Effect of Symbicort on GR Localisation in Asthma

• Sponsor: Imperial College London (Other)
• Overall Status: Completed
• CT.gov ID: NCT00159263
• Collaborator: AstraZeneca (Industry)
• Enrollment: 10
• Location: 1
• Arms: 6
• Actual Duration (Months): 24
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

To investigate a possible interaction between formoterol and budesonide on GR-translocation and to compare the effect of different doses of Symbicort (80/4.5 and 2x80/4.5 mcg) with the effect of budesonide (200 mcg and 800 mcg) on GR translocation, and to investigate the effect of the study drugs on exhaled NO (bronchial and alveolar fraction.

Condition or Disease	Intervention/Treatment	Phase
Asthma	Drug: Placebos; Drug: Formoterol Inhalant Powder; Drug: Budesonide Powder; Drug: Budesonide and Formoterol Product	N/A

Detailed Description

Combination therapy with inhaled corticosteroids (ICS) and long-acting β(2)-adrenergic agonists (LABA) is reported to have superior effects on controlling asthma symptoms to ICS alone; however, there is no molecular-based evidence to explain the clinical effects. Here, the effect of the ICS/LABA combination was compared with ICS on glucocorticoid receptor (GR) activation in sputum macrophage.

In a randomised, double-blind cross-over placebo-controlled 6-visit study, 10 patients with mild asthma were given placebo, formoterol (Oxis(®) 12 μg), budesonide (Pulmicort(®) 200 μg :BUD200, or 800 μg :BUD800), or budesonide/formoterol combination (Symbicort(®)) as a single 100/6 μg (SYM100) or double 200/12 μg (SYM200) dose. Sputum macrophages were separated by plate adhesion from induced sputum. GR binding to the glucocorticoid-response elements on oligonucleotides (GR-GRE binding) was evaluated by ELISA. mRNA expression of MAP-kinase phosphatase (MKP)-1 and IL-8 were measured by quantitative RT-PCR.

Study Design

• Study Type: Interventional
• Actual Enrollment: 10 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Basic Science
• Official Title: Effect of Symbicort on GR (Glucocorticoid Receptor) Translocation in Induced Sputum in Comparison With Budesonide, Formoterol and Placebo. A Single Dose Exploratory Study in Patients With Mild Asthma
• Actual Study Start Date: Nov 1, 2004
• Actual Primary Completion Date: Nov 1, 2006
• Actual Study Completion Date: Nov 1, 2006

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo placebo	Drug: Placebos; Dry powder inhaler
Experimental: Formoterol Oxis(®) 12 μg	Drug: Formoterol Inhalant Powder; 12ug; Other Names: Oxis
Experimental: Budesonide low dose Pulmicort(®) 200 μg	Drug: Budesonide Powder; Inhaler; Other Names: Pulmicort
Experimental: Budesonide high dose Pulmicort(®) 800 μg	Drug: Budesonide Powder; Inhaler; Other Names: Pulmicort
Experimental: Budesonide/formoterol combination single single 100/6 μg SYM100	Drug: Budesonide and Formoterol Product; Combination Inhaler, Symbicort; Other Names: Combination Inhaler, Symbicort
Experimental: Budesonide/formoterol combination double double 200/12 μg SYM200	Drug: Budesonide and Formoterol Product; Combination Inhaler, Symbicort; Other Names: Combination Inhaler, Symbicort

Outcome Measures

Primary Outcome Measures

1. Changes in GR-GRE Binding [1-2h]

   The GR-GRE binding is the glucocorticoid receptor (GR) DNA binding affinity. GR-GRE activity as assed by enzyme-immunosorbent assay

2. Changes in MKP-1 mRNA [1-2h]

   Changes in MKP-1 mRNA measured by PCR

3. IL8 mRNA [1-2h]

   Measured by PCR

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients with mild steroid-naïve asthma (ATS criteria) of either sex with FEV1 >70 % pred

• Able to produce sputum after sputum induction

• Exhaled NO (flow 50 ml/s) ≥ 20 ppb

• Written informed consent

Exclusion Criteria:

• Current upper respiratory tract infections

• Use of inhaled and/or oral GCS within 4 weeks prior to visit 1

• Treatment with antileukotrienes, theophylline, tiotropium and ipratropium within 2 weeks prior to screening visit

• Hypersensitivity to any of the investigational drugs or lactose

• Use of any beta blocking agent (including eye-drops)

• Women who are pregnant, breast-feeding or planning a pregnancy during the study. Women must be postmenopausal (at least one year must have passed after the last menstruation), surgically sterile or using acceptable contraceptives, as judged by the investigator

• Any significant disease or disorder (e.g. cardiovascular, pulmonary (other than asthma), gastrointestinal, liver, renal, neurological, musculoskeletal, endocrine, metabolic, malignant, psychiatric, major physical impairment) which, in the opinion of the investigator, may either put the subject at risk because of participation in the study, or may influence the results of the study, or the subjects ability to participate in the study

• Inability to tolerate temporary withdrawal of bronchodilatory therapy

• Subjects not considered capable, as judged by the investigator, of following instructions of the study, e.g. because of a history of alcohol or drug abuse or any other reason

• Previous randomization in this study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Section of Airway Disease, Asthma Lab, Imperial College London, Royal Brompton Hospital	London		United Kingdom

Sponsors and Collaborators

• Imperial College London
• AstraZeneca

Investigators

• Principal Investigator: Sergei A Kharitonov, MD PhD, Imperial College London

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Imperial College London
• ClinicalTrials.gov Identifier: NCT00159263
• Other Study ID Numbers: BU-039-0005
• First Posted: Sep 12, 2005
• Last Update Posted: Sep 27, 2019
• Last Verified: Sep 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Imperial College London: Asthma; Glucocorticoid; Long-acting beta2-adrenoceptor; Inhaled corticosteroids
• Additional relevant MeSH terms: Asthma; Budesonide; Formoterol Fumarate

Study Results

Participant Flow

Recruitment Details	10patient recruited mild asthma

Arm/Group Title	Placebo	Formoterol	Budesonide Low Dose	Budesonide High Dose	Budesonide/Formoterol Single	Budesonide/Formoterol Double
Arm/Group Description	first intervention is placebo, then Formoterol, then Budesonide low dose, then Budesonide high dose, then Budesonide/Formoterol single, then Budesonide/Formoterol double	First intervention is formoterol, then placebo, then Budesonide low dose, then Budesonide high dose, then Budesonide/Formoterol single, then Budesonide/Formoterol double	First intervention is Budesonide low dose, then placebo, then Formoterol, then Budesonide high dose, then Budesonide/Formoterol single, then Budesonide/Formoterol double	First intervention is Budesonide high dose, then placebo, then Formoterol, then Budesonide low dose, then Budesonide/Formoterol single, then Budesonide/Formoterol double	First intervention is Budesonide/Formoterol single, then placebo, then Formoterol, then Budesonide low dose, then Budesonide high dose, then Budesonide/Formoterol double	First intervention is Budesonide/Formoterol double, then placebo, then Formoterol, then Budesonide low dose, then Budesonide high dose, then Budesonide/Formoterol single
Period Title: First Intervention
STARTED	1	1	2	2	2	2
COMPLETED	1	1	2	2	2	2
NOT COMPLETED	0	0	0	0	0	0
Period Title: First Intervention
STARTED	1	1	2	2	2	2
COMPLETED	1	1	2	2	2	2
NOT COMPLETED	0	0	0	0	0	0
Period Title: First Intervention
STARTED	1	1	2	2	2	2
COMPLETED	1	1	2	2	2	2
NOT COMPLETED	0	0	0	0	0	0
Period Title: First Intervention
STARTED	1	1	2	2	2	2
COMPLETED	1	1	2	2	2	2
NOT COMPLETED	0	0	0	0	0	0
Period Title: First Intervention
STARTED	1	1	2	2	2	2
COMPLETED	1	1	2	2	2	2
NOT COMPLETED	0	0	0	0	0	0
Period Title: First Intervention
STARTED	1	1	2	2	2	2
COMPLETED	1	1	2	2	2	2
NOT COMPLETED	0	0	0	0	0	0
Period Title: First Intervention
STARTED	1	1	2	2	2	2
COMPLETED	1	1	2	2	2	2
NOT COMPLETED	0	0	0	0	0	0
Period Title: First Intervention
STARTED	1	1	2	2	2	2
COMPLETED	1	1	2	2	2	2
NOT COMPLETED	0	0	0	0	0	0
Period Title: First Intervention
STARTED	1	1	2	2	2	2
COMPLETED	1	1	2	2	2	2
NOT COMPLETED	0	0	0	0	0	0
Period Title: First Intervention
STARTED	1	1	2	2	2	2
COMPLETED	1	1	2	2	2	2
NOT COMPLETED	0	0	0	0	0	0
Period Title: First Intervention
STARTED	1	1	2	2	2	2
COMPLETED	1	1	2	2	2	2
NOT COMPLETED	0	0	0	0	0	0

Baseline Characteristics

Arm/Group Title	Overall Study
Arm/Group Description	Crossover study, same volunteers in all arm, received the following interventions: formoterol, Budesonide low and high dose, or combination of these
Overall Participants	10
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	33 (3)
Sex: Female, Male (Count of Participants)
Female	6 60%
Male	4 40%
Race and Ethnicity Not Collected (Count of Participants)
Region of Enrollment (participants) [Number]
United Kingdom	10 100%

Outcome Measures

1. Primary Outcome

Title	Changes in GR-GRE Binding
Description	The GR-GRE binding is the glucocorticoid receptor (GR) DNA binding affinity. GR-GRE activity as assed by enzyme-immunosorbent assay
Time Frame	1-2h

