Determination of the Optimal Treatment Target in Ulcerative Colitis

Alimentiv Inc.672 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

SINGLE

Enrollment

672

Conditions

Colitis, Ulcerative

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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).

Outcomes

Primary Outcomes

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.

Time frame: From date of treatment target achievement until date of first UC-related complication until end of study (Week 96), whichever came first

Secondary Outcomes

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.

Time frame: 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 2 and 3.

Time frame: 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 subgroups

Time to UC-related complication compared between subgroups on and off corticosteroids at the time of achieving other relevant components of the treatment target.

Time frame: 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.

Time frame: up to 96 weeks

Fecal Calprotectin Levels

Change in fecal calprotectin levels from baseline to Weeks 8, 16, 32, 48, and 96.

Time frame: 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.

Time frame: Baseline, weeks 8, 16, 32, 48, 64, 80, and 96

Difference in time to UC-related complication (as in the primary outcome and secondary outcomes 2 and 3)

Time to UC-related complication (as in the primary outcome and secondary outcomes 2 and 3) in the subgroup of subjects who exclusively reach their assigned target and not a higher target by Week 48.

Time frame: Up to week 96

Evaluate the time to each type of UC-related complication

Evaluate, across the 3 target achievement groups, the time to each type of UC-related complication that comprises the primary endpoint.

Time frame: Up to week 96

Assess the effect of treatment(s) on UC-related complications

Assess the effect of treatment(s) on UC-related complications that is mediated through treatment targets.

Time frame: Up to week 96

Evaluate change in the UC-100 score from baseline to Weeks 16, 32, 48, and 96

To evaluate change in the UC-100 score from baseline to Weeks 16, 32, 48, and 96 (both in the full and the achieved-target populations). The UC-100 is a composite disease activity index consisting of clinical, endoscopic, and histological findings.The total UC-100 score ranges from 1 to 100, with higher scores representing more severe disease activity.

Time frame: Up to week 96

Evaluate changes in the health-related quality of life (HRQoL) using the Inflammatory Bowel Disease Questionnaire (IBDQ)

To evaluate changes in the health-related quality of life (HRQoL) using the Inflammatory Bowel Disease Questionnaire (IBDQ) from baseline to all follow-up visits.The Inflammatory Bowel Disease Questionnaire (IBDQ) includes 32 questions on 4 domains of health-related quality of life (HRQoL); the total score ranges from 32 and 224, with a higher score signifying a better outcome.

Time frame: Up to week 96

Evaluate changes in the Work Productivity and Activity Impairment-UC (WPAI-UC) questionnaire

To evaluate changes in the Work Productivity and Activity Impairment-UC (WPAI-UC) questionnaire from baseline to all follow-up visits.The WPAI-UC (Work Productivity and Activity Impairment Questionnaire) consists of 6 questions that will grade the productivity while the participant is working on a scale from 0 to 10; a higher score signifies a higher impact on work productivity.

Time frame: Up to week 96

Evaluate the change in Mayo Clinic Score (MCS; and subcomponents including the MES)

To evaluate the change in Mayo Clinic Score (MCS; and subcomponents including the MES) from baseline to Week 16,32,48 and 96/end of study (EOS). The Mayo Clinic Score for Ulcerative Colitis is a score that ranges from 0 to 12 with higher scores indicating worse severity. The score has four items (Stool Frequency, Rectal Bleeding, Mucosal appearance at endoscopy, Physician rating of disease activity) each rated from 0 to 3, where 3 means highest severity.

Time frame: Up to week 96

Describe the change in Geboes scores from baseline to baseline to Week 16, 32, 48 and 96/end of study (EOS)

To describe the change in Geboes scores from baseline to baseline to Week 16, 32, 48 and 96/end of study (EOS). Geboes score is the most commonly used histological score in ulcerative colitis \[UC\] and is divided in 6 grades: architectural changes \[grade 0\], chronic inflammatory infiltrate \[grade 1\], lamina propria neutrophils and eosinophils \[grade 2\], neutrophils in epithelium \[grade 3\], crypt destruction \[grade 4\] and erosions or ulcerations \[grade 5\].

Time frame: Up to week 96

Describe the change in RHI scores from baseline to all baseline to Week 16, 32, 48 and 96/end of study (EOS)

To describe the change in RHI scores from baseline to all baseline to Week 16, 32, 48 and 96/end of study (EOS). The Robarts Histopathology Index (RHI) is a validated instrument that measures histological disease activity in ulcerative colitis. The RHI assesses four characteristics of mucosal activity, inflammatory infiltrate, lamina propria neutrophils, neutrophils in epithelium, and erosion or ulceration, all of which are rated on a scale of 0 to 3, with higher scores representing more severe disease activity.

Time frame: Up to week 96

Describe the change in Nancy Histological Index scores from baseline to baseline to Week 16, 32, 48 and 96/end of study (EOS)

To describe the change in Nancy Histological Index scores from baseline to baseline to Week 16, 32, 48 and 96/end of study (EOS). The Nancy Histological Index is made up of 3 items: acute inflammatory cell infiltrates, chronic inflammatory cell infiltrates, and the presence of ulceration. Histological disease activity is graded on a 5-point scale; from grade 0 (no histologically significant disease) to grade 4 (severely active disease), with this grade being determined by the scoring algorithm.

Time frame: Up to week 96

Evaluate the numbers of AEs and SAEs among the 3 randomized groups

To evaluate the numbers of AEs and SAEs among the 3 randomized groups.

Time frame: Up to week 96

Validate the Symptoms and Impacts Questionnaire for UC (SIQ-UC) tool in English-fluent subjects

To validate the Symptoms and Impacts Questionnaire for Ulcerative Colitis (SIQ-UC) tool in English-fluent subjects. SIQ-UC consists of a symptom domain, which includes Gastrointestinal, pain and discomfort, nutrition-related, and fatigue-related symptoms; and an impact domain, which includes concepts related to daily activities, nutrition, emotional well-being, and productivity.

Time frame: Up to week 96

Determination of the Optimal Treatment Target in Ulcerative Colitis

Overview

Conditions

Interventions

Eligibility

Locations (58)

Outcomes

Primary Outcomes

Secondary Outcomes