Safety and Efficacy of AST-120 in Mild to Moderate Crohn's Patients With Fistulas

The experimental drug AST-120 is composed of black, odorless spherical carbon particles in 2g sachets (aluminum foil pouches). The placebo consists of microcrystalline cellulose spheres, Celphere CP-305, stained to match the appearance of AST-120, in 2g sachets (aluminum foil pouches). Both AST-120 and placebo are oral (taken by mouth)preparations. Both are tasteless. To take the product, patients will tear open the sachets, drop the contents directly on their tongue and wash it down with 8 ounces of water.

Patients will be randomly assigned (like the toss of a coin), to receive either AST-120 or placebo. Patients will have a 50/50 chance of receiving placebo. Patients who participate in this study will be required to take a single dose of study drug (AST-120 or placebo) 3 times a day, 30 minutes after a meal, for 8 weeks, and be evaluated at Week 4 and Week 8. This is a 'blinded' treatment, which means that neither the patient nor the study doctor will know if the patient has received study drug or placebo.

If, at the end of the first full course of randomized treatment, (8 weeks), patients are not showing an improvement in their condition, they may have the option to receive the alternate blinded treatment for one treatment course (8 weeks). The study doctor will discuss this option with each patient individually. During this second course of treatment, patients will be evaluated at Week 12 and Week 16. If the patient does not respond to the alternate blinded treatment, or their condition worsens after 4 weeks (assessed at Week 12), they may be removed from the study at the discretion of the investigator.

If patients respond to either the initial treatment or the alternate blinded treatment, they will have monthly doctor/clinic visits for up to 6 months (Week 24), or until their condition worsens or they relapse. Patients will not receive any study drug during this follow-up period.

Relapse is defined for this study as:

• an increase by 1 or more in the number of draining fistulas for 2 sequential visits versus the number present at the time of response (response is defined as at least a 50% reduction in the number of draining fistulas at either Week 8, or for those patients receiving alternate blinded treatment, Week 16).

There are a maximum of 8 patient evaluation visits in this study (Screen, Baseline, Week 4, Week 8, Week 12, Week 16, Week 20 and Week 24). Evaluations at most of these visits include a review of concomitant medications, medical history/adverse events, physical exam, fistula exam, blood draws for safety labs, urine pregnancy tests for females, and measurement of body weight. Patients will also be asked to keep a daily diary to record frequency of bowel movements, general well-being, and use of antidiarrheal medication.

Treatment failure in this study is defined by one or more of the following occurring prior to Week 8:

• The need for additional therapies or dose increase for treatment of Crohn's disease, including an increase of corticosteroid dose to higher than baseline
• Clinical/symptomatic development of an abscess
• Clinical/symptomatic evidence of stricture
• The need for surgical intervention for Crohn's disease
• The patient withdraws from the study

Patients will be discontinued from the study at any time if one or more of the following complications occur:

• Development of an abscess or symptomatic stricture
• The need for surgical intervention for Crohn's disease
• Occurrence of any other event that in the opinion of the investigator warrants discontinuation of the patient from the study

In addition, patients whose CDAI score has risen by > or = 70 points above baseline or risen above 400 will be discontinued from the study.

Administration of any additional therapies or dose increases of concomitant medications (including corticosteroids) to control Crohn's disease to higher than baseline while receiving study drug (initial randomized treatment or alternate blinded treatment) will require discontinuation of the patient from the study.

Discontinued patients will be evaluated in a termination visit to document the lack of treatment efficacy and no further study treatment will be given.

Inclusion criteria

• Body Weight > or = 40kg
• Documented diagnosis of Crohn's disease, including patients with documented diagnosis of ileitis, colitis, or ileocolitis
• Presence of at least one draining fistula. Patients with enterocutaneous fistulas can be included if they have > or = 1 draining perianal fistula. Women with rectovaginal fistulas can be included if they have > or = 1 draining perianal fistula.
• Crohn's Disease Activity Index (CDAI) score < 400
• Platelet count (thrombocytes) > or = 100,000/uL
• Able and willing to comply with all protocol procedures for the duration of the study
• Able and willing to understand, sign and date an informed consent document, and authorize access to protected health information
• Females must be postmenopausal, surgically incapable of bearing children, or practicing a reliable method of birth control (hormonal contraceptives, intrauterine devices, spermicide and barrier). Partner/spouse sterility may also qualify at the Investigator's discretion. Females of child-bearing potential must have a negative urine pregnancy test at baseline.

Exclusion criteria

• Non-response to infliximab or other biological immunosuppressants/ immunomodulators for fistulas associated with Crohn's disease (response is defined as a > or = 50% reduction from baseline in the number of fistulas over at least four weeks); patients who respond once to infliximab and eventually fail can be included
• Infliximab (and/or other biological immunosuppressant/immunomodulatory) therapy within 3 months prior to enrollment in the study
• Presence of symptomatic strictures or suggestion of significant clinical obstruction
• Patients with setons are excluded, unless the setons are removed within 48 hours prior to study entry
• Presence of entero-entero, recto-vesicular, entero-vesicular fistulas
• Platelet count (thrombocytes) < 100,000/uL
• CDAI score of > or = 400
• Patient is unable to stay on a stable dose of concomitant Crohn's disease medication(s) for at least 10 weeks in the opinion of the investigator
• Currently symptomatic untreated diarrhea due to conditions other than mild to moderately active Crohn's disease (e.g., bacterial or parasitic gastroenteritis, bile salt diarrhea, etc.)
• Severe diarrhea defined by > 10 liquid bowel movements per day
• Other local manifestations of mild to moderately active Crohn's disease such as abscesses, or other disease manifestations for which surgery might be indicated or which might preclude utilization of a CDAI to assess response to therapy (e.g., short bowel syndrome)
• Presence of an ileostomy
• Receiving Total Parenteral Nutrition (TPN) as the sole source of nutrition within 3 weeks of Screen
• Poor tolerability of venipuncture or lack of adequate venous access for required blood sampling.
• Hemoglobin < 8.5 g/dL (females) or hemoglobin < 10 g/dL (males) at Screen
• Women who are pregnant, breast feeding, or planning to become pregnant during the study
• Other major physical or major psychiatric illness within the last 6 months that in the opinion of the investigator would affect the patient's ability to complete the trial
• Uncontrolled systemic disease
• Patients undergoing chemotherapy for the treatment of cancer
• Known hypersensitivity or contraindication to any component of the test product (study drugs) or diagnostics used
• Participation in another study within eight (8) weeks prior to the study
• Unable to attend all visits required by the protocol