Atorvastatin to Treat Pulmonary Sarcoidosis

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.

- 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 neurosarcoid) 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 neurosarcoid and cardiac sarcoid) 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,
Chapparal, 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.