Efficacy and Safety of Adalimumab in Pediatric Subjects With Moderate to Severe Ulcerative Colitis

A Multicenter, Randomized, Double-Blind Study of the Human Anti-TNF Monoclonal Antibody Adalimumab in Pediatric Subjects With Moderate to Severe Ulcerative Colitis

The purpose of the study is to demonstrate the efficacy and safety, and to assess the pharmacokinetics of adalimumab administered subcutaneously (SC) in pediatric subjects with moderate to severe ulcerative colitis (UC).

Study Overview

• Status: Completed
• Conditions: Ulcerative Colitis
• Intervention / Treatment: Biological: Adalimumab; Biological: Placebo

• Study Type: Interventional
• Enrollment (Actual): 101
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • South Australia
    • Adelaide, South Australia, Australia, 5006
      • Womens and Childrens Hospital /ID# 127538
• Austria
  • Salzburg, Austria, 5020
    • LKH Salzburg and Paracelsus /ID# 123457
  • Wien
    • Vienna, Wien, Austria, 1090
      • Medizinische Universitat Wien /ID# 120802
• Belgium
  • Brussels, Belgium, 1020
    • Hosp Univ Enfants Reine Fabiol /ID# 120795
  • Bruxelles-Capitale
    • Jette, Bruxelles-Capitale, Belgium, 1090
      • UZ Brussel /ID# 120798
    • Woluwe-Saint-Lambert, Bruxelles-Capitale, Belgium, 1200
      • Cliniques Universitaires Saint Luc /ID# 120797
• Canada
  • Ontario
    • London, Ontario, Canada, N6A 5A5
      • London Health Sciences Centre /ID# 127777
• Czechia
  • Olomouc, Czechia, 779 00
    • Palacky University /ID# 131388
  • Plzen, Czechia, 305 99
    • Univ Hosp, Plzen, CZ /ID# 120813
• Hungary
  • Gyor, Hungary, 9023
    • Petz Aladar Megyei Oktato Korh /ID# 124323
  • Szekszard, Hungary, 7100
    • Balassa Janos County Hospital /ID# 128474
• Israel
  • Be'er Sheva, Israel, 84101
    • Soroka Medical Ctr /ID# 147338
  • Be'er Ya'akov, Israel, 70300
    • Assaf Harofeh Medical Center /ID# 147791
  • Haifa, Israel, 3109601
    • Rambam Health Care Campus /ID# 120827
  • Jerusalem, Israel, 91031
    • Shaare Zedek Medical Center /ID# 120830
  • Petah Tikva, Israel, 4920235
    • Schneider Childrens Med Ctr /ID# 120821
  • Ramat Gan, Israel, 5262100
    • Sheba Medical Center /ID# 124324
  • Rehovot, Israel, 76100
    • Kaplan Medical Center /ID# 150245
• Japan
  • Osaka, Japan, 558-8558
    • Osaka General Medical Center /ID# 124535
  • Fukuoka
    • Kurume-shi, Fukuoka, Japan, 830-0011
      • Kurume University Hospital /ID# 125476
  • Gunma
    • Maebashi-shi, Gunma, Japan, 371-8511
      • Gunma University Hospital /ID# 126345
  • Hokkaido
    • Sapporo-shi, Hokkaido, Japan, 060-0033
      • Hokkaido P.W.F.A.C. Sapporo-Kosei General Hospital /ID# 124482
  • Hyogo
    • Nishinomiya-shi, Hyogo, Japan, 663-8501
      • The Hospital of Hyogo College of Medicine /ID# 131665
  • Kanagawa
    • Yokohama, Kanagawa, Japan, 232-0024
      • Yokohama City Univ Medical Ctr /ID# 147763
    • Yokohama-shi, Kanagawa, Japan, 230-0012
      • Saiseikai Yokohamashi Tobu /ID# 124486
  • Miyagi
    • Sendai-shi, Miyagi, Japan, 989-3126
      • Miyagi Children's Hospital /ID# 125475
  • Saitama
    • Saitama-shi, Saitama, Japan, 330-8777
      • Saitama Children's Medical Center /ID# 124485
  • Tokyo
    • Bunkyo-ku, Tokyo, Japan, 113-8431
