Effect of Omalizumab on Expression of IgE Receptors in Adults With Severe, Inadequately Controlled Allergic Asthma

Double Blind Placebo Controlled Study to Assess the Expression of IgE on Basophils and Dendritic Cells During Omalizumab Treatment.

Status

Completed

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00454051

Enrollment

Registered

2007-03-29

Start date

2006-12-31

Completion date

2008-03-31

Last updated

2011-08-08

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Asthma

Keywords

Asthma, anti-immunoglobulin E, omalizumab, IgE receptors

Brief summary

The aim of this study is to evaluate the expression of IgE high affinity receptors (the part of the cell associated with allergic response) in patients suffering from uncontrolled severe asthma despite long term treatment with high dose of inhaled corticosteroid and long acting Beta-2 agonist.

Detailed description

Double blind placebo controlled study to assess the expression of IgE on blood basophils and dendritic cells in patients with uncontrolled, severe, persistent allergic asthma after a 16-week Omalizumab treatment.

Interventions

DRUGOmalizumab

Omalizumab was supplied as a sterile, freeze dried preparation, to be reconstituted to deliver 150mg of omalizumab. Each vial was reconstituted with 1.4ml of sterile water for injection. The appropriate dose and dosing frequency of omalizumab were determined by baseline total IgE and body weight. A dosing table was used following the European Summary of Product Characteristics (SmPC) of omalizumab.

DRUGplacebo

Placebo was a physiological salt solution, administered according to the same administration scheme to respect the same dosing frequency and injected volume.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* Adults aged \>= 18 years. * Patients with severe persistent allergic asthma with the following characteristics: * FEV1 (Forced Expiratory Volume in One Second) \<80% of predicted. * Frequent daily symptoms (\>=4 days/week on average) or nocturnal awakening (\>=1/week on average). * Multiple severe asthma exacerbations: either \>=2 severe asthma exacerbations having required an unscheduled medical intervention with systemic corticosteroid in the past year, or hospitalization (including emergency room treatment) for an asthma exacerbation in the past year. * Despite a high dose inhaled corticosteroid \>1000 mg beclomethasone dipropionate or equivalent and a inhaled long-acting B2-agonist. * With an allergy to a perennial allergen demonstrated with convincing criteria, i.e. positive prick skin test or in vitro reactivity to a perennial aeroallergen (RAST). * Total serum IgE level \>= 30 to \<=700 IU/ml and suitable serum total IgE level and weight according to Xolair dosing tablets.

Exclusion criteria

* Age \< 18 years. * Smoking history \> 20 pack years. * Patients who have had an asthma exacerbation during the 4 weeks prior to randomization * History of food or drug related severe anaphylactoid or anaphylactic reaction * Elevated serum IgE levels for reasons other than allergy (e.g. parasite infections, hyperimmunoglobulin E syndrome, Wiskott-Aldrich Syndrome or allergic bronchopulmonary aspergillosis). * Patients with active cancer, suspicion of cancer or any history of cancer. * Pregnant women. * Known hypersensitivity to omalizumab or to one of its components. * Patients already treated with omalizumab (indeed a previous treatment with omalizumab could have modified the FceRI expression). * Patients who had participated in a clinical trial in the past 3 months.

Design outcomes

Primary

Measure	Time frame	Description
Change (%) From Baseline in FcεRI (High-affinity IgE Receptor) Expression on Blood Basophils and Dendritic Cells After 16 Weeks of Treatment With Omalizumab as Compared With Placebo	Baseline and Week 16	Blood was drawn from participants at baseline and at Week 16. Basophils and dendritic cells expressing FcεRI were counted and the percentage was calculated. Fluorescence was used to label FcεRI so that they could be visualized. The greater the fluorescence intensity the greater FcεRI expression. The change from baseline is described by the difference (%) between the baseline value, before the first study drug administration, and the value observed at the end of study, expressed as a percent of the baseline value.
Change (%) From Baseline in Mean Fluorescence Intensity of FcεRI After 16 Weeks of Treatment With Omalizumab as Compared With Placebo	Baseline and Week 16	Blood was drawn from participants at baseline and at week 16. Basophils and dendritic cells expressing FcεRI were counted and the percentage was calculated. Fluorescence was used to label FcεRI so that they could be visualized. The greater the fluorescence intensity the greater FcεRI expression. The change from baseline is described by the difference (%) between the baseline value, before the first study drug administration, and the value observed at the end of study, expressed as a percent of the baseline value.

