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Trial registered on ANZCTR


Registration number
ACTRN12606000531516
Ethics application status
Approved
Date submitted
12/12/2006
Date registered
22/12/2006
Date last updated
14/11/2018
Date data sharing statement initially provided
14/11/2018
Date results information initially provided
14/11/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
The role of statin therapy in the management of persistent atopic asthma
Scientific title
A randomised controlled trial to determine if statin therapy provides a beneficial anti-inflammatory effect in the management of persistent atopic asthma
Secondary ID [1] 296596 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Eosinophilic asthma 1502 0
Condition category
Condition code
Respiratory 1600 1600 0 0
Asthma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study will investigate simvastatin as an anti-inflammatory treatment in eosinophilic asthma. It will be a randomised, double-blind, cross-over trial of simvastatin versus placebo. During phase 1 (lasting up to 28 days) participants will undergo steroid withdrawal to determine their type of asthma (eosinophilic or not). Those with eosinophilic asthma will then enter phase 2 and commence high dose inhaled corticosteroid (fluticasone 1000mcg daily) to determine steroid responsiveness over 4 weeks. In phase 3 , participants will commence inhaled fluticasone 500mcg daily and in addition will be randomised to receive either oral simvastatin 40mg daily or oral placebo. Thereafter the fluticasone dose will be reduced every 4 weeks until "poor control" as judged by symptoms, peak flow, requirement for reliever therapy/bronchodilator and spirometry - this part of phase 3 will be of variable duration up to a maximum of 20 weeks if the participant gets off steroid altogether. Dose steps will be 500mcg, 250mcg, 100mcg, 50mcg and 0mcg daily. At “poor control”, each patient will be stepped up to the previous fluticasone dose step for a further four weeks (optimum dose). Thereafter, each patient will be continued on optimal dose of fluticasone for a further 4 weeks but with simvastatin/placebo discontinued. They will then proceed back to the beginning of phase 3 and receive the alternative treatment (simvastatin/ placebo). There will not be a washout period between the 2 runs of phase 3 as for the last 4 weeks of the first run of phase 3 simvastatin/placebo will have been discontinued. The aims will be to determine the optimum dose of fluticasone when the patient is receiving the active drug compared to placebo and to identify any possible steroid sparing effects of simvastatin.
Intervention code [1] 1501 0
Treatment: Drugs
Comparator / control treatment
In phase 3 , participants will commence inhaled fluticasone 500mcg daily and in addition will be randomised to receive oral placebo daily.
Control group
Placebo

Outcomes
Primary outcome [1] 2208 0
The optimized dose of inhaled fluticasone, one step up from the dose at which poor control occurred in each of the two treatment periods
Timepoint [1] 2208 0
During phase 3
Secondary outcome [1] 3850 0
The main secondary end-point will be the number of patients who do not experience poor control in each treatment period despite being reduced to fluticasone 0 µg/day.
Timepoint [1] 3850 0
These will be obtained: at the end of Phase 1, at the end of phase 2, at loss of control on both active and placebo treatments, at the end of each four week period when patients are taking the ‘optimum’ ICS dose on both active and placebo treatments, and four weeks after withdrawal of both active and placebo treatments while still taking ‘optimum’ ICS dose.
Secondary outcome [2] 3851 0
Other end-points will be: airway hyper-responsiveness, exhaled nitric oxide, spirometry, induced sputum cell counts, and induced sputum supernatant levels of various cytokines.
Timepoint [2] 3851 0
These will be obtained: at the end of Phase 1, at the end of phase 2, at loss of control on both active and placebo treatments, at the end of each four week period when patients are taking the ‘optimum’ ICS dose on both active and placebo treatments, and four weeks after withdrawal of both active and placebo treatments while still taking ‘optimum’ ICS dose.

Eligibility
Key inclusion criteria
Patients with chronic persistent asthma, diagnosed according to American Thoracic Society (ATS) criteria. Each patient will be stable at entry with no change in inhaled steroid treatment during the previous 6 weeks.
Minimum age
18 Years
Maximum age
75 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Smokers or ex-smokers with cumulative consumption of >10 pack years; other co-existing respiratory disease, co-morbidity likely to influence the conduct of the study; pregnancy or women of child-bearing potential who are not using regular contraception; history of adverse reaction or contraindication to statin drugs, inability to do without long-acting beta-agonist inhaler.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
sealed opaque envelopes
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation by using procedures such as coin-tossing and dice-rolling
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
participants and data analysts
Phase
Phase 3 / Phase 4
Type of endpoint(s)
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 444 0
New Zealand
State/province [1] 444 0

