Efficacy and Long Term Safety of Adalimumab in Pediatric Subjects Who Have Demonstrated Clinical Response in M06-806

A Multi-center, Open-label Study of the Human Anti-TNF Monoclonal Antibody Adalimumab to Evaluate the Efficacy and the Long-term Safety and Tolerability of Repeated Administration of Adalimumab in Pediatric Subjects With Crohn's Disease Who Have Demonstrated a Clinical Response in the M06-806 Study

This was a multicenter, open-label study to evaluate the human monoclonal anti-TNF-α antibody adalimumab as an effective therapy for maintaining clinical response in pediatric participants with Crohn's disease (CD) and to gather long-term safety and tolerability data in this population. Participants were allowed to enroll in the study if they participated in and successfully completed Study M06-806 (NCT00409682) through Week 52.

Study Overview

• Status: Completed
• Conditions: Crohn's Disease
• Intervention / Treatment: Biological: Adalimumab

• Study Type: Interventional
• Enrollment (Actual): 100
• Phase: Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 7 years to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Participant must have successfully enrolled in and completed Study M06-806 through Week 52.
• Participant must have been a responder at any time point during the M06-806 study (defined as having achieved at least a 15-point reduction in the Pediatric Crohn's Disease Activity Index (PCDAI) from Baseline).

• If female, participants who were sexually active and of child-bearing potential were to be practicing an approved method of birth control throughout the study and for 150 days after study drug administration. Examples of approved methods of birth control included the following:

  1. Condoms, sponge, foam, jellies, diaphragm or intrauterine device (IUD)
  2. Oral, parenteral or intravaginal contraceptives
  3. A vasectomized partner
• Participant of legal age, parent or legal guardian, as required, voluntarily signed and dated an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved informed consent form, after the nature of the study was explained and the participant of legal age, participant's parent, or legal guardian, as required, had the opportunity to ask questions. Participants were to be included in all discussions, and if required, their signature on an assent form was to be obtained.
• Parent or legal guardian of participant who was not of legal age, as required, must have been willing to actively supervise storage and administration of study drug and to ensure that the time of each dose was accurately recorded in the participant's diary.
• Participants of legal age, must have been willing to actively store, administer, and accurately record study drug administration in the participant diary.
• Participant was judged to be in acceptable medical condition, as determined by the Principal Investigator based upon results of clinical and laboratory evaluations done throughout the preceding Crohn's disease study M06-806.

Exclusion Criteria:

• For any reason, the participant was considered by the Investigator to be an unsuitable candidate for continuing therapy in the M06-807 study.
• Participant had abnormal laboratory or other test results that in the opinion of the Investigator would make the participant unsuitable to participate in this study.
• History of cancer or lymphoproliferative disease other than a successfully and completely treated cutaneous squamous cell or basal cell carcinoma or carcinoma in-situ of the cervix.
• History of listeriosis, histoplasmosis, chronic or active hepatitis B infection, human immunodeficiency virus (HIV) infection, any immunodeficiency syndrome, central nervous system (CNS) demyelinating disease or active TB (receiving treatment or not receiving treatment). Ongoing severe infections such as sepsis and opportunistic infections were exclusionary.
• Participant with known, symptomatic obstructive strictures.
• Participant who was planning surgical bowel resection at any time point while enrolled in the study.
• Participant who had short bowel syndrome as determined by the Investigator.
• Participant who was receiving total parenteral nutrition (TPN).
• Participant who was unwilling to discontinue growth hormone prior to the first dose of open-label study drug at the Baseline visit of M06-807.
• Female participant who was pregnant or currently breastfeeding.
• Participant with a history of clinically significant drug or alcohol abuse in the last year.
• Participant with a poorly controlled medical condition such as: uncontrolled diabetes, recurrent infections, unstable ischemic heart disease, moderate to severe heart failure, recent cerebrovascular accidents or any other condition which, in the opinion of the Investigator or the Sponsor, would put the participant at risk by participation in the protocol.
• Participant with any prior exposure to Tysabri (natalizumab).
• Participant with a known hypersensitivity to the excipients of adalimumab as stated in the label.
• Participant with a previous history of dysplasia of the gastrointestinal tract.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Any adalimumab; Adalimumab was administered via subcutaneous injection. Dosage was based on body weight and clinical status, and ranged from 10, 20, or 40 mg every other week to 20 or 40 mg every week.

Biological: Adalimumab; Participants who enrolled into the study from blinded therapy in Study M06-806 received open-label (OL) therapy at a dose dependent on their body weight. Participants weighing ≥ 40 kg received 40 mg of adalimumab every other week (eow), and those who weighed < 40 kg received 20 mg of adalimumab eow. Starting at Week 8, participants who had a disease flare may have been switched to every week (ew) treatment at the same dose of adalimumab received while on eow treatment. Participants who enrolled from OL therapy in Study M06-806 continued to receive the same dose they were receiving (i.e., 40 mg ew or 20 mg ew) at the Week 52 visit of Study M06-806. Adalimumab dose could have been decreased to the next lower treatment level for those with body weight changes. Participants who responded to treatment may have also had their dosage frequency decreased from ew to eow dosing, as well as a decrease in dosage.; Other Names: ABT-D2E7; Humira

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Who Achieved Pediatric Crohn's Disease Activity Index (PCDAI) Clinical Remission Over Time	Pediatric Crohn's Disease Activity Index (PCDAI) is an index used to measure disease activity of pediatric patients with Crohn's disease assessing abdominal pain, stool frequency, patient functioning, hematocrit, erythrocyte sedimentation rate, albumin, weight, height, abdomen, perirectal disease, and extraintestinal manifestations. It ranges from 0 to 100; higher scores indicate more active disease. Clinical remission was defined as PCDAI ≤ 10.	Week 0, 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 144, 168, 192, 216, 240, 264, 288, 312, 336, 360, 384, 408
Number of Participants With Clinical Response as Defined by Pediatric Crohn's Disease Activity Index (PCDAI) Score Over Time	Pediatric Crohn's Disease Activity Index (PCDAI) is an index used to measure disease activity of pediatric patients with Crohn's disease assessing abdominal pain, stool frequency, patient functioning, hematocrit, erythrocyte sedimentation rate, albumin, weight, height, abdomen, perirectal disease, and extraintestinal manifestations. It ranges from 0 to 100; higher scores indicate more active disease. The baseline PCDAI value was defined as the last non-missing value on or before the date of the first dose of study drug during Study M06-806. Clinical response was defined as a PCDAI ≥ 15 points lower than the Study M06-806 baseline PCDAI value.	Week 0, 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 144, 168, 192, 216, 240, 264, 288, 312, 336, 360, 384, 408

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Who Were in Crohn's Disease Activity Index (CDAI) Clinical Remission Over Time	The CDAI includes 8 variables encompassing both subject-reported (symptoms, general well-being) and objective (medication usage, laboratory variables, presence of abdominal mass or complications, and weight) variables. For symptoms scores, participants kept track of daily symptoms on a diary card, and the daily symptom scores were summed for the week. Each item in the CDAI is assigned a specific weight, and the weighted values of the items are totaled to produce the CDAI score. Higher CDAI scores indicate greater disease activity; 0 is the lower limit with no set upper limit. The scale for the score is as follows: < 150 to indicate remission, 150 - 219 to define mildly active disease, 220 - 450 to define moderately active disease, and > 450 to define severely active disease. A CDAI was calculated at each visit for participants who were age 13 or older at Study M06-806 entry. The Study M06-806 Week 52 visit served as the baseline visit for this study.	Week 0, 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 144, 168, 192, 216, 240, 264, 288, 312, 336, 360, 384, 408
Number of Participants Who Were in Crohn's Disease Activity Index (CDAI) Clinical Response Over Time	The CDAI includes 8 variables: subject-reported (symptoms, general well-being) and objective (medication usage, laboratory variables, presence of abdominal mass or complications, and weight). Participants kept track of symptoms on a diary card, and scores were summed for the week. Each item is assigned a specific weight, and the weighted values of the items are totaled to produce the CDAI score. Higher CDAI scores indicate greater disease activity; 0 is the lower limit with no set upper limit. Scale: < 150 (remission), 150 - 219 (mildly active disease), 220 - 450 (moderately active disease), and > 450 (severely active disease). A CDAI was calculated at each visit for participants ≥ 13 yrs old at M06-806 entry. Clinical response was defined as a decrease from M06-806 Baseline CDAI value of ≥ 70 pts. The M06-806 Baseline value was defined as the last non-missing value on or before the date of the 1st dose of study drug in M06-806.	Week 0, 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 144, 168, 192, 216, 240, 264, 288, 312, 336, 360, 384, 408
Number of Participants in Steroid-free Pediatric Crohn's Disease Activity Index (PCDAI) Remission Over Time	Pediatric Crohn's Disease Activity Index (PCDAI) is an index used to measure disease activity of pediatric patients with Crohn's disease assessing abdominal pain, stool frequency, patient functioning, hematocrit, erythrocyte sedimentation rate, albumin, weight, height, abdomen, perirectal disease, and extraintestinal manifestations. It ranges from 0 to 100; higher scores indicate more active disease. PCDAI corticosteroid-free remission was defined as discontinued corticosteroid use at least 90 consecutive days prior to the respective visit, with a PCDAI ≤ 10 at that visit.	Week 0, 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 144, 168, 192, 216, 240, 264, 288, 312, 336, 360, 384
Number of Participants in Steroid-free Crohn's Disease Activity Index (CDAI) Remission Over Time	The CDAI includes 8 variables encompassing subject-reported (symptoms, general well-being) and objective (medication usage, laboratory variables, presence of abdominal mass or complications, and weight) variables. Participants kept track of daily symptoms on a diary card, and the scores were summed for the week. Each item in the CDAI is assigned a specific weight, and the items are totaled to produce the CDAI score. Higher CDAI scores indicate greater disease activity; 0 is the lower limit with no set upper limit. The scale for the score is as follows: < 150 (remission), 150 - 219 (mildly active disease), 220 - 450 (moderately active disease), and > 450 (severely active disease). A CDAI was calculated at each visit for subjects ≥ 13 years old at M06-806 entry. CDAI corticosteroid-free remission was defined as discontinued use at least 90 consecutive days prior to the respective visit and a CDAI < 150 at that visit.	Week 0, 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 144, 168, 192, 216, 240, 264, 288, 312, 336, 360, 384
Mean Change From Baseline in Pediatric Crohn's Disease Activity Index (PCDAI) Over Time	Pediatric Crohn's Disease Activity Index (PCDAI) is an index used to measure disease activity of pediatric patients with Crohn's disease assessing abdominal pain, stool frequency, patient functioning, hematocrit, erythrocyte sedimentation rate, albumin, weight, height, abdomen, perirectal disease, and extraintestinal manifestations. It ranges from 0 to 100; higher scores indicate more active disease. The baseline value was defined as the last non-missing value on or before the date of the first dose of study drug in Study M06-806. Negative changes indicate reductions (improvement) in disease activity.	Week 0, 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 144, 168, 192, 216, 240, 264, 288, 312, 336, 360, 384
Mean Change From Baseline in Crohn's Disease Activity Index (CDAI) Over Time	The CDAI includes 8 variables: participant-reported (symptoms, general well-being) and objective (medication usage, laboratory variables, presence of abdominal mass or complications, and weight) variables. Participants kept track of daily symptoms on a diary card, and the scores were summed for the week. Each item in the CDAI is assigned a specific weight, and the items are totaled to produce the CDAI score. Higher CDAI scores indicate greater disease activity; 0 is the lower limit with no set upper limit. The scale for the score is as follows: < 150 (remission), 150 - 219 (mildly active disease), 220 - 450 (moderately active disease) and > 450 (severely active disease). A CDAI was calculated at each visit for those who were ≥ 13 years old at Study M06-806 entry. The baseline value was defined as the last non-missing value on or before the date of the first dose of study drug in Study M06-806. Negative changes indicate reductions (improvement) in disease activity.	Week 0, 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 144, 168, 192, 216, 240, 264, 288, 312, 336, 360, 384

