Hermansky-Pudlak Syndrome (HPS) is an inherited disease that results in decreased
pigmentation (oculocutaneous albinism), bleeding problems due to a platelet abnormality
(platelet storage pool defect), and storage of an abnormal fat-protein compound (lysosomal
accumulation of ceroid lipofuscin).
The disease can cause poor functioning of the lungs, intestine, kidneys, or heart. The most
serious complication of the disease is pulmonary fibrosis and typically causes death in
patients 40 - 50 years old. The disorder is common in Puerto Rico, where many of the
clinical research studies on the disease have been conducted. Neither the full extent of the
disease nor the basic cause of the disease is known. There is no known treatment for HPS.
The drug pirfenidone blocks the biochemical process of inflammation and has been reported to
slow or reverse pulmonary fibrosis in animal systems.
In this study researchers will select up to 40 HPS patients diagnosed with pulmonary
fibrosis. The patients will be randomly divided into 2 groups. The patients will not know if
they are taking pirfenidone or a placebo "sugar pill".
1. Group one will be patients who will receive pirfenidone.
2. Group two will be patients who will receive a placebo "sugar pill"
The major outcome measurement of the therapy will be a change in the lung function (forced
vital capacity). The study will be stopped if one therapy proves to be more effective than
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. Because the repeated measures analysis had been chosen a
priori as the optimal model, the DSMB stopped the study and directed that all patients
receive pirfenidone. (Of the 23 original patients, 3 are still receiving pirfenidone under
Now, to prove efficacy of pirfenidone, we are conducting a block-randomized,
placebo-controlled, double-blind trial involving up to 40 HPS patients whose forced vital
capacity is 51-85% of predicted. For every patient randomly assigned to the placebo group,
two will receive pirfenidone. Patients are largely drawn from the Puerto Rican population
and are simultaneously enrolled in clinical protocol 95-HG-193. They are admitted to the NIH
Clinical Center for 2-3 day admissions every 4 months. The primary efficacy variable is
change in forced vital capacity, determined on every admission. Secondary efficacy variables
are also examined. A CT scan of the chest and bone densitometry are performed. After 4 years
of patient accrual, 35 patients were enrolled; the original statistical analysis plan (SAP)
called for 39 patients to be enrolled within one year. The NHGRI DSMB revised the original
SAP to perform an interim data analysis 12 months after 30 patients were enrolled, i.e., in
May of 2009. That analysis directed the study to stop due to futility. However, this
protocol will continue to provide pirfenidone to the three original protocol patients still
enrolled, and to any pirfenidone-treated patients who choose to undergo pulmonary lavage to
help us determine the effects of pirfenidone on the cytokine profile of alveolar
macrophages. The lavages would require enrollment in a separate protocol. The treatment drug
will be stopped immediately for all placebo patients and for pirfenidone patients who do not
plan to enroll in the lavage protocol. Pirfenidone treatment will stop just after the lavage
is performed on patients who do enroll in the lavage protocol, 04-HG-0211. All patients will
be invited to continue to come to the NIH annually under the HPS natural history protocol,
- INCLUSION 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.
- History of clinically significant environmental exposure known to cause pulmonary
fibrosis (including but not limited to drugs, asbestos, beryllium, radiation,
- 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 pirfenidone
- 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,
colchicine, 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 m2, 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/mm3, 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.