A Trial of Atorvastatin as an Anti-Inflammatory Agent in Non-Cystic Fibrosis Bronchiectasis

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Brief Title

A Trial of Atorvastatin as an Anti-Inflammatory Agent in Non-Cystic Fibrosis Bronchiectasis

Official Title

A Randomised Controlled Trial of Atorvastatin as an Anti-Inflammatory Agent in Non-Cystic Fibrosis Bronchiectasis

Brief Summary

      The investigators hypothesise that long term statin treatment will improve patients' symptoms
      through its anti-inflammatory effect. The beneficial effects on patient symptoms (cough,
      sputum volume, bacterial load, airway function, exercise tolerance, exacerbation frequency
      and health related quality of life) will be consequent on reduced neutrophilic airways
      inflammation.
    

Detailed Description

      BACKGROUND AND RATIONAL FOR STUDY Bronchiectasis is a chronic debilitating respiratory
      condition. Patients suffer daily cough, excess sputum production and recurrent chest
      infections because of inflamed and permanently damaged airways. It is a common with a
      Scottish incidence of 1 in 1,000 to 1 in 10,000. Over 600 patients in Edinburgh are monitored
      in secondary care. They frequently utilise primary and secondary care resources through
      consultations, A&E attendances and inpatient admissions. The economic burden is huge-
      hospital admissions alone for bronchiectasis cost NHS Lothian just over 1 million pounds
      alone last year.

      LIMITATIONS OF TREATMENT There are few evidence based long term treatments currently
      available. Long term antibiotics are a feasible option, but with the increasing problems of
      antimicrobial resistance and side effects, in particular Clostridium difficile and
      methicillin resistant Staphylococcus aureus (MRSA), there is an international drive to reduce
      antibiotic usage. There is an urgent need for novel non antibiotic treatments.

      Statins as a potential new non antibiotic treatment in bronchiectasis Excessive neutrophilic
      airways inflammation is the central feature of bronchiectasis. This paradoxically both
      promotes bacterial colonisation and perpetuates damage to the airways creating a vicious
      cycle of bacterial colonisation and inflammation.1-3

      Statins have been shown to have powerful anti-inflammatory effects.4-6 In animal models,
      statins can reduce neutrophil recruitment to the inflamed lung and reduce protease activity.7
      Statin treatment has been shown to reduce epithelial cell adherence and invasion by
      Streptococcus pneumoniae in-vitro suggesting a role for statins in preventing bacterial
      colonisation.8 In healthy controls exposed to lipopolysaccharide to induce acute lung
      inflammation, pre-treatment with simvastatin reduced neutrophil accumulation in the lung and
      inhibited production of myeloperoxidase, tumour necrosis factor-alpha, matrix
      metalloproteinases and C-reactive protein.9 There was also an increase in neutrophil
      apoptosis, suggesting that statins may aid the resolution of inflammation in the airway.10

      STUDY HYPOTHESIS The investigators hypothesise that long term statin treatment will improve
      patients' symptoms through its anti-inflammatory effect. The beneficial effects on patient
      symptoms (cough, sputum volume, bacterial load, airway function, exercise tolerance,
      exacerbation frequency and health related quality of life) will be consequent on reduced
      neutrophilic airways inflammation.

      Planned study

        -  This is a randomised double blind placebo controlled trial to assess the efficacy of
           atorvastatin therapy in patients with clinically significant bronchiectasis.

        -  No such study has previously been undertaken (PUBMED Search "statins" and
           "bronchiectasis" 18 March 2010- no relevant articles).

        -  This is a unique proof of principle study assessing a new non antibiotic treatment that
           could benefit all patients with clinically significant bronchiectasis, without the side
           effect profile of long term antibiotics.

        -  Following this proof of principle study, the investigators aim to design a large
           multi-centred study assessing long term statins as a new treatment.

      References

        1. Stockley RA et al. Elastolytic activity of sputum and its relation to purulence and to
           lung function in patients with bronchiectasis. Thorax 1984;39(6):408-413.

        2. Hill AT et al. Association between airway bacterial load and markers of airway
           inflammation in patients with stable chronic bronchitis. Am J Med 2000;109(4):288-95.

        3. Inflammation: a two-edged sword—the model of bronchiectasis. Cole PJ. Eur J Respir Dis
           Suppl. 1986;147:6-15.

        4. Ridker PM et al. C-reactive protein levels and outcomes after statin therapy. N Engl J
           Med 2005;352:20-8.

        5. Terblanche M et al. Statins and Sepsis: multiple modifications at multiple levels.
           Lancet Infect Dis. 2007; 7(5):358-368.

        6. Vaughan CJ, Murphy MB, Buckley BM. Statins do more than just lower cholesterol. Lancet
           1996;348:1079-82.

        7. Fessler MB et al. A role for HMG coenzyme A reductase in pulmonary inflammation and host
           defense. Am J Respir Crit Care Med 2005;171:606-15.

        8. Rosch JW et al. Statins protect against fulminant pneumococcal infection and cytolysin
           toxicity in a mouse model of sickle cell disease. J Clin Invest 2010; 120(2);627-35.

        9. Shyamsundar M et al. Simvastatin decreases lipopolysacchraide-induced pulmonary
           inflammation in healthy volunteers. Am J Respir Crit Care Med. 2009 179:1107-1114.

       10. Watt AP et al. Neutrophil apoptosis, proinflammatory mediators and cell counts in
           bronchiectasis. Thorax 2004;59(3):231-6.
    

Study Phase

Phase 4

Study Type

Interventional


Primary Outcome

The primary endpoint of this study is a reduction in cough at 6 months compared to baseline as measured by the Leicester Cough Questionnaire score.

Secondary Outcome

 pulmonary physiology and assessment of exercise capacity

Condition

Bronchiectasis

Intervention

Atorvastatin

Study Arms / Comparison Groups

 Atorvastatin
Description:  Atorvastatin 80mg once daily

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

60

Start Date

November 2010

Completion Date

August 2013

Primary Completion Date

August 2013

Eligibility Criteria

        Inclusion Criteria:

          -  Patients aged 18-75 will be recruited. All will have an established radiological
             diagnosis of bronchiectasis (CT of the chest). Patients will have clinically
             significant bronchiectasis expectorating mucopurulent or purulent sputum when
             clinically stable with at least 2 chest infections per year.

        Exclusion Criteria:

          -  current smokers or ex-smokers of less than 1 year; >15 pack year history

          -  cystic fibrosis

          -  active allergic bronchopulmonary aspergillosis

          -  active tuberculosis

          -  poorly controlled asthma

          -  pregnancy or breast feeding

          -  known allergy to statins

          -  active malignancy

          -  chronic liver disease

          -  established cardiovascular or cerebrovascular disease

          -  statin use in the last year

          -  patients on long term oral macrolides due to the interaction with statin therapy
             patients chronically colonised with Pseudomonas aeruginosa (defined as two or more
             isolates of Pseudomonas aeruginosa whilst clinically stable in 6 months prior to the
             study).
      

Gender

All

Ages

18 Years - 75 Years

Accepts Healthy Volunteers

No

Contacts

Adam T Hill, MBChB MD, , 

Location Countries

United Kingdom

Location Countries

United Kingdom

Administrative Informations


NCT ID

NCT01299181

Organization ID

2010-022040-20


Responsible Party

Sponsor

Study Sponsor

University of Edinburgh

Collaborators

 NHS Lothian

Study Sponsor

Adam T Hill, MBChB MD, Principal Investigator, NHS Lothian


Verification Date

August 2013