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 (C-early)

• ClinicalTrials.gov Identifier: NCT01519791
• Recruitment Status: Completed
• First Posted: January 27, 2012
• Results First Posted: September 22, 2015
• Last Update Posted: July 31, 2018
• Sponsor: UCB Pharma SA
• Information provided by (Responsible Party): UCB Pharma ( UCB Pharma SA )

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Rheumatoid Arthritis
• Interventions: Biological: Certolizumab Pegol; Other: Placebo; Biological: Methotrexate
• Enrollment: 880

Participant Flow

Recruitment Details	This study started to enroll subjects in January 2012.
Pre-assignment Details	A total of 880 subjects were randomized. Three subjects were randomized in error, were not dosed, and withdrawn shortly afterwards as screen failures. Two of them were included in the Randomized Set 1 (RS1) only and one of these three subjects was conservatively excluded from any output. Therefore, 879 subjects are in RS1.

Arm/Group Title	Placebo + Methotrexate	Certolizumab Pegol + Methotrexate
Arm/Group Description	Placebo + Methotrexate (MTX) 2 syringes Placebo at Baseline, Week 2 and Week 4 + MTX, followed by 1 syringe Placebo every 2 Weeks + MTX. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.	Certolizumab Pegol + Methotrexate (MTX) 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 + MTX at Baseline, Week 2 and Week 4, followed by a maintenance dose of CZP 200 mg + MTX every 2 Weeks until Week 50. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.
Period Title: Overall Study
Started	219	660
Completed Week 52	143	500
Completed	67	292
Not Completed	152	368
Reason Not Completed
SAE,non-fatal + AE,non-serious non-fatal	2	1
Protocol Violation	6	19
Other Reason	87	222
subjects randomized in error	2	0
Lack of Efficacy	16	20
SAE, non-fatal	6	22
AE, serious fatal	0	1
SAE, fatal + SAE, non-fatal	0	1
AE, non-serious non-fatal	12	31
Withdrawal by Subject	15	37
Lost to Follow-up	6	14

Baseline Characteristics

Arm/Group Title		Placebo + Methotrexate	Certolizumab Pegol + Methotrexate	Total Title
Arm/Group Description		Placebo + Methotrexate (MTX) 2 syringes Placebo at Baseline, Week 2 and Week 4 + MTX, followed by 1 syringe Placebo every 2 Weeks + MTX. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.	Certolizumab Pegol + Methotrexate (MTX) 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 + MTX at Baseline, Week 2 and Week 4, followed by a maintenance dose of CZP 200 mg + MTX every 2 Weeks until Week 50. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.	[Not Specified]
Overall Number of Baseline Participants		219	660	879
Baseline Analysis Population Description		Baseline Charactersitics refer to the Randomized Set (RS).
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	219 participants	660 participants	879 participants
	<=18 years	1 0.5%	2 0.3%	3 0.3%
	Between 18 and 65 years	182 83.1%	560 84.8%	742 84.4%
	>=65 years	36 16.4%	98 14.8%	134 15.2%
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	219 participants	660 participants	879 participants
		51.3 (13.2)	50.5 (13.6)	50.7 (13.5)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	219 participants	660 participants	879 participants
	Female	175 79.9%	499 75.6%	674 76.7%
	Male	44 20.1%	161 24.4%	205 23.3%

Outcome Measures

1. Primary Outcome

Title	Percentage of Subjects in Sustained Remission at Week 52
Description	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.
Time Frame	Week 52

Outcome Measure Data

Analysis Population Description

Full Analysis Set Period 1 (FAS1) with Non-Responder Imputation (NRI). FAS1 consisted of all subjects with valid Baseline and valid post-Baseline efficacy measurement within Period 1 for DAS28(ESR). For NRI, a subject having missing data for the time point assessed was conservatively counted as a nonremitter or nonresponder.

Arm/Group Title	Placebo + Methotrexate (Full Analysis Set)	Certolizumab Pegol + Methotrexate (Full Analysis Set)
Arm/Group Description:	Placebo + Methotrexate (MTX) 2 syringes Placebo at Baseline, Week 2 and Week 4 + MTX, followed by 1 syringe Placebo every 2 Weeks + MTX. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.	Certolizumab Pegol + Methotrexate (MTX) 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 + MTX at Baseline, Week 2 and Week 4, followed by a maintenance dose of CZP 200 mg + MTX every 2 Weeks until Week 50. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.
Overall Number of Participants Analyzed	213	655
Measure Type: Number; Unit of Measure: percentage of subjects
	15.0	28.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo + Methotrexate (Full Analysis Set), Certolizumab Pegol + Methotrexate (Full Analysis Set)
	Comments	In order to control the overall study-wise Type I error rate at 5 %, hypothesis testing was performed in the following hierarchical order (each at a 2-sided 95 % alpha level): Primary: sustained DAS28(ESR) remission at Week 52; Key secondary: sustained DAS28(ESR) LDA at Week 52; ACR50 response at Week 52 in relation to Baseline; Change from Baseline in HAQ-DI at Week 52; Change from Baseline in mTSS at Week 52
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Regression, Logistic
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.283
	Confidence Interval	(2-Sided) 95%; 1.503 to 3.468
	Estimation Comments	The Odds ratio measuring the treatment effect was estimated from a logistic regression model including terms for treatment, region and stratification factor. Nonresponder imputation (NRI) was used.

2. Secondary Outcome

Title	Percentage of Subjects in Sustained Low Disease Activity (LDA) at Week 52
Description	Sustained LDA is defined as a Disease Activity Score [Erythrocyte Sedimentation Rate] (DAS28[ESR]) ≤ 3.2 at both Weeks 40 and 52.
Time Frame	Week 52

Outcome Measure Data

Analysis Population Description

Full Analysis Set Period 1 (FAS1) with Non-Responder Imputation (NRI). FAS1 consisted of all subjects with valid Baseline and valid post-Baseline efficacy measurement within Period 1 for DAS28(ESR). For NRI, a subject having missing data for the time point assessed was conservatively counted as a nonremitter or nonresponder.

Arm/Group Title	Placebo + Methotrexate (Full Analysis Set)	Certolizumab Pegol + Methotrexate (Full Analysis Set)
Arm/Group Description:	Placebo + Methotrexate (MTX) 2 syringes Placebo at Baseline, Week 2 and Week 4 + MTX, followed by 1 syringe Placebo every 2 Weeks + MTX. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.	Certolizumab Pegol + Methotrexate (MTX) 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 + MTX at Baseline, Week 2 and Week 4, followed by a maintenance dose of CZP 200 mg + MTX every 2 Weeks until Week 50. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.
Overall Number of Participants Analyzed	213	655
Measure Type: Number; Unit of Measure: percentage of subjects
	28.6	43.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo + Methotrexate (Full Analysis Set), Certolizumab Pegol + Methotrexate (Full Analysis Set)
	Comments	In order to control the overall study-wise Type I error rate at 5 %, hypothesis testing was performed in the following hierarchical order (each at a 2-sided 95 % alpha level): Primary: sustained DAS28(ESR) remission at Week 52; Key secondary: sustained DAS28(ESR) LDA at Week 52; ACR50 response at Week 52 in relation to Baseline; Change from Baseline in HAQ-DI at Week 52; Change from Baseline in mTSS at Week 52
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Regression, Logistic
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.957
	Confidence Interval	(2-Sided) 95%; 1.384 to 2.767
	Estimation Comments	The Odds ratio measuring the treatment effect was estimated from a logistic regression model including terms for treatment, region and stratification factor. Nonresponder imputation (NRI) was used.

