Determination of the Optimal Treatment Target in Ulcerative Colitis

Study Overview
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Brief Summary
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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 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

Official Title
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VERDICT: In actiVE Ulcerative Colitis, a RanDomIzed Controlled Trial for Determination of the Optimal Treatment Target

Conditions
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Colitis, Ulcerative

Intervention / Treatment
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* Biological: Treatment Algorithm A
* Biological: Treatment Algorithm B
* Biological: Treatment Algorithm C


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of UC confirmed by clinical, endoscopic, and histological evidence prior to screening as per standard criteria Moderately to severely active UC with a Mayo rectal bleeding subscore ≥ 1 and a Mayo endoscopic subscore (MES) ≥ 2, with minimum disease extent of 15 cm and objective evidence of inflammation that can be visualized using central endoscopic imaging system Ability of subject to participate fully in all aspects of this clinical trial Written informed consent must be obtained and documented Agree not to participate in an investigational trial for the duration of the trial (observation trials without investigational product may be permitted at the discretion of the investigator) Willing to perform a standard of care tuberculosis (TB) test and hepatitis B and C test prior to starting any biologic drug during the study, unless negative results available from within 12 months prior A male subject 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 A female subject 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 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. Subjects who are not responding to their existing treatment for UC (Netherlands-specific criterion). Exclusion Criteria: Subjects 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 Current or previous treatment with vedolizumab, ertrolizumab, or natalizumab Topical therapy (corticosteroid or 5-aminosalicylate [5-ASA]) use within 2 weeks prior to screening endoscopy Change to oral corticosteroid dosing within 2 weeks prior to screening Known diagnosis of CD, indeterminate colitis, ischemic colitis, radiation colitis, diverticular disease associated with colitis, or microscopic colitis Short gut syndrome Positive stool culture for or active Clostridioides difficile infection (as demonstrated by positive toxin and/or antigen) Known hepatitis B or C infection. If a negative test result is available in the 12 months prior to randomization, retesting is not required Known active or latent TB. If a negative test results is available in the 12 months prior to randomization, confirmatory testing is not required Received any investigational drug within 30 days prior to randomization/target assignment Serious underlying disease other than UC that in the opinion of the investigator may interfere with the subject's ability to participate fully in the study or would compromise subject safety (such as history of malignancies, major neurological disorders, or any unstable or uncontrolled medical disorder) History of alcohol or drug abuse that in the opinion of the investigator may interfere with the subject's ability to comply with the study procedures The subject has active cerebral/meningeal disease, signs, symptoms, or any history of progressive multifocal leukoencephalopathy (PML) prior to randomization Hypersensitivity to any excipient of vedolizumab . Active severe infection such as sepsis, cytomegalovirus, listeriosis, or opportunistic infection. History of HIV or positive test at screening (Italy-specific criterion). Any other contraindication(s)to vedolizumab (Italy-specific criterion). If female, the subject 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. If male, the subject intends to donate sperm during the course of this study or for 18 weeks after the last dose. 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).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: In this study, participants with active UC will be randomized in a 2:3:5 ratio to 1 of 3 treatment target groups. Participants will be assigned a treatment algorithm based on their existing UC treatment at time of entry. Treatment algorithms may include the use of vedolizumab. A key premise is that vedolizumab has a favorable safety profile and can be used to treat subjects who are in symptomatic remission but who have not attained endoscopic or histopathologic remission. Participants will be assessed to determine it remission target is achieved at weeks 16, 32 and 48. If the participant has achieved their treatment target, they will continue that line of therapy. If the participant has not achieved their treatment target, treatment and/or dose escalation will be administered according to the algorithm.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Symptomatic remission<br>Treatment target defined as achievement of corticosteroid-free symptomatic remission. | Biological: Treatment Algorithm A<br>* Participants who are treatment-naïve at randomization will follow treatment algorithm A. Participants, upon entry into the study, will require standard first-line therapy. Either oral 5-ASA and/or immunosuppressive (with optional oral corticosteroid in combination) will be initiated. Participants will be assessed to determine it remission target is achieved at weeks 16, 32 and 48. If the participant has achieved their treatment target, they will continue that line of therapy. If the participant has not achieved their treatment target, treatment and/or dose escalation will be administered according to the algorithm.<br>* Other names: vedolizumab;Biological: Treatment Algorithm B<br>* Participants who are taking non-biologic UC therapies at randomization will follow treatment algorithm B. Participants will change to intravenous vedolizumab therapy. Participants will be assessed to determine it remission target is achieved at weeks 16, 32 and 48. If the participant has achieved their treatment target, they will continue that line of therapy. If the participant has not achieved their treatment target, treatment and/or dose escalation will be administered according to the algorithm.<br>* Other names: vedolizumab;Biological: Treatment Algorithm C<br>* Participants who are taking anti-TNF, tofacitinib or ustekinumab therapy at randomization will follow treatment algorithm C. Participants will change to intravenous vedolizumab therapy. Participants will be assessed to determine it remission target is achieved at weeks 16, 32 and 48. If the participant has achieved their treatment target, they will continue that line of therapy. If the participant has not achieved their treatment target, treatment and/or dose escalation will be administered according to the algorithm.<br>* Other names: vedolizumab;|
| Other: Symptomatic and endoscopic remission<br>Treatment target defined as achievement of corticosteroid-free symptomatic remission plus endoscopic remission. | Biological: Treatment Algorithm A<br>* Participants who are treatment-naïve at randomization will follow treatment algorithm A. Participants, upon entry into the study, will require standard first-line therapy. Either oral 5-ASA and/or immunosuppressive (with optional oral corticosteroid in combination) will be initiated. Participants will be assessed to determine it remission target is achieved at weeks 16, 32 and 48. If the participant has achieved their treatment target, they will continue that line of therapy. If the participant has not achieved their treatment target, treatment and/or dose escalation will be administered according to the algorithm.<br>* Other names: vedolizumab;Biological: Treatment Algorithm B<br>* Participants who are taking non-biologic UC therapies at randomization will follow treatment algorithm B. Participants will change to intravenous vedolizumab therapy. Participants will be assessed to determine it remission target is achieved at weeks 16, 32 and 48. If the participant has achieved their treatment target, they will continue that line of therapy. If the participant has not achieved their treatment target, treatment and/or dose escalation will be administered according to the algorithm.<br>* Other names: vedolizumab;Biological: Treatment Algorithm C<br>* Participants who are taking anti-TNF, tofacitinib or ustekinumab therapy at randomization will follow treatment algorithm C. Participants will change to intravenous vedolizumab therapy. Participants will be assessed to determine it remission target is achieved at weeks 16, 32 and 48. If the participant has achieved their treatment target, they will continue that line of therapy. If the participant has not achieved their treatment target, treatment and/or dose escalation will be administered according to the algorithm.<br>* Other names: vedolizumab;|
| Other: Symptomatic, endoscopic and histological remission<br>Treatment target defined as achievement of corticosteroid-free symptomatic remission plus endoscopic remission plus histological remission. | Biological: Treatment Algorithm A<br>* Participants who are treatment-naïve at randomization will follow treatment algorithm A. Participants, upon entry into the study, will require standard first-line therapy. Either oral 5-ASA and/or immunosuppressive (with optional oral corticosteroid in combination) will be initiated. Participants will be assessed to determine it remission target is achieved at weeks 16, 32 and 48. If the participant has achieved their treatment target, they will continue that line of therapy. If the participant has not achieved their treatment target, treatment and/or dose escalation will be administered according to the algorithm.<br>* Other names: vedolizumab;Biological: Treatment Algorithm B<br>* Participants who are taking non-biologic UC therapies at randomization will follow treatment algorithm B. Participants will change to intravenous vedolizumab therapy. Participants will be assessed to determine it remission target is achieved at weeks 16, 32 and 48. If the participant has achieved their treatment target, they will continue that line of therapy. If the participant has not achieved their treatment target, treatment and/or dose escalation will be administered according to the algorithm.<br>* Other names: vedolizumab;Biological: Treatment Algorithm C<br>* Participants who are taking anti-TNF, tofacitinib or ustekinumab therapy at randomization will follow treatment algorithm C. Participants will change to intravenous vedolizumab therapy. Participants will be assessed to determine it remission target is achieved at weeks 16, 32 and 48. If the participant has achieved their treatment target, they will continue that line of therapy. If the participant has not achieved their treatment target, treatment and/or dose escalation will be administered according to the algorithm.<br>* Other names: vedolizumab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in Time to UC-related Complication Between Treatment Target Groups 1 and 3 | Time to UC-related complication starting when a participant reaches their assigned treatment target, compared between treatment target groups 1 and 3. | From date of treatment target achievement until date of first UC-related complication until end of study (Week 96), whichever came first | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in Time to UC-related Complication Compared Between Treatment Target Groups 1 and 2. | Time to UC-related complication starting when a participant reaches their assigned treatment target, compared between treatment target groups 1 and 2. | From date of treatment target achievement until date of first UC-related complication until end of study (Week 96), whichever came first | 
| Difference in Time to UC-related Complication Compared Between Treatment Target Groups 2 and 3. | Time to UC-related complication starting when a participant reaches their assigned treatment target, compared between treatment target groups 1 and 2. | From date of treatment target achievement until date of first UC-related complication until end of study (Week 96), whichever came first | 
| Difference in Time to UC-related Complication Compared Between Treatment Target Groups (fast responder sub-group) | Time to UC-related complication (as in the primary outcome and secondary outcomes 3 and 4) in the subgroup of subjects who exclusively reach their assigned target and not a higher target by Week 48. | From date of treatment target achievement until date of first UC-related complication until end of study (Week 96), whichever came first | 
| Difference in Time to Achieve Treatment Target | Time taken to achieve the respective targets among the randomized groups. Time will be censored for subjects who do not achieve their assigned target by Week 48. | up to 96 weeks | 
| Fecal Calprotectin Levels | Change in fecal calprotectin levels from baseline to Weeks 8, 16, 32, 48, and 96. | Baseline, weeks 8, 16, 32, 48, and 96. | 
| C-Reactive Protein Concentration | Change in C-Reactive Protein concentration from baseline to Weeks 8, 16, 32, 48, 64, 80, and 96 | Baseline, weeks 8, 16, 32, 48, 64, 80, and 96 |