophylline and Ambrisentan When Administered Orally Alone and in Combination to Healthy Volunteers

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Sequence A n=10 Participants Period 1: Aminophylline 500 mg orally (corresponding to 395 mg theophylline), followed by 48 h washout period. Period 2: Ambrisentan 5 mg orally, followed by 48 h washout period.. Period 3: Aminophylline, 500 mg plus Ambrisentan, 5 mg orally, followed by 48 h washout period.	Sequence B n=8 Participants Period 1: Ambrisentan 5 mg orally, followed by 48 h washout period. Period 2: Aminophylline 500 mg orally (corresponding to 395 mg theophylline), followed by 48 h washout period. Period 3: Aminophylline, 500 mg plus Ambrisentan, 5 mg orally, followed by 48 h washout period.	Total n=18 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	10 Participants n=5 Participants	7 Participants n=7 Participants	17 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Sex: Female, Male Female	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants
Sex: Female, Male Male	8 Participants n=5 Participants	7 Participants n=7 Participants	15 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	6 Participants n=5 Participants	8 Participants n=7 Participants	14 Participants n=5 Participants
Race (NIH/OMB) White	4 Participants n=5 Participants	0 Participants n=7 Participants	4 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: 48 h following each dose

Outcome measures

Outcome measures
Measure	Sequence A n=10 Participants Period 1: Aminophylline 500 mg orally (corresponding to 395 mg theophylline), followed by 48 h washout period. Period 2: Ambrisentan 5 mg orally, followed by 48 h washout period.. Period 3: Aminophylline, 500 mg plus Ambrisentan, 5 mg orally, followed by 48 h washout period.	Sequence B n=8 Participants Period 1: Ambrisentan 5 mg orally, followed by 48 h washout period. Period 2: Aminophylline 500 mg orally (corresponding to 395 mg theophylline), followed by 48 h washout period. Period 3: Aminophylline, 500 mg plus Ambrisentan, 5 mg orally, followed by 48 h washout period.	Ambrisentan Alone	Ambrisentan in Presence of Aminophylline
Mean Number of Adverse Events Following Each Dose Adverse Events after aminophylline	2.5 Mean number of adverse events Standard Deviation 3.6	0.4 Mean number of adverse events Standard Deviation 0.7	—	—
Mean Number of Adverse Events Following Each Dose Adverse Events after ambrisentan	0.8 Mean number of adverse events Standard Deviation 1.3	0.4 Mean number of adverse events Standard Deviation 1.1	—	—
Mean Number of Adverse Events Following Each Dose Adverse Events after combined treatment	2.7 Mean number of adverse events Standard Deviation 3.7	0.5 Mean number of adverse events Standard Deviation 1.4	—	—

PRIMARY outcome

Timeframe: 24 hours after dosing

Aminophylline Alone (Single Dose of 500mg Aminophylline) Aminophylline in Presence of Ambrisentan (Combined Single Dose of 500mg Aminophylline and 5mg Ambrisentan) Ambrisentan Alone (Single Dose of 5mg Ambrisentan) Ambrisentan in Presence of Aminophylline (Combined Single Dose of 500mg Aminophylline and 5mg Ambrisentan) Blood sample collections for plasma Ambrisentan and Theophylline determinations at 0-hour (pre-dose), and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, and 24 hours post dose

Outcome measures

Outcome measures
Measure	Sequence A n=18 Participants Period 1: Aminophylline 500 mg orally (corresponding to 395 mg theophylline), followed by 48 h washout period. Period 2: Ambrisentan 5 mg orally, followed by 48 h washout period.. Period 3: Aminophylline, 500 mg plus Ambrisentan, 5 mg orally, followed by 48 h washout period.	Sequence B n=17 Participants Period 1: Ambrisentan 5 mg orally, followed by 48 h washout period. Period 2: Aminophylline 500 mg orally (corresponding to 395 mg theophylline), followed by 48 h washout period. Period 3: Aminophylline, 500 mg plus Ambrisentan, 5 mg orally, followed by 48 h washout period.	Ambrisentan Alone n=18 Participants	Ambrisentan in Presence of Aminophylline n=17 Participants
Plasma Halflife of Theophylline (Aminophylline) and Ambrisentan When Administered Alone or in Combination	11.11 hours Standard Deviation 3.15	9.96 hours Standard Deviation 3.37	8.27 hours Standard Deviation 1.72	9.12 hours Standard Deviation 3.35

PRIMARY outcome

Timeframe: 24h after dosing

Outcome measures

Outcome measures
Measure	Sequence A n=18 Participants Period 1: Aminophylline 500 mg orally (corresponding to 395 mg theophylline), followed by 48 h washout period. Period 2: Ambrisentan 5 mg orally, followed by 48 h washout period.. Period 3: Aminophylline, 500 mg plus Ambrisentan, 5 mg orally, followed by 48 h washout period.	Sequence B n=17 Participants Period 1: Ambrisentan 5 mg orally, followed by 48 h washout period. Period 2: Aminophylline 500 mg orally (corresponding to 395 mg theophylline), followed by 48 h washout period. Period 3: Aminophylline, 500 mg plus Ambrisentan, 5 mg orally, followed by 48 h washout period.	Ambrisentan Alone n=18 Participants	Ambrisentan in Presence of Aminophylline n=17 Participants
Time Until Maximum Plasma Concentration (Tmax) of Theophylline (Aminophylline) and Ambrisentan When Administered Alone or in Combination	2.0 hours Standard Deviation 0.8	1.50 hours Standard Deviation 0.95	2.0 hours Standard Deviation 1.09	2.0 hours Standard Deviation 0.88

PRIMARY outcome

Timeframe: 24h after dosing

Outcome measures

Outcome measures
Measure	Sequence A n=18 Participants Period 1: Aminophylline 500 mg orally (corresponding to 395 mg theophylline), followed by 48 h washout period. Period 2: Ambrisentan 5 mg orally, followed by 48 h washout period.. Period 3: Aminophylline, 500 mg plus Ambrisentan, 5 mg orally, followed by 48 h washout period.	Sequence B n=17 Participants Period 1: Ambrisentan 5 mg orally, followed by 48 h washout period. Period 2: Aminophylline 500 mg orally (corresponding to 395 mg theophylline), followed by 48 h washout period. Period 3: Aminophylline, 500 mg plus Ambrisentan, 5 mg orally, followed by 48 h washout period.	Ambrisentan Alone n=18 Participants	Ambrisentan in Presence of Aminophylline n=17 Participants
Maximum Plasma Concentration (Cmax) of Theophylline (Aminophylline) and Ambrisentan When Administered Alone or in Combination	6590 ng/ml Standard Deviation 1731.09	6780 ng/ml Standard Deviation 1519.16	464.5 ng/ml Standard Deviation 112.23	562 ng/ml Standard Deviation 110.90

PRIMARY outcome

Timeframe: 24h after dosing

Outcome measures

Outcome measures
Measure	Sequence A n=18 Participants Period 1: Aminophylline 500 mg orally (corresponding to 395 mg theophylline), followed by 48 h washout period. Period 2: Ambrisentan 5 mg orally, followed by 48 h washout period.. Period 3: Aminophylline, 500 mg plus Ambrisentan, 5 mg orally, followed by 48 h washout period.	Sequence B n=17 Participants Period 1: Ambrisentan 5 mg orally, followed by 48 h washout period. Period 2: Aminophylline 500 mg orally (corresponding to 395 mg theophylline), followed by 48 h washout period. Period 3: Aminophylline, 500 mg plus Ambrisentan, 5 mg orally, followed by 48 h washout period.	Ambrisentan Alone n=18 Participants	Ambrisentan in Presence of Aminophylline n=17 Participants
Area Under the Curve Within 24 Hours Post Dosing (AUC_0-24 Hours) of Theophylline (Aminophylline) and Ambrisentan When Administered Alone or in Combination	75970.66 h*ng/ml Standard Deviation 16537.85	74451.38 h*ng/ml Standard Deviation 19726.55	3225.47 h*ng/ml Standard Deviation 700.84	3338.09 h*ng/ml Standard Deviation 837.03

