Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12615000491561
Ethics application status
Approved
Date submitted
23/04/2015
Date registered
18/05/2015
Date last updated
18/05/2015
Type of registration
Prospectively registered

Titles & IDs
Public title
Simvastatin treatment for patients with Chronic obstructive pulmonary disease (COPD) and elevated C-reactive protein (CRP).
Scientific title
Efficacy of simvastatin treatment on CRP levels in patients with COPD and elevated CRP.
Secondary ID [1] 286589 0
Nil
Universal Trial Number (UTN)
U1111-1169-5592
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic Obstructive Pulmonary Disease (COPD) 294862 0
Elevated CRP 294863 0
Condition category
Condition code
Respiratory 295122 295122 0 0
Chronic obstructive pulmonary disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Trial design: A multicentre, prospective randomised controlled trial of ORAL simvastatin 20mg/day vs. simvastatin 40mg/day tablets, over 12 weeks in patients with laboratory confirmed elevated CRP level greater than or equal to 3mg/L who may have reduced quality of life (particularly exercise tolerance) and are at risk for acute COPD exacerbations.
PATIENT IDENTIFICATION/STUDY CENTRES AND RECRUITMENT
Using existing primary care and hospital-based electronic databases across the 3 New Zealand centres potentially eligible patients with COPD will be identified that meet the inclusion criteria.
These patients will undergo a screening telephone interview where inclusion/exclusion criteria will be assessed and a willingness to participate (verbal consent) is established, and basic demographic data recorded. Patients agreeing to be involved will attend a screening visit (V0, -4 weeks) where they will be consented and assessed for eligibility including blood sampling for CRP measurement. Patient’s existing COPD treatment will be optimised with advice on inhaler use and technique updated. Over the following 2-3 weeks, those with a CRP greater than or equal to 3mg/L will be invited back to the pre-treatment visit (V1) and randomised to receive simvastatin either 20 mg or 40 mg daily (N=24 in each group). Subjects will also visit 4 weeks (V3) and 12 weeks (V4) after this visit. Liver function tests and creatinine kinase levels will be tested at V1-V4. Baseline measures will be measured as described for the full study above (except the 6MWD done only once). On the visits V1-V3, the same measures will be assessed, in addition to drug use and exacerbation history documented.

Treatment regime
Randomisation (V2), 4 weeks (V3) and 12 weeks (V4) of simvastatin treatment totalling four visits over four months.
Primary outcome: changes in the CRP before and after treatment with simvastatin 20 or 40 mg mg/day at 4 and 12weeks after treatment was started
Secondary outcome - effects of statin therapy:
*changes in 6MWD (minute walk duration),
*lung function
*quality of life questionnaires
IP adherence will be monitored via a log for dispensed and returned tablets.
Intervention code [1] 291705 0
Treatment: Drugs
Comparator / control treatment
Oral Simvastatin tablets 20 mg/day compared to 40 mg/day. Neither of these doses is considered a control.
Control group
Dose comparison

Outcomes
Primary outcome [1] 294887 0
Changes in serum CRP
Timepoint [1] 294887 0
Randomisation
week 4
Week 12
Secondary outcome [1] 314286 0
Effects of statin therapy on
*lung function (measured with spirometry)
Timepoint [1] 314286 0
Randomisation
week 4
Week 12
Secondary outcome [2] 314535 0
*exercise tolerance (measured by 6 Minute Walk Distance)
Timepoint [2] 314535 0
Randomisation
week 4
Week 12
Secondary outcome [3] 314536 0
*Changes in quality of life questionnaires (CAT, mMRC score, Borg score, EQ-5D and SGRQ),
Timepoint [3] 314536 0
Randomisation
week 4
week 12

