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

• Sponsor: Ocera Therapeutics
• Information provided by (Responsible Party): Ocera Therapeutics

Study Description

Brief Summary:

This is an open-label pilot study in which all patients will receive AST-120 for 4 weeks. Patients will discontinue antibiotics at study entry. They may continue other previously prescribed treatments (e.g., probiotics and/or nutritional agents) at the discretion of the study doctor. The purpose of the study is to assess whether the investigational medication AST-120 will be a safe and effective treatment for the symptoms of pouchitis, a chronic inflammatory condition, in patients whose symptoms have not responded well to antibiotics. An initial group of 10 patients will be enrolled. If there are no serious side effects associated with the study drug and at least 3 of the 10 patients respond, a second group of 10 patients may be enrolled. Patients will have clinic visits at the start of the study and at week 4. Patients will be checked by phone on a weekly basis for symptom response, compliance and development of side effects. Endoscopies will be performed at the start of the study and at week 4 or early termination.

Condition or disease	Intervention/treatment	Phase
Pouchitis	Drug: AST-120	Phase 2

  Show Detailed Description

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 2 participants
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Pilot Study of the Safety and Efficacy of AST-120 in the Treatment of Antibiotic-Refractory Pouchitis
• Study Start Date: March 2007
• Actual Primary Completion Date: December 2008
• Actual Study Completion Date: December 2008

Arms and Interventions

Arm	Intervention/treatment
Experimental: I; Active treatment with AST-120	Drug: AST-120; Oral, 2 grams TID in sachets for 4 weeks

Outcome Measures

Primary Outcome Measures :

1. Response as defined by a decrease in the Pouchitis Diseases Activity Index (PDAI) score of at least 3 points [ Time Frame: 4 weeks ]
2. Safety: Any adverse events (AEs) deemed possibly, probably, or definitely related to treatment with investigational product during 4 weeks of treatment [ Time Frame: 4 weeks ]

Secondary Outcome Measures :

1. Remission, as defined as a PDAI score of less than 7 points [ Time Frame: 4 weeks ]
2. Reduction of PDAI clinical symptom subscore of at least 1 point [ Time Frame: 4 weeks ]
3. Reduction of PDAI endoscopic subscore of at least 1 point [ Time Frame: 4 weeks ]
4. Reduction of PDAI histology subscore of at least 1 point [ Time Frame: 4 weeks ]
5. Need for rescue medication/quantity of antidiarrheal medication used during the last week of the trail compared to usage in the week prior to study entry [ Time Frame: 4 weeks ]
6. Quality of Life as measured by the Cleveland Global QoL instrument and Short Inflammatory Bowel Disease Questionnaire (SIBDQ) [ Time Frame: 4 weeks ]
7. Significant change in clinical laboratory tests [ Time Frame: 4 weeks ]
8. Worsening GI symptoms (diarrhea, abdominal pain, urgency or bleeding) or new GI and extra-GI symptoms (e.g., headache, nausea, vomiting, constipation) [ Time Frame: 4 weeks ]
9. Significant change in physical examination, including vital signs (blood pressure, heart rate, respiration rate and temperature) [ Time Frame: 4 weeks ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Patients with active pouchitis (defined as having a PDAI score > 7) after IPAA for UC, despite at least 14 days of antibiotic therapy. Active pouchitis must be confirmed by endoscopy and histology within 4 weeks of study entry
• Able to give informed consent
• Able and willing to comply with all study procedures

Exclusion Criteria:

• Patients previously treated with infliximab or any investigational immunosuppressant/ immunomodulator for pouchitis
• Patients undergoing chemotherapy for the treatment of cancer
• Presence of other inflammatory diseases of the pouch: Crohn's disease, Cuffitis, active specific infection of the pouch: (e.g., CMV, C. difficile)
• History of non-inflammatory disease of the pouch: decreased pouch compliance, irritable pouch syndrome, afferent or efferent limb obstruction, stricture of pouch
• Ileal pouch patients with familial adenomatous polyposis
• History of other diarrheal illnesses: lactose intolerance, celiac disease, small bowel bacterial overgrowth
• Primary Sclerosing Cholangitis with or without liver transplant
• Uncontrolled systemic disease
• Needing oral or topical 5-ASA, cholestyramine, steroids or immunomodulators
• 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
• Women who are pregnant, breast feeding, or planning to become pregnant during the study
• Women of child-bearing potential who are not willing to use barrier or depot contraception methods
• Use of NSAIDs or aspirin (>3 times per week) within the past 3 weeks

Contacts and Locations

Locations

United States, Minnesota

Mayo Clinic, Inflammatory Bowel Disease Clinic

Rochester, Minnesota, United States, 55905

Sponsors and Collaborators

Ocera Therapeutics

Investigators

• Principal Investigator: Darrell S. Pardi, MD; Mayo Clinic College of Medicine

More Information

Publications:

Sandborn WJ. Pouchitis following ileal pouch-anal anastomosis: definition, pathogenesis, and treatment. Gastroenterology. 1994 Dec;107(6):1856-60. Review.