      • Juntendo University Hospital /ID# 124536
    • Setagaya-ku, Tokyo, Japan, 157-8535
      • National Center for Child Health and Development /ID# 125203
• New Zealand
  • Christchurch, New Zealand, 8011
    • Canterbury District Health Boa /ID# 120837
• Poland
  • Rzeszow, Poland, 35-210
    • Gabinet Lekarski Bartosz Korcz /ID# 120916
  • Wroclaw, Poland, 50-369
    • Samodzielny Publiczny Szpital /ID# 120839
  • Lodzkie
    • Lodz, Lodzkie, Poland, 93-338
      • Polish Mothers Memorial Hosp /ID# 148497
  • Malopolskie
    • Cracow, Malopolskie, Poland, 30-663
      • Uni Szpital Dzieciecy w Krakowie /ID# 120915
  • Mazowieckie
    • Warsaw, Mazowieckie, Poland, 00-635
      • Centrum Zdrowia MDM /ID# 120910
• Slovakia
  • Banska Bystrica, Slovakia, 974 09
    • FN s poliklinikou F.D. Rooseve /ID# 120847
  • Bratislava, Slovakia, 821 01
    • Univerzitna Nemocnica Bratislava /ID# 120842
  • Zilinsky Kraj
    • Martin, Zilinsky Kraj, Slovakia, 036 01
      • Univerzitna nemocnica Martin /ID# 120844
• Spain
  • Barcelona, Spain, 08035
    • Hospital Univ Vall d'Hebron /ID# 120856
  • Madrid, Spain, 28009
    • Hospital Infantil Universitario Nino Jesus /ID# 121862
• United Kingdom
  • Glasgow, United Kingdom, G3 8SJ
    • Royal Hosp for Sick Children /ID# 120864
  • Manchester, United Kingdom, M13 9WL
    • Manchester Royal Infirmary, Ma /ID# 120862
  • London, City Of
    • London, London, City Of, United Kingdom, E1 1BB
      • The Royal London Hospital /ID# 120861
    • London, London, City Of, United Kingdom, NW3 2QG
      • The Royal Free Hospital /ID# 123142
• United States
  • California
    • Los Angeles, California, United States, 90027
      • Childrens Hospital LA /ID# 147452
    • San Francisco, California, United States, 94143-2204
      • Univ California, San Francisco /ID# 120901
  • Florida
    • Orlando, Florida, United States, 32806
      • Arnold Palmer Hosp Children /ID# 120898
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University Hospital /ID# 121858
    • Atlanta, Georgia, United States, 30342
      • Children's Ctr Digestive, US /ID# 121855
  • Illinois
    • Chicago, Illinois, United States, 60637-1443
      • University of Chicago /ID# 120904
    • Maywood, Illinois, United States, 60153
      • Loyola University Medical Ctr /ID# 120900
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University /ID# 120908
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital /ID# 124551
    • Boston, Massachusetts, United States, 02115
      • Boston Childrens Hospital /ID# 147714
  • Minnesota
    • Rochester, Minnesota, United States, 55905-0001
      • Mayo Clinic - Rochester /ID# 121056
    • Saint Paul, Minnesota, United States, 55114
      • Minnesota Gastroenterology P.A /ID# 120895
  • New Jersey
    • Morristown, New Jersey, United States, 07960
      • Goryeb Chidlren's Hospital /ID# 121860
  • New York
    • New Hyde Park, New York, United States, 11040
      • North Shore University Hospital /ID# 120905
    • Rochester, New York, United States, 14642
      • Univ Rochester Med Ctr /ID# 127776
  • Washington
    • Tacoma, Washington, United States, 98405
      • Multicare Institute for Research and Innovation /ID# 147716

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 years to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosis of UC for at least 12 weeks prior to screening, confirmed by endoscopy with biopsy.
• Active ulcerative colitis with a Mayo Score of 6 - 12 points and endoscopy subscore of 2 - 3 despite concurrent treatment with oral corticosteroids or immunosuppressants or both.

Exclusion Criteria:

• Subject with Crohn's disease (CD) or indeterminate colitis (IC).
• Current diagnosis of fulminant colitis and/or toxic megacolon.
• Subjects with disease limited to the rectum (ulcerative proctitis) during the screening endoscopy.
• Chronic recurring infections or active tuberculosis (TB).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Adalimumab Induction Standard Dose; Participants randomized to receive adalimumab 2.4 mg/kg (maximum dose of 160 mg) at Baseline and matching placebo at Week 1, 1.2 mg/kg (maximum dose of 80 mg) at Week 2, followed by 0.6 mg/kg (maximum dose of 40 mg) at Week 4 and Week 6.	Biological: Adalimumab; Subcutaneous (SC) injection; Other Names: Humira; Biological: Placebo; Subcutaneous (SC) injection
Experimental: Adalimumab Induction High Dose; Participants randomized to receive adalimumab 2.4 mg/kg (maximum dose of 160 mg) at Baseline and at Week 1, 1.2 mg/kg (maximum dose of 80 mg) at Week 2, followed by 0.6 mg/kg (maximum dose of 40 mg) at Week 4 and Week 6.	Biological: Adalimumab; Subcutaneous (SC) injection; Other Names: Humira
Experimental: Adalimumab Induction High Dose - Open Label; (After Amendment 4) participants assigned to open-label adalimumab 2.4 mg/kg (maximum dose of 160 mg) at Baseline and at Week 1, 1.2 mg/kg (maximum dose of 80 mg) at Week 2, followed by 0.6 mg/kg (maximum dose of 40 mg) at Week 4 and Week 6.	Biological: Adalimumab; Subcutaneous (SC) injection; Other Names: Humira
Placebo Comparator: Maintenance Placebo; (Prior to Amendment 4) participants demonstrating a clinical response per PMS (defined as a decrease in PMS ≥ 2 points and ≥ 30% from Baseline) at Week 8 randomized to maintenance placebo. Participants were to continue their blinded treatment during the maintenance period until Week 52 unless they had ≥ 2 flares and got open label rescue therapy after the second flare.	Biological: Adalimumab; Subcutaneous (SC) injection; Other Names: Humira; Biological: Placebo; Subcutaneous (SC) injection
Experimental: Adalimumab Maintenance Standard Dose; Participants demonstrating a clinical response per PMS (defined as a decrease in PMS ≥ 2 points and ≥ 30% from Baseline) at Week 8 randomized to adalimumab maintenance standard dose (0.6 mg/kg [maximum dose of 40 mg] every other week). Participants were to continue their blinded treatment during the maintenance period until Week 52 unless they had ≥ 2 flares and got open label rescue therapy after second flare.	Biological: Adalimumab; Subcutaneous (SC) injection; Other Names: Humira
Experimental: Adalimumab Maintenance High Dose; Participants demonstrating a clinical response per PMS (defined as a decrease in PMS ≥ 2 points and ≥ 30% from Baseline) at Week 8 randomized to adalimumab maintenance high dose (0.6 mg/kg [maximum dose of 40 mg] every week). Participants were to continue their blinded treatment during the maintenance period until Week 52 unless they had ≥ 2 flares and got open label rescue therapy after second flare.	Biological: Adalimumab; Subcutaneous (SC) injection; Other Names: Humira

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Co-Primary Endpoint 1: Percentage of Participants Who Achieved Clinical Remission as Measured by Partial Mayo Score (PMS) at Week 8 - Induction Period	The Mayo score is a tool designed to measure disease activity for ulcerative colitis. The PMS (Mayo score without endoscopy) ranges from 0 (normal or inactive disease) to 9 (severe disease) and is calculated as the sum of 3 sub scores (stool frequency, rectal bleeding and physician's global assessment), each of which ranges from 0 (normal) to 3 (severe disease). A negative change in PMS indicates improvement. Clinical remission was defined as a PMS ≤ 2 and no individual subscore > 1.	Week 8
Co-Primary Endpoint 2: Percentage of Participants With Clinical Remission Per Full Mayo Score (FMS) at Week 52 in Week 8 Responders Per PMS - Maintenance Period	The FMS ranges from 0 (normal or inactive disease) to 12 (severe disease) and is calculated as the sum of 4 subscores (stool frequency, rectal bleeding, endoscopy, and physician's global assessment), each of which ranges from 0 (normal) to 3 (severe disease). The PMS (Mayo score without endoscopy) ranges from 0 (normal or inactive disease) to 9 (severe disease) and is calculated as the sum of 3 subscores (stool frequency, rectal bleeding and physician's global assessment). Negative changes indicate improvement. PMS responders are defined as those with a decrease in PMS ≥ 2 points and ≥ 30% from Baseline. Clinical remission per FMS is defined as Mayo Score ≤ 2 and no individual subscore > 1.	Week 52

