GP2013 in the Treatment of RA Patients Refractory to or Intolerant of Standard Therapy

Study Overview
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Brief Summary
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The purpose of this study is to determine the PK/PD, efficacy and safety of GP2013 in patients with severe rheumatoid arthritis.

Official Title
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A Randomized, Double-blind, Controlled Study to Evaluate PK, PD, Safety and Efficacy of GP2013 and Rituximab in Patients With Rheumatoid Arthritis Refractory or Intolerant to Standard DMARDs and up to Three Anti-TNF Therapies.

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Biological: GP2013
* Biological: MabThera
* Biological: Rituxan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Rheumatoid arthritis as defined by the 1987 ACR classification Severe active seropositive disease Inadequate response or intolerance to other DMARDs and anti-TNFs Treatment with Methotrexate Exclusion Criteria: Patients with systemic manifestations of rheumatoid arthritis Female patients nursing Women of childbearing potential unless using birth control Active infection Known immunodeficiency syndrome Positive Hepatitis B surface antigen or antibodies to Hepatitis C History of cancer Other protocol-defined inclusion/exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 18 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: GP2013<br> | Biological: GP2013<br>* 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)<br>|
| Active Comparator: MabThera<br> | Biological: MabThera<br>* 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)<br>* Other names: EU-Rituximab;|
| Active Comparator: Rituxan<br> | Biological: Rituxan<br>* 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)<br>* Other names: US-Rituximab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC(0-inf) of GP2013, MabThera and Rituxan Following IV Infusion in Patients With RA | Area under the curve AUC(0-inf) calculated based on serum samples, collected from baseline up to 24 weeks: Day 1, 4, 8, 15, 18, 29, 57, 85,113 and 169 | From baseline to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Serum Concentration (Cmax) of GP2013, MabThera and Rituxan Following IV Infusion in Patients With RA | Maximum serum concentration (Cmax) after the first infusion of GP2013, MabThera and Rituxan in patients with RA. Samples collected from baseline up to 24 weeks: Day 1, 4, 8, 15, 18, 29, 57, 85,113 and 169. | From baseline to week 24 | 
| Area Under the Effect Curve From Baseline to Day 14 (AUEC(0-14d)) of Percent B-cells of GP2013, MabThera and Rituxan in Patients With RA | Area under the effect curve of percent change of peripheral B-cell count from baseline to Day 14 (AUEC(0-14d)) of GP2013, MabThera and Rituxan in patients with RA | 14 days | 
| Change From Baseline in DAS28(CRP) at Week 24 | Change from baseline in Disease Activity Score 28 joint count - C-reactive proteine DAS28(CRP) at Week 24. In order to calculate the DAS28(CRP) the number of tender joints and swollen joints were assessed using 28-joint count (tender28 and swollen28).The patient's global assessment of disease activity (GH) measured on a Visual Analogue Scale (VAS from 0mm - best to 100mm - worst) was obtained. DAS28(CRP) = 0.56 * sqrt(tender28) + 0.28* sqrt(swollen28) + 0.36 * ln(CRP+1) + 0.014 * GH + 0.96 The DAS28(CRP) provides a number on a scale from 0 to 10 indicating the current activity of the RA, while lower values correspond with less disease activity. A decrease in DAS28 signifies a clinical improvement. | 24 weeks | 
| Number of Patients With ACR20 (CRP) Response | A patient will be considered as improved according the ACR20 criteria at least 20 % improvement from baseline in tender joint count, using the 68-joint count at least 20 % improvement from baseline in swollen joint count, using the 66-joint count and at least 20% improvement from baseline in a least 3 of the following 5 measures: Patient's assessment of RA pain (VAS 100 mm) Patient's global assessment of disease activity (VAS 100 mm) Physician's global assessment of disease activity (VAS 100 mm) Patient self-assessed disability (Health Assessment Questionnaire disability index) Acute phase reactant (C-reactive protein or erythrocyte sedimentation rate) | 24 weeks | 
| Summary of Disease Activity According to CDAI | In order to calculate the Clinical Disease Activity Index (CDAI) the number of tender and swollen joints were assessed using the 28 -joint count (tender28 and swollen28). The patient's global assessment of disease activity and the physician's global assessment of disease activity were measured using a Visual Analogue Scale (VAS) of 10 cm (from 0=best to 10=worst). CDAI = tender28 + swollen28 + patient's global assessment (in cm) + physician's global assessment (in cm) | At week 24 | 
| Summary of Disease Activity According to SDAI | In order to calculate the Simplified Disease Activity Index (SDAI) the number of tender and swollen joints were assessed using the 28 -joint count (tender28 and swollen28). The patient's global assessment of disease activity and the physician's global assessment of disease activity were measured using a Visual Analogue Scale (VAS) of 10 cm (from 0=best to 10=worst). SDAI = CDAI + CRP (in mg/dL) (CDAI = tender28 + swollen28 + patient's global assessment (in cm) + physician's global assessment (in cm)) | At week 24 | 
| Participant Response as Assessed by EULAR Response Criteria | Present DAS28 ≤ 3.2 (low): good response (if improvement > 1.2), moderate response (if improvement >0.6 and ≤ 1.2), no response (if improvement ≤ 0.6). Present DAS28 > 3.2 to ≤ 5.1 (moderate): moderate response (if improvement > 1.2), moderate response (if improvement >0.6 and ≤ 1.2), no response (if improvement ≤ 0.6). Present DAS28 > 5.1 (high): moderate response (if improvement > 1.2), no response (if improvement >0.6 and ≤ 1.2), no response (if improvement ≤ 0.6). | At week 24 |