Comparative Efficacy and Safety Study of GP2015 and Enbrel® in Patients With Rheumatoid Arthritis

Study Overview
=================
Brief Summary
-----------------
Demonstrate equivalent efficacy of GP2015 and EU-authorized Enbrel in patients with moderate to severe, active (RA) who had an inadequate response to disease modifying anti-rheumatic drugs (DMARD) including methotrexate (MTX).

Detailed Description
-----------------
Demonstrate equivalent efficacy of GP2015 and EU-authorized Enbrel in patients with moderate to severe, active (RA) who had an inadequate response to disease modifying anti-rheumatic drugs (DMARD) including methotrexate (MTX). In addition, data on the safety profiles of both products, including immunogenicity and local tolerability at the injection sites, will be collected and compared. An additional study objective is to identify any potential risk of the transition from Enbrel to GP2015 in terms of general safety and immunogenicity in RA patients

Official Title
-----------------
A Randomized, Double-blind, Parallel-group Phase III Study to Demonstrate Equivalent Efficacy and to Compare Safety & Immunogenicity of GP2015 and Enbrel® (EU Authorized) in Patients With Moderate to Severe, Active Rheumatoid Arthritis

Conditions
-----------------
Rheumatoid Arthritis

Intervention / Treatment
-----------------
* Drug: GP2015


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients at least 18 years of age with RA diagnosis according to ACR 1987 or ACR/EULAR 20110 criteria >/= 6 months at the time of baseline visit Patient must have active disease defined as DAS28-CRP>/=3.2 Patients must have CRP level above ULN >5mg/l) or erythrocyte sedimentation rate (ESR) >/=28mm/h Patients must have inadequate clinical response to MTX at a dose of 10-25 mg/wk after proper dose escalation according to local standards Exclusion Criteria: Previous exposure to etanercept in the past Patients with functional status class IV according to the ACR 1991 revised criteria History of active tuberculosis (TB) or Presence of latent (inactive)TB detected by imaging and/or by the QuantiFERON-TB Gold test at screening

