Study of Two Doses of ABX464 in Participants With Moderate to Severe Rheumatoid Arthritis

Study Overview
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Brief Summary
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This Phase IIa study aims at investigating the safety and tolerability of 2 dose-levels of ABX464 administered daily in combination with methotrexate (MTX) in patients with moderate to severe active Rheumatoid Arthritis (RA) who had an inadequate response to MTX or/and to one or more anti- tumor necrosis factor alpha (TNFα) therapies.

Detailed Description
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This is a randomized, double-blind, placebo-controlled, multicenter study. The study will consist of 3 phases: a screening phase, a treatment phase, and a follow-up phase. Approximately 60 participants with active Rheumatoid Arthritis will be randomly assigned to receive placebo, 50mg ABX464 or 100mg ABX464 during the treatment phase. The maximum period of active treatment will be 12 weeks. The maximum duration of study participation will be 17 weeks. Participant safety will be monitored throughout the study. In addition, several experimental and clinical endpoints will be assessed to obtain information on preliminary efficacy.

Official Title
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Phase IIa Randomized, Double Blind, Placebo Controlled, Multiple Dose Study on ABX464 in Combination With Methotrexate (MTX), in Patients With Moderate to Severe Active Rheumatoid Arthritis Who Have Inadequate Response to MTX or/and to Anti-Tnfα, or Intolerance to Anti-Tnfα

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: ABX464 50mg
* Drug: Matching Placebo
* Drug: ABX464 100mg
* Drug: Methotrexate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient with a confirmed and documented diagnosis of adult-onset rheumatoid arthritis, for at least 12 weeks, according to the revised 2010 American College of Rheumatology- European League Against Rheumatism (ACR-EULAR) classification criteria, including at least one positive criteria among the following: Rheumatoid Factor (RF), Anti-Citrullinated Peptide Antibody (ACPA) or bone erosion; Swollen joint count (SJC) of ≥ 4 (28-joint count) and tender joint count (TJC) ≥4 (28-joint count) at screening; Patient with a moderate to severe disease activity score Disease Activity Score (28 joints) C-Reactive Protein [DAS28 CRP] ≥ 3.2 and C-reactive Protein (CRP) ≥ 5 mg/L (≥ 4.76 nmol)/L) at screening; Patient who had an inadequate response (IR), or failed either methotrexate (MTX) or/and anti- Tumor Necrosis Factor alpha (TNFα) therapy (both administered for at least 12 weeks before IR) or were intolerant to anti- TNFα therapy. Exclusion Criteria: Patient with a known positive anti-double stranded deoxyribonucleic acid (DNA [anti-dsDNA]) and confirmed diagnosis of systemic lupus erythematosus (SLE); Patient with known active infections at screening such as CytoMegaloVirus (CMV), herpes virus and/or recent infectious hospitalization; Acute, chronic or history of clinically relevant pulmonary, cardiovascular, hepatic, pancreatic or renal functional abnormality, encephalopathy, neuropathy or unstable Central Nervous System (CNS) pathology such as seizure disorder, angina or cardiac arrhythmias, active malignancy or any other clinically significant medical problems as determined by physical examination and/or laboratory screening tests and/or medical history; Acute, chronic or history of immunodeficiency or other autoimmune disease; Patient previously treated with any non-anti-TNF biological Disease-Modifying AntiRheumatic Drugs (bDMARDs), and targeted DMARDs (tDMARDS) prior to baseline.

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: ABX464 50mg + methotrexate<br>Participants will receive one capsule of 50mg ABX464 plus one capsule of matching placebo once daily for 12 weeks + methotrexate | Drug: ABX464 50mg<br>* ABX464 is a new anti-inflammatory drug<br>* Other names: obefazimod 50mg;Drug: Matching Placebo<br>* placebo matching with ABX464<br>* Other names: Placebo;Drug: Methotrexate<br>* MTX ≥ 10 mg/week will be given at previous dose regimen kept stable throughout the study<br>* Other names: MTX;|
| Experimental: ABX464 100mg + methotrexate<br>Participants will receive two capsules of 50mg ABX464 once daily for 12 weeks + methotrexate | Drug: ABX464 100mg<br>* ABX464 is a new anti-inflammatory drug<br>* Other names: obefazimod 100mg;Drug: Methotrexate<br>* MTX ≥ 10 mg/week will be given at previous dose regimen kept stable throughout the study<br>* Other names: MTX;|
| Placebo Comparator: Placebo + methotrexate<br>Participants will receive two capsules of matching placebo once daily for 12 weeks + methotrexate | Drug: Matching Placebo<br>* placebo matching with ABX464<br>* Other names: Placebo;Drug: Methotrexate<br>* MTX ≥ 10 mg/week will be given at previous dose regimen kept stable throughout the study<br>* Other names: MTX;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Treatment-emergent Adverse Events in the ABX464 Treated Patients Versus Placebo | TEAE definition is undesirable events not present prior to medical treatment, or an already present event that worsens either in intensity or frequency following the treatment | through study completion, an average of 15 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Achieving ACR20 Response | The categorical American College of Rheumatology 20% (ACR20) response is a validated index of rheumatoid arthritis disease activity, defined by the number of patients who achieved at least 20% improvement in the ACR response. | at Week 12 | 
| Number of Patients Achieving ACR20/50/70 Response | Number of patients who achieved at least 20%, 50% or 70% improvement in the American College of Rheumatology (ACR) response. | Week 12 | 
| Change From Baseline in C-reactive Protein (CRP) | Change from baseline in C-reactive protein (CRP) at Week 12 | Week 12 | 
| Number of Patients Achieving DAS28-CRP Response | Number of patients achieving categorical Disease Activity Score (DAS) DAS28-C-Reactive Protein (CRP) [DAS28-CRP] response will be measured as moderate/good European League Against Rheumatism (EULAR) response | Week 12 | 
| Change From Baseline in Disease Activity Scores (DAS-CRP) (28 Joints) [DAS28] | The DAS28 is a validated index of rheumatoid arthritis disease activity. The DAS28 assessment include 28 tender and swollen joint counts (TJC and SJC), acute phase reactant (CRP ), and patient's global assessment of disease activity (PtGA). DAS28-CRP = 0.56 √ (TJC28) + 0.28 √ (SJC28) + 0.36 Ln [CRP(mg/L)+1] + 0.014 PtGA(VAS100mm) + 0.96 Score scale range from 0 to 10. A DAS28 score >5.1 indicates high disease activity, a DAS28 score <3.2 indicates low disease activity, and a DAS28 score <2.6 indicates clinical remission. | Week 12 | 
| Change From Baseline in Erythrocyte Sedimentation Rate (ESR) | Change from baseline in erythrocyte sedimentation rate (ESR) at Week 12 | Week 12 | 
| Number of Patients Achieving Disease Activity Score (DAS) DAS28-Erythrocyte Sedimentation Rate (ESR) [DAS28-ESR] Remission | Number of patients achieving Disease Activity Score (DAS) DAS28-Erythrocyte Sedimentation Rate (ESR) [DAS28-ESR]remission, which is defined as DAS2-ESR < 2.6 | Week 12 | 
| Change From Baseline in Disease Activtiy Score (DAS)28-Erythrocyte Sedimentation Rate (ESR) | The DAS28 is a validated index of rheumatoid arthritis disease activity. The DAS28 assessment include 28 tender and swollen joint counts (TJC and SJC), acute phase reactant (ESR), and patient's global assessment of disease activity (PtGA). DAS28-ESR = 0.56 √ (TJC28) + 0.28 √ (SJC28) + 0.70 Ln [ESR(mm/h)] + 0.014 PtGA(VAS100mm) Score scale range from 0 to 10. A DAS28 score >5.1 indicates high disease activity, a DAS28 score <3.2 indicates low disease activity, and a DAS28 score <2.6 indicates clinical remission. change from baseline at weeks 12: the bigger negative score shows a bigger improvment | 12 weeks | 
