Azithromycin a Treatment for Pulmonary Sarcoidosis
Condition: Sarcoidosis, Pulmonary
MeSH terms: Sarcoidosis, Pulmonary; Sarcoidosis
Study type: Interventional
Phase: Phase 2

Summary: 
      Patients with sarcoidosis need treatment options that effectively control their disease
      without causing undesirable side effects. An appealing strategy is to repurpose existing
      drugs which possess beneficial immune modulating activity and are safe for long-term use.
      Recently, increased activity of the mTOR intracellular signalling pathway in inflammatory
      cells has emerged as a key driver of granulomatous inflammation in mouse models and patients
      with sarcoidosis. The macrolide antibiotic azithromycin directly inhibits mTOR activity in
      inflammatory cells, making it a prime target for drug repurposing in sarcoidosis.
      Azithromycin has an acceptable tolerability profile when used for long-term treatment of
      other chronic respiratory disease Single centre open label clinical trial of oral
      azithromycin 250 mg once daily for 3 months in 20-30 patients with pulmonary sarcoidosis.

      The Investigator have opted for an open label study because this will be the first study of
      azithromycin in sarcoidosis. Trial assessments will be performed according to standards of
      Good Clinical Practice with assessments at baseline, 1, and 3 months. All other clinical
      care, investigations, and treatment (if indicated) will remain the responsibility of the
      treating physician and based on clinical MDT consensus decisions.
    

Detailed description: 
      Disease behavior in sarcoidosis is variable and difficult to predict. Spontaneous improvement
      may occur, but even then evidence of persistent low grade granulomatous inflammation is
      common and disabling symptoms such as fatigue may persist. Patients with milder chronic
      sarcoidosis may suffer significant symptoms and disability, but active monitoring and
      supportive care are the only currently suitable management options. Recurrence after
      remission is a problem, with some patients suffering from chronic ill health, progressive
      disease and fibrosis, potentially leading to organ failure and death or transplantation.
      Management is further complicated because some patients with symptomatic, progressive
      sarcoidosis have a high burden of granulomatous disease, often affecting the lungs, whereas
      other patients have limited disease in a dangerous location such as the heart or nervous
      system.

      Cure is not a realistic option whilst the cause(s) of sarcoidosis remain unknown. Ideally,
      treatment should be aimed at preventing or slowing progression to irreversible fibrosis and
      organ failure, reducing symptoms, and improving quality of life. The evidence that currently
      used treatments achieve these aims is weak, and the risk of adverse effects is concerning for
      patients and may outweigh perceived benefits. Treatment with corticosteroids is suppressive
      rather than curative, and guidelines recommend at least 1 years' therapy for patients with
      progressive disease. In the BTS sarcoidosis study, long term corticosteroids given to
      patients with non-resolving pulmonary disease after six months' initial observation improved
      lung function and chest x-ray appearances by a small amount. Importantly, of patients who
      were given early steroids for troublesome symptoms, almost half were still taking steroids 5
      years later. Yet whether steroids prevent fibrosis or improve clinically meaningful outcomes
      that are important to patients in the longer term is unknown. Worryingly, there is evidence
      that early steroid therapy may promote more aggressive disease later on. Side effects of
      steroid therapy are often distressing and disfiguring, and sometimes serious or fatal. When
      sarcoidosis is refractory to steroid treatment, second line immunomodulators such as
      methotrexate, azathioprine, or mycophenolate are commonly prescribed based on their efficacy
      in treating rheumatic diseases, and are recommended in guidelines. In sarcoidosis, the best
      evidence is that they are steroid sparing (i.e. permit a lower dose of corticosteroid to be
      used). As with steroids, long term benefits have not been demonstrated and liver and bone
      marrow toxicity is a concern, requiring regular blood testing.

      Whilst a unifying cause of sarcoidosis remains elusive, it has been established that
      inflammatory cells including T lymphocytes, monocytes, and macrophages become hyper-activated
      in the lungs and peripheral blood. Recently, using mouse models it has been shown that
      chronic signalling through the mTOR complex 1 (mTORC1) in macrophages pathway drives the
      formation of sarcoid-like granulomas that closely mimic non-resolving sarcoidosis in humans.
      mTOR (mammalian/mechanistic target of rapamycin) links growth factors and availability of
      amino acids to protein synthesis and cell growth, proliferation, and differentiation. mTOR
      activity and gene targets correlating to sarcoidosis progression in lung biopsies have
      implicated a potential role for targeting mTOR in human disease. These datasets indicate a
      key role for mTOR pathways and the metabolic status of tissue macrophages in triggering and
      driving disease pathology.

      The macrolide antibiotic azithromycin is immunomodulatory and anti-bacterial, both of which
      are plausible beneficial properties in sarcoidosis. Many studies have implicated bacteria as
      triggers for sarcoidosis, and although convincing evidence implicating a specific organism is
      lacking, improvements in sarcoidosis have been described in antibiotic combination studies
      that included azithromycin. Beneficial immunomodulatory properties of macrolides became
      apparent in the treatment of Asian diffuse panbronchiolitis, where reduced inflammatory
      cytokine production in several cell types was demonstrated. Recently, it has been determined
      that azithromycin directly suppresses mTOR activity in a subset of T lymphocytes (CD4+
      T-cells).

      Patients with pulmonary sarcoidosis need treatment options that effectively modulate disease
      activity, reduce risk of disease progression, and improve symptoms and quality of life, with
      an acceptable side effect profile. Azithromycin is a cheap, readily available generic drug.
      Long term treatment with azithromycin has been shown to be safe in other chronic lung
      diseases. Azithromycin is preferable to other macrolide antibiotics because of its safety
      data for long term use, once daily administration, and lack of inhibition of liver CYP3A
      isoenzymes. The safety profile of azithromycin makes it preferable to non-antibiotic
      macrolide mTOR inhibitors such as rapamycin (sirolimus, used to treat transplant rejection))
      and everolimus (an anti-cancer drug). Whether azithromycin will benefit patients with
      sarcoidosis can only be answered definitively by a large multicenter clinical trial. The
      Investigators proposed exploratory study aims to facilitate this aim by exploring mechanisms
      and evaluating potential blood biomarkers, and assessing feasibility of a subsequent large
      clinical trial.
    

Intervention name(s): Azithromycin 250Mg Capsule
Intervention type(s): Drug
Intervention description(s): 250 mg OD
Intervention MeSH terms: Azithromycin
Intervention model: Single Group Assignment
Intervention model description: single centre, open label study
Masking: None (Open Label)
Primary purpose: Treatment