Clinical trial NCT03138655: Vedolizumab IV in Pediatric Participants With Ulcerative Colitis (UC) or Crohn's Disease (CD)
Official title: A Phase 2, Randomized, Double-Blind, Dose-Ranging Study to Determine the Pharmacokinetics, Safety and Tolerability of Vedolizumab IV in Pediatric Subjects With Ulcerative Colitis or Crohn's Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Ulcerative Colitis
Crohn's Disease
Keywords: Drug therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
Collaborators: name: Takeda Development Center Americas, Inc.
First posted: 2017-05-03
Enrollment: 89
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: The purpose of this study is to evaluate vedolizumab pharmacokinetics (PK), safety and tolerability in pediatric participants with moderately to severely active UC or CD.

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 or CD. This study will look at the PK, efficacy, immunogenicity, safety, and tolerability in participants who take vedolizumab.

The study will enroll approximately 80 participants. Participants will be randomly assigned (by chance, like flipping a coin) to one of the two dose regimens (high or low) per weight group \>=30 kg and 10 kg to \<30 kg in ratio 1:1-which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need):

* Vedolizumab high dose group - Vedolizumab 300 mg or 200 mg
* Vedolizumab low dose group - Vedolizumab 150 mg or 100 mg

All participants will be administered vedolizumab via IV infusion. Participants assigned to the low dose group who do not achieve clinical response (based on pediatric UC/CDAI) at Week 14 will receive the high dose (that is, 300 mg for participants \>=30 kg baseline weight and 200 mg for participants 10 kg to \<30 kg baseline weight) of vedolizumab IV at Week 14. Participants assigned to the high dose group who had not achieved clinical response continued on the same blinded high dose at Week 14.

This multi-center trial will be conducted worldwide. The overall time to participate in this study is up to 36 weeks. After completing the Week 22 Visit procedures, eligible participants may enter a blinded extension study. Participants will make multiple visits to the clinic, and those who do not enter extension study will have a final visit 18 weeks after last dose of study drug for a follow-up assessment. Participants who do not enter the extension study will also participate in a long-term safety follow-up, by telephone, 6 months after the last dose of study drug.

Eligibility criteria: Inclusion Criteria:

1. Participants weighs \>=10 kg at the time of randomization.
2. Has a medical history of moderately to severely active UC during Screening defined as complete Mayo score of 6 to 12, and a total Mayo subscores of stool frequency and rectal bleeding \>=4 and Mayo endoscopy subscore \>=2, or has moderately to severely active CD defined as simple endoscopic score for Crohn's disease (SES-CD) \>=7, and the CDAI components of average daily abdominal pain score of greater than (\>) 1 for the 7 days prior, and total number of liquid/very soft stools \>10 within 7 days prior to first dose of study drug.
3. Has evidence of UC extending proximal to the rectum (that is, not limited to proctitis) or evidence of CD involving the ileum and/or colon, at a minimum.
4. Has extensive colitis or pancolitis of \>8 years duration or left-sided colitis of \>12 years duration must have documented evidence that a surveillance colonoscopy was performed within 12 months prior to their first dose of study drug.
5. Has a family history of colorectal cancer (that is, first-degree relative), personal history of increased colorectal cancer risk, or other known risk factor must be up-to-date on colorectal cancer surveillance.
6. The participant's vaccinations are up to date.
7. Has demonstrated an inadequate response to, loss of response to, or intolerance of at least 1 of the following agents as defined below:

   Corticosteroids:

   • Signs and/or symptoms of persistently active disease despite a history of at least one 4-week induction regimen that included a dose equivalent to or more than prednisone 1 milligram per kilogram (mg/kg) daily orally for 2 weeks or IV for 1 week.

   OR

   • Two failed attempts to taper corticosteroids to below a dose equivalent to prednisone 10 mg daily orally on 2 separate occasions.

   OR

   • History of significant intolerance to corticosteroids (including, but not limited to, Cushing's syndrome, osteopenia/osteoporosis, hyperglycemia, insomnia, and infection).

   Immunomodulators:

   • Signs and symptoms of persistently active disease despite a history of at least one 8-week regimen of oral azathioprine (AZA) (\>=1.5 milligram per kilogram per day \[mg/kg/day\]) or 6-mercaptopurine (6-MP) mg/kg (\>=1.0 mg/kg/day) or methotrexate (MTX) (\>=10 milligram per square meter \[mg/m\^2\] once a week).

   OR

   • History of intolerance of at least 1 immunomodulator (including, but not limited to, nausea/vomiting, abdominal pain, pancreatitis, liver function test (LFT) abnormalities, lymphopenia, thiopurine methyltransferase genetic mutation, infection).

   Tumor necrosis factor-alpha (TNF-α) antagonists:

   • Signs and symptoms of persistently active disease despite a history of at least 1 induction regimen of infliximab 5 mg/kg IV at Week 0 and Weeks 2 and 6 or adalimumab 2-week regimen of 160 mg on Day 1 and 80 mg on Day 15 if \>=40 kg or 80 mg on Day 1 and 40 mg on Day 15 if \<40 kg. For any other TNF-α antagonist, the participant must demonstrate signs and symptoms of persistently active disease despite a history of at least 1 induction regimen, as determined by the investigator.

   OR

   • Recurrence of symptoms during maintenance dosing following prior clinical benefit, that is, fitting clinically with secondary loss of response (discontinuation despite clinical benefit does not qualify).

   OR

   • History of intolerance of infliximab or adalimumab (including, but not limited to, infusion-related reaction, demyelination, congestive heart failure, infection).
8. The participant may be receiving a therapeutic dose of the following drugs:

   1. Oral 5-aminosalicylic acid (5-ASA) compounds, providing the dose has been stable for the 2 weeks prior to first dose of study drug.
   2. Oral corticosteroid therapy (prednisolone at a stable dose \<=50 mg/day, or equivalent steroid), provided that the dose has been stable for the 4 weeks prior to first dose of study drug if corticosteroids have been initiated, or for the 2 weeks prior to first dose of study drug if corticosteroids are being tapered.
   3. Probiotics (example, Saccharomyces boulardii), provided the dose has been stable for the 2 weeks prior to first dose of study drug.
   4. Antidiarrheals (example, loperamide, diphenoxylate with atropine) for control of chronic diarrhea.
   5. Antibiotics used for the treatment of CD (example, ciprofloxacin, metronidazole), providing the dose has been stable for the 2 weeks prior to first dose of study drug.
   6. Azathioprine or 6-MP, provided the dose has been stable for the 8 weeks prior to first dose of study drug.
   7. Methotrexate (MTX), provided the dose has been stable for the 8 weeks prior to first dose of study drug.

Exclusion Criteria:

1. Has had previous exposure to approved or investigational anti-integrins (example, natalizumab, efalizumab, etrolizumab, or AMG 181) or MAdCAM-1 antagonists, or rituximab.
2. Has had prior exposure to vedolizumab.
3. Has a positive progressive multifocal leukoencephalopathy (PML) subjective symptom checklist prior to the administration of the first dose of study drug.
4. Requires surgical intervention for UC or CD, or is anticipated to require surgical intervention for UC or CD during this study.
5. Use of topical (rectal) treatment with 5-ASA or corticosteroid enemas/suppositories within 2 weeks of the administration of the first dose of study drug.
6. Has any unstable or uncontrolled cardiovascular, heart failure moderate to severe (New York Class Association III or IV), pulmonary, hepatic, renal, gastrointestinal (GI), genitourinary, hematological, coagulation, immunological, endocrine/metabolic, neurological, or other medical disorder that, in the opinion of the investigator, would confound the study results or compromise participant safety.
7. 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 millimeter (mm). Participants with documented previously treated TB with a negative QuantiFERON test can be included in the study.
8. Clinically significant current or recent history (within 1 year prior to enrollment) of alcohol dependence or illicit drug use.
9. Has a current diagnosis of indeterminate colitis (Inflammatory bowel disease unclassified \[IBDU\]). For participants less than 6 years of age, any findings that suggest monogenic very early onset inflammatory bowel disease should be excluded.
10. Has evidence of abdominal abscess or toxic megacolon at the initial Screening Visit.
11. Has ileostomy, colostomy, ileo-anal pouch, or known fixed symptomatic stenosis of the intestine.
12. Has extensive colonic resection, example, subtotal or total colectomy.
13. Has a history or evidence of adenomatous colonic polyps that have not been removed.
14. Has a history or evidence of colonic mucosal dysplasia.
15. Has chronic hepatitis B virus (HBV) infection\* or chronic hepatitis C virus (HCV) infection. \* HBV immune participants (that is, being hepatitis B surface antigen \[HBsAg\] negative and hepatitis B antibody positive) may be included, however.
16. Has any identified congenital or acquired immunodeficiency (example, common variable immunodeficiency, human immunodeficiency virus \[HIV\] infection, organ transplantation).
17. Has evidence of or treatment for Clostridium difficile (C difficile) infection within 60 days or other intestinal pathogen within 30 days prior to first dose of study drug.
18. Has any history of malignancy, except for the following: (a) adequately treated nonmetastatic basal cell skin cancer; (b) squamous cell skin cancer that has been adequately treated and that has not recurred for at least 1 year prior to enrollment; and (c) history of cervical carcinoma in situ that has been adequately treated and that has not recurred for at least 3 years prior to first dose of study drug. Participants with remote history of malignancy (example, \>10 years since completion of curative therapy without recurrence) will be considered based on the nature of the malignancy and the therapy received, and inclusion must be discussed with the sponsor on a case-by-case basis prior to enrollment.
19. Has a history of any major neurological disorders, including stroke, multiple sclerosis, brain tumor, or neurodegenerative disease.
20. Has history of lupus.
21. Has had a surgical procedure requiring general anesthesia within 30 days prior to screening or is planning to undergo major surgery during the study period.

