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

NCT00467831 | Terminated Phase 1 Results

• 2 other identifiers: 07013207-HG-0132
• Study Type: interventional
• Target: 3
• Locations: 1 country
• Sites: 1

Brief Summary

This study will examine whether five drugs (pravastatin, Losartan, Zileuton, N-acetylcysteine and erythromycin) used together can slow the course of pulmonary fibrosis (scarring of the lung tissue) in patients with Hermansky-Pudlak Syndrome (HPS). Patients with this disease have decreased skin color (albinism), bleeding problems, and sometimes colon problems. Two of the known types of Hermansky Pudlak syndrome, type 1 and type 4, are at high risk of pulmonary fibrosis between the ages of 30 and 50. Patients 18 to 70 years of age who have Hermansky-Pudlak Syndrome with a serious loss of lung function due to pulmonary fibrosis may be eligible for this study. Participants begin taking pravastatin on study day 2 and start a new drug every 3 days. Patients who experience no problems with the medicines return home and continue on the drugs for the next 2 years. They return to the NIH Clinical Center every 3 months for a medical history, physical examination, and blood, urine and lung function tests. CT and bone density scans are done every year. The study may continue for up to 3 years.

Conditions

Hermansky-Pudlak Syndrome (HPS); Pulmonary Fibrosis; Oculocutaneous Albinism; Platelet Storage Pool Deficiency; Metabolic Disease

Keywords

Restrictive Lung Disease; Pulmonary Fibrosis; Albinism; Platelet Storage Pool Deficiency; Metabolic Disease; Hermansky-Pudlak Syndrome; HPS; Lung Disease

Outcome Measures

Primary Outcomes (1)

• Survival at 2 Years

  The number of subjects surviving after 24 months on study.

  24 months

Study Arms (1)

Multi-Drug Regimen

EXPERIMENTAL

Losartan, 25 mg by mouth every night at bedtime; Zileuton, 1200 mg by mouth twice daily; N-acetylcysteine, 600 mg by mouth three times daily; Pravastatin, 20 mg by mouth every night at bedtime; Erythromycin, 333 mg by mouth three times daily.

Drug: Losartan; Drug: Zileuton; Drug: N-Acetylcysteine; Drug: Pravastatin; Drug: Erythromycin

Interventions

Losartan DRUG

Losartan potassium tablet, 25 mg by mouth every night at bedtime.

Also known as: Cozaar

Multi-Drug Regimen

Zileuton DRUG

Zileuton tablet, 1200 mg by mouth twice daily.

Also known as: Zyflo

Multi-Drug Regimen

N-Acetylcysteine DRUG

N-acetylcysteine solution, 600 mg by mouth three times daily.

Also known as: acetylcysteine

Multi-Drug Regimen

Pravastatin DRUG

Pravastatin sodium tablet, 20 mg by mouth every night at bedtime.

Also known as: Pravachol

Multi-Drug Regimen

Erythromycin DRUG

Erythromycin tablet, 333 mg by mouth three times daily.

Also known as: E-mycin, Ery-tab

Multi-Drug Regimen

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.:
• A FVC less than or equal to 45% of predicted
• Reduced exercise tolerance lasting longer than 1 week on the Dyspnea Perception Scale
• 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.

You may not qualify if:

• 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;
• 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

Sponsors & Collaborators

• National Human Genome Research Institute (NHGRI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• Witkop CJ, Nunez Babcock M, Rao GH, Gaudier F, Summers CG, Shanahan F, Harmon KR, Townsend D, Sedano HO, King RA, et al. Albinism and Hermansky-Pudlak syndrome in Puerto Rico. Bol Asoc Med P R. 1990 Aug;82(8):333-9.

  PMID: 2261023 BACKGROUND

• HERMANSKY F, PUDLAK P. Albinism associated with hemorrhagic diathesis and unusual pigmented reticular cells in the bone marrow: report of two cases with histochemical studies. Blood. 1959 Feb;14(2):162-9. No abstract available.

  PMID: 13618373 BACKGROUND

• Huizing M, Gahl WA. Disorders of vesicles of lysosomal lineage: the Hermansky-Pudlak syndromes. Curr Mol Med. 2002 Aug;2(5):451-67. doi: 10.2174/1566524023362357.

  PMID: 12125811 BACKGROUND

• Introne WJ, Huizing M, Malicdan MCV, O'Brien KJ, Gahl WA. Hermansky-Pudlak Syndrome. 2000 Jul 24 [updated 2023 May 25]. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from http://www.ncbi.nlm.nih.gov/books/NBK1287/

  PMID: 20301464 BACKGROUND

MeSH Terms

Conditions

Hermanski-Pudlak Syndrome; Pulmonary Fibrosis; Albinism, Oculocutaneous; Platelet Storage Pool Deficiency; Metabolic Diseases; Albinism; Lung Diseases

Interventions

Losartan; zileuton; Acetylcysteine; Pravastatin; Erythromycin

Condition Hierarchy (Ancestors)

Eye Diseases, Hereditary; Eye Diseases; Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Blood Platelet Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Amino Acid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Skin Diseases, Genetic; Hypopigmentation; Pigmentation Disorders; Skin Diseases; Skin and Connective Tissue Diseases; Nutritional and Metabolic Diseases; Lung Diseases, Interstitial; Respiratory Tract Diseases; Fibrosis; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Biphenyl Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Tetrazoles; Cysteine; Amino Acids, Sulfur; Sulfur Compounds; Amino Acids; Amino Acids, Peptides, and Proteins; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds; Macrolides; Polyketides; Lactones

Limitations and Caveats

The study was terminated because enrollment was too low. The results shown are not statistically significant.

Results Point of Contact

• Title: Dr. Thomas Markello
• Organization: NHGRI/NIH

markellot@mail.nih.gov

301-451-1305

Study Officials

• Thomas Markello, M.D.

  National Human Genome Research Institute (NHGRI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 28, 2007
• First Posted: May 1, 2007
• Study Start: April 1, 2007
• Primary Completion: November 1, 2012
• Study Completion: November 1, 2012
• Last Updated: August 2, 2013
• Results First Posted: August 2, 2013

Record last verified: 2013-06

Locations

US (1)