Outcome Measure Data

Analysis Population Description

Crossover, each patient had all treatments

Arm/Group Title	Placebo	Formoterol	Budesonide Low Dose	Budesonide High Dose	Budesonide/Formoterol Combination Single	Budesonide/Formoterol Combination Double
Arm/Group Description	placebo Placebos: Dry powder inhaler	Oxis(®) 12 μg Formoterol Inhalant Powder: 12ug	Pulmicort(®) 200 μg Budesonide Powder: Inhaler	Pulmicort(®) 800 μg Budesonide Powder: Inhaler	single 100/6 μg SYM100 Budesonide and Formoterol Product: Combination Inhaler, Symbicort	double 200/12 μg SYM200 Budesonide and Formoterol Product: Combination Inhaler, Symbicort
Measure Participants	10	10	10	10	10	10
Median (Inter-Quartile Range) [GRE activity (OD)]	1.4	1.4	1.6	2.3	3.5	3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Budesonide/Formoterol Combination Single
	Comments
	Type of Statistical Test	Other
	Comments	Friedman ANOVA followed Dunn's pairwise comparisons
Statistical Test of Hypothesis	p-Value	0.04
	Comments
	Method	ANOVA
	Comments

2. Primary Outcome

Title	Changes in MKP-1 mRNA
Description	Changes in MKP-1 mRNA measured by PCR
Time Frame	1-2h

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Formoterol	Budesonide Low Dose	Budesonide High Dose	Budesonide/Formoterol Combination Single	Budesonide/Formoterol Combination Double
Arm/Group Description	placebo Placebos: Dry powder inhaler	Oxis(®) 12 μg Formoterol Inhalant Powder: 12ug	Pulmicort(®) 200 μg Budesonide Powder: Inhaler	Pulmicort(®) 800 μg Budesonide Powder: Inhaler	single 100/6 μg SYM100 Budesonide and Formoterol Product: Combination Inhaler, Symbicort	double 200/12 μg SYM200 Budesonide and Formoterol Product: Combination Inhaler, Symbicort
Measure Participants	10	10	10	10	10	10
Median (Inter-Quartile Range) [MKP1/GNB2L1 ratio]	1	3	3	4	5	5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Budesonide/Formoterol Combination Double
	Comments
	Type of Statistical Test	Other
	Comments	Friedman Anova
Statistical Test of Hypothesis	p-Value	0.01
	Comments
	Method	ANOVA
	Comments

3. Primary Outcome

Title	IL8 mRNA
Description	Measured by PCR
Time Frame	1-2h

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Formoterol	Budesonide Low Dose	Budesonide High Dose	Budesonide/Formoterol Combination Single	Budesonide/Formoterol Combination Double
Arm/Group Description	placebo Placebos: Dry powder inhaler	Oxis(®) 12 μg Formoterol Inhalant Powder: 12ug	Pulmicort(®) 200 μg Budesonide Powder: Inhaler	Pulmicort(®) 800 μg Budesonide Powder: Inhaler	single 100/6 μg SYM100 Budesonide and Formoterol Product: Combination Inhaler, Symbicort	double 200/12 μg SYM200 Budesonide and Formoterol Product: Combination Inhaler, Symbicort
Measure Participants	10	10	10	10	10	10
Median (Inter-Quartile Range) [IL8/GNB2L1 ratio]	1	4	4	0.4	0.2	0.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Budesonide/Formoterol Combination Double
	Comments
	Type of Statistical Test	Other
	Comments	Friedman Anova
Statistical Test of Hypothesis	p-Value	0.04
	Comments
	Method	ANOVA
	Comments

Adverse Events

Time Frame	1 year
Arm/Group Title	Placebo		Formoterol		Budesonide Low Dose		Budesonide High Dose		Budesonide/Formoterol Single		Budesonide/Formoterol Double
Arm/Group Description	Patients who received placebo treatment		Patients who received Formoterol treatment		Patients who received Budesonide low dose treatment		Patients who received Budesonide high dose treatment		Patients who received Budesonide/Formoterol single dose treatment		Patients who received Budesonide/Formoterol double dose treatment
All Cause Mortality
	Placebo		Formoterol		Budesonide Low Dose		Budesonide High Dose		Budesonide/Formoterol Single		Budesonide/Formoterol Double
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)		0/10 (0%)		0/10 (0%)		0/10 (0%)		0/10 (0%)
Serious Adverse Events
	Placebo		Formoterol		Budesonide Low Dose		Budesonide High Dose		Budesonide/Formoterol Single		Budesonide/Formoterol Double
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)		0/10 (0%)		0/10 (0%)		0/10 (0%)		0/10 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Formoterol		Budesonide Low Dose		Budesonide High Dose		Budesonide/Formoterol Single		Budesonide/Formoterol Double
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)		0/10 (0%)		0/10 (0%)		0/10 (0%)		0/10 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.