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

Official Title: “Phase 1/2 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”

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.

Intervention(s) in this Clinical Trial

• Drug: epinephrine inhalation aerosol, 90 mcg/actuation
  • epinephrine inhalation aerosol, 90 mcg/actuation, 2 actuations, single dose crossover, 1 -14 day washout period
• Drug: Placebo HFA
  • Placebo HFA, 0 mcg epinephrine inhalation aerosol, 2 actuations, 1 -14 day washout period
• Drug: epinephrine inhalation aerosol, 125 mcg
  • epinephrine inhalation aerosol, 125 mcg/actuation, 2 actuations, single dose crossover, 1 - 14 day washout period
• Drug: epinephrine inhalation aerosol, 220 mcg
  • epinephrine inhalation aerosol, 220 mcg/actuation, 2 actuations, single dose crossover, 1 14 days washout period
• Drug: epinephrine inhalation aerosol, CFC propelled
  • epinephrine inhalation aerosol, 220 mcg/actuation, 2 actuations, single dose crossover, 1 14 day washout period
• Drug: epinephrine inhalation aerosol, 160 mcg
  • epinephrine inhalation aerosol, 160 mcg/actuation, 2 actuations, single dose crossover, 1 - 14 days washout period

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: T1 - 90 mcg/actuation
  • treatment by 2 actuations of experimental drug at 90 mcg/actuation
• Experimental: T2 - 125 mcg/actuation
  • 125 mcg epinephrine inhalation aerosol, 2 actuations, single dose crossover, 1 - 14 day washout period
• Experimental: T3 - 160 mcg/actuation
  • epinephrine inhalation aerosol, 160 mcg/ actuation, 2 actuations
• Experimental: T4 - 220 mcg/actuation
  • epinephrine inhalation aerosol, 220 mcg/actuation, 2 actuations
• Active Comparator: A - Active control
  • 220 mcg Epinephrine Inhalation Aerosol, CFC-MDI, 2 actuations
• Placebo Comparator: P, Placebo HFA
  • single treatment with 2 inhalations of Placebo HFA

Primary Measures

• 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).
  • Time Frame: 360 minutes post-dose
    Safety Issue?: No

Secondary Measures

• Dose response relationship of Epinephrine HFA-MDI, analyzed using efficacy data from all E004 doses.
  • Time Frame: 360 minutes post dose
    Safety Issue?: No
• AUC of FEV1 volume post-dose changes (Δ Volume) from the Pre-dose baseline.
  • Time Frame: 306 minutes post dose
    Safety Issue?: No
• 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.
  • Time Frame: 30 (±5) min post-dose
    Safety Issue?: No
• The peak bronchodilator response (Fmax), defined as the maximum post-dose FEV1 percent change.
  • Time Frame: 360 minutes post dose
    Safety Issue?: No
• The time to peak FEV1 effect (Tmax), defined as the time of Fmax.
  • Time Frame: 360 minutes post dose
    Safety Issue?: No
• 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.
  • Time Frame: 360 minutes post dose
    Safety Issue?: No
• Response Rate of responders who demonstrate 12.0 percent or greater FEV1 changes from the Pre-dose baseline.
  • Time Frame: 360 minutes post dose
    Safety Issue?: No
• Vital signs, i.e., blood pressure and heart rate,at Screening baseline and 15(±5) min post dosing for reversibility
  • Time Frame: screening and 15 minutes post dose
    Safety Issue?: Yes
• 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.
  • Time Frame: 360 minutes post dose
    Safety Issue?: Yes
• Post-dose 20(±5) min ECG recordings (Routine and QT, QTc analysis) at each Study Visit, compared to the Screening baseline recording.
  • Time Frame: 20 minutes post dose
    Safety Issue?: Yes
• Data for physical examinations, CBC, serum comprehensive metabolic panel, and urinalysis for all subjects, and urinary pregnancy test for women of child-bearing potential
  • Time Frame: Screening and end of study
    Safety Issue?: Yes
• Monitoring of adverse drug events (ADE)
  • Time Frame: Ongoing through End of Study
    Safety Issue?: Yes

Inclusion Criteria:

• 1. 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;
• 2. Demonstrating a baseline forced expiratory volume in 1 second (FEV1) at 50-90 percent of predicted normal at Screening;
• 3. 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;
• 4. Females of child-bearing potential must be non-pregnant, non-lactating, and practicing a clinically acceptable form of birth control;
• 5. Demonstration of proficiency in the use of a MDI inhaler after training;
• 6. Having properly consented to participate in the trial.

Exclusion Criteria:

• 1. A smoking history of 10 or more pack-years, or having smoked within 6 months prior to Screening;
• 2. Upper respiratory tract infections within 2 wk, or lower respiratory tract infection within 4 wk, prior to Screening;
• 3. Asthma exacerbations that required emergency care or hospitalized treatment, within 4 wk prior to Screening;
• 4. 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;
• 5. 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;
• 6. 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);
• 7. Use of prohibited drugs or failure to observe the drug washout restrictions;
• 8. Having been on other investigational drug/device studies in the last 30 days prior to Screening.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 55 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Investigator: Amphastar Pharmaceuticals, Inc. Industry

Overall Clinical Trial Officials and Contacts

Jim Shi, M.D., Ph.D. Study Chair Amphastar Pharmaceuticals, Inc.  

Information obtained from ClinicalTrials.gov on February 09, 2012

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT01025648

Study ID Number: API-E004-CL-A

ClinicalTrials.gov Identifier: NCT01025648

Health Authority: United States: Food and Drug Administration