Assessment and Evaluation of Pharmacokinetic Profile of E004 in Healthy Adults

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01737892
Recruitment Status : Terminated (unable to validate analytical method)
First Posted : November 30, 2012
Last Update Posted : March 17, 2016
Information provided by (Responsible Party):
Amphastar Pharmaceuticals, Inc.

Brief Summary:
This study examines the pharmacokinetic profile of Armstrong's proposed Epinephrine Inhalation Aerosol USP, an HFA-MDI (E004), using a stable isotope deuterium-labeled epinephrine (epinephrine-d3) to differentiate the administered drug from the endogenous epinephrine, in healthy male and female adult volunteers. The current study is designed to complement an earlier PK study, API-E004-CL-B, for a more thorough evaluation of the E004 PK. Safety of E004 will also be evaluated.

Condition or disease Intervention/treatment Phase
Asthma Drug: Arm T Epinephrine Inhalation Aerosol HFA, 125 mcg, 1 inhalation Drug: Arm C-Epinephrine Inhalation Aerosol CFC Phase 1 Phase 2

Detailed Description:

This study is a randomized, evaluator-blind, single dose, two-arm, crossover, PK study, to be conducted in ~18 healthy, male and female, adult volunteers. PK will be studied using E004-d3 at 125 mcg per inhalation (Arm T). A previously marketed Epinephrine CFC-MDI, labeled "For Investigational Use Only" will be used as a Reference Control (Arm C).

The main features of the study design are:

(1) All candidates must be screened and must satisfy all enrollment criteria. All enrolled subjects will participate in two Study Visits, corresponding to two randomized treatments. Each Study Visit consists of a pre-dose baseline assessment and a post-dose evaluation for 6 hours.

(2) It is important to minimize physical and psychological disturbances to the endogenous epinephrine concentrations in the study subjects, before and during the study visits. All subjects must maintain a reclining or recumbent resting position during the entire Study Visit, with physical activities restricted to a minimum necessity for bathroom trips and study activities. Caffeine-containing (including de-caffeinated) foods or beverages are prohibited. Physical exercise, unnecessary physical activities, and video games are prohibited throughout the study visit.

(3)At the Screening Visit and the beginning of each Study Visit, each subject will be trained on the correct self-administration of MDI, using a simulation MDI unit that contains no active drug. The following two randomized treatments will be self-administered at two Study Visits:

Treatment T: Two (2) inhalations of E004-d3 (125 mcg/inhalation), totaling 250 mcg of epinephrine-d3;

Treatment C: Two (2) inhalations of Epinephrine CFC-MDI (220 mcg/inhalation, totaling 440 mcg of epinephrine base equivalent).

(4) PK blood samples will be taken from a vein in a hand or arm via an indwelling anticoagulated IV catheter, or by venipunctures, at scheduled time points of predose baseline (within 30 minutes of dosing), and at 2±1, 5±1, 7.5±1, 10±1, 12.5, 15, 20, 25, 30, 45, 60, 90, 120, 240 and 360 minutes postdose. The total volume of blood taken per subject shall not exceed 500 mL in any 30-day period. Study visit schedule may be adjusted to avoid overdrawing blood in any 30-day period.

(5) At each PK sampling point, blood samples (~ 5mL), will be collected in ice-chilled potassium-EDTA sample tubes, each containing pre-added 1% (V:V) of a 1.0 M sodium metabisulfite solution as an antioxidant. Sample tubes will be labeled with a sample ID# (consisting of subject ID#, Study Visit#, and sample#). The sample tubes will be kept on ice or refrigerated, and will be centrifuged within 60 minutes of collection. The harvested plasma from each sample tube will be transferred to, and stored in, 2 storage tubes, respectively, and frozen at NMT -20 degrees C until analysis.

(6) PK samples will be analyzed with an established LC/MS/MS method, with a quantitative detection limit of 5 pg/mL, for both epinephrine-d3 (MW=186) and epinephrine (MW=183).

(7) Safety parameters and adverse drug events, if any, will be monitored and documented at each study visit. An End-of-Study (EOS) safety evaluation will be conducted at the end of, or within 7 days after, Study Visit-2.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 21 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Assessment and Evaluation of Pharmacokinetic Profile of E004 in Healthy Adults (A Randomized, Evaluator-Blind, Single-Dose, Two Arm, Crossover, PK Study in Healthy Volunteers)
Study Start Date : November 2012
Actual Primary Completion Date : November 2012
Actual Study Completion Date : November 2012

Arm Intervention/treatment
Experimental: Arm T-Epinephrine Inhalation Aerosol HFA
Experimental arm utilizing Epinephrine HFA-MDI (E004)
Drug: Arm T Epinephrine Inhalation Aerosol HFA, 125 mcg, 1 inhalation
Epinephrine Inhalation Aerosol HFA, Single dose 125 mcg, 1 inhalation
Active Comparator: Arm C-Epinephrine Inhalation Aerosol CFC
Active comparator arm utilizing Epinephrine CFC-MDI
Drug: Arm C-Epinephrine Inhalation Aerosol CFC
Epinephrine Inhalation Aerosol - CFC, Single dose 220 mcg, 1 inhalation
Other Name: Primatene Mist

Primary Outcome Measures :
  1. Calculation and Comparison of relative Bioavailability of Epinephrine [ Time Frame: up to 30 min predose and at 2, 5, 7.5, 10, 12.5, 15, 20, 25, 30, 45, 60, 90, 120, 240 and 360 minutes postdose ]
    Blood PK samples will be collected at each visit for both study arms, then the Area Under the Curve (s) will be calculated for both arms and compared to give relative bioavailability

Secondary Outcome Measures :
  1. Vital Signs [ Time Frame: up to 30 min predose and at 2, 5, 7.5, 10, 12.5, 15, 20, 25, 30, 45, 60, 90, 120, 240 and 360 minutes postdose ]
    Vital signs (SBP/DBP, blood pressure and heart rate) will be documented and summarized

  2. 12-lead ECG (Routine and QT/QTc analysis) [ Time Frame: up to 30 min predose and at 5, 10, 15, 20, 30, 60, 120, and 360 minutes postdose ]
    A 12-lead ECG (Routine and QT/QTc analysis) will be documented.

  3. Physical Examinations [ Time Frame: up to 30 min predose and after 360 min post last dose ]
    Physical examinations will be documented at screening and end of study

  4. Lab tests [ Time Frame: up to 30 min predose ]
    Lab tests, including CBC, serum comprehensive metabolic panel, urinalysis, and drug/alcohol screens for all subjects and urinary pregnancy test for women of child-bearing potential will be performed and documented

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Ages Eligible for Study:   18 Years to 30 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes

Inclusion Criteria:

  • Generally healthy, male and female adults, 18-30 yrs of age at Screening
  • Having no clinically significant respiratory, cardiovascular and other systemic or organic illnesses, per investigator discretion;
  • Body weight greater than or equal to 50 kg for men and greater than or equal to 45 kg for women, and BMI within the range of 18.5 - 30.0 kg/m2 inclusive
  • Sitting blood pressure less than or equal to 135/90 mmHg;
  • Demonstrating negative alcohol/drug screen tests;
  • Demonstrating negative HIV, HBsAg and HCV-Ab screen tests;
  • Women of child-bearing potential must be non-pregnant, non-lactating, and practicing a clinically acceptable form of birth control;
  • Having properly consented and satisfied all other inclusion/exclusion criteria as required for this protocol.

Exclusion Criteria:

  • A smoking history of more than or equal to 10 pack-years, or having smoked within 6 months prior to Screening;
  • Upper respiratory tract infections within 2 weeks, or lower respiratory tract infection within 4 weeks, prior to Screening
  • Any current or recent respiratory conditions that, per investigator discretion, might significantly affect pharmacodynamic response to the study drugs, including but not limited to: asthma, COPD, cystic fibrosis, bronchiectasis, tuberculosis, emphysema, etc.
  • Concurrent clinically significant cardiovascular, hematological, renal, neurologic, hepatic, endocrine (including diabetes), psychiatric, neoplastic or other illnesses that in the opinion of the investigator could impact on the conduct, safety and evaluation of the study
  • Known intolerance or hypersensitivity to any of the study MDI ingredients (i.e., epinephrine, HFA-134a, CFC-12, CFC-114, polysorbate-80, ethanol, thymol, nitric acid and ascorbic acid)
  • Use of prohibited drugs or failure to observe the drug washout restrictions
  • Having been on other investigational drug/device studies, or donated blood, in the last 30 days prior to Screening.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01737892

United States, California
West Coast Clinical Trials, LLC
Cypress, California, United States, 90630
Sponsors and Collaborators
Amphastar Pharmaceuticals, Inc.
Study Director: Vladimir Evilevitch, M.D. Amphastar Pharmaceuticals, Inc.

Responsible Party: Amphastar Pharmaceuticals, Inc. Identifier: NCT01737892     History of Changes
Other Study ID Numbers: API-E004-CL-B4
First Posted: November 30, 2012    Key Record Dates
Last Update Posted: March 17, 2016
Last Verified: February 2016

Keywords provided by Amphastar Pharmaceuticals, Inc.:
Metered dose inhaler

Additional relevant MeSH terms:
Epinephryl borate
Adrenergic alpha-Agonists
Adrenergic Agonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Adrenergic beta-Agonists
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Anti-Asthmatic Agents
Respiratory System Agents
Vasoconstrictor Agents