Eligibility
Key inclusion criteria
Inclusion Criteria:
1. Male and female subjects, greater than or equal to 40 – less than or equal to 80 years of age.
2. Statin naive (no statin therapy for the last 12 months).
3. Clinical diagnosis of at least moderate-to-severe COPD but who are clinically stable with no exacerbation (or escalation of therapy) within the preceding 4 weeks.
For the purposes of this study, COPD will be defined by the GOLD criteria being:
a. post-bronchodilator (Ventolin 400 mcg ) FEV1/FVC <70%
b. post-bronchodilator FEV1 <80% of predicted for age and height, with or without chronic symptoms (i.e., cough, sputum production).
Clinically stable is defined as the absence of clinical worsening of symptoms beyond normal daily variation and with no need for increasing habitual inhaler medications or taking antibiotics or prednisone in the 4 weeks prior to the baseline and randomisation visits.
3. Cigarette consumption of at least 10 pack- years (or more), including current and ex-smokers.
4. Have been hospitalised with an acute COPD exacerbation anytime in the past or had an acute exacerbation in the past year treated with antibiotics or prednisone.
5. Subjects giving informed written consent to partake in the study.
6. Willing to make return visits and availability by telephone for duration of the study.
7. Free of unstable coronary or atherosclerotic vascular disease – heart attack or stroke in last 3 months.
8. Patients with an expected life expectancy >12 months.
9. Not pregnant and not intending to become pregnant during the period of the study.
NB. For randomisation to treatment subjects must have a laboratory confirmed elevated CRP level of 3mg/L or more.
Minimum age
40 Years
Maximum age
80 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion Criteria:
1. Diagnosis not meeting the spirometry defined GOLD criteria for COPD as above.
2. The presence of a diagnosis other than COPD that results in the patient being either medically unstable, or having a predicted life expectancy < 12 months.
3. Currently taking statin or on statin in the last 12 months. 4. Patients with a history of hypersensitivity or other adverse drug reaction (intolerability) to statin.
5. Women who are at risk of becoming pregnant during the study (pre-menopausal) and who refuse to use acceptable birth control (hormone-based oral or barrier contraceptive) for the duration of the study.
6. Special patient groups: prisoners, pregnant women, institutionalised patients.
7. Patients otherwise meeting the inclusion criteria will not be enrolled until they are a minimum of four weeks from their most recent acute exacerbation, (i.e., they will not have received a course of systemic corticosteroids, an increased dose of chronically administered systemic corticosteroids, and/or antibiotics for an acute exacerbation for a minimum of four weeks).
8. Clinically relevant bronchiectasis as judged by the investigator
9. Documented history of CHD, such as angina, recent myocardial infarction, stroke, peripheral vascular disease, congestive heart failure within the past 3 months.
10. Medications: concurrent use of niacin, azole antifungals, fibrate therapy and cyclosporine (to decrease the incidence of myopathy). Magnesium containing antacids (decrease statin absorption and will be avoided). Simvastatin may increase digoxin levels by 20% on repeated dosing and digoxin levels will be monitored in those taking digoxin. Simvastatin co-administration with estradiol compounds used for contraception may increase the AUC values for these compounds by 30% and patients using these compounds for contraception will be avoided or other forms of contraception will be used.
11. Long-term macrolide treatment (greater than or equal to 3 months) in the past 6 months. Macrolide antibiotics may increase simvastatin levels by 40% and short-term macrolide antibiotic use will be discouraged for patients enrolled into this trial.
12. Renal and /or haematological disease that precludes statin therapy.
13. Obvious exclusions on the basis of x-ray results.

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 will be concealed by numbered containers (medication packs)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Patients will be randomly assigned in a 1:1 ratio, with a permuted block and sequential assignment, stratified by centre.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Assuming a 30-50% reduction in CRP is achieved, comparable to that previously reported in COPD, then power calculations by Mr Greg Gamble indicate that our feasibility study has adequate power (90%) at the 5% significance level to detect a difference or more than 1 SD between statin treatment groups (even with 10% loss to follow up, N=24 in each group).
The outcomes described above will be assessed at randomisation (V2), 4 weeks (V3) and 12 weeks (V4) of simvastatin treatment totalling four visits over four months. The results of the study will be examined using standard statistical methods by Mr Greg Gamble (biostatistician) comparing results from baseline (V1) and randomisation assessments (V2) with post-treatment assessments at weeks 4 and12 (V3-V4).

