Back to resultsMedical Treatment of Colitis in Patients With Hermansky-Pudlak Syndrome
Primary Purpose
Hermanski-Pudlak Syndrome, Colitis, Cytokines
Status
Withdrawn
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Mesalamine
Infliximab
Corticosteroids
6-Mercaptopurine
Tacrolimus
Adalimumab
Sponsored by
About this trial
This is an interventional treatment trial for Hermanski-Pudlak Syndrome focused on measuring Hermansky-Pudlak Syndrome, Colitis, Medical Therapy, Immunopathogenesis, Cytokine, Hermansky-Pudlak Syndrome Associated Colitis, HPS
Eligibility Criteria
- INCLUSION CRITERIA:
A subject is eligible for the study if all of the following criteria are met:
- Has given written informed consent prior to screening.
- Age 18 years old or greater.
- Has confirmed diagnosis of HPS prior to screening.
- Has confirmed diagnosis of IBD prior to screening.
- The presence of active disease as defined by a SCCAI score greater than or equal to 5.
- Negative results on stool examination for culture of enteric pathogens (Salmonella, Shigella, Yersinia, Campylobacter, Vibrio, E. coli O157/H7), Clostridium difficile toxin assay, enteric parasites and their ova (including Giardia and Cryptosporidia).
- If currently receiving medication for their IBD, patients may be on a stable regimen of one or a combination of the following drug doses and durations:
Corticosteroids (less than or equal to 25 milligrams Prednisone or Prednisone equivalent per day) - greater than or equal to 4 weeks.
5-ASA Sulfasalazine - greater than or equal to 4 weeks.
Azathioprine/6-MP/thioguanine with stable dose for eight weeks - greater than or equal to 12 weeks. (NOTE: Patients receiving azathioprine/6-MP/thioguanine must have been on a stable dose of this medication for greater than or equal to 8 weeks)
Probiotics (live bacterial dietary supplements) - greater than or equal to 4 weeks.
Prebiotics (dietary supplements to produce biologically active substances) - greater than or equal to 4 weeks.
Infliximab (5 to 10 mg/kg IV) - greater than 8 weeks or no response within 4 weeks of an induction dose of 3 infusions.
Adalimumab (40 to 80 mg subq) - greater than or equal to 4 weeks or no response within 2 weeks after induction dose of 2 injections.
EXCLUSION CRITERIA:
A subject is excluded from the study if any of the following criteria are met:
GENERAL CRITERIA:
- Has any clinically significant disease (e.g., renal, hepatic, neurological, cardiovascular, pulmonary, endocrinology, psychiatric, hematological, urologic, or other acute or chronic illness) that in the opinion of the investigator would make the subject an unsuitable candidate for this trial.
- Inability to meet any of the above inclusion criteria.
- Is a woman who has a positive serum pregnancy test or who is breast-feeding.
Has any of the following clinical chemistry values:
- AST greater than 2.5 times the upper limit of normal (ULN).
- ALT greater than 2.5 times the ULN.
- Serum bilirubin greater than 1.5 times the ULN.
- Serum creatinine greater than 1.5 times the ULN.
- Alkaline phosphatase greater than 2.5 times the ULN.
- Has a hemoglobin level less than 8.0 g/dL or hematocrit less than 26 percent.
- Has a PT INR greater than 1.3 or a PTT greater than 3 seconds compared to control value.
Has the following cell counts:
- Platelet count less than 80,000 or greater than 950,000.
- White blood cell count less than 1200.
- Neutrophil count less than 700.
- Has a current infection requiring intravenous antibiotics, a serious local infection (e.g., cellulitis, abscess) or systemic infection (e.g., pneumonia, septicemia).
- Has a history of cancer within the past 5 years, with the exception of excised basal cell carcinoma, squamous cell carcinoma of the skin, or cervical carcinoma in situ.
- Had a dependency for any illicit drug, chemical or alcohol within the past 5 years.
- Has a history of active tuberculosis (TB) (or a positive PPD skin test or chest x-ray with findings suggestive of old TB infection including calcified nodular lesions, apical fibrosis, or pleural scarring), acute or chronic hepatitis B, hepatitis C, human immunodeficiency virus (HIV).
- History of central nervous system demyelinating disease, or systemic lupus erythematosus.
- Unable to keep to the scheduled appointments and other test to watch for changes in symptoms and side effects of treatment.
GASTROINTESTINAL CRITERIA:
- History of colectomy, partial colectomy, current ostomy, pouchitis, or small bowel resection within the past 6 months, or short gut syndrome.
- Presence of current active bowel obstruction, intestinal perforation, known presence of high grade stricture, history of toxic megacolon, history of colonic epithelium high-grade dysplasia or a dysplasia-associated lesion or mass that does not resemble an adenoma (that is a mass lesion, stricture, or broad-based tumor with dysplasia).
Sites / Locations
- National Institutes of Health Clinical Center, 9000 Rockville Pike
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Arm 6
Arm Type
Other
Other
Other
Other
Other
Other
Arm Label
1/Drug #1
1/Drug#2
1/Drug#3
1/Drug#4
1/Drug#5
1/Drug#6
Arm Description
Oral mesalamine will be used as initial therapy in patients who are not taking any medication or have not received any prior treatment for their IBD. Dosing will begin at 2.4 g PO QD and will be increased to 4.8 g QD within 2 weeks. Topical mesalamine (enema 4 g PR HS/BID or suppository 1 g PR HS/BID) may be added for patients with inflammation that is limited to the rectum (proctitis) or who have prominent complaints of urgency, incomplete evacuation or rectal bleeding.
Add oral corticosteroids (prednisone) to mesalamine. The standard induction dose will be 40 mg/day. After 1 week of therapy, if the total SCCAI score has decreased by greater than or equal to 2 points the patient will continue on another week of therapy. If the SCCAI has not decreased by greater than or equal to 2 points (indicative of a reduction in symptoms) at one week, then the dose will be increased to 60 mg/day. Patients on either dosage will have another SCCAI assessment done a week later (2 weeks after beginning corticosteroids), and if they are found to be in remission (SCCAI less than or equal to 2), a steroid-tapering schedule will be initiated.
Infliximab and 6-MP will be added to patients with a SCCAI greater than 2 at week 8. The first infusion of infliximab (5 mg/kg) will be given during that week. In addition, 6-MP will be initiated at doses of 1.0-1.5 mg/kg PO QD to reduce the incidence of infliximab antibody formation and facilitate steroid tapering (the target dose of 6-MP will be decreased accordingly if patients are found to have low TMPT levels/activity by genotypic or phenotypic testing). Also, steroids will also be rapidly tapered off at this time.
Infliximab and 6-MP will be added to patients with a SCCAI greater than 2 at week 8. The first infusion of infliximab (5 mg/kg) will be given during that week. In addition, 6-MP will be initiated at doses of 1.0-1.5 mg/kg PO QD to reduce the incidence of infliximab antibody formation and facilitate steroid tapering (the target dose of 6-MP will be decreased accordingly if patients are found to have low TMPT levels/activity by genotypic or phenotypic testing). Also, steroids will also be rapidly tapered off at this time.
Subjects with a SCCAI greater than 2 after 3 doses of infliximab will continue 6-MP, discontinue infliximab infusions and start adalimumab injections approximately 2 weeks after the 3rd dose of infliximab. Induction dosing will consist of a 160 Micro/g subcutaneous injection, followed by 80 Micro/g 2 weeks after.
Patients who have a SCCAI greater than 2 after 2 doses of adalimumab will continue 6-MP, discontinue adalimumab, and start therapy with tacrolimus 0.01 mg/kg PO BID approximately 2 weeks after the second dose of adalimumab.
Outcomes
Primary Outcome Measures
To detect patterns of immune abnormalities in the colitis associated with Hermansky-Pudlak Syndrome (HPS).
Secondary Outcome Measures
Document the clinical response to and tolerance of conventional inflammatory bowel disease (IBD) therapy for HPS patients with active colitis associated with Hermansky-Pudlak Syndrome (HPS).
Full Information
NCT ID
NCT00514982
First Posted
August 9, 2007
Last Updated
June 30, 2017
Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
1. Study Identification
Unique Protocol Identification Number
NCT00514982
Brief Title
Medical Treatment of Colitis in Patients With Hermansky-Pudlak Syndrome
Official Title
An Observational Study of the Immunopathogenesis of and Response to Step-Up Inflammatory Bowel Disease Therapy for Hermansky-Pudlak Syndrome-Associated Colitis
Study Type
Interventional
2. Study Status
Record Verification Date
March 8, 2011
Overall Recruitment Status
Withdrawn
Study Start Date
August 7, 2007 (undefined)
Primary Completion Date
March 8, 2011 (Actual)
Study Completion Date
March 8, 2011 (Actual)
3. Sponsor/Collaborators
Name of the Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
4. Oversight
5. Study Description
Brief Summary
This study will determine if medical treatment of colitis (inflammation of the colon resulting in loose bowel movements, rectal bleeding, and belly pain) that is used for other colitis conditions, such as Crohn's disease and ulcerative colitis, is safe and effective for treating colitis in patients with Hermansky-Pudlak syndrome (HPS). HPS is a hereditary disorder that causes albinism, visual impairment, and abnormal bleeding. Some patients also develop colitis, pulmonary fibrosis, and kidney disease.
Patients with HPS and colitis who are 18 years of age or older may be eligible for this study. Participants receive treatment for their colitis symptoms with one or more of several study drugs, which include mesalamine (5-ASA), corticosteroids, infliximab and 6-mercaptopurine, adalimumab and tacrolimus. The drugs are added to the treatment plan one at a time to find the combination that works best for the individual patient. Patients who respond to one or more of the medications may continue treatment with that same combination for up to 6 months.
Regular clinic visits are scheduled for blood tests, symptoms ratings questionnaires and periodic physical examinations and colonoscopies to measure the response to treatment and evaluate any side effects.
Detailed Description
The primary purpose of this study is to detect patterns of immune abnormalities in the colitis associated with Hermansky-Pudlak Syndrome (HPS). Additionally we aim to document the clinical response to and tolerance of conventional inflammatory bowel disease (IBD) therapy for HPS patients with active colitis associated with Hermansky-Pudlak Syndrome (HPS). HPS is a rare autosomal recessive disorder causing dysfunctional lysosome-related organelle formation and trafficking resulting in oculocutaneous albinism and a bleeding diathesis secondary to platelet dysfunction. Associated conditions include pulmonary fibrosis, IBD, and systemic ceroid deposition. The associated IBD has been reported to occur at a higher frequency in the HPS-1 and HPS-4 subtypes compared to the prevalence of IBD in non-HPS populations. HPS IBD has clinical features of both ulcerative colitis (UC) and Crohn's disease, but histologically resembles Crohn's disease in that granulomas are commonly seen in the mucosa of the intestine. The pathogenesis of HPS IBD is not fully understood and little data beyond descriptions of the clinical and histologic manifestations have been published. Furthermore reports on treatment of the colitis in HPS patients are largely anecdotal, and our own experience suggests that many patients may be under-treated.
HPS patients with active colitis will be enrolled into this prospective treatment study. Endpoints for the immunopathogenesis studies will include baseline measurements of and changes in immune cell populations, cytokine, and chemokine expression. In the blood and gut mucosa. Endpoints for the study of response to treatment will include changes in clinical, endoscopic, and histologic scores as well as the rate and severity of adverse events. Descriptive summary statistical analysis (n, mean, median, standard deviation, minimum and maximum range) and simple correlations of clinical response variables with immune parameters will be done.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hermanski-Pudlak Syndrome, Colitis, Cytokines, Lymphocytes, Drug Evaluation
Keywords
Hermansky-Pudlak Syndrome, Colitis, Medical Therapy, Immunopathogenesis, Cytokine, Hermansky-Pudlak Syndrome Associated Colitis, HPS
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
0 (Actual)
8. Arms, Groups, and Interventions
Arm Title
1/Drug #1
Arm Type
Other
Arm Description
Oral mesalamine will be used as initial therapy in patients who are not taking any medication or have not received any prior treatment for their IBD. Dosing will begin at 2.4 g PO QD and will be increased to 4.8 g QD within 2 weeks. Topical mesalamine (enema 4 g PR HS/BID or suppository 1 g PR HS/BID) may be added for patients with inflammation that is limited to the rectum (proctitis) or who have prominent complaints of urgency, incomplete evacuation or rectal bleeding.
Arm Title
1/Drug#2
Arm Type
Other
Arm Description
Add oral corticosteroids (prednisone) to mesalamine. The standard induction dose will be 40 mg/day. After 1 week of therapy, if the total SCCAI score has decreased by greater than or equal to 2 points the patient will continue on another week of therapy. If the SCCAI has not decreased by greater than or equal to 2 points (indicative of a reduction in symptoms) at one week, then the dose will be increased to 60 mg/day. Patients on either dosage will have another SCCAI assessment done a week later (2 weeks after beginning corticosteroids), and if they are found to be in remission (SCCAI less than or equal to 2), a steroid-tapering schedule will be initiated.
