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Trial registered on ANZCTR


Registration number
ACTRN12609000272291
Ethics application status
Approved
Date submitted
10/04/2009
Date registered
15/05/2009
Date last updated
10/12/2015
Type of registration
Prospectively registered

Titles & IDs
Public title
The effect of simvastatin, omega-3 fatty acids and antioxidants on lung function in ex-smokers with symptomatic airflow obstruction
Scientific title
A randomized controlled, pilot study of the effect of simvastatin, omega-3 fatty acids and antioxidants on lung function in ex-smokers with symptomatic airflow obstruction
Secondary ID [1] 288124 0
nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
airflow obstruction 4582 0
Condition category
Condition code
Respiratory 4879 4879 0 0
Chronic obstructive pulmonary disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Two interventions:
1. Simvastatin oral tablets 20 mg daily for 6 weeks, then 40 mg daily for 20 weeks, i.e. 26 weeks total duration
2. Dietary supplements:
Fish oil oral capsules, 3x1g capsule per day (each capsule containing 700 mg omega-3, including 400 mg eicosapentaenoic acid [EPA] and 200 mg docosahexaenoic acid [DHA]) for 26 weeks and
Tomato lycopene complex oral capsules, 2x500 mg capsule per day (each capsule containing 15mg lycopene, 5mg tocopherols, 0.6mg beta-carotene) for 26 weeks.

Factorial study design:
Group 1: Simvastatin tablets and active nutrient supplement (fish oil and tomato lycopene capsules)
Group 2: Simvastatin tablets and placebo nutrient supplement capsules
Group 3: No statin tablets and active nutrient supplement (fish oil and tomato lycopene capsules)
Group 4: No statin tablets and placebo nutrient supplement capsules
Intervention code [1] 4345 0
Treatment: Drugs
Intervention code [2] 4346 0
Prevention
Comparator / control treatment
Control treatment for simvastatin: no statin treatment for 26 weeks
Control treatment for dietary supplementation with omega-3 polyunsaturated fatty acids and lycopene complex: placebo for 26 weeks consisting of 3 x 1 g oral oil capsules containing 100% corn oil and 3 x 500mg oral oil capsules containing 100% soy bean oil.
Control group
Placebo

Outcomes
Primary outcome [1] 5728 0
Lung function: forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and FEV1/FVC ratio measured by spirometry
Timepoint [1] 5728 0
at baseline and at 6, 12 and 24 weeks after intervention commencement
Primary outcome [2] 5729 0
high-sensitivity C-Reactive Protein (hs-CRP) in blood sample
Timepoint [2] 5729 0
at baseline and at 6, 12 and 24 weeks after intervention commencement
Secondary outcome [1] 241665 0
Exhaled nitric oxide, measured in a breath test (this involves blowing air into a mouthpiece attached to a machine that measures levels of the gas in each breath)
Timepoint [1] 241665 0
at baseline and at 6,12 and 24 weeks after intervention commencement
Secondary outcome [2] 241666 0
sputum %neutrophils and sputum Interleukin-8 (IL-8), examined with microsopic cytology examination of sputum
Timepoint [2] 241666 0
at baseline and at 6, 12 and 24 weeks after intervention commencement
Secondary outcome [3] 241667 0
Respiratory-related quality of life: St George Respiratory Questionnaire (SGRQ)
Timepoint [3] 241667 0
at baseline and at 6, 12 and 24 weeks after intervention commencement
Secondary outcome [4] 241668 0
Generic quality of life: SF-36 health survey
Timepoint [4] 241668 0
at baseline and at 6, 12 and 24 weeks after intervention commencement
Secondary outcome [5] 241669 0
Exercise capacity, measured by endurance test on a bicycle at 80% of individual peak work capacity
Timepoint [5] 241669 0
at baseline and at 24 weeks after intervention commencement