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
11/06/2015
Actual
Date of last participant enrolment
Anticipated
31/03/2016
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
48
Accrual to date
Final
Recruitment outside Australia
Country [1] 6841 0
New Zealand
State/province [1] 6841 0
Auckland

Funding & Sponsors
Funding source category [1] 291151 0
Government body
Name [1] 291151 0
Health Research Council (HRC)
Country [1] 291151 0
New Zealand
Primary sponsor type
Individual
Name
Associate Professor Robert Young
Address
Level 3 - ProCARE Building, Grafton Mews, at 110 Stanley School of Biological Sciences and Faculty of Medical and Health Sciences
Auckland District Health Board
Country
New Zealand
Secondary sponsor category [1] 289829 0
None
Name [1] 289829 0
Address [1] 289829 0
Country [1] 289829 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 292727 0
Northern B Health and Disability Ethics Committee
Ethics committee address [1] 292727 0
Health and Disability Ethics Committees
Ministry of Health
C/- MEDSAFE, Level 6, Deloitte House
10 Brandon Street
PO Box 5013
Wellington
6011
Ethics committee country [1] 292727 0
New Zealand
Date submitted for ethics approval [1] 292727 0
10/10/2014
Approval date [1] 292727 0
23/12/2014
Ethics approval number [1] 292727 0
14/NTB/166

Summary
Brief summary
Chronic obstructive pulmonary disease (COPD) results from smoking induced damage to the lungs causing
breathlessness, poor exercise and fatigue due to the combined effects of an exaggerated inflammatory response in
both the lungs and cirulation (systemic inflammation). Systemic inflammation affects about 50 - 70% of patients
diagnosed with COPD and directly contributes to poor exercise capacity. The cholesterol lowering drugs statins, are well tolerated and potent inhibitors of systemic inflammation as well as lower cholesterol. In preliminary studies statins appear to improve exercise capacity, particulary in those with underlying systemic inflammation based on an
elevated C-Reactive Protein(hsCRP greater than or equal to 3mg/L).
This feasibility study aims to address 3 factors that will help inform the design of a large randomised control trial (RCT). The first is the ability to recruit moderate severe stable COPD
patients with systemic inflammation (CRP greater than or equal to 3mg/L,) who are not statin users or statin intolerant, for a 12 weeks course of simvastatin. The second is to determine both the tolerance and magnitude of the effect on inhibition of
CRP, by simvastatin 20mg/day compared to 40mg/day. The last aim is to measure clinically relevant outcomes related to symptoms, quality of life and exercise tolerance, to see the magnitude of change with each of these doses. The results of this feasibility study will inform the design and power of a larger RCT. If a randomised control trial subsequently shows that treatment of stable COPD, with a well tolerated drug like simvastain, can improve symptoms or exercise distance then this novel approach to the treament of COPD could become standard clinical practice.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 56758 0
A/Prof Robert P YOUNG
Address 56758 0
School of Biological Sciences and Faculty of Medical and Health Sciences
Auckland District Health Board
Auckland

P.O.Box 26161 Epsom Auckland 1344
Country 56758 0
New Zealand
Phone 56758 0
+649 6309968
Fax 56758 0
+649 6236456
Email 56758 0
roberty@adhb.govt.nz
Contact person for public queries
Name 56759 0
A/Prof Robert P YOUNG
Address 56759 0
School of Biological Sciences and Faculty of Medical and Health Sciences
Auckland District Health Board
Auckland

P.O.Box 26161 Epsom Auckland 1344
Country 56759 0
New Zealand
Phone 56759 0
+649 6309968
Fax 56759 0
+649 6236456
Email 56759 0
roberty@adhb.govt.nz
Contact person for scientific queries
Name 56760 0
A/Prof Robert P YOUNG
Address 56760 0
School of Biological Sciences and Faculty of Medical and Health Sciences
Auckland District Health Board
Auckland

P.O.Box 26161 Epsom Auckland 1344
Country 56760 0
New Zealand
Phone 56760 0
+649 6309968
Fax 56760 0
+649 6236456
Email 56760 0
roberty@adhb.govt.nz

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No Supporting Document Provided



Results publications and other study-related documents

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