A Multi-center, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Certolizumab Pegol in Combination With Methotrexate in the Treatment of Disease Modifying Antirheumatic Drugs (DMARD)-naïve Adults With Early Active Rheumatoid Arthritis

Study Overview
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Brief Summary
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This study is intended to evaluate the efficacy and safety of Certolizumab Pegol (CZP) in combination with Methotrexate (MTX) for inducing and sustaining clinical response in the treatment of Disease Modifying Antirheumatic Drug (DMARD)-naïve adults with early active Rheumatoid Arthritis.

Official Title
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A Multi-center, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Certolizumab Pegol in Combination With Methotrexate for Inducing and Sustaining Clinical Response in the Treatment of DMARD-Naïve Adults With Early Active Rheumatoid Arthritis

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Biological: Certolizumab Pegol
* Other: Placebo
* Biological: Methotrexate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must have a time since diagnosis of adult-onset Rheumatoid Arthritis (RA) less than 1 year as defined by the 2010 ACR/EULAR classification criteria from Screening Visit Positive Rheumatoid Factor (RF) and/or positive anticyclic Citrullinated Peptide Antibody (anti-CCP) Active RA disease DMARD-naïve Subject is naïve to RA related biologics Exclusion Criteria: A diagnosis of any other inflammatory Arthritis History of infected joint prosthesis, or other significant infection and other serious medical condition Known Tuberculosis (TB) disease or high risk of acquiring TB infection

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Certolizumab Pegol + Methotrexate<br> | Biological: Certolizumab Pegol<br>* Prefilled syringes containing an injectable volume of 1 ml of solution for injection CZP for single use at a dosage strength of 200 mg/ml. Injections will be given subcutaneously. CZP 400 mg at Baseline, Week 2 and Week 4, followed by a maintenance dose of 200 mg every 2 Weeks until Week 50.<br>* Other names: CZP;Biological: Methotrexate<br>* The MTX treatment is to be initiated at a dose of 10 mg per Week (oral tablets at the strength of 2.5 mg/tablet). The MTX dosage should be escalated by 5 mg every 2 Weeks such that the maximum dosage of 25 mg per Week is achieved by Week 6 to Week 8. Patients who could not tolerate ≥ 15 mg/week MTX by Week 8 were withdrawn while the maximum tolerated dose per patient (optimized dose) was maintained to Week 52.<br>* Other names: MTX;|
| Placebo Comparator: Placebo + Methotrexate<br> | Other: Placebo<br>* 2 syringes Placebo at Baseline, Week 2 and Week 4, followed by 1 syringe Placebo every 2 Weeks.<br>Biological: Methotrexate<br>* The MTX treatment is to be initiated at a dose of 10 mg per Week (oral tablets at the strength of 2.5 mg/tablet). The MTX dosage should be escalated by 5 mg every 2 Weeks such that the maximum dosage of 25 mg per Week is achieved by Week 6 to Week 8. Patients who could not tolerate ≥ 15 mg/week MTX by Week 8 were withdrawn while the maximum tolerated dose per patient (optimized dose) was maintained to Week 52.<br>* Other names: MTX;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects in Sustained Remission at Week 52 | Sustained remission is defined as a Disease Activity Score [Erythrocyte Sedimentation Rate] (DAS28[ESR]) < 2.6 at both Weeks 40 and 52. DAS28[ESR] is 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 PtGADA, where 28 joints are examined and a lower score indicates less disease activity. | Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects in Sustained Low Disease Activity (LDA) at Week 52 | Sustained LDA is defined as a Disease Activity Score [Erythrocyte Sedimentation Rate] (DAS28[ESR]) ≤ 3.2 at both Weeks 40 and 52. | Week 52 | 
| Change From Baseline in Modified Total Sharp Score (mTSS) to Week 52 | Van der Heijde modified Total Sharp Score (mTSS) is a methodology to assess the degree of joint damage by quantifying the extent of bone erosions and joint space narrowing for 44 and 42 joints, respectively. The mTSS ranges from 0 to 448, with higher scores representing greater damage. | From Baseline (Week 0) to Week 52 | 
| Percentage of Subjects With Radiographic Non-progression From Baseline to Week 52 | Radiographic non-progression is defined as change in mTSS ≤ 0.5. | From Baseline (Week 0) to Week 52 | 
| Change From Baseline in the Joint Erosion Score to Week 52 | Erosions were assessed in 16 locations per hand and 6 joints per foot. Erosions for each hand location were scored from 0 to 5, with 0 indicating no erosion. Scores 1 to 5 may have included combinations of discrete erosion(s) and/or large erosions. Erosions for each foot joint were scored from 0 to 10, with 0 indicating no erosions. The maximum possible erosion score for all 32-hand joints was 160. The maximum possible erosion score for all 12 feet joints was 120. Thus, the maximum possible total erosion score for hands and feet was 280. | From Baseline (Week 0) to Week 52 | 
| Change From Baseline in the Joint Narrowing Score to Week 52 | Joint space narrowing (JSN) was assessed in 15 locations per hand and 6 locations per foot. Joint space narrowing for each location was scored from 0 to 4, with 0 indicating no narrowing. The maximum possible score for JSN in all 30 hand joints was 120. The maximum possible score for JSN in all 12 feet joints was 48. Thus, the maximum possible total JSN score for Hands and feet was 168. | From Baseline (Week 0) to Week 52 | 
| Percentage of Subjects Meeting the American College of Rheumatology 20 % Response Criteria (ACR20) at Week 52 | The assessments are based on a 20 % or greater improvement from Baseline in the number of tender joints, a 20 % or more improvement in the number of swollen joints, and a 20% or greater improvement in 3 of the 5 remaining core set measures: Patient's Global Assessment of Disease Activity (PtGADA), Physician's Global Assessment of Disease Activity (PhGADA), Patient's Assessment of Arthritis Pain (PtAAP), physical function as assessed by the Health Assessment Questionnaire - Disability Index (HAQ-DI) and C-Reactive Protein (CRP). | From Baseline (Week 0) to Week 52 | 
| Percentage of Subjects Meeting the American College of Rheumatology 50 % Response Criteria (ACR50) at Week 52 | The assessments are based on a 50 % or greater improvement from Baseline in the number of tender joints, a 50 %, or more improvement in the number of swollen joints, and a 50 % or greater improvement in 3 of the 5 remaining core set measures: Patient's Global Assessment of Disease Activity (PtGADA), Physician's Global Assessment of Disease Activity (PhGADA), Patient's Assessment of Arthritis Pain (PtAAP), physical function as assessed by the Health Assessment Questionnaire - Disability Index (HAQ-DI) and C-Reactive Protein (CRP). | From Baseline (Week 0) to Week 52 | 
| Percentage of Subjects Meeting the American College of Rheumatology 70 % Response Criteria (ACR70) at Week 52 | The assessments are based on a 70 % or greater improvement from Baseline in the number of tender joints, a 70 %, or more improvement in the number of swollen joints, and a 70 % or greater improvement in 3 of the 5 remaining core set measures: Patient's Global Assessment of Disease Activity (PtGADA), Physician's Global Assessment of Disease Activity (PhGADA), Patient's Assessment of Arthritis Pain (PtAAP), physical function as assessed by the Health Assessment Questionnaire - Disability Index (HAQ-DI) and C-Reactive Protein (CRP). | From Baseline (Week 0) to Week 52 | 
| Percentage of Subjects Meeting the 2011 American College of Rheumatology/ European League Against Rheumatism (ACR/EULAR) Remission Criteria at Week 52 | The ACR/EULAR 2011 remission criteria is defined as: Tender Joint Count (TJC) ≤ 1, Swollen Joint Count (SJC) ≤ 1, C-reactive protein (CRP) ≤ 1 mg/dl and Patient's Global Assessment of Disease Activity (PtGADA) ≤ 1. | Week 52 | 
| Percentage of Subjects With Clinical Disease Activity Index (CDAI) ≤ 2.8 at Week 52 | CDAI is calculated as the sum of tender joint count (TJC), swollen joint count (SJC), Patient's Global Assessment of Disease Activity - Visual Analog Scale (PtGADA-VAS in mm), and Physician's Global Assessment of Disease Activity - Visual Analog Scale (PhGADA-VAS in mm). 28 joints are examined where a lower score indicates less disease activity. | Week 52 | 
| Percentage of Subjects With Simplified Disease Activity Index (SDAI) ≤ 3.3 at Week 52 | SDAI is calculated as the sum of tender joint count (TJC), swollen joint count (SJC), Patient's Global Assessment of Disease Activity - Visual Analog Scale (PtGADA-VAS in mm), Physician's Global Assessment of Disease Activity - Visual Analog Scale (PhGADA-VAS in mm) and C-Reactive Protein (CRP in mg/L). 28 joints are examined where a lower score indicates less disease activity. | Week 52 | 
| Percentage of Subjects With Disease Activity Score 28 [Erythrocyte Sedimentation Rate] (DAS28 [ESR]) < 2.6 at Week 52 | DAS28[ESR] is 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 PtGADA, where 28 joints are examined and a lower score indicates less disease activity. | Week 52 | 
| Percentage of Subjects Meeting the 2011 American College of Rheumatology/ European League Against Rheumatism (ACR/EULAR) Remission Criteria Simplified for Clinical Practice at Week 52 | The 2011 ACR/EULAR remission criteria simplified for clinical practice is defined as: Tender Joint Count (TJC) ≤ 1, Swollen Joint Count (SJC) ≤ 1 and Patient's Global Assessment of Disease Activity (PtGADA) ≤ 1. | Week 52 | 
| Percentage of Subjects Achieving a Good or Moderate European League Against Rheumatism (EULAR) Response at Week 52 | Good response is defined as: DAS28[ESR] ≤ 3.2 and decrease from Baseline by > 1.2; moderate response is defined as achievement of one of the following: DAS28[ESR] ≤ 3.2 and decrease from Baseline > 0.6 and ≤ 1.2 DAS28[ESR] > 3.2 and ≤ 5.1 and decrease from Baseline > 0.6 DAS28[ESR] > 5.1 and decrease from Baseline >1.2. | From Baseline (Week 0) to Week 52 | 
| Change From Baseline in Disease Activity Score 28 [Erythrocyte Sedimentation Rate] (DAS28 [ESR]) to Week 52 | DAS28[ESR] is 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 PtGADA, where 28 joints are examined and a lower score indicates less disease activity. A negative value in DAS28[ESR] change from Baseline indicates an improvement from Baseline. | From Baseline (Week 0) to Week 52 | 
| Change From Baseline in Clinical Disease Activity Index (CDAI) to Week 52 | CDAI is calculated as the sum of tender joint count (TJC), swollen joint count (SJC), Patient's Global Assessment of Disease Activity - Visual Analog Scale (PtGADA-VAS in mm), and Physician's Global Assessment of Disease Activity - Visual Analog Scale (PhGADA-VAS in mm). 28 joints are examined where a lower score indicates less disease activity. The CDAI score ranges from 0 to 76, with a negative value in CDAI change from Baseline indicating an improvement from Baseline. | From Baseline (Week 0) to Week 52 | 
| Change From Baseline in Simplified Disease Activity Index (SDAI) to Week 52 | SDAI is calculated as the sum of tender joint count (TJC), swollen joint count (SJC), Patient's Global Assessment of Disease Activity - Visual Analog Scale (PtGADA-VAS in mm), Physician's Global Assessment of Disease Activity - Visual Analog Scale (PhGADA-VAS in mm) and C-Reactive Protein (CRP in mg/L). 28 joints are examined where a lower score indicates less disease activity. The SDAI score ranges from 0 to 86, with a negative value in SDAI change from Baseline indicating an improvement from Baseline. | From Baseline (Week 0) to Week 52 | 
| Percentage of Subjects With a Health Assessment Questionnaire- Disability Index (HAQ-DI) ≤ 0.5 at Week 52 | Normative physical function is defined as HAQ-DI score ≤ 0.5. The domains of the HAQ-DI are dressing and grooming, arising, eating, walking, hygiene, reach, grip and common daily activities. The total score ranges from 0 to 3 with lower scores meaning lower disability. | Week 52 | 
| Change From Baseline in the Health Assessment Questionnaire - Disability Index (HAQ-DI) to Week 52 | The domains of the HAQ-DI are dressing and grooming, arising, eating, walking, hygiene, reach, grip and common daily activities. The total score ranges from 0 (no difficulty) to 3 (unable to do) with lower scores meaning lower disability. A negative value in HAQ-DI change from Baseline indicates an improvement from Baseline. | From Baseline (Week 0) to Week 52 | 
| Change From Baseline in the Bristol Rheumatoid Arthritis Fatigue- Multidimensional Questionnaire (BRAF-MDQ) Total Score to Week 52 | BRAF-MDQ total score ranges from 0 to 70 (with higher scores indicating worse fatigue). A negative value in BRAF-MDQ change from Baseline indicates an improvement from Baseline. | From Baseline (Week 0) to Week 52 | 
| Number of Work Days Missed (Work Productivity Survey - Rheumatoid Arthritis [WPS-RA]) at Week 52 | Number of work days missed in the last month for employed subjects. | Week 52 | 
| Number of Work Days With Reduced Productivity (Work Productivity Survey - Rheumatoid Arthritis [WPS-RA]) at Week 52 | Number of work days with reduced productivity in the last month for employed subjects. | Week 52 | 
| Interference With Work Productivity (Work Productivity Survey - Rheumatoid Arthritis [WPS-RA]) at Week 52 | The Arthritis interference in the last month with work productivity is measured on a scale that ranges from 0 (no interference) to 10 (complete interference) for employed subjects. | Week 52 | 
| Number of Days With no Household Work (Work Productivity Survey - Rheumatoid Arthritis [WPS-RA]) at Week 52 | Number of days with no household work in the last month. | Week 52 | 
| Number of Days With Reduced Household Work Productivity (Work Productivity Survey - Rheumatoid Arthritis [WPS-RA]) at Week 52 | Number of days with reduced household work productivity in the last month. | Week 52 | 
| Number of Days With Hired Outside Help (Work Productivity Survey - Rheumatoid Arthritis [WPS-RA]) at Week 52 | Number of days with hired outside help in the last month. | Week 52 | 
| Number of Days Missed of Family/Social/Leisure Activities (Work Productivity Survey - Rheumatoid Arthritis [WPS-RA]) at Week 52 | Number of days missed of family/social/leisure activities in the last month. | Week 52 | 
| Interference With Household Work Productivity (Work Productivity Survey - Rheumatoid Arthritis [WPS-RA]) at Week 52 | The Arthritis interference in the last month with household work productivity is measured on a scale that ranges from 0 (no interference) to 10 (complete interference). | Week 52 | 
| Percentage of Subjects Achieving Low Disease Activity (LDA) at Week 52 | LDA is defined as achieving a Disease Activity Score 28 [Erythrocyte Sedimentation Rate] (DAS28 [ESR]) ≤ 3.2. | Week 52 | 

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