G-CSF to Treat Crohn's Disease

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.