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

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.

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Investigator), Placebo Control, Crossover Assignment

Study Primary Completion Date: November 2008

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 We have identified MMP-2, -9 and -14 in the sputum of healthy volunteers (unpublished pilot data) and will utilise this technique in the current study.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.

Intervention(s) in this Clinical Trial

• Drug: Simvastatin
  • 40mg of Simvastatin once daily
• Drug: Placebo
  • 40mg of placebo once daily

Arms, Groups and Cohorts in this Clinical Trial

• Active Comparator: A
  • Simvastatin 40mg
• Placebo Comparator: B
  • Placebo

Primary Measures

• The difference in serum high sensitivity C-reactive protein (HsCRP) between simvastatin and placebo
  • Time Frame: 4 checks over a four month period at 2 weeks, 10 weeks, 14 weeks and 22 weeks.
    Safety Issue?: No

Secondary Measures

• The difference between treatment with simvastatin and placebo for Clinical COPD Questionnaire
  • Time Frame: 4 months
    Safety Issue?: No
• The difference between treatment with simvastatin and placebo for Spirometry - FEV1, FVC, FEV1/FVC ratio
  • Time Frame: 4 months
    Safety Issue?: No
• The difference between treatment with simvastatin and placebo for Induced sputum differential cell count
  • Time Frame: 4 months
    Safety Issue?: No
• The difference between treatment with simvastatin and placebo for Induced sputum mRNA for MMP and TIMPs
  • Time Frame: 4 months
    Safety Issue?: No
• The difference between treatment with simvastatin and placebo for Exhaled breath condensate 8-isoprostane concentration
  • Time Frame: 4 Months
    Safety Issue?: No
• The difference between treatment with simvastatin and placebo for Serum TNFa
  • Time Frame: 4 months
    Safety Issue?: No
• The difference between treatment with simvastatin and placebo for Cholesterol
  • Time Frame: 4 Months
    Safety Issue?: No

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.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 45 Years

Maximum Age for this Clinical Trial: 85 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: University of East Anglia

Overall Clinical Trial Officials and Contacts

Andrew M Wilson, MD, MRCP (UK) Principal Investigator Clinical Senior Lecturer, University of East Anglia  

Overall Contact: Sundari N Ampikaipakan, MRCP(UK)  sundari.ampi@nnuh.nhs.uk

Information obtained from ClinicalTrials.gov on July 02, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00680641

Study ID Number: 2007RESP06

ClinicalTrials.gov Identifier: NCT00680641

Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency