High Altitude Pulmonary Hypertension
Conditions
Keywords
High altitude induced fatigue, High altitude induced pulmonary Hypertension
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.
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
Interventions
DRUGAminophylline
Drug will be administered as a single oral dose of 500mg, followed by a 48h washout period.
DRUGAmbrisentan
Drug will be administered as a single dose of 5mg, followed by a 48h washout period
DRUGAminophylline plus ambrisentan
Drugs will be given as single doses of 500mg (aminophylline) and 5mg (ambrisentan), followed by a 48h washout period
Sponsors
Thies Schroeder
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 40 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Number of Adverse Events Following Each Dose | 48 h 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) |
| Plasma Halflife of Theophylline (Aminophylline) and Ambrisentan When Administered Alone or in Combination | 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 |
| Time Until Maximum Plasma Concentration (Tmax) of Theophylline (Aminophylline) and Ambrisentan When Administered Alone or in Combination | 24h 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 |
| Maximum Plasma Concentration (Cmax) of Theophylline (Aminophylline) and Ambrisentan When Administered Alone or in Combination | 24h 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) |
| Area Under the Curve Within 24 Hours Post Dosing (AUC_0-24 Hours) of Theophylline (Aminophylline) and Ambrisentan When Administered Alone or in Combination | 24h 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 |
| Area Under the Curve Post Dosing (AUC_0-infinity) of Theophylline (Aminophylline) and Ambrisentan When Administered Alone or in Combination | 24h 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 |
Countries
United States
Participant flow
Recruitment details
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).
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| Sequence A 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. | 10 |
| Sequence B 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. | 8 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Washout (24h) | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Sequence A | Sequence B | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 1 Participants | 1 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 7 Participants | 17 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 8 Participants | 14 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 0 Participants | 4 Participants |
| Sex: Female, Male Female | 2 Participants | 1 Participants | 3 Participants |
| Sex: Female, Male Male | 8 Participants | 7 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 7 / 18 | 5 / 18 | 6 / 18 |
| serious Total, serious adverse events | 0 / 18 | 0 / 18 | 0 / 18 |
Outcome results
Primary
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
Time frame: 24h after dosing
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Sequence A | 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 |
| Sequence B | Area Under the Curve Post Dosing (AUC_0-infinity) of Theophylline (Aminophylline) and Ambrisentan When Administered Alone or in Combination | 88545.08 h*ng/ml | Standard Deviation 33678.29 |
| Ambrisentan Alone | Area Under the Curve Post Dosing (AUC_0-infinity) of Theophylline (Aminophylline) and Ambrisentan When Administered Alone or in Combination | 3703.01 h*ng/ml | Standard Deviation 866.21 |
| Ambrisentan in Presence of Aminophylline | Area Under the Curve Post Dosing (AUC_0-infinity) of Theophylline (Aminophylline) and Ambrisentan When Administered Alone or in Combination | 3779.21 h*ng/ml | Standard Deviation 977.93 |
Primary
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
Time frame: 24h after dosing
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Sequence A | 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 |
| Sequence B | Area Under the Curve Within 24 Hours Post Dosing (AUC_0-24 Hours) of Theophylline (Aminophylline) and Ambrisentan When Administered Alone or in Combination | 74451.38 h*ng/ml | Standard Deviation 19726.55 |
| Ambrisentan Alone | Area Under the Curve Within 24 Hours Post Dosing (AUC_0-24 Hours) of Theophylline (Aminophylline) and Ambrisentan When Administered Alone or in Combination | 3225.47 h*ng/ml | Standard Deviation 700.84 |
| Ambrisentan in Presence of Aminophylline | Area Under the Curve Within 24 Hours Post Dosing (AUC_0-24 Hours) of Theophylline (Aminophylline) and Ambrisentan When Administered Alone or in Combination | 3338.09 h*ng/ml | Standard Deviation 837.03 |
Primary
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)
Time frame: 24h after dosing
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Sequence A | Maximum Plasma Concentration (Cmax) of Theophylline (Aminophylline) and Ambrisentan When Administered Alone or in Combination | 6590 ng/ml | Standard Deviation 1731.09 |
| Sequence B | Maximum Plasma Concentration (Cmax) of Theophylline (Aminophylline) and Ambrisentan When Administered Alone or in Combination | 6780 ng/ml | Standard Deviation 1519.16 |
| Ambrisentan Alone | Maximum Plasma Concentration (Cmax) of Theophylline (Aminophylline) and Ambrisentan When Administered Alone or in Combination | 464.5 ng/ml | Standard Deviation 112.23 |
| Ambrisentan in Presence of Aminophylline | Maximum Plasma Concentration (Cmax) of Theophylline (Aminophylline) and Ambrisentan When Administered Alone or in Combination | 562 ng/ml | Standard Deviation 110.9 |
Primary
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)
Time frame: 48 h following each dose
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sequence A | Mean Number of Adverse Events Following Each Dose | Adverse Events after aminophylline | 2.5 Mean number of adverse events | Standard Deviation 3.6 |
| Sequence A | Mean Number of Adverse Events Following Each Dose | Adverse Events after ambrisentan | 0.8 Mean number of adverse events | Standard Deviation 1.3 |
| Sequence A | Mean Number of Adverse Events Following Each Dose | Adverse Events after combined treatment | 2.7 Mean number of adverse events | Standard Deviation 3.7 |
| Sequence B | Mean Number of Adverse Events Following Each Dose | Adverse Events after ambrisentan | 0.4 Mean number of adverse events | Standard Deviation 1.1 |
| Sequence B | Mean Number of Adverse Events Following Each Dose | Adverse Events after aminophylline | 0.4 Mean number of adverse events | Standard Deviation 0.7 |
| Sequence B | Mean Number of Adverse Events Following Each Dose | Adverse Events after combined treatment | 0.5 Mean number of adverse events | Standard Deviation 1.4 |
Primary
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
Time frame: 24 hours after dosing
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Sequence A | Plasma Halflife of Theophylline (Aminophylline) and Ambrisentan When Administered Alone or in Combination | 11.11 hours | Standard Deviation 3.15 |
| Sequence B | Plasma Halflife of Theophylline (Aminophylline) and Ambrisentan When Administered Alone or in Combination | 9.96 hours | Standard Deviation 3.37 |
| Ambrisentan Alone | Plasma Halflife of Theophylline (Aminophylline) and Ambrisentan When Administered Alone or in Combination | 8.27 hours | Standard Deviation 1.72 |
| Ambrisentan in Presence of Aminophylline | Plasma Halflife of Theophylline (Aminophylline) and Ambrisentan When Administered Alone or in Combination | 9.12 hours | Standard Deviation 3.35 |
Primary
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
Time frame: 24h after dosing
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Sequence A | Time Until Maximum Plasma Concentration (Tmax) of Theophylline (Aminophylline) and Ambrisentan When Administered Alone or in Combination | 2.0 hours | Standard Deviation 0.8 |
| Sequence B | Time Until Maximum Plasma Concentration (Tmax) of Theophylline (Aminophylline) and Ambrisentan When Administered Alone or in Combination | 1.50 hours | Standard Deviation 0.95 |
| Ambrisentan Alone | Time Until Maximum Plasma Concentration (Tmax) of Theophylline (Aminophylline) and Ambrisentan When Administered Alone or in Combination | 2.0 hours | Standard Deviation 1.09 |
| Ambrisentan in Presence of Aminophylline | Time Until Maximum Plasma Concentration (Tmax) of Theophylline (Aminophylline) and Ambrisentan When Administered Alone or in Combination | 2.0 hours | Standard Deviation 0.88 |