PRIMARY outcome

Timeframe: 24h after dosing

Outcome measures

Outcome measures
Measure	Sequence A n=18 Participants Period 1: Aminophylline 500 mg orally (corresponding to 395 mg theophylline), followed by 48 h washout period. Period 2: Ambrisentan 5 mg orally, followed by 48 h washout period.. Period 3: Aminophylline, 500 mg plus Ambrisentan, 5 mg orally, followed by 48 h washout period.	Sequence B n=17 Participants Period 1: Ambrisentan 5 mg orally, followed by 48 h washout period. Period 2: Aminophylline 500 mg orally (corresponding to 395 mg theophylline), followed by 48 h washout period. Period 3: Aminophylline, 500 mg plus Ambrisentan, 5 mg orally, followed by 48 h washout period.	Ambrisentan Alone n=18 Participants	Ambrisentan in Presence of Aminophylline n=17 Participants
Area Under the Curve Post Dosing (AUC_0-infinity) of Theophylline (Aminophylline) and Ambrisentan When Administered Alone or in Combination	99799.27 h*ng/ml Standard Deviation 28062.69	88545.08 h*ng/ml Standard Deviation 33678.29	3703.01 h*ng/ml Standard Deviation 866.21	3779.21 h*ng/ml Standard Deviation 977.93

Adverse Events

Aminophylline Only

Serious events: 0 serious events

Other events: 7 other events

Deaths: 0 deaths

Ambrisentan Only

Serious events: 0 serious events

Other events: 5 other events

Deaths: 0 deaths

Combined Aminophylline and Ambrisentan

Serious events: 0 serious events

Other events: 6 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Dr. Thies Schroeder

Duke University Medical Center

Phone: 919 681 4721

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Aminophylline Only n=18 participants at risk Aminophylline 500 mg orally (corresponding to 395 mg theophylline), followed by 48 h washout period.	Ambrisentan Only n=18 participants at risk Ambrisentan 5 mg orally, followed by 48 h washout period. lowed by 48 h washout period.	Combined Aminophylline and Ambrisentan n=18 participants at risk Combined single doses of Aminophylline 400 mg and ambrisentan 5 mg, followed by a 48 h washout period
Musculoskeletal and connective tissue disorders Cramping	11.1% 2/18 • Number of events 5 • Adverse events were assessed starting from the time of first dosing, for the entire period of containment in the Duke Clinical Research Unit until discharge, and as part of the final visit.	16.7% 3/18 • Number of events 3 • Adverse events were assessed starting from the time of first dosing, for the entire period of containment in the Duke Clinical Research Unit until discharge, and as part of the final visit.	11.1% 2/18 • Number of events 5 • Adverse events were assessed starting from the time of first dosing, for the entire period of containment in the Duke Clinical Research Unit until discharge, and as part of the final visit.
Nervous system disorders Headache	11.1% 2/18 • Number of events 2 • Adverse events were assessed starting from the time of first dosing, for the entire period of containment in the Duke Clinical Research Unit until discharge, and as part of the final visit.	27.8% 5/18 • Number of events 6 • Adverse events were assessed starting from the time of first dosing, for the entire period of containment in the Duke Clinical Research Unit until discharge, and as part of the final visit.	11.1% 2/18 • Number of events 3 • Adverse events were assessed starting from the time of first dosing, for the entire period of containment in the Duke Clinical Research Unit until discharge, and as part of the final visit.
Nervous system disorders Tremors	22.2% 4/18 • Number of events 7 • Adverse events were assessed starting from the time of first dosing, for the entire period of containment in the Duke Clinical Research Unit until discharge, and as part of the final visit.	0.00% 0/18 • Adverse events were assessed starting from the time of first dosing, for the entire period of containment in the Duke Clinical Research Unit until discharge, and as part of the final visit.	11.1% 2/18 • Number of events 3 • Adverse events were assessed starting from the time of first dosing, for the entire period of containment in the Duke Clinical Research Unit until discharge, and as part of the final visit.
Renal and urinary disorders Urinary Frequency	0.00% 0/18 • Adverse events were assessed starting from the time of first dosing, for the entire period of containment in the Duke Clinical Research Unit until discharge, and as part of the final visit.	5.6% 1/18 • Number of events 1 • Adverse events were assessed starting from the time of first dosing, for the entire period of containment in the Duke Clinical Research Unit until discharge, and as part of the final visit.	22.2% 4/18 • Number of events 4 • Adverse events were assessed starting from the time of first dosing, for the entire period of containment in the Duke Clinical Research Unit until discharge, and as part of the final visit.
Nervous system disorders Dizziness/ lightheadedness	11.1% 2/18 • Number of events 3 • Adverse events were assessed starting from the time of first dosing, for the entire period of containment in the Duke Clinical Research Unit until discharge, and as part of the final visit.	0.00% 0/18 • Adverse events were assessed starting from the time of first dosing, for the entire period of containment in the Duke Clinical Research Unit until discharge, and as part of the final visit.	11.1% 2/18 • Number of events 2 • Adverse events were assessed starting from the time of first dosing, for the entire period of containment in the Duke Clinical Research Unit until discharge, and as part of the final visit.
Gastrointestinal disorders Nausea	16.7% 3/18 • Number of events 3 • Adverse events were assessed starting from the time of first dosing, for the entire period of containment in the Duke Clinical Research Unit until discharge, and as part of the final visit.	0.00% 0/18 • Adverse events were assessed starting from the time of first dosing, for the entire period of containment in the Duke Clinical Research Unit until discharge, and as part of the final visit.	5.6% 1/18 • Number of events 1 • Adverse events were assessed starting from the time of first dosing, for the entire period of containment in the Duke Clinical Research Unit until discharge, and as part of the final visit.
Cardiac disorders Palpitations and Tachycardia	11.1% 2/18 • Number of events 2 • Adverse events were assessed starting from the time of first dosing, for the entire period of containment in the Duke Clinical Research Unit until discharge, and as part of the final visit.	0.00% 0/18 • Adverse events were assessed starting from the time of first dosing, for the entire period of containment in the Duke Clinical Research Unit until discharge, and as part of the final visit.	11.1% 2/18 • Number of events 2 • Adverse events were assessed starting from the time of first dosing, for the entire period of containment in the Duke Clinical Research Unit until discharge, and as part of the final visit.
General disorders Facial flushing and hot flashes	0.00% 0/18 • Adverse events were assessed starting from the time of first dosing, for the entire period of containment in the Duke Clinical Research Unit until discharge, and as part of the final visit.	5.6% 1/18 • Number of events 1 • Adverse events were assessed starting from the time of first dosing, for the entire period of containment in the Duke Clinical Research Unit until discharge, and as part of the final visit.	5.6% 1/18 • Number of events 2 • Adverse events were assessed starting from the time of first dosing, for the entire period of containment in the Duke Clinical Research Unit until discharge, and as part of the final visit.
General disorders Sweaty clammy hands and feet	0.00% 0/18 • Adverse events were assessed starting from the time of first dosing, for the entire period of containment in the Duke Clinical Research Unit until discharge, and as part of the final visit.	0.00% 0/18 • Adverse events were assessed starting from the time of first dosing, for the entire period of containment in the Duke Clinical Research Unit until discharge, and as part of the final visit.	11.1% 2/18 • Number of events 3 • Adverse events were assessed starting from the time of first dosing, for the entire period of containment in the Duke Clinical Research Unit until discharge, and as part of the final visit.
General disorders Feeling different and increased energy	0.00% 0/18 • Adverse events were assessed starting from the time of first dosing, for the entire period of containment in the Duke Clinical Research Unit until discharge, and as part of the final visit.	0.00% 0/18 • Adverse events were assessed starting from the time of first dosing, for the entire period of containment in the Duke Clinical Research Unit until discharge, and as part of the final visit.	5.6% 1/18 • Number of events 1 • Adverse events were assessed starting from the time of first dosing, for the entire period of containment in the Duke Clinical Research Unit until discharge, and as part of the final visit.
Nervous system disorders Anxiety and restlessness	5.6% 1/18 • Number of events 1 • Adverse events were assessed starting from the time of first dosing, for the entire period of containment in the Duke Clinical Research Unit until discharge, and as part of the final visit.	0.00% 0/18 • Adverse events were assessed starting from the time of first dosing, for the entire period of containment in the Duke Clinical Research Unit until discharge, and as part of the final visit.	5.6% 1/18 • Number of events 1 • Adverse events were assessed starting from the time of first dosing, for the entire period of containment in the Duke Clinical Research Unit until discharge, and as part of the final visit.
General disorders Hiccups	5.6% 1/18 • Number of events 1 • Adverse events were assessed starting from the time of first dosing, for the entire period of containment in the Duke Clinical Research Unit until discharge, and as part of the final visit.	0.00% 0/18 • Adverse events were assessed starting from the time of first dosing, for the entire period of containment in the Duke Clinical Research Unit until discharge, and as part of the final visit.	0.00% 0/18 • Adverse events were assessed starting from the time of first dosing, for the entire period of containment in the Duke Clinical Research Unit until discharge, and as part of the final visit.
Respiratory, thoracic and mediastinal disorders Nasal congestion	0.00% 0/18 • Adverse events were assessed starting from the time of first dosing, for the entire period of containment in the Duke Clinical Research Unit until discharge, and as part of the final visit.	5.6% 1/18 • Number of events 1 • Adverse events were assessed starting from the time of first dosing, for the entire period of containment in the Duke Clinical Research Unit until discharge, and as part of the final visit.	0.00% 0/18 • Adverse events were assessed starting from the time of first dosing, for the entire period of containment in the Duke Clinical Research Unit until discharge, and as part of the final visit.
Skin and subcutaneous tissue disorders Contact dermatitis	0.00% 0/18 • Adverse events were assessed starting from the time of first dosing, for the entire period of containment in the Duke Clinical Research Unit until discharge, and as part of the final visit.	0.00% 0/18 • Adverse events were assessed starting from the time of first dosing, for the entire period of containment in the Duke Clinical Research Unit until discharge, and as part of the final visit.	5.6% 1/18 • Number of events 1 • Adverse events were assessed starting from the time of first dosing, for the entire period of containment in the Duke Clinical Research Unit until discharge, and as part of the final visit.
Skin and subcutaneous tissue disorders Erythema at injection site	0.00% 0/18 • Adverse events were assessed starting from the time of first dosing, for the entire period of containment in the Duke Clinical Research Unit until discharge, and as part of the final visit.	0.00% 0/18 • Adverse events were assessed starting from the time of first dosing, for the entire period of containment in the Duke Clinical Research Unit until discharge, and as part of the final visit.	5.6% 1/18 • Number of events 1 • Adverse events were assessed starting from the time of first dosing, for the entire period of containment in the Duke Clinical Research Unit until discharge, and as part of the final visit.
Hepatobiliary disorders Liver safety panel	0.00% 0/18 • Adverse events were assessed starting from the time of first dosing, for the entire period of containment in the Duke Clinical Research Unit until discharge, and as part of the final visit.	0.00% 0/18 • Adverse events were assessed starting from the time of first dosing, for the entire period of containment in the Duke Clinical Research Unit until discharge, and as part of the final visit.	0.00% 0/18 • Adverse events were assessed starting from the time of first dosing, for the entire period of containment in the Duke Clinical Research Unit until discharge, and as part of the final visit.