Treatment Tapering in JIA With Inactive Disease (AJIBIOREM)

• ClinicalTrials.gov Identifier: NCT02840175
• Recruitment Status: Completed
• First Posted: July 21, 2016
• Last Update Posted: April 1, 2021
• Sponsor: Assistance Publique - Hôpitaux de Paris
• Information provided by (Responsible Party): Assistance Publique - Hôpitaux de Paris

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.

Condition or disease	Intervention/treatment	Phase
Juvenile Idiopathic Arthritis	Drug: etanercept; Drug: adalimumab; Drug: Abatacept; Drug: Tocilizumab	Phase 3

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 62 participants
• Allocation: Randomized
• Intervention Model: Factorial Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Treatment Tapering in Oligoarticular or Rheumatoid Factor Negative Polyarticular Juvenile Idiopathic Arthritis With Inactive Disease on Biologic Therapy
• Actual Study Start Date: May 18, 2017
• Actual Primary Completion Date: October 29, 2019
• Actual Study Completion Date: October 1, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Experimental; 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.	Drug: etanercept; will be tapered from every week to every 2 weeks for 12 weeks then to every 3 weeks for 12 weeks; Other Name: Enbrel®; Drug: adalimumab; will be tapered from every 2 weeks to every 3 weeks for 12 weeks and to every 4 weeks for 12 weeks; Other Name: Humira®; Drug: Abatacept; will be tapered from every 4 weeks to every 6 weeks for 24 weeks; Other Name: Orencia®; Drug: Tocilizumab; will be tapered from every 4 weeks to every 6 weeks for 24 weeks; Other Name: RoActemra®
Active Comparator: Control; 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.	Drug: etanercept; will be tapered from every week to every 2 weeks for 12 weeks then to every 3 weeks for 12 weeks; Other Name: Enbrel®; Drug: adalimumab; will be tapered from every 2 weeks to every 3 weeks for 12 weeks and to every 4 weeks for 12 weeks; Other Name: Humira®; Drug: Abatacept; will be tapered from every 4 weeks to every 6 weeks for 24 weeks; Other Name: Orencia®; Drug: Tocilizumab; will be tapered from every 4 weeks to every 6 weeks for 24 weeks; Other Name: RoActemra®

Outcome Measures

Primary Outcome Measures :

1. Persistence of inactive disease [ Time Frame: 24 weeks ]

   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 :

1. Adverse and serious adverse events or of special interest [ Time Frame: Weeks 12, 24, 36, 48, 60, 72 ]
2. Persistent inactive disease as defined by Wallace criteria [ Time Frame: 72 weeks ]
3. Juvenile Arthritis Disease Activity Score (JADA score) [ Time Frame: Day 0, Weeks 12, 24, 48, 72 ]
4. Biological agent concentrations [ Time Frame: Day 0, weeks 12, 24, 36, 48, 60 ]
   according to drug administration (Etanercept or Abatacept or Tocilizumab or Adalimumab)
5. Anti-drugs antibodies concentrations [ Time Frame: Day 0, weeks 12, 24, 36, 48, 60 ]
   anti-Etanercept or anti-Abatacept or anti-Tocilizumab or anti-Adalimumab
6. Proteins S100 concentrations (MRP8/14 level) [ Time Frame: Day 0, weeks 24, 48, 72 ]
7. Concentration of additional informative markers (cytokines, chemokines) [ Time Frame: Day 0, weeks 24, 48, 72 ]
8. score of quality of life with the Paediatric Quality of Life (PedsQL) [ Time Frame: Day 0, weeks 24, 36, 72 ]
9. score of quality of life with the Childhood Health Assessment Questionnaire (CHAQ) [ Time Frame: Day 0, weeks 12, 24, 36, 72 ]
10. 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 ]
11. cost of early treatment tapering and withdrawal [ Time Frame: weeks 12, 24, 36, 60, 72 ]
12. cost of late treatment tapering and withdrawal [ Time Frame: weeks 12, 24, 36, 60, 72 ]

Eligibility Criteria

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

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).

Contacts and Locations

Locations

France

Necker Children's Hospital

Paris, France, 75015

Sponsors and Collaborators

Assistance Publique - Hôpitaux de Paris

Investigators

• Study Chair: Florence UETTWILLER, PhD; Necker Children's Hospital, Paris, France

More Information

• Responsible Party: Assistance Publique - Hôpitaux de Paris
• ClinicalTrials.gov Identifier: NCT02840175
• Other Study ID Numbers: P 150902; 2016-000312-15 ( EudraCT Number )
• First Posted: July 21, 2016
• Last Update Posted: April 1, 2021
• Last Verified: March 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Assistance Publique - Hôpitaux de Paris:

Treatment tapering; Oligoarticular; Juvenile Idiopathic Arthritis; Inactive disease; Biologic therapy

Additional relevant MeSH terms:

Arthritis; Arthritis, Juvenile; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Adalimumab; Etanercept; Abatacept; Anti-Inflammatory Agents; Antirheumatic Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Gastrointestinal Agents; Immunosuppressive Agents; Immunologic Factors; Immune Checkpoint Inhibitors; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents