Combination of Diet and Oral Budesonide for Ulcerative Colitis (ReDUCE)

Remission With Diet for Ulcerative Colitis Exacerbations: A Single Blinded, International Randomized Controlled Clinical and Translational Trial

The ReDUCE Trial is a multinational single-blinded randomized controlled trial in mild to moderate flare of Ulcerative colitis (UC) disease patients. The purpose of the study is to validate the clinical efficacy of the UCED (Ulcerative colitis Exclusion Diet) with partial enteral nutrition (PEN) using a novel formula. The investigators anticipate that adding a novel specifically designed dietary intervention in addition to drug will lead to superior remission and mucosal healing via changes in the microbiome.

Rational: Ulcerative colitis is currently treated only by medical therapies or surgery and there is no other option to avoid immune suppression. Thus, developing a dietary therapy that would treat the cause of the disease, while having no side effects, would likely lead to immediate implementation and be sought out by patients hesitant to be on lifelong medications or immune suppression. Objectives: To evaluate if the UC Exclusion Diet (UCED), can improve outcomes when administered with an oral budesonide regimen to adult patients with mild to moderate UC. Methods: This will be a 24-week multinational single-blinded randomized controlled trial. After a baseline flexible sigmoidoscopy, Group 1 will receive oral budesonide 9 mg topical therapy + the UCED+PEN phase 1 diet for 6 weeks, while Group 2 will receive oral budesonide 9 mg topical therapy alone for 6 weeks with no dietary intervention. Both groups will continue the previous maintenance therapy through week 12 and both groups will stop budesonide at week 6. Group 1 will continue with the phase 2 diet/PEN from week 7-12 while group 2 will stay on habitual diet. A flexible sigmoidoscopy will be repeated at week 12. Population: adults and adolescents between the ages of 17-65 with a mild to moderate active disease (Simple Clinical Colitis Activity Index (SCCAI) 5-10 with an endoscopic Mayo score 1-3), on an existing maintenance therapy comparing two arms. Time frame: The induction of remission phase will last 8 weeks followed by maintenance phase for a period of 24 weeks Expected outcomes and significance: The investigators anticipate that adding a novel specifically designed dietary intervention in addition to drug will lead to superior remission and mucosal healing via changes in the microbiome.

Participants in Group 1 will receive the UCED combined with partial enteral nutrition (PEN) using a novel nutritional formula for 6 weeks (diet phase 1) that will add to oral budesonide 9 mg topical therapy for 6 weeks and will follow diet + PEN (phase 2: wk6-wk12) and diet phase 3 for 24 weeks.

Participants in Group 2 will receive oral budesonide 9 mg topical therapy alone for 6 weeks with no dietary intervention

The diet will be supplemented by 3 glasses a day (750 m"l) of the formula developed for UC using the UCED principles.

Steroid free intention-to-treat (ITT) remission according to SCCAI<3 at week 12 *The Simple Clinical Colitis Activity Index (SCCAI). score ranges from 0 to 19. clinical remission will be defined according to SCCAI<3

*The Simple Clinical Colitis Activity Index (SCCAI). score ranges from 0 to 19 . Clinical response defined as 3-point reduction in SCCAI or remission.

Steroid free intention-to-treat (ITT) remission according to SCCAI<3 at week 6 *The Simple Clinical Colitis Activity Index (SCCAI). score ranges from 0 to 19. clinical remission will be defined according to SCCAI<3

according to SCCAI<3 at week 24 score ranges from 0 to 19. clinical remission will be defined according to SCCAI<3

Defined as Mayo score 0 or 1. Mayo score 0 or 1 means endoscopic remission. *The Mayo Score for ulcerative colitis disease activity provides an assessement of disease severity and can be used to monitor patients during therapy.

Fecal calprotectin will be analyzed locally, and will be defined as median/mean change in calprotectin from baseline.

Inclusion Criteria: Informed consent Established diagnosis of UC with mild to moderate active disease, 5 ≤ SCCAI ≤ 10 Age: 17-65 years (inclusive) Extent E1-E3 by the Montreal classification Active colitis in the rectum or sigmoid colon on sigmoidoscopy Stable medication use of oral 5ASA for at least 8 weeks, thiopurines, vedolizumabs, Ustekinumab or tofacitinib for at least 12 weeks Exclusion Criteria: Severe colitis (SCCAI>10) hospitalization for acute severe colitis (ASC) in the previous 6 months Use of steroids in the previous 3 months Patients treated with Anti-TNF currently or in patients who had previously failed or lost response to anti TNF Vegans (vegetarians may enroll) Pregnancy Inability use of budesonide due to severe adverse events Extraintestinal manifestations such as arthritis, spondyloarthropathy or uveitis Presence of baseline hypoalbuminemia Fever >38°C Evidence for Clostridioides difficile infection Renal failure Hepatitis or PSC (Primary Sclerosing Cholangitis) Active malignancy (excluding skin BCC).

Sarbagili Shabat C, Scaldaferri F, Zittan E, Hirsch A, Mentella MC, Musca T, Cohen NA, Ron Y, Fliss Isakov N, Pfeffer J, Yaakov M, Fanali C, Turchini L, Masucci L, Quaranta G, Kolonimos N, Godneva A, Weinberger A, Kopylov U, Levine A, Maharshak N. Use of Faecal Transplantation with a Novel Diet for Mild to Moderate Active Ulcerative Colitis: The CRAFT UC Randomised Controlled Trial. J Crohns Colitis. 2022 Mar 14;16(3):369-378. doi: 10.1093/ecco-jcc/jjab165.

Sarbagili-Shabat C, Albenberg L, Van Limbergen J, Pressman N, Otley A, Yaakov M, Wine E, Weiner D, Levine A. A Novel UC Exclusion Diet and Antibiotics for Treatment of Mild to Moderate Pediatric Ulcerative Colitis: A Prospective Open-Label Pilot Study. Nutrients. 2021 Oct 23;13(11):3736. doi: 10.3390/nu13113736.