Trial record 9 of 15 for:    "Pulmonary edema of mountaineers"

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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Thies Schroeder, Duke University Medical Center
ClinicalTrials.gov Identifier:
NCT01530464
First received: February 1, 2012
Last updated: November 28, 2013
Last verified: November 2013
  Purpose

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.


Condition Intervention Phase
High Altitude Pulmonary Hypertension
Drug: Aminophylline
Drug: Ambrisentan
Drug: Aminophylline plus ambrisentan
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: The Safety Evaluation of Aminophylline and Ambrisentan When Administered Orally Alone and in Combination to Healthy Volunteers

Resource links provided by NLM:


Further study details as provided by Duke University:

Primary Outcome Measures:
  • Mean Number of Adverse Events Following Each Dose [ Time Frame: 48 h following each dose ] [ Designated as safety issue: Yes ]

    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)


  • Plasma Halflife of Theophylline (Aminophylline) and Ambrisentan When Administered Alone or in Combination [ Time Frame: 24 hours after dosing ] [ Designated as safety issue: No ]

    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


  • Time Until Maximum Plasma Concentration (Tmax) of Theophylline (Aminophylline) and Ambrisentan When Administered Alone or in Combination [ Time Frame: 24h after dosing ] [ Designated as safety issue: No ]

    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


  • Maximum Plasma Concentration (Cmax) of Theophylline (Aminophylline) and Ambrisentan When Administered Alone or in Combination [ Time Frame: 24h after dosing ] [ Designated as safety issue: No ]
    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)

  • Area Under the Curve Within 24 Hours Post Dosing (AUC_0-24 Hours) of Theophylline (Aminophylline) and Ambrisentan When Administered Alone or in Combination [ Time Frame: 24h after dosing ] [ Designated as safety issue: No ]

    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


  • Area Under the Curve Post Dosing (AUC_0-infinity) of Theophylline (Aminophylline) and Ambrisentan When Administered Alone or in Combination [ Time Frame: 24h after dosing ] [ Designated as safety issue: No ]

    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



Enrollment: 18
Study Start Date: February 2012
Study Completion Date: April 2012
Primary Completion Date: April 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: 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

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

Ages Eligible for Study:   18 Years to 40 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01530464

Locations
United States, North Carolina
Duke Clinical Research Unit
Durham, North Carolina, United States, 27710
Sponsors and Collaborators
Thies Schroeder
Investigators
Principal Investigator: Robert J Noveck, MD Duke University
  More Information

No publications provided

Responsible Party: Thies Schroeder, Assistant Professor, Duke University Medical Center
ClinicalTrials.gov Identifier: NCT01530464     History of Changes
Other Study ID Numbers: Pro00028417
Study First Received: February 1, 2012
Results First Received: September 1, 2013
Last Updated: November 28, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Duke University:
High altitude induced fatigue
High altitude induced pulmonary Hypertension

Additional relevant MeSH terms:
Hypertension
Hypertension, Pulmonary
Altitude Sickness
Vascular Diseases
Cardiovascular Diseases
Lung Diseases
Respiratory Tract Diseases
Respiration Disorders
Aminophylline
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Pharmacologic Actions
Anti-Asthmatic Agents
Respiratory System Agents
Therapeutic Uses
Cardiotonic Agents
Cardiovascular Agents
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Purinergic P1 Receptor Antagonists
Purinergic Antagonists
Purinergic Agents
Neurotransmitter Agents
Protective Agents

ClinicalTrials.gov processed this record on September 16, 2014