Simvastatin in Chronic Obstructive Pulmonary Disease (COPD)

Study Overview
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Brief Summary
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To determine the effects of 2 months therapy with simvastatin 40mg once per day compared to placebo in a double-blind placebo-controlled study of patients with COPD.

Detailed Description
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Statins (HMG-Coenzyme A reductase inhibitors) are widely used clinically as lipid lowering drugs; however they have also been shown to exhibit anti-inflammatory and anti-oxidant properties(1). Recently published large retrospective cohort studies, in patients with chronic obstructive pulmonary disease (COPD), suggest that statins reduce mortality and COPD related admissions(2). Possible mechanisms of action include effects on cell adhesion molecules, changes in inflammatory mediator release, antioxidant effect and increased clearance of apoptoic cells. Simvastatin has been shown to reduce the development of smoking induced emphysema in rats with reductions in MMP-9 activity and simvastatin withdrawal leads to increased MMP levels in hypercholesterolaemic patients. Serum concentrations of TNFa and high sensitive C Reactive protein(3) (hs-CRP) are reduced with simvastatin therapy in patients with hypercholesterolaemia and risk of cardiovascular disease respectively. No clinical trial has directly evaluated the clinical effects of statins in patients with COPD in terms of induced sputum MMP profile, alveolar nitric oxide or pulmonary physiology. We have modified our published method of RNA purification, developed to purify RNA from cartilage, tendon or synovium(4), to yield good quality RNA from sputum with relative simplicity and low cost. We have identified MMP-2, -9 and -14 in the sputum of healthy volunteers (unpublished pilot data) and will utilise this technique in the current study. Exhaled breath condensate (EBC) is completely non-invasive, requires no co-operation from individuals and provides information about a number of inflammatory and oxidation pathways. Markers of oxidative stress (8-isoprostane and hydrogen peroxide) and nitric oxide products can be measured in exhale breath condensate(5) and are related to disease activity in patients with COPD. Markers of oxidative stress increase in concentration in EBC during exacerbations of COPD are reduced after treatment with the antioxidant N-acetyl cysteine(6). Hydrogen peroxide is not stable and therefore 8-isoprostane is a preferable marker of oxidative stress unless the sample is measured on line.

Official Title
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The Effects of Simvastatin in Patients With Chronic Obstructive Pulmonary Disease

Conditions
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COPD, Emphysema

Intervention / Treatment
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* Drug: Simvastatin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, aged more than 45 years. Physician labelled diagnosis of chronic obstructive pulmonary disease,emphysema or chronic bronchitis. Smoker or ex-smoker with a pack year smoking history of greater than 20 pack years FEV1 30-70% predicted FEV1/FVC< 70% Body Mass Index <25kg/m2 Exclusion Criteria: 1. Cardiac or pulmonary disease other than chronic obstructive pulmonary disease. Untreated hypothyroidism Respiratory infection defined as fever, nasal/sinus congestion, fatigue, cough, antibiotic use or yellow/green sputum within 4 weeks prior to study. Receiving current oral corticosteroid therapy or leukotriene modifying therapy. Severe or uncontrolled co-morbid disease History of atopy or asthma Clinical history of bronchiectasis Pregnancy or breastfeeding Women of child-bearing potential, unless adequate contraception is used (ie contraceptive pill or double-barrier contraception - partner using condom and subject using spermicide, diaphragm, intra-uterine device or contraceptive sponge) Unable to give written informed consent Patients receiving a statin prior to entry into the study Hypersensitivity to simvastatin or to any of the excipients.

Ages Eligible for Study
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Minimum Age: 45 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: A<br>Simvastatin 40mg | Drug: Simvastatin<br>* 40mg of Simvastatin once daily<br>|
| Placebo Comparator: B<br>Placebo | Drug: Placebo<br>* 40mg of placebo once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The difference in serum high sensitivity C-reactive protein (HsCRP) between simvastatin and placebo |  | 4 checks over a four month period at 2 weeks, 10 weeks, 14 weeks and 22 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The difference between treatment with simvastatin and placebo for Clinical COPD Questionnaire |  | 4 months | 
| The difference between treatment with simvastatin and placebo for Spirometry - FEV1, FVC, FEV1/FVC ratio |  | 4 months | 
| The difference between treatment with simvastatin and placebo for Induced sputum differential cell count |  | 4 months | 
| The difference between treatment with simvastatin and placebo for Induced sputum mRNA for MMP and TIMPs |  | 4 months | 
| The difference between treatment with simvastatin and placebo for Exhaled breath condensate 8-isoprostane concentration |  | 4 Months | 
| The difference between treatment with simvastatin and placebo for Serum TNFa |  | 4 months | 
| The difference between treatment with simvastatin and placebo for Cholesterol |  | 4 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COPD, Emphysema, Simvastatin