NIH Clinical Research Studies

Protocol Number: 02-I-0019

Active Accrual, Protocols Recruiting New Patients

Title:
Granulocyte-Colony Stimulating Factor Treatment for Crohn's Disease
Number:
02-I-0019
Summary:
This study will examine the effectiveness of G-CSF in treating patients with Crohn's disease-a long-term recurring inflammation of the small and large intestine. Patients may have swelling and bleeding of the intestinal lining, which can lead to infection and abdominal pain, weight loss, fever, diarrhea, bloody stools, fistula (connections between the skin and intestine), intestinal blockages, and abscesses. Although there are various treatments for Crohn's disease, many patients continue to have inflammation that is difficult to control or severe side effects from the medications. G-CSF is an approved drug that is used to increase white blood cell counts. Other cells, immune cells, exposed to G-CSF can develop a specific immune action-a Th-2 response-that decreases the inflammatory response in Crohn's disease-a Th-1 response.

Patients 18 years of age or older who have had mild to moderately severe Crohn's disease for at least 4 months may be eligible for this study. Candidates will be screened with a medical history and possible review of medical records, physical examination, blood tests, electrocardiogram (EKG), urine and stool analyses and, for women, a pregnancy test. They will fill out a Crohn's Disease Activity Index questionnaire daily for 7 days and an Inflammatory Bowel Disease questionnaire.

Participants will have G-CSF therapy. Before starting therapy, they will have a series of pre-treatment tests, including a colonoscopy and leukapheresis. Colonoscopy is an examination of the colon. For the procedure, patients are given a medication to lessen anxiety and any discomfort. An endoscope-a lighted flexible tube-is inserted into the rectum, allowing examination of the extent of inflammation. The endoscope can also be used to take pictures of the colon and extract tissue samples for testing (biopsy). Leukapheresis is a procedure for collecting quantities of white blood cells. Whole blood is collected through a needle placed in an arm vein and circulated through a machine that separates it into its components. The white cells are removed, and the rest of the blood is returned to the body, either through the same needle used to draw the blood or through another needle placed in the other arm.

After the colonoscopy and leukapheresis, patients receive G-CSF injections every day for 29 days. The patient or a caregiver, such as a family member, will be taught to give the injections. Blood samples will be collected on treatment days 4, 8, 11 and 15, and a physical examination and interview, blood tests and a stool exam will be done once a week. Patients will have a repeat colonoscopy and leukapheresis 24 hours after the last treatment dose (day 29).

After the 29-day treatment, patients will be followed in the clinic as follows:

- Week 4 after treatment - physical exam and interview, routine blood work and stool exam

- Week 8 - interview and blood work

- Week 16 - interview, blood work and stool exam

- Week 24 - physical exam and interview, blood work, stool exam and colonoscopy

Sponsoring Institute:
National Institute of Allergy and Infectious Diseases (NIAID)
Recruitment Detail
Type: Active Accrual Of New Subjects
Gender: Male & Female
Referral Letter Required: No
Population Exclusion(s): Children

Eligibility Criteria:
INCLUSION CRITERIA

All subjects must have a verifiable diagnosis of active Crohn's disease of at least 4 months' duration. The diagnosis must be supported by characteristic 1) endoscopic or radiographic findings and 2) histopathologic changes on endoscopic biopsy or resected tissue.

All subjects must be over age 18.

The Crohn's disease is mildly to moderately active based on a Crohn's Disease Activity Index score between 225 and 450 (with either a diarrhea rating or abdominal pain rating of greater than or equal to 25).

If currently receiving any medications for Crohn's disease, subjects may only be on a stable regimen of one or a combination of the following drug doses and durations: antibiotic therapy for greater than or equal to 2 weeks; Corticosteroids (less than or equal to 25 mg Prednisone/d, or Prednisone equivalent) for greater than or equal to 4 weeks; 5-ASA/Sulfasalazine for greater than or equal to 4 weeks; azathioprine/6-MP for greater than or equal to 8 weeks (Note: patients receiving Azathioprine or 6-MP must have been receiving these medications for greater than or equal to 12 weeks before randomization.); Probiotics for greater than or equal to 4 weeks.

Use of barrier or hormonal methods of birth control for male and famale subjects who are not surgicaklly sterile or postmenopausal.

Negative serum beta-hCG for women of child-bearing potential (women who are not surgically sterile or postmenopausal) to exclude early pregnancy.

