OPTIMA: Study of the Optimal Protocol for Methotrexate and Adalimumab Combination Therapy in Early Rheumatoid Arthritis

• Sponsor: Abbott (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00420927
• Collaborator: (none)
• Enrollment: 1,032
• Locations: 170
• Arms: 5
• Duration (Months): 43
• Patients Per Site: 6.1
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This study compared the safety and efficacy of combination therapy with adalimumab plus methotrexate (MTX) to that of MTX monotherapy (i.e., placebo plus MTX) in subjects with early rheumatoid arthritis (RA).

Condition or Disease	Intervention/Treatment	Phase
Rheumatoid Arthritis	Biological: adalimumab; Drug: methotrexate; Biological: placebo	Phase 4

Detailed Description

This was a 78-week, multicenter, randomized, double-blind, double-treatment period study designed to compare the safety and efficacy of adalimumab and MTX with placebo and MTX in subjects with early RA. Subjects were randomized to receive adalimumab 40 mg every other week (eow) or placebo subcutaneous injections in combination with orally administered MTX for 26 weeks (Period 1). All subjects in all arms received open-label MTX weekly throughout the study (both Period 1 and Period 2).

At Weeks 22 and 26, subjects were assessed for achievement of low disease activity, defined as a DAS28 score below 3.2. DAS28 is a measure of RA disease activity calculated using the number of tender and swollen joints (out of a total of 28), C-reactive protein level (CRP, a blood marker of inflammation), and the patient's global assessment of disease activity (indicated by marking a 10 cm line between very good and very bad). Subjects who achieved low disease activity at Week 22 and 26 in the adalimumab arm at the end of Period 1 were randomized to receive MTX monotherapy (placebo and MTX) or combination therapy (adalimumab and MTX) in a 1:1 ratio for the duration of Period 2 (52 weeks, i.e., to Week 78 of the study). Subjects achieving low disease activity at Week 22 and 26 in the placebo arm (MTX monotherapy) at the end of Period 1 continued to receive MTX monotherapy (and placebo injections in a blinded fashion) for the duration of Period 2. Subjects failing to achieve low disease activity at Week 22 and 26 at the end of Period 1 received open-label combination therapy during Period 2 regardless of treatment assignment in Period 1.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1032 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Randomized, Double-Period, Double - Blind Study to Determine the Optimal Protocol for Treatment Initiation With Methotrexate and Adalimumab Combination Therapy in Patients With Early Rheumatoid Arthritis (OPTIMA)
• Study Start Date: Dec 1, 2006
• Actual Primary Completion Date: Jul 1, 2010
• Actual Study Completion Date: Jul 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ADA+MTX/PBO+MTX (Arm 1) Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA) during Period 1, MTX monotherapy plus blinded placebo (PBO) during Period 2	Biological: adalimumab; Adalimumab 40 mg/0.8 mL prefilled syringe injected subcutaneously (SC) every other week (eow); Other Names: Humira D2E7 ; Drug: methotrexate; Methotrexate 2.5 mg tablets administered orally once a week starting at 7.5 mg/week with dose escalation (weekly or every other week) by 2.5 mg intervals to 20 mg/week.; Biological: placebo; Placebo for adalimumab 0.8 mL prefilled syringe injected subcutaneously (SC) every other week (eow)
Experimental: ADA+MTX/ADA+MTX (Arm2) Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA) during Period 1 and Period 2	Biological: adalimumab; Adalimumab 40 mg/0.8 mL prefilled syringe injected subcutaneously (SC) every other week (eow); Other Names: Humira D2E7 ; Drug: methotrexate; Methotrexate 2.5 mg tablets administered orally once a week starting at 7.5 mg/week with dose escalation (weekly or every other week) by 2.5 mg intervals to 20 mg/week.
Experimental: ADA+MTX/OL ADA+MTX (Arm 3) Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA) during Period 1, open-label combination therapy with ADA + MTX during Period 2	Biological: adalimumab; Adalimumab 40 mg/0.8 mL prefilled syringe injected subcutaneously (SC) every other week (eow); Other Names: Humira D2E7 ; Drug: methotrexate; Methotrexate 2.5 mg tablets administered orally once a week starting at 7.5 mg/week with dose escalation (weekly or every other week) by 2.5 mg intervals to 20 mg/week.
Experimental: PBO+MTX/PBO+MTX (Arm 4) Methotrexate (MTX) monotherapy plus blinded placebo (PBO) during Period 1 and Period 2	Drug: methotrexate; Methotrexate 2.5 mg tablets administered orally once a week starting at 7.5 mg/week with dose escalation (weekly or every other week) by 2.5 mg intervals to 20 mg/week.; Biological: placebo; Placebo for adalimumab 0.8 mL prefilled syringe injected subcutaneously (SC) every other week (eow)
Experimental: PBO+MTX/OL ADA+MTX (Arm 5) Methotrexate (MTX) monotherapy plus blinded placebo (PBO) during Period 1, open-label combination therapy with adalimumab (ADA) and MTX during Period 2.	Biological: adalimumab; Adalimumab 40 mg/0.8 mL prefilled syringe injected subcutaneously (SC) every other week (eow); Other Names: Humira D2E7 ; Drug: methotrexate; Methotrexate 2.5 mg tablets administered orally once a week starting at 7.5 mg/week with dose escalation (weekly or every other week) by 2.5 mg intervals to 20 mg/week.; Biological: placebo; Placebo for adalimumab 0.8 mL prefilled syringe injected subcutaneously (SC) every other week (eow)

Outcome Measures

Primary Outcome Measures

1. Number of Subjects With Low Disease Activity (DAS28 Less Than 3.2) and No Radiographic Progression From Baseline (Change in mTSS Less Than or Equal to 0.5) at Week 78, Arm 2 vs. Arm 4 [Week 78]

   The Disease Activity Score (DAS28) is calculated using the number of tender and swollen joints (out of 28 counted), C-reactive protein level, and the patient's global assessment of disease activity. The calculated range of DAS28 is 0.49 to 9.07, with scores below 3.2 indicating low disease activity. For the modified Total Sharp score (mTSS), x-rays of hand/wrist and feet joints are scored for erosions (0 to 5) and joint space narrowing (0 to 4). The erosion score and the narrowing score are added to determine the total score, which ranges from 0 (no damage) to 448.

Secondary Outcome Measures

1. Number of Subjects With Low Disease Activity (DAS28 Less Than 3.2) and No Radiographic Progression From Baseline (Change in mTSS Less Than or Equal to 0.5) at Week 78, Arm 2 vs. Arm 1 [Week 78]

   The Disease Activity Score (DAS28) is calculated using the number of tender and swollen joints (out of 28 counted), C-reactive protein level, and the patient's global assessment of disease activity. The calculated range of DAS28 is 0.49 to 9.07, with scores below 3.2 indicating low disease activity. For the modified Total Sharp score (mTSS), x-rays of hand/wrist and feet joints are scored for erosions (0 to 5) and joint space narrowing (0 to 4). The erosion score and the narrowing score are added to determine the total score, which ranges from 0 (no damage) to 448.

2. Number of Subjects With DAS28 Low Disease Activity (DAS28 Less Than 3.2) at Week 78 [Week 78]

   The Disease Activity Score (DAS28) is calculated using the number of tender and swollen joints (out of 28 counted), C-reactive protein level, and the patient's global assessment of disease activity. The calculated range of DAS28 is 0.49 to 9.07. A DAS28 less than 2.6 indicates clinical remission, DAS28 2.6 to 3.2 indicates low disease activity, DAS28 3.2 to less than 5.1 indicates moderate disease activity, and DAS28 of 5.1 or greater indicates high disease activity.

3. Number of Subjects With DAS28 Remission (DAS28 Less Than 2.6) at Week 78 [Week 78]

   The Disease Activity Score (DAS28) is calculated using the number of tender and swollen joints (out of 28 counted), C-reactive protein level, and the patient's global assessment of disease activity. The calculated range of DAS28 is 0.49 to 9.07. A DAS28 less than 2.6 indicates clinical remission, DAS28 2.6 to 3.2 indicates low disease activity, DAS28 3.2 to less than 5.1 indicates moderate disease activity, and DAS28 of 5.1 or greater indicates high disease activity.

4. Number of Subjects With No Radiographic Progression (Change From Baseline in mTSS Less Than or Equal to 0.5) at Week 78 [Week 78]

   For the modified Total Sharp score (mTSS), x-rays of hand/wrist and feet joints are scored for erosions (0 to 5) and joint space narrowing (0 to 4). The erosion score and the narrowing score are added to determine the total score, which ranges from 0 (no damage) to 448. An increase in mTSS from baseline represents disease progression and/or joint worsening, no change represents halting of disease progression, and a decrease represents improvement.

5. Number of Subjects Meeting American College of Rheumatology 20% (ACR20) Response Criteria at Week 78 [Week 78]

   Subjects were responders if they had greater than or equal to 20% improvement in tender joint count; greater than or equal to 20% improvement in swollen joint count; and greater than or equal to 20% improvement in at least 3 of 5 remaining ACR core measures: patient assessment of pain; patient global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire [HAQ]); and acute phase reactant (C-reactive protein).

6. Number of Subjects Meeting American College of Rheumatology 50% (ACR50) Response Criteria at Week 78 [Week 78]

   Subjects were responders if they had: greater than or equal to 50% improvement in tender joint count; greater than or equal to 50% improvement in swollen joint count; and greater than or equal to 50% improvement in at least 3 of 5 remaining ACR core measures: patient assessment of pain; patient global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire [HAQ]); and acute phase reactant (C-reactive protein).

7. Number of Subjects Meeting American College of Rheumatology 70% (ACR70) Response Criteria at Week 78 [Week 78]

   Subjects were responders if they had: greater than or equal to 70% improvement in tender joint count; greater than or equal to 70% improvement in swollen joint count; and greater than or equal to 70% improvement in at least 3 of 5 remaining ACR core measures: patient assessment of pain; patient global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire [HAQ]); and acute phase reactant (C-reactive protein).

8. Change From Baseline in DAS28 Score at Week 78 [Baseline to Week 78]

   The Disease Activity Score (DAS28) is calculated using the number of tender and swollen joints (out of 28 counted), C-reactive protein level, and the patient's global assessment of disease activity. The calculated range of DAS28 is 0.49 to 9.07. A DAS28 less than 2.6 indicates clinical remission, DAS28 2.6 to 3.2 indicates low disease activity, DAS28 3.2 to less than 5.1 indicates moderate disease activity, and DAS28 of 5.1 or greater indicates high disease activity.

9. Number of Subjects With Clinical Disease Activity Index (CDAI) Low Disease Activity (CDAI Less Than or Equal to 10) at Week 78 [Week 78]

   The CDAI is calculated using number of swollen joints (28 joints assessed), number of tender joints (28 joints assessed), patient's global assessment of disease activity, and physician's global assessment of disease activity. Scores range from 0 to 76.0, with a higher score reflecting worsening disease.

10. Number of Subjects With Simplified Disease Activity Index (SDAI) Low Disease Activity (SDAI Less Than or Equal to 11) at Week 78 [Week 78]

    The SDAI is calculated using number of swollen joints (28 joints assessed), number of tender joints (28 joints assessed), patient's global assessment of disease activity, physician's global assessment of disease activity, and acute phase reactant (C-reactive protein). Scores range from 0.1 to 86.0, with a higher score reflecting worsening disease.

