Back to resultsTreatment Tapering in JIA With Inactive Disease (AJIBIOREM)
Primary Purpose
Juvenile Idiopathic Arthritis
Status
Completed
Phase
Phase 3
Locations
France
Study Type
Interventional
Intervention
etanercept
adalimumab
Abatacept
Tocilizumab
Sponsored by
About this trial
This is an interventional treatment trial for Juvenile Idiopathic Arthritis focused on measuring Treatment tapering, Oligoarticular, Juvenile Idiopathic Arthritis, Inactive disease, Biologic therapy
Eligibility Criteria
Inclusion Criteria:
- Patient aged 2 to 17 years and treated with etanercept or tocilizumab or adalimumab, or patient aged 6 to 17 years and treated with abatacept.
- Patient with an oligoarticular or polyarticular rheumatoid factor negative JIA
- Patient treated with biologic treatment for persistent arthritis according to the marketing authorization.
- Patient who achieved inactive disease within two years of treatment with the last biologic agent administered, according to Wallace criteria : no joints with active arthritis, no active uveitis (as defined by the SUN Working Group), ESR or CRP level within normal limits in the laboratory where tested (or, if elevated, not attributable to JIA), physician's global assessment of disease activity score (< 10/100 visual analogue scale), and duration of morning stiffness < ou = 15 minutes (within 7 days before the visit).
- Patient with inactive disease achieved for less than 12 months.
- Patient with stable doses of non-steroidal anti-inflammatory drugs, Methotrexate (maximum 20 mg/m2/week), and other non biologic DMARD for at least one month before inclusion
- Patient without steroids or joint injection or live vaccines injection for at least one month.
- Signed informed consent by both parents (or legal guardian) and patient's agreement.
- Patient affiliated to the National Health Assurance system.
Exclusion Criteria:
- Patient with systemic form, rheumatoid factor positive, psoriatic or associated with enthesitis related JIA.
- Patient undergoing biologic therapy due to JIA-associated uveitis or with active uveitis at time of randomization.
- Patient with any contraindication to continue ongoing biologic treatment, notably ongoing uncontrolled infection, suspicion or evidence of demyelinating disease of the central nervous system.
- Patient previously treated with the same biotherapy for which dose decreasing or biotherapy withdrawal was already tested in the past for inactive disease and then reintroduced.
- Pregnancy or absence of effective contraception (including abstinence) in a pubertal patient.
- Patient suffering from tuberculosis.
- Patient with moderate to severe cardiac failure (NYHA class III / IV).
Sites / Locations
- Necker Children's Hospital
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Active Comparator
Arm Label
Experimental
Control
Arm Description
Day 0 at Weeks 24 : Increase the interval between 2 doses of the biological agent (etanercept, adalimumab, tocilizumab, abatacept) Weeks 24 at Weeks 72: Stop the biological agent if inactive disease is maintained.
Day 0 at Weeks 24: Maintain the biological agent (etanercept, adalimumab, tocilizumab, abatacept) at the same dose. Weeks 24 at Weeks 48 : Increase the interval between 2 doses of the biological agent. Weeks 48 at Weeks 72: Stop the biological agent if inactive disease is maintained.
Outcomes
Primary Outcome Measures
Persistence of inactive disease
Inactive disease is defined by the criterion of Wallace :
No joints with active arthritis,
No active uveitis as defined by the SUN Working Group2 (The Standardization of Uveitis Nomenclature (SUN) Working Group defines inactive anterior uveitis as "grade zero cells," indicating <1 cell in field sizes of 1 mm by a 1-mm slit beam),
Erythrocyte sedimentation rate (ESR) ≤ 20 mm or C-reactive protein (CRP) level ≤ 10 mg/L (or ≤ 1 mg/dl or ≤ 100 µg/dl) or, if elevated, not attributable to JIA (if both ESR and CRP are available, both of them should be in the normal range)
Physician's global assessment of disease activity score (< 10/100 visual analogue scale),
and duration of morning stiffness < or egal to 15 minutes (within 7 days before the visit).
For all the visits, joint counts and physician global assessment of disease activity will be performed by an investigator blinded from patient study group.
Secondary Outcome Measures
Adverse and serious adverse events or of special interest
Persistent inactive disease as defined by Wallace criteria
Juvenile Arthritis Disease Activity Score (JADA score)
Biological agent concentrations
according to drug administration (Etanercept or Abatacept or Tocilizumab or Adalimumab)
Anti-drugs antibodies concentrations
anti-Etanercept or anti-Abatacept or anti-Tocilizumab or anti-Adalimumab
Proteins S100 concentrations (MRP8/14 level)
Concentration of additional informative markers (cytokines, chemokines)
score of quality of life with the Paediatric Quality of Life (PedsQL)
score of quality of life with the Childhood Health Assessment Questionnaire (CHAQ)
score of quality of life with the Life Quality Questionnaire related to the health (EQ-5D Y)
cost of early treatment tapering and withdrawal
cost of late treatment tapering and withdrawal
Full Information
NCT ID
NCT02840175
First Posted
July 19, 2016
Last Updated
March 31, 2021
Sponsor
Assistance Publique - Hôpitaux de Paris
1. Study Identification
Unique Protocol Identification Number
NCT02840175
Brief Title
Treatment Tapering in JIA With Inactive Disease
Acronym
AJIBIOREM
Official Title
Treatment Tapering in Oligoarticular or Rheumatoid Factor Negative Polyarticular Juvenile Idiopathic Arthritis With Inactive Disease on Biologic Therapy
Study Type
Interventional
2. Study Status
Record Verification Date
March 2021
Overall Recruitment Status
Completed
Study Start Date
May 18, 2017 (Actual)
Primary Completion Date
October 29, 2019 (Actual)
Study Completion Date
October 1, 2020 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Assistance Publique - Hôpitaux de Paris
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
As biologic treatments are expensive and associated with some concerns regarding long-term safety, investigator hypothesize that early tapering and then withdrawal of biological agent, in an homogenous group of children with juvenile idiopathic arthritis achieving inactive disease, is safe and not inferior to the maintenance of stable treatment intensity over 24 weeks. In addition, investigator also hypothesize that an earlier tapering of treatment is associated with a better quality-of-life and a general cost saving effect. MRP8/14 will be studied as a potential biomarker for the risk of relapse. A study for biologic agent, anti-biologic agent antibodies and a pharmacogenomic approach will complete the research, as pharmacokinetic study during withdrawal of biologic treatment are rare in children.
Detailed Description
Juvenile idiopathic arthritis (JIA) is characterized by chronic arthritis of unknown etiology starting before the age of 16. There are four to five thousand paediatric patients with JIA in France. Most of these patients are diagnosed with oligoarticular or rheumatoid factor negative polyarticular JIA. The prognosis of the disease has dramatically improved thanks to the introduction of biologic agents in patients with an extended oligoarticular or rheumatoid factor negative polyarticular JIA and inadequate response to methotrexate. Inactive disease and long-lasting clinical remission are achieved in most cases. "Treat to target" approaches are increasingly recommended, with earlier introduction of biologics, however the way to taper or withdraw treatment in patients achieving inactive disease is not codified. As biologic treatments are expensive and associated with some concerns regarding long-term safety, this study aim to test, in a randomized fashion, the hypothesis that early tapering of biologic agents (i.e. increasing the intervals between injections as soon as inactive disease is documented) is safe and non-inferior to the maintenance of stable treatment intensity over 24 weeks, and therefore test the possibility of early biologic agent withdrawal. It will also study concentrations of different biological agent, the occurrence of anti-drugs antibodies while tapering and then withdrawing biologics, and their possible association with a higher risk of relapse. In addition, investigators will test if the serum level of proteins 100 (MRP8/14) could be predictive of flares. Finally, pharmaco-economic analyses and quality of life studies will be conducted.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Juvenile Idiopathic Arthritis
Keywords
Treatment tapering, Oligoarticular, Juvenile Idiopathic Arthritis, Inactive disease, Biologic therapy
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Factorial Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
62 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Experimental
Arm Type
Experimental
Arm Description
Day 0 at Weeks 24 : Increase the interval between 2 doses of the biological agent (etanercept, adalimumab, tocilizumab, abatacept)
Weeks 24 at Weeks 72: Stop the biological agent if inactive disease is maintained.
Arm Title
Control
Arm Type
Active Comparator
Arm Description
Day 0 at Weeks 24: Maintain the biological agent (etanercept, adalimumab, tocilizumab, abatacept) at the same dose.
Weeks 24 at Weeks 48 : Increase the interval between 2 doses of the biological agent.
Weeks 48 at Weeks 72: Stop the biological agent if inactive disease is maintained.
Intervention Type
Drug
Intervention Name(s)
etanercept
Other Intervention Name(s)
Enbrel®
Intervention Description
will be tapered from every week to every 2 weeks for 12 weeks then to every 3 weeks for 12 weeks
Intervention Type
Drug
Intervention Name(s)
adalimumab
Other Intervention Name(s)
Humira®
Intervention Description
will be tapered from every 2 weeks to every 3 weeks for 12 weeks and to every 4 weeks for 12 weeks
Intervention Type
Drug
Intervention Name(s)
Abatacept
Other Intervention Name(s)
Orencia®
Intervention Description
will be tapered from every 4 weeks to every 6 weeks for 24 weeks
Intervention Type
Drug
Intervention Name(s)
Tocilizumab
Other Intervention Name(s)
RoActemra®
Intervention Description
will be tapered from every 4 weeks to every 6 weeks for 24 weeks
Primary Outcome Measure Information:
Title
Persistence of inactive disease
Description
Inactive disease is defined by the criterion of Wallace :
No joints with active arthritis,
No active uveitis as defined by the SUN Working Group2 (The Standardization of Uveitis Nomenclature (SUN) Working Group defines inactive anterior uveitis as "grade zero cells," indicating <1 cell in field sizes of 1 mm by a 1-mm slit beam),
Erythrocyte sedimentation rate (ESR) ≤ 20 mm or C-reactive protein (CRP) level ≤ 10 mg/L (or ≤ 1 mg/dl or ≤ 100 µg/dl) or, if elevated, not attributable to JIA (if both ESR and CRP are available, both of them should be in the normal range)
Physician's global assessment of disease activity score (< 10/100 visual analogue scale),
and duration of morning stiffness < or egal to 15 minutes (within 7 days before the visit).
For all the visits, joint counts and physician global assessment of disease activity will be performed by an investigator blinded from patient study group.
Time Frame
24 weeks
Secondary Outcome Measure Information:
Title
Adverse and serious adverse events or of special interest
Time Frame
Weeks 12, 24, 36, 48, 60, 72
Title
Persistent inactive disease as defined by Wallace criteria
Time Frame
72 weeks
Title
Juvenile Arthritis Disease Activity Score (JADA score)
Time Frame
Day 0, Weeks 12, 24, 48, 72
Title
Biological agent concentrations
Description
according to drug administration (Etanercept or Abatacept or Tocilizumab or Adalimumab)
Time Frame
Day 0, weeks 12, 24, 36, 48, 60
Title
Anti-drugs antibodies concentrations
Description
anti-Etanercept or anti-Abatacept or anti-Tocilizumab or anti-Adalimumab
Time Frame
Day 0, weeks 12, 24, 36, 48, 60
Title
Proteins S100 concentrations (MRP8/14 level)
Time Frame
Day 0, weeks 24, 48, 72
Title
Concentration of additional informative markers (cytokines, chemokines)
Time Frame
Day 0, weeks 24, 48, 72
Title
score of quality of life with the Paediatric Quality of Life (PedsQL)
Time Frame
Day 0, weeks 24, 36, 72
Title
score of quality of life with the Childhood Health Assessment Questionnaire (CHAQ)
Time Frame
Day 0, weeks 12, 24, 36, 72
Title
score of quality of life with the Life Quality Questionnaire related to the health (EQ-5D Y)
Time Frame
Day 0, weeks 24, 36, 72
Title
cost of early treatment tapering and withdrawal
Time Frame
weeks 12, 24, 36, 60, 72
Title
cost of late treatment tapering and withdrawal
Time Frame
weeks 12, 24, 36, 60, 72
10. Eligibility
Sex
All
Minimum Age & Unit of Time
2 Years
Maximum Age & Unit of Time
17 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Patient aged 2 to 17 years and treated with etanercept or tocilizumab or adalimumab, or patient aged 6 to 17 years and treated with abatacept.
Patient with an oligoarticular or polyarticular rheumatoid factor negative JIA
Patient treated with biologic treatment for persistent arthritis according to the marketing authorization.
Patient who achieved inactive disease within two years of treatment with the last biologic agent administered, according to Wallace criteria : no joints with active arthritis, no active uveitis (as defined by the SUN Working Group), ESR or CRP level within normal limits in the laboratory where tested (or, if elevated, not attributable to JIA), physician's global assessment of disease activity score (< 10/100 visual analogue scale), and duration of morning stiffness < ou = 15 minutes (within 7 days before the visit).
Patient with inactive disease achieved for less than 12 months.
Patient with stable doses of non-steroidal anti-inflammatory drugs, Methotrexate (maximum 20 mg/m2/week), and other non biologic DMARD for at least one month before inclusion
Patient without steroids or joint injection or live vaccines injection for at least one month.
Signed informed consent by both parents (or legal guardian) and patient's agreement.
Patient affiliated to the National Health Assurance system.
Exclusion Criteria:
Patient with systemic form, rheumatoid factor positive, psoriatic or associated with enthesitis related JIA.
Patient undergoing biologic therapy due to JIA-associated uveitis or with active uveitis at time of randomization.
Patient with any contraindication to continue ongoing biologic treatment, notably ongoing uncontrolled infection, suspicion or evidence of demyelinating disease of the central nervous system.
Patient previously treated with the same biotherapy for which dose decreasing or biotherapy withdrawal was already tested in the past for inactive disease and then reintroduced.
Pregnancy or absence of effective contraception (including abstinence) in a pubertal patient.
Patient suffering from tuberculosis.
Patient with moderate to severe cardiac failure (NYHA class III / IV).
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Florence UETTWILLER, PhD
Organizational Affiliation
Necker Children's Hospital, Paris, France
Official's Role
Study Chair
Facility Information:
Facility Name
Necker Children's Hospital
City
Paris
ZIP/Postal Code
75015
Country
France
12. IPD Sharing Statement
Plan to Share IPD
No
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Treatment Tapering in JIA With Inactive Disease
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