• Change in Forced Vital Capacity [ Time Frame: 3 years; measured every 4 months ] [ Designated as safety issue: No ]
  

• Change in other pulmonary function parameters; 6 minute walk [ Time Frame: 3 years; measured every 4 months ] [ Designated as safety issue: No ]
  

Hermansky-Pudlak Syndrome (HPS) is a rare autosomal recessive disease consisting of oculocutaneous albinism and a platelet storage pool defect. The most serious complication of this disorder, which is common in Puerto Rico, is pulmonary fibrosis, generally fatal in the fourth or fifth decade. There is no treatment for the pulmonary disease of HPS, which resembles idiopathic pulmonary fibrosis. However, a drug called pirfenidone has antifibrotic effects in animal models of lung fibrosis. Pirfenidone is an IND drug initially provided by Marnac, Inc.; InterMune, Inc., now holds the license. Pirfenidone inhibits cytokine-induced inflammation. Reported side effects include gastrointestinal upset, a photosensitivity rash, and palpitations. Between 1997 and 2001, we performed a randomized, placebo-controlled trial under this protocol that found pirfenidone to be safe and efficacious when analyzed using a repeated measures model. Using a random coefficients model, however, the data were definitive only in the restricted group of subjects whose initial forced vital capacity was greater than 50% of predicted. Vecause the repeated measures analysis had been chosen a priori as the optimal model, the DSMB stopped the study and directed that all patients receive perfenidone. (Of the 23 original patients, ten are alive and 3 are still receiving pirfenidone under this protocol.) However, to prove efficacy of pirfenidone, a new trial must be initiated in which all patients have an initial FVC greater than 50 percent of predicted, and in which the alpha priori method of analysis is the random coefficients model. Hence, the protocol has been amended to include a stratified, block-randomized, placebo-controlled, double-blind trial involing up to 50 HPS patients whose forced vital capacity is 51-85 percent of predicted. For every patient randomly assigned to the placebo group, two will receive pirfenidone. Patients will largely be drawn from the Puerto Rican population and will be previously or simultaneously enrolled in clinical protocol 95-HG-193. They will be admitted to the NIH Clinical Center for 2-3 day admissions every 4 months. The primary efficacy variable will be rate of change in forced vital capacity, determined on every admission and analyzed by the random coefficients method. Secondary efficacy variables will also be examined. A CT scan of the chest, bone density, and arterial blood gases will be performed yearly.

• INCLUSION/EXCLUSION CRITERIA

For the portion of the protocol involving continuations of pirfenidone treatment, the criteria are simply previous enrollment in 97-HG-0085.

For enrollment in the new clinical trial, the inclusion criteria involve enrollment in protocol 95-HG-0193, "Clinical and Basic Investigations into Hermansky-Pudlak Syndrome". This itself requires a diagnosis of HPS based upon molecular grounds or the electron microscopic demonstration of deficiency of platelet dense bodies. In addition, for protocol 97-HG-0085, patients must:

• Be over 18 years of age.
• Have an FVC greater than 50 percent and less than or equal to 85 percent of predicted OR a hemoglobin-corrected DL(co) greater than 35 percent and less than or equal to 80 percent of predicted, with no evidence of a pulmonary embolism.
• Have evidence of reduced exercise tolerance lasting longer than one week on either the St. George's Hospital Respiratory Questionnaire or the Dyspnea Perception Scale.
• FEV(1)/FVC greater than 80 percent of predicted after bronchodilators.
• No evidence of improvement in pulmonary fibrosis within the past year defined as an FVC increased by 10 percent or a DL(co) increased by 15 percent.
• Distance walked greater than or equal to 150 meters (492 feet) with oxygen saturation greater than or equal to 83 percent on less than or equal to 6 L/min. of oxygen during the 6-Minute Walk Test (6MWT).
• Be available, willing, and able to come to the NIH Clinical Center for admission every 4 months for three years.

EXCLUSION CRITERIA

• History of clinically significant environmental exposure known to cause pulmonary fibrosis (including but not limited to drugs, asbestos, beryllium, radiation, domestic birds).
• An explanation for interstitial lung disease other than HPS, including but not limited to radiation, sarcoidosis, hypersensitivity pneumonitis, bronchiolitis obliterans organizing pneumonia, cancer.
• Diagnosis of any connective tissue disease including but not limited to scleroderma systemic lupus erythematosus, rheumatoid arthritis.
• Listing on a lung transplantation waiting list.
• Pregnancy or lactation
• Cigarette smoking in the past 6 months
• History of ethanol abuse or recreational drug use in the past two years
• History of human immunodeficiency virus (HIV) or chronic viral hepatitis infection
• Chronic use of high-dose steroids (greater than 10 mg prednisone/day)
• Prior use of perfenidone
• Use of any of the following within 28 days of enrollment: investigational therapy, cytotoxic/immunosuppressive agents other than corticosteroids (including but not limited to azathioprine, cyclosphosphamide, methotrexate, cyclosporine); cytokine modulators (including but not limited to etanercept and infliximab); therapies targeted to treat pulmonary fibrosis (including but not limited to D-penicillamine, colchicines, interferon gamma- 1b, bosentan, N-acetylcysteine
• Any severe medical complication including but not be limited to uncontrolled seizures, repeated transient ischemic attacks, abnormal mental status, severe ataxia, uncontrolled migraine headaches, diplopia, repeated episodes of syncope, untreated clinical depression, recent myocardial infarction (past 6 months), unstable angina, clinically relevant arrhythmias, uncontrolled hypotension or hypertension (systolic blood pressure less than 80 or greater than 180 mm Hg), myocarditis, hepatomegaly, (liver greater than 3 cm below the right costal margin), renal glomerular impairment (creatinine clearance less than 35 ml/min/1.73 m(2), pancreatitis, toxic thyroiditis, malignancy (except basal cell carcinoma)
• Medications with a high frequency of life threatening side effects
• Significant laboratory abnormalities, including but not limited to serum potassium less than 3.0 or greater than 5.4 mEq/L, SGPT greater than 100 U/L, CK greater than 700 U/L, hemoglobin less than 9.0 g/dL, platelets less than 70 k/mm(3), leucocyte count less than 2.0 k/microliter, or cholesterol greater than 400 mg/dL.
• For women of child bearing age, failure to have an effective method of birth control.