Effect of Two Methotrexate in Sync With the First Adalimumab to Prevent the Immunisation Anti Ada in Spondyloarthritis

Study Overview
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Brief Summary
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Preliminary report have demonstrated that methotrexate induces an anti bio-medicament tolerization whan administrated just before the first administration of the bio-medicament. Once this tolerization is obtained it seems useless to continue the methotrexate because this treatment has no efficacity in cases of spondyloarthritis.

Detailed Description
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spondyloarthritis are treated in first intention by NSAIDs but in case of inefficacity biotherapies that inhib the TNF are used. Adalimumab is the most used anti TNF in this indication. Monoclonal antibody uses in therapy is immunogene, and there is a clear link between increase of anti drug antibody and in one hand decrease of drug serum concentration and in an other failure of the therapeutic response. With adalimumab there is an apparition of ADAb in 30%. There are reports suggesting that adding methotrexate to the therapy in a specific timeline allow to prevent the immunization. A previous study shows that association in long terms between methotrexate and adalimumab induce less immunized patients. The investigator's goal is to assess if two methotrexate subcutaneous injections at day 1 and 2 could prevent anti adalimumab antibodies formation.

Official Title
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Effect of Two Methotrexate Injections in Sync With the First Adalimumab Injection to Prevent the Immunisation Anti Adalimumab During Treatment of Spondyloarthritis

Conditions
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Spondyloarthritis

Intervention / Treatment
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* Drug: Methotrexate


Participation Criteria
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Eligibility Criteria
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Inclusion criteria : Patients aged from 18 to 90 Patients suffering from axial SpA, radiographic or non-radiographic according to ASAS criteria (peripheral involvement and/or Inflammatory bowel diseases could be present). Indication for anti TNF treatment: resistance to at least 2 NSAIDs and no contraindication to adalimumab No previous treatment with methotrexate in the last 3 months Stable dosage of steroids (less than 10mg/day of prednisone equivalent) and/or of NSAIDs for at least 10 days Contraception feminine or masculine Informed and written consent Social insurance Exclusion criteria : Contraindication to methotrexate Previous treatment with adalimumab Steroids more than 10mg/day of prednisone equivalent Previous treatment with: Etanercept in the last month Infliximab, golimumab, certolizumab in the last 2 months (Previous treatment hereafter these dates with anti-TNF except adalimumab or secukinumab are not a counterindication) Current immunosuppressive drugs except methotrexate Current and proven pregnancy Project of pregnancy in the next 3 months following inclusion Legal safeguards Inclusion in another interventional research project

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Methotrexate + Adalimumab<br>Experimental group : patients will receive 2 subcutaneous injections of methotrexate in addition of the usual adalimumab | Drug: Methotrexate<br>* Patients randomized in this arm will have one subcutaneous injection of methotrexate 15min before and one 24h after their first injection of adalimumab prescribed as usual<br>|
| No Intervention: Adalimumab<br>Reference group : patient will receive adalimumab as usual to treat spondyloarthritis | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| serum concentrations of ADAb anti adalimumab | To assess if 2 subcutaneous injections of methotrexate could prevent anti adalimumab antibodies formation at month 6 in patients with spondyloarthritis | 6 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| residual serum concentration of adalimumab | To compare trough levels of adalimumab at month 1, 3, 6 and 12 in the 2 groups. | At 1, 3, 6 and 12 months | 
| serum concentrations of ADAb anti adalimumab | To compare the percentage of immunized patients at month 1, 3 and 12 in the 2 groups | At 1, 3 and 12 months | 
| Incidence of Treatment-Emergent Adverse Events | Incidence of Treatment-Emergent Adverse Events as assessed by the number of AE and SAE related to the treatment that occur during the participation of the patient | At 1, 3, 6 and 12 months | 
| Comparison of Adalimumab Therapeutic efficacity in term of Activity disease using ASDAS (Ankylosing Spondylitis Disease Activity Score) score. | A therapeutic efficacity will be described as a clinical pertinent change of ASDAS : Ankylosing Spondylitis Disease Activity Score (at least 1,1 point) (a higher score means a worse outcome) | At 3, 6 and 12 months | 
| Comparison of Adalimumab Therapeutic efficacity in term of Activity disease using BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) score. | A therapeutic efficacity will be described as a clinical pertinent change of BASDAI : Bath Ankylosing Spondylitis Disease Activity Index (0 to 50 points - a higher score means a worse outcome) | At 3, 6 and 12 months | 
| Comparison of Adalimumab Therapeutic efficacity in term of therapeutic maintenance | Assess by Number of patient who didn't switch treatment | At 3, 6 and 12 months | 
| Comparison of Adalimumab Therapeutic efficacity in term of nonsteroidal anti inflammatory drugs ' reduction | Assess by ASAS-NSAIDS score (Assessment of SpondyloArthritis international Society - nonsteroidal antiinflammatory drugs) (minimum 0. a higher score means a worse outcome) | At 3, 6 and 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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tolerization, adalimumab, anti-drug antibodies, methotrexate, spondyloarthritis