Trial of Early Aggressive Drug Therapy in Juvenile Idiopathic Arthritis

• Sponsor: Seattle Children's Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT00443430
• Collaborator: National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) (NIH), Amgen (Industry)
• Enrollment: 85
• Locations: 15
• Arms: 2
• Duration (Months): 41
• Patients Per Site: 5.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to compare two aggressive drug regimens for children with poly-juvenile idiopathic arthritis (JIA) and extended oligo JIA.

Condition or Disease	Intervention/Treatment	Phase
Juvenile Chronic Polyarthritis; Juvenile Idiopathic Arthritis; Juvenile Rheumatoid Arthritis	Drug: methotrexate; Drug: methotrexate - etanercept - prednisolone arm	Phase 4

Detailed Description

JIA is a type of arthritis with no definite cause and an onset prior to 16 years of age. JIA causes joint destruction, pain, and permanent disability. There are multiple types of JIA; collectively, they represent one of the most common chronic diseases in children and the most prevalent pediatric rheumatic illness. Poly-JIA, one type of JIA, affects at least five joints in the body within the first 6 months of disease. Long-term remission of poly-JIA is uncommon, and most children must remain on multiple combinations of medications for many years. The usual treatment for poly-JIA is based upon the gradual addition of medications that might be more effective in treating this disease. There is a need to find uniformly effective treatments for children with poly-JIA. Based on previous adult arthritis studies, there appears to be an early window of opportunity in the disease progression during which aggressive therapy has a profound beneficial long-term effect. The purpose of this study is to compare the effectiveness of two aggressive drug regimens in treating children with poly-JIA. Specifically, the study will determine whether aggressive therapy started in the first 6 months of disease onset can result in inactive disease and clinical remission while on these medications.

All participants will receive weekly methotrexate shots while in the study. In addition, participants will be randomly assigned to one of two groups:

• Group 1 participants will receive placebo etanercept shots for up to 12 months and daily placebo prednisolone liquid for 4 months.

• Group 2 participants will receive etanercept shots for up to 12 months and daily prednisolone liquid for 4 months.

The study will last up to 12 months and include two parts. Part A will last 1 to 6 months, depending on response to assigned treatments. If participants are still experiencing active arthritis at 6 months, they will be offered open-label treatment with etanercept and prednisolone. If participants experience inactive disease any time prior to 6 months, they will enter Part B of the study. During Part B, which will last up to 6 months, participants will remain on the same treatment regimen that they were provided in Part A. If participants experience inactive disease followed by a flare of disease any time during the study, they will stop participating.

During the study, there will be 11 study visits for all participants. Study visits will include a physical exam, including joint evaluations; blood and urine collection; and questionnaires regarding function, quality of life, medication compliance, other medications used, infections, and adverse symptoms.

Blood will be collected for translational studies.

Study Design

• Study Type: Interventional
• Actual Enrollment: 85 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Trial of Early Aggressive Therapy in Juvenile Idiopathic Arthritis (TREAT in JIA)
• Study Start Date: May 1, 2007
• Actual Primary Completion Date: Oct 1, 2010
• Actual Study Completion Date: Oct 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Methotrexate Arm Methotrexate 0.5 mg/kg given by subcutaneous injection once per week, plus placebo etanercept and placebo prednisolone	Drug: methotrexate; Methotrexate 0.5 mg/kg given by sub cutaneous injection once per week, plus placebo etanercept and and placebo prednisolone; Other Names: placebo enbrel placebo prednisolone
Active Comparator: Methotrexate-Etanercept-Prednisolone Arm Methotrexate 0.5 mg/kg given by subcutaneous injection once per week, plus etanercept 0.8 mg/kg given by subcutaneous injection once per week, plus prednisolone by mouth daily with decreasing dose tapered over 16 weeks	Drug: methotrexate - etanercept - prednisolone arm; methotrexate 0.5 mg/kg given by sub cutaneous injection once per week, plus etanercept 0.8 mg/kg given by sub cutaneous injection once per week, plus prednisolone, by mouth daily with decreasing dose tapered over 16 weeks.; Other Names: enbrel prednisone

Outcome Measures

Primary Outcome Measures

1. Proportion of Participants Who Attain Inactive Disease by 6 Months [6 months after initiation of study intervention]

Secondary Outcome Measures

1. Safety Profiles, Including the Number of Treatment-emergent, Serious, or Unexpected Adverse Events and Other Important Medical Events [Over 12 months maximum study participation per subject]

2. Clinical Remission on Medication [12 months or end of study]

   6 months of clinical inactive disease

Eligibility Criteria

Criteria

• Ages Eligible for Study: 2 Years to 17 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Diagnosis of active poly-JIA as determined by International League of Associations for Rheumatology (ILAR) criteria

• Onset of signs and symptoms of poly-JIA for 12 months or less prior to study screening

• Willing to use acceptable forms of contraception for the duration of the study and for 3 months after the study

• Parent or guardian willing to provide informed consent

• Able to attend all study visits

Exclusion Criteria:

• Received or currently receiving disease-modifying antirheumatic drugs (DMARDs), biologic, or prednisone for any duration for treatment of poly-JIA, with the following exceptions:

1. Methotrexate duration must be less than or equal to 6 weeks at a dose of less than or equal to 0.5 mg/kg/week (40 mg max),

2. Steroid use has been less than or equal to 4 weeks and the subject is off of steroids for at least 1 week prior to enrollment

• Received intramuscular or soft-tissue injections of corticosteroids for treatment of poly-JIA before receiving the first dose of study medication. Up to 2 joint injections with intra-articular steroids (IAS) will be allowed up to 7 days after the baseline visit.

• History of or active cancer of any type

• Active gastrointestinal disease (e.g., inflammatory bowel disease)

• Chronic or acute kidney or liver disorder

• Significant blood clotting defect

• AST (SGOT), ALT (SGPT), or BUN levels more than two times the upper level of normal, creatinine levels more than 1.5 mg/dl, or any other laboratory abnormality considered to be clinically significant within 28 days prior to baseline

• Chronic condition (e.g., diabetes, epilepsy) that is either not stable or poorly controlled and may interfere with study participation

• Received any investigational medication within 30 days prior to the first dose of study medication or scheduled to receive an investigational drug (other than the study medications) during the course of the study

• Chronic or active infection or any major episode of infection requiring hospitalization or treatment with intravenous antibiotics within 30 days prior to study screening

• HIV infected

• Known past or current hepatitis infection

• Received a live virus vaccine within 1 month prior to baseline

• Purified protein derivative (PPD) positive (positive tuberculosis [TB] test)

• Pregnancy

• Any medical condition that would make study participation difficult or inadvisable in the opinion of the investigator

• History of or current psychiatric illness that would interfere with study participation

• History of alcohol or drug abuse within the 6 months prior to study entry that would interfere with study participation

• Inability to comply with study requirements for any reason

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Stanford University Medical Center	Palo Alto	California	United States	94305
2	Rady Children's Hospital	San Diego	California	United States	92123-4282
3	University of California San Francisco Medical Center	San Francisco	California	United States	94143
4	Children's Hospital of Boston	Boston	Massachusetts	United States	02115
5	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
6	Children's Hospital at Montefiore	Bronx	New York	United States	10467
7	Schneider Children's Hospital	New Hyde Park	New York	United States	11040
8	Duke University	Durham	North Carolina	United States	27710
9	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229-3039
10	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
11	Children's Hospital of Columbus	Columbus	Ohio	United States	43205
12	Oklahoma University Health Science Center	Oklahoma City	Oklahoma	United States	73104
13	Texas Scottish Rite Hospital	Dallas	Texas	United States	75219
14	University of Utah	Salt Lake City	Utah	United States	84132
15	Seattle Children's Hospital and Regional Medical Center	Seattle	Washington	United States	98105

Sponsors and Collaborators

• Seattle Children's Hospital
• National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
• Amgen

Investigators

• Principal Investigator: Carol A. Wallace, MD, Childrens Hospital and Regional Medical Center

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Click here for the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Web site

Publications

• Lovell DJ, Reiff A, Jones OY, Schneider R, Nocton J, Stein LD, Gedalia A, Ilowite NT, Wallace CA, Whitmore JB, White B, Giannini EH; Pediatric Rheumatology Collaborative Study Group. Long-term safety and efficacy of etanercept in children with polyarticular-course juvenile rheumatoid arthritis. Arthritis Rheum. 2006 Jun;54(6):1987-94.
• Wallace CA, Ruperto N, Giannini E; Childhood Arthritis and Rheumatology Research Alliance; Pediatric Rheumatology International Trials Organization; Pediatric Rheumatology Collaborative Study Group. Preliminary criteria for clinical remission for select categories of juvenile idiopathic arthritis. J Rheumatol. 2004 Nov;31(11):2290-4.
• Wallace CA. Current management of juvenile idiopathic arthritis. Best Pract Res Clin Rheumatol. 2006 Apr;20(2):279-300. Review.

• Responsible Party: Carol Wallace, Principal Investigator, Seattle Children's Hospital
• ClinicalTrials.gov Identifier: NCT00443430
• Other Study ID Numbers: R01AR049762; 5R01AR049762-02
• First Posted: Mar 6, 2007
• Last Update Posted: May 31, 2013
• Last Verified: May 1, 2013

• Keywords provided by Carol Wallace, Principal Investigator, Seattle Children's Hospital: Childhood Arthritis; Juvenile Arthritis; Juvenile Arthritis Treatment; Childhood Arthritis Drug Treatment; Juvenile Arthritis Remission; Inactive Disease in Juvenile Arthritis; Childhood Polyarthritis; Extended Oligoarthritis
• Additional relevant MeSH terms: Arthritis; Arthritis, Juvenile; Prednisone; Prednisolone; Methylprednisolone Acetate; Methylprednisolone; Methylprednisolone Hemisuccinate; Prednisolone acetate; Etanercept; Methotrexate; Prednisolone hemisuccinate; Prednisolone phosphate

Study Results

Participant Flow

Recruitment Details	85 children with poly JIA within 12 months of onset recruited from pediatric rheumatology clinics at 15 sites
Pre-assignment Detail	Eligible patients were permitted to have received up to 2 intra-articular corticosteroid injections before or up to 2 weeks after baseline; and oral prednisolone for up to 4 weeks, but must have been off corticosteroids for at least 1 week prior to enrollment. Patients with past or current JIA-associated uveitis were excluded.

Arm/Group Title	Methotrexate Arm	Methotrexate-Prednisolone-Etanercept Arm
Arm/Group Description	Methotrexate 0.5 mg/kg given by subcutaneous injection once per week, plus placebo etanercept and placebo prednisolone	Methotrexate 0.5 mg/kg given by subcutaneous injection once per week, plus etanercept 0.8 mg/kg given by subcutaneous injection once per week, plus prednisolone by mouth daily with decreasing dose tapered over 16 weeks
Period Title: Overall Study
STARTED	43	42
COMPLETED	39	38
NOT COMPLETED	4	4

Baseline Characteristics

Arm/Group Title	Methotrexate Arm	Methotrexate-Prednisolone-Etanercept Arm	Total
Arm/Group Description	Methotrexate 0.5 mg/kg given by subcutaneous injection once per week, plus placebo etanercept and placebo prednisolone	Methotrexate 0.5 mg/kg given by subcutaneous injection once per week, plus etanercept 0.8 mg/kg given by subcutaneous injection once per week, plus prednisolone by mouth daily with decreasing dose tapered over 16 weeks	Total of all reporting groups
Overall Participants	43	42	85
Age (Count of Participants)
<=18 years	43 100%	42 100%	85 100%
Between 18 and 65 years	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	11.1 (4.1)	9.9 (4.6)	10.5 (4.3)
Sex: Female, Male (Count of Participants)
Female	34 79.1%	29 69%	63 74.1%
Male	9 20.9%	13 31%	22 25.9%
Region of Enrollment (participants) [Number]
United States	43 100%	42 100%	85 100%

