Atorvastatin to Treat Pulmonary Sarcoidosis
Condition: Sarcoidosis, Pulmonary
MeSH terms: Sarcoidosis, Pulmonary; Sarcoidosis
Study type: Interventional
Phase: Phase 2

Summary: 
      This study will determine if atorvastatin (Lipitor) can help patients with pulmonary (lung)
      sarcoidosis and replace or reduce the need for patients to take steroids, such as prednisone.
      Sarcoidosis is an inflammatory disease that can affect nearly any part of the body. Pulmonary
      sarcoidosis may resolve on its own or it may progress to irreversible lung damage,
      disability, and death. Many sarcoidosis patients are treated with prednisone, but the drug is
      not effective in all patients, and it can cause serious side effects, such as high blood
      pressure, sugar diabetes, eye cataracts, and bone thinning.

      Patients with stage II or III pulmonary sarcoidosis between 18 and 70 years of age who
      require prednisone may be eligible for this study. Candidates are screened with the tests and
      procedures described below.

      Participants are randomly assigned to one of two treatment groups: one group takes
      atorvastatin; the other takes a placebo (a look-alike pill that has no active ingredient to
      fight sarcoidosis). Both groups take the pills by mouth once a day for 12 months. When
      treatment begins, participants begin to have their prednisone dosage tapered (reduced). The
      tapering is done over 8 weeks until the dose is reduced by 90 percent. Patients are evaluated
      periodically to determine if the two groups differ in how long they can remain on the reduced
      dose of prednisone without having their symptoms recur, requiring an increase in the
      prednisone dose. A full battery of tests is done at the initial screening visit and at the
      26- and 52-week follow-up visits, requiring hospitalization for 3-5 days. Additional interim
      outpatient assessments are done at 6, 12, 18 and 36 weeks.

      The full battery of tests at the initial screening and the 26- and 52-week visits includes
      the following:

        -  Medical history, physical examination, blood and urine tests, assessment of disease
           severity and activity.

        -  Questionnaires.

        -  Chest x-ray (CXR) and computed tomography (CT) scan.

        -  Abdominal ultrasound.

        -  Six-minute walk test (6MWT)

        -  Exercise testing and blood gases

        -  Pulmonary function tests (PFT)

        -  Maximum incremental ventilatory performance test (MIVP)

        -  Exhaled nitric oxide and carbon monoxide (Exhaled NO and CO)

        -  Bronchoscopy and lavage

      Interim testing at 6, 12, 18 and 36 weeks includes PFT, MIVP, Exhaled NO and CO, CXR,
      questionnaire, blood tests, and 6MWT.

      Six months after completing the study, participants fill out a questionnaire.
    

Detailed description: 
      Background

      Sarcoidosis is a multi-system granulomatous inflammatory disease. Pulmonary involvement is
      most common. Patients typically experience fatigue, weakness and dyspnea. Respiratory muscle
      weakness, which may be secondary to granulomatous inflammation, is associated with dyspnea
      and decreased quality of life (QOL). The disease can remit spontaneously or become chronic,
      with exacerbations and remissions. In some patients, it can progress to pulmonary fibrosis
      and death. Granulomatous inflammation is characterized primarily by accumulation of
      monocytes, macrophages and activated T-lymphocytes, with increased production of key
      inflammatory mediators, TNF-alpha, INF-gamma, IL-2 and IL-12, characteristic of a
      Th1-polarized response (T-helper lymphocyte-1 response). Corticosteroids are the current
      mainstay of treatment, but their long-term benefits are not certain. Because steroids often
      produce undesirable side effects, investigations to identify alternative therapies are
      warranted. There is sufficient evidence to test the proof of concept that pathways targeted
      by statins will have a therapeutic effect in sarcoidosis, since, in pre-clinical studies,
      statins blunt Th1-mediated inflammatory responses.

      Aims

      The study involves a double-blind placebo-controlled, randomized trial which aims to
      determine if atorvastatin administration results in less steroid use and longer steroid-free
      intervals in patients with pulmonary sarcoidosis who require prednisone treatment.

      Methods

      Patients, who are 18-70 years old, with stage II or III pulmonary sarcoidosis, diagnosed by a
      compatible clinical history and supported by a lung, lymph node, or tissue biopsy, will be
      enrolled in the study, if they require prednisone therapy. The patients will be randomly
      assigned to two groups; as prednisone is tapered, one group will receive placebo and the
      other, atorvastatin. The two study drugs will be administered for twelve months, during which
      time patients will be periodically evaluated as to their clinical status and prednisone
      requirements. Pill counts and patient diaries will be used to determine the amount of steroid
      use during the study period. Patients with pulmonary fibrosis greater than 50 percent of
      total lung volume or severe co-morbidities will be excluded from the trial.

      The primary endpoint is the duration of the steroid-sparing period. Secondary clinical and
      physiological endpoints are intended to analyze possible anti-inflammatory and beneficial
      effects of the drugs. Since there is no gold standard outcome measure in sarcoidosis, four
      categories of secondary endpoints will be used to characterize the effects of the therapeutic
      agent on the clinical course of the disease: imaging (high resolution chest CT); quality of
      life assessments (SF-36, and SGRQ), anti-inflammatory effects (biomarkers and relapse rates),
      and functional effects (CPET, PFTs). Finally, we will study the utility of exhaled nitric
      oxide and carbon monoxide in monitoring disease activity.
    

Intervention name(s): Atorvastatin; Placebo Oral Tablet
Intervention type(s): Drug; Other
Intervention description(s): Placebo vs. Atorvastatin; Placebo: Sham Therapy in an oral tablet formulation
Other intervention name(s): Lipitor; Placebo
Intervention MeSH terms: Atorvastatin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Granulomatous Inflammation; Steroid-Sparing; Pulmonary Function; Sarcoidosis, Pulmonary; Statins (Atorvastatin); Biomarkers; Nitric Oxide; Disease Activity; Quality of Life; Corticosteroids; Pulmonary Sarcoidosis; Sarcoidosis