Funding & Sponsors
Funding source category [1] 1744 0
Charities/Societies/Foundations
Name [1] 1744 0
Asthma and Respiratory Foundation of New Zealand
Address [1] 1744 0
The Asthma Foundation
Level 3, Greenock House
39 The Terrace
Wellington 6011
Country [1] 1744 0
New Zealand
Primary sponsor type
Individual
Name
Professor D Robin Taylor
Address
Dunedin School of Medicine
University of Otago
PO Box 56, Dunedin 9054
Country
New Zealand
Secondary sponsor category [1] 1539 0
None
Name [1] 1539 0
NA
Address [1] 1539 0
Country [1] 1539 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 3222 0
Lower South Regional Ethics Committee,
Ethics committee address [1] 3222 0
South Island
Ethics committee country [1] 3222 0
New Zealand
Date submitted for ethics approval [1] 3222 0
28/11/2006
Approval date [1] 3222 0
13/02/2007
Ethics approval number [1] 3222 0
LRS/06/12/059

Summary
Brief summary
In atopic asthma the airways are infiltrated with eosinophils (a type of white blood cell). Usually it is responsive to inhaled steroid (ICS) therapy. However, the response to steroid is very variable. In some cases very high doses of inhaled steroid are needed, with the risk of side effects such as skin thinning and cataracts. There is a question of whether there may be steroid resistance. Thus there is a need for alternative and/or additional non-steroidal anti-inflammatory therapies in bronchial asthma.

Statins, which lower cholesterol, have anti-inflammatory effects. This study will investigate simvastatin as an anti-inflammatory treatment in eosinophilic asthma. It will be a randomised, double-blind, cross-over trial of simvastatin versus placebo. Participants will initially undergo steroid withdrawal to determine their type of asthma (eosinophilic or not). Those with eosinophilic asthma will commence high dose ICS, followed by back titration of the dose on both simvastatin and placebo. The aim will be to determine the optimum dose when the patient is receiving the active drug compared to placebo. We will measure inflammatory markers during both arms of the study. The data obtained will confirm whether or not statin therapy has a beneficial anti-inflammatory effect.
Trial website
Trial related presentations / publications
Simvastatin in the treatment of asthma: Lack of steroid-sparing effect
Cowan, D.C., Cowan, J.O., Palmay, R., Williamson, A., Taylor, D.R.
Thorax
volume 65, issue 10, year 2010, pp. 891 - 896
Biomarker-based asthma phenotypes of corticosteroid response
Cowan, D.C., Taylor, D.R., Peterson, L.E., Cowan, J.O., Palmay, R., Williamson, A., Hammel, J., Erzurum, S.C., Hazen, S.L., Comhair, S.A.A.
Journal of Allergy and Clinical Immunology
volume 135, issue 4, year 2015, pp. 877 - 883.e1
Public notes

Contacts
Principal investigator
Name 27435 0
Prof Professor D Robin Taylor
Address 27435 0
Dunedin School of Medicine
University of Otago
PO Box 56
Dunedin 9054
Country 27435 0
New Zealand
Phone 27435 0
+64 3 4709362
Fax 27435 0
Email 27435 0
jan.cowan@otago.ac.nz
Contact person for public queries
Name 10690 0
Dr Douglas Cowan
Address 10690 0
Otago Respiratory Research Unit
Dunedin School of Medicine
Dunedin Hospital
Great King Street
Dunedin
Country 10690 0
New Zealand
Phone 10690 0
+64 3 4709362
Fax 10690 0
+64 3 4776246
Email 10690 0
jan.cowan@otago.ac.nz
Contact person for scientific queries
Name 1618 0
Prof Professor D Robin Taylor
Address 1618 0
Dunedin School of Medicine
P.O.Box 913
Dunedin
Country 1618 0
New Zealand
Phone 1618 0
+64 3 4709362
Fax 1618 0
+64 3 4776246
Email 1618 0
robin.taylor@stonebow.otago.ac.nz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Not available
What supporting documents are/will be available?
No other documents available
Summary results
Have study results been published in a peer-reviewed journal?
Yes
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary
43 patients completed the study. There was no significant difference in ‘minimum’ inhaled corticosteroid (ICS) dose requirement between simvastatin and placebo: (median (IQR) 50 µg daily (0–250) vs 100 µg daily (0–250)). ‘Minimum’ dose distribution was similar . The fluticasone dose at which loss of control occurred did not differ significantly between simvastatin and placebo . In patients with loss of control in both treatment arms, fluticasone dose at loss of control was similar with simvastatin and placebo (median (IQR) 50 µg daily (0–100) for both). In those patients who reached 0 µg/day (n=18), Astma Control Questionnaire (ACQ) was lower, forced expiratory volume in 1 s (FEV1) higher and sputum eosinophils lower with simvastatin compared with placebo (9.5% compared with 25.4%).

Conclusions Simvastatin does not have clinically important steroid-sparing effects in patients with eosinophilic asthma. In the absence of steroid, simvastatin is associated with minor improvements in symptoms and lung function, and a reduction in sputum eosinophils.