Fazio VW, Ziv Y, Church JM, Oakley JR, Lavery IC, Milsom JW, Schroeder TK. Ileal pouch-anal anastomoses complications and function in 1005 patients. Ann Surg. 1995 Aug;222(2):120-7.

Simchuk EJ, Thirlby RC. Risk factors and true incidence of pouchitis in patients after ileal pouch-anal anastomoses. World J Surg. 2000 Jul;24(7):851-6.

Salemans JM, Nagengast FM, Lubbers EJ, Kuijpers JH. Postoperative and long-term results of ileal pouch-anal anastomosis for ulcerative colitis and familial polyposis coli. Dig Dis Sci. 1992 Dec;37(12):1882-9.

Marcello PW, Roberts PL, Schoetz DJ Jr, Coller JA, Murray JJ, Veidenheimer MC. Long-term results of the ileoanal pouch procedure. Arch Surg. 1993 May;128(5):500-3; discussion 503-4.

Meagher AP, Farouk R, Dozois RR, Kelly KA, Pemberton JH. J ileal pouch-anal anastomosis for chronic ulcerative colitis: complications and long-term outcome in 1310 patients. Br J Surg. 1998 Jun;85(6):800-3.

Svaninger G, Nordgren S, Oresland T, Hultén L. Incidence and characteristics of pouchitis in the Kock continent ileostomy and the pelvic pouch. Scand J Gastroenterol. 1993 Aug;28(8):695-700.

Shepherd NA, Hultén L, Tytgat GN, Nicholls RJ, Nasmyth DG, Hill MJ, Fernandez F, Gertner DJ, Rampton DS, Hill MJ, et al. Pouchitis. Int J Colorectal Dis. 1989 Dec;4(4):205-29. Review.

Sandborn WJ. Pouchitis: risk factors, frequency, natural history, classification and public health perspective. Kluwer Academic Publishers, 1997.

Sandborn WJ, Pardi DS. Clinical management of pouchitis. Gastroenterology. 2004 Dec;127(6):1809-14.

Sagar PM, Pemberton JH. Ileo-anal pouch function and dysfunction. Dig Dis. 1997 May-Jun;15(3):172-88. Review.

Lohmuller JL, Pemberton JH, Dozois RR, Ilstrup D, van Heerden J. Pouchitis and extraintestinal manifestations of inflammatory bowel disease after ileal pouch-anal anastomosis. Ann Surg. 1990 May;211(5):622-7; discussion 627-9.

Tytgat GN, van Deventer SJ. Pouchitis. Int J Colorectal Dis. 1988 Nov;3(4):226-8. Review.

Shen B, Achkar JP, Lashner BA, Ormsby AH, Remzi FH, Bevins CL, Brzezinski A, Petras RE, Fazio VW. Endoscopic and histologic evaluation together with symptom assessment are required to diagnose pouchitis. Gastroenterology. 2001 Aug;121(2):261-7.

Hurst RD, Molinari M, Chung TP, Rubin M, Michelassi F. Prospective study of the incidence, timing and treatment of pouchitis in 104 consecutive patients after restorative proctocolectomy. Arch Surg. 1996 May;131(5):497-500; discussion 501-2.

Duffy M, O'Mahony L, Coffey JC, Collins JK, Shanahan F, Redmond HP, Kirwan WO. Sulfate-reducing bacteria colonize pouches formed for ulcerative colitis but not for familial adenomatous polyposis. Dis Colon Rectum. 2002 Mar;45(3):384-8.

Gosselink MP, Schouten WR, van Lieshout LM, Hop WC, Laman JD, Ruseler-van Embden JG. Eradication of pathogenic bacteria and restoration of normal pouch flora: comparison of metronidazole and ciprofloxacin in the treatment of pouchitis. Dis Colon Rectum. 2004 Sep;47(9):1519-25. Epub 2004 Jul 8.

Gionchetti P, Rizzello F, Venturi A, Ugolini F, Rossi M, Brigidi P, Johansson R, Ferrieri A, Poggioli G, Campieri M. Antibiotic combination therapy in patients with chronic, treatment-resistant pouchitis. Aliment Pharmacol Ther. 1999 Jun;13(6):713-8.

Kmiot WA, Youngs D, Tudor R, Thompson H, Keighley MR. Mucosal morphology, cell proliferation and faecal bacteriology in acute pouchitis. Br J Surg. 1993 Nov;80(11):1445-9.

Nasmyth DG, Godwin PG, Dixon MF, Williams NS, Johnston D. Ileal ecology after pouch-anal anastomosis or ileostomy. A study of mucosal morphology, fecal bacteriology, fecal volatile fatty acids, and their interrelationship. Gastroenterology. 1989 Mar;96(3):817-24.

Schmidt CM, Lazenby AJ, Hendrickson RJ, Sitzmann JV. Preoperative terminal ileal and colonic resection histopathology predicts risk of pouchitis in patients after ileoanal pull-through procedure. Ann Surg. 1998 May;227(5):654-62; discussion 663-5.

Ståhlberg D, Gullberg K, Liljeqvist L, Hellers G, Löfberg R. Pouchitis following pelvic pouch operation for ulcerative colitis. Incidence, cumulative risk, and risk factors. Dis Colon Rectum. 1996 Sep;39(9):1012-8.

Hata K, Watanabe T, Shinozaki M, Nagawa H. Patients with extraintestinal manifestations have a higher risk of developing pouchitis in ulcerative colitis: multivariate analysis. Scand J Gastroenterol. 2003 Oct;38(10):1055-8.

Penna C, Dozois R, Tremaine W, Sandborn W, LaRusso N, Schleck C, Ilstrup D. Pouchitis after ileal pouch-anal anastomosis for ulcerative colitis occurs with increased frequency in patients with associated primary sclerosing cholangitis. Gut. 1996 Feb;38(2):234-9.

Achkar JP, Al-Haddad M, Lashner B, Remzi FH, Brzezinski A, Shen B, Khandwala F, Fazio V. Differentiating risk factors for acute and chronic pouchitis. Clin Gastroenterol Hepatol. 2005 Jan;3(1):60-6.

Shen B, Fazio VW, Remzi FH, Delaney CP, Bennett AE, Achkar JP, Brzezinski A, Khandwala F, Liu W, Bambrick ML, Bast J, Lashner B. Comprehensive evaluation of inflammatory and noninflammatory sequelae of ileal pouch-anal anastomoses. Am J Gastroenterol. 2005 Jan;100(1):93-101.

Sandborn WJ, Landers CJ, Tremaine WJ, Targan SR. Antineutrophil cytoplasmic antibody correlates with chronic pouchitis after ileal pouch-anal anastomosis. Am J Gastroenterol. 1995 May;90(5):740-7.

Aisenberg J, Legnani PE, Nilubol N, Cobrin GM, Ellozy SH, Hegazi RA, Yager J, Bodian C, Gorfine SR, Bauer JJ, Plevy SE, Sachar DB. Are pANCA, ASCA, or cytokine gene polymorphisms associated with pouchitis? Long-term follow-up in 102 ulcerative colitis patients. Am J Gastroenterol. 2004 Mar;99(3):432-41.

Merrett MN, Mortensen N, Kettlewell M, Jewell DO. Smoking may prevent pouchitis in patients with restorative proctocolectomy for ulcerative colitis. Gut. 1996 Mar;38(3):362-4.

Di Febo G, Miglioli M, Lauri A, Biasco G, Paganelli GM, Poggioli G, Gozzetti G, Barbara L. Endoscopic assessment of acute inflammation of the ileal reservoir after restorative ileo-anal anastomosis. Gastrointest Endosc. 1990 Jan-Feb;36(1):6-9.

Moskowitz RL, Shepherd NA, Nicholls RJ. An assessment of inflammation in the reservoir after restorative proctocolectomy with ileoanal ileal reservoir. Int J Colorectal Dis. 1986 Jul;1(3):167-74.

Shen B, Shermock KM, Fazio VW, Achkar JP, Brzezinski A, Bevins CL, Bambrick ML, Remzi FH, Lashner BA. A cost-effectiveness analysis of diagnostic strategies for symptomatic patients with ileal pouch-anal anastomosis. Am J Gastroenterol. 2003 Nov;98(11):2460-7.

Shepherd NA, Jass JR, Duval I, Moskowitz RL, Nicholls RJ, Morson BC. Restorative proctocolectomy with ileal reservoir: pathological and histochemical study of mucosal biopsy specimens. J Clin Pathol. 1987 Jun;40(6):601-7.

Parsi MA, Shen B, Achkar JP, Remzi FF, Goldblum JR, Boone J, Lin D, Connor JT, Fazio VW, Lashner BA. Fecal lactoferrin for diagnosis of symptomatic patients with ileal pouch-anal anastomosis. Gastroenterology. 2004 May;126(5):1280-6.

Johnson MW, Dewar DH, Ciclitira P, Forbes A, Nicholls RJ, Bjarnason I. Use of fecal lactoferrin to diagnose irritable pouch syndrome: a word of caution. Gastroenterology. 2004 Nov;127(5):1647-8; author reply 1648.

Mann SD, Pitt J, Springall RG, Thillainayagam AV. Clostridium difficile infection--an unusual cause of refractory pouchitis: report of a case. Dis Colon Rectum. 2003 Feb;46(2):267-70. Review.

Seggerman RE, Chen MY, Waters GS, Ott DJ. Pictorial essay. Radiology of ileal pouch-anal anastomosis surgery. AJR Am J Roentgenol. 2003 Apr;180(4):999-1002.

Libicher M, Scharf J, Wunsch A, Stern J, Düx M, Kauffmann GW. MRI of pouch-related fistulas in ulcerative colitis after restorative proctocolectomy. J Comput Assist Tomogr. 1998 Jul-Aug;22(4):664-8.

Shen B, Lashner BA, Bennett AE, Remzi FH, Brzezinski A, Achkar JP, Bast J, Bambrick ML, Fazio VW. Treatment of rectal cuff inflammation (cuffitis) in patients with ulcerative colitis following restorative proctocolectomy and ileal pouch-anal anastomosis. Am J Gastroenterol. 2004 Aug;99(8):1527-31.

Thompson-Fawcett MW, Mortensen NJ, Warren BF. "Cuffitis" and inflammatory changes in the columnar cuff, anal transitional zone, and ileal reservoir after stapled pouch-anal anastomosis. Dis Colon Rectum. 1999 Mar;42(3):348-55.

Keighley MR. Review article: the management of pouchitis. Aliment Pharmacol Ther. 1996 Aug;10(4):449-57. Review.

Muñoz-Juarez M, Pemberton JH, Sandborn WJ, Tremaine WJ, Dozois RR. Misdiagnosis of specific cytomegalovirus infection of the ileoanal pouch as refractory idiopathic chronic pouchitis: report of two cases. Dis Colon Rectum. 1999 Jan;42(1):117-20.

Moonka D, Furth EE, MacDermott RP, Lichtenstein GR. Pouchitis associated with primary cytomegalovirus infection. Am J Gastroenterol. 1998 Feb;93(2):264-6.

Salfiti N, Loftus EV, Tremaine WJ, Pardi DS, et al. Clinical features and outcomes of cytomegalovirus colitis or pouchitis in patients with inflammatory bowel disease. Am J Gastroenterol 100:S316, 2005

Shen B, Achkar JP, Lashner BA, Ormsby AH, Brzezinski A, Soffer EE, Remzi FH, Bevins CL, Fazio VW. Irritable pouch syndrome: a new category of diagnosis for symptomatic patients with ileal pouch-anal anastomosis. Am J Gastroenterol. 2002 Apr;97(4):972-7.

Prudhomme M, Dozois RR, Godlewski G, Mathison S, Fabbro-Peray P. Anal canal strictures after ileal pouch-anal anastomosis. Dis Colon Rectum. 2003 Jan;46(1):20-3.

Madden MV, McIntyre AS, Nicholls RJ. Double-blind crossover trial of metronidazole versus placebo in chronic unremitting pouchitis. Dig Dis Sci. 1994 Jun;39(6):1193-6.

Shen B, Achkar JP, Lashner BA, Ormsby AH, Remzi FH, Brzezinski A, Bevins CL, Bambrick ML, Seidner DL, Fazio VW. A randomized clinical trial of ciprofloxacin and metronidazole to treat acute pouchitis. Inflamm Bowel Dis. 2001 Nov;7(4):301-5.

Sambuelli A, Boerr L, Negreira S, Gil A, Camartino G, Huernos S, Kogan Z, Cabanne A, Graziano A, Peredo H, Doldán I, Gonzalez O, Sugai E, Lumi M, Bai JC. Budesonide enema in pouchitis--a double-blind, double-dummy, controlled trial. Aliment Pharmacol Ther. 2002 Jan;16(1):27-34.

Mimura T, Rizzello F, Helwig U, Poggioli G, Schreiber S, Talbot IC, Nicholls RJ, Gionchetti P, Campieri M, Kamm MA. Four-week open-label trial of metronidazole and ciprofloxacin for the treatment of recurrent or refractory pouchitis. Aliment Pharmacol Ther. 2002 May;16(5):909-17.

