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 Crohn's Disease Who Achieved Clinical Response Following Open-Label Vedolizumab Intravenous Therapy
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 发起方
- 入组人数
- 120
- 试验地点
- 191
- 主要终点
- Percentage of Participants With Clinical Remission at Week 54 Based on Pediatric Crohn's Disease Activity Index (PCDAI) Score ≤10
研究概览
简要总结
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 Crohn's disease will be treated with vedolizumab.
The main aim of the study is to check if participants achieve remission after treatment with the vedolizumab. Remission means symptoms improve or disappear and an endoscopy shows no signs of inflammation.
Participants will receive 3 infusions of vedolizumab over 6 weeks. Then, those who have a clinical response will receive either a high dose or low dose of vedolizumab once every 8 weeks. They will receive the same dose every time.
详细描述
The drug being tested in this study is called vedolizumab. Vedolizumab is being tested to treat pediatric participants who have moderately to severely active CD. The drug is tested and approved in adults in approximately 70 countries. 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 CD including exclusive and/or partial enteral nutrition therapy, immunomodulators (e.g., azathioprine [AZA], 6-mercaptopurine [6-MP], methotrexate [MTX]), and tumor necrosis factor-alpha (TNF-α) antagonists.
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 as:
- Participants 10 to 15 kg, Vedolizumab 150 mg
- Participants >15 to <30 kg, Vedolizumab 200 mg
- Participants ≥30 kg, Vedolizumab 300 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 by weight groups. Participants will receive vedolizumab IV infusions every 8 weeks (Q8W) up to Week 46 during the Maintenance Period as follows:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 2 Years 至 17 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Main Inclusion Criteria:
- •The participants has moderately to severely active CD, unresponsive or intolerant to their current standard of care (SOC).
- •The participants weigh ≥10 kg at the time of screening and enrollment into the study.
- •Participants with Crohn's disease (CD) diagnosed at least 1 month before screening. Participants with moderately to severely active CD defined by a Pediatric Crohn's Disease Activity Index (PCDAI) >30 and an simple endoscopic score for Crohn's Disease (SES-CD) >6 (or an SES-CD ≥4 if disease is confined to terminal ileum) at screening endoscopy.
- •Participants who have failed, lost response to, or been intolerant to treatment with at least 1 of the following agents: corticosteroids, immunomodulators (eg, azathioprine (AZA), 6-mercaptopurine (6-MP), methotrexate [MTX]), and/or tumor necrosis factor (TNF)-α antagonist therapy (eg, infliximab, adalimumab). This includes participants who are dependent on corticosteroids or exclusive or partial enteral nutrition to control symptoms and who are experiencing worsening of disease in the moderate-to-severe range when attempting to wean off corticosteroids or discontinue exclusive enteral nutrition.
- •Participants with 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.
- •Participants with vaccinations that are up-to-date based on the countrywide accepted schedule of childhood vaccines.
排除标准
- •Participants who have received either (1) an investigational biologic (other than those listed in Exclusion Criterion #1) within 60 days or 5 half-lives before screening (whichever is longer); or (2) an approved biologic or biosimilar agent within 2 weeks before the first dose of study drug or at any time during the screening period.
- •Participants with 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.
- •The participants had a clinically significant infection (eg, pneumonia, pyelonephritis, coronavirus disease 2019 [COVID-19]) within 30 days prior to first dose of study drug.
- •The participants has received any live vaccinations within 30 days prior to first dose.
- •Participants who currently require surgical intervention or are anticipated to require surgical intervention for CD during this study.
- •Participants who have had subtotal or total colectomy or have a jejunostomy, ileostomy, colostomy, ileo-anal pouch, known fixed stenosis of the intestine, short bowel syndrome, or >3 small intestine resections.
- •Participants with a current diagnosis of indeterminate colitis.
- •Participants with clinical features suggesting monogenic very early-onset inflammatory bowel disease.
- •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.
- •Participants with evidence of positive hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb). Hepatitis B virus (HBV) immune participants(i.e., 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: Participants 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]).
