Randomized, Placebo/Active Crossover Dose-ranging Study for Safety and Efficacy in Asthma Patients.

Study Overview
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Brief Summary
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The main objective of this study is to evaluate the efficacy and safety of the Armstrong's Epinephrine HFA-MDI (E004) formulation, in comparison to the Placebo (Placebo-HFA) and an Active Control (Epinephrine CFC-MDI), and to identify the optimum E004 dose strength(s) for the ensuing pivotal clinical trials. The study will be conducted in adult patients who have intermittent, or mild-to-moderate persistent, asthma, but are otherwise healthy. The bronchodilatory efficacy of E004, is evaluated in terms of post-dose area under the curves (AUC) of FEV1 changes (% and volumes), from the pre-dose baseline values, in comparison to the Placebo Control and the Active Control.

Official Title
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A Randomized, Double-blinded or Evaluator-blinded, Placebo and Active Controlled, Six-arm, Crossover, Single Dose, Dose-ranging Study, for Initial Evaluation of Safety and Efficacy in Asthma Patients

Conditions
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Asthma

Intervention / Treatment
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* Drug: E004 (epinephrine inhalation aerosol), 90 mcg/actuation
* Drug: E004 Placebo
* Drug: E004 (epinephrine inhalation aerosol), 125 mcg
* Drug: E004 (epinephrine inhalation aerosol), 220 mcg
* Drug: epinephrine inhalation aerosol, CFC propelled
* Drug: E004 (epinephrine inhalation aerosol), 160 mcg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Generally healthy, male and female adults aged 18 to 55 years at Screening. Clinical diagnosis of intermittent, or mild-to-moderate persistent, asthma for at least 6 months before Screening, and having used inhaled epinephrine or β-agonist(s) for asthma control; Demonstrating a baseline forced expiratory volume in 1 second (FEV1) at 50-90 percent of predicted normal at Screening; Demonstrating a 12.0 percent or greater airway reversibility in FEV1 within 30 min after inhaling 2 actuations of Epinephrine CFC-MDI (440 mcg Epinephrine base) at Screening; Females of child-bearing potential must be non-pregnant, non-lactating, and practicing a clinically acceptable form of birth control; Demonstration of proficiency in the use of a MDI inhaler after training; Having properly consented to participate in the trial. Exclusion Criteria: A smoking history of 10 or more pack-years, or having smoked within 6 months prior to Screening; Upper respiratory tract infections within 2 wk, or lower respiratory tract infection within 4 wk, prior to Screening; Asthma exacerbations that required emergency care or hospitalized treatment, within 4 wk prior to Screening; Any current or recent respiratory conditions that, per investigator discretion, might significantly affect pharmacodynamic response to the study drugs, including cystic fibrosis, bronchiectasis, tuberculosis, emphysema, and other significant respiratory diseases besides asthma; 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 in the last 30 days prior to Screening.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

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 |
| --- | --- |
| Experimental: T1 - E004 90 mcg/actuation<br>T1 - E004 (epinephrine inhalation aerosol) 90 mcg/actuation - treatment by 2 actuations of E004 at 90 mcg/actuation | Drug: E004 (epinephrine inhalation aerosol), 90 mcg/actuation<br>* E004 (epinephrine inhalation aerosol), 90 mcg/actuation, 2 actuations, single dose crossover, 1 -14 day washout period<br>* Other names: Primatene Mist HFA;|
| Experimental: T2 - E004 125 mcg/actuation<br>E004 (epinephrine inhalation aerosol), 125 mcg, 2 actuations | Drug: E004 (epinephrine inhalation aerosol), 125 mcg<br>* E004 (epinephrine inhalation aerosol), 125 mcg/actuation, 2 actuations, single dose crossover, 1 - 14 day washout period<br>* Other names: Primatene Mist HFA;|
| Experimental: T3 - 160 mcg/actuation<br>E004 (epinephrine inhalation aerosol), 160 mcg - E004 (epinephrine inhalation aerosol), 160 mcg/ actuation, 2 actuations | Drug: E004 (epinephrine inhalation aerosol), 160 mcg<br>* E004 (epinephrine inhalation aerosol), 160 mcg/actuation, 2 actuations, single dose crossover, 1 - 14 days washout period<br>* Other names: Primatene Mist HFA;|
| Experimental: T4 - 220 mcg/actuation<br>E004 (epinephrine inhalation aerosol), 220 mcg - 220 mcg/actuation, 2 actuations | Drug: E004 (epinephrine inhalation aerosol), 220 mcg<br>* E004 (epinephrine inhalation aerosol), 220 mcg - 220 mcg/actuation, 2 actuations, single dose crossover, 1 - 14 days washout period<br>* Other names: Primatene Mist HFA;|
| Active Comparator: A - Active control<br>epinephrine inhalation aerosol, CFC propelled 220 mcg Epinephrine Inhalation Aerosol, CFC-MDI, 2 actuations | Drug: epinephrine inhalation aerosol, CFC propelled<br>* epinephrine inhalation aerosol, 220 mcg/actuation, 2 actuations, single dose crossover, 1 - 14 day washout period<br>* Other names: Primatene Mist;|
| Placebo Comparator: P, Placebo HFA<br>E004 placebo single treatment with 2 inhalations | Drug: E004 Placebo<br>* E004 Placebo, 0 mcg epinephrine inhalation aerosol, 2 actuations, 1 -14 day washout period<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The AUC of post-dose FEV1 percentage changes (Δ%) from the Pre-dose baseline. The primary analysis of the primary endpoint is the difference of Δ% FEV1, compared between the E004 treatment arms (T1, T2, T3 and T4) and the Placebo control (Arm P). |  | 360 minutes post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose response relationship of Epinephrine HFA-MDI, analyzed using efficacy data from all E004 doses. |  | 360 minutes post dose | 
| AUC of FEV1 volume post-dose changes (Δ Volume) from the Pre-dose baseline. |  | 360 minutes post dose | 
| Time to onset of bronchodilator effect, determined by linear interpolation as the point where FEV1 first reaches 12.0 percent from the Pre-dose Baseline. |  | 30 (±5) min post-dose | 
| The peak bronchodilator response (Fmax), defined as the maximum post-dose FEV1 percent change. |  | 360 minutes post dose | 
| The time to peak FEV1 effect (Tmax), defined as the time of Fmax. |  | 360 minutes post dose | 
| Duration of effect, calculated as the total duration of bronchodilator effects when post-dose FEV1 reaches and stays 12.0 percent above the Pre-dose Baseline. |  | 360 minutes post dose | 
| Response Rate of responders who demonstrate 12.0 percent or greater FEV1 changes from the Pre-dose baseline. |  | 360 minutes post dose | 
| Vital signs, i.e., blood pressure and heart rate,at Screening baseline and 15(±5) min post dosing for reversibility |  | screening and 15 minutes post dose | 
| Vital signs, i.e., blood pressure (SBP/DBP) and heart rate (HR), at: Pre-dose baseline, and 15(±5) min and 360(±15) post-dose, at each Study Visit. |  | 360 minutes post dose | 
| Post-dose 20(±5) min ECG recordings (Routine and QT, QTc analysis) at each Study Visit, compared to the Screening baseline recording. |  | 20 minutes post dose | 
| Data for physical examinations, CBC, serum comprehensive metabolic panel, and urinalysis for all subjects, and urinary pregnancy test for women of child-bearing potential |  | Screening and end of study | 
| Monitoring of adverse drug events (ADE) |  | Ongoing through End of Study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mild to Moderate Asthma, Dyspnea, Wheezing, Status Asthmaticus