11. Number of Subjects With Clinical Disease Activity Index (CDAI) Remission (CDAI Less Than or Equal to 2.8) at Week 78 [Week 78]

    The CDAI is calculated using number of swollen joints (28 joints assessed), number of tender joints (28 joints assessed), patient's global assessment of disease activity, and physician's global assessment of disease activity. Scores range from 0 to 76.0, with a higher score reflecting worsening disease.

12. Number of Subjects With Simplified Disease Activity Index (SDAI) Remission (SDAI Less Than or Equal to 3.3) at Week 78 [Week 78]

    The SDAI is calculated using number of swollen joints (28 joints assessed), number of tender joints (28 joints assessed), patient's global assessment of disease activity, physician's global assessment of disease activity, and acute phase reactant (C-reactive protein). Scores range from 0.1 to 86.0, with a higher score reflecting worsening disease.

13. Change From Baseline in CDAI Score at Week 78 [Baseline to Week 78]

    The CDAI is calculated using number of swollen joints (28 joints assessed), number of tender joints (28 joints assessed), patient's global assessment of disease activity, and physician's global assessment of disease activity. Scores range from 0 to 76.0, with a higher score reflecting worsening disease.

14. Change From Baseline in SDAI Score at Week 78 [Baseline to Week 78]

    The SDAI is calculated using number of swollen joints (28 joints assessed), number of tender joints (28 joints assessed), patient's global assessment of disease activity, physician's global assessment of disease activity, and acute phase reactant (C-reactive protein). Scores range from 0.1 to 86.0, with a higher score reflecting worsening disease.

15. Change From Baseline in Synovitis Score According to the Rheumatoid Arthritis Magnetic Resonance Imaging (RA MRI) Scoring System (RAMRIS) at Week 78 [Baseline to Week 78]

    Synovitis was assessed using high-field magnetic resonance imaging (MRI) of the hand and wrist. Images were read and scored according to the Outcomes Measures in Rheumatology Clinical Trials' Rheumatoid Arthritis MRI Scoring System (OMERACT RAMRIS). Synovitis in the wrist and finger joints in the most affected hand was scored from 0 (normal) to 3 (severe), for a maximum total score of 21.

16. Number of Subjects With No Radiographic Progression (Change From Baseline in mTSS of Less Than or Equal to 0.5) and Normal Function (HAQ-DI Less Than 0.5) at Week 78 [Week 78]

    In the Health Assessment Questionnaire Disability Index (HAQ-DI), participants rated their ability to perform daily tasks on a scale of 0 (without any difficulty) to 3 (unable to do). A mean score of 0-1 represents mild to moderate functional disability, 1-2 represents moderate to severe, 2-3 severe to very severe disability. For the modified Total Sharp score (mTSS), x-rays of hand/wrist and feet joints are scored for erosions (0 to 5) and joint space narrowing (0 to 4). The erosion score and the narrowing score are added to determine the total score, which ranges from 0 (no damage) to 448.

17. Number of Subjects With No Radiographic Progression (Change From Baseline in mTSS of Less Than or Equal to 0.5), Normal Function (HAQ-DI Less Than or Equal to 0.5), and ACR70 Response at Week 78 [Week 78]

    In the Health Assessment Questionnaire Disability Index (HAQ-DI), a score of 0-1 represents mild to moderate, 1-2 moderate to severe, 2-3 severe to very severe disability. The modified Total Sharp score (mTSS) ranges from 0 (no joint damage) to 448 (worst joint damage). American College of Rheumatology 70% (ACR70) response indicates at least 70% improvement in tender and swollen joint counts and at least 3 of 5 remaining ACR core measures: patient assessment of pain; patient global assessment of disease activity; physician global assessment of disease activity; HAQ-DI; and C-reactive protein.

18. Number of Subjects With No Radiographic Progression (Change From Baseline in mTSS of Less Than or Equal to 0.5), Normal Function (HAQ-DI Less Than 0.5), and DAS28 Remission (DAS28 Less Than 2.6) at Week 78 [Week 78]

    In the Health Assessment Questionnaire Disability Index (HAQ-DI), a score of 0-1 represents mild to moderate, 1-2 moderate to severe, 2-3 severe to very severe disability. The modified Total Sharp score (mTSS) ranges from 0 (no joint damage) to 448 (severe joint damage). The Disease Activity Score (DAS28) ranges from 0.49 to 9.07, with scores less than 2.6 indicating clinical remission.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria

• Subject must be 18 or older and in good health

• Subject must meet the definition of early rheumatoid arthritis (RA) defined by the 1987-revised American College of Rheumatology (ACR) classification criteria and had disease duration of less than 1 year from diagnosis

• Subject must have a Disease Activity Score (DAS28, based on C-reactive protein) greater than 3.2, at least 6 swollen joints out of the 66 assessed, and at least 8 tender joints out of the 68 assessed

• Subject must fulfill at least one of the following three criteria:

• Rheumatoid factor positive

• Greater than 1 joint erosion

• Anti-cyclic citrullinated peptide (CCP) antibody positive.

Exclusion Criteria

• Subject has previously received systemic anti-tumor necrosis factor (TNF) therapy

• Subject has received any biologic or investigational therapy within 6 weeks prior to Baseline

• Subject has been previously treated with more than 2 disease-modifying antirheumatic drugs (DMARDs) or MTX, had been treated with intra-articular or parenteral administration of corticosteroids in preceding 4 weeks, or had undergone joint surgery within the preceding 2 months at joints to be assessed during the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Site Reference ID/Investigator# 4560	Birmingham	Alabama	United States	35205
2	Site Reference ID/Investigator# 4547	Birmingham	Alabama	United States	35294-7201
3	Site Reference ID/Investigator# 6222	Huntsville	Alabama	United States	35801
4	Site Reference ID/Investigator# 4537	Mobile	Alabama	United States	36608
5	Site Reference ID/Investigator# 6758	Tuscaloosa	Alabama	United States	35406
6	Site Reference ID/Investigator# 9323	Hemet	California	United States	92543
7	Site Reference ID/Investigator# 4568	La Jolla	California	United States	92037-0943
8	Site Reference ID/Investigator# 4535	Palm Desert	California	United States	92260
9	Site Reference ID/Investigator# 4571	Santa Monica	California	United States	90404
10	Site Reference ID/Investigator# 9271	Torrance	California	United States	90505
11	Site Reference ID/Investigator# 10746	Victorville	California	United States	92395
12	Site Reference ID/Investigator# 4559	Denver	Colorado	United States	80230
13	Site Reference ID/Investigator# 6229	Aventura	Florida	United States	33180
14	Site Reference ID/Investigator# 10603	Lake Mary	Florida	United States	32746
15	Site Reference ID/Investigator# 9325	Orange Park	Florida	United States	32073
16	Site Reference ID/Investigator# 4550	Palm Harbor	Florida	United States	34684
17	Site Reference ID/Investigator# 4570	Sarasota	Florida	United States	34239
18	Site Reference ID/Investigator# 4601	Tampa	Florida	United States	33614
19	Site Reference ID/Investigator# 4552	Vero Beach	Florida	United States	32960
20	Site Reference ID/Investigator# 10745	Meridian	Idaho	United States	83642
21	Site Reference ID/Investigator# 4548	Chicago	Illinois	United States	60612
22	Site Reference ID/Investigator# 4557	Springfield	Illinois	United States	62704
23	Site Reference ID/Investigator# 4605	Wichita	Kansas	United States	67203
24	Site Reference ID/Investigator# 10741	Wheaton	Maryland	United States	20902
25	Site Reference ID/Investigator# 6417	Fall River	Massachusetts	United States	02720
26	Site Reference ID/Investigator# 4561	Dover	New Hampshire	United States	03820
27	Site Reference ID/Investigator# 11222	Freehold	New Jersey	United States	07728
28	Site Reference ID/Investigator# 6228	Passaic	New Jersey	United States	07055
29	Site Reference ID/Investigator# 4544	Albuquerque	New Mexico	United States	87102
30	Site Reference ID/Investigator# 12821	Bronx	New York	United States	10461
31	Site Reference ID/Investigator# 4534	Orchard Park	New York	United States	14127
32	Site Reference ID/Investigator# 9324	Plainview	New York	United States	11803
33	Site Reference ID/Investigator# 4600	Smithtown	New York	United States	11787
34	Site Reference ID/Investigator# 4549	Mayfield Village	Ohio	United States	44143
35	Site Reference ID/Investigator# 6227	Bend	Oregon	United States	97701
36	Site Reference ID/Investigator# 4546	Duncansville	Pennsylvania	United States	16635
37	Site Reference ID/Investigator# 4564	West Reading	Pennsylvania	United States	19611-1124
38	Site Reference ID/Investigator# 4558	Wexford	Pennsylvania	United States	15090
39	Site Reference ID/Investigator# 4533	Charleston	South Carolina	United States	29406
40	Site Reference ID/Investigator# 7482	Greenville	South Carolina	United States	29601
41	Site Reference ID/Investigator# 10743	Jackson	Tennessee	United States	38305
42	Site Reference ID/Investigator# 4562	Nashville	Tennessee	United States	37205
43	Site Reference ID/Investigator# 4536	Dallas	Texas	United States	75231
44	Site Reference ID/Investigator# 4538	Houston	Texas	United States	77074
45	Site Reference ID/Investigator# 6899	San Antonio	Texas	United States	78217
46	Site Reference ID/Investigator# 6381	Tyler	Texas	United States	75701
47	Site Reference ID/Investigator# 10744	Seattle	Washington	United States	98133
48	Site Reference ID/Investigator# 4545	Glendale	Wisconsin	United States	53217
49	Site Reference ID/Investigator# 4572	Oak Creek	Wisconsin	United States	53154
50	Site Reference ID/Investigator# 3886	Buenos Aires		Argentina	1426AAL
51	Site Reference ID/Investigator# 3888	Buenos Aires		Argentina	C1015ABO
52	Site Reference ID/Investigator# 6346	Buenos Aires		Argentina	C1055AAF
53	Site Reference ID/Investigator# 3887	Quilmes		Argentina
54	Site Reference ID/Investigator# 3889	San Miguel de Tucuman		Argentina	T4000AXL
55	Site Reference ID/Investigator# 8380	Campsie, Sydney		Australia	2194
56	Site Reference ID/Investigator# 6954	Clayton		Australia	3168
57	Site Reference ID/Investigator# 6940	Malvern East		Australia	3145
58	Site Reference ID/Investigator# 3915	Graz		Austria	8036
59	Site Reference ID/Investigator# 3911	Graz		Austria	A-8020
60	Site Reference ID/Investigator# 3880	Vienna		Austria	1090
61	Site Reference ID/Investigator# 3885	Vienna		Austria	1100
62	Site Reference ID/Investigator# 3916	Vienna		Austria	1130
63	Site Reference ID/Investigator# 7792	Vienna		Austria	1160
64	Site Reference ID/Investigator# 3914	Brussels		Belgium	1200
65	Site Reference ID/Investigator# 3909	Genk		Belgium	3600
66	Site Reference ID/Investigator# 3881	Gilly		Belgium	6060
67	Site Reference ID/Investigator# 3376	Liege		Belgium	4000
68	Site Reference ID/Investigator# 6720	Mechelen		Belgium	2800
69	Site Reference ID/Investigator# 6718	Sint-Niklaas		Belgium	9100
70	Site Reference ID/Investigator# 3910	Yvoir		Belgium	5530
71	Site Reference ID/Investigator# 6701	Burlington		Canada	L7R 1E2
72	Site Reference ID/Investigator# 6834	Edmonton		Canada	T5M 0H4
73	Site Reference ID/Investigator# 7197	Halifax		Canada	B3H 4K4
74	Site Reference ID/Investigator# 3883	Hamilton		Canada	L8N 1Y2
75	Site Reference ID/Investigator# 3884	Hamilton		Canada	L8N 2B6
76	Site Reference ID/Investigator# 3907	Montreal		Canada	H2L 1S6
77	Site Reference ID/Investigator# 3903	Montreal		Canada	H3Z 2Z3
78	Site Reference ID/Investigator# 5178	Ottawa		Canada	K2G 6E2
79	Site Reference ID/Investigator# 3904	Richmond		Canada	V7C 5L9
80	Site Reference ID/Investigator# 3912	Sainte-Foy, Quebec		Canada	G1W 4R4
81	Site Reference ID/Investigator# 3901	Sarnia		Canada	N7T 5W6
82	Site Reference ID/Investigator# 3906	St. John's		Canada	A1A 5E8
83	Site Reference ID/Investigator# 6542	Toronto		Canada	M9B 1B1
84	Site Reference ID/Investigator# 3882	Victoria		Canada	V8V 3P9
85	Site Reference ID/Investigator# 5616	Windsor		Canada	N8X 5A6
86	Site Reference ID/Investigator# 5847	Winnipeg		Canada	R3A 1M3
87	Site Reference ID/Investigator# 3905	Winnipeg		Canada	R3A 1M4
88	Site Reference ID/Investigator# 3968	Brno		Czech Republic	65691
89	Site Reference ID/Investigator# 3971	Hradec Kralove		Czech Republic	500 05
90	Site Reference ID/Investigator# 5559	Ostrava		Czech Republic	72200
91	Site Reference ID/Investigator# 3969	Prague 2		Czech Republic	128 50
92	Site Reference ID/Investigator# 5548	Uherske Hradiste		Czech Republic	686 01
93	Site Reference ID/Investigator# 3982	Amiens		France	80054
94	Site Reference ID/Investigator# 3979	Le Mans		France	72037
95	Site Reference ID/Investigator# 3983	Paris Cedex 14		France	75679
96	Site Reference ID/Investigator# 3918	Strasbourg		France	67098
97	Site Reference ID/Investigator# 3926	Bad Nauheim		Germany	D-61231
98	Site Reference ID/Investigator# 3928	Berlin-Buch		Germany	13125
99	Site Reference ID/Investigator# 3978	Damp		Germany	24351
100	Site Reference ID/Investigator# 3924	Duesseldorf		Germany	40225
101	Site Reference ID/Investigator# 3927	Frankfurt/Main		Germany	60596
102	Site Reference ID/Investigator# 3965	Frankfurt		Germany	60590
103	Site Reference ID/Investigator# 3925	Freiburg		Germany	79106
104	Site Reference ID/Investigator# 4291	Halle		Germany	06120
105	Site Reference ID/Investigator# 8489	Hofheim		Germany	D-65719
106	Site Reference ID/Investigator# 3923	Munich		Germany	80336
107	Site Reference ID/Investigator# 8483	Osnabrueck		Germany	D-49074
108	Site Reference ID/Investigator# 8486	Ratingen		Germany	40882
109	Site Reference ID/Investigator# 3919	Vogelsang-Gommern		Germany	39245
110	Site Reference ID/Investigator# 6637	Zerbst		Germany	39261
111	Site Reference ID/Investigator# 3921	Budapest		Hungary	1023
112	Site Reference ID/Investigator# 3922	Budapest		Hungary	1277
113	Site Reference ID/Investigator# 3920	Debrecen		Hungary	4012
114	Site Reference ID/Investigator# 3824	Aguascallentes		Mexico	20230
115	Site Reference ID/Investigator# 3822	Leon, Guanajuato		Mexico	37000
116	Site Reference ID/Investigator# 3825	Mexico City		Mexico	10700
117	Site Reference ID/Investigator# 3951	Mexico City		Mexico	10700
118	Site Reference ID/Investigator# 3890	Mexico City		Mexico	14389
119	Site Reference ID/Investigator# 3823	Mexico City		Mexico	CP 1300
120	Site Reference ID/Investigator# 3891	Mexico City		Mexico	CP 14050
121	Site Reference ID/Investigator# 3947	Arnem		Netherlands	6815 AD
122	Site Reference ID/Investigator# 3948	Hilversum		Netherlands	1213XZ
123	Site Reference ID/Investigator# 8485	Auckland 6		New Zealand
124	Site Reference ID/Investigator# 8488	Hamilton		New Zealand
125	Site Reference ID/Investigator# 8496	Timaru		New Zealand
126	Site Reference ID/Investigator# 8511	Wellington		New Zealand
127	Site Reference ID/Investigator# 7607	Alesund		Norway	N-6026
128	Site Reference ID/Investigator# 7935	Kristiansand S		Norway	4615
129	Site Reference ID/Investigator# 7506	Levanger		Norway	7600
130	Site Reference ID/Investigator# 7511	Lillehammer		Norway	N-2609
131	Site Reference ID/Investigator# 7500	Trondheim		Norway	N-7006
132	Site Reference ID/Investigator# 3963	Bydgoszcz		Poland	85168
133	Site Reference ID/Investigator# 3962	Katowice		Poland	40635
134	Site Reference ID/Investigator# 5560	Lublin		Poland	20954
135	Site Reference ID/Investigator# 3961	Wroclaw		Poland	53-342
136	Site Reference ID/Investigator# 3944	Caguas		Puerto Rico	00725
137	Site Reference ID/Investigator# 3937	Ponce		Puerto Rico	00716
138	Site Reference ID/Investigator# 3934	San Juan		Puerto Rico	00918
139	Site Reference ID/Investigator# 3935	San Juan		Puerto Rico	00936-5067
140	Site Reference ID/Investigator# 3959	Piestany		Slovakia	92112
141	Site Reference ID/Investigator# 3960	Piestany		Slovakia	92112
142	Site Reference ID/Investigator# 7177	Berea, Durban		South Africa	4001
143	Site Reference ID/Investigator# 7175	Cape Town		South Africa	7405
144	Site Reference ID/Investigator# 7178	Cape Town		South Africa	7500
145	Site Reference ID/Investigator# 7176	Port Elizabeth		South Africa	6045
146	Site Reference ID/Investigator# 7172	Pretoria		South Africa	0028
147	Site Reference ID/Investigator# 7174	Soweto		South Africa	2013
148	Site Reference ID/Investigator# 3955	A Coruna		Spain	15006
149	Site Reference ID/Investigator# 13661	Bilbao		Spain	48013
150	Site Reference ID/Investigator# 3930	Elche (Alicante)		Spain	03203
151	Site Reference ID/Investigator# 8524	Madrid		Spain	28006
152	Site Reference ID/Investigator# 3956	Madrid		Spain	28007
153	Site Reference ID/Investigator# 3943	Madrid		Spain	28034
154	Site Reference ID/Investigator# 3931	Madrid		Spain	28046
155	Site Reference ID/Investigator# 3957	Oviedo		Spain	33006
156	Site Reference ID/Investigator# 3954	Santiago de Compostela		Spain	15706
157	Site Reference ID/Investigator# 3932	Zaragoza		Spain	50009
158	Site Reference ID/Investigator# 4015	Eskilstuna		Sweden	SE-631 88
159	Site Reference ID/Investigator# 3984	Falun		Sweden	SE-79182
160	Site Reference ID/Investigator# 4016	Malmoe		Sweden	20502
161	Site Reference ID/Investigator# 4014	Stockholm		Sweden	171 76
162	Site Reference ID/Investigator# 4017	Uppsala		Sweden	75185
163	Site Reference ID/Investigator# 4012	Bath		United Kingdom	BA1 1RL
164	Site Reference ID/Investigator# 8495	Huddersfield		United Kingdom	HD3 3EA
165	Site Reference ID/Investigator# 4048	Leeds		United Kingdom	LS7 4SA
166	Site Reference ID/Investigator# 4013	London		United Kingdom	SE1 9RT
167	Site Reference ID/Investigator# 4046	Newcastle upon Tyne		United Kingdom	NE7 7DN
168	Site Reference ID/Investigator# 4047	Oxford		United Kingdom	OX3 7LD
169	Site Reference ID/Investigator# 3985	Southampton		United Kingdom	S016 6YD
170	Site Reference ID/Investigator# 7977	York		United Kingdom	YO31 8HE

Sponsors and Collaborators

• Abbott

Investigators

• Study Director: Laura Redden, MD, PhD, Abbott

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Abbott
• ClinicalTrials.gov Identifier: NCT00420927
• Other Study ID Numbers: M06-810; 2006-004139-31
• First Posted: Jan 11, 2007
• Last Update Posted: Apr 18, 2012
• Last Verified: Apr 1, 2012

• Keywords provided by Abbott: Early Rheumatoid Arthritis; Tumor Necrosis Factor Optimization
• Additional relevant MeSH terms: Arthritis; Arthritis, Rheumatoid; Adalimumab; Methotrexate

Study Results

Participant Flow

Arm/Group Title	ADA+MTX	PBO+MTX	ADA+MTX/PBO+MTX (Arm 1)	ADA+MTX/ADA+MTX (Arm 2)	ADA+MTX/OL ADA+MTX (Arm 3)	PBO+MTX/PBO+MTX (Arm 4)	PBO+MTX/OL ADA+MTX (Arm 5)
Arm/Group Description	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA) during Period 1	Methotrexate (MTX) monotherapy plus blinded placebo during Period 1	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA) during Period 1, MTX monotherapy plus blinded placebo (PBO) during Period 2	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA) during Period 1 and Period 2	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA) during Period 1, open-label combination therapy with ADA and MTX during Period 2	Methotrexate (MTX) monotherapy plus blinded placebo (PBO) during Period 1 and Period 2	Methotrexate (MTX) monotherapy plus blinded placebo (PBO) during Period 1, open-label combination therapy with adalimumab (ADA) and MTX during Period 2
Period Title: Period 1
STARTED	515	517	0	0	0	0	0
COMPLETED	466	460	0	0	0	0	0
NOT COMPLETED	49	57	0	0	0	0	0
Period Title: Period 1
STARTED	0	0	102	105	259	112	348
COMPLETED	0	0	89	95	216	97	295
NOT COMPLETED	0	0	13	10	43	15	53

Baseline Characteristics

Arm/Group Title	ADA+MTX	PBO+MTX	ADA+MTX/PBO+MTX (Arm 1)	ADA+MTX/ADA+MTX (Arm 2)	ADA+MTX/OL ADA+MTX (Arm 3)	PBO+MTX/PBO+MTX (Arm 4)	PBO+MTX/OL ADA+MTX (Arm 5)	Total
Arm/Group Description	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA) during Period 1	Methotrexate (MTX) monotherapy plus blinded placebo(PBO) during Period 1	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA)during Period 1, MTX monotherapy plus blinded placebo (PBO) during Period 2	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA) during Period 1 and Period 2	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA) during Period 1, open-label combination therapy with ADA and MTX during Period 2	Methotrexate (MTX) monotherapy plus blinded placebo (PBO) during Period 1 and Period 2	Methotrexate (MTX) monotherapy plus blinded placebo (PBO) during Period 1, open-label combination therapy with adalimumab (ADA) and MTX during Period 2	Total of all reporting groups
Overall Participants	515	517	0	0	0	0	0	1032
Age (participants) [Number]
<=18 years	0 0%	0 0%	0 NaN
Between 18 and 65 years	418 81.2%	431 83.4%	849 Infinity
>=65 years	97 18.8%	86 16.6%	183 Infinity
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	50.7 (14.48)	50.4 (13.62)	50.6 (14.05)
Gender (participants) [Number]
Female	380 73.8%	382 73.9%	762 Infinity
Male	135 26.2%	135 26.1%	270 Infinity
Region of Enrollment (participants) [Number]
Argentina	32 6.2%	29 5.6%	61 Infinity
Australia	5 1%	8 1.5%	13 Infinity
Austria	11 2.1%	12 2.3%	23 Infinity
Belgium	41 8%	40 7.7%	81 Infinity
Canada	57 11.1%	58 11.2%	115 Infinity
Czech Republic	22 4.3%	19 3.7%	41 Infinity
France	4 0.8%	8 1.5%	12 Infinity
Germany	43 8.3%	41 7.9%	84 Infinity
Hungary	8 1.6%	10 1.9%	18 Infinity
Mexico	26 5%	27 5.2%	53 Infinity
Netherlands	0 0%	3 0.6%	3 Infinity
New Zealand	3 0.6%	3 0.6%	6 Infinity
Norway	4 0.8%	5 1%	9 Infinity
Poland	12 2.3%	9 1.7%	21 Infinity
Slovakia	6 1.2%	3 0.6%	9 Infinity
South Africa	31 6%	32 6.2%	63 Infinity
Spain	25 4.9%	30 5.8%	55 Infinity
Sweden	10 1.9%	11 2.1%	21 Infinity
United Kingdom	26 5%	17 3.3%	43 Infinity
United States	149 28.9%	152 29.4%	301 Infinity

Outcome Measures

1. Primary Outcome

Title	Number of Subjects With Low Disease Activity (DAS28 Less Than 3.2) and No Radiographic Progression From Baseline (Change in mTSS Less Than or Equal to 0.5) at Week 78, Arm 2 vs. Arm 4
Description	The Disease Activity Score (DAS28) is calculated using the number of tender and swollen joints (out of 28 counted), C-reactive protein level, and the patient's global assessment of disease activity. The calculated range of DAS28 is 0.49 to 9.07, with scores below 3.2 indicating low disease activity. For the modified Total Sharp score (mTSS), x-rays of hand/wrist and feet joints are scored for erosions (0 to 5) and joint space narrowing (0 to 4). The erosion score and the narrowing score are added to determine the total score, which ranges from 0 (no damage) to 448.
Time Frame	Week 78

Outcome Measure Data

Analysis Population Description

The analysis was performed on the ITT Population comprised of all subjects who entered Period 2 and received at least 1 dose of study drug (blinded or open-label) during Period 2. Nonresponder imputation was used for missing data.

Arm/Group Title	ADA+MTX/PBO+MTX (Arm 1)	ADA+MTX/ADA+MTX (Arm 2)	ADA+MTX/OL ADA+MTX (Arm 3)	PBO+MTX/PBO+MTX (Arm 4)	PBO+MTX/OL ADA+MTX (Arm 5)
Arm/Group Description	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA)during Period 1, MTX monotherapy plus blinded placebo (PBO) during Period 2	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA) during Period 1 and Period 2	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA) during Period 1, open-label combination therapy with ADA and MTX during Period 2	Methotrexate (MTX) monotherapy plus blinded placebo (PBO) during Period 1 and Period 2	Methotrexate (MTX) monotherapy plus blinded placebo (PBO) during Period 1, open-label combination therapy with adalimumab (ADA) and MTX during Period 2
Measure Participants	102	105	259	112	348
Number [Participants]	59 11.5%	73 14.1%	94 Infinity	61 Infinity	129 Infinity

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ADA+MTX/ADA+MTX (Arm 2), PBO+MTX/PBO+MTX (Arm 4)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.023
	Comments
	Method	Chi-squared
	Comments	P value is from Pearson's chi-square test.

2. Secondary Outcome

Title	Number of Subjects With Low Disease Activity (DAS28 Less Than 3.2) and No Radiographic Progression From Baseline (Change in mTSS Less Than or Equal to 0.5) at Week 78, Arm 2 vs. Arm 1
Description	The Disease Activity Score (DAS28) is calculated using the number of tender and swollen joints (out of 28 counted), C-reactive protein level, and the patient's global assessment of disease activity. The calculated range of DAS28 is 0.49 to 9.07, with scores below 3.2 indicating low disease activity. For the modified Total Sharp score (mTSS), x-rays of hand/wrist and feet joints are scored for erosions (0 to 5) and joint space narrowing (0 to 4). The erosion score and the narrowing score are added to determine the total score, which ranges from 0 (no damage) to 448.
Time Frame	Week 78

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	ADA+MTX/PBO+MTX (Arm 1)	ADA+MTX/ADA+MTX (Arm 2)	ADA+MTX/OL ADA+MTX (Arm 3)	PBO+MTX/PBO+MTX (Arm 4)	PBO+MTX/OL ADA+MTX (Arm 5)
Arm/Group Description	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA)during Period 1, MTX monotherapy plus blinded placebo (PBO) during Period 2	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA) during Period 1 and Period 2	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA) during Period 1, open-label combination therapy with ADA and MTX during Period 2	Methotrexate (MTX) monotherapy plus blinded placebo (PBO) during Period 1 and Period 2	Methotrexate (MTX) monotherapy plus blinded placebo (PBO) during Period 1, open-label combination therapy with adalimumab (ADA) and MTX during Period 2
Measure Participants	102	105	259	112	348
Number [Participants]	59 11.5%	73 14.1%	94 Infinity	61 Infinity	129 Infinity

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ADA+MTX/PBO+MTX (Arm 1), ADA+MTX/ADA+MTX (Arm 2)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.082
	Comments
	Method	Regression, Logistic
	Comments

3. Secondary Outcome

Title	Number of Subjects With DAS28 Low Disease Activity (DAS28 Less Than 3.2) at Week 78
Description	The Disease Activity Score (DAS28) is calculated using the number of tender and swollen joints (out of 28 counted), C-reactive protein level, and the patient's global assessment of disease activity. The calculated range of DAS28 is 0.49 to 9.07. A DAS28 less than 2.6 indicates clinical remission, DAS28 2.6 to 3.2 indicates low disease activity, DAS28 3.2 to less than 5.1 indicates moderate disease activity, and DAS28 of 5.1 or greater indicates high disease activity.
Time Frame	Week 78

Outcome Measure Data

Analysis Population Description

ITT Population, Nonresponder imputation

Arm/Group Title	ADA+MTX/PBO+MTX (Arm 1)	ADA+MTX/ADA+MTX (Arm 2)	ADA+MTX/OL ADA+MTX (Arm 3)	PBO+MTX/PBO+MTX (Arm 4)	PBO+MTX/OL ADA+MTX (Arm 5)
Arm/Group Description	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA)during Period 1, MTX monotherapy plus blinded placebo (PBO) during Period 2	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA) during Period 1 and Period 2	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA) during Period 1, open-label combination therapy with ADA and MTX during Period 2	Methotrexate (MTX) monotherapy plus blinded placebo (PBO) during Period 1 and Period 2	Methotrexate (MTX) monotherapy plus blinded placebo (PBO) during Period 1, open-label combination therapy with adalimumab (ADA) and MTX during Period 2
Measure Participants	102	105	259	112	348
Number [Participants]	71 13.8%	80 15.5%	108 Infinity	78 Infinity	185 Infinity

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ADA+MTX/ADA+MTX (Arm 2), PBO+MTX/PBO+MTX (Arm 4)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.280
	Comments
	Method	Regression, Logistic
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	ADA+MTX/PBO+MTX (Arm 1), ADA+MTX/ADA+MTX (Arm 2)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.287
	Comments
	Method	Regression, Logistic
	Comments

4. Secondary Outcome

Title	Number of Subjects With DAS28 Remission (DAS28 Less Than 2.6) at Week 78
Description	The Disease Activity Score (DAS28) is calculated using the number of tender and swollen joints (out of 28 counted), C-reactive protein level, and the patient's global assessment of disease activity. The calculated range of DAS28 is 0.49 to 9.07. A DAS28 less than 2.6 indicates clinical remission, DAS28 2.6 to 3.2 indicates low disease activity, DAS28 3.2 to less than 5.1 indicates moderate disease activity, and DAS28 of 5.1 or greater indicates high disease activity.
Time Frame	Week 78

Outcome Measure Data

Analysis Population Description

ITT Population, nonresponder imputation

Arm/Group Title	ADA+MTX/PBO+MTX (Arm 1)	ADA+MTX/ADA+MTX (Arm 2)	ADA+MTX/OL ADA+MTX (Arm 3)	PBO+MTX/PBO+MTX (Arm 4)	PBO+MTX/OL ADA+MTX (Arm 5)
Arm/Group Description	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA)during Period 1, MTX monotherapy plus blinded placebo (PBO) during Period 2	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA) during Period 1 and Period 2	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA) during Period 1, open-label combination therapy with ADA and MTX during Period 2	Methotrexate (MTX) monotherapy plus blinded placebo (PBO) during Period 1 and Period 2	Methotrexate (MTX) monotherapy plus blinded placebo (PBO) during Period 1, open-label combination therapy with adalimumab (ADA) and MTX during Period 2
Measure Participants	102	105	259	112	348
Number [Participants]	57 11.1%	77 14.9%	71 Infinity	66 Infinity	138 Infinity

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ADA+MTX/ADA+MTX (Arm 2), PBO+MTX/PBO+MTX (Arm 4)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.026
	Comments
	Method	Regression, Logistic
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	ADA+MTX/PBO+MTX (Arm 1), ADA+MTX/ADA+MTX (Arm 2)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.009
	Comments
	Method	Regression, Logistic
	Comments

5. Secondary Outcome

Title	Number of Subjects With No Radiographic Progression (Change From Baseline in mTSS Less Than or Equal to 0.5) at Week 78
Description	For the modified Total Sharp score (mTSS), x-rays of hand/wrist and feet joints are scored for erosions (0 to 5) and joint space narrowing (0 to 4). The erosion score and the narrowing score are added to determine the total score, which ranges from 0 (no damage) to 448. An increase in mTSS from baseline represents disease progression and/or joint worsening, no change represents halting of disease progression, and a decrease represents improvement.
Time Frame	Week 78

Outcome Measure Data

Analysis Population Description

ITT Population, nonresponder imputation

Arm/Group Title	ADA+MTX/PBO+MTX (Arm 1)	ADA+MTX/ADA+MTX (Arm 2)	ADA+MTX/OL ADA+MTX (Arm 3)	PBO+MTX/PBO+MTX (Arm 4)	PBO+MTX/OL ADA+MTX (Arm 5)
Arm/Group Description	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA)during Period 1, MTX monotherapy plus blinded placebo (PBO) during Period 2	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA) during Period 1 and Period 2	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA) during Period 1, open-label combination therapy with ADA and MTX during Period 2	Methotrexate (MTX) monotherapy plus blinded placebo (PBO) during Period 1 and Period 2	Methotrexate (MTX) monotherapy plus blinded placebo (PBO) during Period 1, open-label combination therapy with adalimumab (ADA) and MTX during Period 2
Measure Participants	102	102	259	112	348
Number [Participants]	70 13.6%	84 16.2%	182 Infinity	77 Infinity	220 Infinity

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ADA+MTX/ADA+MTX (Arm 2), PBO+MTX/PBO+MTX (Arm 4)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.060
	Comments
	Method	Regression, Logistic
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	ADA+MTX/PBO+MTX (Arm 1), ADA+MTX/ADA+MTX (Arm 2)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.063
	Comments
	Method	Regression, Logistic
	Comments

6. Secondary Outcome

Title	Number of Subjects Meeting American College of Rheumatology 20% (ACR20) Response Criteria at Week 78
Description	Subjects were responders if they had greater than or equal to 20% improvement in tender joint count; greater than or equal to 20% improvement in swollen joint count; and greater than or equal to 20% improvement in at least 3 of 5 remaining ACR core measures: patient assessment of pain; patient global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire [HAQ]); and acute phase reactant (C-reactive protein).
Time Frame	Week 78

Outcome Measure Data

Analysis Population Description

ITT Population, nonresponder imputation

Arm/Group Title	ADA+MTX/PBO+MTX (Arm 1)	ADA+MTX/ADA+MTX (Arm 2)	ADA+MTX/OL ADA+MTX (Arm 3)	PBO+MTX/PBO+MTX (Arm 4)	PBO+MTX/OL ADA+MTX (Arm 5)
Arm/Group Description	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA)during Period 1, MTX monotherapy plus blinded placebo (PBO) during Period 2	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA) during Period 1 and Period 2	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA) during Period 1, open-label combination therapy with ADA and MTX during Period 2	Methotrexate (MTX) monotherapy plus blinded placebo (PBO) during Period 1 and Period 2	Methotrexate (MTX) monotherapy plus blinded placebo (PBO) during Period 1, open-label combination therapy with adalimumab (ADA) and MTX during Period 2
Measure Participants	102	105	259	112	348
Number [Participants]	84 16.3%	89 17.2%	172 Infinity	90 Infinity	257 Infinity

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ADA+MTX/ADA+MTX (Arm 2), PBO+MTX/PBO+MTX (Arm 4)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.395
	Comments
	Method	Regression, Logistic
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	ADA+MTX/PBO+MTX (Arm 1), ADA+MTX/ADA+MTX (Arm 2)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.640
	Comments
	Method	Regression, Logistic
	Comments

7. Secondary Outcome

Title	Number of Subjects Meeting American College of Rheumatology 50% (ACR50) Response Criteria at Week 78
Description	Subjects were responders if they had: greater than or equal to 50% improvement in tender joint count; greater than or equal to 50% improvement in swollen joint count; and greater than or equal to 50% improvement in at least 3 of 5 remaining ACR core measures: patient assessment of pain; patient global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire [HAQ]); and acute phase reactant (C-reactive protein).
Time Frame	Week 78

Outcome Measure Data

Analysis Population Description

ITT Population, nonresponder imputation

Arm/Group Title	ADA+MTX/PBO+MTX (Arm 1)	ADA+MTX/ADA+MTX (Arm 2)	ADA+MTX/OL ADA+MTX (Arm 3)	PBO+MTX/PBO+MTX (Arm 4)	PBO+MTX/OL ADA+MTX (Arm 5)
Arm/Group Description	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA)during Period 1, MTX monotherapy plus blinded placebo (PBO) during Period 2	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA) during Period 1 and Period 2	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA) during Period 1, open-label combination therapy with ADA and MTX during Period 2	Methotrexate (MTX) monotherapy plus blinded placebo (PBO) during Period 1 and Period 2	Methotrexate (MTX) monotherapy plus blinded placebo (PBO) during Period 1, open-label combination therapy with adalimumab (ADA) and MTX during Period 2
Measure Participants	102	105	259	112	348
Number [Participants]	72 14%	82 15.9%	120 Infinity	78 Infinity	198 Infinity

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ADA+MTX/ADA+MTX (Arm 2), PBO+MTX/PBO+MTX (Arm 4)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.159
	Comments
	Method	Regression, Logistic
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	ADA+MTX/PBO+MTX (Arm 1), ADA+MTX/ADA+MTX (Arm 2)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.217
	Comments
	Method	Regression, Logistic
	Comments

8. Secondary Outcome

Title	Number of Subjects Meeting American College of Rheumatology 70% (ACR70) Response Criteria at Week 78
Description	Subjects were responders if they had: greater than or equal to 70% improvement in tender joint count; greater than or equal to 70% improvement in swollen joint count; and greater than or equal to 70% improvement in at least 3 of 5 remaining ACR core measures: patient assessment of pain; patient global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire [HAQ]); and acute phase reactant (C-reactive protein).
Time Frame	Week 78

Outcome Measure Data

Analysis Population Description

ITT Population, nonresponder imputation

Arm/Group Title	ADA+MTX/PBO+MTX (Arm 1)	ADA+MTX/ADA+MTX (Arm 2)	ADA+MTX/OL ADA+MTX (Arm 3)	PBO+MTX/PBO+MTX (Arm 4)	PBO+MTX/OL ADA+MTX (Arm 5)
Arm/Group Description	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA)during Period 1, MTX monotherapy plus blinded placebo (PBO) during Period 2	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA) during Period 1 and Period 2	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA) during Period 1, open-label combination therapy with ADA and MTX during Period 2	Methotrexate (MTX) monotherapy plus blinded placebo (PBO) during Period 1 and Period 2	Methotrexate (MTX) monotherapy plus blinded placebo (PBO) during Period 1, open-label combination therapy with adalimumab (ADA) and MTX during Period 2
Measure Participants	102	105	259	112	348
Number [Participants]	57 11.1%	73 14.1%	78 Infinity	64 Infinity	137 Infinity

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ADA+MTX/ADA+MTX (Arm 2), PBO+MTX/PBO+MTX (Arm 4)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.060
	Comments
	Method	Regression, Logistic
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	ADA+MTX/PBO+MTX (Arm 1), ADA+MTX/ADA+MTX (Arm 2)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.043
	Comments
	Method	Regression, Logistic
	Comments

9. Secondary Outcome

Title	Change From Baseline in DAS28 Score at Week 78
Description	The Disease Activity Score (DAS28) is calculated using the number of tender and swollen joints (out of 28 counted), C-reactive protein level, and the patient's global assessment of disease activity. The calculated range of DAS28 is 0.49 to 9.07. A DAS28 less than 2.6 indicates clinical remission, DAS28 2.6 to 3.2 indicates low disease activity, DAS28 3.2 to less than 5.1 indicates moderate disease activity, and DAS28 of 5.1 or greater indicates high disease activity.
Time Frame	Baseline to Week 78

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	ADA+MTX/PBO+MTX (Arm 1)	ADA+MTX/ADA+MTX (Arm 2)	ADA+MTX/OL ADA+MTX (Arm 3)	PBO+MTX/PBO+MTX (Arm 4)	PBO+MTX/OL ADA+MTX (Arm 5)
Arm/Group Description	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA)during Period 1, MTX monotherapy plus blinded placebo (PBO) during Period 2	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA) during Period 1 and Period 2	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA) during Period 1, open-label combination therapy with ADA and MTX during Period 2	Methotrexate (MTX) monotherapy plus blinded placebo (PBO) during Period 1 and Period 2	Methotrexate (MTX) monotherapy plus blinded placebo (PBO) during Period 1, open-label combination therapy with adalimumab (ADA) and MTX during Period 2
Measure Participants	102	105	259	112	348
Mean (Standard Deviation) [Scores on a scale]	-3.54 (1.259)	-3.71 (1.134)	-2.70 (1.531)	-3.04 (1.513)	-3.07 (1.486)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ADA+MTX/ADA+MTX (Arm 2), PBO+MTX/PBO+MTX (Arm 4)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments
	Method	ANCOVA
	Comments	Analysis of covariance adjusting for baseline

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	ADA+MTX/PBO+MTX (Arm 1), ADA+MTX/ADA+MTX (Arm 2)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.049
	Comments
	Method	ANCOVA
	Comments	Analysis of covariance adjusting for baseline

10. Secondary Outcome

Title	Number of Subjects With Clinical Disease Activity Index (CDAI) Low Disease Activity (CDAI Less Than or Equal to 10) at Week 78
Description	The CDAI is calculated using number of swollen joints (28 joints assessed), number of tender joints (28 joints assessed), patient's global assessment of disease activity, and physician's global assessment of disease activity. Scores range from 0 to 76.0, with a higher score reflecting worsening disease.
Time Frame	Week 78

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	ADA+MTX/PBO+MTX (Arm 1)	ADA+MTX/ADA+MTX (Arm 2)	ADA+MTX/OL ADA+MTX (Arm 3)	PBO+MTX/PBO+MTX (Arm 4)	PBO+MTX/OL ADA+MTX (Arm 5)
Arm/Group Description	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA)during Period 1, MTX monotherapy plus blinded placebo (PBO) during Period 2	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA) during Period 1 and Period 2	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA) during Period 1, open-label combination therapy with ADA and MTX during Period 2	Methotrexate (MTX) monotherapy plus blinded placebo (PBO) during Period 1 and Period 2	Methotrexate (MTX) monotherapy plus blinded placebo (PBO) during Period 1, open-label combination therapy with adalimumab (ADA) and MTX during Period 2
Measure Participants	102	105	259	112	348
Number [Participants]	75 14.6%	84 16.2%	109 Infinity	82 Infinity	195 Infinity

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ADA+MTX/ADA+MTX (Arm 2), PBO+MTX/PBO+MTX (Arm 4)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.240
	Comments
	Method	Regression, Logistic
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	ADA+MTX/PBO+MTX (Arm 1), ADA+MTX/ADA+MTX (Arm 2)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.271
	Comments
	Method	Regression, Logistic
	Comments

11. Secondary Outcome

Title	Number of Subjects With Simplified Disease Activity Index (SDAI) Low Disease Activity (SDAI Less Than or Equal to 11) at Week 78
Description	The SDAI is calculated using number of swollen joints (28 joints assessed), number of tender joints (28 joints assessed), patient's global assessment of disease activity, physician's global assessment of disease activity, and acute phase reactant (C-reactive protein). Scores range from 0.1 to 86.0, with a higher score reflecting worsening disease.
Time Frame	Week 78

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	ADA+MTX/PBO+MTX (Arm 1)	ADA+MTX/ADA+MTX (Arm 2)	ADA+MTX/OL ADA+MTX (Arm 3)	PBO+MTX/PBO+MTX (Arm 4)	PBO+MTX/OL ADA+MTX (Arm 5)
Arm/Group Description	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA)during Period 1, MTX monotherapy plus blinded placebo (PBO) during Period 2	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA) during Period 1 and Period 2	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA) during Period 1, open-label combination therapy with ADA and MTX during Period 2	Methotrexate (MTX) monotherapy plus blinded placebo (PBO) during Period 1 and Period 2	Methotrexate (MTX) monotherapy plus blinded placebo (PBO) during Period 1, open-label combination therapy with adalimumab (ADA) and MTX during Period 2
Measure Participants	102	105	259	112	348
Number [Participants]	73 14.2%	79 15.3%	106 Infinity	76 Infinity	192 Infinity

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ADA+MTX/ADA+MTX (Arm 2), PBO+MTX/PBO+MTX (Arm 4)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.230
	Comments
	Method	Regression, Logistic
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	ADA+MTX/PBO+MTX (Arm 1), ADA+MTX/ADA+MTX (Arm 2)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.550
	Comments
	Method	Regression, Logistic
	Comments

12. Secondary Outcome

Title	Number of Subjects With Clinical Disease Activity Index (CDAI) Remission (CDAI Less Than or Equal to 2.8) at Week 78
Description	The CDAI is calculated using number of swollen joints (28 joints assessed), number of tender joints (28 joints assessed), patient's global assessment of disease activity, and physician's global assessment of disease activity. Scores range from 0 to 76.0, with a higher score reflecting worsening disease.
Time Frame	Week 78

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	ADA+MTX/PBO+MTX (Arm 1)	ADA+MTX/ADA+MTX (Arm 2)	ADA+MTX/OL ADA+MTX (Arm 3)	PBO+MTX/PBO+MTX (Arm 4)	PBO+MTX/OL ADA+MTX (Arm 5)
Arm/Group Description	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA)during Period 1, MTX monotherapy plus blinded placebo (PBO) during Period 2	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA) during Period 1 and Period 2	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA) during Period 1, open-label combination therapy with ADA and MTX during Period 2	Methotrexate (MTX) monotherapy plus blinded placebo (PBO) during Period 1 and Period 2	Methotrexate (MTX) monotherapy plus blinded placebo (PBO) during Period 1, open-label combination therapy with adalimumab (ADA) and MTX during Period 2
Measure Participants	102	105	259	112	348
Number [Participants]	47 9.1%	58 11.2%	39 Infinity	54 Infinity	94 Infinity

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ADA+MTX/ADA+MTX (Arm 2), PBO+MTX/PBO+MTX (Arm 4)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.301
	Comments
	Method	Regression, Logistic
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	ADA+MTX/PBO+MTX (Arm 1), ADA+MTX/ADA+MTX (Arm 2)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.188
	Comments
	Method	Regression, Logistic
	Comments

13. Secondary Outcome

Title	Number of Subjects With Simplified Disease Activity Index (SDAI) Remission (SDAI Less Than or Equal to 3.3) at Week 78
Description	The SDAI is calculated using number of swollen joints (28 joints assessed), number of tender joints (28 joints assessed), patient's global assessment of disease activity, physician's global assessment of disease activity, and acute phase reactant (C-reactive protein). Scores range from 0.1 to 86.0, with a higher score reflecting worsening disease.
Time Frame	Week 78

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	ADA+MTX/PBO+MTX (Arm 1)	ADA+MTX/ADA+MTX (Arm 2)	ADA+MTX/OL ADA+MTX (Arm 3)	PBO+MTX/PBO+MTX (Arm 4)	PBO+MTX/OL ADA+MTX (Arm 5)
Arm/Group Description	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA)during Period 1, MTX monotherapy plus blinded placebo (PBO) during Period 2	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA) during Period 1 and Period 2	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA) during Period 1, open-label combination therapy with ADA and MTX during Period 2	Methotrexate (MTX) monotherapy plus blinded placebo (PBO) during Period 1 and Period 2	Methotrexate (MTX) monotherapy plus blinded placebo (PBO) during Period 1, open-label combination therapy with adalimumab (ADA) and MTX during Period 2
Measure Participants	102	105	259	112	348
Number [Participants]	45 8.7%	55 10.6%	39 Infinity	51 Infinity	92 Infinity

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ADA+MTX/ADA+MTX (Arm 2), PBO+MTX/PBO+MTX (Arm 4)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.314
	Comments
	Method	Regression, Logistic
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	ADA+MTX/PBO+MTX (Arm 1), ADA+MTX/ADA+MTX (Arm 2)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.235
	Comments
	Method	Regression, Logistic
	Comments

14. Secondary Outcome

Title	Change From Baseline in CDAI Score at Week 78
Description	The CDAI is calculated using number of swollen joints (28 joints assessed), number of tender joints (28 joints assessed), patient's global assessment of disease activity, and physician's global assessment of disease activity. Scores range from 0 to 76.0, with a higher score reflecting worsening disease.
Time Frame	Baseline to Week 78

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	ADA+MTX/PBO+MTX (Arm 1)	ADA+MTX/ADA+MTX (Arm 2)	ADA+MTX/OL ADA+MTX (Arm 3)	PBO+MTX/PBO+MTX (Arm 4)	PBO+MTX/OL ADA+MTX (Arm 5)
Arm/Group Description	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA)during Period 1, MTX monotherapy plus blinded placebo (PBO) during Period 2	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA) during Period 1 and Period 2	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA) during Period 1, open-label combination therapy with ADA and MTX during Period 2	Methotrexate (MTX) monotherapy plus blinded placebo (PBO) during Period 1 and Period 2	Methotrexate (MTX) monotherapy plus blinded placebo (PBO) during Period 1, open-label combination therapy with adalimumab (ADA) and MTX during Period 2
Measure Participants	102	105	259	112	348
Mean (Standard Deviation) [Scores on a scale]	-33.30 (12.808)	-33.29 (12.964)	-29.06 (16.561)	-27.63 (15.526)	-31.30 (14.769)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ADA+MTX/ADA+MTX (Arm 2), PBO+MTX/PBO+MTX (Arm 4)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.030
	Comments
	Method	ANCOVA
	Comments	Analysis of covariance adjusting for baseline

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	ADA+MTX/PBO+MTX (Arm 1), ADA+MTX/ADA+MTX (Arm 2)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.403
	Comments
	Method	ANCOVA
	Comments	Analysis of covariance adjusting for baseline

15. Secondary Outcome

Title	Change From Baseline in SDAI Score at Week 78
Description	The SDAI is calculated using number of swollen joints (28 joints assessed), number of tender joints (28 joints assessed), patient's global assessment of disease activity, physician's global assessment of disease activity, and acute phase reactant (C-reactive protein). Scores range from 0.1 to 86.0, with a higher score reflecting worsening disease.
Time Frame	Baseline to Week 78

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	ADA+MTX/PBO+MTX (Arm 1)	ADA+MTX/ADA+MTX (Arm 2)	ADA+MTX/OL ADA+MTX (Arm 3)	PBO+MTX/PBO+MTX (Arm 4)	PBO+MTX/OL ADA+MTX (Arm 5)
Arm/Group Description	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA)during Period 1, MTX monotherapy plus blinded placebo (PBO) during Period 2	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA) during Period 1 and Period 2	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA) during Period 1, open-label combination therapy with ADA and MTX during Period 2	Methotrexate (MTX) monotherapy plus blinded placebo (PBO) during Period 1 and Period 2	Methotrexate (MTX) monotherapy plus blinded placebo (PBO) during Period 1, open-label combination therapy with adalimumab (ADA) and MTX during Period 2
Measure Participants	102	105	259	112	348
Mean (Standard Deviation) [Scores on a scale]	-35.61 (13.527)	-35.16 (13.784)	-31.00 (17.856)	-29.30 (17.120)	-33.43 (15.852)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ADA+MTX/ADA+MTX (Arm 2), PBO+MTX/PBO+MTX (Arm 4)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.036
	Comments
	Method	ANCOVA
	Comments	Analysis of covariance adjusting for baseline

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	ADA+MTX/PBO+MTX (Arm 1), ADA+MTX/ADA+MTX (Arm 2)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.349
	Comments
	Method	ANCOVA
	Comments	Analysis of covariance adjusting for baseline

16. Secondary Outcome

Title	Change From Baseline in Synovitis Score According to the Rheumatoid Arthritis Magnetic Resonance Imaging (RA MRI) Scoring System (RAMRIS) at Week 78
Description	Synovitis was assessed using high-field magnetic resonance imaging (MRI) of the hand and wrist. Images were read and scored according to the Outcomes Measures in Rheumatology Clinical Trials' Rheumatoid Arthritis MRI Scoring System (OMERACT RAMRIS). Synovitis in the wrist and finger joints in the most affected hand was scored from 0 (normal) to 3 (severe), for a maximum total score of 21.
Time Frame	Baseline to Week 78

Outcome Measure Data

Analysis Population Description

The analysis is based on the Primary Analysis Set, a subset of the ITT Analysis Set that includes subjects who participated in the 78-week HF MRI substudy and whose Baseline HF MRI data were collected on or before the first study drug dose. Observed scores are used in the analysis.

Arm/Group Title	ADA+MTX/PBO+MTX (Arm 1)	ADA+MTX/ADA+MTX (Arm 2)	ADA+MTX/OL ADA+MTX (Arm 3)	PBO+MTX/PBO+MTX (Arm 4)	PBO+MTX/OL ADA+MTX (Arm 5)
Arm/Group Description	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA)during Period 1, MTX monotherapy plus blinded placebo (PBO) during Period 2	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA) during Period 1 and Period 2	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA) during Period 1, open-label combination therapy with ADA and MTX during Period 2	Methotrexate (MTX) monotherapy plus blinded placebo (PBO) during Period 1 and Period 2	Methotrexate (MTX) monotherapy plus blinded placebo (PBO) during Period 1, open-label combination therapy with adalimumab (ADA) and MTX during Period 2
Measure Participants	2	4	14	4	13
Mean (Standard Deviation) [Scores on a scale]	2.00 (2.121)	-3.38 (2.562)	-3.25 (3.631)	-3.88 (3.351)	-4.27 (4.211)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ADA+MTX/ADA+MTX (Arm 2), PBO+MTX/PBO+MTX (Arm 4)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.037
	Comments
	Method	ANCOVA
	Comments	Analysis of covariance adjusting for baseline

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	ADA+MTX/PBO+MTX (Arm 1), ADA+MTX/ADA+MTX (Arm 2)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments	Analysis of covariance adjusting for baseline

17. Secondary Outcome

Title	Number of Subjects With No Radiographic Progression (Change From Baseline in mTSS of Less Than or Equal to 0.5) and Normal Function (HAQ-DI Less Than 0.5) at Week 78
Description	In the Health Assessment Questionnaire Disability Index (HAQ-DI), participants rated their ability to perform daily tasks on a scale of 0 (without any difficulty) to 3 (unable to do). A mean score of 0-1 represents mild to moderate functional disability, 1-2 represents moderate to severe, 2-3 severe to very severe disability. For the modified Total Sharp score (mTSS), x-rays of hand/wrist and feet joints are scored for erosions (0 to 5) and joint space narrowing (0 to 4). The erosion score and the narrowing score are added to determine the total score, which ranges from 0 (no damage) to 448.
Time Frame	Week 78

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	ADA+MTX/PBO+MTX (Arm 1)	ADA+MTX/ADA+MTX (Arm 2)	ADA+MTX/OL ADA+MTX (Arm 3)	PBO+MTX/PBO+MTX (Arm 4)	PBO+MTX/OL ADA+MTX (Arm 5)
Arm/Group Description	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA)during Period 1, MTX monotherapy plus blinded placebo (PBO) during Period 2	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA) during Period 1 and Period 2	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA) during Period 1, open-label combination therapy with ADA and MTX during Period 2	Methotrexate (MTX) monotherapy plus blinded placebo (PBO) during Period 1 and Period 2	Methotrexate (MTX) monotherapy plus blinded placebo (PBO) during Period 1, open-label combination therapy with adalimumab (ADA) and MTX during Period 2
Measure Participants	102	105	259	112	348
Number [Participants]	49 9.5%	59 11.4%	65 Infinity	53 Infinity	84 Infinity

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ADA+MTX/ADA+MTX (Arm 2), PBO+MTX/PBO+MTX (Arm 4)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.192
	Comments
	Method	Regression, Logistic
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	ADA+MTX/PBO+MTX (Arm 1), ADA+MTX/ADA+MTX (Arm 2)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.241
	Comments
	Method	Regression, Logistic
	Comments

18. Secondary Outcome

Title	Number of Subjects With No Radiographic Progression (Change From Baseline in mTSS of Less Than or Equal to 0.5), Normal Function (HAQ-DI Less Than or Equal to 0.5), and ACR70 Response at Week 78
Description	In the Health Assessment Questionnaire Disability Index (HAQ-DI), a score of 0-1 represents mild to moderate, 1-2 moderate to severe, 2-3 severe to very severe disability. The modified Total Sharp score (mTSS) ranges from 0 (no joint damage) to 448 (worst joint damage). American College of Rheumatology 70% (ACR70) response indicates at least 70% improvement in tender and swollen joint counts and at least 3 of 5 remaining ACR core measures: patient assessment of pain; patient global assessment of disease activity; physician global assessment of disease activity; HAQ-DI; and C-reactive protein.
Time Frame	Week 78

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	ADA+MTX/PBO+MTX (Arm 1)	ADA+MTX/ADA+MTX (Arm 2)	ADA+MTX/OL ADA+MTX (Arm 3)	PBO+MTX/PBO+MTX (Arm 4)	PBO+MTX/OL ADA+MTX (Arm 5)
Arm/Group Description	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA)during Period 1, MTX monotherapy plus blinded placebo (PBO) during Period 2	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA) during Period 1 and Period 2	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA) during Period 1, open-label combination therapy with ADA and MTX during Period 2	Methotrexate (MTX) monotherapy plus blinded placebo (PBO) during Period 1 and Period 2	Methotrexate (MTX) monotherapy plus blinded placebo (PBO) during Period 1, open-label combination therapy with adalimumab (ADA) and MTX during Period 2
Measure Participants	102	105	259	112	348
Number [Participants]	37 7.2%	56 10.8%	40 Infinity	43 Infinity	67 Infinity

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ADA+MTX/ADA+MTX (Arm 2), PBO+MTX/PBO+MTX (Arm 4)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.028
	Comments
	Method	Regression, Logistic
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	ADA+MTX/PBO+MTX (Arm 1), ADA+MTX/ADA+MTX (Arm 2)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.014
	Comments
	Method	Regression, Logistic
	Comments

19. Secondary Outcome

Title	Number of Subjects With No Radiographic Progression (Change From Baseline in mTSS of Less Than or Equal to 0.5), Normal Function (HAQ-DI Less Than 0.5), and DAS28 Remission (DAS28 Less Than 2.6) at Week 78
Description	In the Health Assessment Questionnaire Disability Index (HAQ-DI), a score of 0-1 represents mild to moderate, 1-2 moderate to severe, 2-3 severe to very severe disability. The modified Total Sharp score (mTSS) ranges from 0 (no joint damage) to 448 (severe joint damage). The Disease Activity Score (DAS28) ranges from 0.49 to 9.07, with scores less than 2.6 indicating clinical remission.
Time Frame	Week 78

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	ADA+MTX/PBO+MTX (Arm 1)	ADA+MTX/ADA+MTX (Arm 2)	ADA+MTX/OL ADA+MTX (Arm 3)	PBO+MTX/PBO+MTX (Arm 4)	PBO+MTX/OL ADA+MTX (Arm 5)
Arm/Group Description	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA)during Period 1, MTX monotherapy plus blinded placebo (PBO) during Period 2	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA) during Period 1 and Period 2	Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA) during Period 1, open-label combination therapy with ADA and MTX during Period 2	Methotrexate (MTX) monotherapy plus blinded placebo (PBO) during Period 1 and Period 2	Methotrexate (MTX) monotherapy plus blinded placebo (PBO) during Period 1, open-label combination therapy with adalimumab (ADA) and MTX during Period 2
Measure Participants	102	105	259	112	348
Number [Participants]	39 7.6%	53 10.3%	38 Infinity	43 Infinity	63 Infinity

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ADA+MTX/ADA+MTX (Arm 2), PBO+MTX/PBO+MTX (Arm 4)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.074
	Comments
	Method	Regression, Logistic
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	ADA+MTX/PBO+MTX (Arm 1), ADA+MTX/ADA+MTX (Arm 2)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.077
	Comments
	Method	Regression, Logistic
	Comments

Adverse Events

Time Frame	Adverse events reported during Period 1 (Weeks 0 to 26) are presented by Period 1 treatment group. Adverse events reported during Period 2 (Weeks 26 to 78) are presented by Period 2 treatment arm (Arm 1 through Arm 5).
Arm/Group Title	ADA+MTX/PBO+MTX (Arm 1)		ADA+MTX/ADA+MTX (Arm 2)		ADA+MTX/OL ADA+MTX (Arm 3)		PBO+MTX/PBO+MTX (Arm 4)		PBO+MTX/OL ADA+MTX (Arm 5)		Period 1 ADA+MTX		Period 1 PBO+MTX
Arm/Group Description	Blinded combination ADA+MTX therapy during Period 1 and blinded MTX monotherapy during Period 2		Blinded combination ADA+MTX therapy during Period 1 and Period 2		Blinded combination therapy during Period 1, open-label combination therapy during Period 2		Blinded MTX monotherapy during Period 1 and Period 2		Blinded MTX monotherapy during Period 1, open-label combination therapy during Period 2		Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA) during Period 1		Combination therapy with methotrexate (MTX) and blinded placebo (PBO) during Period 1
All Cause Mortality
	ADA+MTX/PBO+MTX (Arm 1)		ADA+MTX/ADA+MTX (Arm 2)		ADA+MTX/OL ADA+MTX (Arm 3)		PBO+MTX/PBO+MTX (Arm 4)		PBO+MTX/OL ADA+MTX (Arm 5)		Period 1 ADA+MTX		Period 1 PBO+MTX
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	ADA+MTX/PBO+MTX (Arm 1)		ADA+MTX/ADA+MTX (Arm 2)		ADA+MTX/OL ADA+MTX (Arm 3)		PBO+MTX/PBO+MTX (Arm 4)		PBO+MTX/OL ADA+MTX (Arm 5)		Period 1 ADA+MTX		Period 1 PBO+MTX
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/102 (10.8%)		12/105 (11.4%)		18/259 (6.9%)		9/112 (8%)		32/348 (9.2%)		37/515 (7.2%)		32/517 (6.2%)
Cardiac disorders
Acute myocardial infarction	0/102 (0%)		1/105 (1%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		0/517 (0%)
Angina unstable	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		1/517 (0.2%)
Atrial fibrillation	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		1/515 (0.2%)		1/517 (0.2%)
Bradycardia	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		1/517 (0.2%)
Cardiac failure	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		1/348 (0.3%)		0/515 (0%)		0/517 (0%)
Cardiac failure congestive	0/102 (0%)		0/105 (0%)		1/259 (0.4%)		0/112 (0%)		1/348 (0.3%)		0/515 (0%)		1/517 (0.2%)
Coronary artery disease	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		1/348 (0.3%)		2/515 (0.4%)		0/517 (0%)
Coronary artery insufficiency	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		1/517 (0.2%)
Myocardial infarction	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		1/517 (0.2%)
Right ventricular failure	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		1/515 (0.2%)		0/517 (0%)
Sinus bradycardia	1/102 (1%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		0/517 (0%)
Supraventricular tachycardia	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		1/517 (0.2%)
Congenital, familial and genetic disorders
Microgenia	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		1/348 (0.3%)		0/515 (0%)		0/517 (0%)
Ear and labyrinth disorders
Cerumen impaction	0/102 (0%)		0/105 (0%)		1/259 (0.4%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		0/517 (0%)
Vertigo	0/102 (0%)		0/105 (0%)		1/259 (0.4%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		0/517 (0%)
Eye disorders
Cataract	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		1/515 (0.2%)		0/517 (0%)
Gastrointestinal disorders
Abdominal hernia	0/102 (0%)		0/105 (0%)		0/259 (0%)		1/112 (0.9%)		0/348 (0%)		0/515 (0%)		0/517 (0%)
Abdominal pain	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		1/515 (0.2%)		0/517 (0%)
Colitis ulcerative	0/102 (0%)		0/105 (0%)		1/259 (0.4%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		0/517 (0%)
Diarrhoea	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		1/515 (0.2%)		0/517 (0%)
Duodenal ulcer	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		1/515 (0.2%)		0/517 (0%)
Gastric dilatation	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		1/515 (0.2%)		0/517 (0%)
Gastric ulcer	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		1/348 (0.3%)		0/515 (0%)		2/517 (0.4%)
Gastritis haemorrhagic	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		1/348 (0.3%)		0/515 (0%)		0/517 (0%)
Gastrointestinal haemorrhage	1/102 (1%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		1/517 (0.2%)
Haemorrhoids	0/102 (0%)		0/105 (0%)		0/259 (0%)		1/112 (0.9%)		0/348 (0%)		0/515 (0%)		0/517 (0%)
Intestinal perforation	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		1/515 (0.2%)		0/517 (0%)
Nausea	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		1/515 (0.2%)		0/517 (0%)
Oedematous pancreatitis	0/102 (0%)		1/105 (1%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		0/517 (0%)
Oesophageal achalasia	0/102 (0%)		0/105 (0%)		1/259 (0.4%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		0/517 (0%)
Oesophageal ulcer	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		1/515 (0.2%)		0/517 (0%)
Vomiting	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		1/515 (0.2%)		0/517 (0%)
General disorders
Death	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		1/515 (0.2%)		0/517 (0%)
Drug intolerance	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		1/515 (0.2%)		1/517 (0.2%)
Medical device complication	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		1/515 (0.2%)		0/517 (0%)
Pyrexia	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		1/348 (0.3%)		0/515 (0%)		0/517 (0%)
Sudden death	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		1/517 (0.2%)
Hepatobiliary disorders
Cholecystitis	0/102 (0%)		0/105 (0%)		0/259 (0%)		1/112 (0.9%)		0/348 (0%)		0/515 (0%)		1/517 (0.2%)
Cholelithiasis	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		1/348 (0.3%)		0/515 (0%)		0/517 (0%)
Ischaemic hepatitis	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		1/348 (0.3%)		0/515 (0%)		0/517 (0%)
Infections and infestations
Atypical mycobacterial infection	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		1/515 (0.2%)		0/517 (0%)
Bronchitis	0/102 (0%)		0/105 (0%)		0/259 (0%)		1/112 (0.9%)		0/348 (0%)		0/515 (0%)		0/517 (0%)
Bronchopneumonia	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		1/348 (0.3%)		0/515 (0%)		0/517 (0%)
Bronchopulmonary aspergillosis	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		1/348 (0.3%)		0/515 (0%)		0/517 (0%)
Candida sepsis	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		1/348 (0.3%)		0/515 (0%)		0/517 (0%)
Cellulitis	0/102 (0%)		1/105 (1%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		2/515 (0.4%)		1/517 (0.2%)
Diverticulitis	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		1/348 (0.3%)		0/515 (0%)		0/517 (0%)
Enterocolitis infectious	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		1/515 (0.2%)		0/517 (0%)
Erysipelas	0/102 (0%)		0/105 (0%)		1/259 (0.4%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		0/517 (0%)
Gangrene	0/102 (0%)		0/105 (0%)		1/259 (0.4%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		0/517 (0%)
Gastroenteritis	1/102 (1%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		0/517 (0%)
Herpes zoster	1/102 (1%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		1/515 (0.2%)		0/517 (0%)
Infection	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		1/348 (0.3%)		0/515 (0%)		0/517 (0%)
Influenza	0/102 (0%)		0/105 (0%)		0/259 (0%)		1/112 (0.9%)		0/348 (0%)		0/515 (0%)		0/517 (0%)
Lobar pneumonia	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		1/348 (0.3%)		0/515 (0%)		0/517 (0%)
Lower respiratory tract infection	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		1/517 (0.2%)
Lower respiratory tract infection bacterial	0/102 (0%)		0/105 (0%)		1/259 (0.4%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		0/517 (0%)
Orchitis	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		1/517 (0.2%)
Osteomyelitis	1/102 (1%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		0/517 (0%)
Peritoneal tuberculosis	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		1/515 (0.2%)		0/517 (0%)
Pharyngitis	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		1/515 (0.2%)		0/517 (0%)
Pneumonia	1/102 (1%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		2/348 (0.6%)		4/515 (0.8%)		1/517 (0.2%)
Pneumonia bacterial	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		1/515 (0.2%)		0/517 (0%)
Pneumonia legionella	0/102 (0%)		0/105 (0%)		1/259 (0.4%)		0/112 (0%)		1/348 (0.3%)		0/515 (0%)		0/517 (0%)
Pulmonary tuberculosis	1/102 (1%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		2/348 (0.6%)		0/515 (0%)		0/517 (0%)
Respiratory tract infection	0/102 (0%)		1/105 (1%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		1/517 (0.2%)
Sepsis	0/102 (0%)		1/105 (1%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		0/517 (0%)
Sinusitis	0/102 (0%)		0/105 (0%)		1/259 (0.4%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		0/517 (0%)
Staphylococcal abscess	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		1/515 (0.2%)		0/517 (0%)
Staphylococcal infection	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		1/517 (0.2%)
Staphylococcal sepsis	0/102 (0%)		1/105 (1%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		0/517 (0%)
Urinary tract infection	0/102 (0%)		1/105 (1%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		0/517 (0%)
Viral infection	0/102 (0%)		1/105 (1%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		0/517 (0%)
Vulvovaginitis	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		1/515 (0.2%)		0/517 (0%)
Injury, poisoning and procedural complications
Femur fracture	0/102 (0%)		1/105 (1%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		1/515 (0.2%)		0/517 (0%)
Forearm fracture	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		1/515 (0.2%)		0/517 (0%)
Hip fracture	0/102 (0%)		1/105 (1%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		1/515 (0.2%)		0/517 (0%)
Intentional overdose	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		1/517 (0.2%)
Kidney rupture	1/102 (1%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		0/517 (0%)
Overdose	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		1/517 (0.2%)
Rib fracture	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		1/515 (0.2%)		0/517 (0%)
Thoracic vertebral fracture	1/102 (1%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		0/517 (0%)
Upper limb fracture	0/102 (0%)		0/105 (0%)		1/259 (0.4%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		0/517 (0%)
Vaccination complication	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		1/348 (0.3%)		0/515 (0%)		0/517 (0%)
Wrist fracture	1/102 (1%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		1/348 (0.3%)		0/515 (0%)		0/517 (0%)
Metabolism and nutrition disorders
Gout	0/102 (0%)		0/105 (0%)		1/259 (0.4%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		0/517 (0%)
Hypoglycaemia	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		1/348 (0.3%)		0/515 (0%)		0/517 (0%)
Malnutrition	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		1/517 (0.2%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		1/515 (0.2%)		1/517 (0.2%)
Back pain	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		1/515 (0.2%)		0/517 (0%)
Intervertebral disc protrusion	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		1/515 (0.2%)		1/517 (0.2%)
Knee deformity	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		1/348 (0.3%)		0/515 (0%)		0/517 (0%)
Monarthritis	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		1/515 (0.2%)		0/517 (0%)
Osteoarthritis	0/102 (0%)		0/105 (0%)		1/259 (0.4%)		0/112 (0%)		1/348 (0.3%)		0/515 (0%)		2/517 (0.4%)
Osteoporotic fracture	0/102 (0%)		0/105 (0%)		0/259 (0%)		1/112 (0.9%)		0/348 (0%)		0/515 (0%)		0/517 (0%)
Polyarthritis	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		1/515 (0.2%)		0/517 (0%)
Rheumatoid arthritis	0/102 (0%)		0/105 (0%)		1/259 (0.4%)		0/112 (0%)		4/348 (1.1%)		1/515 (0.2%)		2/517 (0.4%)
Synovitis	0/102 (0%)		1/105 (1%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		0/517 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		2/348 (0.6%)		0/515 (0%)		0/517 (0%)
Benign mediastinal neoplasm	1/102 (1%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		0/517 (0%)
Bile duct cancer	0/102 (0%)		0/105 (0%)		0/259 (0%)		1/112 (0.9%)		0/348 (0%)		0/515 (0%)		0/517 (0%)
Breast cancer	0/102 (0%)		0/105 (0%)		2/259 (0.8%)		1/112 (0.9%)		1/348 (0.3%)		0/515 (0%)		0/517 (0%)
Lung neoplasm malignant	0/102 (0%)		0/105 (0%)		1/259 (0.4%)		0/112 (0%)		1/348 (0.3%)		0/515 (0%)		0/517 (0%)
Oesophageal squamous cell carcinoma	1/102 (1%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		0/517 (0%)
Nervous system disorders
Carotid artery aneurysm	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		1/517 (0.2%)
Cerebrovascular accident	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		1/515 (0.2%)		0/517 (0%)
Dizziness	1/102 (1%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		0/517 (0%)
Facial palsy	0/102 (0%)		0/105 (0%)		1/259 (0.4%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		0/517 (0%)
Headache	1/102 (1%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		0/517 (0%)
Syncope	0/102 (0%)		0/105 (0%)		1/259 (0.4%)		0/112 (0%)		0/348 (0%)		1/515 (0.2%)		1/517 (0.2%)
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		1/517 (0.2%)
Psychiatric disorders
Acute stress disorder	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		1/348 (0.3%)		0/515 (0%)		0/517 (0%)
Confusional state	0/102 (0%)		0/105 (0%)		1/259 (0.4%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		0/517 (0%)
Suicide attempt	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		1/517 (0.2%)
Renal and urinary disorders
Nephrolithiasis	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		1/517 (0.2%)
Renal failure acute	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		1/348 (0.3%)		0/515 (0%)		0/517 (0%)
Ureteric obstruction	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		1/517 (0.2%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	0/102 (0%)		2/105 (1.9%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		0/517 (0%)
Cervical dysplasia	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		1/517 (0.2%)
Metrorrhagia	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		1/515 (0.2%)		0/517 (0%)
Micromastia	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		1/517 (0.2%)
Prostatitis	0/102 (0%)		1/105 (1%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		0/517 (0%)
Uterine prolapse	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		1/517 (0.2%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		1/515 (0.2%)		0/517 (0%)
Alveolitis allergic	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		2/515 (0.4%)		0/517 (0%)
Asthma	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		1/517 (0.2%)
Chronic obstructive pulmonary disease	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		1/517 (0.2%)
Emphysema	0/102 (0%)		0/105 (0%)		1/259 (0.4%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		0/517 (0%)
Haemothorax	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		1/515 (0.2%)		0/517 (0%)
Interstitial lung disease	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		2/348 (0.6%)		2/515 (0.4%)		0/517 (0%)
Pleural effusion	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		1/515 (0.2%)		0/517 (0%)
Pneumonitis	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		2/515 (0.4%)		1/517 (0.2%)
Pulmonary embolism	0/102 (0%)		0/105 (0%)		0/259 (0%)		1/112 (0.9%)		0/348 (0%)		0/515 (0%)		0/517 (0%)
Pulmonary fibrosis	0/102 (0%)		1/105 (1%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		0/517 (0%)
Respiratory failure	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		1/348 (0.3%)		0/515 (0%)		1/517 (0.2%)
Skin and subcutaneous tissue disorders
Dermatitis allergic	0/102 (0%)		0/105 (0%)		1/259 (0.4%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		0/517 (0%)
Social circumstances
Physical abuse	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		1/348 (0.3%)		0/515 (0%)		0/517 (0%)
Surgical and medical procedures
Abortion induced	0/102 (0%)		0/105 (0%)		0/259 (0%)		1/112 (0.9%)		0/348 (0%)		0/515 (0%)		0/517 (0%)
Vascular disorders
Aortic stenosis	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		1/517 (0.2%)
Deep vein thrombosis	0/102 (0%)		0/105 (0%)		1/259 (0.4%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		0/517 (0%)
Hypertension	0/102 (0%)		0/105 (0%)		1/259 (0.4%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		0/517 (0%)
Thrombophlebitis superficial	0/102 (0%)		0/105 (0%)		0/259 (0%)		0/112 (0%)		0/348 (0%)		0/515 (0%)		1/517 (0.2%)
Other (Not Including Serious) Adverse Events
	ADA+MTX/PBO+MTX (Arm 1)		ADA+MTX/ADA+MTX (Arm 2)		ADA+MTX/OL ADA+MTX (Arm 3)		PBO+MTX/PBO+MTX (Arm 4)		PBO+MTX/OL ADA+MTX (Arm 5)		Period 1 ADA+MTX		Period 1 PBO+MTX
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	28/102 (27.5%)		38/105 (36.2%)		106/259 (40.9%)		44/112 (39.3%)		134/348 (38.5%)		149/515 (28.9%)		128/517 (24.8%)
Gastrointestinal disorders
Diarrhoea	1/102 (1%)		1/105 (1%)		10/259 (3.9%)		1/112 (0.9%)		15/348 (4.3%)		23/515 (4.5%)		27/517 (5.2%)
Nausea	7/102 (6.9%)		4/105 (3.8%)		15/259 (5.8%)		9/112 (8%)		27/348 (7.8%)		60/515 (11.7%)		55/517 (10.6%)
Infections and infestations
Bronchitis	3/102 (2.9%)		2/105 (1.9%)		14/259 (5.4%)		6/112 (5.4%)		19/348 (5.5%)		16/515 (3.1%)		20/517 (3.9%)
Influenza	3/102 (2.9%)		6/105 (5.7%)		9/259 (3.5%)		3/112 (2.7%)		11/348 (3.2%)		22/515 (4.3%)		12/517 (2.3%)
Nasopharyngitis	5/102 (4.9%)		6/105 (5.7%)		23/259 (8.9%)		4/112 (3.6%)		23/348 (6.6%)		34/515 (6.6%)		25/517 (4.8%)
Sinusitis	3/102 (2.9%)		2/105 (1.9%)		9/259 (3.5%)		8/112 (7.1%)		19/348 (5.5%)		13/515 (2.5%)		15/517 (2.9%)
Upper respiratory tract infection	5/102 (4.9%)		5/105 (4.8%)		29/259 (11.2%)		7/112 (6.3%)		27/348 (7.8%)		35/515 (6.8%)		38/517 (7.4%)
Urinary tract infection	2/102 (2%)		5/105 (4.8%)		12/259 (4.6%)		5/112 (4.5%)		22/348 (6.3%)		25/515 (4.9%)		22/517 (4.3%)
Investigations
Alanine aminotransferase increased	5/102 (4.9%)		4/105 (3.8%)		16/259 (6.2%)		3/112 (2.7%)		16/348 (4.6%)		11/515 (2.1%)		14/517 (2.7%)
Nervous system disorders
Headache	2/102 (2%)		3/105 (2.9%)		9/259 (3.5%)		2/112 (1.8%)		10/348 (2.9%)		26/515 (5%)		24/517 (4.6%)
Respiratory, thoracic and mediastinal disorders
Cough	3/102 (2.9%)		7/105 (6.7%)		13/259 (5%)		4/112 (3.6%)		14/348 (4%)		20/515 (3.9%)		18/517 (3.5%)
Vascular disorders
Hypertension	1/102 (1%)		5/105 (4.8%)		6/259 (2.3%)		6/112 (5.4%)		7/348 (2%)		18/515 (3.5%)		19/517 (3.7%)

Limitations/Caveats

[Not Specified]

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

Any investigator or institution that plans on presenting/publishing results disclosure, should provide written notification to Abbott within 60 days of their presentation/publication. Abbott requests that no presentation/publication will be allowed until 12 months after a study is completed, or after the first presentation/publication whichever occurs first. A delay of any proposed presentation/publication maybe requested if Abbott needs to secure patent or other proprietary protection.