Arm Title
1/Drug#3
Arm Type
Other
Arm Description
Infliximab and 6-MP will be added to patients with a SCCAI greater than 2 at week 8. The first infusion of infliximab (5 mg/kg) will be given during that week. In addition, 6-MP will be initiated at doses of 1.0-1.5 mg/kg PO QD to reduce the incidence of infliximab antibody formation and facilitate steroid tapering (the target dose of 6-MP will be decreased accordingly if patients are found to have low TMPT levels/activity by genotypic or phenotypic testing). Also, steroids will also be rapidly tapered off at this time.
Arm Title
1/Drug#4
Arm Type
Other
Arm Description
Infliximab and 6-MP will be added to patients with a SCCAI greater than 2 at week 8. The first infusion of infliximab (5 mg/kg) will be given during that week. In addition, 6-MP will be initiated at doses of 1.0-1.5 mg/kg PO QD to reduce the incidence of infliximab antibody formation and facilitate steroid tapering (the target dose of 6-MP will be decreased accordingly if patients are found to have low TMPT levels/activity by genotypic or phenotypic testing). Also, steroids will also be rapidly tapered off at this time.
Arm Title
1/Drug#5
Arm Type
Other
Arm Description
Subjects with a SCCAI greater than 2 after 3 doses of infliximab will continue 6-MP, discontinue infliximab infusions and start adalimumab injections approximately 2 weeks after the 3rd dose of infliximab. Induction dosing will consist of a 160 Micro/g subcutaneous injection, followed by 80 Micro/g 2 weeks after.
Arm Title
1/Drug#6
Arm Type
Other
Arm Description
Patients who have a SCCAI greater than 2 after 2 doses of adalimumab will continue 6-MP, discontinue adalimumab, and start therapy with tacrolimus 0.01 mg/kg PO BID approximately 2 weeks after the second dose of adalimumab.
Intervention Type
Drug
Intervention Name(s)
Mesalamine
Intervention Description
5-Aminosalicylic Acid Derivative used to treat mild to moderate Ulcerative Colitis
Intervention Type
Drug
Intervention Name(s)
Infliximab
Intervention Description
Antirheumatic, Disease Modifying Gastrointestinal Agent, Miscellaneous, Monoclonal Antibody, Tumor Necrosis Factor (TNF) Blocking Agent used to treat gastrointestinal disorders.
Intervention Type
Drug
Intervention Name(s)
Corticosteroids
Intervention Description
Systemic Corticosteroid used to treat inflammatory conditions.
Intervention Type
Drug
Intervention Name(s)
6-Mercaptopurine
Intervention Description
Antineoplastic Agent, Antimetabolite, Immunosuppressant Agent used traditionally to treat Acute lymphoblastic leukemia. Unlabeled use as steroid-sparing agent for corticosteroid-dependent Crohn's disease (CD) and ulcerative colitis (UC); maintenance of remission in CD; fistulizing Crohn's disease.
Intervention Type
Drug
Intervention Name(s)
Tacrolimus
Intervention Description
Immunosuppressant Agent used to treat Liver, Heart, Kidney transplant, prevent host vs graft disease, severe atopic dermatitis.
Intervention Type
Drug
Intervention Name(s)
Adalimumab
Intervention Description
Antirheumatic, Monoclonal Antibody, Tumor Necrosis Factor (TNF) Blocking Agent used to treat Rheumatoid arthritis and Crohn's disease.
Primary Outcome Measure Information:
Title
To detect patterns of immune abnormalities in the colitis associated with Hermansky-Pudlak Syndrome (HPS).
Time Frame
60 weeks
Secondary Outcome Measure Information:
Title
Document the clinical response to and tolerance of conventional inflammatory bowel disease (IBD) therapy for HPS patients with active colitis associated with Hermansky-Pudlak Syndrome (HPS).
Time Frame
60 weeks
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
INCLUSION CRITERIA:
A subject is eligible for the study if all of the following criteria are met:
Has given written informed consent prior to screening.
Age 18 years old or greater.
Has confirmed diagnosis of HPS prior to screening.
Has confirmed diagnosis of IBD prior to screening.
The presence of active disease as defined by a SCCAI score greater than or equal to 5.
Negative results on stool examination for culture of enteric pathogens (Salmonella, Shigella, Yersinia, Campylobacter, Vibrio, E. coli O157/H7), Clostridium difficile toxin assay, enteric parasites and their ova (including Giardia and Cryptosporidia).
