Randomised, placebo-controlled Phase II proof of concept study of efficacy and safety of a novel rifamycin SV in situ gelling rectal solution administered by enema to patients with mild to moderate left-sided ulcerative colitis

Prior treatment

• Prior and concomitant gastrointestinal diseases: a. severe left-sided ulcerative colitis or ulcerative proctitis defined as presenting with a modified Mayo score >7 at baseline; b. ulcerative proctitis with inflammation involving less than 8 cm from the anal canal; c. extensive ulcerative colitis (defined by Montreal classification system of ulcerative colitis) extending beyond the splenic flexure (partial or total involvement of either the caecum or the transverse colon or the ascending colon), as assessed through screening endoscopic examination (Mayo endoscopic score >1 in any of these segments) or available endoscopic documentation not older than 12 months; d. acute severe or fulminant colitis, as defined by Truelove & Witts ; e. Crohn’s disease; f. active peptic ulcer disease; g. infectious colitis; h. positive for Clostridium difficile as detected by stool test; i. current or recurrent disease that could affect the colon or the action, absorption or disposition of the study medication including diverticulitis, collagenous colitis, recurrent pancreatic or known gallbladder disease (except for asymptomatic gallstones or chronic, non-inflammatory gallbladder disease under the Investigator’s judgment), toxic megacolon, fistula (except for non-inflammatory bowel disease fistulas), perforation or abscess or any other significant condition which the Investigator considers may affect the safety of the patient or the outcome of the study; j. clinically significant caecal patch, i.e., indicative of Crohn’s disease or extensive ulcerative colitis or which the Investigator considers may affect the safety of the patient or the outcome of the study; k. colonic dysplasia or polypoid lesions; l. participants with a recently diagnosed (within the previous 6 months) coeliac disease who are not following a strict gluten-free diet and continue to experience coeliac disease-related gastrointestinal symptoms. Participants with prior diagnosis who are on a strict gluten-free diet and have no on-going symptoms may be included.
• Prior surgeries or medical procedures: cytapheresis therapy < 4 weeks prior to screening; previous colonic surgery (excluding appendectomy)
• Prior and concomitant treatments: a. injectable systemic steroids within 2 weeks prior to screening; b. rectal steroids within 2 weeks prior to baseline; c. oral systemic steroids unless on a stable dose for at least 2 weeks before screening and allowing to be tapered during the screening period; d. enteric or colonic oral steroids (e.g., budesonide 9 mg extended-release tablets) can be stopped before screening without tapering; e. mesalamine (also known as 5-ASA or mesalazine) or sulfasalazine therapy unless on a stable dose for at least 2 weeks before screening; f. rectal treatments other than those with steroids within 2 weeks before screening; g. immunosuppressant or immunomodulator agents (for instance, azathioprine, 6-mercaptopurine, cyclosporine, tofacitinib, filgotinib, ozanimod, etc.), within 6 weeks prior to baseline excluding systemic immunosuppressant or immunomodulator therapies used for indications other than ulcerative colitis, provided that: • they have no established therapeutic effect on ulcerative colitis • they are taken at a stable dose for at least 12 weeks before screening; h. monoclonal antibodies (for instance, infliximab, adalimumab, vedolizumab, etc.) within 4 weeks prior to baseline or any intake in the screening period; i. ustekinumab within 16 weeks prior to baseline; j. antibiotics within 14 days before screening; k. repeatedly used non-steroidal anti-inflammatory drugs (e.g. aspirin or ibuprofen) other than mesalamine or sulfasalazine within 7 days prior to baseline. Prophylactic use of a stable dose of aspirin up to 100 mg/day for cardiac disease is permitted.

Lab values

• Prior and concomitant diseases other than gastroenteric: a. bleeding disorders; b. history of chronic liver disease (e.g. liver cirrhosis) with platelets under 50,000 and international normalised ratio >1.5; c. current or relevant previous history of serious, severe or unstable (acute or progressive) physical or psychiatric illness; d. any medical disorder that may require treatment or make the patient unlikely to fully complete the study or any condition that presents undue risk from the study medication or procedures; e. clinically significant metabolic /electrolyte imbalance; f. malignancy in the last 5 years prior to screening; g. active cytomegalovirus infection, i.e., with positive or negative IgG and positive IgM, that is symptomatic or clinically significant

• Main selection criteria: Adult subjects, 18 years or older, with a diagnosis of mildly to moderately active left-sided ulcerative colitis or ulcerative proctitis will be enrolled in the study. Disease extent will be defined according to the Montreal classification of ulcerative colitis, as follows: 1. Ulcerative proctitis: involvement limited to the rectum (that is, proximal extent of inflammation is distal to the rectosigmoid junction), with at least 8 cm of inflammation extent from the anal canal. 2.Left-sided ulcerative colitis (distal ulcerative colitis): involvement limited to a proportion of the colorectum distal to the splenic flexure. The final classification of a participant’s underlying disease as ulcerative proctitis or left-sided colitis will be made by the central endoscopist based on his assessment of the video of the endoscopy performed at Visit 2.
• Informed consent: signed written informed consent before inclusion in the study
• Sex and age: men/women, ≥18 years old inclusive
• Ulcerative colitis: a ≥1 month old diagnosis of mildly to moderately active left-sided ulcerative colitis or ulcerative proctitis with at least 8 cm of inflammation extent from the anal canal (defined by Montreal classification system of ulcerative colitis) even in cases involving only one of the distal regions, i.e. rectum, sigmoid or descending colon, confirmed by endoscopy and histology as follows: a. modified Mayo score ≥4 and ≤7; b. modified Mayo endoscopic subscore ≥2; c. Geboes histology score ≥2 in at least one segment of the left colon segments (descending colon, sigmoid colon or rectum)
• Contraception (women only): women of childbearing potential must use at least one of the following highly effective methods of contraception. a. Hormonal combined oral, intravaginal, or transdermal, contraceptives for at least 2 months before the screening visit b. Progestogen-only hormonal oral, implantable, or injectable contraceptives for at least 2 months before the screening visit c. A non-hormonal intrauterine device or an intrauterine hormone-releasing system for at least 2 months before the screening visit d. Bilateral tubal occlusion e. A sterile sexual partner f. True abstinence, i.e., refraining from heterosexual intercourse when this is in line with the preferred and usual lifestyle of the subject. Women of non-childbearing potential or in post-menopausal status must have been in that status for at least one year. For all women of childbearing potential, serum pregnancy test result must be negative at screening
• Full comprehension: ability to comprehend the full nature and purpose of the study, including possible risks and side effects; ability to co-operate with the investigator and to comply with the requirements of the study
• Compliance with baseline diary entry: a minimum of 3 consecutive days of completed diary entries or 4 non-consecutive days within a 7-day period are necessary (not including the day of bowel preparation day and day of endoscopy)