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ranked Secondary Endpoint 1: Percentage of Participants With Clinical Response Per FMS at Week 52 in Week 8 Responders Per PMS - Maintenance Period	The FMS ranges from 0 (normal or inactive disease) to 12 (severe disease) and is calculated as the sum of 4 subscores (stool frequency, rectal bleeding, endoscopy, and physician's global assessment), each of which ranges from 0 (normal) to 3 (severe disease). The PMS (Mayo score without endoscopy) ranges from 0 (normal or inactive disease) to 9 (severe disease) and is calculated as the sum of 3 subscores (stool frequency, rectal bleeding and physician's global assessment). Negative changes indicate improvement. PMS responders are defined as those with a decrease in PMS ≥ 2 points and ≥ 30% from Baseline. Clinical response per FMS is defined as a decrease in FMS ≥ 3 points and ≥ 30% from Baseline.	Week 52
Ranked Secondary Endpoint 2: Percentage of Participants With Mucosal Healing at Week 52 in Week 8 Responders Per PMS - Maintenance Period	The FMS ranges from 0 (normal or inactive disease) to 12 (severe disease) and is calculated as the sum of 4 subscores (stool frequency, rectal bleeding, endoscopy, and physician's global assessment), each of which ranges from 0 (normal) to 3 (severe disease). The PMS (Mayo score without endoscopy) ranges from 0 (normal or inactive disease) to 9 (severe disease) and is calculated as the sum of 3 subscores (stool frequency, rectal bleeding and physician's global assessment). Negative changes indicate improvement. PMS responders are defined as those participants with a decrease in PMS ≥ 2 points and ≥ 30% from Baseline. Mucosal healing per Mayo endoscopy subscore is defined as a subscore of ≤ 1.	Week 52
Ranked Secondary Endpoint 3: Percentage of Participants With Clinical Remission Per FMS at Week 52 in Week 8 Remitters Per PMS - Maintenance Period	The FMS ranges from 0 (normal or inactive disease) to 12 (severe disease) and is calculated as the sum of 4 subscores (stool frequency, rectal bleeding, endoscopy, and physician's global assessment), each of which ranges from 0 (normal) to 3 (severe disease). The PMS (Mayo score without endoscopy) ranges from 0 (normal or inactive disease) to 9 (severe disease) and is calculated as the sum of 3 subscores (stool frequency, rectal bleeding and physician's global assessment). Negative changes indicate improvement. PMS remitters are defined as those participants with a PMS ≤ 2 and no individual subscore > 1. Clinical remission per FMS is defined as Mayo Score ≤ 2 and no individual subscore > 1.	Week 52
Ranked Secondary Endpoint 4: Percentage of Participants With Corticosteroid-Free Clinical Remission Per FMS at Week 52 in Week 8 Responders Per PMS - Maintenance Period	The FMS ranges from 0 (normal or inactive disease) to 12 (severe disease) and is calculated as the sum of 4 subscores (stool frequency, rectal bleeding, endoscopy, and physician's global assessment), each of which ranges from 0 (normal) to 3 (severe disease). The PMS (Mayo score without endoscopy) ranges from 0 (normal or inactive disease) to 9 (severe disease) and is calculated as the sum of 3 subscores (stool frequency, rectal bleeding and physician's global assessment). Negative changes indicate improvement. PMS responders are defined as those with a decrease in PMS ≥ 2 points and ≥ 30% from baseline. Among participants receiving systemic corticosteroids at Baseline, corticosteroid-free clinical remission per FMS at Week 52 is defined as having discontinued systemic corticosteroids prior to Week 52 and being in FMS clinical remission at Week 52 (defined as Mayo Score ≤ 2 and no individual subscore > 1).	Week 52

Collaborators and Investigators

• Sponsor: AbbVie

Publications and helpful links

General Publications

• Croft NM, Faubion WA Jr, Kugathasan S, Kierkus J, Ruemmele FM, Shimizu T, Mostafa NM, Venetucci M, Finney-Hayward T, Sanchez Gonzalez Y, Bereswill M, Lazar A, Turner D. Efficacy and safety of adalimumab in paediatric patients with moderate-to-severe ulcerative colitis (ENVISION I): a randomised, controlled, phase 3 study. Lancet Gastroenterol Hepatol. 2021 Aug;6(8):616-627. doi: 10.1016/S2468-1253(21)00142-4. Epub 2021 Jun 19.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): October 13, 2014
• Primary Completion (Actual): February 7, 2020
• Study Completion (Actual): February 7, 2020

Study Registration Dates

• First Submitted: February 17, 2014
• First Submitted That Met QC Criteria: February 17, 2014
• First Posted (Estimate): February 19, 2014

Study Record Updates

• Last Update Posted (Actual): October 5, 2020
• Last Update Submitted That Met QC Criteria: September 10, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Keywords: Ulcerative Colitis; adalimumab
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Gastrointestinal Diseases; Gastroenteritis; Colonic Diseases; Intestinal Diseases; Inflammatory Bowel Diseases; Ulcer; Colitis; Colitis, Ulcerative; Anti-Inflammatory Agents; Antirheumatic Agents; Adalimumab
• Other Study ID Numbers: M11-290; 2013-003032-77 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual and trial-level data (analysis data sets), as well as other information (e.g., protocols and clinical study reports), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications.
• IPD Sharing Time Frame: Data requests can be submitted at any time and the data will be accessible for 12 months, with possible extensions considered.
• IPD Sharing Access Criteria: Access to this clinical trial data can be requested by any qualified researchers who engage in rigorous, independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing Agreement (DSA). For more information on the process, or to submit a request, visit the following link.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No