- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01892787
Effects of Particle Size in Small Airways Dysfunction (MAN03)
Randomised Controlled Single and Chronic Dosing Crossover Comparison of Extra Fine Particle Formoterol and Coarse Particle Salmeterol in Asthmatic Patients With Persistent Small Airways Dysfunction
Study Overview
Detailed Description
The small airways are gaining greater recognition for their role in the pathophysiology of persistent asthma and as a relevant target for asthma treatment(1). Pathological abnormalities in the small airways have been demonstrated regardless of asthma severity and seem to persist even in patients with stable asthma(2, 3).
Historically, the small airways have been difficult to assess. Spirometry generally reflects large airways function although the mean forced expiratory flow (FEF) between 25% and 75% of FVC (FEF25-75) has been used to assess small airway obstruction.(4) More recently, impulse oscillometry (IOS) has been used to assess the role of small airways in asthma(5). IOS is an effort-independent test, using oscillation of differing sound waves to derive a variety of output measurements determining both the degree of total and peripheral airway resistance. Resistance at 5 Hz reflects total airway resistance and central airway resistance is approximated using resistance at 20 Hz (R20). The peripheral or small airway component can thus be evaluated by calculating the difference between these two measurements i.e. R5 - R20.
We have identified from our database of primary care referrals, a cohort of patients who appear to have evidence of an unmet physiological need in terms of persistent small airways dysfunction, on the basis of impairment of R5 and R5-R20 despite taking step 2/3/4 asthma treatment(6). Approximately 32% of patients across steps 2/3/4 had severely abnormal values for both R5-R20 (>0.05 kPa/L.s) and R5 (> 150%). Such small airway dysfunction at step 3/4 occurred despite patients being prescribed ICS with LABA, although there were no patients being prescribed extra fine ICS/LABA or extra fine LABA (i.e. Fostair or Atimos). In terms of the ICS moiety, observational data has shown that patients taking extra fine HFA-beclometasone solution (Qvar) have equal or better control than those taking Fluticasone suspension, while receiving a lower maintenance dose of ICS(7). In another study, patients switched from beclometasone suspension to solution at half the dose had an improvement in asthma quality of life. In neither of these studies was there any information available regarding small airway dysfunction in order to explain the potential improvements with HFA-beclometasone(8).
There is a paucity of information on the potential benefits of extra fine formoterol on the small airways. In a single dosing study comparing extra fine HFA versus coarse particle dry powder formulations of formoterol, there was a 30% difference (absolute difference of 2.9 kPa/L.s.min)in R5 AUC0-60min and 63% difference (absolute difference of 2.4 kPa/L.s.min) in R5-R20 AUC0-60min, although this was not the primary end point(9).
1.2 RATIONALE Thus, the primary objective for the present study is to compare the two extremes of available long acting beta-agonist formulations - i.e. extra fine HFA formoterol ( Atimos ) versus coarse particle DPI salmeterol (i.e. Serevent Accuhaler). If there turns out to be a significant improvement in small airways function conferred by extra fine formoterol, then this would in turn support the rationale for performing a further chronic study to assess the clinical impact of treating persistent small airways dysfunction at step 3/4 by switching patients to Fostair HFA and comparing to Seretide DPI, in terms of improving asthma control in patients with the small airway phenotype who are already taking conventional ICS/LABA formulations. We will use impulse oscillometry to assess the small airways response using the difference between resistance measured at 5Hz and 20Hz (R5-R20) as the primary outcome. In this regard we have previously reported in asthmatic patients receiving propranolol that there was a 104.1 % (95%CI 22.6-185.6%) worsening of R5-R20 in terms of the bronchoconstrictor response to propranolol, and following subsequent histamine challenge, there was a 115.6 % (95%CI 55.6-175.7% ) improvement in R5-R20 in terms of the bronchodilator response to nebulised salbutamol.(10)
Study Type
Enrollment (Actual)
Phase
- Phase 4
Contacts and Locations
Study Locations
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-
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Dundee, United Kingdom, DD1 3AU
- Brian Lipworth
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Male or female volunteers aged at least 16 years with a diagnosis of asthma
- Persistent severe small airways dysfunction on impulse oscillometry with R5 > 150% and R5-R20 > 0.05 kPa/L.s despite taking ICS or inhaled corticosteroids / long-acting beta-agonists
- FEV1 > 60 %
- Ability to give informed consent
- Agreement for their GP to be made aware of study participation and to receive feedback as relevant to the participant's well being
Exclusion Criteria:
- Participants already receiving extra-fine particle long-acting beta agonists
- Other respiratory diseases such as chronic obstructive pulmonary disease, bronchiectasis or alergic allergic bronchopulmonary aspergillosis
- An asthma exacerbation or respiratory tract infection requiring systemic steroids and/or antibiotics within 3 months of the study commencement
- Smoking within one year or 10 pack year history
- Any clinically significant medical condition that may endanger the health or safety of the participant
- Participation in another trial within 30 days before the commencement of the study
- Pregnancy or lactation
Study Plan
How is the study designed?
Design Details
- Primary Purpose: TREATMENT
- Allocation: RANDOMIZED
- Interventional Model: CROSSOVER
- Masking: NONE
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
EXPERIMENTAL: Formoterol (Atimos Modulite)
Atimos Modulite 1 puff (12 micrograms) twice a day
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Participants receive Atimos for 1 to 2 weeks.Partcipants then enter a washout period and after the washout period receive the alternative treatment arm.
Other Names:
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ACTIVE_COMPARATOR: Salmeterol (Serevent Accuhaler)
Serevent Accuhaler 1 puff (50 micrograms) of twice a day
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Participants receive Serevent for 1 to 2 weeks.
Participants then enter a washout period and after the washout period receive the alternative treatment arm.
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change in R5-R20 as change from baseline after first and last dose
Time Frame: At baseline & after 1-2 weeks
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R5 - Resistance at 5Hz, R20 - Resistance at 20Hz
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At baseline & after 1-2 weeks
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change in remaining impulse oscillometry variables (R5,R20,X5,AX,RF) after first and last dose
Time Frame: Baseline and after 1-2 weeks
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R5 - Resistance at 5Hz, R20 - Resistance at 20Hz, X5 - Reactance at 5Hz, RF - Frequency of resonance, AX - Area under reactance curve
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Baseline and after 1-2 weeks
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Area under the curve from 0 to 60 min
Time Frame: Baseline and 1-2 weeks
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Baseline and 1-2 weeks
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Spirometry
Time Frame: Baseline & 1-2 weeks
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Forced expiratory volume in 1 second (FEV1); forced vital capacity (FVC); forced expriatory flow between 25-75% of vital capacity.
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Baseline & 1-2 weeks
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Domiciliary peak expiratory flow
Time Frame: 1-2 weeks
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1-2 weeks
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Asthma Control Questionnaire
Time Frame: 1-2 weeks
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1-2 weeks
|
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Exhaled nitirc oxide
Time Frame: 2 weeks
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2 weeks
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Collaborators and Investigators
Sponsor
Collaborators
Publications and helpful links
Study record dates
Study Major Dates
Study Start
Primary Completion (ACTUAL)
Study Completion (ACTUAL)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (ESTIMATE)
Study Record Updates
Last Update Posted (ACTUAL)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
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
- Salmeterol Xinafoate
- Formoterol Fumarate
Other Study ID Numbers
- 2013RC01
- 2013-001103-36 (EUDRACT_NUMBER)
- 13/ES/0050 (OTHER: East of Scotland Research Ethics Service REC2)
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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