3. Secondary Outcome

Title	Change From Baseline in Modified Total Sharp Score (mTSS) to Week 52
Description	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.
Time Frame	From Baseline (Week 0) to Week 52

Outcome Measure Data

Analysis Population Description

The Radiographic Set Period 1 (RAD1) consisted of those subjects in the FAS1 who had provided valid radiographs (ie, radiographs resulting in a nonmissing mTSS score) at Baseline and at Week 52 or the Withdrawal Visit.

Arm/Group Title	Placebo + Methotrexate (Radiographic Set)	Certolizumab Pegol + Methotrexate (Radiographic Set)
Arm/Group Description:	Placebo + Methotrexate (MTX) 2 syringes Placebo at Baseline, Week 2 and Week 4 + MTX, followed by 1 syringe Placebo every 2 Weeks + MTX. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.	Certolizumab Pegol + Methotrexate (MTX) 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 + MTX at Baseline, Week 2 and Week 4, followed by a maintenance dose of CZP 200 mg + MTX every 2 Weeks until Week 50. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.
Overall Number of Participants Analyzed	163	528
Mean (Standard Deviation); Unit of Measure: units on a scale
	1.8 (4.3)	0.2 (3.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo + Methotrexate (Radiographic Set), Certolizumab Pegol + Methotrexate (Radiographic Set)
	Comments	In order to control the overall study-wise Type I error rate at 5 %, hypothesis testing was performed in the following hierarchical order (each at a 2-sided 95 % alpha level): Primary: sustained DAS28(ESR) remission at Week 52; Key secondary: sustained DAS28(ESR) LDA at Week 52; ACR50 response at Week 52 in relation to Baseline; Change from Baseline in HAQ-DI at Week 52; Change from Baseline in mTSS at Week 52
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	ANCOVA on ranks
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hodges-Lehmann point estimate of shift
	Estimated Value	-0.978
	Confidence Interval	(2-Sided) 95%; -1.005 to -0.500
	Estimation Comments	ANCOVA model on the ranks with the terms for treatment, region, and time since RA diagnosis at Baseline (≤4 months or >4 months) as factors and rank Baseline value as a covariate. Confidence Interval is an asymptotic Moses CI.

4. Secondary Outcome

Title	Percentage of Subjects With Radiographic Non-progression From Baseline to Week 52
Description	Radiographic non-progression is defined as change in mTSS ≤ 0.5.
Time Frame	From Baseline (Week 0) to Week 52

Outcome Measure Data

Analysis Population Description

The Radiographic Set Period 1 (RAD1) consisted of those subjects in the FAS1 who had provided valid radiographs (ie, radiographs resulting in a nonmissing mTSS score) at Baseline and at Week 52 or the Withdrawal Visit.

Arm/Group Title	Placebo + Methotrexate (Radiographic Set)	Certolizumab Pegol + Methotrexate (Radiographic Set)
Arm/Group Description:	Placebo + Methotrexate (MTX) 2 syringes Placebo at Baseline, Week 2 and Week 4 + MTX, followed by 1 syringe Placebo every 2 Weeks + MTX. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.	Certolizumab Pegol + Methotrexate (MTX) 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 + MTX at Baseline, Week 2 and Week 4, followed by a maintenance dose of CZP 200 mg + MTX every 2 Weeks until Week 50. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.
Overall Number of Participants Analyzed	163	528
Measure Type: Number; Unit of Measure: percentage of subjects
	49.7	70.3

5. Secondary Outcome

Title	Change From Baseline in the Joint Erosion Score to Week 52
Description	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.
Time Frame	From Baseline (Week 0) to Week 52

Outcome Measure Data

Analysis Population Description

The Radiographic Set Period 1 (RAD1) consisted of those subjects in the FAS1 who had provided valid radiographs (ie, radiographs resulting in a nonmissing mTSS score) at Baseline and at Week 52 or the Withdrawal Visit.

Arm/Group Title	Placebo + Methotrexate (Radiographic Set)	Certolizumab Pegol + Methotrexate (Radiographic Set)
Arm/Group Description:	Placebo + Methotrexate (MTX) 2 syringes Placebo at Baseline, Week 2 and Week 4 + MTX, followed by 1 syringe Placebo every 2 Weeks + MTX. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.	Certolizumab Pegol + Methotrexate (MTX) 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 + MTX at Baseline, Week 2 and Week 4, followed by a maintenance dose of CZP 200 mg + MTX every 2 Weeks until Week 50. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.
Overall Number of Participants Analyzed	163	528
Mean (Standard Deviation); Unit of Measure: units on a scale
	1.1 (3.0)	0.1 (2.1)

6. Secondary Outcome

Title	Change From Baseline in the Joint Narrowing Score to Week 52
Description	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.
Time Frame	From Baseline (Week 0) to Week 52

Outcome Measure Data

Analysis Population Description

The Radiographic Set Period 1 (RAD1) consisted of those subjects in the FAS1 who had provided valid radiographs (ie, radiographs resulting in a nonmissing mTSS score) at Baseline and at Week 52 or the Withdrawal Visit.

Arm/Group Title	Placebo + Methotrexate (Radiographic Set)	Certolizumab Pegol + Methotrexate (Radiographic Set)
Arm/Group Description:	Placebo + Methotrexate (MTX) 2 syringes Placebo at Baseline, Week 2 and Week 4 + MTX, followed by 1 syringe Placebo every 2 Weeks + MTX. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.	Certolizumab Pegol + Methotrexate (MTX) 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 + MTX at Baseline, Week 2 and Week 4, followed by a maintenance dose of CZP 200 mg + MTX every 2 Weeks until Week 50. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.
Overall Number of Participants Analyzed	163	528
Mean (Standard Deviation); Unit of Measure: units on a scale
	0.7 (2.3)	0.1 (1.7)

7. Secondary Outcome

Title	Percentage of Subjects Meeting the American College of Rheumatology 20 % Response Criteria (ACR20) at Week 52
Description	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).
Time Frame	From Baseline (Week 0) to Week 52

Outcome Measure Data

Analysis Population Description

Full Analysis Set Period 1 (FAS1) with Non-Responder Imputation (NRI). FAS1 consisted of all subjects with valid Baseline and valid post-Baseline efficacy measurement within Period 1 for DAS28(ESR). For NRI, a subject having missing data for the time point assessed was conservatively counted as a nonremitter or nonresponder.

Arm/Group Title	Placebo + Methotrexate (Full Analysis Set)	Certolizumab Pegol + Methotrexate (Full Analysis Set)
Arm/Group Description:	Placebo + Methotrexate (MTX) 2 syringes Placebo at Baseline, Week 2 and Week 4 + MTX, followed by 1 syringe Placebo every 2 Weeks + MTX. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.	Certolizumab Pegol + Methotrexate (MTX) 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 + MTX at Baseline, Week 2 and Week 4, followed by a maintenance dose of CZP 200 mg + MTX every 2 Weeks until Week 50. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.
Overall Number of Participants Analyzed	213	655
Measure Type: Number; Unit of Measure: percentage of subjects
	61.5	69.0

8. Secondary Outcome

Title	Percentage of Subjects Meeting the American College of Rheumatology 50 % Response Criteria (ACR50) at Week 52
Description	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).
Time Frame	From Baseline (Week 0) to Week 52

Outcome Measure Data

Analysis Population Description

Full Analysis Set Period 1 (FAS1) with Non-Responder Imputation (NRI). FAS1 consisted of all subjects with valid Baseline and valid post-Baseline efficacy measurement within Period 1 for DAS28(ESR). For NRI, a subject having missing data for the time point assessed was conservatively counted as a nonremitter or nonresponder.

Arm/Group Title	Placebo + Methotrexate (Full Analysis Set)	Certolizumab Pegol + Methotrexate (Full Analysis Set)
Arm/Group Description:	Placebo + Methotrexate (MTX) 2 syringes Placebo at Baseline, Week 2 and Week 4 + MTX, followed by 1 syringe Placebo every 2 Weeks + MTX. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.	Certolizumab Pegol + Methotrexate (MTX) 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 + MTX at Baseline, Week 2 and Week 4, followed by a maintenance dose of CZP 200 mg + MTX every 2 Weeks until Week 50. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.
Overall Number of Participants Analyzed	213	655
Measure Type: Number; Unit of Measure: percentage of subjects
	52.6	61.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo + Methotrexate (Full Analysis Set), Certolizumab Pegol + Methotrexate (Full Analysis Set)
	Comments	In order to control the overall study-wise Type I error rate at 5 %, hypothesis testing was performed in the following hierarchical order (each at a 2-sided 95 % alpha level): Primary: sustained DAS28(ESR) remission at Week 52; Key secondary: sustained DAS28(ESR) LDA at Week 52; ACR50 response at Week 52 in relation to Baseline; Change from Baseline in HAQ-DI at Week 52; Change from Baseline in mTSS at Week 52
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	=0.023
	Comments	[Not Specified]
	Method	Regression, Logistic
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.446
	Confidence Interval	(2-Sided) 95%; 1.052 to 1.989
	Estimation Comments	The Odds ratio was estimated from a logistic regression model including terms for treatment, region and stratification factor. Nonresponder imputation (NRI) was used.

9. Secondary Outcome

Title	Percentage of Subjects Meeting the American College of Rheumatology 70 % Response Criteria (ACR70) at Week 52
Description	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).
Time Frame	From Baseline (Week 0) to Week 52

Outcome Measure Data

Analysis Population Description

Full Analysis Set Period 1 (FAS1) with Non-Responder Imputation (NRI). FAS1 consisted of all subjects with valid Baseline and valid post-Baseline efficacy measurement within Period 1 for DAS28(ESR). For NRI, a subject having missing data for the time point assessed was conservatively counted as a nonremitter or nonresponder.

Arm/Group Title	Placebo + Methotrexate (Full Analysis Set)	Certolizumab Pegol + Methotrexate (Full Analysis Set)
Arm/Group Description:	Placebo + Methotrexate (MTX) 2 syringes Placebo at Baseline, Week 2 and Week 4 + MTX, followed by 1 syringe Placebo every 2 Weeks + MTX. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.	Certolizumab Pegol + Methotrexate (MTX) 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 + MTX at Baseline, Week 2 and Week 4, followed by a maintenance dose of CZP 200 mg + MTX every 2 Weeks until Week 50. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.
Overall Number of Participants Analyzed	213	655
Measure Type: Number; Unit of Measure: percentage of subjects
	39.9	51.3

10. Secondary Outcome

Title	Percentage of Subjects Meeting the 2011 American College of Rheumatology/ European League Against Rheumatism (ACR/EULAR) Remission Criteria at Week 52
Description	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.
Time Frame	Week 52

Outcome Measure Data

Analysis Population Description

Full Analysis Set Period 1 (FAS1) with Non-Responder Imputation (NRI). FAS1 consisted of all subjects with valid Baseline and valid post-Baseline efficacy measurement within Period 1 for DAS28(ESR). For NRI, a subject having missing data for the time point assessed was conservatively counted as a nonremitter or nonresponder.

Arm/Group Title	Placebo + Methotrexate (Full Analysis Set)	Certolizumab Pegol + Methotrexate (Full Analysis Set)
Arm/Group Description:	Placebo + Methotrexate (MTX) 2 syringes Placebo at Baseline, Week 2 and Week 4 + MTX, followed by 1 syringe Placebo every 2 Weeks + MTX. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.	Certolizumab Pegol + Methotrexate (MTX) 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 + MTX at Baseline, Week 2 and Week 4, followed by a maintenance dose of CZP 200 mg + MTX every 2 Weeks until Week 50. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.
Overall Number of Participants Analyzed	213	655
Measure Type: Number; Unit of Measure: percentage of subjects
	20.7	32.4

11. Secondary Outcome

Title	Percentage of Subjects With Clinical Disease Activity Index (CDAI) ≤ 2.8 at Week 52
Description	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.
Time Frame	Week 52

Outcome Measure Data

Analysis Population Description

Full Analysis Set Period 1 (FAS1) with Non-Responder Imputation (NRI). FAS1 consisted of all subjects with valid Baseline and valid post-Baseline efficacy measurement within Period 1 for DAS28(ESR). For NRI, a subject having missing data for the time point assessed was conservatively counted as a nonremitter or nonresponder.

Arm/Group Title	Placebo + Methotrexate (Full Analysis Set)	Certolizumab Pegol + Methotrexate (Full Analysis Set)
Arm/Group Description:	Placebo + Methotrexate (MTX) 2 syringes Placebo at Baseline, Week 2 and Week 4 + MTX, followed by 1 syringe Placebo every 2 Weeks + MTX. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.	Certolizumab Pegol + Methotrexate (MTX) 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 + MTX at Baseline, Week 2 and Week 4, followed by a maintenance dose of CZP 200 mg + MTX every 2 Weeks until Week 50. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.
Overall Number of Participants Analyzed	213	655
Measure Type: Number; Unit of Measure: percentage of subjects
	26.3	38.9

12. Secondary Outcome

Title	Percentage of Subjects With Simplified Disease Activity Index (SDAI) ≤ 3.3 at Week 52
Description	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.
Time Frame	Week 52

Outcome Measure Data

Analysis Population Description

Full Analysis Set Period 1 (FAS1) with Non-Responder Imputation (NRI). FAS1 consisted of all subjects with valid Baseline and valid post-Baseline efficacy measurement within Period 1 for DAS28(ESR). For NRI, a subject having missing data for the time point assessed was conservatively counted as a nonremitter or nonresponder.

Arm/Group Title	Placebo + Methotrexate (Full Analysis Set)	Certolizumab Pegol + Methotrexate (Full Analysis Set)
Arm/Group Description:	Placebo + Methotrexate (MTX) 2 syringes Placebo at Baseline, Week 2 and Week 4 + MTX, followed by 1 syringe Placebo every 2 Weeks + MTX. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.	Certolizumab Pegol + Methotrexate (MTX) 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 + MTX at Baseline, Week 2 and Week 4, followed by a maintenance dose of CZP 200 mg + MTX every 2 Weeks until Week 50. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.
Overall Number of Participants Analyzed	213	655
Measure Type: Number; Unit of Measure: percentage of subjects
	24.9	38.9

13. Secondary Outcome

Title	Percentage of Subjects With Disease Activity Score 28 [Erythrocyte Sedimentation Rate] (DAS28 [ESR]) < 2.6 at Week 52
Description	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.
Time Frame	Week 52

Outcome Measure Data

Analysis Population Description

Full Analysis Set Period 1 (FAS1) with Non-Responder Imputation (NRI). FAS1 consisted of all subjects with valid Baseline and valid post-Baseline efficacy measurement within Period 1 for DAS28(ESR). For NRI, a subject having missing data for the time point assessed was conservatively counted as a nonremitter or nonresponder.

Arm/Group Title	Placebo + Methotrexate (Full Analysis Set)	Certolizumab Pegol + Methotrexate (Full Analysis Set)
Arm/Group Description:	Placebo + Methotrexate (MTX) 2 syringes Placebo at Baseline, Week 2 and Week 4 + MTX, followed by 1 syringe Placebo every 2 Weeks + MTX. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.	Certolizumab Pegol + Methotrexate (MTX) 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 + MTX at Baseline, Week 2 and Week 4, followed by a maintenance dose of CZP 200 mg + MTX every 2 Weeks until Week 50. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.
Overall Number of Participants Analyzed	213	655
Measure Type: Number; Unit of Measure: percentage of subjects
	26.8	42.6

14. Secondary Outcome

Title	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
Description	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.
Time Frame	Week 52

Outcome Measure Data

Analysis Population Description

Full Analysis Set Period 1 (FAS1) with Non-Responder Imputation (NRI). FAS1 consisted of all subjects with valid Baseline and valid post-Baseline efficacy measurement within Period 1 for DAS28(ESR). For NRI, a subject having missing data for the time point assessed was conservatively counted as a nonremitter or nonresponder.

Arm/Group Title	Placebo + Methotrexate (Full Analysis Set)	Certolizumab Pegol + Methotrexate (Full Analysis Set)
Arm/Group Description:	Placebo + Methotrexate (MTX) 2 syringes Placebo at Baseline, Week 2 and Week 4 + MTX, followed by 1 syringe Placebo every 2 Weeks + MTX. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.	Certolizumab Pegol + Methotrexate (MTX) 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 + MTX at Baseline, Week 2 and Week 4, followed by a maintenance dose of CZP 200 mg + MTX every 2 Weeks until Week 50. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.
Overall Number of Participants Analyzed	213	655
Measure Type: Number; Unit of Measure: percentage of subjects
	24.9	35.3

15. Secondary Outcome

Title	Percentage of Subjects Achieving a Good or Moderate European League Against Rheumatism (EULAR) Response at Week 52
Description	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.
Time Frame	From Baseline (Week 0) to Week 52

Outcome Measure Data

Analysis Population Description

Full Analysis Set Period 1 (FAS1). The FAS1 consisted of all subjects who had a valid Baseline and valid post-Baseline efficacy measurement within Period 1 for the primary efficacy assessment of DAS28(ESR).

Arm/Group Title	Placebo + Methotrexate (Full Analysis Set)	Certolizumab Pegol + Methotrexate (Full Analysis Set)
Arm/Group Description:	Placebo + Methotrexate (MTX) 2 syringes Placebo at Baseline, Week 2 and Week 4 + MTX, followed by 1 syringe Placebo every 2 Weeks + MTX. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.	Certolizumab Pegol + Methotrexate (MTX) 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 + MTX at Baseline, Week 2 and Week 4, followed by a maintenance dose of CZP 200 mg + MTX every 2 Weeks until Week 50. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.
Overall Number of Participants Analyzed	213	655
Measure Type: Number; Unit of Measure: percentage of subjects
	82.2	89.9

16. Secondary Outcome

Title	Change From Baseline in Disease Activity Score 28 [Erythrocyte Sedimentation Rate] (DAS28 [ESR]) to Week 52
Description	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.
Time Frame	From Baseline (Week 0) to Week 52

Outcome Measure Data

Analysis Population Description

Full Analysis Set Period 1 (FAS1) with Last Observation Carried Forward (LOCF). The FAS1 consisted of all subjects who had a valid Baseline and valid post-Baseline efficacy measurement within Period 1 for the primary efficacy assessment of DAS28(ESR). Missing DAS28(ESR) values were imputed using LOCF.

Arm/Group Title	Placebo + Methotrexate (Full Analysis Set)	Certolizumab Pegol + Methotrexate (Full Analysis Set)
Arm/Group Description:	Placebo + Methotrexate (MTX) 2 syringes Placebo at Baseline, Week 2 and Week 4 + MTX, followed by 1 syringe Placebo every 2 Weeks + MTX. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.	Certolizumab Pegol + Methotrexate (MTX) 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 + MTX at Baseline, Week 2 and Week 4, followed by a maintenance dose of CZP 200 mg + MTX every 2 Weeks until Week 50. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.
Overall Number of Participants Analyzed	210	646
Least Squares Mean (Standard Error); Unit of Measure: units on a scale
	-3.014 (0.109)	-3.615 (0.069)

17. Secondary Outcome

Title	Change From Baseline in Clinical Disease Activity Index (CDAI) to Week 52
Description	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.
Time Frame	From Baseline (Week 0) to Week 52

Outcome Measure Data

Analysis Population Description

Full Analysis Set Period 1 (FAS1) with Last Observation Carried Forward (LOCF). The FAS1 consisted of all subjects who had a valid Baseline and valid post-Baseline efficacy measurement within Period 1 for the primary efficacy assessment of DAS28(ESR). Missing CDAI values were imputed using LOCF.

Arm/Group Title	Placebo + Methotrexate (Full Analysis Set)	Certolizumab Pegol + Methotrexate (Full Analysis Set)
Arm/Group Description:	Placebo + Methotrexate (MTX) 2 syringes Placebo at Baseline, Week 2 and Week 4 + MTX, followed by 1 syringe Placebo every 2 Weeks + MTX. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.	Certolizumab Pegol + Methotrexate (MTX) 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 + MTX at Baseline, Week 2 and Week 4, followed by a maintenance dose of CZP 200 mg + MTX every 2 Weeks until Week 50. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.
Overall Number of Participants Analyzed	210	644
Least Squares Mean (Standard Error); Unit of Measure: units on a scale
	-29.09 (0.84)	-33.11 (0.52)

18. Secondary Outcome

Title	Change From Baseline in Simplified Disease Activity Index (SDAI) to Week 52
Description	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.
Time Frame	From Baseline (Week 0) to Week 52

Outcome Measure Data

Analysis Population Description

Full Analysis Set Period 1 (FAS1) with Last Observation Carried Forward (LOCF). The FAS1 consisted of all subjects who had a valid Baseline and valid post-Baseline efficacy measurement within Period 1 for the primary efficacy assessment of DAS28(ESR). Missing SDAI values were imputed using LOCF.

Arm/Group Title	Placebo + Methotrexate (Full Analysis Set)	Certolizumab Pegol + Methotrexate (Full Analysis Set)
Arm/Group Description:	Placebo + Methotrexate (MTX) 2 syringes Placebo at Baseline, Week 2 and Week 4 + MTX, followed by 1 syringe Placebo every 2 Weeks + MTX. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.	Certolizumab Pegol + Methotrexate (MTX) 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 + MTX at Baseline, Week 2 and Week 4, followed by a maintenance dose of CZP 200 mg + MTX every 2 Weeks until Week 50. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.
Overall Number of Participants Analyzed	210	644
Least Squares Mean (Standard Error); Unit of Measure: units on a scale
	-30.24 (0.88)	-34.55 (0.55)

19. Secondary Outcome

Title	Percentage of Subjects With a Health Assessment Questionnaire- Disability Index (HAQ-DI) ≤ 0.5 at Week 52
Description	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.
Time Frame	Week 52

Outcome Measure Data

Analysis Population Description

Full Analysis Set Period 1 (FAS1) with Non-Responder Imputation (NRI). FAS1 consisted of all subjects with valid Baseline and valid post-Baseline efficacy measurement within Period 1 for DAS28(ESR). For NRI, a subject having missing data for the time point assessed was conservatively counted as a nonremitter or nonresponder.

Arm/Group Title	Placebo + Methotrexate (Full Analysis Set)	Certolizumab Pegol + Methotrexate (Full Analysis Set)
Arm/Group Description:	Placebo + Methotrexate (MTX) 2 syringes Placebo at Baseline, Week 2 and Week 4 + MTX, followed by 1 syringe Placebo every 2 Weeks + MTX. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.	Certolizumab Pegol + Methotrexate (MTX) 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 + MTX at Baseline, Week 2 and Week 4, followed by a maintenance dose of CZP 200 mg + MTX every 2 Weeks until Week 50. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.
Overall Number of Participants Analyzed	213	655
Measure Type: Number; Unit of Measure: percentage of subjects
	35.7	48.1

20. Secondary Outcome

Title	Change From Baseline in the Health Assessment Questionnaire - Disability Index (HAQ-DI) to Week 52
Description	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.
Time Frame	From Baseline (Week 0) to Week 52

Outcome Measure Data

Analysis Population Description

Full Analysis Set Period 1 (FAS1) with Last Observation Carried Forward (LOCF). The FAS1 consisted of all subjects who had a valid Baseline and valid post-Baseline efficacy measurement within Period 1 for the primary efficacy assessment of DAS28(ESR). Missing HAQ-DI values were imputed using LOCF.

Arm/Group Title	Placebo + Methotrexate (Full Analysis Set)	Certolizumab Pegol + Methotrexate (Full Analysis Set)
Arm/Group Description:	Placebo + Methotrexate (MTX) 2 syringes Placebo at Baseline, Week 2 and Week 4 + MTX, followed by 1 syringe Placebo every 2 Weeks + MTX. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.	Certolizumab Pegol + Methotrexate (MTX) 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 + MTX at Baseline, Week 2 and Week 4, followed by a maintenance dose of CZP 200 mg + MTX every 2 Weeks until Week 50. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.
Overall Number of Participants Analyzed	210	645
Least Squares Mean (Standard Error); Unit of Measure: units on a scale
	-0.819 (0.044)	-0.997 (0.028)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo + Methotrexate (Full Analysis Set), Certolizumab Pegol + Methotrexate (Full Analysis Set)
	Comments	In order to control the overall study-wise Type I error rate at 5 %, hypothesis testing was performed in the following hierarchical order (each at a 2-sided 95 % alpha level): Primary: sustained DAS28(ESR) remission at Week 52; Key secondary: sustained DAS28(ESR) LDA at Week 52; ACR50 response at Week 52 in relation to Baseline; Change from Baseline in HAQ-DI at Week 52; Change from Baseline in mTSS at Week 52
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in Least Squares (LS) Means
	Estimated Value	-0.177
	Confidence Interval	(2-Sided) 95%; -0.273 to -0.082
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.049
	Estimation Comments	The CfB in HAQ-DI at Week 52 was analyzed using an ANCOVA model with terms for treatment, region, and time since Rheumatoid Arthritis (RA) diagnosis at Baseline (≤4 months or >4 months) as factors and Baseline value as a covariate.

21. Secondary Outcome

Title	Change From Baseline in the Bristol Rheumatoid Arthritis Fatigue- Multidimensional Questionnaire (BRAF-MDQ) Total Score to Week 52
Description	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.
Time Frame	From Baseline (Week 0) to Week 52

Outcome Measure Data

Analysis Population Description

Full Analysis Set Period 1 (FAS1) with Last Observation Carried Forward (LOCF). The FAS1 consisted of all subjects who had a valid Baseline and valid post-Baseline efficacy measurement within Period 1 for the primary efficacy assessment of DAS28(ESR). Missing BRAF-MDQ values were imputed using LOCF.

Arm/Group Title	Placebo + Methotrexate (Full Analysis Set)	Certolizumab Pegol + Methotrexate (Full Analysis Set)
Arm/Group Description:	Placebo + Methotrexate (MTX) 2 syringes Placebo at Baseline, Week 2 and Week 4 + MTX, followed by 1 syringe Placebo every 2 Weeks + MTX. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.	Certolizumab Pegol + Methotrexate (MTX) 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 + MTX at Baseline, Week 2 and Week 4, followed by a maintenance dose of CZP 200 mg + MTX every 2 Weeks until Week 50. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.
Overall Number of Participants Analyzed	205	636
Least Squares Mean (Standard Error); Unit of Measure: units on a scale
	-15.6 (1.0)	-17.8 (0.6)

22. Secondary Outcome

Title	Number of Work Days Missed (Work Productivity Survey - Rheumatoid Arthritis [WPS-RA]) at Week 52
Description	Number of work days missed in the last month for employed subjects.
Time Frame	Week 52

Outcome Measure Data

Analysis Population Description

Full Analysis Set Period 1 (FAS1) with Last Observation Carried Forward (LOCF). The FAS1 consisted of all subjects who had a valid Baseline and valid post-Baseline efficacy measurement within Period 1 for the primary efficacy assessment of DAS28(ESR). Missing WPS-RA values were imputed using LOCF.

Arm/Group Title	Placebo + Methotrexate (Full Analysis Set)	Certolizumab Pegol + Methotrexate (Full Analysis Set)
Arm/Group Description:	Placebo + Methotrexate (MTX) 2 syringes Placebo at Baseline, Week 2 and Week 4 + MTX, followed by 1 syringe Placebo every 2 Weeks + MTX. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.	Certolizumab Pegol + Methotrexate (MTX) 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 + MTX at Baseline, Week 2 and Week 4, followed by a maintenance dose of CZP 200 mg + MTX every 2 Weeks until Week 50. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.
Overall Number of Participants Analyzed	106	351
Mean (Standard Deviation); Unit of Measure: days
	0.9 (2.5)	0.6 (2.6)

23. Secondary Outcome

Title	Number of Work Days With Reduced Productivity (Work Productivity Survey - Rheumatoid Arthritis [WPS-RA]) at Week 52
Description	Number of work days with reduced productivity in the last month for employed subjects.
Time Frame	Week 52

Outcome Measure Data

Analysis Population Description

Full Analysis Set Period 1 (FAS1) with Last Observation Carried Forward (LOCF). The FAS1 consisted of all subjects who had a valid Baseline and valid post-Baseline efficacy measurement within Period 1 for the primary efficacy assessment of DAS28(ESR). Missing WPS-RA values were imputed using LOCF.

Arm/Group Title	Placebo + Methotrexate (Full Analysis Set)	Certolizumab Pegol + Methotrexate (Full Analysis Set)
Arm/Group Description:	Placebo + Methotrexate (MTX) 2 syringes Placebo at Baseline, Week 2 and Week 4 + MTX, followed by 1 syringe Placebo every 2 Weeks + MTX. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.	Certolizumab Pegol + Methotrexate (MTX) 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 + MTX at Baseline, Week 2 and Week 4, followed by a maintenance dose of CZP 200 mg + MTX every 2 Weeks until Week 50. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.
Overall Number of Participants Analyzed	106	351
Mean (Standard Deviation); Unit of Measure: days
	1.8 (4.7)	1.0 (3.4)

24. Secondary Outcome

Title	Interference With Work Productivity (Work Productivity Survey - Rheumatoid Arthritis [WPS-RA]) at Week 52
Description	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.
Time Frame	Week 52

Outcome Measure Data

Analysis Population Description

Full Analysis Set Period 1 (FAS1) with Last Observation Carried Forward (LOCF). The FAS1 consisted of all subjects who had a valid Baseline and valid post-Baseline efficacy measurement within Period 1 for the primary efficacy assessment of DAS28(ESR). Missing WPS-RA values were imputed using LOCF.

Arm/Group Title	Placebo + Methotrexate (Full Analysis Set)	Certolizumab Pegol + Methotrexate (Full Analysis Set)
Arm/Group Description:	Placebo + Methotrexate (MTX) 2 syringes Placebo at Baseline, Week 2 and Week 4 + MTX, followed by 1 syringe Placebo every 2 Weeks + MTX. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.	Certolizumab Pegol + Methotrexate (MTX) 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 + MTX at Baseline, Week 2 and Week 4, followed by a maintenance dose of CZP 200 mg + MTX every 2 Weeks until Week 50. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.
Overall Number of Participants Analyzed	106	351
Mean (Standard Deviation); Unit of Measure: units on a scale
	1.9 (2.3)	1.4 (2.0)

25. Secondary Outcome

Title	Number of Days With no Household Work (Work Productivity Survey - Rheumatoid Arthritis [WPS-RA]) at Week 52
Description	Number of days with no household work in the last month.
Time Frame	Week 52

Outcome Measure Data

Analysis Population Description

Full Analysis Set Period 1 (FAS1) with Last Observation Carried Forward (LOCF). The FAS1 consisted of all subjects who had a valid Baseline and valid post-Baseline efficacy measurement within Period 1 for the primary efficacy assessment of DAS28(ESR). Missing WPS-RA values were imputed using LOCF.

Arm/Group Title	Placebo + Methotrexate (Full Analysis Set)	Certolizumab Pegol + Methotrexate (Full Analysis Set)
Arm/Group Description:	Placebo + Methotrexate (MTX) 2 syringes Placebo at Baseline, Week 2 and Week 4 + MTX, followed by 1 syringe Placebo every 2 Weeks + MTX. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.	Certolizumab Pegol + Methotrexate (MTX) 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 + MTX at Baseline, Week 2 and Week 4, followed by a maintenance dose of CZP 200 mg + MTX every 2 Weeks until Week 50. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.
Overall Number of Participants Analyzed	206	640
Mean (Standard Deviation); Unit of Measure: days
	3.0 (6.7)	1.9 (5.1)

26. Secondary Outcome

Title	Number of Days With Reduced Household Work Productivity (Work Productivity Survey - Rheumatoid Arthritis [WPS-RA]) at Week 52
Description	Number of days with reduced household work productivity in the last month.
Time Frame	Week 52

Outcome Measure Data

Analysis Population Description

Full Analysis Set Period 1 (FAS1) with Last Observation Carried Forward (LOCF). The FAS1 consisted of all subjects who had a valid Baseline and valid post-Baseline efficacy measurement within Period 1 for the primary efficacy assessment of DAS28(ESR). Missing WPS-RA values were imputed using LOCF.

Arm/Group Title	Placebo + Methotrexate (Full Analysis Set)	Certolizumab Pegol + Methotrexate (Full Analysis Set)
Arm/Group Description:	Placebo + Methotrexate (MTX) 2 syringes Placebo at Baseline, Week 2 and Week 4 + MTX, followed by 1 syringe Placebo every 2 Weeks + MTX. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.	Certolizumab Pegol + Methotrexate (MTX) 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 + MTX at Baseline, Week 2 and Week 4, followed by a maintenance dose of CZP 200 mg + MTX every 2 Weeks until Week 50. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.
Overall Number of Participants Analyzed	206	640
Mean (Standard Deviation); Unit of Measure: days
	3.0 (6.6)	2.1 (5.3)

27. Secondary Outcome

Title	Number of Days With Hired Outside Help (Work Productivity Survey - Rheumatoid Arthritis [WPS-RA]) at Week 52
Description	Number of days with hired outside help in the last month.
Time Frame	Week 52

Outcome Measure Data

Analysis Population Description

Full Analysis Set Period 1 (FAS1) with Last Observation Carried Forward (LOCF). The FAS1 consisted of all subjects who had a valid Baseline and valid post-Baseline efficacy measurement within Period 1 for the primary efficacy assessment of DAS28(ESR). Missing WPS-RA values were imputed using LOCF.

Arm/Group Title	Placebo + Methotrexate (Full Analysis Set)	Certolizumab Pegol + Methotrexate (Full Analysis Set)
Arm/Group Description:	Placebo + Methotrexate (MTX) 2 syringes Placebo at Baseline, Week 2 and Week 4 + MTX, followed by 1 syringe Placebo every 2 Weeks + MTX. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.	Certolizumab Pegol + Methotrexate (MTX) 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 + MTX at Baseline, Week 2 and Week 4, followed by a maintenance dose of CZP 200 mg + MTX every 2 Weeks until Week 50. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.
Overall Number of Participants Analyzed	206	640
Mean (Standard Deviation); Unit of Measure: days
	0.7 (3.3)	0.6 (3.2)

28. Secondary Outcome

Title	Number of Days Missed of Family/Social/Leisure Activities (Work Productivity Survey - Rheumatoid Arthritis [WPS-RA]) at Week 52
Description	Number of days missed of family/social/leisure activities in the last month.
Time Frame	Week 52

Outcome Measure Data

Analysis Population Description

Full Analysis Set Period 1 (FAS1) with Last Observation Carried Forward (LOCF). The FAS1 consisted of all subjects who had a valid Baseline and valid post-Baseline efficacy measurement within Period 1 for the primary efficacy assessment of DAS28(ESR). Missing WPS-RA values were imputed using LOCF.

Arm/Group Title	Placebo + Methotrexate (Full Analysis Set)	Certolizumab Pegol + Methotrexate (Full Analysis Set)
Arm/Group Description:	Placebo + Methotrexate (MTX) 2 syringes Placebo at Baseline, Week 2 and Week 4 + MTX, followed by 1 syringe Placebo every 2 Weeks + MTX. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.	Certolizumab Pegol + Methotrexate (MTX) 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 + MTX at Baseline, Week 2 and Week 4, followed by a maintenance dose of CZP 200 mg + MTX every 2 Weeks until Week 50. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.
Overall Number of Participants Analyzed	206	640
Mean (Standard Deviation); Unit of Measure: days
	0.9 (3.1)	0.9 (3.6)

29. Secondary Outcome

Title	Interference With Household Work Productivity (Work Productivity Survey - Rheumatoid Arthritis [WPS-RA]) at Week 52
Description	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).
Time Frame	Week 52

Outcome Measure Data

Analysis Population Description

Full Analysis Set Period 1 (FAS1) with Last Observation Carried Forward (LOCF). The FAS1 consisted of all subjects who had a valid Baseline and valid post-Baseline efficacy measurement within Period 1 for the primary efficacy assessment of DAS28(ESR). Missing WPS-RA values were imputed using LOCF.

Arm/Group Title	Placebo + Methotrexate (Full Analysis Set)	Certolizumab Pegol + Methotrexate (Full Analysis Set)
Arm/Group Description:	Placebo + Methotrexate (MTX) 2 syringes Placebo at Baseline, Week 2 and Week 4 + MTX, followed by 1 syringe Placebo every 2 Weeks + MTX. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.	Certolizumab Pegol + Methotrexate (MTX) 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 + MTX at Baseline, Week 2 and Week 4, followed by a maintenance dose of CZP 200 mg + MTX every 2 Weeks until Week 50. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.
Overall Number of Participants Analyzed	206	640
Mean (Standard Deviation); Unit of Measure: units on a scale
	2.5 (2.8)	1.9 (2.5)

30. Secondary Outcome

Title	Percentage of Subjects Achieving Low Disease Activity (LDA) at Week 52
Description	LDA is defined as achieving a Disease Activity Score 28 [Erythrocyte Sedimentation Rate] (DAS28 [ESR]) ≤ 3.2.
Time Frame	Week 52

Outcome Measure Data

Analysis Population Description

Full Analysis Set Period 1 (FAS1) with Non-Responder Imputation (NRI). FAS1 consisted of all subjects with valid Baseline and valid post-Baseline efficacy measurement within Period 1 for DAS28(ESR). For NRI, a subject having missing data for the time point assessed was conservatively counted as a nonremitter or nonresponder.

Arm/Group Title	Placebo + Methotrexate (Full Analysis Set)	Certolizumab Pegol + Methotrexate (Full Analysis Set)
Arm/Group Description:	Placebo + Methotrexate (MTX) 2 syringes Placebo at Baseline, Week 2 and Week 4 + MTX, followed by 1 syringe Placebo every 2 Weeks + MTX. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.	Certolizumab Pegol + Methotrexate (MTX) 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 + MTX at Baseline, Week 2 and Week 4, followed by a maintenance dose of CZP 200 mg + MTX every 2 Weeks until Week 50. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.
Overall Number of Participants Analyzed	213	655
Measure Type: Number; Unit of Measure: percentage of subjects
	39.4	54.7