Primary outcomes:
measure: AUCWeek 14: Area Under the Serum Concentration-time Curve at Week 14
timeFrame: From Day 43 (Week 6) post-dose up to pre-dose Day 99 (Week 14)
measure: Cav,Week 14: Average Serum Concentration During a Dosing Interval at Week 14
timeFrame: From Day 43 (week 6) post-dose up to pre-dose Day 99 (Week 14)
measure: Ctrough,Week 14: Observed Serum Concentration at the End of a Dosing Interval at Week 14
timeFrame: At the end of a dosing interval at Week 14
Secondary outcomes:
measure: Percentage of UC Participants Who Achieve Clinical Response Based on Complete Mayo Score
timeFrame: Baseline (Day 1) and Week 14
measure: Percentage of CD Participants Who Achieve Clinical Response Based on Crohn's Disease Activity Index (CDAI)
timeFrame: Baseline (Day 1) and Week 14
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: Orange
country: United States
facility: Children's Hospital of Orange County
state: California
city: San Francisco
country: United States
facility: University of California San Francisco
state: California
city: Hartford
country: United States
facility: Connecticut Children's Medical Center
state: Connecticut
city: Wilmington
country: United States
facility: Nemours Children's Clinic
state: Delaware
city: Jacksonville
country: United States
facility: Nemours Childrens Specialty Care - Jacksonville
state: Florida
city: Miami
country: United States
facility: Nicklaus Children's Hospital
state: Florida
city: Atlanta
country: United States
facility: Children's Center for Digestive Healthcare
state: Georgia
city: Chicago
country: United States
facility: Ann & Robert H. Lurie Children's Hospital of Chicago
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University School of Medicine - Indianapolis
state: Indiana
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic - Rochester
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University in St. Louis
state: Missouri
city: Bronx
country: United States
facility: The Children's Hospital at Montefiore
state: New York
city: Lake Success
country: United States
facility: Northwell Health
state: New York
city: New York
country: United States
facility: Mount Sinai Medical Center
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Cleveland
country: United States
facility: University Hospitals Rainbow Babies & Children's Hospital
state: Ohio
city: Philadelphia
country: United States
facility: The Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Dallas
country: United States
facility: Childrens Medical Center of Dallas
state: Texas
city: Houston
country: United States
facility: Texas Children's Hospital
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Norfolk
country: United States
facility: Children's Specialty Group - Medical Center Location
state: Virginia
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Brussel
country: Belgium
facility: Universitair Ziekenhuis Brussel
state: Brussels
city: Bruxelles
country: Belgium
facility: Hopital Universitaire des Enfants Reine Fabiola
state: Brussels
city: Leuven
country: Belgium
facility: Universitair Ziekenhuis Leuven
state: Flemish Brabant
city: Brussels
country: Belgium
facility: Cliniques Universitaires Saint-Luc
city: Calgary
country: Canada
facility: Alberta Children's Hospital
state: Alberta
city: Edmonton
country: Canada
facility: University of Alberta
state: Alberta
city: Vancouver
country: Canada
facility: Children's and Women's Health Centre of British Columbia
state: British Columbia
city: Winnipeg
country: Canada
facility: Children's Hospital of Winnipeg
state: Manitoba
city: Halifax
country: Canada
facility: IWK Health Centre
state: Nova Scotia
city: Hamilton
country: Canada
facility: McMaster Children's Hospital
state: Ontario
city: London
country: Canada
facility: London Health Sciences Centre University Hospital
state: Ontario
city: Toronto
country: Canada
facility: Toronto Hospital for Sick Children
state: Ontario
city: Montreal
country: Canada
facility: Centre Hospitalier Universitaire Sainte-Justine
state: Quebec
city: Montreal
country: Canada
facility: McGill University Health Centre Glen Site
state: Quebec
city: Paris Cedex 15
country: France
facility: Hopital Necker-Enfants Malades
state: Ile-de-france
city: Paris Cedex 19
country: France
facility: Hopital Robert Debre
state: Ile-de-france
city: Lille
country: France
facility: Hopital Jeanne de Flandre
state: NORD Pas-de-calais
city: Marseille Cedex 5
country: France
facility: Hopital de la Timone
state: Provence Alpes COTE D'azur
city: Ulm
country: Germany
facility: Universitatsklinikum Ulm
state: Baden-wuerttemberg
city: Munchen
country: Germany
facility: Ludwig-Maximillians-Universitat Munchen
state: Bayern
city: Rostock
country: Germany
facility: Universitatsmedizin Rostock - Kinder und Jugendklinik
state: Mecklenburg-vorpommern
city: Aachen
country: Germany
facility: Universitatsklinikum Aachen
state: Nordrhein-westfalen
city: Leipzig
country: Germany
facility: Universitaetsklinikum Leipzig AoeR
state: Sachsen
city: Miskolc
country: Hungary
facility: BAZ Megyei Korhaz es Egyetemi Oktatokorhaz
state: Borsod-abauj-zemplen
city: Szeged
country: Hungary
facility: Szegedi Tudomanyegyetem Szent-Gyorgyi Albert Klinikai Kozpont
state: Csongrad
city: Sopron
country: Hungary
facility: Soproni Erzsebet Oktato Korhaz es Rehabilitacios Intezet
state: Gyor-moson-sopron
city: Debrecen
country: Hungary
facility: Debreceni Egyetem Klinikai Kozpont
state: Hajdu-bihar
city: Budapest
country: Hungary
facility: Semmelweis Egyetem
city: Beer-sheva
country: Israel
facility: Soroka University Medical Center
state: Beersheba
city: Petach Tikvah
country: Israel
facility: Schneider Children's Medical Center of Israel
state: Petah Tiqwa
city: Zerifin
country: Israel
facility: Assaf Harofeh Medical Center
state: Rehoboth
city: Ramat Gan
country: Israel
facility: The Edmond and Lily Safra Children's Hospital - Sheba Medical Center
state: Tel Aviv
city: Haifa
country: Israel
facility: Rambam Health Care Campus - Rambam Medical Center
city: Haifa
country: Israel
facility: Carmel Medical Center
city: Jerusalem
country: Israel
facility: Shaare Zedek Medical Center
city: Tel Aviv
country: Israel
facility: Tel Aviv Sourasky Medical Center
city: Nijmegen
country: Netherlands
facility: Radboud Universitair Medisch Centrum
state: GA
city: Amsterdam
country: Netherlands
facility: Emma Kinderziekenhuis AMC
state: Noord-holland
city: Zwolle
country: Netherlands
facility: Isala Klinieken
state: Overijssel
city: Rotterdam
country: Netherlands
facility: Erasmus University Medical Center
state: Zuid-holland
city: Wroclaw
country: Poland
facility: Uniwersytecki Szpital Kliniczny im. Jana Mikulicza-Radeckiego we Wroclawiu
state: Dolnoslaskie
city: Lodz
country: Poland
facility: Centralny Szpital Kliniczny Uniwersytetu Medycznego w Lodzi Osrodek Pediatryczny im Marii Konopnic
state: Lodzkie
city: Lodz
country: Poland
facility: Instytut Centrum Zdrowia Matki Polki
state: Lodzkie
city: Krakow
country: Poland
facility: Uniwersytecki Szpital Dzieciecy w Krakowie
state: Malopolskie
city: Warsaw
country: Poland
facility: Warszawski Uniwersytet Medyczny
state: Mazowieckie
city: Rzeszow
country: Poland
facility: Gabinet Lekarski Dr. Hab. N. Med. Bartosz Korczowski
state: Podkarpackie
city: Bialystok
country: Poland
facility: Uniwersytecki Dzieciecy Szpital Kliniczny im. L. Zamenhofa w Bialymstoku
state: Podlaskie
city: Gdansk
country: Poland
facility: Copernicus Podmiot Leczniczy
state: Pomorskie
city: Szczecin
country: Poland
facility: Samodzielny Publiczny Specjalistyczny Zaklad Opieki Zdrowotnej ZDROJE
state: Zachodniopomorskie
city: Kyiv
country: Ukraine
facility: National Scientific Center of Radiological Medicine of NAMS of Ukraine
state: Kiev City
city: Kharkiv
country: Ukraine
facility: Kharkiv Regional Clinical Children's Hospital
city: Birmingham
country: United Kingdom
facility: Birmingham Women's and Children's NHS Foundation Trust
state: England
city: Cambridge
country: United Kingdom
facility: Cambridge University Hospitals NHS Foundation Trust
state: England
city: London
country: United Kingdom
facility: Barts and The London NHS Trust
state: England
city: London
country: United Kingdom
facility: King's College Hospital
state: England
city: London
country: United Kingdom
facility: Great Ormond Street Hospital for Children NHS Trust
state: England
city: Manchester
country: United Kingdom
facility: Central Manchester University Hospitals NHS Foundation Trust
state: England
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals NHS Trust
state: England
city: Oxford
country: United Kingdom
facility: Oxford University Hospitals NHS Foundation Trust
state: England
city: Sheffield
country: United Kingdom
facility: Sheffield Children's NHS Foundation Trust
state: England
city: Glasgow
country: United Kingdom
facility: NHS Greater Glasgow and Clyde
state: Scotland
Study officials:
affiliation: Takeda
name: Medical Monitor Clinical Science
role: STUDY_DIRECTOR
References: