Clinical trial NCT04779307: A Study of Vedolizumab in Children and Teenagers with Moderate to Severe Ulcerative Colitis (UC)
Official title: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Colitis, Ulcerative
Keywords: Drug Therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2021-03-03
Enrollment: 121
Sex: ALL
Minimum age (years): 2
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Percentage of Participants with Clinical Remission at Week 54 Based on Modified Mayo Score
timeFrame: Week 54
Secondary outcomes:
measure: Percentage of Participants with Clinical Remission at Week 14 Based on Modified Mayo Score
timeFrame: Week 14
measure: Percentage of Participants with Sustained Clinical Remission at Week 14 Based on Modified Mayo Score
timeFrame: Week 14
measure: Percentage of Participants with Sustained Clinical Remission at Week 54 Based on Modified Mayo Score
timeFrame: Week 54
measure: Percentage of Participants with Sustained Endoscopic Remission at Week 14
timeFrame: Week 14
measure: Percentage of Participants with Sustained Endoscopic Remission at Week 54
timeFrame: Week 54
measure: Percentage of Participants with Endoscopic Response at Week 14
timeFrame: Week 14
measure: Percentage of Participants with Endoscopic Response at Week 54
timeFrame: Week 54
measure: Percentage of Participants with Corticosteroid-free Clinical Remission at Week 54
timeFrame: Week 54
measure: Percentage of Participants with Clinical Remission at Week 54 Based on Complete Mayo Score
timeFrame: Week 54
measure: Serum Trough Concentrations of Vedolizumab over Time
timeFrame: Predose and postdose at multiple time points (up to 54 weeks)
measure: Percentage of Participants with Positive Anti-vedolizumab Antibodies (AVA)
timeFrame: Predose (up to 54 weeks)
measure: Percentage of Participants with Positive Neutralizing AVA
timeFrame: Predose (up to 54 weeks)
measure: Percentage of Participants with Sustained Clinical Response at Week 14 Based on Complete Mayo Score
timeFrame: Week 14
measure: Percentage of Participants with Sustained Clinical Response at Week 54 Based on Complete Mayo Score
timeFrame: Week 54
measure: Percentage of Participants with Clinical Response up to Week 54 Based on Partial Mayo Score
timeFrame: Weeks 2, 6, 10, 14, 22, 30, 38, 46, and 54
measure: Percentage of Participants with Clinical Remission up to Week 54 Based on Partial Mayo Score
timeFrame: Weeks 2, 6, 10, 14, 22, 30, 38, 46, and 54
measure: Percentage of Participants with at least One Adverse Event (AE), Serious Adverse Event (SAE), and Adverse Event of Special Interest (AESI)
timeFrame: Up to 158 weeks
measure: Change from Baseline in Weight
timeFrame: Baseline, up to Week 54
measure: Change from Baseline in Linear Growth Z-score
timeFrame: Baseline, up to Week 54
measure: Change in Tanner Stage at Week 54 Compared with Baseline
timeFrame: Week 54
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Phoenix Childrens Hospital -1919 E Thompson Rd
state: Arizona
city: San Diego
country: United States
facility: Rady Childrens Hospital San Diego - PIN
state: California
city: Atlanta
country: United States
facility: Childrens Center For Digestive Healthcare
state: Georgia
city: Park Ridge
country: United States
facility: Advocate Children's Hospital Park Ridge
state: Illinois
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Minneapolis
country: United States
facility: MNGI Digestive Health PA-Plymouth
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic - PIN
state: Minnesota
city: Morristown
country: United States
facility: Goryeb Children's Hospital
state: New Jersey
city: Pittsburgh
country: United States
facility: UPMC Children's Hospital of Pittsburgh-120 Lytton Ave
state: Pennsylvania
city: Houston
country: United States
facility: Texas Childrens Hospital West Campus
state: Texas
city: Roanoke
country: United States
facility: Carilion Children's Tanglewood Center
state: Virginia
city: Westmead
country: Australia
facility: Children's Hospital at Westmead
state: New South Wales
city: South Brisbane
country: Australia
facility: Queensland Childrens Hospital
state: Queensland
city: Clayton
country: Australia
facility: Monash Health, Monash Medical Centre
state: Victoria
city: Parkville
country: Australia
facility: Royal Children's Hospital Melbourne - PIN
state: Victoria
city: Edegem
country: Belgium
facility: UZ Antwerpen
state: Antwerpen
city: Jette
country: Belgium
facility: Universitair Ziekenhuis Brussel - PIN
state: Brussels
city: Leuven
country: Belgium
facility: Universitaire Ziekenhuizen(UZ)Leuven-Campus Gasthuisberg
