An Observational Study of the Immunopathogenesis of and Response to Step-Up Inflammatory Bowel Disease Therapy for Hermansky-Pudlak Syndrome-Associated Colitis
18 Years
N/A
Both
Hermanski-Pudlak Syndrome, Colitis, Cytokines, Lymphocytes, Drug Evaluation
Trial Information
An Observational Study of the Immunopathogenesis of and Response to Step-Up Inflammatory Bowel Disease Therapy for Hermansky-Pudlak Syndrome-Associated Colitis
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.
Inclusion 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:
1. AST greater than 2.5 times the upper limit of normal (ULN).
2. ALT greater than 2.5 times the ULN.
3. Serum bilirubin greater than 1.5 times the ULN.
4. Serum creatinine greater than 1.5 times the ULN.
5. 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:
1. Platelet count less than 80,000 or greater than 950,000.
2. White blood cell count less than 1200.
3. 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).
Type of Study:
Interventional
Study Design:
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
To detect patterns of immune abnormalities in the colitis associated with Hermansky-Pudlak Syndrome (HPS).
Outcome Time Frame:
60 weeks
Safety Issue:
No
Authority:
United States: Federal Government
Study ID:
070205
NCT ID:
NCT00514982
Start Date:
August 2007
Completion Date:
March 2011
Related Keywords:
- Hermanski-Pudlak Syndrome
- Colitis
- Cytokines
- Lymphocytes
- Drug Evaluation
- Hermansky-Pudlak Syndrome
- Colitis
- Medical Therapy
- Immunopathogenesis
- Cytokine
- Hermansky-Pudlak Syndrome Associated Colitis
- HPS
- Colitis
- Inflammatory Bowel Diseases
- Hermanski-Pudlak Syndrome
Name | Location |
|---|---|
| National Institutes of Health Clinical Center, 9000 Rockville Pike | Bethesda, Maryland 20892 |
