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

• Sponsor: Amgen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03780959
• Collaborator: (none)
• Enrollment: 69
• Arms: 2
• Actual Duration (Months): 14.2

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Juvenile Rheumatoid Arthritis	Drug: Etanercept; Drug: Placebo	Phase 2/Phase 3

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 Design

• Study Type: Interventional
• Actual Enrollment: 69 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Safety, Population Pharmacokinetics, and Efficacy of Recombinant Human Tumor Necrosis Factor Receptor Fusion Protein (TNFR:Fc) in Children With Juvenile Rheumatoid Arthritis
• Actual Study Start Date: May 1, 1997
• Actual Primary Completion Date: Jul 8, 1998
• Actual Study Completion Date: Jul 8, 1998

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Disease Flare in Part 2 [End of part 1 (day 90) and months 4 to 7]

   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).

Secondary Outcome Measures

1. Time to Flare in Part 2 [Months 4 to 7]

   The time from day 90 to flare. Participants who withdrew without flare were censored at the time of withdrawal.

2. 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).]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 4 Years to 18 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Amgen

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT03780959
• Other Study ID Numbers: 20021616; 016.0016
• First Posted: Dec 19, 2018
• Last Update Posted: Aug 2, 2019
• Last Verified: Jun 1, 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Arthritis; Arthritis, Rheumatoid; Arthritis, Juvenile; Necrosis; Etanercept

Study Results

Participant Flow

Recruitment Details	Participants were enrolled at 9 sites in the United States and Canada. The study consisted of an open-label treatment period (part 1) where all participants received 0.4 mg etanercept twice weekly for 3 months, followed by a randomized double-blind treatment period (part 2).
Pre-assignment Detail	At the end of part 1 participants with disease response were randomized to part 2, with stratification according to study center and number of active joints (≤ 2 vs. > 2) at the end of month 3.

Arm/Group Title	Part 1: Etanercept 0.4 mg/kg	Part 2: Placebo	Part 2: Etanercept 0.4 mg/kg
Arm/Group Description	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.	In Part 2 participants were randomized to continue receiving 0.4 mg/kg etanercept twice weekly for up to 4 additional months.
Period Title: Part 1
STARTED	69	0	0
COMPLETED	64	0	0
NOT COMPLETED	5	0	0
Period Title: Part 1
STARTED	0	26	25
COMPLETED	0	7	19
NOT COMPLETED	0	19	6

Baseline Characteristics

Arm/Group Title	Part 1: Etanercept 0.4 mg/kg	Part 2: Placebo	Part 2: Etanercept 0.4 mg/kg	Total
Arm/Group Description	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.	In Part 2 participants were randomized to continue receiving 0.4 mg/kg etanercept twice weekly for up to 4 additional months.	Total of all reporting groups
Overall Participants	69	26	25	120
Age (years) [Mean (Standard Deviation) ]
Part 1	10.5 (3.9)	10.5 (3.9)
Part 2	12.2 (3.5)	8.9 (3.7)	10.6 (3.9)
Age, Customized (Count of Participants)
4 - 8 years	25 36.2%	25 96.2%
9 - 12 years	14 20.3%	14 53.8%
13 - 17 years	30 43.5%	30 115.4%
4 - 8 years	5 7.2%	13 50%	18 72%
9 - 12 years	4 5.8%	5 19.2%	9 36%
13 - 17 years	17 24.6%	7 26.9%	24 96%
Sex: Female, Male (Count of Participants)
Female	43 62.3%	43 165.4%
Male	26 37.7%	26 100%
Female	15 21.7%	19 73.1%	34 136%
Male	11 15.9%	6 23.1%	17 68%
Race/Ethnicity, Customized (Count of Participants)
Black	6 8.7%	6 23.1%
White	52 75.4%	52 200%
Asian	1 1.4%	1 3.8%
Hispanic	9 13%	9 34.6%
Native American	1 1.4%	1 3.8%
Black	1 1.4%	3 11.5%	4 16%
White	23 33.3%	14 53.8%	37 148%
Asian	0 0%	1 3.8%	1 4%
Hispanic	2 2.9%	6 23.1%	8 32%
Native American	0 0%	1 3.8%	1 4%
Type of Onset of Juvenile Rheumatoid Arthritis (JRA) (Count of Participants)
Pauciarticular	7 10.1%	7 26.9%
Polyarticular	40 58%	40 153.8%
Systemic	22 31.9%	22 84.6%
Pauciarticular	1 1.4%	2 7.7%	3 12%
Polyarticular	17 24.6%	14 53.8%	31 124%
Systemic	8 11.6%	9 34.6%	17 68%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Disease Flare in Part 2
Description	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).
Time Frame	End of part 1 (day 90) and months 4 to 7

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	Part 2: Placebo	Part 2: Etanercept 0.4 mg/kg
Arm/Group Description	In Part 2 participants were randomized to receive placebo subcutaneous injection twice weekly for up to 4 months.	In Part 2 participants were randomized to continue receiving 0.4 mg/kg etanercept twice weekly for up to 4 additional months.
Measure Participants	26	25
Number [percentage of participants]	81 117.4%	28 107.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part 2: Placebo, Part 2: Etanercept 0.4 mg/kg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0030
	Comments
	Method	Mantel Haenszel
	Comments	Stratified by study center and the number of active joints at randomization

