Anti-Biopharmaceutical Immunization: Prediction and Analysis of Clinical Relevance to Minimize the Risk of Immunization in Rheumatoid Arthritis Patients or Juvenile Idiopathic Arthritis Patients (ABI-RA)

Multi-center Prospective European Cohort Study in Patients With Rheumatoid Arthritis or Juvenile Idiopathic Arthritis Planned to be Treated Independently of the Present Study, With the First Line of Adalimumab, Etanercept, Infliximab Therapy or With Rituximab or Tocilizumab (After Anti-Tumor Necrosis Factor Therapy or Another Biotherapy or in First Line)

One of the main potential causes of these failures of BP therapy response is the development of Anti-drug Anti-body (ADAb) in some patients. ADAb may decrease the efficacy of BPs by neutralizing them or modifying their clearance and they may be associated with BP-specific hypersensitivity reactions. The prediction, prevention and cure of anti-drug (AD) immunization are thus major goals in BP development. This prospective study (ABI-RA) will assess the occurrence of ADAb using standardized and validated assay(s) and also cellular, genetic and molecular parameters in RA/JIA patients treated with adalimumab, etanercept, infliximab and rituximab or tocilizumab, to address the mechanism of immunogenicity. Patient-related factors that might predispose an individual to an immune response will be taken into account: underlying disease, genetic background, immune status, including immunomodulating therapy and dosing schedule.

Study Overview

• Status: Unknown
• Conditions: Rheumatoid Arthritis; Juvenile Idiopathic Arthritis
• Intervention / Treatment: Procedure: Sampling of blood

Detailed Description

The ABIRISK (Anti-biopharmaceutical Immunization: Prediction and analysis of clinical relevance to minimize the risk) consortium, within the IMI (Innovative Medicines Initiative), is a Public Private Partnership between pharmaceutical companies, academic institutions and clinical centers. The ABIRISK aims are to better analyze and predict the phenomenon of immunogenicity in order to reduce its occurrence. One of the main objectives of ABIRISK is to set up prospective cohort (ABI-RA) of patients with rheumatoid arthritis (RA) or juvenile idiopathic arthritis (JIA) to provide, using an integrated approach, new tools for being able to detect earlier and even before the beginning of the therapy, immunization to biopharmaceutical (BP). The introduction of BP has been a critical step forward in care for RA/JIA and 9 BP are now licensed for the treatment of RA/JIA. In spite of this progress, failure of response to BP is frequent and in most of the registries, less than 50 % of patients are still on drug at 5 years. These failures may be primary failures or secondary failures. The fact is that the low level of responses becomes insufficient compared to the expectations. One of the main potential causes of these failures of BP therapy response is the development of Anti-drug Anti-body (ADAb) in some patients. ADAb may decrease the efficacy of BPs by neutralizing them or modifying their clearance and they may be associated with BP-specific hypersensitivity reactions. The prediction, prevention and cure of anti-drug (AD) immunization are thus major goals in BP development. This prospective study (ABI-RA) will assess the occurrence of ADAb using standardized and validated assay(s) and also cellular, genetic and molecular parameters in RA/JIA patients treated with adalimumab, etanercept, infliximab and rituximab or tocilizumab, to address the mechanism of immunogenicity. Patient-related factors that might predispose an individual to an immune response will be taken into account: underlying disease, genetic background, immune status, including immunomodulating therapy and dosing schedule.

• Study Type: Interventional
• Enrollment (Actual): 156
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Le Kremlin-Bicêtre, France, 94275
    • CHU Bicêtre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male and female patients of more than 18 years old diagnosed with RA according to 2010 ACR/EULAR criteria Or Male and female patients Age > 2 years and <18 years, diagnosed with JIA according to the Internal League Against Rheumatism (ILAR) classification criteria.
• Patient for whom the Treating Physician has decided to prescribe in the usual manner in accordance with the terms of the marketing authorization and independently from entry into this study:
• etanercept, adalimumab, infliximab, infliximab Biosimilar, rituximab OR tocilizumab in first line or after failure with other biotherapy. In case of previous rituximab, inclusion may be possible at least 6 months after the last rituximab infusion therapy or,
• Subcutaneous form of Tocilizumab, either as first line or after switch from infusion tocilizumab form is allowed.
• Having given written informed consent prior to undertaking any study-related procedures. For JIA patients, written informed consent signed by parents or legal representative and assent of the minor child
• Covered by a health insurance system where applicable, and/or in compliance with the recommendations of the national laws in force relating to biomedical research

Exclusion Criteria:

• Under any administrative or legal supervision.
• Patients having previously anti-TNF if they are going to receive another anti-TNF therapy
• Patients having previously received rituximab in the past 6 months.

• Conditions/situations such as:

  • Patients with conditions/concomitant diseases making them non evaluable for the primary endpoint
  • Impossibility to meet specific protocol requirements (e.g. blood sampling)
  • Patient is the Investigator or any sub-investigator, research assistant, pharmacist, study coordinator, other staff or relative thereof directly involved in the conduct of the protocol
  • Uncooperative or any condition that could make the patient potentially non-compliant to the study procedures
• Pregnant or breast-feeding women

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Health Services Research
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Global population; All included patients : Sampling of blood	Procedure: Sampling of blood; Sampling of blood for dosage of antibodies

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Immunization against the Biopharmaceutical defined by the presence of ADAb within the first 12 months (or W52)	52 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quantification of ADAb		at Week 0
Quantification of ADAb		at Week 4
Quantification of ADAb		at Week 12
Quantification of ADAb		at Week 26
Quantification of ADAb		at Week 52
Quantification of ADAb		at Week 64
Quantification of ADAb		at Week 78
Clinical response and remission	European League Against Rheumatism (EULAR) response	at Week 4
Clinical response and remission	European League Against Rheumatism (EULAR) response	at Week 12
Clinical response and remission	European League Against Rheumatism (EULAR) response	at Week 26
Clinical response and remission	European League Against Rheumatism (EULAR) response	at Week 52
Clinical response and remission	European League Against Rheumatism (EULAR) response	at Week 64
Clinical response and remission	European League Against Rheumatism (EULAR) response	at Week 78
ADAb-associated adverse clinical events at any time point		Until Week 78
Drug levels	Concentration in mg/L	Until week 78

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: GlaxoSmithKline; Institut National de la Santé Et de la Recherche Médicale, France; Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA); Leiden University Medical Center; University of Florence; University Hospital, Tours; Istituto Giannina Gaslini; University College London (UCL) Cancer Institute; Pediatric Rheumatology International Trials Organization

Publications and helpful links

General Publications

• Paoletti A, Ly B, Bitoun S, Nocturne G, Rivière E, Manson JJ, Matucci A, Pallardy M, De Vries N, Mariette X. Restoration of Default Blood Monocyte-Derived Macrophage Polarization With Adalimumab But Not Etanercept in Rheumatoid Arthritis. Front Immunol. 2022 Feb 23;13:832117. doi: 10.3389/fimmu.2022.832117. eCollection 2022.
• Duhaze J, Caubet M, Hassler S, Bachelet D, Allez M, Deisenhammer F, Fogdell-Hahn A, Gleizes A, Hacein-Bey-Abina S, Mariette X, Pallardy M, Broet P; ABIRISK Consortium. Assessing the effect of genetic markers on drug immunogenicity from a mechanistic model-based approach. BMC Med Res Methodol. 2020 Mar 20;20(1):69. doi: 10.1186/s12874-020-00941-z.
• Bitoun S, Nocturne G, Ly B, Krzysiek R, Roques P, Pruvost A, Paoletti A, Pascaud J, Donnes P, Florence K, Gleizes A, Hincelin-Mery A, Allez M, Hacein-Bey-Abina S, Mackay F, Pallardy M, Le Grand R, Mariette X. Methotrexate and BAFF interaction prevents immunization against TNF inhibitors. Ann Rheum Dis. 2018 Oct;77(10):1463-1470. doi: 10.1136/annrheumdis-2018-213403. Epub 2018 Jun 23. Erratum In: Ann Rheum Dis. 2021 May;80(5):e84.

Study record dates

Study Major Dates

• Study Start: April 1, 2014
• Primary Completion (Actual): April 1, 2016
• Study Completion (Anticipated): November 1, 2017

Study Registration Dates

• First Submitted: April 3, 2014
• First Submitted That Met QC Criteria: April 15, 2014
• First Posted (Estimate): April 17, 2014

Study Record Updates

• Last Update Posted (Estimate): November 28, 2016
• Last Update Submitted That Met QC Criteria: November 24, 2016
• Last Verified: August 1, 2016

More Information

Terms related to this study

• Keywords: Immunogenicity; Rheumatoid arthritis; Juvenile Idiopathic Arthritis; Prediction; Biopharmaceutical; Anti-Drug Antibody
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid; Arthritis, Juvenile
• Other Study ID Numbers: ABI-RA-P01; 2013-A01268-37 (Other Identifier: ANSM)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No