- •The participants has any identified congenital or acquired immunodeficiency (eg, common variable immunodeficiency, human immunodeficiency virus [HIV] infection, organ transplantation).
- •The participant has evidence of dysplasia or history of malignancy other than a successfully treated non-metastatic cutaneous squamous cell or basal cell carcinoma or localized carcinoma in situ of the cervix.
- •Participants with positive stool studies for ova and/or parasites or stool culture at screening visit.
- •Participants with positive Clostridioides difficile (C difficile) stool test at screening visit.
- •Other inclusion/exclusion criteria may apply.
研究组 & 干预措施
Maintenance Period: 10 to 15 kg Vedolizumab 150 mg
Vedolizumab 150 mg, IV infusion, once every 8 weeks (Q8W) from Week 14 up to Week 46 in the Maintenance Period. Participants with Week 14 weight of 10 to 15 kg who achieved clinical response at Week 14 randomized to this high dose arm group will receive vedolizumab 150 mg.
干预措施: Vedolizumab IV (Drug)
Maintenance Period: 10 to 15 kg Vedolizumab 100 mg
Vedolizumab 100 mg, IV infusion, Q8W from Week 14 up to Week 46 in the Maintenance Period. Participants with Week 14 weight of 10 to 15 kg who achieved clinical response at Week 14 randomized to this low dose arm group will receive vedolizumab 100 mg.
干预措施: Vedolizumab IV (Drug)
Maintenance Period: ≥30 kg: Vedolizumab 150 mg
Vedolizumab 150 mg, IV infusion, Q8W from Week 14 up to Week 46 in the Maintenance Period. Participants with Week 14 weight of ≥30 kg who achieved clinical response at Week 14 randomized to this low dose arm group will receive vedolizumab 150 mg.
干预措施: Vedolizumab IV (Drug)
Maintenance Period: ≥30 kg, Vedolizumab 300 mg
Vedolizumab 300 mg, IV infusion, Q8W from Week 14 up to Week 46 in the Maintenance Period. Participants with Week 14 weight of ≥30 kg who achieved clinical response at Week 14 randomized to this high dose arm group will receive vedolizumab 300 mg.
干预措施: Vedolizumab IV (Drug)
Induction Period: >15 to <30 kg, Vedolizumab 200 mg
Vedolizumab 200 mg, IV infusion, at Day 1, Weeks 2 and 6 in Induction Period. Participants with CD having Baseline weight of >15 to <30 kg will be included in this arm group.
干预措施: Vedolizumab IV (Drug)
Induction Period: ≥30 kg, Vedolizumab 300 mg
Vedolizumab 300 mg, IV infusion, at Day 1, Weeks 2 and 6 in Induction Period. Participants with CD having Baseline weight of ≥30 kg will be included in this arm group.
干预措施: Vedolizumab IV (Drug)
Induction Period: 10 to 15 kg, Vedolizumab 150 mg
Vedolizumab 150 mg, intravenous (IV) infusion, at Day 1, Weeks 2 and 6 in Induction Period. Participants with CD having Baseline weight of 10 to 15 kg will be included in this arm group.
干预措施: Vedolizumab IV (Drug)
Maintenance Period: >15 to <30 kg, Vedolizumab 200 mg
Vedolizumab 200 mg, IV infusion, Q8W from Week 14 up to Week 46 in the Maintenance Period. Participants with Week 14 weight of >15 to <30 kg who achieved clinical response at Week 14 randomized to this high dose arm group will receive vedolizumab 200 mg.
干预措施: Vedolizumab IV (Drug)
Maintenance Period: >15 to <30 kg Vedolizumab 100 mg
Vedolizumab 100 mg, IV infusion, Q8W from Week 14 up to Week 46 in the Maintenance Period. Participants with Week 14 weight of >15 to <30 kg who achieved clinical response at Week 14 randomized to this low dose arm group will receive vedolizumab 100 mg.