Eligibility
Key inclusion criteria
Ex-smokers with a smoking history of at least 10 pack-years. Ex-smokers are defined for this study as those who have stopped smoking for at least 12 months prior to Visit 1. Pack year is a term used to describe the number of cigarettes a person has smoked over time. One pack year is defined as 20 manufactured cigarettes (one pack) smoked per day for one year. For example smoking 1 1/2 packs per day for 26 years, equals 39 pack-years).
FEV1/FVC ratio < 2 standard deviations (SD) below expected value for age, sex and height
Age 35-60 years
History of lower respiratory tract illness in the last 12 months OR history of chronic cough, sputum production or breathlessness in the last 12 months, AND
C-reactive protein level greater than or equal to 3 mg/L.
Minimum age
35 Years
Maximum age
60 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Current respiratory disorders other than chronic obstructive pulmonary disease (COPD) and asthma (e.g. lung cancer, sarcoidosis, tuberculosis, lung fibrosis, bronchiectasis)
Subjects who have a moderate exacerbation (that required systemic corticosteroid therapy or antibiotics) of COPD in the previous month or a severe exacerbation (that required hospitalization) in the 3 months prior to baseline visit.
Receiving long-term oral corticosteroid therapy
Subjects who are already on statin treatment
Allergies or intolerance to statins or one of the dietary supplements
On any medication known to interact with statins
Myopathies, Creatine phosphokinase (CPK) greater than 1.5 upper limits of normal.
Active liver disease or unexplained persistent elevations of serum transaminases (> 1.5 x upper limits of normal), cholestasis
Alcohol abuse (greater than 4 standard drinks/day)
Renal impairment (Creatinine clearance [ClCr] < 30 mL/min)
Hyperlipidaemia, coronary heart disease, cerebrovascular disease, peripheral vascular disease and diabetes mellitus
Serious, uncontrolled non-respiratory disease (including serious psychological disorders) likely to interfere with the study and/or likely to cause death within the 6-month study duration.
Participation in any other interventional research study in the last 4 weeks before baseline visit.
Pregnant or breast-feeding women

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)
Allocation concealment will be achieved by the use of opaque, sealed envelopes. The generation of the randomisation list and preparation of the sealed envelopes will be done by an individual not involved with the study.
Subjects will be enrolled by a research assistant. When a subject is eligible and signs the consent form, he/she will be assigned using the next available sealed envelope.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The randomisation list will be generated by computer program using random permuted blocks and equal allocation to each group. There will be stratification by study centre (Sydney or Newcastle).
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Factorial
Other design features
Study is blinded for dietary supplement intervention only. Open label administration of simvastatin
Phase
Phase 3
Type of endpoint/s
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Stopped early
Data analysis
Reason for early stopping/withdrawal
Date of first participant enrolment
Anticipated
18/05/2009
Actual
10/08/2009
Date of last participant enrolment
Anticipated
Actual
10/08/2009
Date of last data collection
Anticipated
Actual
Sample size
Target
40
Accrual to date
Final
1
Recruitment in Australia
Recruitment state(s)
Recruitment postcode(s) [1] 1590 0
2037
Recruitment postcode(s) [2] 1591 0
2305

Funding & Sponsors
Funding source category [1] 4770 0
Government body
Name [1] 4770 0
National Health and Medical Research Council (NHMRC) Centre for Clinical Research Excellence (CCRE) in Respiratory and Sleep Medicine
Country [1] 4770 0
Australia
Primary sponsor type
Government body
Name
NHMRC CCRE in Respiratory and Sleep Medicine
Address
431 Glebe Point Road, Glebe NSW 2037
Country
Australia
Secondary sponsor category [1] 4420 0
None
Name [1] 4420 0
Address [1] 4420 0
Country [1] 4420 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 6818 0
Sydney South West Area Health Service (SSWAHS) Ethics Committee, Royal Prince Alfred Hospital (RPAH) Zone
Ethics committee address [1] 6818 0
Level 3, Building 92, Royal Prince Alfred Hospital, Camperdown NSW 2050
Ethics committee country [1] 6818 0
Australia
Date submitted for ethics approval [1] 6818 0
Approval date [1] 6818 0
02/03/2009
Ethics approval number [1] 6818 0
HREC Ref: 08/RPAH/402
Protocol No X08-0237

