Pilot Study of a Multi-Drug Regimen for Severe Pulmonary Fibrosis in Hermansky-Pudlak Syndrome
Primary Purpose
Hermansky-Pudlak Syndrome (HPS), Pulmonary Fibrosis, Oculocutaneous Albinism
Status
Terminated
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Losartan
Zileuton
N-Acetylcysteine
Pravastatin
Erythromycin
Sponsored by
About this trial
This is an interventional treatment trial for Hermansky-Pudlak Syndrome (HPS) focused on measuring Restrictive Lung Disease, Pulmonary Fibrosis, Albinism, Platelet Storage Pool Deficiency, Metabolic Disease, Hermansky-Pudlak Syndrome, HPS, Lung Disease
Eligibility Criteria
- INCLUSION CRITERIA:
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.
EXCLUSION CRITERIA:
- 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;
- Any severe medical complication including but not be limited to uncontrolled seizures, repeated transient ischemic attacks, severe ataxia, uncontrolled migraine headaches, diplopia, repeated episodes of syncope, an untreated psychiatric disorder, recent myocardial infarction (past 6 months), unstable angina, clinically relevant and untreated arrhythmias, uncontrolled hypotension or hypertension (systolic blood pressure less than 80 or greater than 180 mm Hg), myocarditis, severe congestive left sided heart failure, hepatomegaly not due to right heart failure, renal glomerular impairment (creatinine clearance less than 35 ml/min/1.73 m(2)), pancreatitis, toxic thyroiditis, life-threatening malignancy;NOTE: right sided heart failure due to pulmonary hypertension as a result of pulmonary fibrosis will not be considered an exclusion criteria.
- 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
Sites / Locations
- National Institutes of Health Clinical Center, 9000 Rockville Pike
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Multi-Drug Regimen
Arm Description
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.
Outcomes
Primary Outcome Measures
Survival at 2 Years
The number of subjects surviving after 24 months on study.
Secondary Outcome Measures
Full Information
NCT ID
NCT00467831
First Posted
April 28, 2007
Last Updated
June 3, 2013
Sponsor
National Human Genome Research Institute (NHGRI)
1. Study Identification
Unique Protocol Identification Number
NCT00467831
Brief Title
Pilot Study of a Multi-Drug Regimen for Severe Pulmonary Fibrosis in Hermansky-Pudlak Syndrome
Official Title
Pilot Study of a Multi-Drug Regimen for Severe Pulmonary Fibrosis in Hermansky-Pudlak Syndrome
Study Type
Interventional
2. Study Status
Record Verification Date
June 2013
Overall Recruitment Status
Terminated
Why Stopped
insufficient enrollment
Study Start Date
April 2007 (undefined)
Primary Completion Date
November 2012 (Actual)
Study Completion Date
November 2012 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Human Genome Research Institute (NHGRI)
4. Oversight
Data Monitoring Committee
No
5. Study Description
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.
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, pulmonary fibrosis, occurs only in genetic subtypes HPS-1 and HPS-4 and is generally fatal in the fourth or fifth decade. HPS-1 is very common in northwest Puerto Rico. There is no effective treatment for the pulmonary disease of HPS (HPS-PF), which resembles idiopathic pulmonary fibrosis (IPF). A preliminary study of the antifibrotic drug, pirfenidone, gave promising results for mild to moderate HPS-PF, but not for severe pulmonary fibrosis. A second study is currently addressing only mild to moderate HPS-PF. Other drugs, studied in IPF as single agents, have some efficacy for mild to moderate disease, but none has had a major effect on mortality. Recently, a call has been made for consideration of multi-drug therapy (i.e., an oncologic approach) for severe pulmonary fibrosis. Based upon positive responses from companies producing relevant drugs, we propose a multi-drug trial using five agents: Losartan, Zileuton, a generic statin (Pravastatin), generic N-acetylcysteine, and generic Erythromycin. Participants with severe pulmonary fibrosis will be drawn largely from the Puerto Rican population. Eligibility will require a molecular diagnosis of HPS-1 or HPS-4, radiographic evidence of interstitial lung disease, persistent pulmonary function testing less than or equal to 45% of predicted after bronchodilation, and absence of other causes of lung dysfunction. Participants will be admitted to the NIH Clinical Center for a 21-day admission to establish baseline function and to begin medication therapy. Follow-up admissions (3 days) will occur every 3 months. The primary outcome parameter will be survival at 2 years.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
3 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Multi-Drug Regimen
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Losartan
Other Intervention Name(s)
Cozaar
Intervention Description
Losartan potassium tablet, 25 mg by mouth every night at bedtime.
Intervention Type
Drug
Intervention Name(s)
Zileuton
Other Intervention Name(s)
Zyflo
Intervention Description
Zileuton tablet, 1200 mg by mouth twice daily.
Intervention Type
Drug
Intervention Name(s)
N-Acetylcysteine
Other Intervention Name(s)
acetylcysteine
Intervention Description
N-acetylcysteine solution, 600 mg by mouth three times daily.
Intervention Type
Drug
Intervention Name(s)
Pravastatin
Other Intervention Name(s)
Pravachol
Intervention Description
Pravastatin sodium tablet, 20 mg by mouth every night at bedtime.
Intervention Type
Drug
Intervention Name(s)
Erythromycin
Other Intervention Name(s)
E-mycin, Ery-tab
Intervention Description
Erythromycin tablet, 333 mg by mouth three times daily.
Primary Outcome Measure Information:
Title
Survival at 2 Years
Description
The number of subjects surviving after 24 months on study.
Time Frame
24 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
INCLUSION CRITERIA:
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.
EXCLUSION CRITERIA:
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;
Any severe medical complication including but not be limited to uncontrolled seizures, repeated transient ischemic attacks, severe ataxia, uncontrolled migraine headaches, diplopia, repeated episodes of syncope, an untreated psychiatric disorder, recent myocardial infarction (past 6 months), unstable angina, clinically relevant and untreated arrhythmias, uncontrolled hypotension or hypertension (systolic blood pressure less than 80 or greater than 180 mm Hg), myocarditis, severe congestive left sided heart failure, hepatomegaly not due to right heart failure, renal glomerular impairment (creatinine clearance less than 35 ml/min/1.73 m(2)), pancreatitis, toxic thyroiditis, life-threatening malignancy;NOTE: right sided heart failure due to pulmonary hypertension as a result of pulmonary fibrosis will not be considered an exclusion criteria.
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Thomas Markello, M.D.
Organizational Affiliation
National Human Genome Research Institute (NHGRI)
Official's Role
Principal Investigator
Facility Information:
Facility Name
National Institutes of Health Clinical Center, 9000 Rockville Pike
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
2261023
Citation
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.
Results Reference
background
PubMed Identifier
13618373
Citation
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.
Results Reference
background
PubMed Identifier
12125811
Citation
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.
Results Reference
background
PubMed Identifier
20301464
Citation
Introne WJ, Huizing M, Malicdan MCV, O'Brien KJ, Gahl WA. Hermansky-Pudlak Syndrome. 2000 Jul 24 [updated 2023 May 25]. In: Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from http://www.ncbi.nlm.nih.gov/books/NBK1287/
Results Reference
background
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Pilot Study of a Multi-Drug Regimen for Severe Pulmonary Fibrosis in Hermansky-Pudlak Syndrome
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