G-CSF to Treat Crohn's Disease
G-CSF to Treat Crohn's Disease
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
The purpose of this pilot study is to evaluate the immunologic and the clinical response to
 granulocyte-colony stimulating factor (G-CSF, Filgrastim, Neupogen) administered to patients
 with Crohn's Disease. Crohn's disease, an incurable, chronic, relapsing inflammation of the
 small and large intestine, affects approximately 500,000 people in the United States. The
 disease is characterized by full-thickness involvement of the gut wall leading to episodes of
 abdominal pain, diarrhea, hematochezia, weight loss and complications such as bowel
 obstruction, fistula formation and extraintestinal manifestations. The rationale for this
 study is based on several observations. First, it has been shown that effector T cells and
 dendritic cells harvested following G-CSF administration display a Th2 phenotype. Second,
 Crohn's disease in animal models has been characterized as a Th1 inflammatory disease that is
 susceptible to Th2 counter-regulation. Lastly, G-CSF has been an effective treatment in
 Crohn's disease as well as other colitides with resemblance to Crohn's disease according to
 published case reports. Despite the standard therapeutic use of steroids, aminosalicylates,
 antibiotics, antimetabolite immunosuppressants (6-MP, methotrexate), and early agents of the
 emerging biologics class of drugs (anti-TNFalpha antibodies, e.g.), the treatment of Crohn's
 disease is still troubled by loss of effectiveness of standard therapy over time, outright
 nonresponsiveness, and serious medication side effects. For these reasons newer agents and
 strategies for the treatment of Crohn's disease need to be developed and tested.

 This pilot study proposes to measure the immunologic and clinical effect of two dose levels
 of G-CSF administered subcutaneously to patients with active Crohn's disease. The primary
 outcomes include documenting changes in immune parameters by measuring peripheral and lamina
 propria CD4 T cell cytokine release, dendritic cell phenotype and cytokine release, and
 changes in clinical parameters such as the Crohn's Disease Activity Index and endoscopic and
 histologic scores. Secondary endpoints include the rate and severity of adverse events. Our
 short-term goal is to document production of effector cells that have a Th2-cytokine profile
 and associate clinical improvement with these changes. The long-term goal of this study is to
 establish G-CSF as an effective alternative or adjunctive therapy with a low risk profile for
 the treatment of Crohn's disease.
-  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 surgically 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:

 If any one of the above eligibility requirements is not met.

 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), Thalidomide, or Mycophenolate mofetil (CellCept) (4 weeks), or any
 biological therapy (cytokine, anti-cytokine, or integrin-based therapy); Monoclonal
 antibodies to TNF (4 months); any experimental agent (1 month); use of greater than 500
 mg/d aspirin or any dose of other NSAID (24 hours).

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

 Use of 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: a.) scleroderma b.) 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 two to four times a week, peak expiratory flow (PEF) or
 forced expiratory volume (FEV1) greater than 60 percent to less than 80 percent of
 predicted, variability greater than 30 percent;

 Daily medication required to maintain control:

 Daily controller medication (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 more than 4 times a week, daily physical activities limited by
 asthma symptoms, PEF or FEV1 less than 60 percent predicted, variability greater than 30
 percent;

 Daily medication required to maintain control:

 Multiple 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 structure

 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 percent; 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.