Safety and Efficacy of AST-120 in the Treatment of Antibiotic-Refractory Pouchitis

Patients with acute pouchitis are typically treated with metronidazole or ciprofloxacin for 10-14 days. Most patients with pouchitis respond to these or other antibiotics. Patients who experience frequent relapses and those with chronic pouchitis will require long term maintenance antibiotics. Probiotics may be considered as an alternate to chronic antibiotic therapy for maintenance of remission in chronic antibiotic-dependent pouchitis. In practice, we would institute maintenance therapy for patients who relapse at least 3 times within one year, or within 1 month of discontinuation of antibiotics. Among patients receiving maintenance antibiotics who develop loss of clinical benefit after prolonged treatment, rotation of three or four antibiotics in 1-week intervals may be beneficial. Patients who do not improve with single antibiotics may respond to combination therapy with two antibiotics. If not, they can be treated with topical or oral budesonide. Other options include topical mesalamine (enemas or suppositories), oral sulfasalazine or mesalamine, other topical or oral steroids, and possibly oral bismuth, azathioprine, 6-mercaptopurine or infliximab. However, there is little evidence base for these therapies in the literature, and many of these therapies are expensive and/or potentially toxic. A therapy that does not suppress the immune system, and that has little or no toxicity would be attractive for patients with antibiotic-refractory pouchitis.

AST-120 is manufactured by Kureha Corporation, Japan. The agent was approved in Japan in 1991 for the treatment of patients with chronic kidney disease(CKD). It is comprised of highly adsorptive, porous, spherical carbon particles and is packaged in 2 g sachets for oral administration designed for the treatment of gastrointestinal diseases. AST-120 consists of black microspheres approximately 0.2-0.4 mm in diameter with high adsorption ability and large surface area. Composed mainly of carbon (approximately 96%), the clinical utility of AST-120 is thought to reside in its ability to adsorb small molecular weight toxins, inflammatory mediators, and harmful bile acid products from the gastrointestinal tract, preventing local toxicity and their systemic absorption. AST-120 has a selective adsorption profile for certain acidic and basic organic compounds, and has a significantly lower adsorptive capacity than activated charcoal for digestive enzymes.

In this study, patients with active pouchitis after ileal pouch-anal anastomosis (IPAA) for Ulcerative Colitis with primary symptoms such as increased stool frequency and abdominal pain, and refractory to antibiotics (do not respond to antibiotic therapy for a minimum of 14 days) will be enrolled. Patients must have active pouchitis confirmed by endoscopy and biopsy within 4 weeks of study entry. The diagnosis of active pouchitis will be defined by a PDAI score >7 points, with a combined assessment of symptoms, endoscopy and histology.

Eligible patients will receive AST-120 sachets at 2g three times daily (TID) to be taken between meals at 10:00 am, 3:00 pm and immediately before going to bed for 4 complete weeks. AST-120 is a tasteless, odorless, oral preparation. 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 evaluated at baseline and week 4 or early termination by the study physician, including endoscopies with histology and routine laboratory tests. Patients will be checked on a weekly basis by the study coordinator by phone for symptom response, compliance, and development of adverse events. Quality of Life Assessments (Cleveland Global Quality of Life and Short Inflammatory Bowel Questionnaire) will be conducted at baseline and week 4 or early termination. A patient is defined as having completed study treatment if he/she has received investigational product and is followed for safety through the last on-site visit of the 4 week treatment course.

Any co-prescribed medicine must be given at least 30 minutes before AST-120 administration. The following drugs for pouchitis can be co-prescribed/maintained during AST-120 treatment and their utilization will be recorded as secondary endpoints:

• Antidiarrheal therapy with loperamide (Imodium)
• Nutritional agents and Probiotics at the same dose as previously prescribed, if the dose has been stable for 2 weeks at study entry.

Antibiotics must be stopped by the time of entry into the study. However, antibiotics prescribed to treat infection other than pouchitis will be allowed and recorded.

The need to prescribe any of the following drugs during the study will constitute treatment failure:

• Oral or topical corticosteroids
• Oral or topical 5-ASA
• Nutritional agents (SCFA enemas or suppositories, glutamine, dietary fibers)
• Probiotics
• Narcotic-based antidiarrheal agents

In addition patients will be considered to have failed treatment if they have a PDAI score improvement of < or = 2 points at the end of the trial. Patients will be discontinued from the study if they become pregnant or if warranted by treatment-emergent safety concerns or if, in the opinion of the investigator, it is in the patient's best interest to discontinue the study.

A first cohort of 10 patients will be treated; based on outcome (efficacy and safety: no significant Adverse Event (AE) associated with study drug and at least 3/10 patients responding) a second cohort of 10 patients may be enrolled.