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

• ClinicalTrials.gov Identifier: NCT01025648
• Recruitment Status: Terminated
• First Posted: December 3, 2009
• Last Update Posted: May 16, 2018
• Sponsor: Amphastar Pharmaceuticals, Inc.
• Information provided by (Responsible Party): Amphastar Pharmaceuticals, Inc.

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Asthma	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	Phase 1; Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 9 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: December 2009
• Actual Primary Completion Date: December 2009
• Actual Study Completion Date: December 2009

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

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). [ Time Frame: 360 minutes post-dose ]

Secondary Outcome Measures :

1. Dose response relationship of Epinephrine HFA-MDI, analyzed using efficacy data from all E004 doses. [ Time Frame: 360 minutes post dose ]
2. AUC of FEV1 volume post-dose changes (Δ Volume) from the Pre-dose baseline. [ Time Frame: 360 minutes post dose ]
3. 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 ]
4. The peak bronchodilator response (Fmax), defined as the maximum post-dose FEV1 percent change. [ Time Frame: 360 minutes post dose ]
5. The time to peak FEV1 effect (Tmax), defined as the time of Fmax. [ Time Frame: 360 minutes post dose ]
6. 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 ]
7. Response Rate of responders who demonstrate 12.0 percent or greater FEV1 changes from the Pre-dose baseline. [ Time Frame: 360 minutes post dose ]
8. 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 ]
9. 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 ]
10. 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 ]
11. 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 ]
12. Monitoring of adverse drug events (ADE) [ Time Frame: Ongoing through End of Study ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 55 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Generally healthy, male and female adults aged 18 to 55 years at Screening.
2. 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;
3. Demonstrating a baseline forced expiratory volume in 1 second (FEV1) at 50-90 percent of predicted normal at Screening;
4. 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;
5. Females of child-bearing potential must be non-pregnant, non-lactating, and practicing a clinically acceptable form of birth control;
6. Demonstration of proficiency in the use of a MDI inhaler after training;
7. 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.

Contacts and Locations

Locations

United States, California

Amphastar Site 0001

San Jose, California, United States, 95117

Amphastar Site 0003

Stockton, California, United States, 95207

Sponsors and Collaborators

Amphastar Pharmaceuticals, Inc.

Investigators

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

More Information

Publications:

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Hendeles L, Marshik PL, Ahrens R, Kifle Y, Shuster J. Response to nonprescription epinephrine inhaler during nocturnal asthma. Ann Allergy Asthma Immunol. 2005 Dec;95(6):530-4.

Warren JB, Doble N, Dalton N, Ewan PW. Systemic absorption of inhaled epinephrine. Clin Pharmacol Ther. 1986 Dec;40(6):673-8.

Cripps A, Riebe M, Schulze M, Woodhouse R. Pharmaceutical transition to non-CFC pressurized metered dose inhalers. Respir Med. 2000 Jun;94 Suppl B:S3-9.

Dickinson BD, Altman RD, Deitchman SD, Champion HC. Safety of over-the-counter inhalers for asthma: report of the council on scientific affairs. Chest. 2000 Aug;118(2):522-6.

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.

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.

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.

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

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

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

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.

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:

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.

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

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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(®) 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.

• Responsible Party: Amphastar Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT01025648
• Other Study ID Numbers: API-E004-CL-A
• First Posted: December 3, 2009
• Last Update Posted: May 16, 2018
• Last Verified: May 2018

Keywords provided by Amphastar Pharmaceuticals, Inc.:

Mild to Moderate Asthma; Dyspnea; Wheezing; Status Asthmaticus

Additional relevant MeSH terms:

Asthma; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases; Epinephrine; Racepinephrine; 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; Mydriatics; Sympathomimetics; Vasoconstrictor Agents