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

NCT01530464 | Completed Phase 1 Results

• 1 other identifier: Pro00028417
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

High Altitude Pulmonary Hypertension

Keywords

High altitude induced fatigue; High altitude induced pulmonary Hypertension

Outcome Measures

Primary Outcomes (6)

• 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

Study Arms (3)

Aminophylline

ACTIVE COMPARATOR

Drug: Aminophylline

Ambrisentan

ACTIVE COMPARATOR

Drug: Ambrisentan

Aminophylline and ambrisentan

EXPERIMENTAL

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

Drug: Aminophylline plus ambrisentan

Interventions

Aminophylline DRUG

Drug will be administered as a single oral dose of 500mg, followed by a 48h washout period.

Aminophylline

Ambrisentan DRUG

Drug will be administered as a single dose of 5mg, followed by a 48h washout period

Also known as: Letairis

Ambrisentan

Aminophylline plus ambrisentan DRUG

Drugs will be given as single doses of 500mg (aminophylline) and 5mg (ambrisentan), followed by a 48h washout period

Aminophylline and ambrisentan

Eligibility Criteria

• Age: 18 Years - 40 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Thies Schroeder: lead

Study Sites (1)

Duke Clinical Research Unit

Durham, North Carolina, 27710, United States

Location

MeSH Terms

Conditions

Pulmonary edema of mountaineers

Interventions

Aminophylline; ambrisentan

Intervention Hierarchy (Ancestors)

Ethylenediamines; Diamines; Polyamines; Amines; Organic Chemicals; Theophylline; Xanthines; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Drug Combinations; Pharmaceutical Preparations

Results Point of Contact

• Title: Dr. Thies Schroeder
• Organization: Duke University Medical Center

thies.schroeder@duke.edu

919 681 4721

Study Officials

• Robert J Noveck, MD

  Duke University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Assistant Professor

Study Record Dates

• First Submitted: February 1, 2012
• First Posted: February 10, 2012
• Study Start: February 1, 2012
• Primary Completion: April 1, 2012
• Study Completion: April 1, 2012
• Last Updated: January 16, 2014
• Results First Posted: January 16, 2014

Record last verified: 2013-11

Locations

US (1)