Back to results

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

Primary Purpose

Asthma

Status

Terminated

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

E004 (epinephrine inhalation aerosol), 90 mcg/actuation

E004 Placebo

E004 (epinephrine inhalation aerosol), 125 mcg

E004 (epinephrine inhalation aerosol), 220 mcg

epinephrine inhalation aerosol, CFC propelled

E004 (epinephrine inhalation aerosol), 160 mcg

About this trial

This is an interventional treatment trial for Asthma focused on measuring Mild to Moderate Asthma, Dyspnea, Wheezing, Status Asthmaticus

Eligibility Criteria

18 Years - 55 Years (Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Amphastar Site 0001
Amphastar Site 0003

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Experimental

Active Comparator

Placebo Comparator

Arm Label

T1 - E004 90 mcg/actuation

T2 - E004 125 mcg/actuation

T3 - 160 mcg/actuation

T4 - 220 mcg/actuation

A - Active control

P, Placebo HFA

Arm Description

T1 - E004 (epinephrine inhalation aerosol) 90 mcg/actuation - treatment by 2 actuations of E004 at 90 mcg/actuation

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

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

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

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

E004 placebo single treatment with 2 inhalations

Outcomes

Primary Outcome 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).

Secondary Outcome Measures

Dose response relationship of Epinephrine HFA-MDI, analyzed using efficacy data from all E004 doses.

AUC of FEV1 volume post-dose changes (Δ Volume) from the Pre-dose baseline.

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.

The peak bronchodilator response (Fmax), defined as the maximum post-dose FEV1 percent change.

The time to peak FEV1 effect (Tmax), defined as the time of Fmax.

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.

Response Rate of responders who demonstrate 12.0 percent or greater FEV1 changes from the Pre-dose baseline.

Vital signs, i.e., blood pressure and heart rate,at Screening baseline and 15(±5) min post dosing for reversibility

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.

Post-dose 20(±5) min ECG recordings (Routine and QT, QTc analysis) at each Study Visit, compared to the Screening baseline recording.

Data for physical examinations, CBC, serum comprehensive metabolic panel, and urinalysis for all subjects, and urinary pregnancy test for women of child-bearing potential

Monitoring of adverse drug events (ADE)

Full Information

NCT ID

NCT01025648

First Posted

December 1, 2009

Last Updated

May 14, 2018

Sponsor

Amphastar Pharmaceuticals, Inc.

1. Study Identification

Unique Protocol Identification Number

NCT01025648

Brief Title

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

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 Type

Interventional

2. Study Status

Record Verification Date

May 2018

Overall Recruitment Status

Terminated

Why Stopped

Optimization of protocol

Study Start Date

December 2009 (undefined)

Primary Completion Date

December 2009 (Actual)

Study Completion Date

December 2009 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Amphastar Pharmaceuticals, Inc.

4. Oversight

Data Monitoring Committee

5. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Asthma

Keywords

Mild to Moderate Asthma, Dyspnea, Wheezing, Status Asthmaticus

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Crossover Assignment

Masking

ParticipantInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

9 (Actual)

8. Arms, Groups, and Interventions

Arm Title

T1 - E004 90 mcg/actuation

Arm Type

Experimental

Arm Description

T1 - E004 (epinephrine inhalation aerosol) 90 mcg/actuation - treatment by 2 actuations of E004 at 90 mcg/actuation

Arm Title

T2 - E004 125 mcg/actuation

Arm Type

Experimental

Arm Description

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

Arm Title

T3 - 160 mcg/actuation

Arm Type

Experimental

Arm Description

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

Arm Title

T4 - 220 mcg/actuation

Arm Type

Experimental

Arm Description

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

Arm Title

A - Active control

Arm Type

Active Comparator

Arm Description

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

Arm Title

P, Placebo HFA

Arm Type

Placebo Comparator

Arm Description

E004 placebo single treatment with 2 inhalations

Intervention Type

Drug

Intervention Name(s)

E004 (epinephrine inhalation aerosol), 90 mcg/actuation

Other Intervention Name(s)

Primatene Mist HFA

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

E004 Placebo

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

E004 (epinephrine inhalation aerosol), 125 mcg

Other Intervention Name(s)

Primatene Mist HFA

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

E004 (epinephrine inhalation aerosol), 220 mcg

Other Intervention Name(s)

Primatene Mist HFA

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

epinephrine inhalation aerosol, CFC propelled

Other Intervention Name(s)

Primatene Mist

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

E004 (epinephrine inhalation aerosol), 160 mcg

Other Intervention Name(s)

Primatene Mist HFA

Intervention Description

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

Primary Outcome Measure Information:

Title

Time Frame

360 minutes post-dose

Secondary Outcome Measure Information:

Title

Dose response relationship of Epinephrine HFA-MDI, analyzed using efficacy data from all E004 doses.

Time Frame

360 minutes post dose

Title

AUC of FEV1 volume post-dose changes (Δ Volume) from the Pre-dose baseline.

Time Frame

360 minutes post dose

Title

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

Title

The peak bronchodilator response (Fmax), defined as the maximum post-dose FEV1 percent change.

Time Frame

360 minutes post dose

Title

The time to peak FEV1 effect (Tmax), defined as the time of Fmax.

Time Frame

360 minutes post dose

Title

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

Title

Response Rate of responders who demonstrate 12.0 percent or greater FEV1 changes from the Pre-dose baseline.

Time Frame

360 minutes post dose

Title

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

Title

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

Title

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

Title

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

Title

Monitoring of adverse drug events (ADE)

Time Frame

Ongoing through End of Study

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

55 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Jim Shi, M.D., Ph.D.

Organizational Affiliation

Amphastar Pharmaceuticals, Inc.

Official's Role

Study Chair

Facility Information:

Facility Name

Amphastar Site 0001

City

San Jose

State/Province

California

ZIP/Postal Code

95117

Country

United States

Facility Name

Amphastar Site 0003

City

Stockton

State/Province

California

ZIP/Postal Code

95207

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

2019665

Citation

Pinnas JL, Schachtel BP, Chen TM, Roseberry HR, Thoden WR. Inhaled epinephrine and oral theophylline-ephedrine in the treatment of asthma. J Clin Pharmacol. 1991 Mar;31(3):243-7. doi: 10.1002/j.1552-4604.1991.tb04969.x.

Results Reference

background

PubMed Identifier

16400891

Citation

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. doi: 10.1016/S1081-1206(10)61014-9.

Results Reference

background

PubMed Identifier

3780129

Citation

Warren JB, Doble N, Dalton N, Ewan PW. Systemic absorption of inhaled epinephrine. Clin Pharmacol Ther. 1986 Dec;40(6):673-8. doi: 10.1038/clpt.1986.243.

Results Reference

background

PubMed Identifier

10919679

Citation

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.

Results Reference

background

PubMed Identifier

10936150

Citation

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. doi: 10.1378/chest.118.2.522.

Results Reference

background

PubMed Identifier

11061773

Citation

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.

Results Reference

background

PubMed Identifier

16055882

Citation

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.

Results Reference

background

PubMed Identifier

7074238

Citation

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.

Results Reference

background

Citation

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

Results Reference

background

Citation

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

Results Reference

background

Citation

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

Results Reference

background

Citation

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.

Results Reference

background

Citation

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:

Results Reference

background

Citation

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.

Results Reference

background

Citation

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

Results Reference

background

PubMed Identifier

32150492

Citation

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.

Results Reference

derived

Learn more about this trial

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

We'll reach out to this number within 24 hrs