The Safety Evaluation of Aminophylline and Ambrisentan When Administered Orally Alone and in Combination to Healthy Volunteers (GQ01)

This is a Phase I, three period, two sequence, open-label, randomized, crossover study, with the primary objective of testing the safety and tolerability of combined oral doses of aminophylline and ambrisentan in healthy human subjects. The secondary objective is to assess the pharmacokinetic profiles of theophylline (aminophylline) and ambrisentan when administered alone or in combination. It is hypothesized that the combination of these drugs is generally safe, and that no drug interaction can be observed.

Study Overview

• Status: Completed
• Conditions: High Altitude Pulmonary Hypertension
• Intervention / Treatment: Drug: Aminophylline; Drug: Ambrisentan; Drug: Aminophylline plus ambrisentan

Detailed Description

This is a Phase I, three period, two sequence, single-center, open-label, randomized, crossover study design. Periods I and II consist of the oral administration of either a single dose of aminophylline or ambrisentan alone, followed by a 48 hour wash out interval. Subsequently, Period III consists of the simultaneous administration of both drugs. All subjects are to be confined to the Duke Clinical Research Unit throughout all treatment periods [Study Day -1 to Study Day 6 (discharge)]. A sufficient number of healthy adult subjects will be consented in order to enroll 24 and complete 16 subjects who complete all three periods. Replacement of subjects is permitted, if necessary.

Qualified subjects will be randomized into one of two sequences consisting of three Periods as indicated below:

-------------Period 1-----Period 2-----Period 3

Sequence A: Treatment 1 Treatment 2 Treatment 3

Sequence B: Treatment 2 Treatment 1 Treatment 3

TREATMENTS:

Treatment 1: Aminophylline 500 mg (corresponding to 395 mg theophylline).

Treatment 2: Ambrisentan 5 mg.

Treatment 3: Aminophylline, 500 mg plus Ambrisentan, 5 mg.

After completion of each treatment period, the subjects will proceed to the next period provided no Stopping Rules criteria have been met

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke Clinical Research Unit

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Subjects must give written informed consent to participation in the study prior to screening. Consent will be documented by the subject's dated signature that will be counter-signed and dated by a witness. The appropriate HIPAA authorization forms must be signed and dated by the subject.
• Subjects must be healthy non-smoking adult male and female volunteers between the ages of 18 and 40 years, with a BMI of 18-30 kg/m2 and weighing at least 150 lbs. Subjects health status will be determined by the medical history, physical examination, vital signs, electrocardiogram, blood chemistry, hematology, and urinalysis performed at screening.
• Subjects must be willing to fast a minimum of 8 hours prior to screening.
• Subjects must be willing to abstain from alcohol and xanthine-containing food and beverages from the time of admission to the clinical research inpatient unit through at least 48 hours following discharge.
• Subjects must be willing to remain in the clinical research unit continuously for the inpatient portion of the study from admission to discharge.
• Women who are of non-childbearing potential, must be either surgically sterile (removal of both ovaries and/ or uterus at least 12 months prior to dosing), or naturally postmenopausal (spontaneous cessation of menses) for at least 24 consecutive months prior to dosing on Day -1, with an FSH level at screening of ≥ 40 mIU/mL.
• Women of child-bearing potential must have a negative serum pregnancy test within 48 hours of receiving study drug and must agree to avoid pregnancy during study and for one month after the last dose of study drug
• Male subjects of child-fathering potential must agree to avoid causing pregnancy during study and for three months after the last dose of study drug.
• Subjects must agree not to donate blood, plasma, platelets, or any other blood components during the study and for 4 weeks after the last dose.
• Male subjects must agree not to donate sperm during the study and for 12 weeks after the last dose.

Exclusion Criteria:

