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

Information source: Duke University
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: High Altitude Pulmonary Hypertension

Intervention: Aminophylline (Drug); Ambrisentan (Drug); Aminophylline plus ambrisentan (Drug)

Phase: Phase 1

Status: Completed

Sponsored by: Thies Schroeder

Official(s) and/or principal investigator(s):
Robert J Noveck, MD, Principal Investigator, Affiliation: Duke University

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.

Clinical Details

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

Study design: Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome:

Mean Number of Adverse Events Following Each Dose

Plasma Halflife of Theophylline (Aminophylline) and Ambrisentan When Administered Alone or in Combination

Time Until Maximum Plasma Concentration (Tmax) of Theophylline (Aminophylline) and Ambrisentan When Administered Alone or in Combination

Maximum Plasma Concentration (Cmax) of Theophylline (Aminophylline) and Ambrisentan When Administered Alone or in Combination

Area Under the Curve Within 24 Hours Post Dosing (AUC_0-24 Hours) of Theophylline (Aminophylline) and Ambrisentan When Administered Alone or in Combination

Area Under the Curve Post Dosing (AUC_0-infinity) of Theophylline (Aminophylline) and Ambrisentan When Administered Alone or in Combination

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

Eligibility

Minimum age: 18 Years. Maximum age: 40 Years. Gender(s): Both.

Criteria:

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

Locations and Contacts

Duke Clinical Research Unit, Durham, North Carolina 27710, United States
Additional Information

Starting date: February 2012
Last updated: November 28, 2013

Page last updated: August 23, 2015

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