- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00680641
Simvastatin in Chronic Obstructive Pulmonary Disease (COPD)
The Effects of Simvastatin in Patients With Chronic Obstructive Pulmonary Disease
Study Overview
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 We have identified MMP-2, -9 and -14 in the sputum of healthy volunteers (unpublished pilot data) and will utilise this technique in the current study.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 Type
Enrollment (Anticipated)
Phase
- Phase 4
Contacts and Locations
Study Locations
-
-
Norfolk
-
Norwich, Norfolk, United Kingdom, NR47TJ
- CRTU University of East Anglia
-
Norwich, Norfolk, United Kingdom, NR74UY
- CRTU Norfolk and Norwich University Hospital
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Crossover Assignment
- Masking: Double
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Placebo Comparator: B
Placebo
|
40mg of placebo once daily
|
Active Comparator: A
Simvastatin 40mg
|
40mg of Simvastatin once daily
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
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.
|
4 checks over a four month period at 2 weeks, 10 weeks, 14 weeks and 22 weeks.
|
Secondary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
The difference between treatment with simvastatin and placebo for Clinical COPD Questionnaire
Time Frame: 4 months
|
4 months
|
The difference between treatment with simvastatin and placebo for Spirometry - FEV1, FVC, FEV1/FVC ratio
Time Frame: 4 months
|
4 months
|
The difference between treatment with simvastatin and placebo for Induced sputum differential cell count
Time Frame: 4 months
|
4 months
|
The difference between treatment with simvastatin and placebo for Induced sputum mRNA for MMP and TIMPs
Time Frame: 4 months
|
4 months
|
The difference between treatment with simvastatin and placebo for Exhaled breath condensate 8-isoprostane concentration
Time Frame: 4 Months
|
4 Months
|
The difference between treatment with simvastatin and placebo for Serum TNFa
Time Frame: 4 months
|
4 months
|
The difference between treatment with simvastatin and placebo for Cholesterol
Time Frame: 4 Months
|
4 Months
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Andrew M Wilson, MD, MRCP (UK), Clinical Senior Lecturer, University of East Anglia
Publications and helpful links
General Publications
- Pizzichini E, Pizzichini MM, Efthimiadis A, Evans S, Morris MM, Squillace D, Gleich GJ, Dolovich J, Hargreave FE. Indices of airway inflammation in induced sputum: reproducibility and validity of cell and fluid-phase measurements. Am J Respir Crit Care Med. 1996 Aug;154(2 Pt 1):308-17. doi: 10.1164/ajrccm.154.2.8756799.
- van der Molen T, Willemse BW, Schokker S, ten Hacken NH, Postma DS, Juniper EF. Development, validity and responsiveness of the Clinical COPD Questionnaire. Health Qual Life Outcomes. 2003 Apr 28;1:13. doi: 10.1186/1477-7525-1-13.
- Kevorkian L, Young DA, Darrah C, Donell ST, Shepstone L, Porter S, Brockbank SM, Edwards DR, Parker AE, Clark IM. Expression profiling of metalloproteinases and their inhibitors in cartilage. Arthritis Rheum. 2004 Jan;50(1):131-41. doi: 10.1002/art.11433.
- Standardization of spirometry--1987 update. Statement of the American Thoracic Society. Am Rev Respir Dis. 1987 Nov;136(5):1285-98. doi: 10.1164/ajrccm/136.5.1285. No abstract available.
- Hothersall E, McSharry C, Thomson NC. Potential therapeutic role for statins in respiratory disease. Thorax. 2006 Aug;61(8):729-34. doi: 10.1136/thx.2005.057976.
- Soyseth V, Brekke PH, Smith P, Omland T. Statin use is associated with reduced mortality in COPD. Eur Respir J. 2007 Feb;29(2):279-83. doi: 10.1183/09031936.00106406. Epub 2006 Oct 18.
- Hanefeld M, Marx N, Pfutzner A, Baurecht W, Lubben G, Karagiannis E, Stier U, Forst T. Anti-inflammatory effects of pioglitazone and/or simvastatin in high cardiovascular risk patients with elevated high sensitivity C-reactive protein: the PIOSTAT Study. J Am Coll Cardiol. 2007 Jan 23;49(3):290-7. doi: 10.1016/j.jacc.2006.08.054. Epub 2007 Jan 8.
- Montuschi P. Exhaled breath condensate analysis in patients with COPD. Clin Chim Acta. 2005 Jun;356(1-2):22-34. doi: 10.1016/j.cccn.2005.01.012. Epub 2005 Mar 23.
- Kasielski M, Nowak D. Long-term administration of N-acetylcysteine decreases hydrogen peroxide exhalation in subjects with chronic obstructive pulmonary disease. Respir Med. 2001 Jun;95(6):448-56. doi: 10.1053/rmed.2001.1066.
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Anticipated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Pathologic Processes
- Respiratory Tract Diseases
- Lung Diseases
- Lung Diseases, Obstructive
- Pulmonary Disease, Chronic Obstructive
- Pulmonary Emphysema
- Emphysema
- Molecular Mechanisms of Pharmacological Action
- Enzyme Inhibitors
- Antimetabolites
- Anticholesteremic Agents
- Hypolipidemic Agents
- Lipid Regulating Agents
- Hydroxymethylglutaryl-CoA Reductase Inhibitors
- Simvastatin
Other Study ID Numbers
- 2007RESP06
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