| Change From Baseline in Simplified Disease Activity Index Score (SDAI) | SDAI is a validated index of rheumatoid arthritis disease activity. The SDAI calculation is based on 28 tender and swollen joint counts, C-Reactive Protein (CRP), patient's global assessment of disease activity (PtGA) and physician's global assessment of disease activity (PrGA). SDAI score= tender28 + swollen28 + CRP + (PtGA/10) + (PrGA/10). A moderate activity is defined by a SDAI score >11 to 26 included. A high activity is defined by a SDAI score >26. Change from Baseline: the higher negative number shows a bigger improvment | Week 12 | 
| Change From Baseline in Clinical Disease Activity Index Score (CDAI) | CDAI is a validated index of rheumatoid arthritis disease activity. The CDAI calculation is based on 28 tender and swollen joint counts, patient's global assessment of disease activity (PtGA) and physician's global assessment of disease activity (PrGA). CDAI score= tender28 + swollen28 + (PtGA/10) + (PrGA/10). A moderate activity is defined by a CDAI score >10 to 22 included. A high activity is defined by a CDAI score >22. Change from Baseline: the higher negative number shows a bigger improvment | Week 12 | 
| Number of Patients Achieving Low Disease Activity (LDA) | Number of patients achieving a Low Disease Activity (LDA) which is defined as DAS28-ESR <=3.2 | Week 12 | 
| Number of Patients Achieving Simplified Disease Activity Score (SDAI) Remission | Number of patients achieving Simplified Disease Activity Score (SDAI) remission, which is considered achieved if the SDAI score ≤ 3.3 | Week 12 | 
| Number of Patients Achieving Clinical Disease Activity (CDAI) Remission | Number of patients achieving Clinical Disease Activity (CDAI) remission, which is considered achieved if the CDAI score ≤ 2.8 | Week 12 | 
| Number of Patients Achieving American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Boolean Remission | The ACR/EULAR boolean-based remission is a validated criteria based on: Tender/painful Joint Count (28), Swollen Joint Count (28), C-Reactive Protein, patient global assessment of disease, All ≤ 1 | Week 12 | 
| Change From Baseline in Tender/Painful Joint Count (TJC28) | Change from Baseline in Tender/painful joint count based on 28-joint assessment (TJC28) at Week 12 TJC28 score range from 0 to 28 Change from Baseline: the higher the negative number is, the better improvment is | 12 weeks | 
| Change From Baseline in Swollen Joint Count (SJC) | Change from Baseline in Swollen joint count based on 28-joint assessment (SJC28) at Week 12 SJC28 score range from 0 to 28 Change from Baseline: the higher the negative number is, the better improvment is | 12 weeks | 
| Change From Baseline in Pain Visual Analog Scale | Change from Baseline in Pain Visual Analog Scale (Pain-VAS) at week 12 The VAS range from 0 to 10 cm (the higher, the more painful) A bigger negative change from baseline shows a bigger improvment | 12 weeks | 
| Change From Baseline in Patient Global Assessment of Disease (PtGA) | Change from Baseline in Patient Global Assessment of Disease (PtGA) . This is a patient's self assessment of overall RA disease activity on a scale 1-10 where 10 is maximal activity The change from baseline: a bigger negative number shows a bigger improvment | 12 weeks | 
| Change From Baseline in Investigator Global Assessment of Disease (PrGA) | Change from Baseline in Investigator global assessment of disease (PrGA): investigator's assessment of overall RA disease activity on a scale 1-10 where 10 is maximal activity The change from baseline: the higher negative number shows a better improvement | 12 weeks | 
| Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) | Change from Baseline in Health Assessment questionnaire disability index (HAQ-DI) at Week 12 There are 8 sections in this questionnaire: dressing, arising, eating, walking, hygiene, reach, grip, and activities. There are 2 or 3 questions for each section. Scoring within each section is from 0 (without any difficulty) to 3 (unable to do). For each section the score given to that section is the worst score within the section, i.e. if one question is scored 1 and another 2, then the score for the section is 2. In addition, if an aide or device is used or if help is required from another individual, then the minimum score for that section is 2. The 8 scores of the 8 sections are summed and divided by the number of section answered. This gives a score range from 0 to 3 (the bigger the worst activity). The change from Baseline: the bigger negative number shows a bigger improvment | 12 weeks |