Secondary

Measure	Time frame	Description
Change From Baseline in the Number of Days With Asthma Symptoms Per Week	Baseline (the 4 week screening period prior to randomization) and End of Study (Weeks 12 - 16)	Participants maintained a diary to record the number of days with daytime asthma symptoms per week. This analysis compares the mean number of days per week with asthma symptoms during the 4-week screening period prior to randomization with the mean number of days per wek with asthma symptoms in the last 4 weeks of study treatment (Weeks 12 -16).
Change From Baseline in the Number of Puffs of Rescue Medication Per Week	Baseline (the 4 week screening period prior to randomization) and End of Study (Weeks 12 - 16)	Participants maintained a diary to record the daytime number of puffs of rescue Short-acting B2 agonist (SABA) used to treat asthma symptoms per week. This analysis compares the mean number of puffs of rescue medication per week during the 4 week screening period prior to randomization to the mean number of puffs per week during the last 4 weeks on study treatment (Weeks 12 - 16).
Change From Baseline in the Number of Nights With Awakenings Per Week	Baseline (the 4 week screening period prior to randomization) and End of Study (Weeks 12 - 16)	Participants maintained a diary to record the number of nights with awakenings due to asthma symptoms per week. For this analysis, the mean number of nights with awakenings per week during the 4 week screening period prior to randomization was compared with the mean number of nights with awakenings per week during the last 4 weeks of study treatment (Weeks 12 - 16).
Change From Baseline in the Number of Days With Impairment in Daily Activities Per Week	Baseline (the 4 week screening period prior to randomization) and End of Study (Weeks 12 - 16)	Impairment was defined as days with physical activity considered as limited (or not normal) according to patient's assessment and was recorded in a patient daily diary. For this analysis, the mean number of days with impairment per week during the 4 week screening period prior to randomization was compared with the mean number of days with impairment per week during the last 4 weeks on study treatment (Weeks 12 - 16).
Change (%) From Baseline in Percent of Basophils and Dendritic Cells Expressing FcεRI After 4, 8, 12 and 16 Weeks of Treatment	Baseline, Weeks 4, 8, 12 and 16	Blood was drawn from a sub-group of participants at weeks 4, 8, 12, and 16. Basophils and dendritic cells expressing FcεRI were counted and the percentage was calculated. Fluorescence was used to label FcεRI so that they could be visualized. The change from baseline is described by the difference (%) between the baseline value, before the first study drug administration, and the value observed at the specified time point, expressed as a percent of the baseline value.
Change From Baseline in the Number of Days With Hospitalizations	Baseline (the 4 week screening period prior to randomization) and End of Study (Weeks 12 - 16)	Participants maintained a diary to record the number of days with hospitalizations during the study. For this analysis, the number of days with hospitalizations during the screening period (4 weeks prior to randomization) was compared with the number of days with hospitalizations during the last 4 weeks on study treatment (Weeks 12 - 16).
Change From Baseline in the Number of Unscheduled Clinic Visits	Baseline (the 4 week screening period prior to randomization) and End of Study (Weeks 12 - 16)	Participants maintained a diary to record the number of unscheduled clinic visits during the study. For this analysis, the number of unscheduled visits during the 4 week screening period prior to randomization is compared with the number of unscheduled visits during the last 4 weeks on treatment (Weeks 12 - 16).
Change From Baseline in the Morning Daily Peak Expiratory Flow (PEF)	Baseline (the 4 week screening period prior to randomization) and End of Study (Weeks 12 - 16)	Peak Expiratory Flow (PEF) was measured every morning using a peak flow meter, and was recorded in the patient diary. For this analysis, the mean morning PEF during the 4-week screening period prior to randomizaton is compared with the mean morning PEF during the last 4 weeks of study treatment (Weeks 12 - 16).
Physician's Overall Assessment of Treatment Effectiveness	After 16 weeks of treatment	The Physician's overall assessment of treatment effectiveness was graded 1-5 as 1 = Excellent asthma control (complete control) 2 = Good asthma control (marked improvement) 3 = Moderate asthma control (discernible, but limited improvement) 4 = Poor asthma control (no appreciable change) 5 = Very poor asthma control (worsening)
Change From Baseline in the Number of Days With Absence From School or Work Due to Asthma Symptoms	Baseline (the 4 week screening period prior to randomization) and End of Study (Weeks 12 - 16)	Participants maintained a diary to record the number of days with absence from school or work due to asthma symptoms. For this analysis, the number of days with absence from school or work in the four weeks prior to randomization (screening period) were compared with the number of absence days during the last 4 weeks on study treatment (Weeks 12 - 16).
Change (%) From Baseline in the Mean Fluorescence Intensity of FcεRI After 4, 8, 12 and 16 Weeks of Treatment	Baseline, Weeks 4, 8, 12, and 16	Blood was drawn from a sub-group of participants at weeks 4, 8, 12, and 16. Basophils and dendritic cells expressing FcεRI were counted and the percentage was calculated. Fluorescence was used to label FcεRI so that they could be visualized. The change from baseline is described by the difference (%) between the baseline value, before the first study drug administration, and the value observed at the specified time point, expressed as a percent of the baseline value.

Countries

France

Participant flow

Participants by arm

Arm	Count
Omalizumab Omalizumab was injected subcutaneously every 2 weeks or every 4 weeks for 16 weeks. Dose and dosing interval were determined based on patient body weight and pre-treatment serum IgE level.	20
Placebo Placebo was injected subcutaneously every 2 weeks or every 4 weeks for 16 weeks.	11
Total	31

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	1	2
Overall Study	Protocol Violation	1	1
Overall Study	Withdrawal by Subject	1	0

Baseline characteristics

Characteristic	Omalizumab	Placebo	Total
Age Continuous	45.7 years STANDARD_DEVIATION 13.3	50.6 years STANDARD_DEVIATION 16.31	47.4 years STANDARD_DEVIATION 14.37
Sex: Female, Male Female	14 Participants	5 Participants	19 Participants
Sex: Female, Male Male	6 Participants	6 Participants	12 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	13 / 20	7 / 11
serious Total, serious adverse events	0 / 20	1 / 11

Outcome results

Primary

Change (%) From Baseline in FcεRI (High-affinity IgE Receptor) Expression on Blood Basophils and Dendritic Cells After 16 Weeks of Treatment With Omalizumab as Compared With Placebo

Blood was drawn from participants at baseline and at Week 16. Basophils and dendritic cells expressing FcεRI were counted and the percentage was calculated. Fluorescence was used to label FcεRI so that they could be visualized. The greater the fluorescence intensity the greater FcεRI expression. The change from baseline is described by the difference (%) between the baseline value, before the first study drug administration, and the value observed at the end of study, expressed as a percent of the baseline value.

Time frame: Baseline and Week 16

Population: The Intent-to-treat (ITT) population analyzable for FcεRI expression was a subset of the ITT population and included the 27 participants with accurate measurements before and after 16 weeks of treatment.

Arm	Measure	Group	Value (MEAN)	Dispersion
Omalizumab	Change (%) From Baseline in FcεRI (High-affinity IgE Receptor) Expression on Blood Basophils and Dendritic Cells After 16 Weeks of Treatment With Omalizumab as Compared With Placebo	% Change in Basophils expressing FcεRI	-0.1 percent change in FcεRI expression	Standard Deviation 8.39
Omalizumab	Change (%) From Baseline in FcεRI (High-affinity IgE Receptor) Expression on Blood Basophils and Dendritic Cells After 16 Weeks of Treatment With Omalizumab as Compared With Placebo	% Change in Dendritic cells expressing FcεRI	-5.9 percent change in FcεRI expression	Standard Deviation 27.14
Placebo	Change (%) From Baseline in FcεRI (High-affinity IgE Receptor) Expression on Blood Basophils and Dendritic Cells After 16 Weeks of Treatment With Omalizumab as Compared With Placebo	% Change in Basophils expressing FcεRI	3.9 percent change in FcεRI expression	Standard Deviation 7
Placebo	Change (%) From Baseline in FcεRI (High-affinity IgE Receptor) Expression on Blood Basophils and Dendritic Cells After 16 Weeks of Treatment With Omalizumab as Compared With Placebo	% Change in Dendritic cells expressing FcεRI	14.8 percent change in FcεRI expression	Standard Deviation 22.8

Primary

Change (%) From Baseline in Mean Fluorescence Intensity of FcεRI After 16 Weeks of Treatment With Omalizumab as Compared With Placebo

Blood was drawn from participants at baseline and at week 16. Basophils and dendritic cells expressing FcεRI were counted and the percentage was calculated. Fluorescence was used to label FcεRI so that they could be visualized. The greater the fluorescence intensity the greater FcεRI expression. The change from baseline is described by the difference (%) between the baseline value, before the first study drug administration, and the value observed at the end of study, expressed as a percent of the baseline value.

Time frame: Baseline and Week 16

Arm	Measure	Group	Value (MEAN)	Dispersion
Omalizumab	Change (%) From Baseline in Mean Fluorescence Intensity of FcεRI After 16 Weeks of Treatment With Omalizumab as Compared With Placebo	% Change in Basophil fluorescence intensity	-77.5 percent change in fluorescence intensity	Standard Deviation 20.83
Omalizumab	Change (%) From Baseline in Mean Fluorescence Intensity of FcεRI After 16 Weeks of Treatment With Omalizumab as Compared With Placebo	% Change in Dendritic cell fluorescence intensity	-41.4 percent change in fluorescence intensity	Standard Deviation 36.9
Placebo	Change (%) From Baseline in Mean Fluorescence Intensity of FcεRI After 16 Weeks of Treatment With Omalizumab as Compared With Placebo	% Change in Basophil fluorescence intensity	20.0 percent change in fluorescence intensity	Standard Deviation 76.7
Placebo	Change (%) From Baseline in Mean Fluorescence Intensity of FcεRI After 16 Weeks of Treatment With Omalizumab as Compared With Placebo	% Change in Dendritic cell fluorescence intensity	36.7 percent change in fluorescence intensity	Standard Deviation 101.66

Secondary

Change (%) From Baseline in Percent of Basophils and Dendritic Cells Expressing FcεRI After 4, 8, 12 and 16 Weeks of Treatment

Blood was drawn from a sub-group of participants at weeks 4, 8, 12, and 16. Basophils and dendritic cells expressing FcεRI were counted and the percentage was calculated. Fluorescence was used to label FcεRI so that they could be visualized. The change from baseline is described by the difference (%) between the baseline value, before the first study drug administration, and the value observed at the specified time point, expressed as a percent of the baseline value.

Time frame: Baseline, Weeks 4, 8, 12 and 16

Population: A subset of the ITT population analyzable for FcεRI expression at select sites had repeat measurements of FcεRI expression at all time points.

Arm	Measure	Group	Value (MEAN)	Dispersion
Omalizumab	Change (%) From Baseline in Percent of Basophils and Dendritic Cells Expressing FcεRI After 4, 8, 12 and 16 Weeks of Treatment	% change Basophils expressing FcεRI at Week 4	1.9 percent change in cells expressing FcεRI	Standard Deviation 7.89
Omalizumab	Change (%) From Baseline in Percent of Basophils and Dendritic Cells Expressing FcεRI After 4, 8, 12 and 16 Weeks of Treatment	% change Basophils expressing FcεRI at Week 8	2.5 percent change in cells expressing FcεRI	Standard Deviation 8.6
Omalizumab	Change (%) From Baseline in Percent of Basophils and Dendritic Cells Expressing FcεRI After 4, 8, 12 and 16 Weeks of Treatment	% change Basophils expressing FcεRI at Week 12	3.7 percent change in cells expressing FcεRI	Standard Deviation 23.49
Omalizumab	Change (%) From Baseline in Percent of Basophils and Dendritic Cells Expressing FcεRI After 4, 8, 12 and 16 Weeks of Treatment	% change Basophils expressing FcεRI at Week 16	4.6 percent change in cells expressing FcεRI	Standard Deviation 9.4
Omalizumab	Change (%) From Baseline in Percent of Basophils and Dendritic Cells Expressing FcεRI After 4, 8, 12 and 16 Weeks of Treatment	% change Dendritic cells expressing FcεRI Week 4	-16.1 percent change in cells expressing FcεRI	Standard Deviation 33.54
Omalizumab	Change (%) From Baseline in Percent of Basophils and Dendritic Cells Expressing FcεRI After 4, 8, 12 and 16 Weeks of Treatment	% change Dendritic cells expressing FcεRI Week 8	-1.9 percent change in cells expressing FcεRI	Standard Deviation 14.66
Omalizumab	Change (%) From Baseline in Percent of Basophils and Dendritic Cells Expressing FcεRI After 4, 8, 12 and 16 Weeks of Treatment	% change Dendritic cells expressing FcεRI Week 12	-10.3 percent change in cells expressing FcεRI	Standard Deviation 19.62
Omalizumab	Change (%) From Baseline in Percent of Basophils and Dendritic Cells Expressing FcεRI After 4, 8, 12 and 16 Weeks of Treatment	% change Dendritic cells expressing FcεRI Week 16	-9.8 percent change in cells expressing FcεRI	Standard Deviation 11.07
Placebo	Change (%) From Baseline in Percent of Basophils and Dendritic Cells Expressing FcεRI After 4, 8, 12 and 16 Weeks of Treatment	% change Dendritic cells expressing FcεRI Week 16	23.0 percent change in cells expressing FcεRI	Standard Deviation 24.7
Placebo	Change (%) From Baseline in Percent of Basophils and Dendritic Cells Expressing FcεRI After 4, 8, 12 and 16 Weeks of Treatment	% change Basophils expressing FcεRI at Week 4	-5.2 percent change in cells expressing FcεRI	Standard Deviation 8.46
Placebo	Change (%) From Baseline in Percent of Basophils and Dendritic Cells Expressing FcεRI After 4, 8, 12 and 16 Weeks of Treatment	% change Dendritic cells expressing FcεRI Week 4	-4.7 percent change in cells expressing FcεRI	Standard Deviation 17.73
Placebo	Change (%) From Baseline in Percent of Basophils and Dendritic Cells Expressing FcεRI After 4, 8, 12 and 16 Weeks of Treatment	% change Basophils expressing FcεRI at Week 8	0.9 percent change in cells expressing FcεRI	Standard Deviation 1.49
Placebo	Change (%) From Baseline in Percent of Basophils and Dendritic Cells Expressing FcεRI After 4, 8, 12 and 16 Weeks of Treatment	% change Dendritic cells expressing FcεRI Week 12	-2.8 percent change in cells expressing FcεRI	Standard Deviation 27.98
Placebo	Change (%) From Baseline in Percent of Basophils and Dendritic Cells Expressing FcεRI After 4, 8, 12 and 16 Weeks of Treatment	% change Basophils expressing FcεRI at Week 12	-6.4 percent change in cells expressing FcεRI	Standard Deviation 11.92
Placebo	Change (%) From Baseline in Percent of Basophils and Dendritic Cells Expressing FcεRI After 4, 8, 12 and 16 Weeks of Treatment	% change Dendritic cells expressing FcεRI Week 8	6.2 percent change in cells expressing FcεRI	Standard Deviation 7.03
Placebo	Change (%) From Baseline in Percent of Basophils and Dendritic Cells Expressing FcεRI After 4, 8, 12 and 16 Weeks of Treatment	% change Basophils expressing FcεRI at Week 16	-1.4 percent change in cells expressing FcεRI	Standard Deviation 3.29

Secondary

Change (%) From Baseline in the Mean Fluorescence Intensity of FcεRI After 4, 8, 12 and 16 Weeks of Treatment

Time frame: Baseline, Weeks 4, 8, 12, and 16

Population: A subset of the ITT population analyzable for FcεRI expression at select sites had repeat measurements of FcεRI expression at all time points.

Arm	Measure	Group	Value (MEAN)	Dispersion
Omalizumab	Change (%) From Baseline in the Mean Fluorescence Intensity of FcεRI After 4, 8, 12 and 16 Weeks of Treatment	% change on basophils at Week 4	-85.1 % change in fluorescence intensity	Standard Deviation 6.09
Omalizumab	Change (%) From Baseline in the Mean Fluorescence Intensity of FcεRI After 4, 8, 12 and 16 Weeks of Treatment	% change on basophils at Week 8	-81.0 % change in fluorescence intensity	Standard Deviation 9.08
Omalizumab	Change (%) From Baseline in the Mean Fluorescence Intensity of FcεRI After 4, 8, 12 and 16 Weeks of Treatment	% change on basophils at Week 12	-86.8 % change in fluorescence intensity	Standard Deviation 6.36
Omalizumab	Change (%) From Baseline in the Mean Fluorescence Intensity of FcεRI After 4, 8, 12 and 16 Weeks of Treatment	% change on basophils at Week 16	-88.6 % change in fluorescence intensity	Standard Deviation 4.39
Omalizumab	Change (%) From Baseline in the Mean Fluorescence Intensity of FcεRI After 4, 8, 12 and 16 Weeks of Treatment	% change on dendritic cells at Week 4	-38.6 % change in fluorescence intensity	Standard Deviation 42.76
Omalizumab	Change (%) From Baseline in the Mean Fluorescence Intensity of FcεRI After 4, 8, 12 and 16 Weeks of Treatment	% change on dendritic cells at Week 8	-27.1 % change in fluorescence intensity	Standard Deviation 40.13
Omalizumab	Change (%) From Baseline in the Mean Fluorescence Intensity of FcεRI After 4, 8, 12 and 16 Weeks of Treatment	% change on dendritic cells at Week 12	-31.2 % change in fluorescence intensity	Standard Deviation 60.61
Omalizumab	Change (%) From Baseline in the Mean Fluorescence Intensity of FcεRI After 4, 8, 12 and 16 Weeks of Treatment	% change on dendritic cells at Week 16	-49.2 % change in fluorescence intensity	Standard Deviation 30.21
Placebo	Change (%) From Baseline in the Mean Fluorescence Intensity of FcεRI After 4, 8, 12 and 16 Weeks of Treatment	% change on dendritic cells at Week 16	47.1 % change in fluorescence intensity	Standard Deviation 92.44
Placebo	Change (%) From Baseline in the Mean Fluorescence Intensity of FcεRI After 4, 8, 12 and 16 Weeks of Treatment	% change on basophils at Week 4	-45.8 % change in fluorescence intensity	Standard Deviation 41.14
Placebo	Change (%) From Baseline in the Mean Fluorescence Intensity of FcεRI After 4, 8, 12 and 16 Weeks of Treatment	% change on dendritic cells at Week 4	-36.6 % change in fluorescence intensity	Standard Deviation 27.95
Placebo	Change (%) From Baseline in the Mean Fluorescence Intensity of FcεRI After 4, 8, 12 and 16 Weeks of Treatment	% change on basophils at Week 8	-11.5 % change in fluorescence intensity	Standard Deviation 40.83
Placebo	Change (%) From Baseline in the Mean Fluorescence Intensity of FcεRI After 4, 8, 12 and 16 Weeks of Treatment	% change on dendritic cells at Week 12	-14.1 % change in fluorescence intensity	Standard Deviation 55.42
Placebo	Change (%) From Baseline in the Mean Fluorescence Intensity of FcεRI After 4, 8, 12 and 16 Weeks of Treatment	% change on basophils at Week 12	-24.2 % change in fluorescence intensity	Standard Deviation 60.18
Placebo	Change (%) From Baseline in the Mean Fluorescence Intensity of FcεRI After 4, 8, 12 and 16 Weeks of Treatment	% change on dendritic cells at Week 8	-12.2 % change in fluorescence intensity	Standard Deviation 42.56
Placebo	Change (%) From Baseline in the Mean Fluorescence Intensity of FcεRI After 4, 8, 12 and 16 Weeks of Treatment	% change on basophils at Week 16	54.2 % change in fluorescence intensity	Standard Deviation 11.71

Secondary

Change From Baseline in the Morning Daily Peak Expiratory Flow (PEF)

Peak Expiratory Flow (PEF) was measured every morning using a peak flow meter, and was recorded in the patient diary. For this analysis, the mean morning PEF during the 4-week screening period prior to randomizaton is compared with the mean morning PEF during the last 4 weeks of study treatment (Weeks 12 - 16).

Time frame: Baseline (the 4 week screening period prior to randomization) and End of Study (Weeks 12 - 16)