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

Study Description

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Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Asthma	Drug: formoterol; Device: Dry Powder Inhaler (Twisthaler)	Not Applicable

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 Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	37 participants
Allocation:	Randomized
Intervention Model:	Crossover Assignment
Masking:	None (Open Label)
Official Title:	A Pilot Study to Evaluate the Dose-response of Inhaled Formoterol to Inhibit Airway Responsiveness to Methacholine in Patients With Mild Asthma
Study Start Date :	March 2008
Actual Primary Completion Date :	January 2009
Actual Study Completion Date :	January 2009

Arms and Interventions

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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) 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 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

Outcome Measures

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Primary Outcome Measures :

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

Secondary Outcome Measures :

1. FEV1 [ Time Frame: 1 hour after dose ]
   The forced expiratory volume in the first second, expressed as a percent predicted.

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 60 Years (Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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.

Contacts and Locations

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Locations

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

Sponsors and Collaborators

University of Florida

Teva Branded Pharmaceutical Products, R&D Inc.

Investigators

Principal Investigator:	Leslie Hendeles, PharmD	University of Florida

More Information

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Publications:

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.

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.

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. 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.

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.

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.

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.

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.

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.

Responsible Party:	University of Florida
ClinicalTrials.gov Identifier:	NCT00643578 History of Changes
Other Study ID Numbers:	Ivax-65307
First Posted:	March 26, 2008
Results First Posted:	November 18, 2011
Last Update Posted:	December 5, 2011
Last Verified:	November 2011

Keywords provided by University of Florida:

formoterol; methacholine challenge

Additional relevant MeSH terms:

Asthma; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases; Formoterol Fumarate; Methacholine Chloride; Bronchodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs	Anti-Asthmatic Agents; Respiratory System Agents; Adrenergic beta-2 Receptor Agonists; Adrenergic beta-Agonists; Adrenergic Agonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Miotics; Parasympathomimetics; Bronchoconstrictor Agents; Muscarinic Agonists; Cholinergic Agonists; Cholinergic Agents