Safety and Efficacy of Etanercept (Recombinant Human Tumor Necrosis Factor Receptor Fusion Protein [TNFR:Fc]) in Children With Juvenile Rheumatoid Arthritis (JRA)

Safety, Population Pharmacokinetics, and Efficacy of Recombinant Human Tumor Necrosis Factor Receptor Fusion Protein (TNFR:Fc) in Children With Juvenile Rheumatoid Arthritis

The primary objective of this study was to determine the efficacy of etanercept in children with polyarticular course JRA.

Study Overview

• Status: Completed
• Conditions: Juvenile Rheumatoid Arthritis
• Intervention / Treatment: Drug: Etanercept; Drug: Placebo

Detailed Description

This was a two-part study. In the first part of the study, all participants received open-label etanercept twice a week for 90 days. At the end of the 90 days, participants with disease response as defined by the JRA Definition of Improvement (DOI) using the JRA Core Set Criteria were randomized in part 2 of the study to receive placebo or continued administration of etanercept until either disease flare occurred or 4 months elapsed, whichever was earlier.

Participants who did not meet the DOI at day 90, participants who had disease flare during part 2 and participants who completed the blinded part of the study were eligible to receive open-label treatment with etanercept under protocol 16.0018 (NCT00357903).

• Study Type: Interventional
• Enrollment (Actual): 69
• Phase: Phase 2; Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 years to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosis of JRA by the American College of Rheumatology (ACR) criteria.
• Disease course must be polyarticular with disease duration long enough to have been given an adequate trial of non-steroidal anti-inflammatory drugs (NSAIDs) and low-dose methotrexate at a dose of at least 10 mg/m²/week
• Continuing active disease, defined as ≥ 5 swollen joints and ≥ 3 joints with limitation of motion accompanied by pain, tenderness or warmth.
• Disease refractory to methotrexate or intolerant of methotrexate.
• Have not received disease-modifying anti-rheumatic drugs (DMARDs) within 28 days prior to enrollment.
• Have not received methotrexate within 14 days prior to dosing of study drug.

Exclusion Criteria:

• Pregnant or nursing female
• Functional class IV by ACR criteria
• Unable to meet concomitant medication restrictions
• Intraarticular corticosteroid injection within 4 weeks prior to enrollment

• Clinically significant deviations from normal, defined as:

  • thrombocytopenia; platelet count < 100,000/cmm
  • leukopenia; total white cell count < 4000 cells/cmm
  • neutropenia; neutrophils < 1000 cells/cmm
  • hepatic transaminase levels > two times the upper limit of normal (ULN)
  • serum bilirubin > 2 times ULN
  • creatinine clearance < 90 mL/min/1.73 m² body surface area (BSA) and/or a glomerular filtration rate (GFR) < 90 mL/min/1.73 m² BSA.
  • known human immunodeficiency virus (HIV), hepatitis B surface antigen positivity, or hepatitis C positivity.
  • anti-double-stranded deoxyribonucleic acid (dsDNA) antibodies or anti-cardiolipin antibodies present.
• Previously received antibody to TNF, antibody to cluster of differentiation (CD)4, or diphtheria interleukin (IL)-2-fusion protein (DAB-IL-2)
• Participated in a study of an investigational drug or biologic requiring informed consent within 3 months prior to study entry.
• Any concurrent medical condition which would, in the investigator's opinion, compromise the patient's ability to tolerate the study drug or make the patient unable to cooperate with the protocol.
• History of or current psychiatric illness that would interfere with ability to comply with protocol requirements or informed consent.
• History or drug or alcohol abuse that would interfere with ability to comply with protocol requirements

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Etanercept/Placebo; Participants received 0.4 mg/kg etanercept twice weekly for 90 days during Part 1. In Part 2 participants were randomized to receive placebo subcutaneous injection twice weekly for up to 4 months.	Drug: Etanercept; Administered twice weekly by subcutaneous injection; Other Names: Enbrel; TNFR:Fc; Drug: Placebo; Administered twice weekly by subcutaneous injection
Experimental: Etanercept/Etanercept; Participants received 0.4 mg/kg etanercept twice weekly for 90 days during Part 1. In Part 2 participants were randomized to continue receiving etanercept twice weekly for up to 4 additional months.	Drug: Etanercept; Administered twice weekly by subcutaneous injection; Other Names: Enbrel; TNFR:Fc

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Disease Flare in Part 2	Disease flare was defined as a 30% or greater worsening in three of the six JRA Core Set Criteria and ≥ 30% improvement in one or less of the six JRA Core Set Criteria compared to day 90 and a minimum of two active joints (joints with swelling or limitation of movement plus pain and/or tenderness). The JRA Core Set criteria consisted of: Physician global assessment of disease severity assessed on a visual analog scale (VAS) from 0 (asymptomatic) to 10 (severe symptoms);; Patient/parent global assessment of overall well-being assesses on a VAS from 0 (asymptomatic) to 10 (severe symptoms);; Number of active joints;; Number of joints with limitation of motion (LOM) and with pain, tenderness, or both;; Childhood Health Assessment Questionnaire (CHAQ) disability domain;; Erythrocyte sedimentation rate (ESR).	End of part 1 (day 90) and months 4 to 7

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Flare in Part 2	The time from day 90 to flare. Participants who withdrew without flare were censored at the time of withdrawal.	Months 4 to 7
Number of Participants With Adverse Events		Part 1: 90 days (months 1-3) plus 30 days for participants who were not randomized into part 2. Part 2: From first dose of randomized treatment to 30 days after last dose (150 days; months 4-8).

Collaborators and Investigators

• Sponsor: Amgen

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 1997
• Primary Completion (Actual): July 8, 1998
• Study Completion (Actual): July 8, 1998

Study Registration Dates

• First Submitted: December 18, 2018
• First Submitted That Met QC Criteria: December 18, 2018
• First Posted (Actual): December 19, 2018

Study Record Updates

• Last Update Posted (Actual): August 2, 2019
• Last Update Submitted That Met QC Criteria: June 10, 2019
• Last Verified: June 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid; Necrosis; Arthritis, Juvenile; Physiological Effects of Drugs; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Immunosuppressive Agents; Immunologic Factors; Gastrointestinal Agents; Etanercept
• Other Study ID Numbers: 20021616; 016.0016 (Other Identifier: Immunex Corporation)

Drug and device information, study documents

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