Title:

Food supplementation with the probiotic preparation VSL#3 as a support to standard pharmaceutical therapy in patient with mild to moderate active Ulcerative Colitis. A double-blind, randomized, placebo controlled study.

Study Design:

Double blind, randomised, parallel groups, placebo controlled, multicentre, national study.

Study Period:

February 2006 - October 2007 (recruitment: 12 months; food supplementation with VSL#3: 8 weeks).

Study Population:

The study population will comprise 144 patients with mild to moderate active ulcerative colitis on top of standard pharmaceutical therapy. 72 patients will be randomised to receive food supplementation VSL#3 and 72 to receive placebo.

Total Number of centers:

Approximately 16

Study Objectives:

To assess the beneficial effects of food supplementation with VSL#3 in patients affected by mild to moderate active ulcerative colitis in a double-blind, placebo-controlled study.

Study product:

VSL#3 consists of sachets each containing 900 billion viable lyophilised bacteria, comprising 4 strains of Lactobacillus (L. paracasei, L. plantarum, L. acidophilus and L. delbrueckii subsp. bulgaricus), 3 strains of Bifidobacterium (B. longum, B. breve and B. infantis) and 1 strain of Streptococcus thermophilus, in maltose and silicon dioxide as excipients. The placebo is in the form of identical sachets containing only maltose and silicon dioxide.

The dose which will receive each patients is two sachets of VSL#3 or placebo to take twice a day orally (total amount of bacteria: 3.600 billion organisms per day).

Assessments:

Primary Outcome The primary outcome is the evaluation of the beneficial effects of food supplementation with VSL#3 in patients affected by UC, assessed by a decrease in the UCDAI of 50% or more, from baseline to week 8.

Secondary Outcomes:

Assessment of the beneficial effects of the food supplementation with the probiotic preparation VSL#3 on:

• activity of ulcerative colitis.

• change in subjective symptoms (rectal bleeding and stool frequency) from baseline to weeks 2, 4 and 8 of food supplementation with VSL#3.

• lack of beneficial effects, defined by need for further food supplementation or inability to stay on study till week 8.

• quality of life questionnaire (IBDQ)

• concordance between the Physician and Patient Global Assessment Scale at each time point.

Physical Status Evaluations:

Assessment of haematological laboratory tests, vital signs (blood pressure, pulse rate and respiratory rate), medical history and physical examination.

Inclusion Criteria:

1. Male and female patients aged more than 18 years;

2. Diagnosis of ulcerative colitis established by previous colonoscopy, with consistent histology and clinical course;

3. Ulcerative colitis extending for more than 15 cm from the anal verge, that is involving at least the rectosigmoid. This is based on colonoscopy at any time since the onset of ulcerative colitis. Activity (not extent) must be confirmed by colonoscopy at the beginning of the study;

4. Mild to moderate active ulcerative colitis. Patients must have a minimum score of 3 and a maximum score of 8 on the 12 point UCDAI (Ulcerative Colitis Disease Activity Index - see Appendix 3) that measures stool frequency, rectal bleeding, endoscopic findings and physician’s overall assessment of disease severity;

5. Symptomatic (current episode) for less than 4 weeks;

6. Minimum endoscopic score of 2 on the UCDAI at screening (mucosal appearance);

7. Use of oral 5-ASA at least 4 weeks prior to study entry, at same dose; and/or use of Azathioprine or 6-mercaptopurine at least 3 months prior to study entry, at same dose;

8. Negative pregnancy test on screening and agreeing to use valid contraception for the duration of the study;

9. Patient not requiring hospitalisation;

   1. Willing an able to provide written informed consent

Exclusion Criteria:

1. Crohn’s disease or pouchitis;

2. UCDAI greater than 8 (need for emergency surgery or presence of severe disease;

3. Use of oral steroids within the last 4 weeks prior to study entry;

4. Use of antibiotics within the last 2 weeks prior to study entry;

5. Change in dose of oral 5-ASA within the last 4 weeks prior to study entry and throughout the 8 week study period, or change in dose of oral 6-mercaptopurine and azathioprine drugs within the last 3 months prior to study entry and throughout the 8 week study period;

6. Use of rectal 5-ASA or steroids for one week before and throughout the 8 week study period;

7. Use of probiotic preparations either prescribed or over-the-counter within 2 weeks prior to study entry;

8. Use of NSAIDS for one week before and throughout the 8 week study period;

9. Significant hepatic, renal, endocrine, respiratory, neurological or cardiovascular disease as determined by the Investigator;

   1. History of severe adverse reaction or known hypersensitivity to maltose and/or silicon dioxide;

   2. Patient requiring hospitalisation;

   3. Pregnant or lactating women, or women of child bearing potential not using an acceptable form of birth control (negative pregnancy test also required);

   4. Use of any investigational drug and/or participation in any clinical trial within 3 months of entry to this study;

   5. Inability to give a valid informed consent or to properly follow the protocol