Atorvastatin to Treat Pulmonary Sarcoidosis
Condition: Sarcoidosis, Pulmonary
MeSH terms: Sarcoidosis, Pulmonary; Sarcoidosis
Intervention: Atorvastatin; Placebo Oral Tablet
Intervention description: Placebo vs. Atorvastatin; Placebo: Sham Therapy in an oral tablet formulation
Intervention MeSH terms: Atorvastatin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 55.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No
Keywords: Granulomatous Inflammation; Steroid-Sparing; Pulmonary Function; Sarcoidosis, Pulmonary; Statins (Atorvastatin); Biomarkers; Nitric Oxide; Disease Activity; Quality of Life; Corticosteroids; Pulmonary Sarcoidosis; Sarcoidosis

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.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

        Patients are eligible for the trial if they are 18-70 years old with radiographic stages II
        and III pulmonary sarcoidosis, and are on prednisone, methotrexate, or azathioprine for
        pulmonary sarcoidosis or who are steroid-requiring. Patients with extra-pulmonary
        sarcoidosis (except cardiac and neurosarcoidosis) may be eligible as long as they have
        active pulmonary (stage II or III) sarcoidosis.

        Steroid-Requiring History:

        A steroid-requiring patient is one who was previously stable but who ultimately experiences
        (a) increased symptoms associated with radiographic deterioration, and/or, (b) met the
        criteria for relapse and/or functional deterioration. In addition, patients who were
        prescribed prednisone for sarcoidosis, but have self-discontinued it (yet still have
        clinical and symptomatic disease and/or evidence of pulmonary functional deterioration)
        will be considered steroid-requiring.

        This latter group of steroid-requiring patients is eligible for enrollment if they are
        willing to resume taking their latest stabilizing dose of prednisone for at least four
        weeks prior to study entry. If their dose cannot be determined, then 40 mg will be used.

        Therefore, a history of symptomatic or clinical deterioration leading to therapy
        initiation, or a history of decline associated with attempts to decrease therapy should be
        established. Medical records review and discussion with the prescribing physician will be
        used to establish this history.

        Radiographic Stages of Pulmonary Sarcoidosis:

        STAGE< TAB> DESCRIPTION

        0< TAB> Normal Chest Radiograph

        I< TAB> Bilateral Hilar Lymphadenopathy

        II< TAB> Pulmonary Infiltration and Bilateral Hilar Lymphadenopathy

        III< TAB> Pulmonary Infiltration alone

        Steroid-requiring refers to one of three situations:

        Patients who meet relapse criteria or functional deterioration.

        Functional deterioration criteria that warrants prednisone therapy includes:

        If VC fell to 75% of the best recorded value for the patient before any treatment

        If VC fell to greater than 50% of predicted value

        IF DLCO fell to less than 60% of the best recorded value prior to their treatment

        Patients who are on a previously prescribed systemic steroid, or alternative agent such as
        methotrexate or azathioprine, primarily for pulmonary sarcoidosis. Alternative agents must
        first be changed to roughly equivalent anti-inflammatory dose of prednisone and the patient
        should be stable on this dose for at least four weeks prior to randomization.

        Patients who have substantial respiratory symptoms (distressing cough or dyspnea, which
        interferes with daily activities that would warrant therapy as per the standard of practice
        in the US.

        Extra Pulmonary Sarcoidosis:

        Patients with extra pulmonary sarcoidosis (except neurosarcoidosis and cardiac sarcoidosis)
        may be eligible as long as they have active pulmonary (stage II or III) sarcoidosis. All
        patients will be referred to an NIH ophthalmologist. Steroid therapy may be modified based
        upon the recommendations of the consultants, as well as per the lapse criteria described
        above.

        EXCLUSION CRITERIA:

          -  Moderate to severe pulmonary fibrosis (stage IV sarcoidosis greater than 50% fibrosis)

          -  Lung Disease such as asthma, COPD, ILD (other than sarcoid-related)

          -  History of significant beryllium or asbestos exposure

          -  Pregnancy; or Active lactation/ child-bearing age female without appropriate birth
             control methods

          -  HIV disease

          -  Hepatitis C and Active Hepatitis B

          -  Other intervention protocols

          -  Immunosuppressive therapy (systemic or inhaled) other than corticosteroids or
             methotrexate

          -  Significant cardiac disease (NYSHA class greater than III), or serious coronary
             disease (unstable angina)

          -  Use of statins within 12 weeks of enrollment

          -  Allergies or intolerance to statins

          -  Liver disease (transaminases greater than 1.5X upper limits of normal) or cirrhosis

          -  Bleeding diathesis that is not correctable

          -  Inability to perform CPET (cycle ergometer) or PFT maneuvers

          -  Inability to understand the risks of the trial and the inability to complete the
             questionnaire

          -  Malignancy-- requiring chemotherapy or radiation therapy; except certain types of skin
             cancer that have been excised and have not spread.

          -  Myopathy, diagnosed via muscle biopsy (other than sarcoid-related myopathy); CPK
             grater than 1.5 upper limits of normal

          -  Surgical Risk Category [American Society of Anesthesiologists (ASA) class IV

          -  Ingestion of grapefruit juice or certain herbal preparations (see below), or
             medications that are potent inhibitors or inducers of the CYP3A4 system (see section
             12.4 under precautions)

          -  Alcohol abuse (greater than 4 drinks/day)

          -  Bleeding into the brain or parts of the eyes (retina) (within the past year prior to
             enrollment)

          -  Uncontrolled Hypertension (SBP greater than 185 or DBP greater than 100 on two or more
             visits or assessments)

          -  Uncontrolled Diabetes Mellitus (Serum glucose level on two or more tests per day
             greater than 250 mg/dl or erratic blood sugar levels, noted on at least 2 or more
             assessments; and/or HgbA1C greater than 2x the upper limits of normal).

          -  Neurosarcoidosis

          -  Sarcoid Uveitis (Posterior Uveitis) or any Uveitis that cannot be managed with topical
             steroids alone, as determined by an ophthalmologist

          -  (Clinically apparent) Cardiac Sarcoidosis

          -  Active Smoker (Smoked within the past 2 months prior to randomization)

          -  Sickle cell disease (SS, SC, and sickle cell-beta thalassemia)

          -  Aseptic necrosis of the hip joints

        Patients taking the following preparations will not be allowed to participate in the study
        unless they agree to discontinue usage at least two weeks prior to randomization and for
        the duration of the study period: grapefruit juice and herbal remedies that may lead to
        severe liver injury and/or muscle injury if taken with atorvastatin, including: Skullcap,
        chaparral, Germander, Jin Bu Huan, Valerian, Comfrey, and Eucalyptus. Since other products
        such as St. John s Wort, oat bran, and pectin can reduce the effectiveness of atorvastatin,
        they and similar agents, should also be discontinued at least two weeks before
        randomization and for the duration of the study period.

        Subjects with inactive hepatitis B will require antiviral prophylaxis with an agent such as
        lamivudine, while on prednisone therapy.