Negative results on stool examination for culture of enteric pathogens (Salmonella, Shigella, Yersinia, Campylobacter, Vibrio, E. coli O157/H7), Clostridia difficile toxin assay, enteric parasites and their ova (including Giardia and Cryptosporidia).

EXCLUSION CRITERIA

Use of any the following medications within the specified time period prior to the first dose of study drug or at any time during the study: Corticosteroid enema or 5-ASA enema or suppositories (7 days); Thalidomide (2 weeks); Corticosteroids (greater than 25 mg Prednisone/d or Prednisone equivalent) (4 weeks); Methotrexate, Cyclosporin, Tacrolimus (FK506, Prograf), Mycophenolate mofetil (CellCept), or any biological therapy (cytokine, anti-cytokine, or integrin-based therapy) (4 weeks); Monoclonal antibodies to TNF (4 months); any experimental agent (1 month).

Multiple bowel resections (greater than or equal to 200 cm) AND enteral or parenteral therapy to maintain weight.

Use any other investigational agent within 30 days beginning the treatment phase of this study.

Any of the following abnormalities on an electrocardiogram: QT(c) greater than 0.48 sec, Mobitz type II second or third degree atrioventricular block, left bundle branch block or right bundle branch block with any fascicular block, changes consistent with acute ischemia.

A diagnosis of ulcerative colitis or indeterminate colitis;

Cushing's syndrome;

Coexisting Th2-type inflammatory diseases, such as scleroderma and MODERATE persistent asthma defined as the presence of one of the features listed below:

Clinical features before treatment: daily symptoms, exacerbations that affect activity and sleep, nighttime asthma symptoms greater than 1 time a week, peak expiratory flow (PEF) or forced expiratory volume (FEV1) greater than 60% to less than 80% of predicted, variability greater than 30%;

Daily medication required to maintain control:

Daily controller medications (especially for nighttime symptoms): inhaled corticosteroids and long acting bronchodilators

SEVERE persistent asthma defined as the presence of one of the features listed below:

Clinical features before treatment: continuous symptoms, frequent exacerbations, frequent nighttime asthma symptoms, physical activities limited by asthma symptoms, PEF or FEV1 less than 60% predicted, variability greater than 30%;

Daily medication required to maintain control:

Multible daily controller medications (long-term);

high-dose inhaled corticosteroids or bronchodilators

oral corticosteroids

Current active bowel obstruction, intestinal perforation, significant GI hemorrhage, or known presence of high grade stricture

HIV positivity or signs and symptoms consistent with HIV infection

Acute systemic or intestinal infection requiring antibiotics

Active hepatitis B or C

Decompensated liver disease (Childs-Pugh class B or C)

Hematocrit less than 30%; Platelet count less than 100,000 or greater than 700,000; PT INR greater than 1.3 or PTT prolonged by greater than 3 seconds; serum creatinine or BUN greater than 1.5 times the upper limit of normal (ULN); ALT(SGPT or AST(SGOT) greater than 2 times the ULN; total bilirubin greater than 1.25 times the ULN; alkaline phosphatase greater than 1.5 times the ULN.

Pregnant or nursing women

History of cancer (other than resected cutaneous basal or squamous cell carcinoma; and in situ cervical cancer) with less than 5 years documentation of a disease-free state

History of myocardial infarction within the last 12 months

Patients expected to require surgery for their Crohn's disease within 12 weeks of study entry.

Any condition that, in the investigator's opinion, places the patient at undue risk by participating in the study.

History of anaphylactic reaction or hypersensitivity to G-CSF (Filgrastim) or proteins derived from E. coli

Presence of splenomegaly defined as a palpable spleen on physical exam.

Special Instructions: Currently Not Provided
Keywords:
Cytokines
Th1 Th2 Response
Inflammatory Bowel Dx
Lymphocyte
Colonoscopy
Recruitment Keywords:
Crohn's Disease
Crohn's
Conditions:
Crohn's Disease
Investigational Drug(s):
None
Investigational Device(s):
None

Contacts:
Patient Recruitment and Public Liaison Office
Building 61
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793

Electronic Mail:prpl@mail.cc.nih.gov

Citations:
Interferon expression in Crohn's disease patients: increased interferon-gamma and -alpha mRNA in the intestinal lamina propria mononuclear cells

Interleukin 12 is expressed and actively released by Crohn's disease intestinal lamina propria mononuclear cells

Animal models of mucosal inflammation and their relation to human inflammatory bowel disease

Active Accrual, Protocols Recruiting New Patients

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