Clinical trial NCT00134758: Ursodeoxycholic Acid in the Treatment of Duodenal Adenomas in Familial Adenomatous Polyposis (FAP) Patients
Official title: Efficiency of Ursodesoxycholic Acid in the Treatment of Duodenal Adenomas in Familial Adenomatous Polyposis Patients. URSOPAF
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
PHASE3
Conditions: Adenomatous Polyposis Coli, Familial
Keywords: Treatment of adenomas of the duodenum in FAP patients.
Adenoma
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: Axcan Pharma
First posted: 2005-08-25
Enrollment: 90
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Malignant transformation of adenomas of the duodenum is now the leading cause of death in familial adenomatous polyposis (FAP) patients who had a restorative proctocolectomy. Ursodeoxycholic acid (UDCA) modifies the biliary acid profile and could reduce the severity of duodenal adenomas and prevent such transformation.

Detailed description: We designed a randomized double blinded study to evaluate the efficiency of UDCA in the treatment of duodenal adenomas. One hundred patients are planned to be included. Fifty will receive UDCA and fifty a placebo. Three duodenoscopies are planned: one before inclusion, one at the end of the first year of follow-up and one after two years of follow-up at the end of the protocol. These duodenoscopies are associated to endoscopies of the ileal reservoir performed at the time of restorative proctocolectomy and are recorded numerically. Severity of the duodenal adenomas are evaluated according to the SPIGELMAN score. Patients are seen every 6 months. Before each endoscopy, blood samples are collected for biliary acid profile analysis. Moreover, during endoscopies, duodenal fluid and ileal fluid are collected for biliary acid profile analysis, also.

At the end of the follow-up of the last patients included (nov 2008), biliary acid profile analysis will be performed and statistical analysis of the results will be performed.

Eligibility criteria: Inclusion Criteria:

* Male or female patients between 18 and 65 years of age
* Weight less than or equal to 100 kg
* Restorative proctocolectomy
* Activated protein C (APC) mutation identified or more than 100 polyps on the colectomy specimen
* SPIGELMAN score of duodenal adenoma greater than or equal to 1
* Efficient contraceptive treatment for pre-menopausal women
* Cooperative patient
* Signed consent
* Social security insurance

Exclusion Criteria:

* SPIGELMAN score of duodenal adenoma equal to 4 with severe dysplasia
* Hepatic disease
* Intermesenteric desmoid tumour
* Any severe disease
* Daily use during the last 3 months of:

  * aspirin;
  * non-steroid anti-inflammatory drugs;
  * tamoxifen;
  * cholestyramine.
* Pregnancy
* Breast-feeding

Primary outcomes:
measure: SPIGELMAN severity score of duodenal lesion after 2 years of follow-up
timeFrame: Baseline, 1 and 2 years
Secondary outcomes:
measure: Cellular proliferation (Ki 67 and PCNA)
timeFrame: At the baseline, 1 and 2 years
measure: Biliary acid profile
timeFrame: At the baseline, 1 and 2 years
measure: Compliance to the treatment
timeFrame: Every 6 months during 2 years
Other outcomes:
Locations:
city: Paris
country: France
facility: Saint-Antoine Hospital
Study officials:
affiliation: Department of Digestive Surgery, Saint-Antoine Hospital, Hospital of Paris (AP/HP), Pierre et Marie Curie University, 184 rue du Faubourg Saint-Antoine, 75012 Paris, France
name: Yann RA Parc, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Spigelman AD, Williams CB, Talbot IC, Domizio P, Phillips RK. Upper gastrointestinal cancer in patients with familial adenomatous polyposis. Lancet. 1989 Sep 30;2(8666):783-5. doi: 10.1016/s0140-6736(89)90840-4.
citation: Nugent KP, Farmer KC, Spigelman AD, Williams CB, Phillips RK. Randomized controlled trial of the effect of sulindac on duodenal and rectal polyposis and cell proliferation in patients with familial adenomatous polyposis. Br J Surg. 1993 Dec;80(12):1618-9. doi: 10.1002/bjs.1800801244.
citation: Jarvinen HJ, Nyberg M, Peltokallio P. Biliary involvement in familial adenomatosis coli. Dis Colon Rectum. 1983 Aug;26(8):525-8. doi: 10.1007/BF02563746.
citation: Spigelman AD, Owen RW, Hill MJ, Phillips RK. Biliary bile acid profiles in familial adenomatous polyposis. Br J Surg. 1991 Mar;78(3):321-5. doi: 10.1002/bjs.1800780318.
citation: Mower HF, Ray RM, Shoff R, Stemmermann GN, Nomura A, Glober GA, Kamiyama S, Shimada A, Yamakawa H. Fecal bile acids in two Japanese populations with different colon cancer risks. Cancer Res. 1979 Feb;39(2 Pt 1):328-31.
citation: Hill MJ, Drasar BS, Williams RE, Meade TW, Cox AG, Simpson JE, Morson BC. Faecal bile-acids and clostridia in patients with cancer of the large bowel. Lancet. 1975 Mar 8;1(7906):535-9. doi: 10.1016/s0140-6736(75)91556-1.
citation: Tanida N, Hikasa Y, Shimoyama T, Setchell KD. Comparison of faecal bile acid profiles between patients with adenomatous polyps of the large bowel and healthy subjects in Japan. Gut. 1984 Aug;25(8):824-32. doi: 10.1136/gut.25.8.824.
citation: van der Werf SD, Nagengast FM, van Berge Henegouwen GP, Huijbregts AW, van Tongeren JH. Colonic absorption of secondary bile-acids in patients with adenomatous polyps and in matched controls. Lancet. 1982 Apr 3;1(8275):759-62. doi: 10.1016/s0140-6736(82)91810-4. No abstract available.
citation: Wilpart M, Mainguet P, Maskens A, Roberfroid M. Structure-activity relationship amongst biliary acids showing comutagenic activity towards 1,2-dimethylhydrazine. Carcinogenesis. 1983 Oct;4(10):1239-41. doi: 10.1093/carcin/4.10.1239.
citation: Earnest DL, Holubec H, Wali RK, Jolley CS, Bissonette M, Bhattacharyya AK, Roy H, Khare S, Brasitus TA. Chemoprevention of azoxymethane-induced colonic carcinogenesis by supplemental dietary ursodeoxycholic acid. Cancer Res. 1994 Oct 1;54(19):5071-4.
citation: Serfaty L, De Leusse A, Rosmorduc O, Desaint B, Flejou JF, Chazouilleres O, Poupon RE, Poupon R. Ursodeoxycholic acid therapy and the risk of colorectal adenoma in patients with primary biliary cirrhosis: an observational study. Hepatology. 2003 Jul;38(1):203-9. doi: 10.1053/jhep.2003.50311.
citation: Parc Y, Piquard A, Dozois RR, Parc R, Tiret E. Long-term outcome of familial adenomatous polyposis patients after restorative coloproctectomy. Ann Surg. 2004 Mar;239(3):378-82. doi: 10.1097/01.sla.0000114216.90947.f6.
citation: Parc Y, Desaint B, Flejou JF, Lefevre JH, Serfaty L, Vienne A, Kotti S, Simon T, Tiret E. The effect of ursodesoxycholic acid on duodenal adenomas in familial adenomatous polyposis: a prospective randomized placebo-control trial. Colorectal Dis. 2012 Jul;14(7):854-60. doi: 10.1111/j.1463-1318.2011.02816.x.