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 50mg GP2015<br>Group 1 will receive treatment with 50mg GP2015 by subcutaneous injection every week up to 24 weeks (Treatment Period 1) after which patients achieving at least a moderate clinical response continue treatment with 50mg GP2015 subcutaneous injection every week up to 48 weeks (Treatment Period 2). | Drug: GP2015<br>* Enbrel comparator<br>|
| Active Comparator: 50mg EU-authorized Enbrel<br>Group 2 will receive treatment with 50mg EU-authorized Enbrel by subcutaneous injection every week up to 24 weeks (Treatment Period 1) after which patients achieving at least a moderate clinical response will be switched to 50 mg GP2015 subcutaneous injection every week up to 48 weeks (Treatment Period 2). | Drug: GP2015<br>* Enbrel comparator<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety: Change in DAS28-CRP Score From Baseline to Week 24 in Patients Treated With GP2015 and Patients Treated With Enbrel | Disease activity score (DAS) 28-CRP is based on 28-joint count (tender and swollen joints), C-reactive protein and patient's assessment of global disease activity, values range from 0.96 to 10.0 while higher values mean a higher disease activity. • A DAS28-CRP value >5.1 corresponds to a high disease activity • A DAS28-CRP value between 3.2 and 5.1 corresponds to a moderate disease activity • A DAS28-CRP value between 2.6 and 3.2 corresponds to a low disease activity • A DAS28-CRP value < 2.6 corresponds to remission DAS28-CRP = 0.56 * sqrt(tender28) + 0.28* sqrt(swollen28) + 0.36 * ln(CRP+1) + 0.014 * GDA + 0.96 where • tender28 and swollen28 are the number of tender and swollen joints as assessed using 28-joint count • CRP is C-reactive protein (mg/l) • GDA is the global disease activity measured on a Visual Analogue Scale (VAS) of 100 mm | treatment period 1: up to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment Period 1: Frequency and Severity of Injection Site Reactions in GP2015 and Enbrel | Frequency of participants with injection site reactions in GP2015 and Enbrel | Treatment Period 1, up to 24 weeks | 
| Treatment Period 1 - Safety : Immunogenicity by Measuring the Rate of Anti-drug Antibody (ADA) Positive Patients | Frequency of patients having anti-drug antibody (ADA) during 24 weeks (Treatment Period 1) using 1% false positive rate | baseline, week 2, week 4, week 12, week 24 | 
| Treatment Period 1- DAS28-CRP and DAS28-erythrocyte Sedimentation Rate (ESR) Scores at Baseline and Weeks 4, 12 and 24; | DAS28-CRP is a disease activity score and defined in primary outcome measure. DAS28-ESR is the DAS28 erythrocyte sedimentation rate score. DAS28-CRP and DAS28-ESR: best is 0, < 2.6 - remission, ≥ 2.6 to ≤ 3.2 - low disease activity > 3.2 to ≤ 5.1 - moderate disease activity > 5.1 - high disease activity DAS28-ESR = 0.56 * sqrt(tender28) + 0.28* sqrt(swollen28) + 0.7 * ln(ESR) + 0.014 * GDA where • tender28 and swollen28 are the number of tender and swollen joints as assessed using 28-joint count • CRP is C-reactive protein (mg/l) • ESR is erythrocyte sedimentation rate (mm/h) • GDA is the global disease activity measured on a Visual Analogue Scale (VAS) of 100 mm | week 4, 12, 24 | 
| Treatment Period 1 - Changes From Baseline in DAS28-CRP and DAS-ESR Scores to Weeks 4, 12 and 24 |  | baseline, Week 4, week 12, week 24 | 
| Treatment Period 1- Proportion of Patients Achieving EULAR Response | Proportion of patients achieving European League against Rheumatism (EULAR) good response (defined as DAS28 ≤ 3.2 and DAS28 improvement from Baseline > 1.2) and moderate response (defined as DAS28 ≤ 3.2 and DAS28 improvement > 0.6 and ≤ 1.2, or DAS28 > 3.2 and ≤ 5.1 and DAS28 improvement > 0.6 or DAS28 > 5.1 but DAS28 improvement > 1.2) ; | week 4, week 12 and week 24 | 
| Treatment Period 1- Proportion of Patients Achieving DAS28 < 2.6 at Weeks 4, 12 and 24 | % patients in DAS28-ESR categories up to week 24 | week 4, week 12 and week 24 | 
| Treatment Period 1- Proportion of Patients Achieving EULAR/ACR Boolean Remission Criteria | Proportion of patients achieving EULAR/American College of Rheumatology (EULAR/ACR) Boolean remission criteria (defined as number of tender joints/swollen joints ≤ 1 and CRP (mg/dL) ≤ 1 and patient global assessment (1-10) ≤ 1) at Weeks 4, 12 and 24; | week 4, week 12, week 24 | 
| Treatment Period 1- Proportion of Patients Achieving ACR20/50/70 Response at Weeks 4, 12 and 24; | ACR20 response was defined if a patient fulfilled all 3 criteria below: 20% improvement in tender 68 joint-count 20% improvement in swollen 68 joint-count; And 20% improvement in at least 3 of the following 5 measures: Patient's assessment of RA pain (visual analogue scale (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 (HAQ score), Acute phase reactant (CRP or ESR). ACR50 and ACR70 responses were defined as ACR20 response replacing 20% improvement by 50% improvement and 70% improvement, respectively. | Week 4, week 12 and week 24 | 
| Treatment Period 1- ACR-N Scores at Weeks 4, 12 and 24; | ACR-N (American College of Rheumatology percentage of improvement): negative is worsening, positive (up to 100) is an improvement. ACR-N is a single number that characterizes the percentage of improvement from Baseline that a patient has experienced in analogy to ACR20 described above. ACR-N of X (such as 38) means that the patient had achieved an improvement of at least X% (such as 38%) in tender and swollen joints, and an improvement of at least X% (such as 38%) in 3 of the 5 other parameters mentioned above. | Weeks 4, 12 and 24; | 
| Treatment Period 1 - Proportion of Patients in Each Disease Activity Category as Defined by SDAI | Proportion of patients in each disease activity category as defined by the Simplified Disease Activity Index (SDAI): high disease activity, SDAI > 26, moderate disease activity, SDAI > 11 to ≤ 26, low disease activity, SDAI > 3.3 to ≤ 11, and remission, SDAI ≤ 3.3 at Weeks 4, 12 and 24; SDAI and CDAI are measures of disease activity in RA. The scores were calculated by numerical summation of the number of tender and swollen joints (using the 28-joint count), and the patient's and physician's global assessment of disease activity. | Weeks 4, 12 and 24; | 
| Treatment Period 1 - Proportion of Patients in Each Disease Activity Category as Defined by CDAI | Proportion of patients in each disease activity category as defined by the Clinical Disease Activity Index (CDAI): high disease activity, CDAI > 22, moderate disease activity, CDAI > 10 to ≤ 22, low disease activity, CDAI > 2.8 to ≤ 10, and remission, CDAI ≤ 2.8 at Weeks 4, 12 and 24; SDAI and CDAI are measures of disease activity in RA. The scores were calculated by numerical summation of the number of tender and swollen joints (using the 28-joint count), and the patient's and physician's global assessment of disease activity. | Weeks 4, 12 and 24; | 
| Treatment Period 1- Proportion of Patients Achieving HAQ Index in Normal Range (≤ 0.5) at Weeks 4, 12 and 24; | Health assessment questionnaire (HAQ) disability index ranges from 0 (best) to 3 (worst) | Weeks 4, 12 and 24; | 
| Treatment Period 1 - Health Assessment Questionnaire (HAQ) Index at Baseline, Weeks 4, 12 and 24; | Health assessment questionnaire (HAQ) disability index ranges from 0 (best) to 3 (worst) | Baseline, Weeks 4, 12 and 24; | 
| Treatment Period 1 - Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale Relative to Baseline at Weeks 4, 12 and 24; | FACIT fatigue scale is a 13- item questionnaire that assesses self-reported fatigue and its impact upon daily activities and function, ranging from 0 (worst) to 52 (best). A score of less than 30 indicates severe fatigue. | Baseline, Weeks 4, 12 and 24; | 
| Treatment Period 1 - CRP Levels at Baseline and Weeks 4, 12 and 24 |  | Weeks 4, 12 and 24 | 
| Treatment Period 1 - ESR Levels at Baseline and Weeks 4, 12 and 24 |  | Weeks 4, 12 and 24 | 
| Treatment Period 2: DAS28-CRP and DAS28-ESR Scores up to Week 48; | DAS28-CRP and DAS28-ESR: best is 0, < 2.6 - remission, ≥ 2.6 to ≤ 3.2 - low disease activity > 3.2 to ≤ 5.1 - moderate disease activity > 5.1 - high disease activity | Baseline, week 4, week 12, week 24, week 36 and week 48. | 
| Treatment Period 2 : Changes From Baseline in DAS28-CRP and DAS28-ESR Scores From Week 4 up to Week 48 |  | week 4, week 12, week 24, week 36, week 48 | 
| Treatment Period 2: Proportion of Patients Achieving EULAR Reponse | Proportion of patients achieving EULAR good response (defined as DAS28 ≤ 3.2 and DAS28 improvement from Baseline > 1.2) and moderate response (defined as DAS28 ≤ 3.2 and DAS28 improvement > 0.6 and ≤ 1.2, or DAS28 > 3.2 and ≤ 5.1 and DAS28 improvement > 0.6 or DAS28 > 5.1 but DAS28 improvement > 1.2) at Weeks 36 and 48; | week 4, week 12, week 24, week 36 and week 48 | 
| Treatment Period 2 : Proportion of Patients Achieving DAS28 < 2.6 at Weeks 36 and 48; | percentage of participants in DAS28-ESR categories up to week 48 | week 36 and week 48 | 
| Treatment Period 2 : Proportion of Patients Achieving EULAR/ACR Boolean Remission Criteria | Proportion of patients achieving EULAR/ACR Boolean remission criteria (defined as number of tender joints/swollen joints ≤ 1 and CRP (mg/dL) ≤ 1 and patient global assessment (1-10) ≤ 1) at Weeks 36 and 48; | week 4, week 12, week 24, week 36, week 48 | 
| Treatment Period 2 : Proportion of Patients Achieving ACR20/50/70 Response at Weeks 36 and 48; |  | week 36 and week 48 | 
| Treatment Period 2 : ACR-N Scores at Weeks 36 and 48; | ACR-N: negative is worsening, positive (up to 100) is an improvement | week 36 and week 48 | 
| Treatment Period 2 : Proportion of Patients in Each Disease Activity Category as Defined by SDAI | Proportion of patients in each disease activity category as defined by the Simplified Disease Activity Index (SDAI): high disease activity, SDAI > 26, moderate disease activity, SDAI > 11 to ≤ 26, low disease activity, SDAI > 3.3 to ≤ 11, and remission, SDAI ≤ 3.3 at Weeks 36 and 48. | baseline, week 4, week 12, week 24, week 36. week 48 | 
| Treatment Period 2 : Proportion of Patients in Each Disease Activity Category as Defined by CDAI | Proportion of patients in each disease activity category as defined by the Clinical Disease Activity Index (CDAI): high disease activity, CDAI > 22, moderate disease activity, CDAI > 10 to ≤ 22, low disease activity, CDAI > 2.8 to ≤ 10, and remission, CDAI ≤ 2.8 at Weeks 36 and 48; | baseline, week 4, week 12, week 24, week 36 and week 48 | 
| Treatment Period 2 :Proportion of Patients Achieving HAQ Index in Normal Range (≤ 0.5) at Weeks 36 and 48; |  | baseline, week 4, week 12, week 24, week 36, week 48 | 
| Treatment Period 2 :HAQ Index at Weeks 36 and 48; | HAQ: from 0 (best) to 3 (worst) | baseline, week 4, week 12, week 24, week 36, week 48 | 
| Treatment Period 2 : Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale Relative to Baseline at Weeks 36 and 48; | FACIT: from 0 (worst) to 52 (best), a score of less than 30 indicates severe fatigue | baseline, week 4, week 12, week 24, week 36, week 48 | 
| Treatment Period 2 : CRP Levels at Week 36 and 48 |  | baseline, week 4, week 12, week 24, week 36, week 48 | 
| Treatment Period 2 : ESR Levels at Week 36 and 48 |  | baseline, week 4, week 12, week 24, week 36, week 48 | 
| Safety - Overall Study : Frequency and Severity of Injection Site Reactions in GP2015 and Enbrel | Frequency of participants with injection site reactions in GP2015 and Enbrel | up to 48 weeks | 
| Safety : Overall Study: Immunogenicity by Measuring the Rate of Anti-drug Antibody (ADA) Positive Patients | To assess the immunogenicity of continuous GP2015 treatment versus a treatment transition from Enbrel to GP2015 after 24 weeks of treatment by measuring the rate of ADA positive participants at Weeks 24, 30, 36 and 48. summary of ADA positive data up to week 48 using a 1% false positive cut point | baseline, week 4, week 12, week 24, week 36, week 48 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Biosimilars, Rheumatoid Arthritis, Etanercept