干预措施: Vedolizumab IV (Drug)
结局指标
主要结局
Percentage of Participants With Clinical Remission at Week 54 Based on Pediatric Crohn's Disease Activity Index (PCDAI) Score ≤10
时间窗: Week 54
Clinical remission is defined by PCDAI score ≤10. The PCDAI was specifically designed for use in children. The PCDAI includes a child-specific item: the height velocity variable as well as three laboratory parameters: hematocrit (HCT) (adjusted for age and sex), erythrocyte sedimentation rate (ESR), and albumin level. The PCDAI score ranges from 0 to 100, with higher scores indicating more active disease. A score of \<10 will be consistent with inactive disease, 11 to 30 will indicate mild disease, and \>30 will indicate moderate to severe disease. A decrease of 12.5 points is taken as evidence of improvement.
Percentage of Participants With Endoscopic Response at Week 54 Based on Simple Endoscopic Score for Crohn's Disease [SES-CD] Score
时间窗: Week 54
Endoscopic response is defined as at least a 50% reduction in SES-CD score from Baseline. The overall SES-CD score ranges from 0 to 56 and is the sum of 4 variables (ie, size of ulcers \[cm\], ulcerated surface, affected surface \[%\], and presence of narrowing) across 5 bowel segments (ie, rectum, descending and sigmoid colon, transverse colon, ascending colon, and ileum). Each variable is coded from 0 to 3 based on severity, where 0 is none or not severe and 3 is the most severe case, with the sum of the scores for each variable ranging from 0 to 15, except for presence of narrowing. Presence of narrowing ranges from 0 to 11 since a severity of 3 represents a narrowing which a colonoscope cannot be passed and, thus, can only be observed once among the bowel segments. The segmental SES-CD score is the sum of the 4 variables for each bowel segment and can range from 0 to 12, where each individual variable score ranges from 0 to 3.
次要结局
- Percentage of Participants with Clinical and Endoscopic Remission at Week 14 Based on Both PCDAI Score and SES-CD Score(Week 14)
- Percentage of Participants with Clinical and Endoscopic Remission at Week 54 Based on Both PCDAI Score and SES-CD Score(Week 54)
- Percentage of Participants with Sustained Clinical and Endoscopic Remission at Week 54(Week 54)
- Percentage of Participants with Corticosteroid-free Remission at Week 54 Based on PCDAI Score(Week 54)
- Percentage of Participants with Sustained Clinical Remission at Week 14 Based on PCDAI Score(Week 14)
- Serum Trough Concentrations of Vedolizumab Over Time(Predose and postdose at multiple time points (up to 54 weeks))
- Percentage of Participants With Positive Neutralizing Antivedolizumab Antibody Titers(Pre-dose (up to 54 weeks))
- Sustained Clinical Response at Week 54 Based on PCDAI Score(Week 54)
- Percentage of Participants with Clinical Remission at Weeks 2, 6, 10, 14, 22, 30, 38, 46, and 54(Weeks 2, 6, 10, 14, 22, 30, 38, 46, and 54)
- Change from Baseline in Weight(Baseline up to Week 54)
- Percentage of Participants with Sustained Endoscopic Remission Based on SES-CD Score(Week 54)
- Percentage of Participants with Sustained Clinical Remission at Week 54 Based on PCDAI Score(Week 54)
- Percentage of Participants With Positive Antivedolizumab Antibodies(Pre-dose (up to 54 weeks))
- Sustained Clinical Response at Week 14 Based on PCDAI Score(Week 14)
- Percentage of Participants with Change in Baseline in Clinical Response at Weeks 2, 6, 10, 14, 22, 30, 38, 46, and 54(Baseline, weeks 2, 6, 10, 14, 22, 30, 38, 46, and 54)
- Percentage of Participants with at Least One Adverse Event (AE), Serious Adverse Event (SAE), and AE of special interest (AESI)(From first dose of study drug before each dose on dosing days through the Week 72)
- Change from Baseline in Tanner Stages at Week 54(Week 54)
- Change from Baseline in Linear Growth Z-score(Baseline up to Week 54)