Pilot Study of a Multi-Drug Regimen for Severe Pulmonary Fibrosis in Hermansky-Pudlak Syndrome

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, pulmonary fibrosis, occurs only in genetic subtypes HPS-1 and HPS-4 and is
generally fatal in the fourth or fifth decade. HPS-1 is very common in northwest Puerto
Rico. There is no effective treatment for the pulmonary disease of HPS (HPS-PF), which
resembles idiopathic pulmonary fibrosis (IPF). A preliminary study of the antifibrotic drug,
pirfenidone, gave promising results for mild to moderate HPS-PF, but not for severe
pulmonary fibrosis. A second study is currently addressing only mild to moderate HPS-PF.
Other drugs, studied in IPF as single agents, have some efficacy for mild to moderate
disease, but none has had a major effect on mortality. Recently, a call has been made for
consideration of multi-drug therapy (i.e., an oncologic approach) for severe pulmonary
fibrosis. Based upon positive responses from companies producing relevant drugs, we propose
a multi-drug trial using five agents: Losartan, Zileuton, a generic statin (Pravastatin),
generic N-acetylcysteine, and generic Erythromycin. Participants with severe pulmonary
fibrosis will be drawn largely from the Puerto Rican population. Eligibility will require a
molecular diagnosis of HPS-1 or HPS-4, radiographic evidence of interstitial lung disease,
persistent pulmonary function testing less than or equal to 45% of predicted after
bronchodilation, and absence of other causes of lung dysfunction. Participants will be
admitted to the NIH Clinical Center for a 21-day admission to establish baseline function
and to begin medication therapy. Follow-up admissions (3 days) will occur every 3 months.
The primary outcome parameter will be survival at 2 years. The main secondary outcome
parameter will be rate of decline of forced vital capacity (FVC), but serum markers of
interstitial lung disease, change in findings on CT scan of the chest, 6-min walk test, and
results of arterial blood gases will also be followed.

- INCLUSION CRITERIA:

To be eligible for this protocol, participants must:

- Have a molecular diagnosis of HPS-1 or HPS-4

- Be 18-70 years of age

- Have the expectation to live more than 3 months, i.e., an FVC greater than or equal
to 30% of predicted

- Have evidence of severe pulmonary fibrosis, i.e.:

1. A FVC less than or equal to 45% of predicted

2. Reduced exercise tolerance lasting longer than 1 week on the Dyspnea Perception
Scale

3. No evidence of improvement in pulmonary fibrosis within the past year, as
defined by an FVC increase of 10% or a DLco increase of 15%.

- Be available, willing, and able to come to the NIH Clinical Center for admission
every 3 months.

EXCLUSION CRITERIA:

- An explanation for interstitial lung disease other than HPS, including but not
limited to radiation, sarcoidosis, hypersensitivity pneumonitis, bronchiolitis
obliterans organizing pneumonia, cancer

- Pregnancy or lactation

- 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) intended for
ongoing treatment of their interstitial lung disease

- 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, colchicine,
interferon gamma-1b, bosentan;

- Any severe medical complication including but not be limited to uncontrolled
seizures, repeated transient ischemic attacks, severe ataxia, uncontrolled migraine
headaches, diplopia, repeated episodes of syncope, an untreated psychiatric disorder,
recent myocardial infarction (past 6 months), unstable angina, clinically relevant
and untreated arrhythmias, uncontrolled hypotension or hypertension (systolic blood
pressure less than 80 or greater than 180 mm Hg), myocarditis, severe congestive left
sided heart failure, hepatomegaly not due to right heart failure, renal glomerular
impairment (creatinine clearance less than 35 ml/min/1.73 m(2)), pancreatitis, toxic
thyroiditis, life-threatening malignancy;NOTE: right sided heart failure due to
pulmonary hypertension as a result of pulmonary fibrosis will not be considered an
exclusion criteria.

- 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), leukocyte
count less than 2.0 k/microL;

- For women of child-bearing age, failure to have an effective method of birth control.
Oral contraceptives will be considered inadequate without a second method due to
risk of reduced efficacy of BCP while taking Zileuton.

- Severe psychiatric disease untreated. Inability to give informed consent after
reading or having the consent read to the participant in their native language. Any
concern that there is a therapeutic misconception will be evaluated by genetic
counselor and/or appropriate mental health professionals prior to acceptance into the
study