Determination of the Optimal Treatment Target in Ulcerative Colitis

Disease activity and response to therapy in ulcerative colitis (UC) can be assessed by a range of endpoints including symptoms, endoscopic mucosal activity, histological disease activity, and biomarkers. This study aims to determine the optimal treatment target, which is a research priority for the management of UC both to inform clinical practice and to help inform regulatory endpoints and targets for drug development.

Participants with active UC will be randomized in a 5:4:1 (initially 2:3:5) ratio to 1 of 3 groups, each with a different treatment target. Treatment targets will be defined as:

* Group 1: corticosteroid-free symptomatic remission
* Group 2: corticosteroid-free endoscopic + symptomatic remission
* Group 3: corticosteroid-free histological + endoscopic + symptomatic remission

An interim analysis was performed to assess the proportion of subjects that reached their assigned treatment target after 50 subjects in each group had reached the first 32-week assessment. The interim analysis and projections made based on target achievement rates for all subjects included in the interim analysis resulted in a recommendation to adjust the randomization ratio from 2:3:5 to 5:4:1 for Groups 1, 2 and 3 respectively as of May 5th, 2023. This change was necessary in order to complete the study with approximately 100 subjects achieving treatment target within each group.


Eligibility Criteria:
Inclusion Criteria:

1. Age ≥ 18 years.
2. Diagnosis of UC confirmed by clinical, endoscopic, and histological evidence prior to screening as per standard criteria.
3. Moderately to severely active UC with a Mayo rectal bleeding subscore ≥ 1 and a MES ≥ 2, with minimum disease extent of 15 cm and objective evidence of inflammation that can be visualized using central endoscopic imaging system.
4. Ability of participant to participate fully in all aspects of this clinical trial.
5. Written informed consent must be obtained and documented.
6. Agree not to participate in an investigational trial for the duration of the trial (observation or other noninterventional trials may be permitted at the discretion of the investigator).
7. Negative standard of care tuberculosis (TB) test and hepatitis B and C test prior to randomization unless negative results available from within 12 months prior.
8. A male participant who is nonsterilized\* and sexually active with a female partner of childbearing potential\* agrees to use adequate contraception\* from signing of informed consent throughout the duration of the study and for 18 weeks after last dose.
9. A female participant of childbearing potential\* who is sexually active with a nonsterilized\* male partner agrees to use routinely adequate contraception\* from signing of informed consent throughout the duration of the study and for 18 weeks after last dose.
10. Up to date with colorectal carcinoma surveillance according to local standards and guidelines. If a subject is not up to date at screening, a standard of care surveillance assessment may be performed during the screening period.
11. Participants who are not responding to their existing treatment for UC (Netherlands-specific criterion).

Exclusion Criteria:

1. Participants who have historically failed (i.e., had an inadequate response with, lost response to, or were intolerant to) 2 or more compounds or classes of advanced therapeutic options (biologics or small molecules; e.g., anti-TNFs, ustekinumab, or tofacitinib) for the treatment of their UC.
2. Current or previous treatment with vedolizumab, etrolizumab, or natalizumab.
3. Topical therapy (corticosteroid or 5-aminosalicylate \[5-ASA\]) use within 2 weeks prior to screening endoscopy.
4. Change to oral corticosteroid dosing within 2 weeks prior to randomization or a corticosteroid dose of \> 30 mg of prednisone or equivalent at randomization.
5. Known diagnosis of CD, indeterminate colitis, ischemic colitis, radiation colitis, diverticular disease associated with colitis, or microscopic colitis.
6. Short gut syndrome.
7. Positive stool culture for or active Clostridioides difficile infection (as demonstrated by positive toxin and/or antigen).
8. Known hepatitis B or C infection. If a negative test result is available in the 12 months prior to randomization, retesting is not required.
9. Known active or latent TB; if a negative test result is available in the 12 months prior to randomization, confirmatory testing (per standard of care) is not required before randomization.
10. Received any investigational drug within 30 days prior to randomization/target assignment.
11. Serious underlying disease other than UC that in the opinion of the investigator may interfere with the participant's ability to participate fully in the study or would compromise participant safety (such as history of malignancies, major neurological disorders, or any unstable or uncontrolled medical disorder).
12. History of alcohol or drug abuse that in the opinion of the investigator may interfere with the participant's ability to comply with the study procedures.
13. The participant has active cerebral/meningeal disease, signs, symptoms, or any history of progressive multifocal leukoencephalopathy (PML) prior to randomization.
14. Hypersensitivity to any excipient of vedolizumab.
15. Active severe infection such as sepsis, cytomegalovirus, listeriosis, or opportunistic infection.
16. History of HIV or positive test at screening (Italy-specific criterion).
17. Any other contraindication(s)to vedolizumab (Italy-specific criterion).
18. If female, the participant is pregnant or lactating or intending to become pregnant before, during, or within 18 weeks after the last dose; or intending to donate ova during such time period.
19. If male, the participant intends to donate sperm during the course of this study or for 18 weeks after the last dose.
20. Vaccination with a live or live-attenuated vaccine within 4 weeks prior to randomization, or planned vaccination during conduct of the study, except vaccination for coronavirus disease of 2019 (COVID-19).