Study to Investigate the Safety and Efficacy of Tregalizumab in Subjects (MTX-IR) With Active Rheumatoid Arthritis

Study Overview
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Brief Summary
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The purpose of this study is to determine the efficacy and safety of three different Tregalizumab doses in combination with Methotrexate (MTX) in subjects who have active rheumatoid arthritis and an inadequate response to MTX alone. The overall study duration is 24 weeks followed by a 24 week extension phase.

Detailed Description
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The planned clinical study 986 (TREAT 2b) is a 24-week study in patients with Active rheumatoid arthritis (RA) who have had an inadequate response to Methotrexate (MTX) alone. The main phase of this study is followed by a 24-week extension phase for subjects meeting the respective entry criteria. Patients will be randomized to one of three different Active treatment groups or Placebo. The primary efficacy variable is the proportion of subjects with an ACR20 response after 12 weeks of double blinded treatment with the study medication based on observed cases in the FAS. At Week 12, all subjects who had a minimum improvement of at least 20% (from baseline) in their tender joint count (TJC) and swollen joint count (SJC) continued on the same treatment. Subjects who had not demonstrated an improvement of at least 20% of TJC and SJC were assessed as non-responders. Non-responders who received placebo were randomized to an active treatment dose in a blinded manner. Non-responders who received active treatment were rolled up to the next highest dose in a blinded manner, apart from those already on the highest dose. These subjects remained on the highest dose.

Official Title
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A 24-week Phase IIb, Randomized, Double-blind, Placebo-controlled, Multicenter Study to Investigate the Efficacy and Safety of Tregalizumab (BT061) in Combination With Methotrexate in the Treatment of Subjects With Active Rheumatoid Arthritis Who Have Had an Inadequate Response to Methotrexate Alone, Followed by a 24-week Extension Phase: T Cell REgulating Arthritis Trial 2b (TREAT 2b)

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Tregalizumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject demonstrates active RA according to the 1987 American College of Rheumatology (ACR) or 2010 ACR/European League Against Rheumatism (EULAR) classification criteria for RA with functional class I-III for ≥6 months. Subject receives oral or parenteral MTX treatment for ≥12 weeks (overall), with an unchanged mode of application and stable MTX dose of ≥15 mg per week (or ≥12.5 mg per week in case of MTX intolerance), but no more than the highest locally approved dose for RA, for ≥8 weeks prior to baseline. The dose of MTX is expected to remain stable throughout the study and may be adjusted only for safety reasons. If applicable, the dose of folic acid must be unchanged for ≥8 weeks prior to baseline. Subject meets the following two criteria at both screening and baseline: - At least 6 swollen joints at 28-joint assessment. - At least 6 tender joints at 28-joint assessment. Subject has an erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) above the upper limit of normal (ULN) at screening. These tests may be repeated once during the screening period at the discretion of the investigator. Subject is ≥18 and ≤75 years of age. Subject has a body mass index ≥18 and ≤35 kg/m². Subject receives treatment with corticosteroids ≤10 mg prednisone equivalent, stable for at least 4 weeks prior to baseline and during the study, if applicable. Subject receives treatment with non-steroidal anti-inflammatory drugs (NSAIDs), stable for at least 2 weeks prior to baseline and during the study, if applicable. Female subjects of childbearing potential: has both a negative serum pregnancy test at screening and a negative urine pregnancy test at baseline. Subject is judged to be in good general health as determined by the investigator based upon the results of medical history, laboratory profile, physical examination, chest X-ray (within 3 months before screening date is acceptable), and 12-lead electrocardiogram (ECG). Subject has a cluster of differentiation 4 (CD4) cell count of > 400/µl at screening. Exclusion Criteria: Subject has previous exposure to any systemic biologic therapy (e.g., etanercept, adalimumab, rituximab, abatacept, tocilizumab), to Janus kinase (JAK) or spleen tyrosine kinase (SYK) inhibitors, or to Tregalizumab. Previous treatment with an anti-TNF agent is allowed only, if all of the following criteria apply: - treatment was stopped for reasons other than lack of efficacy or adverse events (AEs) - treatment was stopped at least 12 weeks or five half-lives of the compound prior to baseline (whichever is longer), and - the treatment period did not exceed 6 weeks. Subject received treatment with conventional disease-modifying anti-rheumatic drugs (DMARDs) apart from MTX in the 12 weeks prior to baseline, and for DMARD leflunomide in the 24 weeks prior to baseline (except where specific leflunomide wash-out procedures were completed, following applicable guidelines). Subject has been treated with intra-articular or parenteral administration of corticosteroids in the 4 weeks prior to baseline. Inhaled corticosteroids for stable medical conditions are allowed. Subject has undergone joint surgery in the 12 weeks prior to baseline (at joints to be assessed within the study) or has undergone major surgery (e.g., abdominal surgery) in the 8 weeks prior to baseline. Subject has a history of acute inflammatory joint disease of an origin other than RA or subject has any other rheumatic disease other than RA (e.g., mixed connective tissue disease, seronegative spondylarthropathy, psoriatic arthritis, Reiter's syndrome, fibromyalgia, systemic lupus erythematosus or any arthritis with onset prior to age 17 years). However, subjects may have secondary Sjögren's syndrome.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Level 1 Tregalizumab<br>25mg Tregalizumab s.c. weekly | Drug: Tregalizumab<br>* humanized anti-CD4 mAb<br>* Other names: BT061;|
| Experimental: Dose Level 2 Tregalizumab<br>100mg Tregalizumab s.c. weekly | Drug: Tregalizumab<br>* humanized anti-CD4 mAb<br>* Other names: BT061;|
| Experimental: Dose Level 3 Tregalizumab<br>200mg Tregalizumab s.c. weekly | Drug: Tregalizumab<br>* humanized anti-CD4 mAb<br>* Other names: BT061;|
| Placebo Comparator: Placebo<br>Placebo s.c. weekly | Drug: Placebo<br>* identical end formulation buffer<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Proportion of Subjects Who Achieve an ACR20 at Week 12 Following Treatment With Tregalizumab + MTX Compared With Subjects Treated on Placebo + MTX | The primary efficacy variable was the proportion of subjects with an ACR20 response after 12 weeks of double-blind treatment with the study medication. The analysis of the primary endpoint was performed using observed cases (OC) on the FAS. | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportions of Subjects With an ACR 20 Response. |  | Week 24 | 
| Proportions of Subjects With an ACR 50 & 70 Response. |  | Week 12 & Week 24 | 
| Proportions of Subjects With an Disease Activity Score DAS28 <2.6 |  | Week 12 & Week 24 | 
| Proportions of Subjects With Low Disease Activity DAS28 ≤3.2 |  | Week 12 & Week 24 | 
| ACR Score |  | up to 48 weeks | 
| Simple Disease Activity Index [SDAI] ≤11 |  | week 12 & 24 | 
| Clinical Disease Activity Index [CDAI] ≤10 |  | week 12 & 24 | 
| DAS28 |  | up to 48 weeks | 
| EULAR Response |  | up to 48 weeks | 
| ACR Score Individual Components |  | up to 48 weeks | 
| DAS28 Score Individual Components |  | up to 48 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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inadequate response to MTX, Methotrexate, rheumatoid Arthritis, Phase 2b