A Study of Vedolizumab in Children and Teenagers With Moderate to Severe Ulcerative Colitis (UC)

A Randomized, Double-Blind, Phase 3 Study to Evaluate the Efficacy and Safety of Vedolizumab Intravenous as Maintenance Therapy in Pediatric Subjects With Moderately to Severely Active Ulcerative Colitis Who Achieved Clinical Response Following Open-Label Vedolizumab Intravenous Therapy

Vedolizumab is a medicine that helps to reduce inflammation and pain in the digestive system. In this study, children and teenagers with moderate to severe ulcerative colitis will be treated with vedolizumab.

The main aim of the study is to check if participants achieve remission after treatment with vedolizumab. Remission means symptoms improve or disappear and an endoscopy shows no or limited signs of disease.

The study is also evaluating side effects of vedolizumab in the children and teenager with moderately to severely active ulcerative colitis.

Participants will receive 3 infusions of vedolizumab over 6 weeks. Then, those who have a clinical response will receive 1 of 3 doses of vedolizumab once every 8 weeks. They will receive the same dose every time.

The drug being tested in this study is called vedolizumab. Vedolizumab is being tested to treat pediatric participants who have moderately to severely active UC. Participants to be enrolled must have failed response to, lost response to, or been intolerant to at least 1 of the current standard of care (SOC) induction and maintenance therapies for UC including immunomodulators (eg, azathioprine [AZA], 6-mercaptopurine [6-MP], methotrexate [MTX]), and tumor necrosis factor-alpha (TNF-α) antagonists (eg, infliximab, adalimumab).

The study will enroll approximately 120 patients.

During the Induction Period participants will receive 3 doses of vedolizumab IV infusion at Day 1, Week 2, and Week 6 based on their weight at Baseline:

• Participants ≥30 kg, Vedolizumab 300 mg
• Participants >15 to <30 kg, Vedolizumab 200 mg
• Participants 10 to 15 kg, Vedolizumab 150 mg

At Week 14, participants who achieve clinical response will be randomly assigned (by chance, like flipping a coin) in a 1:1 ratio to one of the 2 double-blind dose groups (high dose and low dose), stratified by previous exposure/failure to TNF-α antagonists therapy or naive to TNF-α antagonists therapy, and weight. Participants will receive vedolizumab IV infusions every 8 weeks (Q8W) up to Week 46 during the Maintenance Period as follows:

• Participants ≥30 kg, Vedolizumab 300 mg (High dose) or 150 mg (Low dose)
• Participants >15 to <30 kg, Vedolizumab 200 mg (High dose) or 100 mg (Low dose)
• Participants 10 to 15 kg, Vedolizumab 150 mg (High dose) or 100 mg (Low dose)

The dose will remain blinded to the participant and study doctor and staff during the study (unless there is an urgent medical need). All participants will be administered vedolizumab via IV infusion. In participants who demonstrate lack of maintenance of clinical response during the Maintenance Period the dose will be escalated in a blinded fashion based on the weight at the time of the worsening of disease. In addition one-time rescue therapy with corticosteroids is allowed during Maintenance period.

This multi-center trial will be conducted worldwide. After the Week 54 visit, participants who are younger than 18 years may be eligible to continue receiving vedolizumab in extension study MLN0002-3029 (NCT05442567). Participants who do not maintain corticosteroid-free clinical response at Week 54 or who discontinue study drug at any time during the induction or maintenance periods of this study will undergo an end of study (EOS) or early termination (ET) visit, as well as a safety visit 18 weeks after the last dose of vedolizumab, in addition these participants would enter study MLN0002-3029 for an observational long-term follow-up (LTFU) period of 2 years after the last dose of study drug in the current study. During the LTFU period, data will be collected either by clinic visit OR, if site attendance is not feasible, by phone call every 6 months.

Inclusion Criteria:

1. Has moderately to severely active UC, unresponsive or intolerant to their current standard of care (SOC).
2. Weighs ≥10 kg at the time of screening and enrollment into the study.
3. Participants with UC diagnosed at least 1 month before screening. Participants with moderately to severely active UC based on a modified Mayo score of 5 to 9 (sum of Mayo endoscopic subscore, stool frequency subscore, and rectal bleeding subscore) with a Mayo endoscopic subscore of ≥2 (with the presence of mucosal friability excluding an endoscopic subscore of 1 and mandating a score of at least 2) at screening endoscopy.
4. Has failed, lost response to, or been intolerant to treatment with at least 1 of the following agents: corticosteroids (eg, azathioprine [AZA], 6-mercaptopurine [6-MP], methotrexate [MTX]), immunomodulators, and/or tumor necrosis factor alpha (TNF-α) antagonist therapy (eg, infliximab, adalimumab). This includes participants who are dependent on corticosteroids to control symptoms and who are experiencing worsening of disease in the moderate-to-severe range when attempting to wean off corticosteroids.
5. Has evidence of UC extending proximal to the rectum (i.e., not limited to proctitis), at a minimum.
6. Has extensive colitis or pancolitis of >8 years' duration or left-sided colitis of >12 years' duration must have documented evidence of a negative surveillance colonoscopy within 12 months before screening.
7. Participants with vaccinations that are up-to-date based on the countrywide, accepted schedule of childhood vaccines.

Exclusion Criteria:

1. Has previous exposure to approved or investigational anti-integrins including, but not limited to natalizumab, efalizumab, etrolizumab, or Abrilumab (AMG 181), or mucosal addressin cell adhesion molecule-1 (MAdCAM-1) antagonists or rituximab.

2. Has received an investigational biologic within 60 days or 5 half-lives before screening (whichever is longer); or an approved biologic or biosimilar agent within 2 weeks before the first dose of study drug or at any time during the screening period.

3. Has active cerebral/meningeal disease, signs/symptoms or history of progressive multifocal leukoencephalopathy (PML) or any other major neurological disorders including stroke, multiple sclerosis, brain tumor or neurodegenerative disease.

4. Has had clinically significant infection (eg, pneumonia, pyelonephritis, coronavirus disease 2019 [COVID-19]) within 30 days prior to first dose of study drug.

5. Has received any live vaccinations within 30 days prior to first dose of study drug.

6. Participants who currently require surgical intervention or are anticipated to require surgical intervention for UC during this study.

7. Has had subtotal or total colectomy or have a jejunostomy, ileostomy, colostomy, ileo-anal pouch, or known fixed stenosis of the intestine.

8. Participants with a current diagnosis of indeterminate colitis.

9. Participants with clinical features suggesting monogenic very early onset inflammatory bowel disease.

10. Participant with active or latent tuberculosis (TB), as evidenced by a diagnostic TB test performed within 30 days of screening or during the screening period that is positive, defined as:

    • Positive QuantiFERON test or 2 successive indeterminate QuantiFERON tests, OR
    • A TB skin test reaction ≥5 mm. NOTE: If participants have received Bacillus Calmette-Guérin vaccine then a QuantiFERON TB Gold test should be performed instead of the TB skin test.

11. Participants with evidence of positive hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb). Hepatitis B virus (HBV) immune participants (ie, hepatitis B surface antigen [HBsAg]-negative and hepatitis B antibody-positive) may, however, be included. Note: If a participant tests negative for HBsAg, but positive for HBcAb, the participant would be considered eligible if the absence of HBV DNA is confirmed by HBV DNA polymerase chain reaction reflex testing performed in the central laboratory.

    Participants with chronic hepatitis C virus (HCV) (ie, positive HCV antibody [HCVAb] and HCV RNA). Note: Subjects who are HCVAb-positive without evidence of HCV RNA may be considered eligible (spontaneous viral clearance or previously treated and cured [defined as no evidence of HCV RNA at least 12 weeks before baseline]).

12. The participant has evidence of dysplasia or history of malignancy other than a successfully treated nonmetastatic cutaneous squamous cell or basal cell carcinoma or localized carcinoma in situ of the cervix.

13. Has positive stool studies for ova and/or parasites or stool culture at screening visit.

14. Has positive Clostridioides difficile (C difficile) stool test at screening visit.

Other inclusion/exclusion criteria may apply.