Collaborators and Investigators

• Sponsor: AbbVie (prior sponsor, Abbott)
• Investigators: Study Director: Andreas Lazar, AbbVie

Publications and helpful links

General Publications

• Horneff G, Seyger MMB, Arikan D, Kalabic J, Anderson JK, Lazar A, Williams DA, Wang C, Tarzynski-Potempa R, Hyams JS. Safety of Adalimumab in Pediatric Patients with Polyarticular Juvenile Idiopathic Arthritis, Enthesitis-Related Arthritis, Psoriasis, and Crohn's Disease. J Pediatr. 2018 Oct;201:166-175.e3. doi: 10.1016/j.jpeds.2018.05.042. Epub 2018 Jul 25.
• Ruemmele FM, Rosh J, Faubion WA, Dubinsky MC, Turner D, Lazar A, Eichner S, Maa JF, Alperovich G, Robinson AM, Hyams JS. Efficacy of Adalimumab for Treatment of Perianal Fistula in Children with Moderately to Severely Active Crohn's Disease: Results from IMAgINE 1 and IMAgINE 2. J Crohns Colitis. 2018 Nov 9;12(10):1249-1254. doi: 10.1093/ecco-jcc/jjy087.
• Faubion WA, Dubinsky M, Ruemmele FM, Escher J, Rosh J, Hyams JS, Eichner S, Li Y, Reilly N, Thakkar RB, Robinson AM, Lazar A. Long-term Efficacy and Safety of Adalimumab in Pediatric Patients with Crohn's Disease. Inflamm Bowel Dis. 2017 Mar;23(3):453-460. doi: 10.1097/MIB.0000000000001021.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: May 1, 2008
• Primary Completion (Actual): April 4, 2017
• Study Completion (Actual): April 4, 2017

Study Registration Dates

• First Submitted: May 27, 2008
• First Submitted That Met QC Criteria: May 27, 2008
• First Posted (Estimate): May 29, 2008

Study Record Updates

• Last Update Posted (Actual): July 2, 2018
• Last Update Submitted That Met QC Criteria: June 1, 2018
• Last Verified: March 1, 2018

More Information

Terms related to this study

• Keywords: adalimumab; Crohn's Disease
• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis; Intestinal Diseases; Inflammatory Bowel Diseases; Crohn Disease; Anti-Inflammatory Agents; Antirheumatic Agents; Adalimumab
• Other Study ID Numbers: M06-807; 2007-006494-90 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No