Magnetic Resonance Image Verified Early Response to Certolizumab Pegol in Subjects With Active Rheumatoid Arthritis (RA) (MARVELOUS)

• ClinicalTrials.gov Identifier: NCT01235598
• Recruitment Status: Completed
• First Posted: November 5, 2010
• Results First Posted: February 5, 2014
• Last Update Posted: March 12, 2014
• Sponsor: UCB Pharma
• Information provided by (Responsible Party): UCB Pharma

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Rheumatoid Arthritis
• Interventions: Other: Placebo; Biological: Certolizumab Pegol (CZP) 200 mg; Biological: Certolizumab Pegol (CZP) 400 mg
• Enrollment: 41

Participant Flow

Recruitment Details	The Participant Flow refers to the Randomized Set (RS) population which consists of all subjects randomized into the study.
Pre-assignment Details	The study population consists of subjects with a diagnosis of adult-onset Rheumatoid Arthritis of at least 3 months duration but not longer than 15 years. In addition, subjects must be on Disease Modifying Anti-Rheumatic Drugs (DMARD) therapy for at least 12 weeks with a stable dose / route of administration for at least 8 weeks prior to Baseline.

Arm/Group Title	Placebo Followed by Certolizumab Pegol (CZP)	Certolizumab Pegol (CZP)
Arm/Group Description	Placebo, saline solution for subcutaneous injection at Week 0 followed by Certolizumab Pegol (CZP) 400 mg at Weeks 2, 4, and 6, then Certolizumab Pegol (CZP) 200 mg 2-weekly from Week 8 to Week 40	Certolizumab Pegol (CZP) 400 mg for subcutaneous injection at Weeks 0, 2 and 4 followed by 200 mg 2-weekly from Week 6 to Week 40
Period Title: Overall Study
Started	13	28 [1]
Completed	12	24
Not Completed	1	4
Reason Not Completed
Adverse Event	0	3
Lack of Efficacy	0	1
Withdrawal by Subject	1	0
[1] One subject was randomized to the CZP Arm but never received an injection (due to pre-treatment AE)

Baseline Characteristics

Arm/Group Title		Placebo Followed by Certolizumab Pegol (CZP)	Certolizumab Pegol (CZP)	Total
Arm/Group Description		Placebo, saline solution for subcutaneous injection at Week 0 followed by Certolizumab Pegol (CZP) 400 mg at Weeks 2, 4, and 6, then Certolizumab Pegol (CZP) 200 mg 2-weekly from Week 8 to Week 40	Certolizumab Pegol (CZP) 400 mg for subcutaneous injection at Weeks 0, 2 and 4 followed by 200 mg 2-weekly from Week 6 to Week 40	Total of all reporting groups
Overall Number of Baseline Participants		13	27	40
Baseline Analysis Population Description		The Baseline characteristics refer to the Safety Set (SS) population. The Safety Population includes all subjects enrolled who received at least 1 injection of study treatment.
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	13 participants	27 participants	40 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	11 84.6%	21 77.8%	32 80.0%
	>=65 years	2 15.4%	6 22.2%	8 20.0%
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	13 participants	27 participants	40 participants
		48.3 (14.4)	51.3 (12.6)	50.4 (13.1)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	13 participants	27 participants	40 participants
	Female	10 76.9%	22 81.5%	32 80.0%
	Male	3 23.1%	5 18.5%	8 20.0%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants	Number Analyzed	13 participants	27 participants	40 participants
Poland		2	7	9
Denmark		6	11	17
Netherlands		1	3	4
Sweden		4	6	10

Outcome Measures

1. Primary Outcome

Title	Change in Synovitis Measured by Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) Rheumatoid Arthritis Magnetic Resonance Image Scoring System (RAMRIS) Score at Week 16 Compared to Baseline for Certolizumab Pegol Arm
Description	Rheumatoid Arthritis Magnetic Resonance Image Scoring System (RAMRIS): Synovitis is defined as an area in the synovial compartment that shows above normal postgadolinium enhancement of a thickness greater than the width of the normal synovium. T1-weighted images were acquired before and after the administration of intravenous contrast agent containing gadolinium. Intravenous contrast was required to demonstrate enhancing synovitis. Synovitis was scored 0 to 3 in 3 wrist regions and in each of the second through fifth metacarpophalangeal (MCP) joints. A score of 0 is normal, with no enhancement or enhancement up to the thickness of normal synovium, while scores of 1 to 3 (mild, moderate, severe) refer to increments of one-third of the presumed maximum volume of enhancing tissue in the synovial compartment. Total synovitis score ranges from a minimum of 0 to a maximum of 21. A negative value in synovitis change from Baseline score indicates an improvement.
Time Frame	From Baseline to Week 16

Outcome Measure Data

Analysis Population Description

The Analysis Population refers to the Full Analysis Set (FAS) (last observation carried forward) which consists of all randomized subjects that received at least one dose of study medication. As pre-specified in the protocol, this analysis is restricted to the Certolizumab Pegol (CZP) arm.

Arm/Group Title	Certolizumab Pegol (CZP)
Arm/Group Description:	Certolizumab Pegol (CZP) 400 mg for subcutaneous injection at Weeks 0, 2 and 4 followed by 200 mg 2-weekly from Week 6 to Week 40
Overall Number of Participants Analyzed	27
Mean (Standard Deviation); Unit of Measure: scores on a scale
	-1.0 (2.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Certolizumab Pegol (CZP)
	Comments	A fixed-sequence stepwise hypothesis testing procedure was followed using a pre-specified set of ordered hypotheses. Hypotheses were ordered and tested in that order, beginning with change from Baseline at Week 16, and continuing to earlier time points (Week 8, 4, 2, 1 in that order) only if the previous null hypothesis of zero difference was rejected (p <0.05). Hypothesis testing was stopped if and when a non-significant result was obtained.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.049
	Comments	Two-sided p-value is presented, with p < 0.05 as the threshold for statistical significance.
	Method	Permutation test with general scores
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Median difference within group changes
	Estimated Value	-1.5
	Confidence Interval	(2-Sided) 95%; -3.0 to 0.0
	Estimation Comments	Hodges-Lehmann estimate of median difference and associated exact 95 % 2-sided confidence interval are provided.

2. Primary Outcome

Title	Change in Synovitis Measured by Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) Rheumatoid Arthritis Magnetic Resonance Image Scoring System (RAMRIS) Score at Week 8 Compared to Baseline for Certolizumab Pegol Arm
Description	Rheumatoid Arthritis Magnetic Resonance Image Scoring System (RAMRIS): Synovitis is defined as an area in the synovial compartment that shows above normal postgadolinium enhancement of a thickness greater than the width of the normal synovium. T1-weighted images were acquired before and after the administration of intravenous contrast agent containing gadolinium. Intravenous contrast was required to demonstrate enhancing synovitis. Synovitis was scored 0 to 3 in 3 wrist regions and in each of the second through fifth metacarpophalangeal (MCP) joints. A score of 0 is normal, with no enhancement or enhancement up to the thickness of normal synovium, while scores of 1 to 3 (mild, moderate, severe) refer to increments of one-third of the presumed maximum volume of enhancing tissue in the synovial compartment. Total synovitis score ranges from a minimum of 0 to a maximum of 21. A negative value in synovitis change from Baseline score indicates an improvement.
Time Frame	From Baseline to Week 8

Outcome Measure Data

Analysis Population Description

The Analysis Population refers to the Full Analysis Set (FAS) (last observation carried forward) which consists of all randomized subjects that received at least one dose of study medication. As pre-specified in the protocol, this analysis is restricted to the Certolizumab Pegol (CZP) arm.

Arm/Group Title	Certolizumab Pegol (CZP)
Arm/Group Description:	Certolizumab Pegol (CZP) 400 mg for subcutaneous injection at Weeks 0, 2 and 4 followed by 200 mg 2-weekly from Week 6 to Week 40
Overall Number of Participants Analyzed	27
Mean (Standard Deviation); Unit of Measure: scores on a scale
	-0.7 (2.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Certolizumab Pegol (CZP)
	Comments	A fixed-sequence stepwise hypothesis testing procedure was followed using a pre-specified set of ordered hypotheses. Hypotheses were ordered and tested in that order, beginning with change from Baseline at Week 16, and continuing to earlier time points (Week 8, 4, 2, 1 in that order) only if the previous null hypothesis of zero difference was rejected (p < 0.05). Hypothesis testing was stopped if and when a non-significant result was obtained. Testing was stopped in the next step.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.206
	Comments	Two-sided p-value is presented, with p < 0.05 as the threshold for statistical significance. A fixed-sequence stepwise hypothesis testing procedure was followed using a pre-specified set of ordered hypotheses.
	Method	Permutation test with general scores
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Median Difference within group changes
	Estimated Value	-1.0
	Confidence Interval	(2-Sided) 95%; -3.0 to 1.0
	Estimation Comments	Hodges-Lehmann estimate of median difference and associated exact 95 % 2-sided confidence interval are provided.

3. Primary Outcome

Title	Change in Synovitis Measured by Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) Rheumatoid Arthritis Magnetic Resonance Image Scoring System (RAMRIS) Score at Week 4 Compared to Baseline for Certolizumab Pegol Arm
Description	Rheumatoid Arthritis Magnetic Resonance Image Scoring System (RAMRIS): Synovitis is defined as an area in the synovial compartment that shows above normal postgadolinium enhancement of a thickness greater than the width of the normal synovium. T1-weighted images were acquired before and after the administration of intravenous contrast agent containing gadolinium. Intravenous contrast was required to demonstrate enhancing synovitis. Synovitis was scored 0 to 3 in 3 wrist regions and in each of the second through fifth metacarpophalangeal (MCP) joints. A score of 0 is normal, with no enhancement or enhancement up to the thickness of normal synovium, while scores of 1 to 3 (mild, moderate, severe) refer to increments of one-third of the presumed maximum volume of enhancing tissue in the synovial compartment. Total synovitis score ranges from a minimum of 0 to a maximum of 21. A negative value in synovitis change from Baseline score indicates an improvement.
Time Frame	From Baseline to Week 4

Outcome Measure Data

Analysis Population Description

The Analysis Population refers to the Full Analysis Set (FAS) (last observation carried forward) which consists of all randomized subjects that received at least one dose of study medication. As pre-specified in the protocol, this analysis is restricted to the Certolizumab Pegol (CZP) arm.

Arm/Group Title	Certolizumab Pegol (CZP)
Arm/Group Description:	Certolizumab Pegol (CZP) 400 mg for subcutaneous injection at Weeks 0, 2 and 4 followed by 200 mg 2-weekly from Week 6 to Week 40
Overall Number of Participants Analyzed	27
Mean (Standard Deviation); Unit of Measure: scores on a scale
	-0.4 (1.6)

4. Primary Outcome

Title	Change in Synovitis Measured by Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) Rheumatoid Arthritis Magnetic Resonance Image Scoring System (RAMRIS) Score at Week 2 Compared to Baseline for Certolizumab Pegol Arm
Description	Rheumatoid Arthritis Magnetic Resonance Image Scoring System (RAMRIS): Synovitis is defined as an area in the synovial compartment that shows above normal postgadolinium enhancement of a thickness greater than the width of the normal synovium. T1-weighted images were acquired before and after the administration of intravenous contrast agent containing gadolinium. Intravenous contrast was required to demonstrate enhancing synovitis. Synovitis was scored 0 to 3 in 3 wrist regions and in each of the second through fifth metacarpophalangeal (MCP) joints. A score of 0 is normal, with no enhancement or enhancement up to the thickness of normal synovium, while scores of 1 to 3 (mild, moderate, severe) refer to increments of one-third of the presumed maximum volume of enhancing tissue in the synovial compartment. Total synovitis score ranges from a minimum of 0 to a maximum of 21. A negative value in synovitis change from Baseline score indicates an improvement.
Time Frame	From Baseline to Week 2

Outcome Measure Data

Analysis Population Description

The Analysis Population refers to the Full Analysis Set (FAS) (last observation carried forward) which consists of all randomized subjects that received at least one dose of study medication. As pre-specified in the protocol, this analysis is restricted to the Certolizumab Pegol (CZP) arm.

Arm/Group Title	Certolizumab Pegol (CZP)
Arm/Group Description:	Certolizumab Pegol (CZP) 400 mg for subcutaneous injection at Weeks 0, 2 and 4 followed by 200 mg 2-weekly from Week 6 to Week 40
Overall Number of Participants Analyzed	27
Mean (Standard Deviation); Unit of Measure: scores on a scale
	-0.4 (1.6)

5. Primary Outcome

Title	Change in Synovitis Measured by Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) Rheumatoid Arthritis Magnetic Resonance Image Scoring System (RAMRIS) Score at Week 1 Compared to Baseline for Certolizumab Pegol Arm
Description	Rheumatoid Arthritis Magnetic Resonance Image Scoring System (RAMRIS): Synovitis is defined as an area in the synovial compartment that shows above normal postgadolinium enhancement of a thickness greater than the width of the normal synovium. T1-weighted images were acquired before and after the administration of intravenous contrast agent containing gadolinium. Intravenous contrast was required to demonstrate enhancing synovitis. Synovitis was scored 0 to 3 in 3 wrist regions and in each of the second through fifth metacarpophalangeal (MCP) joints. A score of 0 is normal, with no enhancement or enhancement up to the thickness of normal synovium, while scores of 1 to 3 (mild, moderate, severe) refer to increments of one-third of the presumed maximum volume of enhancing tissue in the synovial compartment. Total synovitis score ranges from a minimum of 0 to a maximum of 21. A negative value in synovitis change from Baseline score indicates an improvement.
Time Frame	From Baseline to Week 1

Outcome Measure Data

Analysis Population Description

The Analysis Population refers to the Full Analysis Set (FAS) (last observation carried forward) which consists of all randomized subjects that received at least one dose of study medication. As pre-specified in the protocol, this analysis is restricted to the Certolizumab Pegol (CZP) arm.

Arm/Group Title	Certolizumab Pegol (CZP)
Arm/Group Description:	Certolizumab Pegol (CZP) 400 mg for subcutaneous injection at Weeks 0, 2 and 4 followed by 200 mg 2-weekly from Week 6 to Week 40
Overall Number of Participants Analyzed	27
Mean (Standard Deviation); Unit of Measure: scores on a scale
	-0.6 (1.8)

6. Secondary Outcome

Title	Change From Baseline to Week 16 in the Dynamic Magnetic Resonance Image (MRI) Parameter, Initiation Rate of Enhancement (IRE)
Description	Contrast enhancement can be quantified in terms of the dynamic MRI parameters initial rate of enhancement (IRE), maximum enhancement (ME), and number of voxels (Nvox) with Plateau and Washout pattern. These parameters are extracted by examining individual signal intensity versus time curves derived from defined regions of interest. Nvox indicates the number of voxels showing enhancement patterns. It is representative of the size or volume of enhancement and representative of underlying inflammation. The higher the value, the higher the volume . ME and IRE values quantify the intensity of signal within the enhancing voxels. The absolute values and changes from Baseline in the MRI parameters of IRE, ME, and Nvox of the selected hand and wrist were estimated at Weeks 1, 2, 4, 8, and 16. The values presented are for Proximal Interphalangeal (PIP) and Metacarpophalangeal (MCP) joints combined. A negative value in IRE change from Baseline score indicates an improvement.
Time Frame	From Baseline to Week 16

Outcome Measure Data

Analysis Population Description

The Analysis Population refers to the Full Analysis Set (FAS) (last observation carried forward) which consists of all randomized subjects that received at least one dose of study medication. As pre-specified in the protocol, this analysis is restricted to the Certolizumab Pegol (CZP) arm.

Arm/Group Title	Certolizumab Pegol (CZP)
Arm/Group Description:	Certolizumab Pegol (CZP) 400 mg for subcutaneous injection at Weeks 0, 2 and 4 followed by 200 mg 2-weekly from Week 6 to Week 40
Overall Number of Participants Analyzed	22
Mean (Standard Deviation); Unit of Measure: percent per second
	-0.0044 (0.0140)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Certolizumab Pegol (CZP)
	Comments	A fixed-sequence stepwise hypothesis testing procedure was followed using a pre-specified set of ordered hypotheses. Hypotheses were ordered and tested in that order, beginning with change from Baseline at Week 16, and continuing to earlier time points (Week 8, 4, 2, 1 in that order) only if the previous null hypothesis of zero difference was rejected (p <0.05). Hypothesis testing was stopped if and when a non-significant result was obtained.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.164
	Comments	Two-sided p-value is presented, with p <0.05 as the threshold for statistical significance. A fixed-sequence stepwise hypothesis testing procedure was followed using a pre-specified set of ordered hypotheses.
	Method	Permutation test with general scores
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Median difference within group changes
	Estimated Value	-0.0035
	Confidence Interval	(2-Sided) 95%; -0.0120 to 0.0025
	Estimation Comments	Hodges-Lehmann estimate of median difference and associated exact 95 % 2-sided confidence interval are provided.

7. Secondary Outcome

Title	Change From Baseline to Week 16 in the Dynamic Magnetic Resonance Image (MRI) Parameter, Maximal Enhancement (ME)
Description	Contrast enhancement can be quantified in terms of the dynamic MRI parameters initial rate of enhancement (IRE), maximum enhancement (ME), and number of voxels (Nvox) with Plateau and Washout pattern. These parameters are extracted by examining individual signal intensity versus time curves derived from defined regions of interest. Nvox indicates the number of voxels showing enhancement patterns. It is representative of the size or volume of enhancement and representative of underlying inflammation. The higher the value, the higher the volume . ME and IRE values quantify the intensity of signal within the enhancing voxels. The absolute values and changes from Baseline in the MRI parameters of IRE, ME, and Nvox of the selected hand and wrist were estimated at Weeks 1, 2, 4, 8, and 16. The values presented are for Proximal Interphalangeal (PIP) and Metacarpophalangeal (MCP) joints combined. A negative value in ME change from Baseline score indicates an improvement.
Time Frame	From Baseline to Week 16

Outcome Measure Data

Analysis Population Description

The Analysis Population refers to the Full Analysis Set (FAS) (last observation carried forward) which consists of all randomized subjects that received at least one dose of study medication. As pre-specified in the protocol, this analysis is restricted to the Certolizumab Pegol (CZP) arm.

Arm/Group Title	Certolizumab Pegol (CZP)
Arm/Group Description:	Certolizumab Pegol (CZP) 400 mg for subcutaneous injection at Weeks 0, 2 and 4 followed by 200 mg 2-weekly from Week 6 to Week 40
Overall Number of Participants Analyzed	22
Mean (Standard Deviation); Unit of Measure: percent change over pre-contrast
	-0.0172 (0.4459)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Certolizumab Pegol (CZP)
	Comments	A fixed-sequence stepwise hypothesis testing procedure was followed using a pre-specified set of ordered hypotheses. Hypotheses were ordered and tested in that order, beginning with change from Baseline at Week 16, and continuing to earlier time points (Week 8, 4, 2, 1 in that order) only if the previous null hypothesis of zero difference was rejected (p <0.05). Hypothesis testing was stopped if and when a non-significant result was obtained.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.865
	Comments	Two-sided p-value is presented, with p <0.05 as the threshold for statistical significance. A fixed-sequence stepwise hypothesis testing procedure was followed using a pre-specified set of ordered hypotheses.
	Method	Permutation test with general scores
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Median difference within group changes
	Estimated Value	-0.0690
	Confidence Interval	(2-Sided) 95%; -0.2010 to 0.1380
	Estimation Comments	Hodges-Lehmann estimate of median difference and associated exact 95 % 2-sided confidence interval are provided.

8. Secondary Outcome

Title	Change From Baseline to Week 16 in the Dynamic Magnetic Resonance Image (MRI) Parameter, Number of Voxels (Nvox) With Plateau and Washout Pattern
Description	Contrast enhancement can be quantified in terms of the dynamic MRI parameters initial rate of enhancement (IRE), maximum enhancement (ME), and number of voxels (Nvox) with Plateau and Washout pattern. These parameters are extracted by examining individual signal intensity versus time curves derived from defined regions of interest. Nvox indicates the number of voxels showing enhancement patterns. It is representative of the size or volume of enhancement and representative of underlying inflammation. The higher the value, the higher the volume . ME and IRE values quantify the intensity of signal within the enhancing voxels. The absolute values and changes from Baseline in the MRI parameters of IRE, ME, and Nvox of the selected hand and wrist were estimated at Weeks 1, 2, 4, 8, and 16. The values presented are for Proximal Interphalangeal (PIP) and Metacarpophalangeal (MCP) joints combined. A negative value in Nvox change from Baseline score indicates an improvement.
Time Frame	From Baseline to Week 16

Outcome Measure Data

Analysis Population Description

The Analysis Population refers to the Full Analysis Set (FAS) (last observation carried forward) which consists of all randomized subjects that received at least one dose of study medication. As pre-specified in the protocol, this analysis is restricted to the Certolizumab Pegol (CZP) arm.

Arm/Group Title	Certolizumab Pegol (CZP)
Arm/Group Description:	Certolizumab Pegol (CZP) 400 mg for subcutaneous injection at Weeks 0, 2 and 4 followed by 200 mg 2-weekly from Week 6 to Week 40
Overall Number of Participants Analyzed	22
Mean (Standard Deviation); Unit of Measure: voxels
	-813.3 (1457.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Certolizumab Pegol (CZP)
	Comments	A fixed-sequence stepwise hypothesis testing procedure was followed using a pre-specified set of ordered hypotheses. Hypotheses were ordered and tested in that order, beginning with change from Baseline at Week 16, and continuing to earlier time points (Week 8, 4, 2, 1 in that order) only if the previous null hypothesis of zero difference was rejected (p <0.05). Hypothesis testing was stopped if and when a non-significant result was obtained.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.015
	Comments	Two-sided p-value is presented, with p <0.05 as the threshold for statistical significance. A fixed-sequence stepwise hypothesis testing procedure was followed using a pre-specified set of ordered hypotheses.
	Method	Permutation test with general scores
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Median difference within group changes
	Estimated Value	-421.5
	Confidence Interval	(2-Sided) 95%; -1542.5 to -47.0
	Estimation Comments	Hodges-Lehmann estimate of median difference and associated exact 95 % 2-sided confidence interval are provided.

9. Secondary Outcome

Title	Percentage of Subjects Achieving a Good European League Against Rheumatism (EULAR) Response at Week 16
Description	EULAR (European League Against Rheumatism) response: EULAR response is based upon current Disease Activity Score 28 (DAS28) level and corresponding change from Baseline in DAS28. Good EULAR response is defined as: DAS28 C-Reactive Protein (CRP) ≤ 3.2 and decrease from Baseline by > 1.2; moderate response is defined as achievement of one of the following: DAS28(CRP) ≤ 3.2 and decrease from Baseline > 0.6 and ≤ 1.2; DAS28(CRP) > 3.2 and ≤ 5.1 and decrease from Baseline > 0.6; DAS28(CRP) > 5.1 and decrease from Baseline > 1.2
Time Frame	From Baseline to Week 16

Outcome Measure Data

Analysis Population Description

The Analysis Population refers to the Full Analysis Set (FAS) (observed case) which consists of all randomized subjects that received at least one dose of study medication.

Arm/Group Title	Certolizumab Pegol (CZP)	Placebo Followed by Certolizumab Pegol (CZP)
Arm/Group Description:	Certolizumab Pegol (CZP) 400 mg for subcutaneous injection at Weeks 0, 2 and 4 followed by 200 mg 2-weekly from Week 6 to Week 40	Placebo, saline solution for subcutaneous injection at Week 0 followed by Certolizumab Pegol (CZP) 400 mg at Weeks 2, 4, and 6, then Certolizumab Pegol (CZP) 200 mg 2-weekly from Week 8 to Week 40
Overall Number of Participants Analyzed	21	12
Measure Type: Number; Unit of Measure: percentage of subjects
Good Response	71.4	66.7
Moderate Response	23.8	25.0
No Response	4.8	8.3

10. Secondary Outcome

Title	Percentage of Subjects Meeting the American College of Rheumatology 20 % Criteria (ACR20) at Week 16
Description	Subjects who meet the ACR20 criteria are those subjects with at least 20 % improvement from Baseline for Tender Joint Count (TJC), Swollen Joint Count (SJC), and at least 3 of the 5 remaining core set measures: 1) Health Assessment Questionnaire-Disability Index (HAQ-DI), 2) C-Reactive Protein (CRP), 3) Patient's Assessment of Arthritis Pain-Visual Analog Scale (PAAP-VAS), 4) Patient's Global Assessment of Disease Activity-Visual Analog Scale (PtGADA-VAS), 5) Physician's Global Assessment of Disease Activity-Visual Analog Scale (PhGA-VAS).
Time Frame	From Baseline to Week 16

Outcome Measure Data

Analysis Population Description

The Analysis Population refers to the Full Analysis Set (FAS) (observed case) which consists of all randomized subjects that received at least one dose of study medication.

Arm/Group Title	Certolizumab Pegol (CZP)	Placebo Followed by Certolizumab Pegol (CZP)
Arm/Group Description:	Certolizumab Pegol (CZP) 400 mg for subcutaneous injection at Weeks 0, 2 and 4 followed by 200 mg 2-weekly from Week 6 to Week 40	Placebo, saline solution for subcutaneous injection at Week 0 followed by Certolizumab Pegol (CZP) 400 mg at Weeks 2, 4, and 6, then Certolizumab Pegol (CZP) 200 mg 2-weekly from Week 8 to Week 40
Overall Number of Participants Analyzed	22	12
Measure Type: Number; Unit of Measure: percentage of subjects
Response	86.4	75.0
No Response	13.6	25.0

11. Secondary Outcome

Title	Percentage of Subjects Meeting the American College of Rheumatology 50 % Criteria (ACR50) at Week 16
Description	Subjects who meet the ACR50 criteria are those subjects with at least 50 % improvement from Baseline for Tender Joint Count (TJC), Swollen Joint Count (SJC), and at least 3 of the 5 remaining core set measures: 1) Health Assessment Questionnaire-Disability Index (HAQ-DI), 2) C-Reactive Protein (CRP), 3) Patient's Assessment of Arthritis Pain-Visual Analog Scale (PAAP-VAS), 4) Patient's Global Assessment of Disease Activity-Visual Analog Scale (PtGADA-VAS), 5) Physician's Global Assessment of Disease Activity-Visual Analog Scale (PhGA-VAS).
Time Frame	From Baseline to Week 16

Outcome Measure Data

Analysis Population Description

The Analysis Population refers to the Full Analysis Set (FAS) (observed case) which consists of all randomized subjects that received at least one dose of study medication.

Arm/Group Title	Certolizumab Pegol (CZP)	Placebo Followed by Certolizumab Pegol (CZP)
Arm/Group Description:	Certolizumab Pegol (CZP) 400 mg for subcutaneous injection at Weeks 0, 2 and 4 followed by 200 mg 2-weekly from Week 6 to Week 40	Placebo, saline solution for subcutaneous injection at Week 0 followed by Certolizumab Pegol (CZP) 400 mg at Weeks 2, 4, and 6, then Certolizumab Pegol (CZP) 200 mg 2-weekly from Week 8 to Week 40
Overall Number of Participants Analyzed	22	12
Measure Type: Number; Unit of Measure: percentage of subjects
Response	68.2	58.3
No Response	31.8	41.7

12. Secondary Outcome

Title	Percentage of Subjects Meeting the American College of Rheumatology 70 % Criteria (ACR70) at Week 16
Description	Subjects who meet the ACR70 criteria are those subjects with at least 70 % improvement from Baseline for Tender Joint Count (TJC), Swollen Joint Count (SJC), and at least 3 of the 5 remaining core set measures: 1) Health Assessment Questionnaire-Disability Index (HAQ-DI), 2) C-Reactive Protein (CRP), 3) Patient's Assessment of Arthritis Pain-Visual Analog Scale (PAAP-VAS), 4) Patient's Global Assessment of Disease Activity-Visual Analog Scale (PtGADA-VAS), 5) Physician's Global Assessment of Disease Activity-Visual Analog Scale (PhGA-VAS).
Time Frame	From Baseline to Week 16

Outcome Measure Data

Analysis Population Description

The Analysis Population refers to the Full Analysis Set (FAS) (observed case) which consists of all randomized subjects that received at least one dose of study medication.

Arm/Group Title	Certolizumab Pegol (CZP)	Placebo Followed by Certolizumab Pegol (CZP)
Arm/Group Description:	Certolizumab Pegol (CZP) 400 mg for subcutaneous injection at Weeks 0, 2 and 4 followed by 200 mg 2-weekly from Week 6 to Week 40	Placebo, saline solution for subcutaneous injection at Week 0 followed by Certolizumab Pegol (CZP) 400 mg at Weeks 2, 4, and 6, then Certolizumab Pegol (CZP) 200 mg 2-weekly from Week 8 to Week 40
Overall Number of Participants Analyzed	22	12
Measure Type: Number; Unit of Measure: percentage of subjects
Response	45.5	58.3
No Response	54.5	41.7

13. Secondary Outcome

Title	Change From Baseline to Week 16 in the Disease Activity Score-28 (C-Reactive Protein) (DAS28 (CRP)) Response
Description	DAS28[CRP] is a composite index and is calculated using the Tender Joint Count (TJC), Swollen Joint Count (SJC) C-reactive protein (CRP in mg/l), and the Patient's Global Assessment of Disease Activity - Visual Analog Scale (VAS in mm) using the following formula: 0.56 x √(TJC) + 0.28 x √(SJC) + 0.36 x lognat (CRP+1) + 0.014 x Global Assessment of Arthritis + 0.96 where 28 joints are examined and a lower score indicates less disease activity. A DAS(28) score of higher than 5.1 is indicative of high disease activity whereas a DAS score below 3.2 indicates low disease activity. A patient is considered to be in remission if they have a DAS28 lower than 2.6. A negative value in DAS28[CRP] change from Baseline indicates an improvement from Baseline.
Time Frame	From Baseline to Week 16

Outcome Measure Data

Analysis Population Description

The Analysis Population refers to the Full Analysis Set (FAS) (observed case) which consists of all randomized subjects that received at least one dose of study medication.

Arm/Group Title	Certolizumab Pegol (CZP)	Placebo Followed by Certolizumab Pegol (CZP)
Arm/Group Description:	Certolizumab Pegol (CZP) 400 mg for subcutaneous injection at Weeks 0, 2 and 4 followed by 200 mg 2-weekly from Week 6 to Week 40	Placebo, saline solution for subcutaneous injection at Week 0 followed by Certolizumab Pegol (CZP) 400 mg at Weeks 2, 4, and 6, then Certolizumab Pegol (CZP) 200 mg 2-weekly from Week 8 to Week 40
Overall Number of Participants Analyzed	21	12
Mean (Standard Deviation); Unit of Measure: units on a scale
	-2.27 (0.86)	-2.50 (1.23)

14. Secondary Outcome

Title	Percentage of Subjects Achieving Disease Activity Score 28 (DAS28 (CRP)) Remission Status (DAS28 (CRP) < 2.6) at Week 16
Description	DAS28[CRP] is a composite index and is calculated using the Tender Joint Count (TJC), Swollen Joint Count (SJC) C-reactive protein (CRP in mg/l), and the Patient's Global Assessment of Disease Activity - Visual Analog Scale (VAS in mm) using the following formula: 0.56 x √(TJC) + 0.28 x √(SJC) + 0.36 x lognat (CRP+1) + 0.014 x Global Assessment of Arthritis + 0.96 where 28 joints are examined and a lower score indicates less disease activity. A DAS(28) score of higher than 5.1 is indicative of high disease activity whereas a DAS score below 3.2 indicates low disease activity. A patient is considered to be in remission if they have a DAS28 lower than 2.6.
Time Frame	From Baseline to Week 16

Outcome Measure Data

Analysis Population Description

The Analysis Population refers to the Full Analysis Set (FAS) (observed case) which consists of all randomized subjects that received at least one dose of study medication, and had a valid Baseline efficacy assessment and at least one valid post-Baseline efficacy assessment.

Arm/Group Title	Certolizumab Pegol (CZP)	Placebo Followed by Certolizumab Pegol (CZP)
Arm/Group Description:	Certolizumab Pegol (CZP) 400 mg for subcutaneous injection at Weeks 0, 2 and 4 followed by 200 mg 2-weekly from Week 6 to Week 40	Placebo, saline solution for subcutaneous injection at Week 0 followed by Certolizumab Pegol (CZP) 400 mg at Weeks 2, 4, and 6, then Certolizumab Pegol (CZP) 200 mg 2-weekly from Week 8 to Week 40
Overall Number of Participants Analyzed	21	12
Measure Type: Number; Unit of Measure: percentage of subjects
Remission	57.1	58.3
No Remission	42.9	41.7

15. Secondary Outcome

Title	Change From Baseline to Week 16 in Bone Mineral Density as Measured by Digital XRay (DXR)
Description	Radiographic assessment of bone mineral density in one hand and wrist were conducted by Digital X Ray (DXR) using a standardized imaging methodology. The hand and wrist to be assessed by DXR were the same as for the Magnetic Resonance Images (MRIs). The same hand and wrist were used for all x rays. The evaluation of all DXRs was performed centrally. A positive value in Bone Mineral Density change from Baseline indicates an improvement.
Time Frame	From Baseline to Week 16

Outcome Measure Data

Analysis Population Description

The Analysis Population refers to the Full Analysis Set (FAS) (observed case) which consists of all randomized subjects that received at least one dose of study medication.

Arm/Group Title	Certolizumab Pegol (CZP)	Placebo Followed by Certolizumab Pegol (CZP)
Arm/Group Description:	Certolizumab Pegol (CZP) 400 mg for subcutaneous injection at Weeks 0, 2 and 4 followed by 200 mg 2-weekly from Week 6 to Week 40	Placebo, saline solution for subcutaneous injection at Week 0 followed by Certolizumab Pegol (CZP) 400 mg at Weeks 2, 4, and 6, then Certolizumab Pegol (CZP) 200 mg 2-weekly from Week 8 to Week 40
Overall Number of Participants Analyzed	20	11
Mean (Standard Deviation); Unit of Measure: g/cm^2
	-0.00606 (0.01185)	-0.00630 (0.01032)

16. Secondary Outcome

Title	Change From Baseline to Week 16 in Tender Joint Count (TJC)
Description	The joint assessment was carried out on 28 joints. Swelling and tenderness were graded on a 2-point scale (answered with Yes/No). "No" indicated "Not tender"; "Yes" indicated a positive tenderness response that was defined as a positive response to questioning (tender), spontaneous response elicited (tender and winced) or withdrawal by subject on examination (tender, winced, and withdrew)." If there were missing observations in the TJC, then the remaining observations were assessed and weighted by dividing by the number of non-missing joint counts and multiplying by 28. TJC ranges from 0 to 28 with 0 indicating no tender joints and 28 indicating tenderness in all joints. A negative value in TJC change from Baseline indicates an improvement.
Time Frame	From Baseline to Week 16

Outcome Measure Data

Analysis Population Description

The Analysis Population refers to the Full Analysis Set (FAS) (observed case) which consists of all randomized subjects that received at least one dose of study medication.

Arm/Group Title	Certolizumab Pegol (CZP)	Placebo Followed by Certolizumab Pegol (CZP)
Arm/Group Description:	Certolizumab Pegol (CZP) 400 mg for subcutaneous injection at Weeks 0, 2 and 4 followed by 200 mg 2-weekly from Week 6 to Week 40	Placebo, saline solution for subcutaneous injection at Week 0 followed by Certolizumab Pegol (CZP) 400 mg at Weeks 2, 4, and 6, then Certolizumab Pegol (CZP) 200 mg 2-weekly from Week 8 to Week 40
Overall Number of Participants Analyzed	23	12
Mean (Standard Deviation); Unit of Measure: units on a scale
	-9.28 (5.85)	-9.92 (8.55)

17. Secondary Outcome

Title	Change From Baseline to Week 16 in Swollen Joint Count (SJC)
Description	The joint assessment was carried out on 28 joints. Swelling and tenderness were graded on a 2-point scale (answered with Yes/No). "No" indicated "None" swelling response and "Yes" indicated that there was "a detectable synovial thickening with or without loss of bony contours, or bulging synovial proliferation with or without cystic characteristics." If there were missing observations in the SJC, then the remaining observations were assessed and weighted by dividing by the number of non-missing joint counts and multiplying by 28. SJC ranges from 0 to 28 with 0 indicating no swollen joints and 28 indicating swelling in all joints. A negative value in SJC change from Baseline indicates an improvement.
Time Frame	From Baseline to Week 16

Outcome Measure Data

Analysis Population Description

The Analysis Population refers to the Full Analysis Set (FAS) (observed case) which consists of all randomized subjects that received at least one dose of study medication.

Arm/Group Title	Certolizumab Pegol (CZP)	Placebo Followed by Certolizumab Pegol (CZP)
Arm/Group Description:	Certolizumab Pegol (CZP) 400 mg for subcutaneous injection at Weeks 0, 2 and 4 followed by 200 mg 2-weekly from Week 6 to Week 40	Placebo, saline solution for subcutaneous injection at Week 0 followed by Certolizumab Pegol (CZP) 400 mg at Weeks 2, 4, and 6, then Certolizumab Pegol (CZP) 200 mg 2-weekly from Week 8 to Week 40
Overall Number of Participants Analyzed	23	12
Mean (Standard Deviation); Unit of Measure: units on a scale
	-7.06 (4.67)	-7.92 (5.81)

18. Secondary Outcome

Title	Change From Baseline to Week 16 in Health Assessment Questionnaire - Disability Index (HAQ-DI)
Description	The Health Assessment Questionnaire-Disability Index (HAQ-DI) is a subject reported questionnaire that provides an assessment of the impact of the disease and its treatment on physical function. The HAQ-DI assesses the degree of difficulty experienced in 8 domains of daily living activities using 20 questions. The domains are dressing and grooming, arising, eating, walking, hygiene, reach, grip, and common daily activities, and each domain (activity) consists of 2 or 3 items. For each question the level of difficulty is scored from 0 to 3 where 0 = no difficulty, 1 = some difficulty, 2 = much difficulty and 3 = unable to do. A total score is computed from the item scores using the scoring rules provided by the author (Fries, 1980). The total score ranges from 0 to 3 with lower scores meaning lower disability. A negative value in HAQ-DI change from Baseline indicates an improvement.
Time Frame	From Baseline to Week 16

Outcome Measure Data

Analysis Population Description

The Analysis Population refers to the Full Analysis Set (FAS) (observed case) which consists of all randomized subjects that received at least one dose of study medication.

Arm/Group Title	Certolizumab Pegol (CZP)	Placebo Followed by Certolizumab Pegol (CZP)
Arm/Group Description:	Certolizumab Pegol (CZP) 400 mg for subcutaneous injection at Weeks 0, 2 and 4 followed by 200 mg 2-weekly from Week 6 to Week 40	Placebo, saline solution for subcutaneous injection at Week 0 followed by Certolizumab Pegol (CZP) 400 mg at Weeks 2, 4, and 6, then Certolizumab Pegol (CZP) 200 mg 2-weekly from Week 8 to Week 40
Overall Number of Participants Analyzed	23	12
Mean (Standard Deviation); Unit of Measure: scores on a scale
	-0.54 (0.49)	-0.79 (0.49)

19. Secondary Outcome

Title	C-Reactive Protein (CRP) Ratio to Baseline at Week 16
Description	The C-Reactive Protein (CRP) is considered a marker of inflammation in subjects with Rheumatoid Arthritis. A ratio to Baseline < 1 indicates an improvement.
Time Frame	From Baseline to Week 16

Outcome Measure Data

Analysis Population Description

The Analysis Population refers to the Full Analysis Set (FAS) (observed case) which consists of all randomized subjects that received at least one dose of study medication, and had a valid Baseline efficacy assessment and at least one valid post-Baseline efficacy assessment.

Arm/Group Title	Certolizumab Pegol (CZP)	Placebo Followed by Certolizumab Pegol (CZP)
Arm/Group Description:	Certolizumab Pegol (CZP) 400 mg for subcutaneous injection at Weeks 0, 2 and 4 followed by 200 mg 2-weekly from Week 6 to Week 40	Placebo, saline solution for subcutaneous injection at Week 0 followed by Certolizumab Pegol (CZP) 400 mg at Weeks 2, 4, and 6, then Certolizumab Pegol (CZP) 200 mg 2-weekly from Week 8 to Week 40
Overall Number of Participants Analyzed	21	12
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: ratio
	0.491; (0.179% to 0.947%)	0.219; (147.9%)

20. Secondary Outcome

Title	Correlation of Change in Synovitis From Baseline as Measured by Magnetic Resonance Image (MRI) With European League Against Rheumatism (EULAR) Response at Week 16
Description	EULAR (European League Against Rheumatism) response: EULAR response is based upon current Disease Activity Score 28 (DAS28) level and corresponding change from Baseline in DAS28. Good EULAR response is defined as: DAS28 C-Reactive Protein (CRP) ≤ 3.2 and decrease from Baseline by > 1.2; moderate response is defined as achievement of one of the following: DAS28(CRP) ≤ 3.2 and decrease from Baseline > 0.6 and ≤ 1.2; DAS28(CRP) > 3.2 and ≤ 5.1 and decrease from Baseline > 0.6; DAS28(CRP) > 5.1 and decrease from Baseline > 1.2 A negative correlation coefficient indicates that reductions in synovitis from Baseline to Week 16 are associated with better EULAR responses.
Time Frame	From Baseline to Week 16

Outcome Measure Data

Analysis Population Description

The Analysis Population refers to the Full Analysis Set (FAS) (observed case) which consists of all randomized subjects that received at least one dose of study medication. Correlations between the change from Baseline in total synovitis score at Week 16 and the clinical efficacy variables are restricted to the Certolizumab Pegol (CZP) arm only.

Arm/Group Title	Certolizumab Pegol (CZP)
Arm/Group Description:	Certolizumab Pegol (CZP) 400 mg for subcutaneous injection at Weeks 0, 2 and 4 followed by 200 mg 2-weekly from Week 6 to Week 40
Overall Number of Participants Analyzed	20
Measure Type: Number; Unit of Measure: Spearman rank correlation coefficient
	-0.20

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Certolizumab Pegol (CZP)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.394
	Comments	[Not Specified]
	Method	Spearman rank correlation
	Comments	[Not Specified]

21. Secondary Outcome

Title	Correlation of Change in Synovitis From Baseline as Measured by Magnetic Resonance Image (MRI) With American College of Rheumatology 20 % Criteria (ACR20) at Week 16
Description	Subjects who meet the ACR20 criteria are those subjects with at least 20 % improvement from Baseline for Tender Joint Count (TJC), Swollen Joint Count (SJC), and at least 3 of the 5 remaining core set measures: 1) Health Assessment Questionnaire-Disability Index (HAQ-DI), 2) C-Reactive Protein (CRP), 3) Patient's Assessment of Arthritis Pain-Visual Analog Scale (PAAP-VAS), 4) Patient's Global Assessment of Disease Activity-Visual Analog Scale (PtGADA-VAS), 5) Physician's Global Assessment of Disease Activity-Visual Analog Scale (PhGA-VAS). A negative correlation coefficient indicates that reductions in synovitis from Baseline to Week 16 are associated with an ACR20 response at Week 16.
Time Frame	From Baseline to Week 16

Outcome Measure Data

Analysis Population Description

The Analysis Population refers to the Full Analysis Set (FAS) (observed case) which consists of all randomized subjects that received at least one dose of study medication. Correlations between the change from Baseline in total synovitis score at Week 16 and the clinical efficacy variables are restricted to the Certolizumab Pegol (CZP) arm only.

Arm/Group Title	Certolizumab Pegol (CZP)
Arm/Group Description:	Certolizumab Pegol (CZP) 400 mg for subcutaneous injection at Weeks 0, 2 and 4 followed by 200 mg 2-weekly from Week 6 to Week 40
Overall Number of Participants Analyzed	21
Measure Type: Number; Unit of Measure: Spearman rank correlation coefficient
	-0.11

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Certolizumab Pegol (CZP)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.625
	Comments	[Not Specified]
	Method	Spearman rank correlation
	Comments	[Not Specified]

22. Secondary Outcome

Title	Correlation of Change in Synovitis From Baseline as Measured by Magnetic Resonance Image (MRI) With American College of Rheumatology 50 % Criteria (ACR50) at Week 16
Description	Subjects who meet the ACR50 criteria are those subjects with at least 50 % improvement from Baseline for Tender Joint Count (TJC), Swollen Joint Count (SJC), and at least 3 of the 5 remaining core set measures: 1) Health Assessment Questionnaire-Disability Index (HAQ-DI), 2) C-Reactive Protein (CRP), 3) Patient's Assessment of Arthritis Pain-Visual Analog Scale (PAAP-VAS), 4) Patient's Global Assessment of Disease Activity-Visual Analog Scale (PtGADA-VAS), 5) Physician's Global Assessment of Disease Activity-Visual Analog Scale (PhGA-VAS). A negative correlation coefficient indicates that reductions in synovitis from Baseline to Week 16 are associated with an ACR50 response at Week 16.
Time Frame	From Baseline to Week 16

Outcome Measure Data

Analysis Population Description

The Analysis Population refers to the Full Analysis Set (FAS) (observed case) which consists of all randomized subjects that received at least one dose of study medication. Correlations between the change from Baseline in total synovitis score at Week 16 and the clinical efficacy variables are restricted to the Certolizumab Pegol (CZP) arm only.

Arm/Group Title	Certolizumab Pegol (CZP)
Arm/Group Description:	Certolizumab Pegol (CZP) 400 mg for subcutaneous injection at Weeks 0, 2 and 4 followed by 200 mg 2-weekly from Week 6 to Week 40
Overall Number of Participants Analyzed	21
Measure Type: Number; Unit of Measure: Spearman rank correlation coefficient
	-0.34

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Certolizumab Pegol (CZP)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.128
	Comments	[Not Specified]
	Method	Spearman rank correlation
	Comments	[Not Specified]

23. Secondary Outcome

Title	Correlation of Change in Synovitis From Baseline as Measured by Magnetic Resonance Image (MRI) With American College of Rheumatology 70 % Criteria (ACR70) at Week 16
Description	Subjects who meet the ACR70 criteria are those subjects with at least 70 % improvement from Baseline for Tender Joint Count (TJC), Swollen Joint Count (SJC), and at least 3 of the 5 remaining core set measures: 1) Health Assessment Questionnaire-Disability Index (HAQ-DI), 2) C-Reactive Protein (CRP), 3) Patient's Assessment of Arthritis Pain-Visual Analog Scale (PAAP-VAS), 4) Patient's Global Assessment of Disease Activity-Visual Analog Scale (PtGADA-VAS), 5) Physician's Global Assessment of Disease Activity-Visual Analog Scale (PhGA-VAS). A negative correlation coefficient indicates that reductions in synovitis from Baseline to Week 16 are associated with an ACR70 response at Week 16.
Time Frame	From Baseline to Week 16

Outcome Measure Data

Analysis Population Description

The Analysis Population refers to the Full Analysis Set (FAS) (observed case) which consists of all randomized subjects that received at least one dose of study medication. Correlations between the change from Baseline in total synovitis score at Week 16 and the clinical efficacy variables are restricted to the Certolizumab Pegol (CZP) arm only.

Arm/Group Title	Certolizumab Pegol (CZP)
Arm/Group Description:	Certolizumab Pegol (CZP) 400 mg for subcutaneous injection at Weeks 0, 2 and 4 followed by 200 mg 2-weekly from Week 6 to Week 40
Overall Number of Participants Analyzed	21
Measure Type: Number; Unit of Measure: Spearman rank correlation coefficient
	-0.08

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Certolizumab Pegol (CZP)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.732
	Comments	[Not Specified]
	Method	Spearman rank correlation
	Comments	[Not Specified]

24. Secondary Outcome

Title	Correlation of Change in Synovitis From Baseline as Measured by Magnetic Resonance Image (MRI) With Disease Activity Score-28 (DAS28 (CRP)) Response at Week 16
Description	The DAS28(CRP) was calculated using the tender joint count (TJC) and swollen joint count (SJC), C-Reactive Protein (CRP in mg/L) and the Patient's Global Assessment of Disease Activity - Visual Analog Scale (PtGADA-VAS in mm). A positive correlation coefficient indicates that reductions in synovitis from Baseline to Week 16 are associated with reductions in DAS28(CRP) at Week 16.
Time Frame	From Baseline to Week 16

Outcome Measure Data

Analysis Population Description

The Analysis Population refers to the Full Analysis Set (FAS) (observed case) which consists of all randomized subjects that received at least one dose of study medication. Correlations between the change from Baseline in total synovitis score at Week 16 and the clinical efficacy variables are restricted to the Certolizumab Pegol (CZP) arm only.

Arm/Group Title	Certolizumab Pegol (CZP)
Arm/Group Description:	Certolizumab Pegol (CZP) 400 mg for subcutaneous injection at Weeks 0, 2 and 4 followed by 200 mg 2-weekly from Week 6 to Week 40
Overall Number of Participants Analyzed	20
Measure Type: Number; Unit of Measure: Spearman rank correlation coefficient
	0.19

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Certolizumab Pegol (CZP)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.411
	Comments	[Not Specified]
	Method	Spearman rank correlation
	Comments	[Not Specified]

25. Secondary Outcome

Title	Correlation of Change in Synovitis From Baseline as Measured by Magnetic Resonance Image (MRI) With Changes in Hand Bone Mineral Density as Measured by Digital XRay (DXR) at Week 16
Description	Radiographic assessment of bone mineral density in one hand and wrist were conducted by Digital X Ray (DXR) using a standardized imaging methodology. The hand and wrist to be assessed by DXR were the same as for the Magnetic Resonance Images (MRIs). The same hand and wrist were used for all x rays. The evaluation of all DXRs was performed centrally. A negative correlation coefficient indicates that reductions in synovitis from Baseline to Week 16 are associated with increases in bone mineral density at Week 16.
Time Frame	From Baseline to Week 16

Outcome Measure Data

Analysis Population Description

The Analysis Population refers to the Full Analysis Set (FAS) (observed case) which consists of all randomized subjects that received at least one dose of study medication. Correlations between the change from Baseline in total synovitis score at Week 16 and the clinical efficacy variables are restricted to the Certolizumab Pegol (CZP) arm only.

Arm/Group Title	Certolizumab Pegol (CZP)
Arm/Group Description:	Certolizumab Pegol (CZP) 400 mg for subcutaneous injection at Weeks 0, 2 and 4 followed by 200 mg 2-weekly from Week 6 to Week 40
Overall Number of Participants Analyzed	17
Measure Type: Number; Unit of Measure: Spearman rank correlation coefficient
	0.32

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Certolizumab Pegol (CZP)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.208
	Comments	[Not Specified]
	Method	Spearman rank correlation
	Comments	[Not Specified]

26. Secondary Outcome

Title	Change From Baseline for the Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) Rheumatoid Arthritis Magnetic Resonance Image Scoring System (RAMRIS) Synovitis Score at Week 1 Placebo (PBO) Versus Certolizumab Pegol (CZP)
Description	Rheumatoid Arthritis Magnetic Resonance Image Scoring System (RAMRIS): Synovitis is defined as an area in the synovial compartment that shows above normal postgadolinium enhancement of a thickness greater than the width of the normal synovium. T1-weighted images were acquired before and after the administration of intravenous contrast agent containing gadolinium. Intravenous contrast was required to demonstrate enhancing synovitis. Synovitis was scored 0 to 3 in 3 wrist regions (the distal radioulnar; the radiocarpal joint; the intercarpal and carpometacarpal joints) and in each of the second through fifth metacarpophalangeal (MCP) joints. A score of 0 is normal, with no enhancement or enhancement up to the thickness of normal synovium, while scores of 1 to 3 (mild, moderate, severe) refer to increments of one-third of the presumed maximum volume of enhancing tissue in the synovial compartment. A negative value in synovitis change from Baseline score indicates an improvement.
Time Frame	From Baseline to Week 1

Outcome Measure Data

Analysis Population Description

The Analysis Population refers to the Full Analysis Set (FAS) (last observation carried forward) which consists of all randomized subjects that received at least one dose of study medication, and had a valid Baseline efficacy assessment and at least one valid post-Baseline efficacy assessment.

Arm/Group Title	Placebo Followed by Certolizumab Pegol (CZP)	Certolizumab Pegol (CZP)
Arm/Group Description:	Placebo, saline solution for subcutaneous injection at Week 0 followed by Certolizumab Pegol (CZP) 400 mg at Weeks 2, 4, and 6, then Certolizumab Pegol (CZP) 200 mg 2-weekly from Week 8 to Week 40	Certolizumab Pegol (CZP) 400 mg for subcutaneous injection at Weeks 0, 2 and 4 followed by 200 mg 2-weekly from Week 6 to Week 40
Overall Number of Participants Analyzed	13	27
Mean (Standard Deviation); Unit of Measure: scores on a scale
	0.1 (1.0)	-0.6 (1.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Followed by Certolizumab Pegol (CZP), Certolizumab Pegol (CZP)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.254
	Comments	Two-sided p-value is presented, with p <0.05 as the threshold for statistical significance.
	Method	Wilcoxon Rank-Sum Test
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; -1.0 to 0.0
	Estimation Comments	Hodges-Lehmann estimate of median difference and associated exact 95 % 2-sided confidence interval are provided.

27. Secondary Outcome

Title	Change From Baseline for the Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) Rheumatoid Arthritis Magnetic Resonance Image Scoring System (RAMRIS) Synovitis Score at Week 2 Placebo (PBO) Versus Certolizumab Pegol (CZP)
Description	Rheumatoid Arthritis Magnetic Resonance Image Scoring System (RAMRIS): Synovitis is defined as an area in the synovial compartment that shows above normal postgadolinium enhancement of a thickness greater than the width of the normal synovium. T1-weighted images were acquired before and after the administration of intravenous contrast agent containing gadolinium. Intravenous contrast was required to demonstrate enhancing synovitis. Synovitis was scored 0 to 3 in 3 wrist regions (the distal radioulnar; the radiocarpal joint; the intercarpal and carpometacarpal joints) and in each of the second through fifth metacarpophalangeal (MCP) joints. A score of 0 is normal, with no enhancement or enhancement up to the thickness of normal synovium, while scores of 1 to 3 (mild, moderate, severe) refer to increments of one-third of the presumed maximum volume of enhancing tissue in the synovial compartment. A negative value in synovitis change from Baseline score indicates an improvement.
Time Frame	From Baseline to Week 2

Outcome Measure Data

Analysis Population Description

The Analysis Population refers to the Full Analysis Set (FAS) (last observation carried forward) which consists of all randomized subjects that received at least one dose of study medication, and had a valid Baseline efficacy assessment and at least one valid post-Baseline efficacy assessment.

Arm/Group Title	Placebo Followed by Certolizumab Pegol (CZP)	Certolizumab Pegol (CZP)
Arm/Group Description:	Placebo, saline solution for subcutaneous injection at Week 0 followed by Certolizumab Pegol (CZP) 400 mg at Weeks 2, 4, and 6, then Certolizumab Pegol (CZP) 200 mg 2-weekly from Week 8 to Week 40	Certolizumab Pegol (CZP) 400 mg for subcutaneous injection at Weeks 0, 2 and 4 followed by 200 mg 2-weekly from Week 6 to Week 40
Overall Number of Participants Analyzed	13	27
Mean (Standard Deviation); Unit of Measure: scores on a scale
	0.2 (1.4)	-0.4 (1.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Followed by Certolizumab Pegol (CZP), Certolizumab Pegol (CZP)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.472
	Comments	Two-sided p-value is presented, with p <0.05 as the threshold for statistical significance.
	Method	Wilcoxon Rank-Sum Test
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; -2.0 to 1.0
	Estimation Comments	Hodges-Lehmann estimate of median difference and associated exact 95 % 2-sided confidence interval are provided.

Adverse Events

Time Frame	Treatment Emergent Adverse Events (TEAEs) were reported from Baseline (Week 0) to the end of the study (Week 50).
Adverse Event Reporting Description	Subjects that did not receive at least one dose of Certolizumab Pegol (CZP) were excluded. Only Treatment Emergent Adverse Events (TEAEs) occurring while receiving CZP are reported.
Arm/Group Title	Certolizumab Pegol (CZP) at Any Time
Arm/Group Description	Eligible subjects were allocated to the following study treatments in a 2:1 ratio: Certolizumab Pegol (CZP) 400mg for subcutaneous injection (sc) at Weeks 0, 2, and 4, followed by CZP 200mg sc and placebo (saline solution) at Week 6 and CZP 200mg at Weeks 8, 10, 12, 14, and 16 or; Placebo (saline solution) at Day 0 and then CZP 400mg sc at Weeks 2, 4, and 6 followed by CZP 200mg sc at Weeks 8, 10, 12, 14, and 16
All-Cause Mortality
	Certolizumab Pegol (CZP) at Any Time
	Affected / at Risk (%)
Total	--/--
Serious Adverse Events
	Certolizumab Pegol (CZP) at Any Time
	Affected / at Risk (%)	# Events
Total	4/40 (10.00%)
Cardiac disorders
Splinter haemorrhages * 1	1/40 (2.50%)	1
Coronary artery disease * 1	1/40 (2.50%)	1
Injury, poisoning and procedural complications
Post procedural haemorrhage * 1	1/40 (2.50%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder transitional cell carcinoma stage I * 1	1/40 (2.50%)	1
Bladder cancer * 1	1/40 (2.50%)	1
Nervous system disorders
Sensory Loss * 1	1/40 (2.50%)	1
Surgical and medical procedures
Tonsillectomy * 1	1/40 (2.50%)	1
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA 16.0
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Certolizumab Pegol (CZP) at Any Time
	Affected / at Risk (%)	# Events
Total	26/40 (65.00%)
Gastrointestinal disorders
Nausea * 1	2/40 (5.00%)	2
General disorders
Injection site pain * 1	3/40 (7.50%)	5
Injection site discolouration * 1	2/40 (5.00%)	5
Nodule * 1	2/40 (5.00%)	5
Injection site swelling * 1	2/40 (5.00%)	3
Fatigue * 1	2/40 (5.00%)	2
Pyrexia * 1	2/40 (5.00%)	2
Infections and infestations
Nasopharyngitis * 1	8/40 (20.00%)	8
Urinary tract infection * 1	5/40 (12.50%)	5
Oral herpes * 1	4/40 (10.00%)	9
Viral infection * 1	4/40 (10.00%)	5
Influenza * 1	3/40 (7.50%)	3
Pharyngitis bacterial * 1	2/40 (5.00%)	5
Abscess * 1	2/40 (5.00%)	2
Pneumonia * 1	2/40 (5.00%)	2
Investigations
Alanine aminotransferase increased * 1	3/40 (7.50%)	3
Aspartate aminotransferase increased * 1	2/40 (5.00%)	2
Hepatic enzyme increased * 1	2/40 (5.00%)	2
Metabolism and nutrition disorders
Hypercholesterolaemia * 1	2/40 (5.00%)	2
Musculoskeletal and connective tissue disorders
Tendonitis * 1	2/40 (5.00%)	3
Tendon pain * 1	2/40 (5.00%)	2
Nervous system disorders
Headache * 1	4/40 (10.00%)	14
Dizziness * 1	3/40 (7.50%)	4
Paraesthesia * 1	2/40 (5.00%)	2
Renal and urinary disorders
Haematuria * 1	2/40 (5.00%)	2
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain * 1	6/40 (15.00%)	6
Cough * 1	4/40 (10.00%)	4
Skin and subcutaneous tissue disorders
Rash * 1	2/40 (5.00%)	2
Vascular disorders
Hypertension * 1	3/40 (7.50%)	3
Hot flush * 1	2/40 (5.00%)	2
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA 16.0

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 Clinical Trials Call Center
• Organization: UCB
• Phone: +1 877 822 9493

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Ostergaard M, Jacobsson LT, Schaufelberger C, Hansen MS, Bijlsma JW, Dudek A, Rell-Bakalarska M, Staelens F, Haake R, Sundman-Engberg B, Bliddal H. MRI assessment of early response to certolizumab pegol in rheumatoid arthritis: a randomised, double-blind, placebo-controlled phase IIIb study applying MRI at weeks 0, 1, 2, 4, 8 and 16. Ann Rheum Dis. 2015 Jun;74(6):1156-63. doi: 10.1136/annrheumdis-2014-206359. Epub 2014 Dec 15.

• Responsible Party: UCB Pharma
• ClinicalTrials.gov Identifier: NCT01235598
• Other Study ID Numbers: RA0028; 2009-013758-33 ( EudraCT Number )
• First Submitted: November 4, 2010
• First Posted: November 5, 2010
• Results First Submitted: September 26, 2013
• Results First Posted: February 5, 2014
• Last Update Posted: March 12, 2014