Atorvastatin in Bronchiectasis in Patients With Pseudomonas Aeruginosa

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Brief Title

Atorvastatin in Bronchiectasis in Patients With Pseudomonas Aeruginosa

Official Title

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

Brief Summary

      Statins are a class of drug used to prevent heart attacks and strokes by lowering blood
      cholesterol levels. They have also been found to have a beneficial "side effect" of lowering
      the level of inflammation in the body. This is thought to be one of the reasons they are
      effective in treating heart attacks and strokes. Laboratory experiments have shown that
      statins reduce lung inflammation in response to bacteria and this is a promising development
      for the treatment of chest infections.

      Bronchiectasis is a chronic disabling lung disease characterised by chronic sputum production
      and recurrent chest infections. 2/3 of patients are chronically colonised with bacteria
      (normally the lungs are sterile) and this leads inflammation in the lung and in the rest of
      the body.

      There are no effective treatments for bronchiectasis other than antibiotics for chest
      infections. With increasing antibiotic use, there is increasing antibiotic resistance and new
      treatments for this disease are needed.

      The investigators intend to study Atorvastatin in patients with bronchiectasis with
      colonization with pseudomonas aeruginosa. The investigators will give Atorvastatin to 16
      patients with this disease while 16 patients will receive placebo. This will be a crossover
      study where patients will receive atorvastatin or placebo for 3 months, followed by a statin
      wash out period of 6 weeks. Thereafter the groups will cross over and the group receiving
      atorvastatin will now receive placebo and those receiving placebo will receive atorvastatin
      for 3 months. The investigators will measure inflammation in their lungs and in the rest of
      their body before and after treatment with atorvastatin. The investigators will also assess
      their quality of life and number of chest infections over a 7.5 month period.

      This pilot study will determine if there is any role for statins are an anti-inflammatory
      agent in patients with bronchiectasis.

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 We 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 cross over 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, we aim to design a large multi-centred study
           assessing long term statins as a new treatment.

             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

             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;

             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


Primary Outcome

The primary endpoint of this study is a reduction in cough at 3 months compared to baseline as measured by the Leicester Cough Questionnaire score.

Secondary Outcome

 pulmonary physiology and assessment of exercise capacity





Study Arms / Comparison Groups

Description:  Atorvastatin 80mg once daily for 3 months, 1.5 month wash out, then Placebo for 3 months


* 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


Estimated Enrollment


Start Date

November 2010

Completion Date

May 2017

Primary Completion Date

June 2015

Eligibility Criteria

        Inclusion Criteria:

          -  Patients aged 18-80 will be recruited.

          -  All will have an established radiological diagnosis of bronchiectasis (CT of the

          -  Patients colonised with Pseudomonas Aeruginosa.

          -  Able to give informed consent.

        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




18 Years - 80 Years

Accepts Healthy Volunteers



Adam T Hill, MBChB MD, , 

Location Countries

United Kingdom

Location Countries

United Kingdom

Administrative Informations



Organization ID


Responsible Party


Study Sponsor

University of Edinburgh


 NHS Lothian

Study Sponsor

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

Verification Date

May 2017