2. Secondary Outcome

Title	Time to Flare in Part 2
Description	The time from day 90 to flare. Participants who withdrew without flare were censored at the time of withdrawal.
Time Frame	Months 4 to 7

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	Part 2: Placebo	Part 2: Etanercept 0.4 mg/kg
Arm/Group Description	In Part 2 participants were randomized to receive placebo subcutaneous injection twice weekly for up to 4 months.	In Part 2 participants were randomized to continue receiving 0.4 mg/kg etanercept twice weekly for up to 4 additional months.
Measure Participants	26	25
Median (Full Range) [days]	28.0	116.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part 2: Placebo, Part 2: Etanercept 0.4 mg/kg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0001
	Comments
	Method	Log Rank
	Comments

3. Secondary Outcome

Title	Number of Participants With Adverse Events
Time Frame	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).

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study drug

Arm/Group Title	Part 1: Etanercept 0.4 mg/kg	Part 2: Placebo	Part 2: Etanercept 0.4 mg/kg
Arm/Group Description	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.	In Part 2 participants were randomized to continue receiving 0.4 mg/kg etanercept twice weekly for up to 4 additional months.
Measure Participants	69	26	25
Noninfectious adverse events	51 73.9%	9 34.6%	13 52%
Injection site reactions	27 39.1%	1 3.8%	1 4%
Infections	43 62.3%	8 30.8%	15 60%
Serious adverse events	1 1.4%	0 0%	1 4%
Deaths	0 0%	0 0%	0 0%

Adverse Events

Time Frame	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).
Adverse Event Reporting Description	Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
Arm/Group Title	Part 1: Etanercept 0.4 mg/kg		Part 2: Placebo		Part 2: Etanercept 0.4 mg/kg
Arm/Group Description	Participants received 0.4 mg/kg etanercept twice weekly for 90 days during Part 1.		n Part 2 participants were randomized to receive placebo subcutaneous injection twice weekly for up to 4 months.		In Part 2 participants were randomized to continue receiving 0.4 mg/kg etanercept twice weekly for up to 4 additional months.
All Cause Mortality
	Part 1: Etanercept 0.4 mg/kg		Part 2: Placebo		Part 2: Etanercept 0.4 mg/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Part 1: Etanercept 0.4 mg/kg		Part 2: Placebo		Part 2: Etanercept 0.4 mg/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/69 (1.4%)		0/26 (0%)		1/25 (4%)
Infections and infestations
Gastroenteritis	1/69 (1.4%)		0/26 (0%)		0/25 (0%)
Psychiatric disorders
Abnormal behaviour	0/69 (0%)		0/26 (0%)		1/25 (4%)
Other (Not Including Serious) Adverse Events
	Part 1: Etanercept 0.4 mg/kg		Part 2: Placebo		Part 2: Etanercept 0.4 mg/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	59/69 (85.5%)		12/26 (46.2%)		19/25 (76%)
Gastrointestinal disorders
Abdominal pain upper	7/69 (10.1%)		1/26 (3.8%)		1/25 (4%)
Diarrhoea	4/69 (5.8%)		0/26 (0%)		2/25 (8%)
Nausea	7/69 (10.1%)		0/26 (0%)		2/25 (8%)
Vomiting	10/69 (14.5%)		0/26 (0%)		3/25 (12%)
General disorders
Fatigue	4/69 (5.8%)		1/26 (3.8%)		1/25 (4%)
Injection site erythema	23/69 (33.3%)		1/26 (3.8%)		0/25 (0%)
Injection site pain	10/69 (14.5%)		1/26 (3.8%)		0/25 (0%)
Injection site pruritus	13/69 (18.8%)		1/26 (3.8%)		0/25 (0%)
Injection site swelling	13/69 (18.8%)		1/26 (3.8%)		1/25 (4%)
Pyrexia	2/69 (2.9%)		0/26 (0%)		2/25 (8%)
Infections and infestations
Ear infection	6/69 (8.7%)		2/26 (7.7%)		1/25 (4%)
Gastroenteritis	5/69 (7.2%)		1/26 (3.8%)		3/25 (12%)
Influenza	2/69 (2.9%)		2/26 (7.7%)		2/25 (8%)
Pharyngitis	10/69 (14.5%)		0/26 (0%)		3/25 (12%)
Tinea pedis	0/69 (0%)		0/26 (0%)		2/25 (8%)
Upper respiratory tract infection	24/69 (34.8%)		4/26 (15.4%)		10/25 (40%)
Nervous system disorders
Headache	14/69 (20.3%)		3/26 (11.5%)		5/25 (20%)
Respiratory, thoracic and mediastinal disorders
Cough	4/69 (5.8%)		1/26 (3.8%)		1/25 (4%)
Nasal congestion	8/69 (11.6%)		1/26 (3.8%)		2/25 (8%)
Oropharyngeal pain	4/69 (5.8%)		0/26 (0%)		2/25 (8%)
Rhinorrhoea	4/69 (5.8%)		0/26 (0%)		3/25 (12%)
Skin and subcutaneous tissue disorders
Rash	5/69 (7.2%)		2/26 (7.7%)		0/25 (0%)
Vasculitic rash	0/69 (0%)		2/26 (7.7%)		1/25 (4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to1 review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.