Pulmonary Fibrosis Clinical Trial
Official title:
Therapeutic Clinical Trial of Oral Pirfenidone for the Pulmonary Fibrosis of Hermansky-Pudlak Syndrome
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
the other.
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 this protocol.)
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, 95-HG-0193.
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