state: Vlaams Brabant
city: Edmonton
country: Canada
facility: University of Alberta Hospital
state: Alberta
city: Vancouver
country: Canada
facility: British Columbia Children's Hospital
state: British Columbia
city: London
country: Canada
facility: London Health Sciences Centre
state: Ontario
city: Beijing
country: China
facility: Beijing Children's Hospital, Capital Medical University - PIN
state: Beijing
city: Zhengzhou
country: China
facility: Henan Children's Hospital Zhengzhou Children's Hospital
state: Henan
city: Shanghai
country: China
facility: Children's Hospital of Fudan University
state: Shanghai
city: Hangzhou
country: China
facility: The Children's Hospital Zhejiang University School of Medicine
state: Zhejiang
city: Zagreb
country: Croatia
facility: Klinika Za Djecje Bolesti Zagreb
state: Grad Zagreb
city: Athens
country: Greece
facility: Children's Hospital "Agia Sofia"
state: Attiki
city: Chaidari
country: Greece
facility: Attikon University General Hospital
state: Attiki
city: Thessaloniki
country: Greece
facility: Ippokratio General Hospital of Thessaloniki
city: Budapest
country: Hungary
facility: Clinexpert Gyogycentrum
city: Budapest
country: Hungary
facility: Semmelweis Egyetem
city: Miskolc
country: Hungary
facility: Borsod-Abauj-Zemplen Varmegyei Kozponti Korhaz es Egyetemi Oktatokorhaz
city: Jerusalem
country: Israel
facility: Shaare Zedek Medical Center
state: Yerushalayim
city: Jerusalem
country: Israel
facility: Hadassah Medical Center - PPDS
state: Yerushalayim
city: Haifa
country: Israel
facility: Rambam Medical Center - PPDS
city: Haifa
country: Israel
facility: Carmel Medical Center
city: Petah Tikva
country: Israel
facility: Schneider Childrens Medical Center of Israel Petah Tikvah PIN
city: Tel Aviv
country: Israel
facility: Tel Aviv Sourasky Medical Center
city: Napoli
country: Italy
facility: Azienda Ospedaliera Universitaria Federico II
state: Campania
city: Bologna
country: Italy
facility: Azienda USL di Bologna
state: Emilia-Romagna
city: Roma
country: Italy
facility: Azienda Ospedaliera Universitaria Policlinico Umberto I - Universita di Roma La Sapienza
state: Lazio
city: Monza
country: Italy
facility: Fondazione IRCCS San Gerardo dei Tintori - ASST di Monza A. O. San Gerardo
state: Monza e Brianza
city: Firenze
country: Italy
facility: Azienda Ospedaliero Universitaria A Meyer - INCIPIT - PIN
state: Toscana
city: Napoli
country: Italy
facility: AOU dell'Universita degli Studi della Campania Luigi Vanvitelli - Piazza Luigi Miraglia, 2
city: Kurume
country: Japan
facility: Kurume University Hospital
state: Hukuoka
city: Bunkyo-Ku
country: Japan
facility: Juntendo University Hospital
state: Tokyo
city: Setagaya-ku
country: Japan
facility: National Center for Child Health and Development
state: Tokyo
city: Kumamoto
country: Japan
facility: Japanese Red Cross Kumamoto Hospital
city: Saitama
country: Japan
facility: Saitama Children's Medical Center
city: Daegu
country: Korea, Republic of
facility: Kyungpook National University Chilgok Hospital
state: Daegu Gwang'yeogsi
city: Seoul
country: Korea, Republic of
facility: Gachon University Gil Medical Center
state: Incheon Gwang'yeogsi
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
state: Seoul Teugbyeolsi
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
state: Seoul Teugbyeolsi
city: Lodz
country: Poland
facility: SPZOZ Centralny Szpital Kliniczny UM w Lodzi - ul. Pomorska 251
state: Lodzkie
city: Lodz
country: Poland
facility: Instytut Centrum Zdrowia Matki Polki
state: Lodzkie
city: Krakow
country: Poland
facility: Uniwersytecki Szpital Dzieciecy
state: Malopolskie
city: Warszawa
country: Poland
facility: WIP Warsaw IBD Point Profesor Kierkus
state: Mazowieckie
city: Warszawa
country: Poland
facility: Instytut 'Pomnik - Centrum Zdrowia Dziecka'
state: Mazowieckie
city: Rzeszow
country: Poland
facility: Korczowski Bartosz, Gabinet Lekarski
state: Podkarpackie
city: Katowice
country: Poland
facility: Gornoslaskie Centrum Zdrowia Dziecka Im. Sw. Jana Pawla II Spsk Nr 6 Sum W Katowicach
state: Slaskie
city: Szczecin
country: Poland
facility: Twoja Przychodnia SCM
state: Zachodniopomorskie
city: London
country: United Kingdom
facility: The Royal London Hospital
state: London, City of
city: London
country: United Kingdom
facility: Great Ormond Street Hospital
state: London, City of
city: Birmingham
country: United Kingdom
facility: Birmingham Women's and Children's NHS Foundation Trust
state: West Midlands
city: Cardiff
country: United Kingdom
facility: Noahs Ark Childrens Hospital for Wales
Study officials:
References: