Clinical trial NCT04779320: A Study of Vedolizumab in Children and Teenagers With Moderate to Severe Crohn's Disease (CD)
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 Crohn's Disease Who Achieved Clinical Response Following Open-Label Vedolizumab Intravenous Therapy
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Crohn's Disease (CD)
Keywords: Drug Therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2021-03-03
Enrollment: 120
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 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.

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 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:

* Participants ≥30 kg, Vedolizumab 300 mg (High dose) or 150 mg (Low dose)
* Participants \>15 to \<30 kg, Vedolizumab 200 mg (High dose) 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 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 to the high dose in their weight group 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, participants may be eligible to continue receiving vedolizumab in extension study MLN0002-3029. Participants who do not maintain corticosteroid-free clinical response at week 54 will undergo an end-of-study (EOS) or ET visit, and a safety visit 18 weeks after the last dose of vedolizumab followed by 2 years of long term follow-up (up to 104 weeks), in addition these participants will then be eligible to enter study MLN0002-3029 for an observational LTFU period of 2 years after the last dose of study drug.

Eligibility criteria: Main Inclusion Criteria:

1. The participants has moderately to severely active CD, unresponsive or intolerant to their current standard of care (SOC).
2. The participants weigh ≥10 kg at the time of screening and enrollment into the study.
3. 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.
4. 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.
5. 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.
6. Participants with vaccinations that are up-to-date based on the countrywide accepted schedule of childhood vaccines.

Main Exclusion Criteria:

1. 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.
2. 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.
3. 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.
4. The participants has received any live vaccinations within 30 days prior to first dose.
5. Participants who currently require surgical intervention or are anticipated to require surgical intervention for CD during this study.
6. 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.
7. Participants with a current diagnosis of indeterminate colitis.
8. Participants with clinical features suggesting monogenic very early-onset inflammatory bowel disease.
9. 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.
10. 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.
11. 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 \[defined as no evidence of HCV RNA at least 12 weeks before baseline\]).
12. The participants has any identified congenital or acquired immunodeficiency (eg, common variable immunodeficiency, human immunodeficiency virus \[HIV\] infection, organ transplantation).
13. 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.
14. Participants with positive stool studies for ova and/or parasites or stool culture at screening visit.
15. Participants with 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 Pediatric Crohn's Disease Activity Index (PCDAI) Score ≤10
timeFrame: Week 54
measure: Percentage of Participants With Endoscopic Response at Week 54 Based on Simple Endoscopic Score for Crohn's Disease [SES-CD] Score
timeFrame: Week 54
Secondary outcomes:
measure: Percentage of Participants with Clinical and Endoscopic Remission at Week 14 Based on Both PCDAI Score and SES-CD Score
timeFrame: Week 14
measure: Percentage of Participants with Clinical and Endoscopic Remission at Week 54 Based on Both PCDAI Score and SES-CD Score
timeFrame: Week 54
measure: Percentage of Participants with Sustained Clinical and Endoscopic Remission at Week 54
timeFrame: Week 54
measure: Percentage of Participants with Corticosteroid-free Remission at Week 54 Based on PCDAI Score
timeFrame: Week 54
measure: Percentage of Participants with Sustained Endoscopic Remission Based on SES-CD Score
timeFrame: Week 14
measure: Percentage of Participants with Sustained Endoscopic Remission Based on SES-CD Score
timeFrame: Week 54
measure: Percentage of Participants with Sustained Clinical Remission at Week 14 Based on PCDAI Score
timeFrame: Week 14
measure: Percentage of Participants with Sustained Clinical Remission at Week 54 Based on PCDAI 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 Antivedolizumab Antibodies
timeFrame: Pre-dose (up to 54 weeks)
measure: Percentage of Participants With Positive Neutralizing Antivedolizumab Antibody Titers
timeFrame: Pre-dose (up to 54 weeks)
measure: Sustained Clinical Response at Week 14 Based on PCDAI Score
timeFrame: Week 14
measure: Sustained Clinical Response at Week 54 Based on PCDAI Score
timeFrame: Week 54
measure: Percentage of Participants with Clinical Remission at Weeks 2, 6, 10, 14, 22, 30, 38, 46, and 54
timeFrame: Weeks 2, 6, 10, 14, 22, 30, 38, 46, and 54
measure: Percentage of Participants with Change in Baseline in Clinical Response at Weeks 2, 6, 10, 14, 22, 30, 38, 46, and 54
timeFrame: Baseline, 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 AE of special interest (AESI)
timeFrame: From first dose of study drug before each dose on dosing days through the Week 72
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 from Baseline in Tanner Stages at Week 54
timeFrame: Week 54
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Phoenix Childrens Hospital
state: Arizona
city: Los Angeles
country: United States
facility: Cedars Sinai Medical Center
state: California
city: San Diego
country: United States
facility: Rady Childrens Hospital San Diego - PIN
state: California
city: San Francisco
country: United States
facility: University of California San Francisco
state: California
city: Kissimmee
country: United States
facility: I.H.S Health LLC
state: Florida
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: Indianapolis
country: United States
facility: Riley Hospital For Children
state: Indiana
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Minneapolis
country: United States
facility: MNGI Digestive Health, PA
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: New Hyde Park
country: United States
facility: The Steven and Alexandra Cohen Childrens Medical Center of New York - BRANY - PPDS
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center PPDS
state: New York
city: Stony Brook
country: United States
facility: Stony Brook University Medical Center
state: New York
city: Syracuse
country: United States
facility: SUNY Upstate Medical Center
state: New York
city: Cleveland
country: United States
facility: University Hospitals Cleveland Medical Center
state: Ohio
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh
state: Pennsylvania
city: Providence
country: United States
facility: Hasbro Children's Hospital
state: Rhode Island
city: Houston
country: United States
facility: Texas Children's Hospital
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: UZ Leuven
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: Montreal
country: Canada
facility: Centre Hospitalier Universitaire Sainte-Justine
state: Quebec
city: Beijing
country: China
facility: Beijing Children Hospital,Capital Medical University
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 UniversitySchool of Medicine
state: Zhejiang
city: Zagreb
country: Croatia
facility: Klinika Za Djecje Bolesti Zagreb
state: Grad Zagreb
city: Zagreb
country: Croatia
facility: University Hospital Center Zagreb
state: Grad Zagreb
city: Split
country: Croatia
facility: University Hospital Centre Split
city: Prague
country: Czechia
facility: Fakultni nemocnice Kralovske Vinohrady
state: Praha, Hlavni Mesto
city: Praha
country: Czechia
facility: Fakultni Thomayerova Nemocnice
state: Praha, Hlavni Mesto
city: Ostrava
country: Czechia
facility: Fakultni nemocnice Ostrava
city: Athens
country: Greece
facility: Attikon University General Hospital
state: Attiki
city: Athens
country: Greece
facility: Children's Hospital "Agia Sofia"
city: Thessaloniki
country: Greece
facility: Ippokratio General Hospital of Thessaloniki
city: Thessaloniki
country: Greece
facility: Ippokratio General Hospital of Thessaloniki
city: Miskolc
country: Hungary
facility: Borsod-Abauj-Zemplen Megyei Kozponti Korhaz es Egyetemi Oktato Korhaz
state: Borsod-Abauj-Zemplen
city: Szeged
country: Hungary
facility: Szegedi Tudomanyegyetem Szent-Gyorgyi Albert Klinikai Kozpont
state: Csongrad
city: Budapest
country: Hungary
facility: Semmelweis Egyetem
city: Petah Tikva
country: Israel
facility: Schneider Childrens Medical Center of Israel Petah Tikvah PIN
state: HaMerkaz
city: Jerusalem
country: Israel
facility: Tel Aviv Sourasky Medical Center PPDS
state: Yerushalayim
city: Beer Sheba
country: Israel
facility: Soroka University Medical Centre
city: Haifa
country: Israel
facility: Rambam Medical Center - PPDS
city: Haifa
country: Israel
facility: Carmel Medical Center
city: Jerusalem
country: Israel
facility: Shaare Zedek Medical Center
city: Jerusalem
country: Israel
facility: Hadassah Medical Center - PPDS
city: Napoli
country: Italy
facility: AOU dell'Universita degli Studi della Campania Luigi Vanvitelli
state: Campania
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: Sapienza University of Rome
state: Lazio
city: Monza
country: Italy
facility: ASST di Monza - Azienda Ospedaliera San Gerardo
state: Lombardia
city: Padova
country: Italy
facility: Universita degli Studi di Padova
state: Veneto
city: Kurume-Shi
country: Japan
facility: Kurume University Hospital
state: Hukuoka
city: Kumamoto-shi
country: Japan
facility: Japanese Red Cross Kumamoto Hospital
state: Kumamoto
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: Daegu
country: Korea, Republic of
facility: Kyungpook National University Chilgok hospital
state: Daegu Gwang'yeogsi
city: Incheon
country: Korea, Republic of
facility: Gachon University Gil Medical Center
state: Incheon Gwang'yeogsi
city: Seongnam
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center - PPDS
city: Kaunas
country: Lithuania
facility: Hospital of Lithuanian University of Health Sciences Kaunas Clinics
state: Kauno Apskritis
city: Vilnius
country: Lithuania
facility: Vilnius University Hospital Santaros Klinikos
state: Vilniaus Apskritis
city: Wroclaw
country: Poland
facility: Uniwersytecki Szpital Kliniczny im. Jana Mikulicza Radeckiego we Wroclawiu
state: Dolnoslaskie
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: Gdansk
country: Poland
facility: Copernicus Podmiot Leczniczy Sp. z o.o.
state: Pomorskie
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: Lodz
country: Poland
facility: SPZOZ Centralny Szpital Kliniczny UM w Lodzi
city: Banska Bystrica
country: Slovakia
facility: Detska fakultna nemocnica s poliklinikou Banska Bystrica
city: Bratislava
country: Slovakia
facility: Narodny ustav detskych chorob
city: Esplugues de Llobregat
country: Spain
facility: Hospital Sant Joan de Deu - PIN
state: Barcelona
city: Sagunto
country: Spain
facility: Hospital de Sagunto
state: Valencia
city: Madrid
country: Spain
facility: Hospital Infantil Universitario Nino Jesus - PIN
city: Malaga
country: Spain
facility: Hospital Regional Universitario de Malaga - Hospital Materno Infantil
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio - PPDS
city: London
country: United Kingdom
facility: Kings College Hospital
state: London, City Of
city: London
country: United Kingdom
facility: Great Ormond Street Hospital (GOSH)
state: London, City Of
city: Cardiff
country: United Kingdom
facility: Noahs Ark Childrens Hospital for Wales - PPDS - PIN
state: South Glamorgan
city: Birmingham
country: United Kingdom
facility: Birmingham Children's Hospital NHS Foundation Trust
state: West Midlands
city: London
country: United Kingdom
facility: Barts Health NHS Trust
city: Manchester
country: United Kingdom
facility: Royal Manchester Children's Hospital - PPDS
Study officials:
References: