A Study of the Safety and Efficacy of Golimumab in Subjects With Rheumatoid Arthritis That Are Methotrexate-naive - Study Results

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Safety/Efficacy Study; Intervention Model: Parallel Assignment; Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Condition:	Rheumatoid Arthritis
Interventions:	Biological: golimumab Drug: placebo; methotrexate Biological: Golimumab Drug: golimumab; methotrexate

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
637 subjects were randomized at 90 centers: 25 sites in Asia, 34 sites in Europe/Australia/New Zealand, 10 sites in Latin America and 21 sites in North America.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups

	Description
Group I: Placebo + Methotrexate (MTX)	Placebo SC injections every 4 wks from Wk 0 to Wk 48 (unless early escape at Wk 28); MTX - 10 to 20 mg from Wk 0 for up to 5 years; golimumab - If early escape, 50 mg SC injection every 4 wks from Wk 28 up to 5 yrs; golimumab - Dr's discretion after unblinding (last patients enrolled completes the Wk 52 evaluation and database is locked), dose adjust from 50 to 100 mg.
Group II: Golimumab 100 mg + Placebo	Golimumab 100 mg SC injection every 4 wks from Wk 0 for up to 5 yrs, placebo capsule MTX weekly from Wk 0 to unblinding (last patients enrolled completes the Wk 52 evaluation and database is locked) unless early escape at Wk 28; MTX - If early escape start 10 mg weekly during blinded period; MTX - Dr's discretion, adjust weekly dose after unblinding.
Group III: Golimumab 50 mg + Methotrexate (MTX)	Golimumab 50 mg SC injections every 4 wks from Wk 0-48 (Wk 28 if early escape); MTX - 10 to 20 mg from Wk 0 for up to 5 years; golimumab - If early escape, 100 mg beginning at Wk 28 for up to 5 yrs; golimumab - Dr's discretion after unblinding (last patients enrolled completes the Wk 52 evaluation and database is locked), dose adjust from 50 to 100 mg.
Group IV: Golimumab 100 mg + Methotrexate (MTX)	Golimumab 100 mg SC injections every 4 wks from Wk 0 up to 5 yrs; MTX - 10 to 20 mg from Wk 0 for up to 5 years.

Participant Flow: Overall Study

	Group I: Placebo + Methotrexate (MTX)	Group II: Golimumab 100 mg + Placebo	Group III: Golimumab 50 mg + Methotrexate (MTX)	Group IV: Golimumab 100 mg + Methotrexate (MTX)
STARTED	160	159	159	159
COMPLETED	150 ^[1]	150 ^[1]	151 ^[1]	149 ^[1]
NOT COMPLETED	10	9	8	10
Adverse Event	1	1	5	6
Unsatisfactory therapeutic effect	1	3	0	0
Lost to Follow-up	3	0	1	1
Death	0	0	1	1
Patient relocated	1	0	0	0
Not specified	4	5	1	2

[1]	Number of patients continuing subcutaneous study agent at Week 24

Baseline Characteristics

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Reporting Groups

	Description
Group I: Placebo + Methotrexate (MTX)	Placebo SC injections every 4 wks from Wk 0 to Wk 48 (unless early escape at Wk 28); MTX - 10 to 20 mg from Wk 0 for up to 5 years; golimumab - If early escape, 50 mg SC injection every 4 wks from Wk 28 up to 5 yrs; golimumab - Dr's discretion after unblinding (last patients enrolled completes the Wk 52 evaluation and database is locked), dose adjust from 50 to 100 mg.
Group II: Golimumab 100 mg + Placebo	Golimumab 100 mg SC injection every 4 wks from Wk 0 for up to 5 yrs, placebo capsule MTX weekly from Wk 0 to unblinding (last patients enrolled completes the Wk 52 evaluation and database is locked) unless early escape at Wk 28; MTX - If early escape start 10 mg weekly during blinded period; MTX - Dr's discretion, adjust weekly dose after unblinding.
Group III: Golimumab 50 mg + Methotrexate (MTX)	Golimumab 50 mg SC injections every 4 wks from Wk 0-48 (Wk 28 if early escape); MTX - 10 to 20 mg from Wk 0 for up to 5 years; golimumab - If early escape, 100 mg beginning at Wk 28 for up to 5 yrs; golimumab - Dr's discretion after unblinding (last patients enrolled completes the Wk 52 evaluation and database is locked), dose adjust from 50 to 100 mg.
Group IV: Golimumab 100 mg + Methotrexate (MTX)	Golimumab 100 mg SC injections every 4 wks from Wk 0 up to 5 yrs; MTX - 10 to 20 mg from Wk 0 for up to 5 years.
Total	Total of all reporting groups

Baseline Measures

	Group I: Placebo + Methotrexate (MTX)	Group II: Golimumab 100 mg + Placebo	Group III: Golimumab 50 mg + Methotrexate (MTX)	Group IV: Golimumab 100 mg + Methotrexate (MTX)	Total
Number of Participants [units: participants]	160	159	159	159	637
Age [units: years] Mean ± Standard Deviation	48.6 ± 12.91	48.2 ± 12.85	50.9 ± 11.32	50.2 ± 11.87	49.5 ± 12.28
Gender [units: participants]
Female	134	134	135	125	528
Male	26	25	24	34	109

Outcome Measures

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1. Primary:

Number of Participants Who Achieved American College of Rheumatology (ACR) 50 Response at Week 24 [ Time Frame: Week 24 ]

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Measure Type	Primary
Measure Title	Number of Participants Who Achieved American College of Rheumatology (ACR) 50 Response at Week 24
Measure Description	ACR 50 response is an improvement of greater than or equal to 50% in both tender and swollen joint count and in 3 to 5 assessments- patient's assessment of pain visual analog scale (VAS) (0 [no pain] to 10 [worst pain]); patient's and physician's global assessment of disease activity VAS scales: overall disease activity, (0 [very well] to 10 [very poor] and 0 [no arthritis activity] to 10 [extremely active], respectively); Health Assessment Questionnaire (HAQ): 20-questions on life activities (0 [no difficulty] to 3 [inability to perform a task];and assessment of C-reactive protein [CRP].
Time Frame	Week 24
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intent to Treat (ITT): Patients considered non-responder if used any pre-specified prohibited medications or discontinued subcutaneous (SC) study agent due to lack of efficacy. Missing ACR components were imputed by Last Observation Carried Forward (LOCF) unless all ACR components are missing in which case considered non-responders.

Reporting Groups

	Description
Group I: Placebo + Methotrexate (MTX)	Placebo SC injections every 4 wks from Wk 0 to Wk 48 (unless early escape at Wk 28); MTX - 10 to 20 mg from Wk 0 for up to 5 years; golimumab - If early escape, 50 mg SC injection every 4 wks from Wk 28 up to 5 yrs; golimumab - Dr's discretion after unblinding, dose adjust from 50 to 100 mg.
Group II: Golimumab 100 mg + Placebo	Golimumab 100 mg SC injection every 4 wks from Wk 0 for up to 5 yrs, placebo capsule MTX weekly from Wk 0 to unblinding (last patients enrolled completes the Wk 52 evaluation and database is locked) unless early escape at Wk 28; MTX - If early escape start 10 mg weekly during blinded period; MTX - Dr's discretion, adjust weekly dose after unblinding.
Group III: Golimumab 50 mg + Methotrexate (MTX)	Golimumab 50 mg SC injections every 4 wks from Wk 0-48 (Wk 28 if early escape); MTX - 10 to 20 mg from Wk 0 for up to 5 years; golimumab - If early escape, 100 mg beginning at Wk 28 for up to 5 yrs; golimumab - Dr's discretion after unblinding, dose adjust from 50 to 100 mg.
Group IV: Golimumab 100 mg + Methotrexate (MTX)	Golimumab 100 mg SC injections every 4 wks from Wk 0 up to 5 yrs; MTX - 10 to 20 mg from Wk 0 for up to 5 years.
Combined: Group III & IV	Combines Group III (golimumab 50 mg + methotrexate (MTX)) and Group IV (golimumab 100 mg + MTX)

Measured Values

	Group I: Placebo + Methotrexate (MTX)	Group II: Golimumab 100 mg + Placebo	Group III: Golimumab 50 mg + Methotrexate (MTX)	Group IV: Golimumab 100 mg + Methotrexate (MTX)	Combined: Group III & IV
Number of Participants Analyzed [units: participants]	160	159	159	159	318
Number of Participants Who Achieved American College of Rheumatology (ACR) 50 Response at Week 24 [units: Participants]	47	52	64	58	122

Statistical Analysis 1 for Number of Participants Who Achieved American College of Rheumatology (ACR) 50 Response at Week 24

Groups ^[1]	Group I: Placebo + Methotrexate (MTX) vs. Combined: Group III & IV
Method ^[2]	Cochran-Mantel-Haenszel
P Value ^[3]	0.053

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Null hypothesis: No difference in ACR 50 response comparing Groups I vs III and Groups I vs IV. The sample size of 150 patients per treatment group will provide >98% power to detect a difference in ACR 50 response between treatment groups at alpha=0.05, assuming 50% of patients with screening C-reactive protein (CRP)<1.5mg/dL, and the difference in ACR 50 response of 15-20% in patients with screening CRP<1.5mg/dL and 20-25% in subjects with screening CRP>=1.5mg/dL, between Groups I vs III or IV
[2]	Other relevant information, such as adjustments or degrees of freedom:
	Cochran-Mantel-Haenszel (CMH) test stratified by screening CRP (< 1.5 mg/dL; >= 1.5 mg/dL)
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	A positive test is concluded if there is a significant difference between golimumab+MTX and placebo+MTX and at least one of the pair-wise comparisons at a 0.05 level.

Statistical Analysis 2 for Number of Participants Who Achieved American College of Rheumatology (ACR) 50 Response at Week 24

Groups ^[1]	Group I: Placebo + Methotrexate (MTX) vs. Group III: Golimumab 50 mg + Methotrexate (MTX)
Method ^[2]	Cochran-Mantel-Haenszel
P Value ^[3]	0.042

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Null hypothesis: No difference in ACR 50 response comparing Groups I vs III.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	Cochran-Mantel-Haenszel (CMH) test stratified by screening C-reactive protein (CRP) (< 1.5 mg/dL; >= 1.5 mg/dL)
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

Statistical Analysis 3 for Number of Participants Who Achieved American College of Rheumatology (ACR) 50 Response at Week 24

Groups ^[1]	Group I: Placebo + Methotrexate (MTX) vs. Group IV: Golimumab 100 mg + Methotrexate (MTX)
Method ^[2]	Cochran-Mantel-Haenszel
P Value ^[3]	0.177

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Null hypothesis: No difference in ACR 50 response comparing Groups I vs IV.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	Cochran-Mantel-Haenszel (CMH) test stratified by screening C-reactive protein (CRP) (< 1.5 mg/dL; >= 1.5 mg/dL)
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.

Statistical Analysis 4 for Number of Participants Who Achieved American College of Rheumatology (ACR) 50 Response at Week 24

Groups ^[1]	Group I: Placebo + Methotrexate (MTX) vs. Group II: Golimumab 100 mg + Placebo
Non-Inferiority/Equivalence Test ^[2]	Yes
Method ^[3]	Cochran-Mantel-Haenszel
P Value ^[4]	0.521
Difference in ACR 50 Response Rate(%) ^[5]	3.3
95% Confidence Interval	( -6.8 to 99.999 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Null hypothesis: Group II is inferior to Group I. Noninferiority of golimumab will be demonstrated if the lower bound of the 2-sided 95% CI is above -10%. The 10% non-inferiority margin was chosen because this difference is not clinically admissible. Under the above noted assumed response rates, this corresponds to preservation of at least 70% [(33% - 10%)/33%*100] of the expected "MTX benefit".
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	This sample size (150 patients per treatment group) will provide approximately 85% power to claim non-inferiority of golimumab alone (Group II) compared with MTX alone (Group I) at alpha= 0.05 using a one-sided equivalence test assuming the proportion of golimumab alone (Group II) treated patients with ACR 50 response is not less than 10% compared with proportion of patients with ACR 50 response in MTX alone (Group I) treated group.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Lower bound of the 2-sided 95% Confidence Interval
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	The positive difference indicates in favor of golimumab+placebo compared to placebo+MTX; The upper bound of CI is not applicable.

2. Primary:

Change From Baseline in Total Van Der Heijde Modified Sharp (vdH-S) Score at Week 52 [ Time Frame: Baseline and Week 52 ]

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3. Secondary:

Number of Participants Who Achieved American College of Rheumatology (ACR) 20 Response at Week 24 [ Time Frame: Week 24 ]

Show Outcome Measure 3

4. Secondary:

Number of Patients With Abnormal Baseline C-reactive Protein (CRP) Who Achieved American College of Rheumatology (ACR) 50 Response at Week 24 [ Time Frame: Week 24 ]

Show Outcome Measure 4

5. Secondary:

Change From Baseline in Total Van Der Heijde Modified Sharp (vdH-S) Score at Week 52 in Patients With Abnormal C-reactive Protein (CRP Greater Than 1.0 mg/dL) at Baseline [ Time Frame: Baseline and Week 52 ]

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Serious Adverse Events

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Other Adverse Events

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More Information

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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.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: Generally, the only disclosure restriction on the PI is that the sponsor has 60 days to review results communications prior to public release and can embargo communications regarding trial results for a period that does not exceed 180 days from the time submitted to the sponsor for review. The sponsor cannot require changes to the communication and cannot extend the embargo.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
The count of patients with any nonserious adverse events (NAE) excludes patients who only had NAE that occurred in less than or equal to 5% of patients. This information may vary from existing approved labeling and publications.

Results Point of Contact:

Name/Title: Director Clinical Research
Organization: Centocor Research & Development, Inc.
phone: 1-800-457-6399

No publications provided by Centocor, Inc.

Publications automatically indexed to this study:

Østergaard M, Emery P, Conaghan PG, Fleischmann R, Hsia EC, Xu W, Rahman MU. Significant improvement in synovitis, osteitis, and bone erosion following golimumab and methotrexate combination therapy as compared with methotrexate alone: a magnetic resonance imaging study of 318 methotrexate-naive rheumatoid arthritis patients. Arthritis Rheum. 2011 Dec;63(12):3712-22.

Responsible Party:	Centocor, Inc.
ClinicalTrials.gov Identifier:	NCT00264537 History of Changes
Other Study ID Numbers:	CR006331, GO-BEFORE, C0524T05
Study First Received:	December 11, 2005
Results First Received:	May 21, 2009
Last Updated:	February 18, 2013
Health Authority:	United States: Food and Drug Administration