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

NCT01025648 | Terminated Phase 1

• 1 other identifier: API-E004-CL-A
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 2

Brief Summary

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.

Conditions

Asthma

Keywords

Mild to Moderate Asthma; Dyspnea; Wheezing; Status Asthmaticus

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (12)

• 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

Study Arms (6)

T1 - E004 90 mcg/actuation

EXPERIMENTAL

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

T2 - E004 125 mcg/actuation

EXPERIMENTAL

E004 (epinephrine inhalation aerosol), 125 mcg, 2 actuations

Drug: E004 (epinephrine inhalation aerosol), 125 mcg

T3 - 160 mcg/actuation

EXPERIMENTAL

E004 (epinephrine inhalation aerosol), 160 mcg - E004 (epinephrine inhalation aerosol), 160 mcg/ actuation, 2 actuations

Drug: E004 (epinephrine inhalation aerosol), 160 mcg

T4 - 220 mcg/actuation

EXPERIMENTAL

E004 (epinephrine inhalation aerosol), 220 mcg - 220 mcg/actuation, 2 actuations

Drug: E004 (epinephrine inhalation aerosol), 220 mcg

A - Active control

ACTIVE COMPARATOR

epinephrine inhalation aerosol, CFC propelled 220 mcg Epinephrine Inhalation Aerosol, CFC-MDI, 2 actuations

Drug: epinephrine inhalation aerosol, CFC propelled

P, Placebo HFA

PLACEBO COMPARATOR

E004 placebo single treatment with 2 inhalations

Drug: E004 Placebo

Interventions

E004 (epinephrine inhalation aerosol), 90 mcg/actuation DRUG

E004 (epinephrine inhalation aerosol), 90 mcg/actuation, 2 actuations, single dose crossover, 1 -14 day washout period

Also known as: Primatene Mist HFA

T1 - E004 90 mcg/actuation

E004 Placebo DRUG

E004 Placebo, 0 mcg epinephrine inhalation aerosol, 2 actuations, 1 -14 day washout period

P, Placebo HFA

E004 (epinephrine inhalation aerosol), 125 mcg DRUG

E004 (epinephrine inhalation aerosol), 125 mcg/actuation, 2 actuations, single dose crossover, 1 - 14 day washout period

Also known as: Primatene Mist HFA

T2 - E004 125 mcg/actuation

E004 (epinephrine inhalation aerosol), 220 mcg DRUG

E004 (epinephrine inhalation aerosol), 220 mcg - 220 mcg/actuation, 2 actuations, single dose crossover, 1 - 14 days washout period

Also known as: Primatene Mist HFA

T4 - 220 mcg/actuation

epinephrine inhalation aerosol, CFC propelled DRUG

epinephrine inhalation aerosol, 220 mcg/actuation, 2 actuations, single dose crossover, 1 - 14 day washout period

Also known as: Primatene Mist

A - Active control

E004 (epinephrine inhalation aerosol), 160 mcg DRUG

E004 (epinephrine inhalation aerosol), 160 mcg/actuation, 2 actuations, single dose crossover, 1 - 14 days washout period

Also known as: Primatene Mist HFA

T3 - 160 mcg/actuation

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Amphastar Pharmaceuticals, Inc.: lead

Study Sites (2)

Amphastar Site 0001

San Jose, California, 95117, United States

Location

Amphastar Site 0003

Stockton, California, 95207, United States

Location

Related Publications (16)

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  PMID: 2019665 BACKGROUND

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  PMID: 3780129 BACKGROUND

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  PMID: 10919679 BACKGROUND

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  PMID: 10936150 BACKGROUND

• Simons FE, Gu X, Johnston LM, Simons KJ. Can epinephrine inhalations be substituted for epinephrine injection in children at risk for systemic anaphylaxis? Pediatrics. 2000 Nov;106(5):1040-4. doi: 10.1542/peds.106.5.1040.

  PMID: 11061773 BACKGROUND

• Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Crapo R, Enright P, van der Grinten CP, Gustafsson P, Jensen R, Johnson DC, MacIntyre N, McKay R, Navajas D, Pedersen OF, Pellegrino R, Viegi G, Wanger J; ATS/ERS Task Force. Standardisation of spirometry. Eur Respir J. 2005 Aug;26(2):319-38. doi: 10.1183/09031936.05.00034805. No abstract available.

  PMID: 16055882 BACKGROUND

• Crapo RO, Morris AH, Clayton PD, Nixon CR. Lung volumes in healthy nonsmoking adults. Bull Eur Physiopathol Respir. 1982 May-Jun;18(3):419-25.

  PMID: 7074238 BACKGROUND

• Dauphinee B, Tashkin DP, et al: Placebo-controlled evaluation of the speed of onset of epinephrine metered-dose aerosol (Primatene Mist) in mild to moderate asthmatics. Am J Respir Crit Care Med, 149:A204, 1994

  BACKGROUND

• Armstrong Pharmaceuticals: Package Insert of Epinephrine Inhalation Aerosol USP, a CFC-MDI, current as of 2008

  BACKGROUND

• Westfall TC, Westfall DP: Adrenergic agonists and antagonists, in Brunton LL, Lazo JS, Parker KL (eds): Goodman & Gilman's Ther Pharmacological Basis of Therapeitucs, 11th Ed. P237-296, 1986

  BACKGROUND

• Montreal Protocol on substances that deplete the ozone layer, Montreal, Spet 1987; Adjusted and/or amended in London 1990; Copenhagen 1992; Vienna 1995; Montreal 1997 and Beijing 1999.

  BACKGROUND

• NHLBI/NAEPP (National Heart, Lund and Blood Institute; Natuinak /asthma Education and Prevention Program) Expert Panel Report 3 (2007): Guidelines for the diagnosis and management of asthma, Section 3, Component 1, Figure 3-4C:

  BACKGROUND

• Wyeth Consumer Healthcare: 2005N-0374, Use of ozone-depleting substances: Essential-use determination of over-the-counter (OTC) epinephrine metered dose inhalers. Submitted to teh Nonprescription Drugs and Pulmonary-Allergy Drugs Advisory Committees. Dec 2005.

  BACKGROUND

• Global Initiative for Asthma (GINA): Pocket guide for asthma management and prevention,

  BACKGROUND

• Kerwin EM, Tashkin DP, Murphy TR, Bensch GW, Marrs T, Luo MZ, Zhang JY. A Dose-Ranging Study of Epinephrine Hydrofluroalkane Metered-Dose Inhaler (Primatene(R) MIST) in Subjects with Intermittent or Mild-to-Moderate Persistent Asthma. J Aerosol Med Pulm Drug Deliv. 2020 Aug;33(4):186-193. doi: 10.1089/jamp.2019.1558. Epub 2020 Mar 6.

  PMID: 32150492 DERIVED

MeSH Terms

Conditions

Asthma; Dyspnea; Respiratory Sounds; Status Asthmaticus

Interventions

Epinephrine

Condition Hierarchy (Ancestors)

Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases; Respiration Disorders; Signs and Symptoms, Respiratory; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Ethanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Amines; Biogenic Monoamines; Biogenic Amines; Catecholamines; Catechols; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons

Study Officials

• Jim Shi, M.D., Ph.D.

  Amphastar Pharmaceuticals, Inc.

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 1, 2009
• First Posted: December 3, 2009
• Study Start: December 1, 2009
• Primary Completion: December 1, 2009
• Study Completion: December 1, 2009
• Last Updated: May 16, 2018

Record last verified: 2018-05

Locations

US (2)