• Subjects with laboratory results outside the normal range, if considered clinically significant by the Investigator. In addition, subjects must have a normal hematocrit and hemoglobin concentration and be ≥ 36% and ≥ 12.0 g/dL, respectively.
• A mental capacity that is limited to the extent that the subject cannot provide legal consent or understand information regarding the side effects of the study drug.
• Currently abusing drugs or alcohol or with a history of drug or alcohol abuse within the past two years.
• Unwillingness or lack of ability to comply with the protocol, or to reside in the inpatient unit during the required time period, or to cooperate fully with the Principle Investigator and site personnel.
• Use of any of the following: Any concomitant medication including oral contraceptive hormones. Subjects who have received any prescribed or non-prescribed (over-the-counter [OTC]) systemic medication, topical medications, or herbal supplements within 14 days from Day 1. St. John's Wort (hypericin) must not have been taken for at least 30 days prior to Period 1, Day 1. Any drugs, foods or substances known to be strong inhibitors or strong inducers of CYP enzymes (also known as cytochrome P450 enzymes); especially CYP 1A2, or Pgp within 30 days prior to Period 1, Day 1
• Clinically significant ECG abnormality in the opinion of the Investigator. Vital signs or clinically significant laboratory values at the screening visit that in the opinion of the Investigator would make the subject an inappropriate candidate for the study.
• Has taken any other investigational drug during the 30 days prior to the screening visit or is currently participating in another investigational clinical trial.
• Made any significant donation (including plasma) or have had a significant loss of blood within 30 or 90 days prior to Period 1, Day 1.
• History or manifestation of clinically significant neurological, gastrointestinal, renal, hepatic, cardiovascular, psychological, pulmonary, metabolic, endocrine, hematologic or other medical disorders.
• Subjects who are carriers of the Hepatitis B surface antigen (HbsAg), Hepatitis C antibody, or HIV antibody
• Serious mental or physical illness within the past year.
• Male subjects who consume more than 28 units of alcohol per week and female subjects who consume more than 21 units of alcohol per week (one unit of alcohol equals 250 mL of beer, 100 mL or a medium glass of wine, or 25 mL of spirits) or those subjects who have a significant history of alcoholism or drug/ chemical abuse within the last 2 years
• Failure to agree to abstain from alcohol, cola, tea, coffee, chocolate and other caffeinated drink/ food from 2 days before dosing and throughout confinement
• Positive results on screening tests for drugs of abuse, cotinine or alcohol at screening or the pre-dose assessment at check-in
• Subjects who have used tobacco products or nicotine-containing products (including smoking cessation aids, such as gums or patches) within 12 months prior to Period 1, Day 1
• Women of childbearing potential who are pregnant (as based on test results) or are breast feeding
• Subjects who have a history of hypersensitivity or idiosyncratic reaction to any of the products administered during the study.
• Subjects who, in the opinion of the Investigator, should not participate in the study.
• Subjects who are employed by the DCRU
• Subjects who have a history of unexplained syncope; i.e., autonomic dysfunction.
• Subjects who have a history of hypotension, including orthostatic hypotension
• A positive test for hepatitis B surface antigen, hepatitis C antibody, or HIV antibody at screening.
• Lack of ability to understand verbal and/ or written English
• History of severe hypersensitivity or allergic reaction to study medication
• Failure to agree to abstain from grapefruit and grapefruit juice as well as oranges and orange juice from 10 days before the first dose and throughout the study
• History of clinically significant illness within 4 weeks prior to Day 1
• Receipt of a transfusion or any blood products within 90 days prior to Period 1, Day 1
• History of participation in another investigational study or who have participated in an investigational study within the past 30 days prior to Period 1, Day 1

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Aminophylline	Drug: Aminophylline; Drug will be administered as a single oral dose of 500mg, followed by a 48h washout period.
Active Comparator: Ambrisentan	Drug: Ambrisentan; Drug will be administered as a single dose of 5mg, followed by a 48h washout period; Other Names: Letairis
Experimental: Aminophylline and ambrisentan; Treatment 3: Aminophylline, 500 mg plus Ambrisentan, 5 mg	Drug: Aminophylline plus ambrisentan; Drugs will be given as single doses of 500mg (aminophylline) and 5mg (ambrisentan), followed by a 48h washout period

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Number of Adverse Events Following Each Dose	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)	48 h following each dose
Plasma Halflife of Theophylline (Aminophylline) and Ambrisentan When Administered Alone or in Combination	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	24 hours after dosing
Time Until Maximum Plasma Concentration (Tmax) of Theophylline (Aminophylline) and Ambrisentan When Administered Alone or in Combination	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	24h after dosing
Maximum Plasma Concentration (Cmax) of Theophylline (Aminophylline) and Ambrisentan When Administered Alone or in Combination	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)	24h after dosing
Area Under the Curve Within 24 Hours Post Dosing (AUC_0-24 Hours) of Theophylline (Aminophylline) and Ambrisentan When Administered Alone or in Combination	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	24h after dosing
Area Under the Curve Post Dosing (AUC_0-infinity) of Theophylline (Aminophylline) and Ambrisentan When Administered Alone or in Combination	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	24h after dosing

Collaborators and Investigators

• Sponsor: Thies Schroeder
• Investigators: Principal Investigator: Robert J Noveck, MD, Duke University

Study record dates

Study Major Dates

• Study Start: February 1, 2012
• Primary Completion (Actual): April 1, 2012
• Study Completion (Actual): April 1, 2012

Study Registration Dates

• First Submitted: February 1, 2012
• First Submitted That Met QC Criteria: February 7, 2012
• First Posted (Estimate): February 10, 2012

Study Record Updates

• Last Update Posted (Estimate): January 16, 2014
• Last Update Submitted That Met QC Criteria: November 28, 2013
• Last Verified: November 1, 2013

More Information

Terms related to this study

• Keywords: High altitude induced fatigue; High altitude induced pulmonary Hypertension
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension; Hypertension, Pulmonary; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Purinergic Antagonists; Purinergic Agents; Protective Agents; Cardiotonic Agents; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Phosphodiesterase Inhibitors; Purinergic P1 Receptor Antagonists; Aminophylline; Ambrisentan
• Other Study ID Numbers: Pro00028417