Dose-response of Inhaled Formoterol Using Methacholine Challenge as a Bioassay

A Pilot Study to Evaluate the Dose-response of Inhaled Formoterol to Inhibit Airway Responsiveness to Methacholine in Patients With Mild Asthma

The purpose of this study is to find out whether a difference between two doses of formoterol can be detected by methacholine challenge.

Study Overview

• Status: Completed
• Conditions: Asthma
• Intervention / Treatment: Drug: formoterol; Drug: formoterol; Device: Dry Powder Inhaler (Twisthaler)

Detailed Description

During the screening visit, subjects'vital signs (heart rate, blood pressure and temperature) will be measured and they will perform standard spirometry. If the results of this test are 70% of normal or greater, they will be examined by a physician, and blood (1 teaspoonful) and urine will be collected for routine laboratory tests (CBC and routine urinalysis). If they are a female, a pregnancy test will be performed.

During the second visit, subjects will inhale 1 or 2 doses of formoterol, (Foradil Aerolizer 12 mcg/capsule) a long-acting bronchodilator and 1 hour later, perform a methacholine test.

At the end of the methacholine test, they will be given albuterol to reverse the effects of methacholine. On the third study day, they will repeat the second visit but with the opposite dose of Foradil.

• Study Type: Interventional
• Enrollment (Actual): 37
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Florida
    • Gainesville, Florida, United States, 32610-0486
      • University of Florida Asthma Research Lab

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Non-smoking male or female 18 60 years of age, with a previous diagnosis of asthma that has been stable for at least 4 weeks and which is unlikely to exacerbate during the study because of, for example, seasonal allergen exposure. Women of childbearing age must not be pregnant or nursing, and must be using an acceptable method of contraception.
• Ability to perform ATS/ERS-acceptable and reproducible spirometry7
• Screening FEV1 ≥70% of predicted for height, age, sex, and race when short-acting inhaled bronchodilators are withheld for at least 6 hours
• At least a 20% decrease in FEV1 after inhaling ≤4 mg/mL of methacholine (i.e., a PC20 FEV1 ≤4 mg/mL)
• Can be taught to use the dry powder device in accordance with the product's medication guide.
• If using an oral inhaled or intranasal corticosteroid, dosage must be stable for at least 4 weeks.

Exclusion Criteria:

• Allergy or sensitivity to inhaled methacholine, formoterol or to other β2 agonists
• Intolerance to other components of the inhaler or sensitivity to milk proteins
• Cigarette smoking in past year or >10 pack-year smoking history
• Respiratory tract infection within the last four weeks
• History of severe asthma attack requiring hospitalization in the previous 12 months
• Short course of oral and/or systemic corticosteroids in the past 4 weeks
• Inability to withhold caffeinated beverages for 12 hours or medications for appropriate intervals prior to each methacholine challenge
• Require treatment with beta-blockers (administered by any route), MAO inhibitors, tricyclic antidepressants, and/or maintenance therapy with systemic corticosteroids
• History and/or presence of pulmonary conditions (including but not limited to cystic fibrosis and bronchiectasis) other than asthma
• History of clinically-significant cardiovascular, renal, neurologic, liver or endocrine dysfunction. Patients with well-controlled hypertension, hypercholesterolemia or diabetes will not be excluded.
• If female, a positive urine β-HCG test
• Known or suspected substance abuse (e.g., alcohol, marijuana, etc.) and/or any other medical or psychological conditions that in the investigator's opinion should preclude study enrollment.

Study Plan

How is the study designed?

Design Details

• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 2; a single dose of 24 mcg of formoterol	Drug: formoterol; a single dose of 24 mcg of formoterol delivered by dry powder inhaler (Twisthaler); Drug: formoterol; a single dose of 12 mcg of formoterol delivered by dry powder inhaler (Twisthaler); Device: Dry Powder Inhaler (Twisthaler); subjects inhaled deeply and forcefully and held their breath for 10 seconds for each dose
Active Comparator: 1; a single dose of 12 mcg of formoterol	Drug: formoterol; a single dose of 24 mcg of formoterol delivered by dry powder inhaler (Twisthaler); Drug: formoterol; a single dose of 12 mcg of formoterol delivered by dry powder inhaler (Twisthaler); Device: Dry Powder Inhaler (Twisthaler); subjects inhaled deeply and forcefully and held their breath for 10 seconds for each dose

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Post-dose PC20	The PC20 is the provocational dose of methacholine causing a 20% drop in forced expiratory volume in the first second.	3-7 days after visits 1 and 2

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
FEV1	The forced expiratory volume in the first second, expressed as a percent predicted.	1 hour after dose

Collaborators and Investigators

• Sponsor: University of Florida
• Collaborators: Teva Branded Pharmaceutical Products R&D, Inc.

Publications and helpful links

General Publications

• 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.
• Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a sample of the general U.S. population. Am J Respir Crit Care Med. 1999 Jan;159(1):179-87. doi: 10.1164/ajrccm.159.1.9712108.
• Ahrens RC, Harris JB, Milavetz G, Annis L, Ries R. Use of bronchial provocation with histamine to compare the pharmacodynamics of inhaled albuterol and metaproterenol in patients with asthma. J Allergy Clin Immunol. 1987 Jun;79(6):876-82. doi: 10.1016/0091-6749(87)90235-1.
• Blake KV, Hoppe M, Harman E, Hendeles L. Relative amount of albuterol delivered to lung receptors from a metered-dose inhaler and nebulizer solution. Bioassay by histamine bronchoprovocation. Chest. 1992 Feb;101(2):309-15. doi: 10.1378/chest.101.2.309.
• Hendeles L, Beaty R, Ahrens R, Stevens G, Harman EM. Response to inhaled albuterol during nocturnal asthma. J Allergy Clin Immunol. 2004 Jun;113(6):1058-62. doi: 10.1016/j.jaci.2004.03.046. Erratum In: J Allergy Clin Immunol. 2006 Apr;117(4):773.
• Parameswaran KN, Inman MD, Ekholm BP, Morris MM, Summers E, O'Byrne PM, Hargreave FE. Protection against methacholine bronchoconstriction to assess relative potency of inhaled beta2-agonist. Am J Respir Crit Care Med. 1999 Jul;160(1):354-7. doi: 10.1164/ajrccm.160.1.9812035.
• Ahrens RC, Hendeles L, Clarke WR, Dockhorn RJ, Hill MR, Vaughan LM, Lux C, Han SH. Therapeutic equivalence of Spiros dry powder inhaler and Ventolin metered dose inhaler. A bioassay using methacholine. Am J Respir Crit Care Med. 1999 Oct;160(4):1238-43. doi: 10.1164/ajrccm.160.4.9806101.
• Creticos PS, Adams WP, Petty BG, Lewis LD, Singh GJ, Khattignavong AP, Molzon JA, Martinez MN, Lietman PS, Williams RL. A methacholine challenge dose-response study for development of a pharmacodynamic bioequivalence methodology for albuterol metered- dose inhalers. J Allergy Clin Immunol. 2002 Nov;110(5):713-20. doi: 10.1067/mai.2002.129036.
• Asmus MJ, Vaughan LM, Hill MR, Chesrown SE, Hendeles L. Stability of frozen methacholine solutions in unit-dose syringes for bronchoprovocation. Chest. 2002 May;121(5):1634-7. doi: 10.1378/chest.121.5.1634.

Study record dates

Study Major Dates

• Study Start: March 1, 2008
• Primary Completion (Actual): January 1, 2009
• Study Completion (Actual): January 1, 2009

Study Registration Dates

• First Submitted: March 20, 2008
• First Submitted That Met QC Criteria: March 20, 2008
• First Posted (Estimate): March 26, 2008

Study Record Updates

• Last Update Posted (Estimate): December 5, 2011
• Last Update Submitted That Met QC Criteria: November 29, 2011
• Last Verified: November 1, 2011

More Information

Terms related to this study

• Keywords: formoterol; methacholine challenge
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Bronchial Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity; Asthma; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Adrenergic Agonists; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Adrenergic beta-2 Receptor Agonists; Adrenergic beta-Agonists; Formoterol Fumarate
• Other Study ID Numbers: Ivax-65307