Targeted Small Airways Therapy in Persistent Asthma
Condition: Asthma
MeSH terms: Asthma
Study type: Interventional
Phase: Phase 4

Summary: 
      The mainstay of asthma treatment is with inhaled steroids (commonly called a 'preventer') to
      keep the symptoms of asthma under control. Increasing strengths of steroid inhaler may be
      required in order to gain control of asthma, and this is usually guided both by symptoms and
      simple measurements of lung function such as peak flow.

      The airways (breathing tubes) 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 don't
      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 steroid inhalers have been developed that have a much smaller particle
      size than other standard inhaled steroids.These have been shown to go deeper into the lungs,
      thus getting into the smaller airways. There have been a few studies suggesting that this
      might improve asthma control. However, we do not know if when small airway function is shown
      to be abnormal, whether this improves with extra-fine particle inhaled steroids, nor whether
      by improving small airway function specifically this translates into improved asthma control.

      In this study we wish to study asthmatic patients who are not completely controlled on
      standard particle size inhaled steroids, in addition to having evidence of abnormal small
      airway function. By doing this we want to find out whether changing to the same dose of an
      extra-fine particle inhaled steroid instead will improve asthma control by getting deeper
      into the lungs and improving small airway function.
    

Detailed description: 
      A single centre, open-label, single subject study over a 12-24 week period. Invited
      participants will receive a written 'Participant Information Sheet' (PIS) detailing the
      requirements of the trial and the extent of their participation before attending for a
      screening visit. Participants will be given at least 24 hours to read the PIS.

      Prior to screen (and any subsequent challenge visit) participants will withhold LABAs (or
      combination inhaler containing LABA) for 48 hours; and salbutamol for 6 hours. Verbal consent
      will be obtained from the patient over the telephone for withholding medications prior to
      screen and it will be explained that this in no way means they have consented to the full
      study at this stage.

      At the screening visit a member of the research team will discuss the PIS with the
      participant, answer any questions posed and written informed consent will be obtained and
      witnessed by the member of staff asking for the consent of the patient.

      A general physical examination will be carried out by a qualified medical practitioner.

      A pregnancy test will be performed on all female patients with advice issued to both male and
      female participants to use contraception throughout the duration of the study.

      The following will be measured:

        -  Asthma Control Questionnaire

        -  Mini-Asthma Quality of Life Questionnaire

        -  Fractional exhaled nitric oxide levels

        -  Impulse oscillometry

        -  Spirometry

        -  Skin prick test to common allergens

        -  Full blood count, renal function, electrolytes, liver enzymes and random blood glucose.

      Participants will be checked against all inclusion and exclusion criteria. Those found to be
      eligible will proceed to the step down and/or run-in period. This will last for a minimum of
      4 weeks.

      Participants will be issued with a pre-labelled container for the collection of an overnight
      urine sample the night prior to visit V1 with written instruction as to how this should be
      done. A sample will be collected prior to visits V2 and V3 as well.

      If a potential participant who at screening is receiving ≥200µg/day ICS (BDP) without
      additional LABA has an ACQ >1.0 they will directly enter the 4 week run-in period.

      At 2 weeks into the run-in period the participant will be contacted to reassess their ACQ
      score. If their ACQ>1.0 they will continue in the run-in period for the remaining 2 weeks at
      the same dose of ICS. If their ACQ is not >1.0 then their ICS dose will be approximately
      halved (or reduced to a minimum of 200µg/day if this is greater than half the original ICS
      dose) and one (if any) second line medication (e.g. theophylline, LTRA) will be discontinued
      at the discretion of a study doctor. They will then restart the 4 week run-in period. If they
      are already receiving 200µg/day ICS (i.e. the dose cannot be reduced further) then they will
      be withdrawn from the study at this juncture.

      At the end of the 4 week period if the participant still has an ACQ>1.0 they will proceed to
      visit V1.

      If a potential participant who at screening is receiving ≥200µg/day ICS (BDP) with additional
      LABA has an ACQ score >1.0, their LABA will be discontinued and they will directly enter the
      4 week run-in period. If the participant is receiving their LABA as part of a combination
      inhaler, they will be converted to an equivalent ICS alone inhaler (i.e. coarse particle ICS)
      and enter the 4 week run-in period. Progress through run-in will then be as described before.

      If a potential participant who at screening is receiving ≥200µg/day ICS (BDP) with additional
      LABA has an ACQ not >1.0, then their LABA will be discontinued as per 3.6.2 and their ICS
      dose will be approximately halved (or reduced to a minimum of 200µg/day if this is greater
      than half the original ICS dose). For example, Seretide 250µg b.i.d. would convert to
      Flixotide 125µg b.i.d. They will subsequently enter the 4 week run-in period progressing
      through it as described..

      Participants will be asked to perform and record twice daily domiciliary PEF and to complete
      a daily diary of reliever use and symptoms from the beginning of the step-down/run-in period
      through to the end of the study. Participants will be advised to contact the investigators if
      they feel their asthma significantly worsening in the interim. They will also be given a card
      with 24 hour emergency contact details.

      At the end of the 4 week run-in period, participants will be checked against all inclusion
      and exclusion criteria to confirm the subject's suitability to receive the study drug
      according to study protocol. Those eligible will proceed to study visit 1. Those who do not
      fulfil the study criteria will be returned to their pre-study medication and their GP
      informed of any medically relevant data.

      Study visits V1, V2 and V3 Full study visits will occur at the end of the run-in period
      (baseline), at 4 weeks and 8 weeks.

      Participants will be asked to withhold their reliever as per the screening visit. (LABAs are
      withheld for the duration of the study).

      Participants will attend the unit on the morning of the visit day. The overnight urine
      collection will be received from the participant for analysis.

      Peak flow records will be reviewed along with daily domiciliary symptom and reliever use
      diaries.

      Participants will be asked to complete an ACQ and Mini-AQLQ. A venous blood sample will be
      drawn for FBC. A venous blood sample will be drawn for ECP. FeNO, IOS, and spirometry will be
      performed in that order. Mannitol bronchial challenge will then be performed

      Participants will be converted to Qvar (HFA-beclometasone) at an equivalent therapeutic dose
      to their original ICS, e.g. Qvar 100µg = Clenil 200µg = Pulmicort 200µg = Flixotide 100µg =
      Asmanex 100µg. A Qvar 50µg or 100µg inhaler will be used to achieve this based on the dose
      requirement. An approximately equivalent inhaler device to the one the patient had been
      originally using will be used. Equally if the participant normally used a spacer device with
      their ICS, this will be provided to use with a Qvar pMDI.

      A Participant Instruction and Appointment Leaflet will be issued, detailing:

      Emergency contact numbers How to perform PEF How to write in the diary Record adverse events
      and concomitant medication use Withholding times for drugs The Patient Instruction Leaflet
      will be discussed fully with the subject and any questions answered

      Participants will be issued with a pre-labelled container for the collection of an overnight
      urine sample the night prior to visits V2 and V3 respectively, with written instruction as to
      how this should be done.

      Visit 2 (V2): Sections 3.7.2 to 3.7.10 and 3.7.13 will be repeated. Visit 3 (V3): Sections
      3.7.2 to 3.7.10 will be repeated. The study will end at this point with the patient returned
      to their prescribed medications.
    

Intervention name(s): Qvar® (beclometasone dipropionate HFA)
Intervention type(s): Drug
Intervention description(s): Participants will be converted to Qvar (HFA-beclometasone) at an equivalent therapeutic dose to their original inhaled corticosteroids. The treatment duration will for 8 weeks after a run-in period.
Intervention MeSH terms: Beclomethasone
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: asthma control; small airways; extra-fine particle inhaled corticosteroids