Medical Treatment of Colitis in Patients With Hermansky-Pudlak Syndrome

NCT00514982 | Withdrawn Phase 2

• 2 other identifiers: 07020507-I-0205
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

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.

Conditions

Hermanski-Pudlak Syndrome; Colitis; Cytokines; Lymphocytes; Drug Evaluation

Keywords

Hermansky-Pudlak Syndrome; Colitis; Medical Therapy; Immunopathogenesis; Cytokine; Hermansky-Pudlak Syndrome Associated Colitis; HPS

Outcome Measures

Primary Outcomes (1)

• To detect patterns of immune abnormalities in the colitis associated with Hermansky-Pudlak Syndrome (HPS).

  60 weeks

Secondary Outcomes (1)

• 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).

  60 weeks

Study Arms (6)

1/Drug #1

OTHER

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.

Drug: Mesalamine

1/Drug#2

OTHER

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.

Drug: Corticosteroids

1/Drug#3

OTHER

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.

Drug: 6-Mercaptopurine

1/Drug#4

OTHER

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.

Drug: Infliximab

1/Drug#5

OTHER

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.

Drug: Adalimumab

1/Drug#6

OTHER

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.

Drug: Tacrolimus

Interventions

Mesalamine DRUG

5-Aminosalicylic Acid Derivative used to treat mild to moderate Ulcerative Colitis

1/Drug #1

Infliximab DRUG

Antirheumatic, Disease Modifying Gastrointestinal Agent, Miscellaneous, Monoclonal Antibody, Tumor Necrosis Factor (TNF) Blocking Agent used to treat gastrointestinal disorders.

1/Drug#4

Corticosteroids DRUG

Systemic Corticosteroid used to treat inflammatory conditions.

1/Drug#2

6-Mercaptopurine DRUG

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.

1/Drug#3

Tacrolimus DRUG

Immunosuppressant Agent used to treat Liver, Heart, Kidney transplant, prevent host vs graft disease, severe atopic dermatitis.

1/Drug#6

Adalimumab DRUG

Antirheumatic, Monoclonal Antibody, Tumor Necrosis Factor (TNF) Blocking Agent used to treat Rheumatoid arthritis and Crohn's disease.

1/Drug#5

Eligibility Criteria

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

You may qualify if:

• 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.
• 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.

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• 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.

  PMID: 16573787 BACKGROUND

• Cappell MS. Gastrointestinal endoscopy in high-risk patients. Dig Dis. 1996 Jul-Aug;14(4):228-44. doi: 10.1159/000171555.

  PMID: 8843979 BACKGROUND

• 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.

  PMID: 17105690 BACKGROUND

MeSH Terms

Conditions

Hermanski-Pudlak Syndrome; Colitis

Interventions

Mesalamine; Infliximab; Adrenal Cortex Hormones; Mercaptopurine; Tacrolimus; Adalimumab

Condition Hierarchy (Ancestors)

Albinism, Oculocutaneous; Albinism; Eye Diseases, Hereditary; Eye Diseases; Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Platelet Storage Pool Deficiency; 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; Metabolic Diseases; Nutritional and Metabolic Diseases; Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Colonic Diseases; Intestinal Diseases

Intervention Hierarchy (Ancestors)

meta-Aminobenzoates; Aminobenzoates; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals; Aminosalicylic Acids; Salicylates; Hydroxybenzoates; Hydroxy Acids; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Phenols; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Sulfhydryl Compounds; Sulfur Compounds; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Macrolides; Lactones; Antibodies, Monoclonal, Humanized

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH

Study Record Dates

• First Submitted: August 9, 2007
• First Posted: August 10, 2007
• Study Start: August 7, 2007
• Primary Completion: March 8, 2011
• Study Completion: March 8, 2011
• Last Updated: July 2, 2017

Record last verified: 2011-03-08

Locations

US (1)