Outcome Measures

1. Primary Outcome

Title	Proportion of Participants Who Attain Inactive Disease by 6 Months
Time Frame	6 months after initiation of study intervention

Outcome Measure Data

Analysis Population Description

all participants receiving study medications

Arm/Group Title	Methotrexate Arm	Methotrexate-Prednisolone-Etanercept Arm
Arm/Group Description	Methotrexate 0.5 mg/kg given by subcutaneous injection once per week, plus placebo etanercept and placebo prednisolone	Methotrexate 0.5 mg/kg given by subcutaneous injection once per week, plus etanercept 0.8 mg/kg given by subcutaneous injection once per week, plus prednisolone by mouth daily with decreasing dose tapered over 16 weeks
Measure Participants	43	42
Number [participants]	10 23.3%	17 40.5%

2. Secondary Outcome

Title	Safety Profiles, Including the Number of Treatment-emergent, Serious, or Unexpected Adverse Events and Other Important Medical Events
Time Frame	Over 12 months maximum study participation per subject

Outcome Measure Data

Analysis Population Description

all participants that received study medications

Arm/Group Title	Methotrexate Arm	Methotrexate-Prednisolone-Etanercept Arm
Arm/Group Description	Methotrexate 0.5 mg/kg given by subcutaneous injection once per week, plus placebo etanercept and placebo prednisolone	Methotrexate 0.5 mg/kg given by subcutaneous injection once per week, plus etanercept 0.8 mg/kg given by subcutaneous injection once per week, plus prednisolone by mouth daily with decreasing dose tapered over 16 weeks
Measure Participants	43	42
Number [events]	1	2

3. Secondary Outcome

Title	Clinical Remission on Medication
Description	6 months of clinical inactive disease
Time Frame	12 months or end of study

Outcome Measure Data

Analysis Population Description

all participants receiving study medications

Arm/Group Title	Methotrexate Arm	Methotrexate-Prednisolone-Etanercept Arm
Arm/Group Description	Methotrexate 0.5 mg/kg given by subcutaneous injection once per week, plus placebo etanercept and placebo prednisolone	Methotrexate 0.5 mg/kg given by subcutaneous injection once per week, plus etanercept 0.8 mg/kg given by subcutaneous injection once per week, plus prednisolone by mouth daily with decreasing dose tapered over 16 weeks
Measure Participants	43	42
Number [participants]	3 7%	9 21.4%

Adverse Events

Arm/Group Title	Methotrexate Arm		Methotrexate-Prednisolone-Etanercept Arm
Arm/Group Description	Methotrexate 0.5 mg/kg given by subcutaneous injection once per week, plus placebo etanercept and placebo prednisolone		Methotrexate 0.5 mg/kg given by subcutaneous injection once per week, plus etanercept 0.8 mg/kg given by subcutaneous injection once per week, plus prednisolone by mouth daily with decreasing dose tapered over 16 weeks
All Cause Mortality
	Methotrexate Arm		Methotrexate-Prednisolone-Etanercept Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Methotrexate Arm		Methotrexate-Prednisolone-Etanercept Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/43 (2.3%)		2/42 (4.8%)
Infections and infestations
pneumonia	0/43 (0%)	0	1/42 (2.4%)	1
septic hip	0/43 (0%)	0	1/42 (2.4%)	1
Psychiatric disorders
psychosis	1/43 (2.3%)	1	0/42 (0%)	0
Other (Not Including Serious) Adverse Events
	Methotrexate Arm		Methotrexate-Prednisolone-Etanercept Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/43 (0%)		3/42 (7.1%)
Hepatobiliary disorders
liver function test elevation	0/43 (0%)	0	3/42 (7.1%)	3

Limitations/Caveats

small number of participants with recent onset poly JIA

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.