If currently receiving medication for their IBD, patients may be on a stable regimen of one or a combination of the following drug doses and durations:
Corticosteroids (less than or equal to 25 milligrams Prednisone or Prednisone equivalent per day) - greater than or equal to 4 weeks.
5-ASA Sulfasalazine - greater than or equal to 4 weeks.
Azathioprine/6-MP/thioguanine with stable dose for eight weeks - greater than or equal to 12 weeks. (NOTE: Patients receiving azathioprine/6-MP/thioguanine must have been on a stable dose of this medication for greater than or equal to 8 weeks)
Probiotics (live bacterial dietary supplements) - greater than or equal to 4 weeks.
Prebiotics (dietary supplements to produce biologically active substances) - greater than or equal to 4 weeks.
Infliximab (5 to 10 mg/kg IV) - greater than 8 weeks or no response within 4 weeks of an induction dose of 3 infusions.
Adalimumab (40 to 80 mg subq) - greater than or equal to 4 weeks or no response within 2 weeks after induction dose of 2 injections.
EXCLUSION CRITERIA:
A subject is excluded from the study if any of the following criteria are met:
GENERAL CRITERIA:
Has any clinically significant disease (e.g., renal, hepatic, neurological, cardiovascular, pulmonary, endocrinology, psychiatric, hematological, urologic, or other acute or chronic illness) that in the opinion of the investigator would make the subject an unsuitable candidate for this trial.
Inability to meet any of the above inclusion criteria.
Is a woman who has a positive serum pregnancy test or who is breast-feeding.
Has any of the following clinical chemistry values:
AST greater than 2.5 times the upper limit of normal (ULN).
ALT greater than 2.5 times the ULN.
Serum bilirubin greater than 1.5 times the ULN.
Serum creatinine greater than 1.5 times the ULN.
Alkaline phosphatase greater than 2.5 times the ULN.
Has a hemoglobin level less than 8.0 g/dL or hematocrit less than 26 percent.
Has a PT INR greater than 1.3 or a PTT greater than 3 seconds compared to control value.
Has the following cell counts:
Platelet count less than 80,000 or greater than 950,000.
White blood cell count less than 1200.
Neutrophil count less than 700.
Has a current infection requiring intravenous antibiotics, a serious local infection (e.g., cellulitis, abscess) or systemic infection (e.g., pneumonia, septicemia).
Has a history of cancer within the past 5 years, with the exception of excised basal cell carcinoma, squamous cell carcinoma of the skin, or cervical carcinoma in situ.
Had a dependency for any illicit drug, chemical or alcohol within the past 5 years.
Has a history of active tuberculosis (TB) (or a positive PPD skin test or chest x-ray with findings suggestive of old TB infection including calcified nodular lesions, apical fibrosis, or pleural scarring), acute or chronic hepatitis B, hepatitis C, human immunodeficiency virus (HIV).
History of central nervous system demyelinating disease, or systemic lupus erythematosus.
Unable to keep to the scheduled appointments and other test to watch for changes in symptoms and side effects of treatment.
GASTROINTESTINAL CRITERIA:
History of colectomy, partial colectomy, current ostomy, pouchitis, or small bowel resection within the past 6 months, or short gut syndrome.
Presence of current active bowel obstruction, intestinal perforation, known presence of high grade stricture, history of toxic megacolon, history of colonic epithelium high-grade dysplasia or a dysplasia-associated lesion or mass that does not resemble an adenoma (that is a mass lesion, stricture, or broad-based tumor with dysplasia).
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
16573787
Citation
Bergman R, Parkes M. Systematic review: the use of mesalazine in inflammatory bowel disease. Aliment Pharmacol Ther. 2006 Apr 1;23(7):841-55. doi: 10.1111/j.1365-2036.2006.02846.x.
Results Reference
background
PubMed Identifier
8843979
Citation
Cappell MS. Gastrointestinal endoscopy in high-risk patients. Dig Dis. 1996 Jul-Aug;14(4):228-44. doi: 10.1159/000171555.
Results Reference
background
PubMed Identifier
17105690
Citation
D'Haens G, Daperno M. Advances in biologic therapy for ulcerative colitis and Crohn's disease. Curr Gastroenterol Rep. 2006 Dec;8(6):506-12. doi: 10.1007/s11894-006-0041-5.
Results Reference
background
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Medical Treatment of Colitis in Patients With Hermansky-Pudlak Syndrome
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