Pharmacokinetics (PK) Study of Epinephrine Inhalation Aerosol in Healthy Volunteers

Study Overview
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Brief Summary
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This study examines the pharmacokinetic profile of Armstrong's proposed Epinephrine Inhalation Aerosol USP, an HFA-MDI (E004), in healthy male and female adult volunteers. Safety of E004 will also be evaluated, under augmented dose conditions.

Detailed Description
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This study is a randomized, evaluator-blind, single dose, three-arm, crossover, PK study, to be conducted in  18 healthy, male and female, adult volunteers. PK will be studied at two dose strengths (Arm T1 and Arm T2). A currently marketed, non-labeled, Epinephrine CFC-MDI will be used as a Reference Control (Arm C). At the Screening Visit and the beginning of each Study Visit, each subject will be trained on the correct self-administration of MDI. The following three randomized treatments will be self-administered, at three Study Visits: Treatment T1: Ten (10) inhalations of the low dose E004(125 mcg/inhalation), totaling 1.25 mg of epinephrine; Treatment T2: Ten (10) inhalations of the high dose E004 (160 mcg/inhalation), totaling 1.60 mg of epinephrine; Treatment C: Ten (10) inhalations of Epinephrine CFC-MDI (220 mcg/inhalation, totaling 2.2 mg of epinephrine base equivalent). PK blood samples will be taken from a vein at scheduled time points. 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.

Official Title
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Phase I/II Study Epinephrine Inhalation Aerosol USP, an HFA-MDI Clinical Study-B for Assessment of Pharmacokinetics

Conditions
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Asthma

Intervention / Treatment
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* Drug: epinephrine inhalation aerosol
* Drug: epinephrine inhalation aerosol
* Drug: epinephrine inhalation aerosol


Participation Criteria
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Eligibility Criteria
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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; 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. Other criteria apply. Exclusion Criteria: A recent or significant smoking history; Use of prohibited drugs or failure to observe the drug washout restrictions; Having been on other investigational drug/device studies in the last 30 days prior to Screening. Other criteria apply

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Treatment C<br>Active comparator arm utilizing marketed Primatene Mist with CFC propellant at the labeled dose. | Drug: epinephrine inhalation aerosol<br>* Single dose 220 mcg/inhalation, 10 inhalations<br>* Other names: Primatene Mist;|
| Experimental: Treatment 1<br>T1 is HFA propelled epinephrine inhalation aerosol 125 mcg/inhalation | Drug: epinephrine inhalation aerosol<br>* HFA propelled epinephrine inhalation aerosol, 125 mcg/inhalation, 10 inhalations<br>* Other names: Primatene Mist;|
| Experimental: Treatment 2<br>HFA propelled epinephrine inhalation aerosol, 160 mcg/inhalation | Drug: epinephrine inhalation aerosol<br>* HFA propelled epinephrine inhalation aerosol, 160 mcg/inhalation, 10 inhalations<br>* Other names: Primatene Mist;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Baseline Concentration (C0) of Labeled Epinephrine Total Epinephrine | Patient PK blood samples were taken from a vein in a hand or arm via indwelling heparin-anticoagulated IV catheters, or by venipunctures at Baseline (prior to dosing) in each treatment period following a specified washout period (3-14 days), and were analyzed using an established analysis method. Baseline concentration (C0) is the concentration of epinephrine measured in the plasma at this time point. | 0 to 30 minutes prior to dosing | 
| Area Under the Curve From Time Zero to 6 Hours Post-dose (AUC[0-6]) | Patient PK blood samples were taken from a vein in a hand or arm via indwelling heparin-anticoagulated IV catheters, or by venipunctures at 0 (baseline), 5, 15, 30, 45, 60, 90, 120, 180, 240, and 360 minutes post-dose in each treatment period and were analyzed using an established analysis method. Area under the curve from time zero to 6 hours post-dose (AUC[0-6]) was calculated using the trapezoidal rule. | Pre-dose to 6 hours post-dose | 
| Peak Concentration (Cmax) for Total Epinephrine From Time Zero to 6 Hours Post-dose | Patient PK blood samples were taken from a vein in a hand or arm via indwelling heparin-anticoagulated IV catheters, or by venipunctures at 0 (baseline), 5, 15, 30, 45, 60, 90, 120, 180, 240, and 360 minutes post-dose in each treatment period and were analyzed using an established analysis method. Peak (maximum) concentration (Cmax) is the highest concentration of epinephrine measured in plasma during the treatment period. | Pre-dose to 6 hours post-dose | 
| Time to Reach Peak Concentration (Tmax) for Total Epinephrine | Patient PK blood samples were taken from a vein in a hand or arm via indwelling heparin-anticoagulated IV catheters, or by venipunctures at 0 (baseline), 5, 15, 30, 45, 60, 90, 120, 180, 240, and 360 minutes post-dose in each treatment period and were analyzed using an established analysis method. tmax is the amount of time it takes for epinephrine to reach peak concentration in plasma during the treatment period. | Pre-dose to 6 hours post-dose | 
| Half-life (t1/2) for Total Epinephrine | Patient PK blood samples were taken from a vein in a hand or arm via indwelling heparin-anticoagulated IV catheters, or by venipunctures at 0 (baseline), 5, 15, 30, 45, 60, 90, 120, 180, 240, and 360 minutes post-dose in each treatment period and were analyzed using an established analysis method. Half-life (t1/2) is the amount of time it takes for epinephrine decrease to half the peak concentration in plasma during the treatment period. | Pre-dose to 6 hours post-dose | 
| Concentration vs. Time for Total Epinephrine From Time Zero to 6 Hours Post-dose | Patient PK blood samples were taken from a vein in a hand or arm via indwelling heparin-anticoagulated IV catheters, or by venipunctures at 0 (baseline), 5, 15, 30, 45, 60, 90, 120, 180, 240, and 360 minutes post-dose in each treatment period and were analyzed using an established analysis method. | Pre-dose to 6 hours post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Vital Signs: Systolic Blood Pressure (SBP) | Subject vital signs, i.e., blood pressure and heart rate, were measured prior to study drug dosing (baseline) and up to 360 minutes after dosing during the study visit. | Pre-dose (baseline) to 360 minutes post-dose | 
| Vital Signs: Diastolic Blood Pressure (DBP) | Subject vital signs, i.e., blood pressure and heart rate, were measured prior to study drug dosing (baseline) and up to 360 minutes after dosing during the study visit. | Pre-dose (baseline) to 360 minutes post-dose | 
| Vital Signs: Heart Rate (HR) | Subject vital signs, i.e., blood pressure and heart rate, were measured prior to study drug dosing (baseline) and up to 360 minutes after dosing during the study visit. | Pre-dose (baseline) to 360 minutes post-dose | 
| ECG: QT Interval | Subject QT and QTc Intervals were recorded using a 12-Lead ECG prior to study drug dosing (baseline) and up to 360 minutes after dosing during the study visit. | Pre-dose (baseline) to 360 minutes post-dose | 
| ECG: QTc Interval | Subject QT and QTc Intervals were recorded using a 12-Lead ECG prior to study drug dosing (baseline) and up to 360 minutes after dosing during the study visit. | Pre-dose (baseline) to 360 minutes post-dose | 
| Serum Glucose Levels | Blood samples used to measure subject serum glucose and potassium levels were collected prior to study drug dosing (baseline) and up to 360 minutes post-dose. | Pre-dose (baseline) to 360 minutes post-dose | 
| Serum Potassium Levels | Blood samples used to measure subject serum glucose and potassium levels were collected prior to study drug dosing (baseline) and up to 360 minutes post-dose. | Pre-dose (baseline) to 360 minutes post-dose | 
| Hand Tremor Scores | Subjects evaluated hand tremor experiences using a scale from 0 to 3 (0: No tremor; 1: Mild, perceivable; 2: Moderate, observable; and 3: Severe, interfering with hand activities). Hand tremors were evaluated prior to study drug dosing (baseline) and up to 360 minutes post-dose. | Pre-dose (baseline) to 360 minutes post-dose | 
| Number of Subjects With Significant Changes in Physical Examination | Physical examinations were performed as a part of Screening and End-of-Study (EOS) procedures. This outcome is a count of the number of subjects that showed a clinically significant change in the EOS physical examination compared to the Screening Visit. | Approximately 6 weeks | 
| Number of Subjects With Significant Changes in Laboratory Tests | Laboratory tests (CBC, serum comprehensive metabolic panel, urinalysis, and urinary pregnancy test for women of childbearing potential) were performed as a part of Screening and End-of-Study (EOS) procedures. This outcome is a count of the number of subjects that showed a clinically significant change in the EOS laboratory tests compared to the Screening Visit. | Approximately 6 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Asthma, Pharmacokinetics, Epinephrine, Bronchodilator, metered dose inhaler