Simvastatin in Chronic Obstructive Pulmonary Disease (COPD)

Sponsor

University of East Anglia (Other)

Overall Status

Unknown status

CT.gov ID

NCT00680641

Collaborator

(none)

Enrollment

Locations

Arms

Duration (Months)

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
COPD Emphysema	Drug: Simvastatin Drug: Placebo	Phase 4

Detailed Description

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 We have identified MMP-2, -9 and -14 in the sputum of healthy volunteers (unpublished pilot data) and will utilise this technique in the current study.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

Study Design

Study Type:

Interventional

Anticipated Enrollment :

20 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

Official Title:

The Effects of Simvastatin in Patients With Chronic Obstructive Pulmonary Disease

Study Start Date :

Apr 1, 2008

Actual Primary Completion Date :

Feb 1, 2011

Anticipated Study Completion Date :

Feb 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: A Simvastatin 40mg	Drug: Simvastatin 40mg of Simvastatin once daily
Placebo Comparator: B Placebo	Drug: Placebo 40mg of placebo once daily

Arm

Intervention/Treatment

Active Comparator: A

Simvastatin 40mg

Drug: Simvastatin

40mg of Simvastatin once daily

Placebo Comparator: B

Placebo

Drug: Placebo

40mg of placebo once daily

Outcome Measures

Primary Outcome Measures

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

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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

45 Years to 85 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.