Study to Assess the Short- and Long-term Efficacy of Certolizumab Pegol Plus Methotrexate Compared to Adalimumab Plus Methotrexate in Subjects With Moderate to Severe Rheumatoid Arthritis (RA) Inadequately Responding to Methotrexate

Study Overview
=================
Brief Summary
-----------------
This study is conducted to evaluate the short (12 Weeks) and long term (104 Weeks) efficacy of Certolizumab Pegol compared with Adalimumab both in combination with Methotrexate (MTX) in the treatment of moderate to severe Rheumatoid Arthritis (RA) that is not responding adequately to MTX.

Official Title
-----------------
A Multicenter, Single-blind, Randomized Parallel-group Study to Assess the Short- and Long-term Efficacy of Certolizumab Pegol Plus Methotrexate Compared to Adalimumab Plus Methotrexate in Subjects With Moderate to Severe Rheumatoid Arthritis Responding Inadequately to Methotrexate

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

Intervention / Treatment
-----------------
* Biological: Certolizumab Pegol (CZP)
* Biological: Adalimumab (ADA)
* Drug: Methotrexate (MTX)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subject must have a diagnosis of Rheumatoid Arthritis (RA) at Screening, as defined by the 2010 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria (Aletaha D et al, 2010) Subject must have a positive Rheumatoid Factor (RF) and/or a positive anti-Cyclic Citrullinated Peptide antibody (anti-CCP) as determined by the central laboratory at Screening Subject must have moderate to severe RA disease at Screening and Baseline defined as: Screening (all criteria required) ≥ 4 swollen joints (of 28 prespecified joints) Disease Activity Score [Erythrocyte Sedimentation Rate] (DAS28[ESR]) > 3.2 C-Reactive Protein (CRP) concentration ≥ 10 mg/L (or 1.0 mg/dL) or Erythrocyte Sedimentation Rate (ESR) (Westergren) ≥ 28 mm/hr Baseline (both criteria required) ≥ 4 swollen joints (of 28 prespecified joints) Disease Activity Score [Erythrocyte Sedimentation Rate] (DAS28[ESR]) > 3.2 Subject must have inadequately responded previously to Methotrexate (MTX) Subject is using MTX 15 to 25 mg/week orally or subcutaneously at Screening and has used the same MTX regimen for a minimum of 28 days prior to Baseline Exclusion Criteria: Subject has previously received any biological Disease Modifying Antirheumatic Drug (DMARD) or has received treatment with cyclophosphamide, chlorambucil, Janus Kinase, phosphodiesterase 4 inhibitors or investigational agents such as spleen tyrosine kinase Diagnosis of any other inflammatory arthritis Infected with Tuberculosis (TB) or high risk of acquiring TB infection Subjects with concurrent acute or chronic viral hepatitis B or C infection Subjects with a history of chronic or recurrent infections or subjects at high risk of infection Use of prohibited medications like nonbiological DMARDs (excluding MTX), biological DMARDs excluding study medications, experimental therapy, IA hyaluronic acid

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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Certolizumab Pegol + Methotrexate (CZP + MTX)<br> | Biological: Certolizumab Pegol (CZP)<br>* Active substance: an injectable volume of 1 ml solution for injection CZP Pharmaceutical form: prefilled syringes CZP Concentration: 200 mg/ml CZP Route of Administration: injections will be given subcutaneously: loading dose of CZP 400 mg at Baseline, and Weeks 2 and 4, followed by a maintenance dose of 200 mg every 2 weeks through Week 102 or withdrawal.<br>* Other names: CZP;Drug: Methotrexate (MTX)<br>* Active substance: Methotrexate Pharmaceutical form: oral tablet Concentration: 15-25 mg/week Route of Administration: MTX orally<br>* Other names: MTX;|
| Active Comparator: Adalimumab + Methotrexate (ADA + MTX)<br> | Biological: Adalimumab (ADA)<br>* Active substance: an injectable volume of 0.8 ml solution for injection ADA Pharmaceutical form: prefilled syringes ADA Concentration: 40 mg/0.8 ml ADA Route of Administration: injections will be given subcutaneously. ADA 40 mg plus an injection with Placebo (to preserve blind) at Baseline, and Weeks 2 and 4, followed by ADA 40 mg every 2 weeks through Week 102 or withdrawal.<br>* Other names: ADA;Drug: Methotrexate (MTX)<br>* Active substance: Methotrexate Pharmaceutical form: oral tablet Concentration: 15-25 mg/week Route of Administration: MTX orally<br>* Other names: MTX;|
| Active Comparator: CZP + MTX followed by ADA + MTX<br>Those subjects who received Certolizumab Pegol (400 mg at Weeks 0, 2, 4 followed by 200 mg every two weeks) + Methotrexate (CZP+ MTX) at Baseline and are Non-Responders at Week 12, switch to Adalimumab (40 mg) + Methotrexate (ADA + MTX) after Week 12. | Biological: Certolizumab Pegol (CZP)<br>* Active substance: an injectable volume of 1 ml solution for injection CZP Pharmaceutical form: prefilled syringes CZP Concentration: 200 mg/ml CZP Route of Administration: injections will be given subcutaneously: loading dose of CZP 400 mg at Baseline, and Weeks 2 and 4, followed by a maintenance dose of 200 mg every 2 weeks through Week 102 or withdrawal.<br>* Other names: CZP;Biological: Adalimumab (ADA)<br>* Active substance: an injectable volume of 0.8 ml solution for injection ADA Pharmaceutical form: prefilled syringes ADA Concentration: 40 mg/0.8 ml ADA Route of Administration: injections will be given subcutaneously. ADA 40 mg plus an injection with Placebo (to preserve blind) at Baseline, and Weeks 2 and 4, followed by ADA 40 mg every 2 weeks through Week 102 or withdrawal.<br>* Other names: ADA;Drug: Methotrexate (MTX)<br>* Active substance: Methotrexate Pharmaceutical form: oral tablet Concentration: 15-25 mg/week Route of Administration: MTX orally<br>* Other names: MTX;|
| Active Comparator: ADA + MTX followed by CZP + MTX<br>Those subjects who received Adalimumab (40 mg + Placebo at Weeks 0, 2, 4 followed by 40 mg ADA every two weeks) + Methotrexate (ADA+ MTX) at Baseline and are Non-Responders at Week 12, switch to Certolizumab Pegol (400 mg at Weeks 12, 14, 16 followed by 200 mg every two weeks) + Methotrexate (CZP+ MTX) after Week 12. | Biological: Certolizumab Pegol (CZP)<br>* Active substance: an injectable volume of 1 ml solution for injection CZP Pharmaceutical form: prefilled syringes CZP Concentration: 200 mg/ml CZP Route of Administration: injections will be given subcutaneously: loading dose of CZP 400 mg at Baseline, and Weeks 2 and 4, followed by a maintenance dose of 200 mg every 2 weeks through Week 102 or withdrawal.<br>* Other names: CZP;Biological: Adalimumab (ADA)<br>* Active substance: an injectable volume of 0.8 ml solution for injection ADA Pharmaceutical form: prefilled syringes ADA Concentration: 40 mg/0.8 ml ADA Route of Administration: injections will be given subcutaneously. ADA 40 mg plus an injection with Placebo (to preserve blind) at Baseline, and Weeks 2 and 4, followed by ADA 40 mg every 2 weeks through Week 102 or withdrawal.<br>* Other names: ADA;Drug: Methotrexate (MTX)<br>* Active substance: Methotrexate Pharmaceutical form: oral tablet Concentration: 15-25 mg/week Route of Administration: MTX orally<br>* Other names: MTX;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects Who Met the American College of Rheumatology 20 % (ACR20) Criteria at Week 12 | Subjects who met the ACR20 criteria were those subjects with at least 20% improvement from Baseline for Tender Joint Count (TJC), Swollen Joint Count (SJC), and at least 3 of the 5 remaining core set measures: 1) Health Assessment Questionnaire-Disability Index (HAQ-DI), 2) C-reactive Protein (CRP), 3) Patient's Assessment of Arthritis Pain-Visual Analog Scale (PAAP-VAS), 4) Patient's Global Assessment of Disease Activity-Visual Analog Scale (PtGADA-VAS), 5) Physician's Global Assessment of Disease Activity-Visual Analog Scale (PhGA-VAS). | Week 12 | 
| Percentage of Subjects Who Had a Disease Activity Score 28 [Erythrocyte Sedimentation Rate] (DAS28 [ESR]) ≤ 3.2 at Week 104 | DAS28 [ESR] was calculated using the Tender Joint Count (TJC), Swollen Joint Count (SJC), Erythrocyte Sedimentation Rate (ESR in mm/hour), and the Patient's Global Assessment of Disease Activity - Visual Analog Scale (PtGADA-VAS in mm) using the following formula: 0.56 x √ (TJC) + 0.28 x √ (SJC) + 0.70 x lognat (ESR) + 0.014 x Patient Global Assessment of Arthritis, where 28 joints were examined and a lower score indicates less disease activity. | Week 104 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Week 12 Responders Who Had a Disease Activity Score 28 [Erythrocyte Sedimentation Rate] (DAS28 [ESR]) ≤ 3.2 at Week 104 | DAS28 [ESR] was calculated using the Tender Joint Count (TJC), Swollen Joint Count (SJC), Erythrocyte Sedimentation Rate (ESR in mm/hour), and the Patient's Global Assessment of Disease Activity - Visual Analog Scale (PtGADA-VAS in mm) using the following formula: 0.56 x √ (TJC) + 0.28 x √ (SJC) + 0.70 x lognat (ESR) + 0.014 x Patient Global Assessment of Arthritis, where 28 joints were examined and a lower score indicates less disease activity. The definition of Week 12 responders was DAS28[ESR] Low Disease Activity (LDA) (ie ≤ 3.2) or an improvement of ≥ 1.2 in DAS28[ESR] relative to Baseline. | Week 104 | 
| Percentage of Subjects Who Met the American College of Rheumatology 20 % (ACR20) Criteria at Week 6 | Subjects who met the ACR20 criteria were those subjects with at least 20% improvement from Baseline for Tender Joint Count (TJC), Swollen Joint Count (SJC), and at least 3 of the 5 remaining core set measures: 1) Health Assessment Questionnaire-Disability Index (HAQ-DI), 2) C-reactive Protein (CRP), 3) Patient's Assessment of Arthritis Pain-Visual Analog Scale (PAAP-VAS), 4) Patient's Global Assessment of Disease Activity-Visual Analog Scale (PtGADA-VAS), 5) Physician's Global Assessment of Disease Activity-Visual Analog Scale (PhGA-VAS). | Week 6 | 
| Percentage of Subjects Who Had a Disease Activity Score 28 [Erythrocyte Sedimentation Rate] (DAS28 [ESR]) ≤ 3.2 at Week 6 | DAS28 [ESR] was calculated using the Tender Joint Count (TJC), Swollen Joint Count (SJC), Erythrocyte Sedimentation Rate (ESR in mm/hour), and the Patient's Global Assessment of Disease Activity - Visual Analog Scale (PtGADA-VAS in mm) using the following formula: 0.56 x √ (TJC) + 0.28 x √ (SJC) + 0.70 x lognat (ESR) + 0.014 x Patient Global Assessment of Arthritis, where 28 joints were examined and a lower score indicates less disease activity. | Week 6 | 
| Percentage of Subjects Who Had a Disease Activity Score 28 [Erythrocyte Sedimentation Rate] (DAS28 [ESR]) ≤ 3.2 at Week 12 | DAS28 [ESR] was calculated using the Tender Joint Count (TJC), Swollen Joint Count (SJC), Erythrocyte Sedimentation Rate (ESR in mm/hour), and the Patient's Global Assessment of Disease Activity - Visual Analog Scale (PtGADA-VAS in mm) using the following formula: 0.56 x √ (TJC) + 0.28 x √ (SJC) + 0.70 x lognat (ESR) + 0.014 x Patient Global Assessment of Arthritis, where 28 joints were examined and a lower score indicates less disease activity. | Week 12 | 
| Percentage of Subjects With a Disease Activity Score 28 [Erythrocyte Sedimentation Rate] (DAS28 [ESR]) ≤ 3.2 at Week 104, in Subjects Responding at Both Week 6 and Week 12 | DAS28 [ESR] was calculated using the Tender Joint Count (TJC), Swollen Joint Count (SJC), Erythrocyte Sedimentation Rate (ESR in mm/hour), and the Patient's Global Assessment of Disease Activity - Visual Analog Scale (PtGADA-VAS in mm) using the following formula: 0.56 x √ (TJC) + 0.28 x √ (SJC) + 0.70 x lognat (ESR) + 0.014 x Patient Global Assessment of Arthritis, where 28 joints were examined and a lower score indicates less disease activity. The definition of Week 6/12 responders was DAS28[ESR] Low Disease Activity (LDA) (ie ≤ 3.2) or an improvement of ≥ 1.2 in DAS28[ESR] relative to Baseline. | Week 104 | 
| Change From Baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI) at Week 104 | HAQ-DI was derived based on the mean of individual scores in 8 categories of daily living actives (using 20 questions). Each question was scored 0-3 (0 = without any difficulty, 1 = with some difficulty, 2 = with much difficulty, and 3 = unable to do), and the total HAQ-DI was scored on the scale of 0-3 as well. Change from Baseline was computed as the value at Week 104 minus the Baseline value. A negative value in Change from Baseline indicates an improvement. | From Baseline to Week 104 | 
| Kaplan-Meier Estimates of Proportion of Subjects Who Discontinued After Response at Week 12 | Response at Week 12 means that a subject had either a Disease Activity Score 28 [Erythrocyte Sedimentation Rate] (DAS28 [ESR]) ≤ 3.2 at Week 12 or had a reduction of DAS28 [ESR] ≥ 1.2 from Baseline to Week 12. Kaplan-Meier Estimates of Proportion of Subjects Discontinued are presented per study week (days relative to Week 12 visit). | From Week 12 up to Week 104 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Certolizumab Pegol, Cimzia, Adalimumab, Humira, Rheumatoid Arthritis