Safety and Efficacy of AST-120 in Patients With Non-Constipating Irritable Bowel Syndrome

• Percent of patients who achieve at least a 50% reduction in the number of days with abdominal pain during the final 2 weeks of the double-blind treatment course. [ Time Frame: Eight weeks ] [ Designated as safety issue: No ]
• Safety endpoint is adverse events (AEs) deemed possibly, probably, or definitely related to treatment with investigational product during the double-blind treatment course. [ Time Frame: 8 weeks ] [ Designated as safety issue: Yes ]

• Percent change in the IBS QOL score. [ Time Frame: Eight weeks ] [ Designated as safety issue: No ]
• Percent change in HADS score. [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
• Percent change in Bristol Scale score. [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
• Percent change in individual items in the IBS Symptom Severity questionnaire. [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
• Durability of effect after the first eight weeks of treatment. [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
• Change in clinical laboratory tests from Baseline to Week 8 and to Week 18. [ Time Frame: 8 weeks ] [ Designated as safety issue: Yes ]
• Any adverse event occurring after Week 8. [ Time Frame: 8 weeks ] [ Designated as safety issue: Yes ]
• Physical examinations, vital signs (blood pressure, heart rate, respiration and temperature). [ Time Frame: 8 weeks ] [ Designated as safety issue: Yes ]

The objective of this study is to evaluate the safety and effectiveness of the experimental drug AST-120 in treating patients with non-constipating IBS. The study will test whether or not patients receiving AST-120 experience at least a 50% reduction in the number of days with abdominal pain compared to placebo.

Patients experiencing non-constipating IBS will be randomized to one of two arms in the study: the experimental drug AST-120 or placebo. Patients will take 2g of AST-120 or placebo three times per day for eight weeks. After the 8 week course, patients will receive an additional 8 weeks single blind treatment, after a one week washout period.

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 sachet, drop the contents directly on their tongue and wash it down with 8 ounces of water.

Patients will be expected to participate in up to 10 visits, approximately three by telephone and the remainder of visits are in-clinic. At these visits, patients will undergo a number of tests including: hematology panel, lactose intolerance testing, physical exams, pregnancy tests, evaluations based on the following scales: The Bristol Stool Scale, IBS Severity Scale, IBS Quality of Life, SCL-90R.

Provided the patient has been stable for eight weeks prior to their baseline visit, they will be allowed to take the following medications: drugs that inhibit gastric secretion (histamine blockers, proton pump inhibitors), benzodiazepines and Imidazopyridines (short acting, nonbenzodiazepine hypnotics) for sleep (dose must be consistent with the use of a sleep agent) aspirin at a cardiovascular prophylactic dose (75-150 mg/day) and paracetamol. Antidepressants for non-IBS symptoms are allowed. Loperamide will be permitted as a rescue for diarrhea only when patients are experiencing at least 3 liquid or soft stools in one day. However, Loperamide is prohibited during the two week screening period.

Patients will not be allowed to take the following medications whilst on trial and these therapies must have been discontinued by at least two weeks prior to their baseline visit: probiotics, neuroleptics, antidepressants for IBS symptoms, daytime tranquilizers, prokinetics, spasmolytics, analgesics, other investigational agents and any over-the-counter medications.

Patient will be required to keep a diary during the study

• Drug: AST-120
  oral, sachet, 2 grams three times daily for 8 weeks
• Drug: Celphere® CP-305
  oral, placebo, sachet, 2 grams three times daily for 8 weeks

• Experimental: 1
  AST-120, 2 gram sachets
  Intervention: Drug: AST-120
• Placebo Comparator: 2
  Celphere® CP-305, stained to match appearance of AST-120, in 2g sachets
  Intervention: Drug: Celphere® CP-305

• Tack JF, Miner PB, Fischer L, Harris MS. Randomised clinical trial: the safety and efficacy of AST-120 in non-constipating irritable bowel syndrome - a double-blind, placebo-controlled study. Aliment Pharmacol Ther. 2011 Oct;34(8):868-77. Epub 2011 Aug 24.
• Drossman DA. The functional gastrointestinal disorders and the Rome III process. Gastroenterology. 2006 Apr;130(5):1377-90. Review. No abstract available.
• Schuster MM. Defining and diagnosing irritable bowel syndrome. Am J Manag Care. 2001 Jul;7(8 Suppl):S246-51. Review.
• Tack J, Broekaert D, Fischler B, Oudenhove LV, Gevers AM, Janssens J. A controlled crossover study of the selective serotonin reuptake inhibitor citalopram in irritable bowel syndrome. Gut. 2006 Aug;55(8):1095-103. Epub 2006 Jan 9.
• Wood JD. Histamine, mast cells, and the enteric nervous system in the irritable bowel syndrome, enteritis, and food allergies. Gut. 2006 Apr;55(4):445-7. No abstract available.

Inclusion Criteria:

• Body weight ≥ 40 kg;
• Recurrent abdominal pain or discomfort for three or more days per month for the last three months which meets Rome III criteria for non-constipating IBS;
• Patients on a stable diet for at least eight weeks;
• Patients ≥ 50 years of age with a negative screening colonoscopy in the last five years;
• Able and willing to comply with all protocol procedures for the planned 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 (intrauterine devices, spermicide and barrier) (Hormonal contraceptives are NOT regarded as adequate for the purpose of this trial.) 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:

• Constipating IBS;
• History of untreated lactose intolerance;
• History of colonic or major abdominal surgery (colectomy, for example);
• Active (untreated) Thyroid disease;
• Current diagnosis of major depression or psychosis;
• Known positive stool cultures for Clostridium difficile or other pathogens;
• Any condition necessitating the administration of analgesics (except paracetamol), probiotics, neuroleptics, antidepressants for IBS symptoms, daytime tranquilizers, prokinetics or spasmolytic medications;
• Poor tolerability of venipuncture or lack of adequate venous access for required blood sampling;
• Other major physical or major psychiatric illness within the last six months that in the opinion of the investigator would affect the patient's ability to complete the trial;
• Uncontrolled systemic disease such as diabetes;
• 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;
• Female patients must be excluded if they are pregnant, breast feeding, or planning to become pregnant during the study.