Summary
Brief summary
In this study, we aim to examine two interventions that could potentially slow disease progression in middle aged ex-smokers with mild to moderate chronic lung disease.
There is evidence that some individuals experience a progressive decline in lung function even after ceasing smoking. This may be related to persistent lung inflammation. We will examine whether omega-3 fatty acids and nutrient antioxidants and/or statins, a treatment used to lower cholesterol, can slow the rate of decline of lung function in people with COPD.
Levels of nutrient antioxidants and omega-3 fatty acids have been shown to be related to levels of lung function in epidemiological studies. Statins, which are widely used as cholesterol lowering drugs, are known to have anti-inflammatory effects. Patients with COPD who are taking statins appear to have a lower risk of death than those not taking statins. Other retrospective studies have shown that statins slow the rate of lung function decline. We propose that nutrient antioxidant and omega-3 fatty acid supplementation and statin treatment will reduce inflammation, and hence slow the progressive decline in lung function in people with obstructive lung disease. This randomised controlled trial will test both nutrient supplements (lycopenes and omega 3-fatty acids) and simvastatin treatment in patients with COPD. Eligible participants will be 35- to 60-year-old ex-smokers with post-bronchodilator airflow obstruction, a history of lower respiratory tract illness in the last 12 months or a history of chronic cough, sputum production or breathlessness in the last 12 months and C-reactive protein = 3 mg/L.
There will be four study groups: Group A (active nutrient supplement intervention, active statin treatment), Group B (active nutrient supplement intervention, no statin treatment), Group C (placebo nutrient supplement intervention, active statin treatment), and Group D (placebo nutrient supplement intervention, no statin treatment). Duration of treatment will be 6 months in the pilot study and 4 years in the main study.
In the pilot study, we aim to recruit a total of 40 participants from the community through advertising. The aim of the pilot study is to assess feasibility of recruitment, implementation of interventions and measurement of outcomes. The number of participants for the final multi-centre study will be determined, in part, by information obtained in the pilot study.
Patients will be seen before treatment commences and then 6, 12 and 24 weeks after treatment commences for the pilot study. The primary outcome is the change in lung function (FEV1 and FVC) over 6 months (24 weeks). Secondary outcomes include systemic inflammatory markers (hs-CRP), questionnaire (regarding quality of life, breathlessness, and exacerbations), exhaled nitric oxide, induced sputum, and exercise capacity. The first hypothesis to be tested is that statins and omega-3 fatty acids/ antioxidants have a synergistic beneficial effect (multiplicative) on outcomes. If this is not supported, the second hypothesis that the two interventions, separately, have an effect on the outcomes. Relationships between the change in lung function and inflammatory markers will also be explored.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 29478 0
Prof Guy Marks
Address 29478 0
Woolcock Institute of Medical Research
431 Glebe Point Road
Glebe NSW 2037
Country 29478 0
Australia
Phone 29478 0
+61 2 9114 0436
Fax 29478 0
Email 29478 0
guy.marks@sydney.edu.au
Contact person for public queries
Name 12725 0
Professor Guy Marks
Address 12725 0
Woolcock Institute of Medical Research
PO Box M77, Missenden Road, Camperdown NSW 2050
Country 12725 0
Australia
Phone 12725 0
+61 2 91140466
Fax 12725 0
+61 2 91140012
Email 12725 0
g.marks@unsw.edu.au
Contact person for scientific queries
Name 3653 0
Professor Guy Marks
Address 3653 0
Woolcock Institute of Medical Research
PO Box M77, Missenden Road, Camperdown NSW 2050
Country 3653 0
Australia
Phone 3653 0
+61 2 91140466
Fax 3653 0
+61 2 91140012
Email 3653 0
g.marks@unsw.edu.au

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Results publications and other study-related documents

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