Nygaard K, Bergan T, Bjørneklett A, Høverstad T, Lassen J, Aase S. Topical metronidazole treatment in pouchitis. Scand J Gastroenterol. 1994 May;29(5):462-7.

Gionchetti P, Rizzello F, Venturi A, Brigidi P, Matteuzzi D, Bazzocchi G, Poggioli G, Miglioli M, Campieri M. Oral bacteriotherapy as maintenance treatment in patients with chronic pouchitis: a double-blind, placebo-controlled trial. Gastroenterology. 2000 Aug;119(2):305-9.

Mimura T, Rizzello F, Helwig U, Poggioli G, Schreiber S, Talbot IC, Nicholls RJ, Gionchetti P, Campieri M, Kamm MA. Once daily high dose probiotic therapy (VSL#3) for maintaining remission in recurrent or refractory pouchitis. Gut. 2004 Jan;53(1):108-14.

Gionchetti P, Rizzello F, Helwig U, Venturi A, Lammers KM, Brigidi P, Vitali B, Poggioli G, Miglioli M, Campieri M. Prophylaxis of pouchitis onset with probiotic therapy: a double-blind, placebo-controlled trial. Gastroenterology. 2003 May;124(5):1202-9.

Shen B, Brzezinski A, Fazio VW, Remzi FH, Achkar JP, Bennett AE, Sherman K, Lashner BA. Maintenance therapy with a probiotic in antibiotic-dependent pouchitis: experience in clinical practice. Aliment Pharmacol Ther. 2005 Oct 15;22(8):721-8.

Chopra A, Pardi DS, Loftus EV Jr, Tremaine WJ, Egan LJ, Faubion WA, Hanson KA, Johnson TA, Sandborn WJ. Budesonide in the treatment of inflammatory bowel disease: the first year of experience in clinical practice. Inflamm Bowel Dis. 2006 Jan;12(1):29-32.

Gionchetti P, Rizzello F, Morselli C, et al. Eight-week trial of oral budesonide for the treatment of refractory pouchitis. Gastroenterology 126:A123, 2004

Miglioli M, Barbara L, Di Febo G, Gozzetti G, Lauri A, Paganelli GM, Poggioli G, Santucci R. Topical administration of 5-aminosalicylic acid: a therapeutic proposal for the treatment of pouchitis. N Engl J Med. 1989 Jan 26;320(4):257.

Viscido A, Habib FI, Kohn A, Papi C, Marcheggiano A, Pimpo MT, Vernia P, Cadau G, Caprilli R. Infliximab in refractory pouchitis complicated by fistulae following ileo-anal pouch for ulcerative colitis. Aliment Pharmacol Ther. 2003 May 15;17(10):1263-71.

Gionchetti P, Rizzello F, Venturi A, Ferretti M, Brignola C, Peruzzo S, Belloli C, Poggioli G, Miglioli M, Campieri M. Long-term efficacy of bismuth carbomer enemas in patients with treatment-resistant chronic pouchitis. Aliment Pharmacol Ther. 1997 Aug;11(4):673-8.

Tremaine WJ, Sandborn WJ, Kenan ML. Bismuth subsalicylate tablets for chronic antibiotic-resistant pouchitis. Gastroenterology 114:A1101, 1998.

Wischmeyer P, Pemberton JH, Phillips SF. Chronic pouchitis after ileal pouch-anal anastomosis: responses to butyrate and glutamine suppositories in a pilot study. Mayo Clin Proc. 1993 Oct;68(10):978-81.

Tremaine WJ, Sandborn WJ, Wolff BG, Carpenter HA, Zinsmeister AR, Metzger PP. Bismuth carbomer foam enemas for active chronic pouchitis: a randomized, double-blind, placebo-controlled trial. Aliment Pharmacol Ther. 1997 Dec;11(6):1041-6.

• Responsible Party: Ocera Therapeutics
• ClinicalTrials.gov Identifier: NCT00583531 History of Changes
• Other Study ID Numbers: 06-007216
• First Posted: December 31, 2007
• Last Update Posted: June 18, 2014
• Last Verified: June 2014

Keywords provided by Ocera Therapeutics:

Antibiotic-refractory Pouchitis; Pouchitis; Ulcerative Colitis

Additional relevant MeSH terms:

Pouchitis; Ileitis; Enteritis; Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Intestinal Diseases; Ileal Diseases; Anti-Bacterial Agents; Antibiotics, Antitubercular; Anti-Infective Agents; Antitubercular Agents