Oral Pirfenidone for the Pulmonary Fibrosis of Hermansky-Pudlak Syndrome - Full Text View

Sponsor:	National Human Genome Research Institute (NHGRI)
Information provided by:	National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:	NCT00001596

Purpose

Hermansky-Pudlak Syndrome (HPS) is an inherited disease which 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 ages 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 40 patients diagnosed with pulmonary fibrosis 20 who have not received steroid therapy in the last 3 months and 20 currently taking steroids. The patients will be randomly divided into 4 groups. The patients will not know if they are taking pirfenidone or a placebo "sugar pill".

Group one will be patients not taking steroids who will receive pirfenidone.
Group two will be patients not taking steroids who will receive a placebo "sugar pill"
Group three will be patients taking steroids who will receive pirfenidone.
Group four will be patients taking steroids 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 others. ...

Condition	Intervention	Phase
Albinism Inborn Errors of Metabolism Oculocutaneous Albinism Platelet Storage Pool Deficiency Pulmonary Fibrosis	Drug: Pirfenidone (Deskar) Drug: Pirfenidone	Phase II

Study Type:	Interventional
Study Design:	Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Parallel Assignment, Safety/Efficacy Study
Official Title:	Therapeutic Clinical Trial of Oral Pirfenidone for the Pulmonary Fibrosis of Hermansky-Pudlak Syndrome

Resource links provided by NLM:

Genetics Home Reference related topics: argininosuccinic aciduria citrullinemia hemophilia Lenz microphthalmia syndrome N-acetylglutamate synthase deficiency oculocutaneous albinism oculofaciocardiodental syndrome ornithine translocase deficiency Peters plus syndrome

MedlinePlus related topics: Pulmonary Fibrosis

Drug Information available for: Pirfenidone

U.S. FDA Resources

Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:

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

Secondary Outcome Measures:

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

Estimated Enrollment:	73
Study Start Date:	March 1997
Estimated Study Completion Date:	December 2012
Estimated Primary Completion Date:	December 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Treatment: Active Comparator	Drug: Pirfenidone (Deskar) Treatment
Placebo: Placebo Comparator	Drug: Pirfenidone Placebo

Detailed Description:

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 stratified, block-randomized, placebo-controlled, double-blind trial involving up to 50 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 rate of change in forced vital capacity, determined on every admission and analyzed by the random coefficients method. Secondary efficacy variables are also examined. A CT scan of the chest, bone density, and arterial blood gases are performed yearly. 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 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.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

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.

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.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00001596

Contacts

Contact: Patient Recruitment and Public Liaison Office	(800) 411-1222	prpl@mail.cc.nih.gov
Contact: TTY	1-866-411-1010

Locations

United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike	Recruiting
Bethesda, Maryland, United States, 20892

Sponsors and Collaborators

National Human Genome Research Institute (NHGRI)

More Information

Additional Information:

NIH Clinical Center Detailed Web Page This link exits the ClinicalTrials.gov site

Publications:

Anikster Y, Huizing M, White J, Shevchenko YO, Fitzpatrick DL, Touchman JW, Compton JG, Bale SJ, Swank RT, Gahl WA, Toro JR. Mutation of a new gene causes a unique form of Hermansky-Pudlak syndrome in a genetic isolate of central Puerto Rico. Nat Genet. 2001 Aug;28(4):376-80.

Gahl WA, Brantly M, Kaiser-Kupfer MI, Iwata F, Hazelwood S, Shotelersuk V, Duffy LF, Kuehl EM, Troendle J, Bernardini I. Genetic defects and clinical characteristics of patients with a form of oculocutaneous albinism (Hermansky-Pudlak syndrome). N Engl J Med. 1998 Apr 30;338(18):1258-64.

Gahl WA, Brantly M, Troendle J, Avila NA, Padua A, Montalvo C, Cardona H, Calis KA, Gochuico B. Effect of pirfenidone on the pulmonary fibrosis of Hermansky-Pudlak syndrome. Mol Genet Metab. 2002 Jul;76(3):234-42.

Responsible Party:	National Institutes of Health ( William A. Gahl, M.D./National Human Genome Research Institute )
Study ID Numbers:	970085, 97-HG-0085
Study First Received:	November 3, 1999
Last Updated:	November 17, 2009
ClinicalTrials.gov Identifier:	NCT00001596 History of Changes
Health Authority:	United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):

Albinism
Platelet Storage Pool Deficiency
Pulmonary Fibrosis
Hermansky-Pudlak Syndrome
Hermansky-Pudlak Syndrome

Additional relevant MeSH terms:

Anti-Inflammatory Agents
Antineoplastic Agents
Fibrosis
Physiological Effects of Drugs
Pulmonary Fibrosis
Albinism
Metabolism, Inborn Errors
Hypopigmentation
Pathologic Processes
Hemorrhagic Disorders
Respiratory Tract Diseases
Sensory System Agents
Therapeutic Uses
Syndrome
Eye Diseases, Hereditary

Anti-Inflammatory Agents, Non-Steroidal
Analgesics
Skin Diseases, Genetic
Lung Diseases, Interstitial
Disease
Metabolic Diseases
Skin Diseases
Amino Acid Metabolism, Inborn Errors
Hematologic Diseases
Eye Diseases
Pigmentation Disorders
Blood Coagulation Disorders
Blood Platelet Disorders
Platelet Storage Pool Deficiency
Pharmacologic Actions

ClinicalTrials.gov processed this record on November 27, 2009