Effects of Particle Size in Small Airways Dysfunction (MAN03)

U

University of Dundee

Status and phase

Completed
Phase 4

Conditions

Asthma

Treatments

Drug: Formoterol
Drug: Salmeterol

Study type

Interventional

Funder types

Other
Industry

Identifiers

NCT01892787
13/ES/0050 (Other Identifier)
2013-001103-36 (EudraCT Number)
2013RC01

Details and patient eligibility

About

The airways in the lungs get smaller the further into the lungs they go. Most simple measurements of lung function only reflect the larger 'central' airways and do not provide information on the smaller 'peripheral' airways. Newer measurements have been developed that can now give us accurate information on how the smaller airways are working. Indeed the small airways seem to play a significant role in asthma in terms of inflammation and airway narrowing. Recently, new types of inhaler formulations have been developed that have a much smaller particle size than other standard formulations. These formulations have been shown to go further into the lungs, thus getting into the smaller airways. In this study we aim to compare the two extremes of available long acting beta agonists in terms of particle size i.e. extra fine formoterol (Atimos) versus coarse particle salmeterol (Serevent)in asthmatics with abnormal small airway function using a breathing test called impulse oscillometry. By using this test we will be able to find out whether using an extrafine particle inhaler improves small airway function.

Full 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)

Enrollment

17 patients

Sex

All

Ages

16+ years old

Volunteers

No Healthy Volunteers

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

Trial design

Primary purpose

Treatment

Allocation

Randomized

Interventional model

Crossover Assignment

Masking

None (Open label)

17 participants in 2 patient groups

Formoterol (Atimos Modulite)
Experimental group
Description:
Atimos Modulite 1 puff (12 micrograms) twice a day
Treatment:
Drug: Formoterol
Salmeterol (Serevent Accuhaler)
Active Comparator group
Description:
Serevent Accuhaler 1 puff (50 micrograms) of twice a day
Treatment:
Drug: Salmeterol

Trial contacts and locations

1

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Data sourced from clinicaltrials.gov

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