Adverse Events

Time Frame	Adverse Events were collected from Screening over Baseline (Week 0) and Treatment Period 1 (Week 2 to Week 52) to the Safety Follow-Up Visit (Week 60).
Adverse Event Reporting Description	Adverse Events presented below refer to the Safety Set 1 (SS1), which consisted of all subjects in the Randomized Set who had received at least 1 dose of study medication (CZP/PBO) in Period 1.
Arm/Group Title	Placebo + Methotrexate		Certolizumab Pegol + Methotrexate
Arm/Group Description	Placebo + Methotrexate (MTX) 2 syringes Placebo at Baseline, Week 2 and Week 4 + MTX, followed by 1 syringe Placebo every 2 Weeks + MTX. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.		Certolizumab Pegol + Methotrexate (MTX) 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 + MTX at Baseline, Week 2 and Week 4, followed by a maintenance dose of CZP 200 mg + MTX every 2 Weeks until Week 50. The MTX treatment is to be initiated at a dose of 10 mg per Week. 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.
All-Cause Mortality
	Placebo + Methotrexate		Certolizumab Pegol + Methotrexate
	Affected / at Risk (%)		Affected / at Risk (%)
Total	--/--		--/--
Serious Adverse Events
	Placebo + Methotrexate		Certolizumab Pegol + Methotrexate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	20/217 (9.22%)		70/659 (10.62%)
Blood and lymphatic system disorders
Anaemia * 1	0/217 (0.00%)	0	3/659 (0.46%)	5
Bone marrow toxicity * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Iron deficiency anaemia * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Pancytopenia * 1	0/217 (0.00%)	0	2/659 (0.30%)	2
Cardiac disorders
Acute myocardial infarction * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Atrial fibrillation * 1	1/217 (0.46%)	1	1/659 (0.15%)	1
Cardiac arrest * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Cardiac failure * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Cardiac tamponade * 1	1/217 (0.46%)	1	0/659 (0.00%)	0
Myocardial infarction * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Myocardial ischaemia * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Pericarditis * 1	1/217 (0.46%)	1	0/659 (0.00%)	0
Gastrointestinal disorders
Colitis * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Duodenal ulcer * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Erosive duodenitis * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Gastritis erosive * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Gastrointestinal ulcer haemorrhage * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Gastrooesophageal reflux disease * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Mesenteric panniculitis * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Mouth ulceration * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Nausea * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Pancreatitis acute * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Rectal haemorrhage * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Upper gastrointestinal haemorrhage * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Hepatobiliary disorders
Bile duct stone * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Cholecystitis * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Cholelithiasis * 1	0/217 (0.00%)	0	2/659 (0.30%)	2
Immune system disorders
Anaphylactic shock * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Food allergy * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Infections and infestations
Abscess limb * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Appendiceal abscess * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Arthritis infective * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Breast abscess * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Bronchitis * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Bronchopneumonia * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Cellulitis * 1	1/217 (0.46%)	1	2/659 (0.30%)	2
Erysipelas * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Gastroenteritis * 1	1/217 (0.46%)	1	0/659 (0.00%)	0
Groin abscess * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Herpes zoster * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Impetigo * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Influenza * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Kidney infection * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Labyrinthitis * 1	1/217 (0.46%)	1	0/659 (0.00%)	0
Latent tuberculosis * 1	2/217 (0.92%)	2	1/659 (0.15%)	1
Localised infection * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Pneumonia * 1	3/217 (1.38%)	3	4/659 (0.61%)	4
Pulmonary tuberculosis * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Sepsis * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Staphylococcal infection * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Tuberculosis gastrointestinal * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Urosepsis * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Wound infection * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Injury, poisoning and procedural complications
Ankle fracture * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Fall * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Femoral neck fracture * 1	0/217 (0.00%)	0	1/659 (0.15%)	2
Joint dislocation * 1	0/217 (0.00%)	0	2/659 (0.30%)	2
Limb injury * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Lumbar vertebral fracture * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Tendon rupture * 1	1/217 (0.46%)	1	0/659 (0.00%)	0
Tibia fracture * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Metabolism and nutrition disorders
Hyperglycaemia * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Musculoskeletal and connective tissue disorders
Intervertebral disc degeneration * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Lupus-like syndrome * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Muscle haemorrhage * 1	1/217 (0.46%)	1	0/659 (0.00%)	0
Osteoarthritis * 1	0/217 (0.00%)	0	4/659 (0.61%)	4
Rheumatoid nodule * 1	0/217 (0.00%)	0	1/659 (0.15%)	2
Synovial cyst * 1	1/217 (0.46%)	1	1/659 (0.15%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
B-cell lymphoma * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Basal cell carcinoma * 1	1/217 (0.46%)	1	0/659 (0.00%)	0
Cervix carcinoma * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Chondrosarcoma * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Endometrial cancer * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Ovarian cancer * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Prostate cancer * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Renal cell carcinoma * 1	1/217 (0.46%)	1	0/659 (0.00%)	0
Nervous system disorders
Carpal tunnel syndrome * 1	1/217 (0.46%)	1	0/659 (0.00%)	0
Cerebrovascular accident * 1	1/217 (0.46%)	1	1/659 (0.15%)	1
Cervicobrachial syndrome * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Ischaemic stroke * 1	1/217 (0.46%)	1	1/659 (0.15%)	1
Loss of consciousness * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Migraine * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Renal and urinary disorders
Bladder outlet obstruction * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Renal failure * 1	1/217 (0.46%)	1	1/659 (0.15%)	1
Reproductive system and breast disorders
Menorrhagia * 1	0/217 (0.00%)	0	2/659 (0.30%)	4
Uterine polyp * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Epiglottic cyst * 1	1/217 (0.46%)	1	0/659 (0.00%)	0
Interstitial lung disease * 1	0/217 (0.00%)	0	2/659 (0.30%)	2
Laryngeal polyp * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Pneumonitis * 1	2/217 (0.92%)	2	0/659 (0.00%)	0
Pulmonary embolism * 1	2/217 (0.92%)	2	1/659 (0.15%)	1
Pulmonary mass * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Respiratory failure * 1	1/217 (0.46%)	1	1/659 (0.15%)	3
Skin and subcutaneous tissue disorders
Urticaria * 1	1/217 (0.46%)	2	0/659 (0.00%)	0
Surgical and medical procedures
Coronary arterial stent insertion * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Hip arthroplasty * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Leg amputation * 1	0/217 (0.00%)	0	1/659 (0.15%)	2
Vascular disorders
Aortic aneurysm * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Aortic stenosis * 1	0/217 (0.00%)	0	1/659 (0.15%)	1
Arteriosclerosis * 1	1/217 (0.46%)	1	0/659 (0.00%)	0
Deep vein thrombosis * 1	1/217 (0.46%)	1	1/659 (0.15%)	1
Orthostatic hypotension * 1	1/217 (0.46%)	1	0/659 (0.00%)	0
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA17.0
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Placebo + Methotrexate		Certolizumab Pegol + Methotrexate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	63/217 (29.03%)		248/659 (37.63%)
Gastrointestinal disorders
Nausea * 1	22/217 (10.14%)	22	83/659 (12.59%)	92
Infections and infestations
Upper respiratory tract infection * 1	11/217 (5.07%)	12	72/659 (10.93%)	86
Urinary tract infection * 1	16/217 (7.37%)	18	48/659 (7.28%)	63
Nasopharyngitis * 1	13/217 (5.99%)	17	46/659 (6.98%)	60
Investigations
Alanine aminotransferase increased * 1	9/217 (4.15%)	13	42/659 (6.37%)	46
Nervous system disorders
Headache * 1	8/217 (3.69%)	11	45/659 (6.83%)	65
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA17.0

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: UCB (Study Director)
• Organization: UCB Clinical Trial Call Center
• Phone: +1 887 822 9493

Publications of Results:

Emery P, Bingham CO 3rd, Burmester GR, Bykerk VP, Furst DE, Mariette X, van der Heijde D, van Vollenhoven R, Arendt C, Mountian I, Purcaru O, Tatla D, VanLunen B, Weinblatt ME. Certolizumab pegol in combination with dose-optimised methotrexate in DMARD-naive patients with early, active rheumatoid arthritis with poor prognostic factors: 1-year results from C-EARLY, a randomised, double-blind, placebo-controlled phase III study. Ann Rheum Dis. 2017 Jan;76(1):96-104. doi: 10.1136/annrheumdis-2015-209057. Epub 2016 May 10.

Weinblatt ME, Bingham CO 3rd, Burmester GR, Bykerk VP, Furst DE, Mariette X, van der Heijde D, van Vollenhoven R, VanLunen B, Ecoffet C, Cioffi C, Emery P. A Phase III Study Evaluating Continuation, Tapering, and Withdrawal of Certolizumab Pegol After One Year of Therapy in Patients With Early Rheumatoid Arthritis. Arthritis Rheumatol. 2017 Oct;69(10):1937-1948. doi: 10.1002/art.40196. Epub 2017 Sep 12.

• Responsible Party: UCB Pharma ( UCB Pharma SA )
• ClinicalTrials.gov Identifier: NCT01519791
• Other Study ID Numbers: RA0055 Period 1; 2011-001729-25 ( EudraCT Number )
• First Submitted: January 19, 2012
• First Posted: January 27, 2012
• Results First Submitted: July 8, 2015
• Results First Posted: September 22, 2015
• Last Update Posted: July 31, 2018