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

• Sponsor: University of Florida (Other)
• Overall Status: Completed
• CT.gov ID: NCT00643578
• Collaborator: Teva Branded Pharmaceutical Products R&D, Inc. (Industry)
• Enrollment: 37
• Location: 1
• Arms: 2
• Duration (Months): 10.1
• Patients Per Site Per Month: 3.7

Study Details

Study Description

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; Drug: formoterol; Device: Dry Powder Inhaler (Twisthaler)	N/A

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

• Study Type: Interventional
• 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: Mar 1, 2008
• Actual Primary Completion Date: Jan 1, 2009
• Actual Study Completion Date: Jan 1, 2009

Arms and Interventions

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

Primary Outcome Measures

1. Post-dose PC20 [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 [1 hour after dose]

   The forced expiratory volume in the first second, expressed as a percent predicted.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Locations

	Site	City	State	Country	Postal Code
1	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

Study Documents (Full-Text)

None provided.

More Information

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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

• Responsible Party: University of Florida
• ClinicalTrials.gov Identifier: NCT00643578
• Other Study ID Numbers: Ivax-65307
• First Posted: Mar 26, 2008
• Last Update Posted: Dec 5, 2011
• Last Verified: Nov 1, 2011

• Keywords provided by University of Florida: formoterol; methacholine challenge
• Additional relevant MeSH terms: Asthma; Formoterol Fumarate

Study Results

Participant Flow

Recruitment Details	Between April and November, 2008, the UF Asthma Research Lab recruited 37 patients for study.
Pre-assignment Detail	Of the 37 subjects who signed informed consent, 25 did not meet inclusion/exclusion criteria. The provocational dose of methacholine causing a 20% drop in forced expiratory volume in the first second (PC20FEV1) was not less than or equal to 4 mg/mL.

Arm/Group Title	Formoterol 12 First	Formoterol 24 First
Arm/Group Description	a single dose of 12 mcg of formoterol was given first, then 24 mcg of formoterol	a single dose of 24 mcg of formoterol was given first, then 12 mcg of formoterol
Period Title: Overall Study
STARTED	6	6
COMPLETED	4	6
NOT COMPLETED	2	0

Baseline Characteristics

Arm/Group Title	All Participants
Arm/Group Description	A single dose of 12 mcg and 24 mcg, on separate days, of formoterol were given.
Overall Participants	12
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	12 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	36.8 (14.5)
Sex: Female, Male (Count of Participants)
Female	7 58.3%
Male	5 41.7%
Region of Enrollment (participants) [Number]
United States	12 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Of the 12 subjects who qualified for randomization, 2 had a PC20 greater than 128 mg/mL (the maximum concentration of methacholine administered), after receiving 12 mcg of formoterol. Therefore, they were discontinued from the study since their PC20 would not be measurable with a higher dose of formoterol.

Arm/Group Title	12 Mcg Formoterol	24 Mcg Formoterol
Arm/Group Description	low dose	high dose
Measure Participants	10	10
Geometric Mean (95% Confidence Interval) [mg/mL]	7	16

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Of the 12 subjects who qualified for randomization, 2 had a PC20 greater than 128 mg/mL (the maximum concentration of methacholine administered), after receiving 12 mcg of formoterol. Therefore, they were discontinued from the study since their PC20 would not be measurable with a higher dose of formoterol.

Arm/Group Title	12 Mcg of Formoterol	24 Mcg of Formoterol
Arm/Group Description	low dose	high dose
Measure Participants	10	10
Mean (Standard Deviation) [percent predicted]	88 (12)	91 (10)

Adverse Events

Arm/Group Title	Formoterol 12		Formoterol 24
Arm/Group Description	A single dose of 12 mcg of formoterol was administered.		A single dose of 24 mcg of formoterol was administered.
All Cause Mortality
	Formoterol 12		Formoterol 24
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Formoterol 12		Formoterol 24
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)
Other (Not Including Serious) Adverse Events
	Formoterol 12		Formoterol 24
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.