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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]

nil known

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

airflow obstruction

Condition category

Condition code

Respiratory

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]

Treatment: Drugs

Intervention code [2]

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]

Lung function: forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and FEV1/FVC ratio measured by spirometry

Timepoint [1]

at baseline and at 6, 12 and 24 weeks after intervention commencement

Primary outcome [2]

high-sensitivity C-Reactive Protein (hs-CRP) in blood sample

Timepoint [2]

at baseline and at 6, 12 and 24 weeks after intervention commencement

Secondary outcome [1]

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]

at baseline and at 6,12 and 24 weeks after intervention commencement

Secondary outcome [2]

sputum %neutrophils and sputum Interleukin-8 (IL-8), examined with microsopic cytology examination of sputum

Timepoint [2]

at baseline and at 6, 12 and 24 weeks after intervention commencement

Secondary outcome [3]

Respiratory-related quality of life: St George Respiratory Questionnaire (SGRQ)

Timepoint [3]

at baseline and at 6, 12 and 24 weeks after intervention commencement

Secondary outcome [4]

Generic quality of life: SF-36 health survey

Timepoint [4]

at baseline and at 6, 12 and 24 weeks after intervention commencement

Secondary outcome [5]

Exercise capacity, measured by endurance test on a bicycle at 80% of individual peak work capacity

Timepoint [5]

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?

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

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

Recruitment postcode(s) [1]

2037

Recruitment postcode(s) [2]

2305

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

National Health and Medical Research Council (NHMRC) Centre for Clinical Research Excellence (CCRE) in Respiratory and Sleep Medicine

Address [1]

431 Glebe Point Road, Glebe NSW 2037

Country [1]

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]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Sydney South West Area Health Service (SSWAHS) Ethics Committee, Royal Prince Alfred Hospital (RPAH) Zone

Ethics committee address [1]

Level 3, Building 92, Royal Prince Alfred Hospital, Camperdown NSW 2050

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

Approval date [1]

02/03/2009

Ethics approval number [1]

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

Prof Guy Marks

Address

Woolcock Institute of Medical Research
431 Glebe Point Road
Glebe NSW 2037

Country

Australia

Phone

+61 2 9114 0436

Fax

[email protected]

Contact person for public queries

Name

Professor Guy Marks

Address

Woolcock Institute of Medical Research
PO Box M77, Missenden Road, Camperdown NSW 2050

Country

Australia

Phone

+61 2 91140466

Fax

+61 2 91140012

[email protected]

Contact person for scientific queries

Name

Professor Guy Marks

Address

Woolcock Institute of Medical Research
PO Box M77, Missenden Road, Camperdown NSW 2050

Country

Australia

Phone

+61 2 91140466

Fax

+61 2 91140012

[email protected]

No information has been provided regarding IPD availability

What supporting documents are/will be available?

No Supporting Document Provided

Results publications and other study-related documents

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