Oral Pirfenidone for the Pulmonary Fibrosis of Hermansky-Pudlak Syndrome

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
William Gahl, National Human Genome Research Institute (NHGRI)
ClinicalTrials.gov Identifier:
NCT00001596
First received: November 3, 1999
Last updated: November 30, 2012
Last verified: November 2012
  Purpose

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.


Condition Intervention Phase
Albinism
Inborn Errors of Metabolism
Oculocutaneous Albinism
Platelet Storage Pool Deficiency
Pulmonary Fibrosis
Drug: Pirfenidone
Drug: Placebo
Phase 2

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

Resource links provided by NLM:


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

Primary Outcome Measures:
  • Change in Forced Vital Capacity (36 Months) [ Time Frame: Measured at baseline and 36 months ] [ Designated as safety issue: No ]
    Change from baseline in the Forced Vital Capacity (FVC) measurement at 36 months. FVC is the volume of air that can be forcibly blown out from the lungs after full inspiration. FVC is recorded as the percentage of predicted volume (predicted FVC volume is calculated based on subject's height, age, sex, and weight).


Secondary Outcome Measures:
  • Change in Forced Vital Capacity (12 Months) [ Time Frame: Measured at baseline and 12 months ] [ Designated as safety issue: No ]
    Change from baseline in the Forced Vital Capacity (FVC) measurement at 12 months. FVC is the volume of air that can be forcibly blown out from the lungs after full inspiration. FVC is recorded as the percentage of predicted volume (predicted FVC volume is calculated based on subject's height, age, sex, and weight).

  • Change in Total Lung Capacity (36 Months) [ Time Frame: Measured at baseline and 36 months ] [ Designated as safety issue: No ]
    Change from baseline in Total Lung Capacity (TLC) measured at 36 months. TLC is the volume in the lungs at maximal inflation. TLC is recorded as the percentage of predicted volume based on subject's height, age, sex, and weight.

  • Change in Total Lung Capacity (12 Months) [ Time Frame: Measured at baseline and 12 months ] [ Designated as safety issue: No ]
    Change from baseline in Total Lung Capacity (TLC) measured at 12 months. TLC is the volume in the lungs at maximal inflation. TLC is recorded as the percentage of predicted volume based on subject's height, age, sex, and weight.

  • Change in Adjusted Diffusing Capacity of the Lung for Carbon Monoxide (36 Months) [ Time Frame: Measured at baseline and 36 months ] [ Designated as safety issue: No ]
    Change from baseline in adjusted Diffusing Capacity of the lung for carbon monoxide (DLCOa) measured at 36 months. DLCOa measures gas uptake during a single inspiration in a standard time, adjusted for subject's hemoglobin levels.

  • Change in Adjusted Diffusing Capacity of the Lung for Carbon Monoxide (12 Months) [ Time Frame: Measured at baseline and 12 months ] [ Designated as safety issue: No ]
    Change from baseline in adjusted Diffusing Capacity of the lung for carbon monoxide (DLCOa) measured at 12 months. DLCOa measures gas uptake during a single inspiration in a standard time, adjusted for subject's hemoglobin levels.

  • Change in 6 Minute Walk Test (36 Months) [ Time Frame: Measured at baseline and 36 months ] [ Designated as safety issue: No ]
    Change from baseline of the 6 minute walk test (6MWT) at 36 months. The 6MWT measures the distance that a patient can quickly walk on a flat hard surface in a period of six minutes.

  • Change in 6 Minute Walk Test (12 Months) [ Time Frame: Measured at baseline and 12 months ] [ Designated as safety issue: No ]
    Change from baseline of the 6 minute walk test (6MWT) at 12 months. The 6MWT measures the distance that a patient can quickly walk on a flat hard surface in a period of six minutes.


Enrollment: 35
Study Start Date: September 2005
Estimated Study Completion Date: September 2020
Primary Completion Date: September 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Pirfenidone
Subjects received pirfenidone 801 mg (3 pills of 267 mg each), three times daily.
Drug: Pirfenidone
Treatment with pirfenidone 801 mg (3 pills of 267 mg each), three times daily.
Other Names:
  • Deskar
  • Esbriet
Placebo Comparator: Placebo
Subjects received placebo (3 pills), three times daily.
Drug: Placebo
Placebo (3 pills), three times daily.
Other Name: Inactive matching 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 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.

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

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
William Gahl
  More Information

Additional Information:
Publications:
Responsible Party: William Gahl, Clinical Director, National Human Genome Research Institute, National Human Genome Research Institute (NHGRI)
ClinicalTrials.gov Identifier: NCT00001596     History of Changes
Other Study ID Numbers: 970085, 97-HG-0085
Study First Received: November 3, 1999
Results First Received: December 12, 2011
Last Updated: November 30, 2012
Health Authority: United States: Federal Government
United States: Food and Drug Administration

Keywords provided by National Institutes of Health Clinical Center (CC):
Albinism
Platelet Storage Pool Deficiency
Pulmonary Fibrosis
Hermansky-Pudlak Syndrome

Additional relevant MeSH terms:
Albinism
Albinism, Oculocutaneous
Fibrosis
Metabolism, Inborn Errors
Platelet Storage Pool Deficiency
Pulmonary Fibrosis
Hermanski-Pudlak Syndrome
Eye Diseases, Hereditary
Eye Diseases
Genetic Diseases, Inborn
Amino Acid Metabolism, Inborn Errors
Skin Diseases, Genetic
Hypopigmentation
Pigmentation Disorders
Skin Diseases
Metabolic Diseases
Pathologic Processes
Blood Coagulation Disorders
Hematologic Diseases
Blood Platelet Disorders
Hemorrhagic Disorders
Lung Diseases
Respiratory Tract Diseases
Blood Coagulation Disorders, Inherited
Pirfenidone
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on April 14, 2014