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Efficacy and Safety of Adalimumab and Methotrexate (MTX) Versus MTX Monotherapy in Subjects With Early Rheumatoid Arthritis (PREMIER)

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ClinicalTrials.gov Identifier: NCT00195663
Recruitment Status : Completed
First Posted : September 20, 2005
Results First Posted : February 25, 2010
Last Update Posted : July 12, 2013
Sponsor:
Information provided by (Responsible Party):
AbbVie ( AbbVie (prior sponsor, Abbott) )

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Early Rheumatoid Arthritis
Interventions Biological: Adalimumab
Drug: Methotrexate
Biological: Adalimumab placebo
Drug: Methotrexate placebo
Enrollment 799
Recruitment Details Patients were enrolled at 94 sites in 15 countries between January 2001 and April 2004.
Pre-assignment Details Patients who had been receiving a previous disease-modifying anti-rheumatic drug (DMARD) participated in a 4-week washout period during which the DMARD was withdrawn. Otherwise, there was a one-week washout period after the Screening visit.
Arm/Group Title Methotrexate Adalimumab Adalimumab + Methotrexate
Hide Arm/Group Description Participants received placebo to adalimumab subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase. Participants received adalimumab 40 mg every other week for up to 8 years in the open-label extension phase. Participants received adalimumab 40 mg subcutaneous injection once every other week and placebo to methotrexate orally once a week during the 2-year double-blind treatment phase and then adalimumab 40 mg every other week for up to 8 years in the open-label extension. Participants received adalimumab 40 mg subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase. Participants received adalimumab 40 mg every other week for up to 8 years in the open-label extension phase.
Period Title: 2-year Double-blind Treatment Period
Started 257 274 268
Completed 164 166 196
Not Completed 93 108 72
Reason Not Completed
Adverse Event             21             27             32
Death             0             2             0
Lost to Follow-up             0             0             1
Withdrawal by Subject             15             18             12
Lack of Efficacy             47             52             13
Protocol Violation             6             6             4
Planned selection criteria             0             1             0
Recovery             1             0             1
Administrative reasons             3             2             9
Period Title: Open-Label Extension Period
Started 155 159 183
Completed 79 85 86
Not Completed 76 74 97
Reason Not Completed
Adverse Event             21             32             36
Lost to Follow-up             9             2             6
Recovery             0             2             2
Protocol Violation             3             4             4
Death             2             2             2
Withdrawal by Subject             16             15             22
Lack of Efficacy             14             6             12
Administrative reasons             11             11             13
Arm/Group Title Methotrexate Adalimumab Adalimumab + Methotrexate Total
Hide Arm/Group Description Participants received placebo to adalimumab subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase. Participants received adalimumab 40 mg every other week for up to 8 years in the open-label extension phase. Participants received adalimumab 40 mg subcutaneous injection once every other week and placebo to methotrexate orally once a week during the 2-year double-blind treatment phase and then adalimumab 40 mg every other week for up to 8 years in the open-label extension. Participants received adalimumab 40 mg subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase. Participants received adalimumab 40 mg every other week for up to 8 years in the open-label extension phase. Total of all reporting groups
Overall Number of Baseline Participants 257 274 268 799
Hide Baseline Analysis Population Description
[Not Specified]
Age Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 257 participants 274 participants 268 participants 799 participants
52.0  (13.1) 52.1  (13.5) 51.9  (14.0) 52.0  (13.5)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 257 participants 274 participants 268 participants 799 participants
Female
190
  73.9%
212
  77.4%
193
  72.0%
595
  74.5%
Male
67
  26.1%
62
  22.6%
75
  28.0%
204
  25.5%
1.Primary Outcome
Title Number of Participants Meeting American College of Rheumatology 50% (ACR50) Response Criteria at Week 52
Hide Description

American College of Rheumatology 50% (ACR50) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met:

  • ≥ 50% improvement in tender joint count;
  • ≥ 50% improvement in swollen joint count; and
  • ≥ 50% improvement in at least 3 of the 5 following parameters:

    • Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]);
    • Patient's global assessment of disease activity (measured on a 100 mm VAS);
    • Physician's global assessment of disease activity (measured on a 100 mm VAS);
    • Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index (HAQ-DI));
    • Acute phase reactant value (C-Reactive Protein).

Participants who withdrew early were considered non-responders.

Time Frame Baseline and 52 Weeks
Hide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set consisted of all patients who were randomized and who received at least one dose of double-blinded study medication. Participants with insufficient data to calculate ACR50 at Week 52 or who withdrew early were considered non-responders.
Arm/Group Title Methotrexate Adalimumab Adalimumab + Methotrexate
Hide Arm/Group Description:
Participants received placebo to adalimumab subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase.
Participants received adalimumab 40 mg subcutaneous injection once every other week and placebo to methotrexate orally once a week during the 2-year double-blind treatment phase.
Participants received adalimumab 40 mg subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase.
Overall Number of Participants Analyzed 257 274 268
Measure Type: Number
Unit of Measure: participants
118 113 165
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Methotrexate, Adalimumab + Methotrexate
Comments The study was powered to demonstrate the superiority of adalimumab + MTX combination therapy vs. MTX monotherapy in the proportion of subjects who achieved an ACR50 response at 52 weeks. Power calculations were based on 250 subjects in each group using a chi-squared test with a continuity correction and an alpha = 0.05 significance level. With 250 subjects in each group, a difference of 0.13 in response rates could be detected with 80% power.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments Statistical tests were performed in a hierarchical manner. If there was a statistically significant difference in favor of adalimumab + MTX combination treatment, the second primary analysis of the modified Total Sharp Score was to be performed.
Method Chi-squared, Corrected
Comments [Not Specified]
2.Primary Outcome
Title Change From Baseline in Modified Total Sharp Score (mTSS) at Week 52
Hide Description The modified Total Sharp Score (mTSS) is a measure of change in joint health. Digitized images of radiographs of hands and feet obtained at screening and Week 52 were scored in a blinded manner. Joints were scored for erosions on a scale from 0 (no damage) to 5 (complete collapse) and joint space narrowing on a scale from 0 (no damage) to 4 (ankylosis or complete dislocation). Erosion scores and narrowing scores were added to obtain the mTSS (range = 0 [normal] to 398 [maximal disease]). 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 Baseline and Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set. For participants with missing data, mTSS was imputed by linear extrapolation.
Arm/Group Title Methotrexate Adalimumab Adalimumab + Methotrexate
Hide Arm/Group Description:
Participants received placebo to adalimumab subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase.
Participants received adalimumab 40 mg subcutaneous injection once every other week and placebo to methotrexate orally once a week during the 2-year double-blind treatment phase.
Participants received adalimumab 40 mg subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase.
Overall Number of Participants Analyzed 257 274 268
Mean (Standard Deviation)
Unit of Measure: units on a scale
5.7  (12.7) 3.0  (11.2) 1.3  (6.5)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Methotrexate, Adalimumab + Methotrexate
Comments Statistical tests were performed in a hierarchical manner. If there was a statistically significant difference in favor of adalimumab + MTX combination treatment on the ACR50 response, the second primary analysis of modified TSS would be performed.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
3.Secondary Outcome
Title Change From Baseline in the Health Assessment Questionnaire - Disability Index (HAQ-DI) at Week 52
Hide Description The Health Assessment Questionnaire - Disability Index is a patient-reported questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and daily activities. Participants assessed their ability to do each task over the past week using the following response categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task were summed and averaged to provide an overall score ranging from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. Negative mean changes from Baseline in the overall score indicate improvement.
Time Frame Baseline and Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set with available data.
Arm/Group Title Methotrexate Adalimumab Adalimumab + Methotrexate
Hide Arm/Group Description:
Participants received placebo to adalimumab subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase.
Participants received adalimumab 40 mg subcutaneous injection once every other week and placebo to methotrexate orally once a week during the 2-year double-blind treatment phase.
Participants received adalimumab 40 mg subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase.
Overall Number of Participants Analyzed 191 191 213
Mean (Standard Deviation)
Unit of Measure: units on a scale
-0.8  (0.6) -0.8  (0.7) -1.1  (0.6)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Methotrexate, Adalimumab + Methotrexate
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
4.Secondary Outcome
Title Number of Participants Meeting American College of Rheumatology 50% (ACR50) Response Criteria at Week 104
Hide Description

American College of Rheumatology 50% (ACR50) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met:

  • ≥ 50% improvement in tender joint count;
  • ≥ 50% improvement in swollen joint count; and
  • ≥ 50% improvement in at least 3 of the 5 following parameters:

    • Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]);
    • Patient's global assessment of disease activity (measured on a 100 mm VAS);
    • Physician's global assessment of disease activity (measured on a 100 mm VAS);
    • Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index [HAQ-DI]);
    • Acute phase reactant value (C-Reactive Protein).

Participants withdrawing early were considered non-responders.

Time Frame Baseline and Week 104
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set. Participants with insufficient data to calculate ACR50 at Week 104 or who withdrew early were considered non-responders.
Arm/Group Title Methotrexate Adalimumab Adalimumab + Methotrexate
Hide Arm/Group Description:
Participants received placebo to adalimumab subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase.
Participants received adalimumab 40 mg subcutaneous injection once every other week and placebo to methotrexate orally once a week during the 2-year double-blind treatment phase.
Participants received adalimumab 40 mg subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase.
Overall Number of Participants Analyzed 257 274 268
Measure Type: Number
Unit of Measure: participants
110 101 158
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Methotrexate, Adalimumab + Methotrexate
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value < 0.001
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
5.Secondary Outcome
Title Change From Baseline in Modified Total Sharp Score (mTSS) at Week 104
Hide Description The modified Total Sharp Score (mTSS) is a measure of change in joint health. Digitized images of radiographs of hands and feet obtained at screening and Week 104 were scored in a blinded manner. Joints were scored for erosions on a scale of 0 (no damage) to 5 (complete collapse) and joint space narrowing on a scale of 0 (no damage) to 4 (ankylosis or complete dislocation). Erosion scores and narrowing scores were added to obtain the mTSS (range = 0 [normal] to 398 [maximal disease]). 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 Baseline and Week 104
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set. For participants with missing data, mTSS was imputed by linear extrapolation.
Arm/Group Title Methotrexate Adalimumab Adalimumab + Methotrexate
Hide Arm/Group Description:
Participants received placebo to adalimumab subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase.
Participants received adalimumab 40 mg subcutaneous injection once every other week and placebo to methotrexate orally once a week during the 2-year double-blind treatment phase.
Participants received adalimumab 40 mg subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase.
Overall Number of Participants Analyzed 257 274 268
Mean (Standard Deviation)
Unit of Measure: units on a scale
10.4  (21.7) 5.5  (15.8) 1.9  (8.3)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Methotrexate, Adalimumab + Methotrexate
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value < 0.001
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
6.Secondary Outcome
Title Number of Participants Who Achieved Clinical Remission, Defined as a Disease Activity 28 (DAS28) Score < 2.6 at Week 52
Hide Description The DAS28 is a validated index of rheumatoid arthritis disease activity. Twenty-eight tender joint counts, 28 swollen joint counts, C reactive protein, and general health were included in the DAS28 score. Scores on the DAS28 range from 0 to 10. A DAS28 score >5.1 indicates high disease activity, a DAS28 score <3.2 indicates low disease activity, and a DAS28 score <2.6 indicates clinical remission.
Time Frame Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set. Participants with insufficient data to calculate DAS28 at Week 52 or who withdrew early were considered non-responders.
Arm/Group Title Methotrexate Adalimumab Adalimumab + Methotrexate
Hide Arm/Group Description:
Participants received placebo to adalimumab subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase.
Participants received adalimumab 40 mg subcutaneous injection once every other week and placebo to methotrexate orally once a week during the 2-year double-blind treatment phase.
Participants received adalimumab 40 mg subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase.
Overall Number of Participants Analyzed 257 274 268
Measure Type: Number
Unit of Measure: participants
53 64 115
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Methotrexate, Adalimumab + Methotrexate
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value < 0.001
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
7.Secondary Outcome
Title Change From Baseline in the Physical Component of the Short Form-36 Health Status Survey (SF-36) at Week 52
Hide Description The SF-36 determined participants' overall quality of life by assessing 1) limitations in physical functioning due to health problems; 2) limitations in usual role because of physical health problems; 3) bodily pain; 4) general health perceptions; 5) vitality; 6) limitations in social functioning because of physical or emotional problems; 7) limitations in usual role due to emotional problems; and 8) general mental health. Items 1-4 comprise the physical component of the SF-36. Scores on each item were summed and averaged (range = 0-100); increases from Baseline indicate improvement.
Time Frame Baseline and Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set with available data.
Arm/Group Title Methotrexate Adalimumab Adalimumab + Methotrexate
Hide Arm/Group Description:
Participants received placebo to adalimumab subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase.
Participants received adalimumab 40 mg subcutaneous injection once every other week and placebo to methotrexate orally once a week during the 2-year double-blind treatment phase.
Participants received adalimumab 40 mg subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase.
Overall Number of Participants Analyzed 181 181 198
Mean (Standard Deviation)
Unit of Measure: units on a scale
12.5  (9.6) 12.6  (10.0) 16.7  (10.2)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Methotrexate, Adalimumab + Methotrexate
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value < 0.001
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
8.Secondary Outcome
Title Number of Participants With Major Clinical Response After 104 Weeks of Treatment
Hide Description

Major clinical response was defined as an American College of Rheumatology 70% (ACR70) response for any six continuous months, over 104 weeks of treatment. A participant was a responder if the following criteria for improvement from Baseline were met:

  • ≥ 70% improvement in tender joint count;
  • ≥ 70% improvement in swollen joint count; and
  • ≥ 70% improvement in at least 3 of the 5 following parameters:

    • Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]);
    • Patient's global assessment of disease activity (measured on a 100 mm VAS);
    • Physician's global assessment of disease activity (measured on a 100 mm VAS);
    • Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index [HAQ-DI]);
    • Acute phase reactant value (C-Reactive Protein).

Participants withdrawing early were non-responders.

Time Frame Any 6 continuous months from Baseline to Week 104
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set.
Arm/Group Title Methotrexate Weekly Adalimumab Adalimumab + Methotrexate
Hide Arm/Group Description:
Participants received placebo to adalimumab subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase.
Participants received adalimumab 40 mg subcutaneous injection once every other week and placebo to methotrexate orally once a week during the 2-year double-blind treatment phase.
Participants received adalimumab 40 mg subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase.
Overall Number of Participants Analyzed 257 274 268
Measure Type: Number
Unit of Measure: participants
70 67 130
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Methotrexate Weekly, Adalimumab + Methotrexate
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value < 0.001
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
9.Secondary Outcome
Title Change From Baseline in the Mental Component of the Short Form-36 Health Status Survey (SF-36) at Week 52
Hide Description The SF-36 determined participants' overall quality of life by assessing 1) limitations in physical functioning due to health problems; 2) limitations in usual role because of physical health problems; 3) bodily pain; 4) general health perceptions; 5) vitality; 6) limitations in social functioning because of physical or emotional problems; 7) limitations in usual role due to emotional problems; and 8) general mental health. Items 5-8 comprise the mental component of the SF-36. Scores on each item were summed and averaged (range = 0-100); increases from Baseline indicate improvement.
Time Frame Baseline and Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set with available data.
Arm/Group Title Methotrexate Adalimumab Adalimumab + Methotrexate
Hide Arm/Group Description:
Participants received placebo to adalimumab subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase.
Participants received adalimumab 40 mg subcutaneous injection once every other week and placebo to methotrexate orally once a week during the 2-year double-blind treatment phase.
Participants received adalimumab 40 mg subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase.
Overall Number of Participants Analyzed 181 181 198
Mean (Standard Deviation)
Unit of Measure: units on a scale
6.5  (11.0) 7.1  (12.3) 7.2  (13.1)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Methotrexate, Adalimumab + Methotrexate
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5402
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
10.Secondary Outcome
Title Number of Participants Meeting American College of Rheumatology 50% (ACR50) Response Criteria at Weeks 26 and 76
Hide Description

American College of Rheumatology 50% (ACR50) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met:

  • ≥ 50% improvement in tender joint count;
  • ≥ 50% improvement in swollen joint count; and
  • ≥ 50% improvement in at least 3 of the 5 following parameters:

    • Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]);
    • Patient's global assessment of disease activity (measured on a 100 mm VAS);
    • Physician's global assessment of disease activity (measured on a 100 mm VAS);
    • Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index [HAQ-DI]);
    • Acute phase reactant value (C-Reactive Protein).

Participants withdrawing early were considered non-responders.

Time Frame Baseline and Weeks 26 and 76
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set. Participants with insufficient data to calculate ACR50 or who withdrew early were considered non-responders.
Arm/Group Title Methotrexate Adalimumab Adalimumab + Methotrexate
Hide Arm/Group Description:
Participants received placebo to adalimumab subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase.
Participants received adalimumab 40 mg subcutaneous injection once every other week and placebo to methotrexate orally once a week during the 2-year double-blind treatment phase.
Participants received adalimumab 40 mg subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase.
Overall Number of Participants Analyzed 257 274 268
Measure Type: Number
Unit of Measure: participants
Week 26 104 96 157
Week 76 114 114 161
11.Secondary Outcome
Title Number of Participants Meeting American College of Rheumatology 20% (ACR20) Response Criteria During the Double-blind Phase
Hide Description

American College of Rheumatology 20% (ACR20) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met:

  • ≥ 20% improvement in tender joint count;
  • ≥ 20% improvement in swollen joint count; and
  • ≥ 20% improvement in at least 3 of the 5 following parameters:

    • Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]);
    • Patient's global assessment of disease activity (measured on a 100 mm VAS);
    • Physician's global assessment of disease activity (measured on a 100 mm VAS);
    • Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index [HAQ-DI]);
    • Acute phase reactant value (C-Reactive Protein).

Participants withdrawing early were considered non-responders.

Time Frame Baseline and Weeks 26, 52, 76, and 104
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set. Participants with insufficient data to calculate ACR20 or who withdrew early were considered non-responders.
Arm/Group Title Methotrexate Adalimumab Adalimumab + Methotrexate
Hide Arm/Group Description:
Participants received placebo to adalimumab subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase.
Participants received adalimumab 40 mg subcutaneous injection once every other week and placebo to methotrexate orally once a week during the 2-year double-blind treatment phase.
Participants received adalimumab 40 mg subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase.
Overall Number of Participants Analyzed 257 274 268
Measure Type: Number
Unit of Measure: participants
Week 26 158 146 184
Week 52 161 149 195
Week 76 154 137 185
Week 104 144 135 186
12.Secondary Outcome
Title Number of Participants Meeting American College of Rheumatology 70% (ACR70) Response Criteria During the Double-blind Phase
Hide Description

American College of Rheumatology 70% (ACR70) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met:

  • ≥ 70% improvement in tender joint count;
  • ≥ 70% improvement in swollen joint count; and
  • ≥ 70% improvement in at least 3 of the 5 following parameters:

    • Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]);
    • Patient's global assessment of disease activity (measured on a 100 mm VAS);
    • Physician's global assessment of disease activity (measured on a 100 mm VAS);
    • Patient's self-assessment of physical function (Health Assessment Questionnaire Disability Index [HAQ-DI]);
    • Acute phase reactant value (C-Reactive Protein).

Participants withdrawing early were considered non-responders.

Time Frame Baseline and Weeks 26, 52, 76, and 104
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set. Participants with insufficient data to calculate ACR70 or who withdrew early were considered non-responders.
Arm/Group Title Methotrexate Adalimumab Adalimumab + Methotrexate
Hide Arm/Group Description:
Participants received placebo to adalimumab subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase.
Participants received adalimumab 40 mg subcutaneous injection once every other week and placebo to methotrexate orally once a week during the 2-year double-blind treatment phase.
Participants received adalimumab 40 mg subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase.
Overall Number of Participants Analyzed 257 274 268
Measure Type: Number
Unit of Measure: participants
Week 26 57 54 114
Week 52 70 71 122
Week 76 75 79 127
Week 104 73 77 125
13.Secondary Outcome
Title Change From Baseline in the Health Assessment Questionnaire - Disability Index (HAQ-DI) During the Double-blind Treatment Phase
Hide Description The Health Assessment Questionnaire - Disability Index is a patient-reported questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and daily activities. Participants assessed their ability to do each task over the past week using the following response categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task were summed and averaged to provide an overall score ranging from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. Negative mean changes from Baseline in the overall score indicate improvement.
Time Frame Baseline and Weeks 12, 26, 76, and 104
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Hide Analysis Population Description
Full analysis set with available data.
Arm/Group Title Methotrexate Adalimumab Adalimumab + Methotrexate
Hide Arm/Group Description:
Participants received placebo to adalimumab subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase.
Participants received adalimumab 40 mg subcutaneous injection once every other week and placebo to methotrexate orally once a week during the 2-year double-blind treatment phase.
Participants received adalimumab 40 mg subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase.
Overall Number of Participants Analyzed 257 274 268
Mean (Standard Deviation)
Unit of Measure: units on a scale
Week 12 [N=236, 246, 252] -0.6  (0.6) -0.6  (0.6) -0.8  (0.6)
Week 26 [N=217, 222, 240] -0.8  (0.6) -0.8  (0.7) -0.9  (0.6)
Week 76 [N= 176, 175, 207] -0.8  (0.6) -0.9  (0.7) -1.0  (0.7)
Week 104 [166, 162, 201] -0.9  (0.6) -0.9  (0.6) -1.0  (0.7)
14.Secondary Outcome
Title Number of Participants With Improvement in the HAQ-DI Score ≥ 0.3 During the Double-blind Treatment Phase
Hide Description The Health Assessment Questionnaire - Disability Index is a patient-reported questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and daily activities. Participants assessed their ability to do each task over the past week using the following response categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task were summed and averaged to provide an overall score ranging from 0 to 3, where zero represents no disability and three very severe, high-dependency disability.
Time Frame Baseline and Weeks 26, 52, 76, and 104
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Hide Analysis Population Description
Full analysis set. Missing values were considered to be < 0.3.
Arm/Group Title Methotrexate Adalimumab Adalimumab + Methotrexate
Hide Arm/Group Description:
Participants received placebo to adalimumab subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase.
Participants received adalimumab 40 mg subcutaneous injection once every other week and placebo to methotrexate orally once a week during the 2-year double-blind treatment phase.
Participants received adalimumab 40 mg subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase.
Overall Number of Participants Analyzed 257 274 268
Measure Type: Number
Unit of Measure: participants
Week 26 172 169 200
Week 52 158 151 186
Week 76 144 145 173
Week 104 137 132 171
15.Secondary Outcome
Title Change From Baseline in Health Utilities Index Mark 2 and Mark 3 (HUI 2/3) During the Double-blind Treatment Phase
Hide Description

The HUI 2/3 is an assessment of various aspects of participants' health and ability to perform various tasks on a day-to-day basis, including reading, seeing, hearing, speaking, general outlook on life, pain/discomfort, ability to walk, use of hands, memory, ability to think/solve, and ability to perform basic activities such as eating, bathing, and dressing. The HUI 2/3 is a combined 15-item questionnaire based on a recall period of the previous 4 weeks. HUI-2 and HUI-3 scores are calculated independently. The HUI-2 score includes 6 attributes: Sensation, Mobility, Emotion, Cognition, Self-Care, and Pain. The HUI-3 score is comprised of 8 attributes: Vision, Hearing, Speech, Ambulation, Dexterity, Emotion, Cognition, and Pain.

The range of each score is from 0 (dead) to 1 (perfect health). An increase from Baseline indicates improvement.

Time Frame Baseline and Weeks 26, 52, and 104
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Full analysis set with available data.
Arm/Group Title Methotrexate Adalimumab Adalimumab + Methotrexate
Hide Arm/Group Description:
Participants received placebo to adalimumab subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase.
Participants received adalimumab 40 mg subcutaneous injection once every other week and placebo to methotrexate orally once a week during the 2-year double-blind treatment phase.
Participants received adalimumab 40 mg subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase.
Overall Number of Participants Analyzed 257 274 268
Mean (Standard Deviation)
Unit of Measure: units on a scale
HUI-2: Week 26 [N=192, 187, 205] 0.2  (0.2) 0.2  (0.2) 0.2  (0.2)
HUI-2: Week 52 [N=179, 162, 189] 0.2  (0.2) 0.2  (0.2) 0.2  (0.2)
HUI-2: Week 104 [N=152, 136, 174] 0.2  (0.2) 0.2  (0.2) 0.2  (0.2)
HUI-3: Week 26 [N=192, 189, 205] 0.3  (0.3) 0.3  (0.3) 0.3  (0.3)
HUI-3: Week 52 [N=177, 164, 190] 0.3  (0.3) 0.3  (0.3) 0.4  (0.3)
HUI-3: Week 104 [N=154, 138, 177] 0.3  (0.2) 0.4  (0.3) 0.4  (0.3)
16.Secondary Outcome
Title Change From Baseline in the Short Form-36 Health Status Survey (SF-36) During the Double-blind Treatment Phase
Hide Description The SF-36 determined participants' overall quality of life by assessing 1) limitations in physical functioning due to health problems; 2) limitations in usual role because of physical health problems; 3) bodily pain; 4) general health perceptions; 5) vitality; 6) limitations in social functioning because of physical or emotional problems; 7) limitations in usual role due to emotional problems; and 8) general mental health. Items 1-4 comprise the physical component and items 5-8 comprise the mental component of the SF-36. Scores on each item were summed and averaged (range = 0-100); increases from Baseline indicate improvement.
Time Frame Baseline and Weeks 26 and 104
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Hide Analysis Population Description
Full analysis set with available data.
Arm/Group Title Methotrexate Adalimumab Adalimumab + Methotrexate
Hide Arm/Group Description:
Participants received placebo to adalimumab subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase.
Participants received adalimumab 40 mg subcutaneous injection once every other week and placebo to methotrexate orally once a week during the 2-year double-blind treatment phase.
Participants received adalimumab 40 mg subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase.
Overall Number of Participants Analyzed 257 274 268
Mean (Standard Deviation)
Unit of Measure: units on a scale
Physical Component: Week 26 [N=199, 204, 221] 11.2  (10.0) 10.8  (10.2) 14.7  (10.2)
Physical Component: Week 104 [160, 157, 189] 12.4  (10.3) 13.4  (9.7) 16.8  (11.2)
Mental Component: Week 26 [N=199, 204, 221] 7.0  (11.6) 5.2  (13.5) 6.3  (12.1)
Mental Component: Week 104 [N=160, 157, 189] 8.1  (10.9) 6.6  (13.5) 6.8  (12.0)
17.Secondary Outcome
Title Numeric American College of Rheumatology (ACR-N) During the Double-blind Treatment Phase
Hide Description ACR-N is a composite, continuous variable which measures the percentage of improvement from Baseline in individual participants based on the 7 core set variables of the ACR. ACR-N is defined as the smallest percent change from Baseline of 3 measures: tender joint counts (TJC), swollen joint counts (SJC), and the median percent improvement in the 5 remaining measures (Patient's Assessment of Pain, Physician's Global Assessment of Disease Activity, Patient's Global Assessment of Disease Activity, Health Assessment Questionnaire - Disability Index [HAQ-DI], and C-Reactive Protein). A positive ACR-N value indicates improvement; a negative ACR-N value indicates worsening; ACR-N of 0 indicates no change.
Time Frame Baseline and Weeks 26, 52, 76, and 104
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Full analysis set with available data.
Arm/Group Title Methotrexate Adalimumab Adalimumab + Methotrexate
Hide Arm/Group Description:
Participants received placebo to adalimumab subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase.
Participants received adalimumab 40 mg subcutaneous injection once every other week and placebo to methotrexate orally once a week during the 2-year double-blind treatment phase.
Participants received adalimumab 40 mg subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase.
Overall Number of Participants Analyzed 257 274 268
Mean (Standard Deviation)
Unit of Measure: percent change
Week 26 [N=218, 224, 244] 44.7  (42.2) 39.1  (43.3) 57.0  (42.2)
Week 52 [N=194, 193, 220] 50.2  (48.2) 44.4  (52.2) 66.3  (34.8)
Week 76 [N=181, 179, 211] 56.1  (38.1) 51.5  (56.8) 68.8  (31.3)
Week 104 [N=168, 167, 203] 57.3  (37.1) 54.0  (42.7) 71.4  (31.0)
18.Secondary Outcome
Title Change From Baseline in Disease Activity Score (DAS28) During the Double-blind Treatment Phase
Hide Description

The DAS28 is a composite score of rheumatoid arthritis disease activity derived from the following variables:

  • 28 tender joint counts,
  • 28 swollen joint counts,
  • C-reactive protein, and
  • Patient's global assessment of disease activity.

Scores on the DAS28 range from 0 to 10. A DAS28 score higher than 5.1 indicates high disease activity, a DAS28 score less than 3.2 indicates low disease activity, and a DAS28 score less than 2.6 indicates clinical remission.

Time Frame Baseline and Weeks 26, 52, 76, and 104
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Hide Analysis Population Description
Full analysis set with available data.
Arm/Group Title Methotrexate Adalimumab Adalimumab + Methotrexate
Hide Arm/Group Description:
Participants received placebo to adalimumab subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase.
Participants received adalimumab 40 mg subcutaneous injection once every other week and placebo to methotrexate orally once a week during the 2-year double-blind treatment phase.
Participants received adalimumab 40 mg subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase.
Overall Number of Participants Analyzed 257 274 268
Mean (Standard Deviation)
Unit of Measure: units on a scale
Week 26 [N=209, 218, 229] -2.6  (1.3) -2.4  (1.4) -3.2  (1.3)
Week 52 [N=184, 185, 206] -2.8  (1.4) -2.8  (1.5) -3.6  (1.3)
Week 76 [N=173, 173, 197] -3.1  (1.2) -3.0  (1.5) -3.7  (1.3)
Week 104 [N=161, 158, 191] -3.1  (1.4) -3.2  (1.4) -3.8  (1.3)
19.Secondary Outcome
Title Change From Baseline in Joint Erosion Score During the Double-blind Treatment Period
Hide Description Digitized images of radiographs of hands and feet obtained at screening and during the study were scored in a blinded manner. Joints on each hand/wrist (17 joints) and each forefoot (6 joints) were scored for erosions on a scale of 0 = no erosions; 1 = 1 discrete erosion or ≤20% joint involvement; 2 = 2 separate quadrants with erosion or 21-40% joint involvement; 3 = 3 separate quadrants with erosion or 41-60% joint involvement; 4 = all 4 quadrants with erosion or 61-80% joint involvement; and 5 = extensive destruction with >80% joint involvement. Scores were summed to calculate the total erosion score, which ranges from 0 (no erosion)to 230 (worst). A large increase in erosion score is indicative of worsening, whereas a small change or no change is indicative of inhibition of joint erosion.
Time Frame Baseline and Weeks 52 and 104
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Hide Analysis Population Description
Full analysis set. Missing values were imputed.
Arm/Group Title Methotrexate Adalimumab Adalimumab + Methotrexate
Hide Arm/Group Description:
Participants received placebo to adalimumab subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase.
Participants received adalimumab 40 mg subcutaneous injection once every other week and placebo to methotrexate orally once a week during the 2-year double-blind treatment phase.
Participants received adalimumab 40 mg subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase.
Overall Number of Participants Analyzed 257 274 268
Mean (Standard Deviation)
Unit of Measure: units on a scale
Week 52 3.7  (8.4) 1.7  (5.7) 0.8  (3.3)
Week 104 6.4  (14.3) 3.0  (8.3) 1.0  (4.7)
20.Secondary Outcome
Title Change From Baseline in Joint Space Narrowing Score During the Double-blind Treatment Period
Hide Description Digitized images of radiographs of hands and feet obtained at screening and during the study were scored in a blinded manner. Joint space narrowing (JSN) scores were recorded for each hand/wrist (16 joints) and each forefoot (5 joints) on a 5-point scale (0 = no narrowing; 1 = up to 25% narrowing; 2 = 26-65% narrowing; 3 = 66-99% narrowing; and 4 = complete narrowing). Scores were summed to calculate the total score ranging from 0 (no narrowing) to 168 (maximum narrowing). A large increase in joint narrowing score is indicative of worsening, whereas a small change or no change is indicative of inhibition of JSN.
Time Frame Baseline and Weeks 52 and 104
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Hide Analysis Population Description
Full analysis set. Missing values were imputed.
Arm/Group Title Methotrexate Adalimumab Adalimumab + Methotrexate
Hide Arm/Group Description:
Participants received placebo to adalimumab subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase.
Participants received adalimumab 40 mg subcutaneous injection once every other week and placebo to methotrexate orally once a week during the 2-year double-blind treatment phase.
Participants received adalimumab 40 mg subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase.
Overall Number of Participants Analyzed 257 274 268
Mean (Standard Deviation)
Unit of Measure: units on a scale
Week 52 2.0  (6.3) 1.3  (6.6) 0.5  (4.2)
Week 104 4.0  (10.9) 2.6  (9.5) 0.9  (5.1)
21.Secondary Outcome
Title Number of Participants With No Worsening in Modified Total Sharp Score or Components During the Double-blind Treatment Phase
Hide Description

The number of participants with no worsening in the modified Total Sharp Score (mTSS) and in erosion and joint space narrowing (JSN) scores, where no worsening is defined as a change from Baseline of ≤ 0 in mTSS, erosion score and JSN score, at Weeks 52 and 104.

Digitized images of radiographs of hands and feet obtained at screening and during the study were scored in a blinded manner. Joints were scored for erosions on a scale of 0 (no damage) to 5 (complete collapse) and joint space narrowing on a scale of 0 (no damage) to 4 (ankylosis or complete dislocation). Erosion scores and narrowing scores were added to obtain the mTSS (range = 0 [normal] to 398 [maximal disease]). 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 Baseline and Weeks 52 and 104
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Hide Analysis Population Description
Full analysis set. Participants with missing data or who withdrew early were considered non-responders.
Arm/Group Title Methotrexate Adalimumab Adalimumab + Methotrexate
Hide Arm/Group Description:
Participants received placebo to adalimumab subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase.
Participants received adalimumab 40 mg subcutaneous injection once every other week and placebo to methotrexate orally once a week during the 2-year double-blind treatment phase.
Participants received adalimumab 40 mg subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase.
Overall Number of Participants Analyzed 257 274 268
Measure Type: Number
Unit of Measure: participants
Modified Total Sharp Score: Week 52 78 112 141
Modified Total Sharp Score: Week 104 70 105 136
Erosion Scoe: Week 52 91 133 158
Erosion Score: Week 104 81 121 148
Joint Space Narrowing Score: Week 52 127 159 190
Joint Space Narrowing Score: Week 104 112 147 175
22.Secondary Outcome
Title Number of Participants With No Erosions at Baseline and No New Erosions at Weeks 52 and 104
Hide Description

The number of participants with no erosions at Baseline and no erosions at Weeks 52 and 104, where no erosions and no new erosions are defined as an erosion score = 0.

Digitized images of radiographs of hands and feet obtained at screening and during the study were scored in a blinded manner. Joints on each hand/wrist (17 joints) and each forefoot (6 joints) were scored for erosions on a scale of 0 = no erosions; 1 = 1 discrete erosion or ≤20% joint involvement; 2 = 2 separate quadrants with erosion or 21-40% joint involvement; 3 = 3 separate quadrants with erosion or 41-60% joint involvement; 4 = all 4 quadrants with erosion or 61-80% joint involvement; and 5 = extensive destruction with >80% joint involvement. Scores were summed to calculate the total erosion score, which ranges from 0 (no erosion) to 230 (worst).

Time Frame Baseline and Weeks 52 and 104
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Hide Analysis Population Description
Full analysis set participants with no erosions at Baseline and non-missing data.
Arm/Group Title Methotrexate Adalimumab Adalimumab + Methotrexate
Hide Arm/Group Description:
Participants received placebo to adalimumab subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase.
Participants received adalimumab 40 mg subcutaneous injection once every other week and placebo to methotrexate orally once a week during the 2-year double-blind treatment phase.
Participants received adalimumab 40 mg subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase.
Overall Number of Participants Analyzed 11 16 20
Measure Type: Number
Unit of Measure: participants
Week 52 8 10 13
Week 104 7 8 11
23.Secondary Outcome
Title Number of Participants With Non-Involved Joints at Baseline and No Newly Involved Joints at Weeks 52 and 104
Hide Description

Number of participants with non-involved joints at Baseline and no newly involved joints at Weeks 52 and 104, where involved joints or no newly involved joints are defined as modified Total Sharp Score (mTSS) = 0.

Digitized images of radiographs of hands and feet obtained at screening and during the study were scored in a blinded manner. Joints were scored for erosions on a scale of 0 (no damage) to 5 (complete collapse) and joint space narrowing on a scale of 0 (no damage) to 4 (ankylosis or complete dislocation). Erosion scores and narrowing scores were added to obtain the mTSS (range = 0 [normal] to 398 [maximal disease]).

Time Frame Baseline and Weeks 52 and 104
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set participants with non-involved joints at Baseline and non-missing data.
Arm/Group Title Methotrexate Adalimumab Adalimumab + Methotrexate
Hide Arm/Group Description:
Participants received placebo to adalimumab subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase.
Participants received adalimumab 40 mg subcutaneous injection once every other week and placebo to methotrexate orally once a week during the 2-year double-blind treatment phase.
Participants received adalimumab 40 mg subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase.
Overall Number of Participants Analyzed 5 14 16
Measure Type: Number
Unit of Measure: participants
Week 52 4 9 12
Week 104 3 7 9
24.Secondary Outcome
Title Number of Participants Meeting ACR20 Response Criteria Over 10 Years by Adalimumab Exposure
Hide Description

American College of Rheumatology 20% (ACR20) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met:

  • ≥ 20% improvement in tender joint count;
  • ≥ 20% improvement in swollen joint count; and
  • ≥ 20% improvement in at least 3 of the 5 following parameters:

    • Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]);
    • Patient's global assessment of disease activity (measured on a 100 mm VAS);
    • Physician's global assessment of disease activity (measured on a 100 mm VAS);
    • Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index [HAQ-DI]);
    • Acute phase reactant value (C-Reactive Protein).

Baseline is the last value prior to the first dose of adalimumab. For participants randomized to the methotrexate (MTX) arm in the double-blind (DB) phase, Baseline was the last visit prior to the first adalimumab dose at Week 106 of the open-label (OL) phase.

Time Frame Baseline and after 1, 2, 5, and 10 years of adalimumab exposure. Baseline was the last value prior to the first dose of adalimumab.
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Intent-to-treat (ITT) Analysis Set (all patients who received at least 1 dose of adalimumab during the study, including patients who received their first dose during the DB phase and those who received MTX during the DB phase and adalimumab in the OL phase) with available ACR data. "N" indicates patients with non-missing data at each time point.
Arm/Group Title Any Adalimumab
Hide Arm/Group Description:
Participants received either methotrexate (MTX), adalimumab, or methotrexate + adalimumab during the 2-year double-blind treatment phase. During the 8-year open-label phase all participants received adalimumab 40 mg every other week.
Overall Number of Participants Analyzed 687
Measure Type: Number
Unit of Measure: participants
Year 1 [N=410] 340
Year 2 [N=385] 332
Year 5 [N=325] 231
Year 10 [N=170] 154
25.Secondary Outcome
Title Number of Participants Meeting ACR50 Response Criteria Over 10 Years by Adalimumab Exposure
Hide Description

American College of Rheumatology 50% (ACR50) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met:

  • ≥ 50% improvement in tender joint count;
  • ≥ 50% improvement in swollen joint count; and
  • ≥ 50% improvement in at least 3 of the 5 following parameters:

    • Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]);
    • Patient's global assessment of disease activity (measured on a 100 mm VAS);
    • Physician's global assessment of disease activity (measured on a 100 mm VAS);
    • Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index [HAQ-DI]);
    • Acute phase reactant value (C-Reactive Protein).

Baseline is the last value prior to the first dose of adalimumab. For patients randomized to the methotrexate (MTX) arm in the double-blind (DB) phase, Baseline was the last visit prior to the first adalimumab dose at Week 106 of the open-label (OL) phase.

Time Frame Baseline and after 1, 2, 5, and 10 years of adalimumab exposure. Baseline was the last value prior to the first dose of adalimumab.
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Analysis Set with available ACR data. "N" indicates patients with non-missing data at each time point.
Arm/Group Title Any Adalimumab
Hide Arm/Group Description:
Participants received either methotrexate (MTX), adalimumab, or methotrexate + adalimumab during the 2-year double-blind treatment phase. During the 8-year open-label phase all participants received adalimumab 40 mg every other week.
Overall Number of Participants Analyzed 687
Measure Type: Number
Unit of Measure: participants
Year 1 [N=410] 269
Year 2 [N=385] 266
Year 5 [N=325] 194
Year 10 [N=170] 127
26.Secondary Outcome
Title Number of Participants Meeting ACR70 Response Criteria Over 10 Years by Adalimumab Exposure
Hide Description

American College of Rheumatology 70% (ACR70) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met:

  • ≥ 70% improvement in tender joint count;
  • ≥ 70% improvement in swollen joint count; and
  • ≥ 70% improvement in at least 3 of the 5 following parameters:

    • Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]);
    • Patient's global assessment of disease activity (measured on a 100 mm VAS);
    • Physician's global assessment of disease activity (measured on a 100 mm VAS);
    • Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index [HAQ-DI]);
    • Acute phase reactant value (C-Reactive Protein).

Baseline is the last value prior to the first dose of adalimumab. For patients randomized to the methotrexate (MTX) arm in the double-blind (DB) phase, Baseline was the last visit prior to the first adalimumab dose at Week 106 of the open-label (OL) phase.

Time Frame Baseline and after 1, 2, 5, and 10 years of adalimumab exposure. Baseline was the last value prior to the first dose of adalimumab.
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Analysis Set with available data. "N" indicates patients with non-missing data at each time point.
Arm/Group Title Any Adalimumab
Hide Arm/Group Description:
Participants received either methotrexate (MTX), adalimumab, or methotrexate + adalimumab during the 2-year double-blind treatment phase. During the 8-year open-label phase all participants received adalimumab 40 mg every other week.
Overall Number of Participants Analyzed 687
Measure Type: Number
Unit of Measure: participants
Year 1 [N=410] 186
Year 2 [N=385] 207
Year 5 [N=325] 153
Year 10 [N=170] 102
27.Secondary Outcome
Title Change From Baseline in the Health Assessment Questionnaire - Disability Index (HAQ-DI) Over 10 Years by Adalimumab Exposure
Hide Description The Health Assessment Questionnaire - Disability Index is a patient-reported questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and daily activities. Participants assessed their ability to do each task over the past week using the following response categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task were summed and averaged to provide an overall score ranging from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. Negative mean changes from Baseline in the overall score indicate improvement.
Time Frame Baseline and Years 1, 2, 5, and 10. Baseline was the last value prior to the first dose of adalimumab. For patients randomized to the MTX arm in the DB phase, Baseline was the last visit prior to the first adalimumab dose at Week 106.
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Analysis Set, with available data. "N" indicates patients with non-missing data at each time point.
Arm/Group Title Any Adalimumab
Hide Arm/Group Description:
Participants received either methotrexate (MTX), adalimumab, or methotrexate + adalimumab during the 2-year double-blind treatment phase. During the 8-year open-label phase all participants received adalimumab 40 mg every other week.
Overall Number of Participants Analyzed 692
Mean (Standard Deviation)
Unit of Measure: units on a scale
Year 1 [N=407] -0.9  (0.68)
Year 2 [N=390] -0.9  (0.70)
Year 5 [N=344] -0.7  (0.73)
Year 10 [N=170] -0.9  (0.73)
28.Secondary Outcome
Title Change From Baseline in DAS28 Over 10 Years by Adalimumab Exposure
Hide Description

The DAS28 is a composite score of rheumatoid arthritis disease activity derived from the following variables:

  • 28 tender joint counts,
  • 28 swollen joint counts,
  • C-reactive protein, and
  • Patient's global assessment of disease activity.

Scores on the DAS28 range from 0 to 10. A DAS28 score higher than 5.1 indicates high disease activity, a DAS28 score less than 3.2 indicates low disease activity, and a DAS28 score less than 2.6 indicates clinical remission.

Time Frame Baseline and Years 1, 2, 5, and 10. Baseline was the last value prior to the first dose of adalimumab. For patients randomized to the MTX arm in the DB phase, Baseline was the last visit prior to the first adalimumab dose at Week 106.
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Analysis Set, with available data. "N" indicates patients with non-missing data at Baseline and the specified time point.
Arm/Group Title Any Adalimumab
Hide Arm/Group Description:
Participants received either methotrexate (MTX), adalimumab, or methotrexate + adalimumab during the 2-year double-blind treatment phase. During the 8-year open-label phase all participants received adalimumab 40 mg every other week.
Overall Number of Participants Analyzed 689
Mean (Standard Deviation)
Unit of Measure: units on a scale
Year 1 [N=403] -3.2  (1.49)
Year 2 [N=386] -3.3  (1.61)
Year 5 [N=330] -2.8  (1.93)
Year 10 [N=158] -3.9  (1.29)
29.Secondary Outcome
Title Number of Participants With DAS28 < 2.6 and < 3.2 Over 10 Years by Adalimumab Exposure
Hide Description

The DAS28 is a composite score of rheumatoid arthritis disease activity derived from the following variables:

  • 28 tender joint counts,
  • 28 swollen joint counts,
  • C-reactive protein, and
  • Patient's global assessment of disease activity.

Scores on the DAS28 range from 0 to 10. A DAS28 score higher than 5.1 indicates high disease activity, a DAS28 score less than 3.2 indicates low disease activity, and a DAS28 score less than 2.6 indicates clinical remission.

Time Frame After 1, 2, 5, and 10 years of adalimumab exposure
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Analysis Set, with available data. The Number of Participants Analyzed indicates patients with non-missing DAS28 scores at any post-baseline time point; "N" indicates patients with non-missing data at each specified time point.
Arm/Group Title Adalimumab: DAS28 < 2.6 Adalimumab: DAS28 < 3.2
Hide Arm/Group Description:
Participants with a DAS28 score less than 2.6, who received either methotrexate (MTX), adalimumab, or methotrexate + adalimumab during the 2-year double-blind treatment phase and adalimumab 40 mg every other week during the 8-year open-label phase.
Participants with a DAS28 score less than 3.2, who received either methotrexate (MTX), adalimumab, or methotrexate + adalimumab during the 2-year double-blind treatment phase and adalimumab 40 mg every other week during the 8-year open-label phase.
Overall Number of Participants Analyzed 694 694
Measure Type: Number
Unit of Measure: participants
Year 1 [N=405] 173 244
Year 2 [N=389] 215 271
Year 5 [N=333] 190 244
Year 10 [N=159] 109 135
30.Secondary Outcome
Title Change From Baseline in Modified Total Sharp Score (mTSS) Over 10 Years
Hide Description The modified TSS (mTSS) is a measure of change in joint health. Digitized images of radiographs of hands and feet obtained at screening and during the study were scored in a blinded manner. Joints were scored for erosions on a scale of 0 (no damage) to 5 (complete collapse) and joint space narrowing on a scale of 0 (no damage) to 4 (ankylosis or complete dislocation). Erosion scores and narrowing scores were added to obtain the mTSS (range = 0 [normal] to 398 [maximal disease]). 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 Baseline (prior to first study drug treatment) and Years 2 and 10
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Analysis Set, with available data. "N" indicates patients with non-missing radiographic data at each time point.
Arm/Group Title Methotrexate Adalimumab Adalimumab + Methotrexate
Hide Arm/Group Description:
Participants received placebo to adalimumab subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase. Participants received adalimumab 40 mg every other week for up to 8 years in the open-label extension phase.
Participants received adalimumab 40 mg subcutaneous injection once every other week and placebo to methotrexate orally once a week during the 2-year double-blind treatment phase and then adalimumab 40 mg every other week for up to 8 years in the open-label extension.
Participants received adalimumab 40 mg subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase. Participants received adalimumab 40 mg every other week for up to 8 years in the open-label extension phase.
Overall Number of Participants Analyzed 83 93 90
Mean (Standard Deviation)
Unit of Measure: units on a scale
Year 2 [N=83, 92, 89] 6.3  (12.44) 5.1  (9.63) 0.3  (3.00)
Year 10 [N= 83, 93, 90] 10.8  (20.01) 9.2  (15.21) 3.9  (9.64)
31.Secondary Outcome
Title Number of Participants With No Radiographic Progression Over 10 Years
Hide Description The modified Total Sharp Score (mTSS) is a measure of change in joint health. Digitized images of radiographs of hands and feet obtained at screening and during the study were scored in a blinded manner. Joints were scored for erosions on a scale of 0 (no damage) to 5 (complete collapse) and joint space narrowing on a scale of 0 (no damage) to 4 (ankylosis or complete dislocation). Erosion scores and narrowing scores were added to obtain the mTSS (range = 0 [normal] to 398 [maximal disease]). 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. The number of participants with change from Baseline ≤ 0.5 and ≤ 0 is reported as a measure of no disease progression.
Time Frame Baseline (prior to first study drug treatment) and Years 2 and 10.
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Analysis Set, with available data. "N" indicates patients with non-missing radiographic data at each time point.
Arm/Group Title Methotrexate Adalimumab Adalimumab + Methotrexate
Hide Arm/Group Description:
Participants received placebo to adalimumab subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase. Participants received adalimumab 40 mg every other week for up to 8 years in the open-label extension phase.
Participants received adalimumab 40 mg subcutaneous injection once every other week and placebo to methotrexate orally once a week during the 2-year double-blind treatment phase and then adalimumab 40 mg every other week for up to 8 years in the open-label extension.
Participants received adalimumab 40 mg subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase. Participants received adalimumab 40 mg every other week for up to 8 years in the open-label extension phase.
Overall Number of Participants Analyzed 83 93 90
Measure Type: Number
Unit of Measure: participants
Change ≤ 0.5 at Year 2 [N=83, 92, 89] 36 40 65
Change ≤ 0.5 at Year 10 [N=83, 93, 90] 26 22 33
Change ≤ 0 at Year 2 [N=83, 92, 89] 22 30 51
Change ≤ 0 at Year 10 [N=83, 93, 90] 19 16 29
32.Secondary Outcome
Title Composite Score of ACR50 Plus No Change in Modified Total Sharp Score
Hide Description [Not Specified]
Time Frame Year 10
Hide Outcome Measure Data
Hide Analysis Population Description
This outcome measure was not analyzed due to a protocol amendment.
Arm/Group Title Methotrexate Adalimumab Adalimumab + Methotrexate
Hide Arm/Group Description:
Participants received placebo to adalimumab subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase. Participants received adalimumab 40 mg every other week for up to 8 years in the open-label extension phase.
Participants received adalimumab 40 mg subcutaneous injection once every other week and placebo to methotrexate orally once a week during the 2-year double-blind treatment phase and then adalimumab 40 mg every other week for up to 8 years in the open-label extension.
Participants received adalimumab 40 mg subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase. Participants received adalimumab 40 mg every other week for up to 8 years in the open-label extension phase.
Overall Number of Participants Analyzed 0 0 0
No data displayed because Outcome Measure has zero total analyzed.
33.Secondary Outcome
Title Number of Participants With a Major Clinical Response Over 10 Years by Adalimumab Exposure
Hide Description

A major clinical response was defined as maintenance of an ACR70 response for at least a 6-month continuous period at any time during the study following the first dose of adalimumab. A participant was a responder if the following criteria for improvement from Baseline were met:

  • ≥ 70% improvement in tender joint count;
  • ≥ 70% improvement in swollen joint count; and
  • ≥ 70% improvement in at least 3 of the 5 following parameters:

    • Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]);
    • Patient's global assessment of disease activity (measured on a 100 mm VAS);
    • Physician's global assessment of disease activity (measured on a 100 mm VAS);
    • Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index [HAQ-DI]);
    • Acute phase reactant value (C-Reactive Protein).
Time Frame From the first dose of adalimumab (at Week 1 or Week 106 for patients initially randomized to methotrexate in the DB phase) to Year 10
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Hide Analysis Population Description
ITT Analysis Set for participants with non-missing ACR data.
Arm/Group Title Any Adalimumab
Hide Arm/Group Description:
Participants received either methotrexate (MTX), adalimumab, or methotrexate + adalimumab during the 2-year double-blind treatment phase. During the 8-year open-label phase all participants received adalimumab 40 mg every other week.
Overall Number of Participants Analyzed 687
Measure Type: Number
Unit of Measure: participants
273
34.Secondary Outcome
Title Number of Participants With Improvement in HAQ-DI by 0.22 and 0.5 Units Over 10 Years by Adalimumab Exposure
Hide Description The Health Assessment Questionnaire - Disability Index (HAQ-DI) is a patient-reported questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and daily activities. Participants assessed their ability to do each task over the past week using the following response categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task were summed and averaged to provide an overall score ranging from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. A decrease in the HAQ-DI score represents an improvement in physical function; a clinically significant improvement is defined as a decrease of least 0.22 from Baseline in the HAQ-DI score. The number of participants with improvement in HAQ-DI of at least 0.22 and 0.5 units from Baseline is reported.
Time Frame Baseline and Years 1, 2, 5, and 10. Baseline was the last value prior to the first dose of adalimumab. For patients randomized to the MTX arm in the DB phase, Baseline was the last visit prior to the first adalimumab dose at Week 106.
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Analysis Set, with available data. The Number of Participants Analyzed indicates patients with non-missing HAQ-DI scores at any post-baseline time point; "N" indicates patients with non-missing data at each specified time point.
Arm/Group Title Adalimumab: HAQ Decrease ≥ 0.22 Adalimumab: HAQ Decrease ≥ 0.5
Hide Arm/Group Description:
Participants with a decrease of least 0.22 in HAQ from baseline, who received either methotrexate (MTX), adalimumab, or methotrexate + adalimumab during the 2-year double-blind treatment phase and adalimumab 40 mg every other week during the 8-year open-label phase.
Participants with a decrease of least 0.5 in HAQ from baseline, who received either methotrexate (MTX), adalimumab, or methotrexate + adalimumab during the 2-year double-blind treatment phase and adalimumab 40 mg every other week during the 8-year open-label phase.
Overall Number of Participants Analyzed 692 692
Measure Type: Number
Unit of Measure: participants
Year 1 [N=407] 353 285
Year 2 [N=390] 324 265
Year 5 [N=344] 239 188
Year 10 [N=170] 140 112
Time Frame For the double-blind treatment phase, up to 2 years (Methotrexate, Adalimumab and Adalimumab + Methotrexate reporting groups). For the Any Adalimumab reporting group, adverse events include the open-label extension, and are reported for up to 10 years.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Methotrexate Adalimumab Adalimumab + Methotrexate Any Adalimumab
Hide Arm/Group Description Participants received placebo to adalimumab subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase. Participants received adalimumab 40 mg subcutaneous injection once every other week and placebo to methotrexate orally once a week during the 2-year double-blind treatment phase. Participants received adalimumab 40 mg subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase.

Participants received either methotrexate, adalimumab, or methotrexate + adalimumab during the 2-year double-blind treatment phase. During the 8-year open-label phase all participants received adalimumab 40 mg every other week.

Adverse events reported include those that occurred at any time during adalimumab exposure (up to 10 years).

All-Cause Mortality
Methotrexate Adalimumab Adalimumab + Methotrexate Any Adalimumab
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/-- 
Hide Serious Adverse Events
Methotrexate Adalimumab Adalimumab + Methotrexate Any Adalimumab
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   47/257 (18.29%)   65/274 (23.72%)   56/268 (20.90%)   320/697 (45.91%) 
Blood and lymphatic system disorders         
Anaemia  1  1/257 (0.39%)  0/274 (0.00%)  0/268 (0.00%)  6/697 (0.86%) 
Eosinophilia  1  0/257 (0.00%)  1/274 (0.36%)  0/268 (0.00%)  1/697 (0.14%) 
Lymphadenopathy  1  1/257 (0.39%)  0/274 (0.00%)  1/268 (0.37%)  1/697 (0.14%) 
Lymphocytosis  1  0/257 (0.00%)  0/274 (0.00%)  1/268 (0.37%)  1/697 (0.14%) 
Bone marrow failure  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Iron deficiency anaemia  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Lymphadenopathy mediastinal  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Pancytopenia  1  1/257 (0.39%)  0/274 (0.00%)  0/268 (0.00%)  0/697 (0.00%) 
Cardiac disorders         
Acute coronary syndrome  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Acute myocardial infarction  1  1/257 (0.39%)  0/274 (0.00%)  0/268 (0.00%)  2/697 (0.29%) 
Angina pectoris  1  1/257 (0.39%)  1/274 (0.36%)  0/268 (0.00%)  2/697 (0.29%) 
Angina unstable  1  0/257 (0.00%)  2/274 (0.73%)  0/268 (0.00%)  3/697 (0.43%) 
Arrhythmia  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Atrial fibrillation  1  0/257 (0.00%)  1/274 (0.36%)  1/268 (0.37%)  8/697 (1.15%) 
Atrial Flutter  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Atrioventricular block  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Bradycardia  1  1/257 (0.39%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Cardiac arrest  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Cardiac failure congestive  1  1/257 (0.39%)  0/274 (0.00%)  0/268 (0.00%)  2/697 (0.29%) 
Cardiac failure  1  1/257 (0.39%)  0/274 (0.00%)  0/268 (0.00%)  0/697 (0.00%) 
Cardiac tamponade  1  1/257 (0.39%)  0/274 (0.00%)  0/268 (0.00%)  0/697 (0.00%) 
Coronary artery disease  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  3/697 (0.43%) 
Coronary artery occlusion  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  2/697 (0.29%) 
Coronary artery stenosis  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Mitral valve stenosis  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Myocardial infarction  1  0/257 (0.00%)  1/274 (0.36%)  0/268 (0.00%)  7/697 (1.00%) 
Myocardial ischaemia  1  0/257 (0.00%)  1/274 (0.36%)  0/268 (0.00%)  2/697 (0.29%) 
Pericarditis  1  1/257 (0.39%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Pleuropericarditis  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Right ventricular failure  1  0/257 (0.00%)  1/274 (0.36%)  0/268 (0.00%)  1/697 (0.14%) 
Sinoatrial block  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Tachyarrhythmia  1  0/257 (0.00%)  0/274 (0.00%)  1/268 (0.37%)  2/697 (0.29%) 
Ear and labyrinth disorders         
Hearing impaired  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Otosclerosis  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  2/697 (0.29%) 
Endocrine disorders         
Goitre  1  1/257 (0.39%)  0/274 (0.00%)  1/268 (0.37%)  1/697 (0.14%) 
Hyperthyroidism  1  0/257 (0.00%)  0/274 (0.00%)  1/268 (0.37%)  2/697 (0.29%) 
Eye disorders         
Blindness  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Blindness unilateral  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Cataract  1  1/257 (0.39%)  2/274 (0.73%)  0/268 (0.00%)  3/697 (0.43%) 
Corneal disorder  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Corneal opacity  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Keratitis  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Necrotising scleritis  1  1/257 (0.39%)  0/274 (0.00%)  0/268 (0.00%)  0/697 (0.00%) 
Ocular hypertension  1  1/257 (0.39%)  0/274 (0.00%)  0/268 (0.00%)  0/697 (0.00%) 
Vitreous detachment  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Retinal detachment  1  0/257 (0.00%)  0/274 (0.00%)  1/268 (0.37%)  4/697 (0.57%) 
Retinal disorder  1  0/257 (0.00%)  0/274 (0.00%)  1/268 (0.37%)  1/697 (0.14%) 
Vitreous haemorrhage  1  0/257 (0.00%)  0/274 (0.00%)  1/268 (0.37%)  1/697 (0.14%) 
Gastrointestinal disorders         
Abdominal adhesions  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  2/697 (0.29%) 
Abdominal hernia  1  1/257 (0.39%)  0/274 (0.00%)  0/268 (0.00%)  0/697 (0.00%) 
Abdominal mass  1  1/257 (0.39%)  0/274 (0.00%)  0/268 (0.00%)  0/697 (0.00%) 
Abdominal pain  1  0/257 (0.00%)  1/274 (0.36%)  2/268 (0.75%)  5/697 (0.72%) 
Abdominal pain upper  1  0/257 (0.00%)  1/274 (0.36%)  0/268 (0.00%)  1/697 (0.14%) 
Abdominal wall cyst  1  1/257 (0.39%)  0/274 (0.00%)  0/268 (0.00%)  0/697 (0.00%) 
Acute abdomen  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Colitis  1  0/257 (0.00%)  1/274 (0.36%)  0/268 (0.00%)  3/697 (0.43%) 
Colitis ischaemic  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Colonic polyp  1  0/257 (0.00%)  0/274 (0.00%)  1/268 (0.37%)  1/697 (0.14%) 
Constipation  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Crohn's Disease  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Diverticulum  1  0/257 (0.00%)  1/274 (0.36%)  0/268 (0.00%)  1/697 (0.14%) 
Duodenal ulcer  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  2/697 (0.29%) 
Dyspepsia  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Gastric haemorrhage  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Gastric Ulcer  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Gastritis  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Gastrointestinal haemorrhage  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Haemorrhoidal haemorrhage  1  0/257 (0.00%)  1/274 (0.36%)  0/268 (0.00%)  1/697 (0.14%) 
Haemorrhoids  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  2/697 (0.29%) 
Ileus  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Ileus paralytic  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Inguinal hernia  1  1/257 (0.39%)  0/274 (0.00%)  0/268 (0.00%)  2/697 (0.29%) 
Intestinal obstruction  1  2/257 (0.78%)  0/274 (0.00%)  1/268 (0.37%)  3/697 (0.43%) 
Inguinal hernia, obstructive  1  0/257 (0.00%)  1/274 (0.36%)  0/268 (0.00%)  1/697 (0.14%) 
Large intestine perforation  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Melaena  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Nausea  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Obstruction gastric  1  1/257 (0.39%)  0/274 (0.00%)  0/268 (0.00%)  0/697 (0.00%) 
Oesophageal achalasia  1  0/257 (0.00%)  1/274 (0.36%)  0/268 (0.00%)  1/697 (0.14%) 
Pancreatitis  1  0/257 (0.00%)  0/274 (0.00%)  1/268 (0.37%)  1/697 (0.14%) 
Pancreatitis acute  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  2/697 (0.29%) 
Rectal haemorrhage  1  0/257 (0.00%)  1/274 (0.36%)  0/268 (0.00%)  1/697 (0.14%) 
Upper gastrointestinal haemorrhage  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Vomiting  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
General disorders         
Asthenia  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Calcinosis  1  1/257 (0.39%)  0/274 (0.00%)  0/268 (0.00%)  0/697 (0.00%) 
Chest pain  1  1/257 (0.39%)  0/274 (0.00%)  1/268 (0.37%)  5/697 (0.72%) 
Death  1  0/257 (0.00%)  1/274 (0.36%)  0/268 (0.00%)  1/697 (0.14%) 
Device dislocation  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Drug ineffective  1  0/257 (0.00%)  1/274 (0.36%)  0/268 (0.00%)  1/697 (0.14%) 
Dysplasia  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Impaired healing  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Medical device complication  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Multi-organ failure  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Non-cardiac chest pain  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  4/697 (0.57%) 
Oedema  1  0/257 (0.00%)  1/274 (0.36%)  0/268 (0.00%)  1/697 (0.14%) 
Oedema peripheral  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Pyrexia  1  2/257 (0.78%)  0/274 (0.00%)  0/268 (0.00%)  3/697 (0.43%) 
Stent-graft endoleak  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Sudden cardiac death  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Hepatobiliary disorders         
Bile duct stone  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Cholangitis  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Cholecystitis  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  3/697 (0.43%) 
Cholecystitis chronic  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Cholelithiasis  1  0/257 (0.00%)  2/274 (0.73%)  3/268 (1.12%)  8/697 (1.15%) 
Hepatic necrosis  1  0/257 (0.00%)  1/274 (0.36%)  0/268 (0.00%)  1/697 (0.14%) 
Immune system disorders         
Anaphylactic reaction  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Anaphylactic shock  1  0/257 (0.00%)  0/274 (0.00%)  1/268 (0.37%)  1/697 (0.14%) 
Drug Hypersensitivity  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Hypersensitivity  1  0/257 (0.00%)  1/274 (0.36%)  0/268 (0.00%)  2/697 (0.29%) 
Seasonal allergy  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Infections and infestations         
Abscess  1  1/257 (0.39%)  0/274 (0.00%)  0/268 (0.00%)  0/697 (0.00%) 
Abdominal abscess  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Appendicitis  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Appendicitis perforated  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Arthritis bacterial  1  1/257 (0.39%)  1/274 (0.36%)  1/268 (0.37%)  4/697 (0.57%) 
Bacterial sepsis  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  2/697 (0.29%) 
Bartholin's abscess  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Bronchitis  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  4/697 (0.57%) 
Bronchopneumonia  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  4/697 (0.57%) 
Bursitis infective  1  0/257 (0.00%)  1/274 (0.36%)  0/268 (0.00%)  2/697 (0.29%) 
Cellulitis  1  0/257 (0.00%)  1/274 (0.36%)  2/268 (0.75%)  4/697 (0.57%) 
Chronic sinusitis  1  0/257 (0.00%)  0/274 (0.00%)  1/268 (0.37%)  1/697 (0.14%) 
Clostridium difficile colitis  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Corneal abscess  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Disseminated tuberculosis  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Diverticulitis  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  3/697 (0.43%) 
Eczema infected  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Endocarditis  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Epstein-barr virus infection  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Erysipelas  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  3/697 (0.43%) 
Extradural abscess  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Gastroenteritis  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  3/697 (0.43%) 
Gastroenteritis salmonella  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Groin abscess  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Helicobacter infection  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Hepatitis B  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Infection  1  0/257 (0.00%)  0/274 (0.00%)  1/268 (0.37%)  1/697 (0.14%) 
Infectious pleural effusion  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Kidney infection  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Lobar pneumonia  1  1/257 (0.39%)  1/274 (0.36%)  1/268 (0.37%)  5/697 (0.72%) 
Localised infection  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  3/697 (0.43%) 
Lower respiratory tract infection  1  0/257 (0.00%)  0/274 (0.00%)  1/268 (0.37%)  1/697 (0.14%) 
Meningitis streptococcal  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Mycobacterium avium complex infection  1  0/257 (0.00%)  0/274 (0.00%)  1/268 (0.37%)  1/697 (0.14%) 
Mycobacterium marinum infection  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Neurological infection  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Otitis media  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Parotitis  1  1/257 (0.39%)  0/274 (0.00%)  0/268 (0.00%)  0/697 (0.00%) 
Pneumonia  1  1/257 (0.39%)  0/274 (0.00%)  2/268 (0.75%)  15/697 (2.15%) 
Pneumonia legionella  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Pneumonia pneumococcal  1  0/257 (0.00%)  0/274 (0.00%)  1/268 (0.37%)  1/697 (0.14%) 
Pyelonephritis  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Respiratory tract infection  1  0/257 (0.00%)  0/274 (0.00%)  1/268 (0.37%)  3/697 (0.43%) 
Sepsis  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  4/697 (0.57%) 
Septic shock  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  2/697 (0.29%) 
Sinusitis  1  1/257 (0.39%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Tuberculosis gastrointestinal  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Tuberculous pleurisy  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Urinary tract infection  1  0/257 (0.00%)  0/274 (0.00%)  1/268 (0.37%)  2/697 (0.29%) 
Urosepsis  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Wound infection  1  0/257 (0.00%)  0/274 (0.00%)  1/268 (0.37%)  1/697 (0.14%) 
Injury, poisoning and procedural complications         
Injury  1  1/257 (0.39%)  0/274 (0.00%)  1/268 (0.37%)  1/697 (0.14%) 
Ankle fracture  1  0/257 (0.00%)  0/274 (0.00%)  1/268 (0.37%)  1/697 (0.14%) 
Concussion  1  0/257 (0.00%)  0/274 (0.00%)  1/268 (0.37%)  2/697 (0.29%) 
Contusion  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  3/697 (0.43%) 
Craniocerebral injury  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Excoriation  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Fall  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  5/697 (0.72%) 
Femoral neck fracture  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Femur fracture  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  4/697 (0.57%) 
Foot fracture  1  0/257 (0.00%)  0/274 (0.00%)  1/268 (0.37%)  1/697 (0.14%) 
Forearm fracture  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Foreign body in eye  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Hip fracture  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  2/697 (0.29%) 
Humerus fracture  1  1/257 (0.39%)  0/274 (0.00%)  0/268 (0.00%)  0/697 (0.00%) 
Laceration  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Lumbar vertebral fracture  1  0/257 (0.00%)  1/274 (0.36%)  1/268 (0.37%)  4/697 (0.57%) 
Meniscus lesion  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Multiple injuries  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Overdose  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Post-operative wound complication  1  0/257 (0.00%)  0/274 (0.00%)  1/268 (0.37%)  1/697 (0.14%) 
Procedural pain  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Road traffic accident  1  1/257 (0.39%)  0/274 (0.00%)  0/268 (0.00%)  0/697 (0.00%) 
Spinal fracture  1  0/257 (0.00%)  1/274 (0.36%)  0/268 (0.00%)  1/697 (0.14%) 
Sternal fracture  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Subcutaneous haematoma  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  2/697 (0.29%) 
Subdural haematoma  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Tendon injury  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Tendon rupture  1  0/257 (0.00%)  0/274 (0.00%)  1/268 (0.37%)  2/697 (0.29%) 
Testicular injury  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Thoracic vertebral fracture  1  0/257 (0.00%)  2/274 (0.73%)  0/268 (0.00%)  2/697 (0.29%) 
Traumatic fracture  1  0/257 (0.00%)  1/274 (0.36%)  0/268 (0.00%)  1/697 (0.14%) 
Upper limb fracture  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  2/697 (0.29%) 
Wrist fracture  1  0/257 (0.00%)  1/274 (0.36%)  1/268 (0.37%)  2/697 (0.29%) 
Investigations         
Alanine aminotransferase increased  1  0/257 (0.00%)  1/274 (0.36%)  0/268 (0.00%)  1/697 (0.14%) 
Aspartate aminotransferase increased  1  0/257 (0.00%)  1/274 (0.36%)  0/268 (0.00%)  1/697 (0.14%) 
Blood creatine phosphokinase increased  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Blood culture positive  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Blood pressure increased  1  0/257 (0.00%)  1/274 (0.36%)  0/268 (0.00%)  1/697 (0.14%) 
CSF pressure increased  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Haemoglobin decreased  1  0/257 (0.00%)  1/274 (0.36%)  0/268 (0.00%)  1/697 (0.14%) 
Heart rate increased  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Hepatitis c antibody positive  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
International normalised ratio increased  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Intraocular pressure increased  1  0/257 (0.00%)  1/274 (0.36%)  0/268 (0.00%)  1/697 (0.14%) 
Weight decreased  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Metabolism and nutrition disorders         
Dehydration  1  1/257 (0.39%)  2/274 (0.73%)  0/268 (0.00%)  3/697 (0.43%) 
Diabetes mellitus  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Gout  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Hypoglycaemia  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Hypokalaemia  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Metabolic acidosis  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Malnutrition  1  1/257 (0.39%)  0/274 (0.00%)  0/268 (0.00%)  0/697 (0.00%) 
Obesity  1  0/257 (0.00%)  0/274 (0.00%)  1/268 (0.37%)  1/697 (0.14%) 
Musculoskeletal and connective tissue disorders         
Arthralgia  1  0/257 (0.00%)  4/274 (1.46%)  0/268 (0.00%)  7/697 (1.00%) 
Arthritis  1  0/257 (0.00%)  1/274 (0.36%)  0/268 (0.00%)  4/697 (0.57%) 
Arthropathy  1  0/257 (0.00%)  1/274 (0.36%)  0/268 (0.00%)  1/697 (0.14%) 
Back pain  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  4/697 (0.57%) 
Bone erosion  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Bone fistula  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Bursitis  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  3/697 (0.43%) 
Cervical spinal stenosis  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Exostosis  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Flank pain  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Bone pain  1  1/257 (0.39%)  0/274 (0.00%)  0/268 (0.00%)  0/697 (0.00%) 
Foot deformity  1  0/257 (0.00%)  2/274 (0.73%)  1/268 (0.37%)  8/697 (1.15%) 
Intervertebral disc degeneration  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Intervertebral disc protrusion  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  7/697 (1.00%) 
Joint destruction  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  4/697 (0.57%) 
Joint range of motion decreased  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Knee deformity  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Lumbar spinal stenosis  1  0/257 (0.00%)  1/274 (0.36%)  0/268 (0.00%)  1/697 (0.14%) 
Metatarsalgia  1  0/257 (0.00%)  1/274 (0.36%)  0/268 (0.00%)  1/697 (0.14%) 
Myalgia  1  0/257 (0.00%)  1/274 (0.36%)  0/268 (0.00%)  1/697 (0.14%) 
Neck pain  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Osteitis  1  0/257 (0.00%)  0/274 (0.00%)  1/268 (0.37%)  1/697 (0.14%) 
Osteoarthritis  1  2/257 (0.78%)  3/274 (1.09%)  2/268 (0.75%)  23/697 (3.30%) 
Osteonecrosis  1  0/257 (0.00%)  1/274 (0.36%)  0/268 (0.00%)  2/697 (0.29%) 
Osteoporosis  1  1/257 (0.39%)  0/274 (0.00%)  0/268 (0.00%)  0/697 (0.00%) 
Rheumatoid arthritis  1  6/257 (2.33%)  16/274 (5.84%)  3/268 (1.12%)  38/697 (5.45%) 
Rheumatoid nodule  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Spinal column stenosis  1  0/257 (0.00%)  1/274 (0.36%)  0/268 (0.00%)  3/697 (0.43%) 
Rotator cuff syndrome  1  0/257 (0.00%)  1/274 (0.36%)  0/268 (0.00%)  2/697 (0.29%) 
Spondylolisthesis  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Synovial cyst  1  0/257 (0.00%)  1/274 (0.36%)  0/268 (0.00%)  2/697 (0.29%) 
Synovitis  1  1/257 (0.39%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Tendonitis  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)         
Adenoma benign  1  0/257 (0.00%)  0/274 (0.00%)  1/268 (0.37%)  1/697 (0.14%) 
B-cell small lymphocytic lymphoma  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Basal cell carcinoma  1  0/257 (0.00%)  0/274 (0.00%)  2/268 (0.75%)  3/697 (0.43%) 
Bladder cancer recurrent  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Bladder cancer stage II  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Bowen's disease  1  0/257 (0.00%)  0/274 (0.00%)  1/268 (0.37%)  1/697 (0.14%) 
Breast cancer  1  1/257 (0.39%)  1/274 (0.36%)  0/268 (0.00%)  5/697 (0.72%) 
Breast cancer in situ  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Colon adenoma  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  2/697 (0.29%) 
Colon cancer  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Colon cancer stage 0  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Colon cancer stage IV  1  0/257 (0.00%)  1/274 (0.36%)  0/268 (0.00%)  1/697 (0.14%) 
Leiomyoma  1  1/257 (0.39%)  0/274 (0.00%)  0/268 (0.00%)  0/697 (0.00%) 
Lymphoma cutis  1  1/257 (0.39%)  0/274 (0.00%)  0/268 (0.00%)  0/697 (0.00%) 
Enchondromatosis  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Gastric cancer  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Haemangioma of liver  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Hair follicle tumour benign  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Hepatic neoplasm  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Histiocytosis haematophagic  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Hodgkin's disease  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  3/697 (0.43%) 
Keratoacanthoma  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Lung adenocarcinoma  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Lung neoplasm malignant  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Lymphoma  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Malignant melanoma  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Malignant melanoma in situ  1  1/257 (0.39%)  0/274 (0.00%)  0/268 (0.00%)  0/697 (0.00%) 
Malignant melanoma stage III  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Meningioma  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Metastases to liver  1  0/257 (0.00%)  1/274 (0.36%)  0/268 (0.00%)  1/697 (0.14%) 
Metastatic squamous cell carcinoma  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Multiple myeloma  1  0/257 (0.00%)  1/274 (0.36%)  0/268 (0.00%)  2/697 (0.29%) 
Non-hodgkin's lymphoma  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Non-small cell lung cancer stage IV  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Ovarian adenoma  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Ovarian cancer  1  0/257 (0.00%)  0/274 (0.00%)  1/268 (0.37%)  2/697 (0.29%) 
Pancreatic neoplasm  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Parathyroid tumour benign  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Prostate cancer  1  0/257 (0.00%)  0/274 (0.00%)  1/268 (0.37%)  2/697 (0.29%) 
Prostate cancer stage I  1  1/257 (0.39%)  0/274 (0.00%)  0/268 (0.00%)  0/697 (0.00%) 
Prostatic adenoma  1  0/257 (0.00%)  1/274 (0.36%)  1/268 (0.37%)  2/697 (0.29%) 
Rectal adenoma  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Rectal cancer  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Renal cell carcinoma  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  3/697 (0.43%) 
Squamous cell carcinoma  1  0/257 (0.00%)  0/274 (0.00%)  1/268 (0.37%)  2/697 (0.29%) 
Thyroid neoplasm  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Tongue neoplasm malignant stage unspecified  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Uterine leiomyoma  1  1/257 (0.39%)  1/274 (0.36%)  0/268 (0.00%)  5/697 (0.72%) 
Nervous system disorders         
Carpal tunnel syndrome  1  0/257 (0.00%)  0/274 (0.00%)  1/268 (0.37%)  2/697 (0.29%) 
Cerebral ischaemia  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  2/697 (0.29%) 
Cerebrovascular accident  1  0/257 (0.00%)  1/274 (0.36%)  0/268 (0.00%)  2/697 (0.29%) 
Cervical myelopathy  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Clonus  1  0/257 (0.00%)  1/274 (0.36%)  0/268 (0.00%)  1/697 (0.14%) 
Dementia  1  0/257 (0.00%)  0/274 (0.00%)  1/268 (0.37%)  1/697 (0.14%) 
Dementia alzheimer's type  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Dizziness  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Encephalopathy  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Hepatic encephalopathy  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Hyperreflexia  1  0/257 (0.00%)  1/274 (0.36%)  1/268 (0.37%)  2/697 (0.29%) 
Intention tremor  1  0/257 (0.00%)  0/274 (0.00%)  1/268 (0.37%)  1/697 (0.14%) 
Nerve compression  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Optic neuritis  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Paraesthesia  1  0/257 (0.00%)  1/274 (0.36%)  0/268 (0.00%)  1/697 (0.14%) 
Peripheral motor neuropathy  1  0/257 (0.00%)  1/274 (0.36%)  0/268 (0.00%)  1/697 (0.14%) 
Peripheral sensory neuropathy  1  0/257 (0.00%)  1/274 (0.36%)  0/268 (0.00%)  1/697 (0.14%) 
Sciatica  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Syncope  1  2/257 (0.78%)  0/274 (0.00%)  1/268 (0.37%)  7/697 (1.00%) 
Transient ischaemic attack  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  3/697 (0.43%) 
Pregnancy, puerperium and perinatal conditions         
Abortion spontaneous  1  0/257 (0.00%)  2/274 (0.73%)  0/268 (0.00%)  3/697 (0.43%) 
Psychiatric disorders         
Alcohol abuse  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Bipolar disorder  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Delirium  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Depression  1  1/257 (0.39%)  0/274 (0.00%)  0/268 (0.00%)  3/697 (0.43%) 
Depression suicidal  1  0/257 (0.00%)  0/274 (0.00%)  1/268 (0.37%)  1/697 (0.14%) 
Mental status changes  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Renal and urinary disorders         
Nephrolithiasis  1  1/257 (0.39%)  0/274 (0.00%)  1/268 (0.37%)  6/697 (0.86%) 
Calculus Ureteric  1  0/257 (0.00%)  0/274 (0.00%)  1/268 (0.37%)  1/697 (0.14%) 
Calculus urinary  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  2/697 (0.29%) 
Renal failure  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Renal failure acute  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  2/697 (0.29%) 
Renal haemorrhage  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Renal mass  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Stress urinary incontinence  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Urethral stenosis  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Urinary incontinence  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Reproductive system and breast disorders         
Bartholin's cyst  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Benign prostatic hyperplasia  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  2/697 (0.29%) 
Cervical dysplasia  1  1/257 (0.39%)  0/274 (0.00%)  1/268 (0.37%)  2/697 (0.29%) 
Dyspareunia  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Endometrial hyperplasia  1  0/257 (0.00%)  0/274 (0.00%)  1/268 (0.37%)  2/697 (0.29%) 
Endometriosis  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Menometrorrhagia  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Menorrhagia  1  1/257 (0.39%)  1/274 (0.36%)  1/268 (0.37%)  4/697 (0.57%) 
Menstrual disorder  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Menstruation irregular  1  0/257 (0.00%)  0/274 (0.00%)  1/268 (0.37%)  2/697 (0.29%) 
Ovarian cyst  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  3/697 (0.43%) 
Pelvic prolapse  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Uterine cyst  1  0/257 (0.00%)  0/274 (0.00%)  1/268 (0.37%)  1/697 (0.14%) 
Uterine prolapse  1  1/257 (0.39%)  0/274 (0.00%)  0/268 (0.00%)  2/697 (0.29%) 
Uterovaginal prolapse  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Vaginal prolapse  1  1/257 (0.39%)  0/274 (0.00%)  0/268 (0.00%)  0/697 (0.00%) 
Respiratory, thoracic and mediastinal disorders         
Asthma  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  2/697 (0.29%) 
Chronic obstructive pulmonary disease  1  0/257 (0.00%)  1/274 (0.36%)  1/268 (0.37%)  4/697 (0.57%) 
Cough  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Interstitial lung disease  1  0/257 (0.00%)  0/274 (0.00%)  1/268 (0.37%)  3/697 (0.43%) 
Dyspnoea  1  0/257 (0.00%)  1/274 (0.36%)  0/268 (0.00%)  2/697 (0.29%) 
Dyspnoea exertional  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  3/697 (0.43%) 
Lung infiltration  1  0/257 (0.00%)  0/274 (0.00%)  1/268 (0.37%)  1/697 (0.14%) 
Nasal congestion  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Nasal polyps  1  0/257 (0.00%)  0/274 (0.00%)  1/268 (0.37%)  1/697 (0.14%) 
Pleural effusion  1  0/257 (0.00%)  0/274 (0.00%)  1/268 (0.37%)  4/697 (0.57%) 
Pleurisy  1  0/257 (0.00%)  0/274 (0.00%)  1/268 (0.37%)  2/697 (0.29%) 
Pulmonary embolism  1  0/257 (0.00%)  0/274 (0.00%)  1/268 (0.37%)  6/697 (0.86%) 
Pulmonary hypertension  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Respiratory failure  1  0/257 (0.00%)  0/274 (0.00%)  1/268 (0.37%)  3/697 (0.43%) 
Vocal cord cyst  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Vocal cord polyp  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Tonsillar hypertrophy  1  1/257 (0.39%)  0/274 (0.00%)  0/268 (0.00%)  0/697 (0.00%) 
Skin and subcutaneous tissue disorders         
Pustular psoriasis  1  0/257 (0.00%)  0/274 (0.00%)  1/268 (0.37%)  1/697 (0.14%) 
Rash  1  0/257 (0.00%)  0/274 (0.00%)  1/268 (0.37%)  1/697 (0.14%) 
Surgical and medical procedures         
Abortion induced  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Foot operation  1  0/257 (0.00%)  0/274 (0.00%)  1/268 (0.37%)  1/697 (0.14%) 
Female sterilization  1  1/257 (0.39%)  0/274 (0.00%)  0/268 (0.00%)  0/697 (0.00%) 
Vascular disorders         
Aortic aneurysm  1  0/257 (0.00%)  1/274 (0.36%)  0/268 (0.00%)  2/697 (0.29%) 
Aortic stenosis  1  1/257 (0.39%)  0/274 (0.00%)  0/268 (0.00%)  0/697 (0.00%) 
Hypotension  1  1/257 (0.39%)  0/274 (0.00%)  0/268 (0.00%)  0/697 (0.00%) 
Aortitis  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Deep vein thrombosis  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  4/697 (0.57%) 
Femoral artery occlusion  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Haematoma  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Haemorrhage  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Hypertensive crisis  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Iliac artery stenosis  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Rheumatoid vasculitis  1  0/257 (0.00%)  1/274 (0.36%)  0/268 (0.00%)  1/697 (0.14%) 
Thrombosis  1  0/257 (0.00%)  0/274 (0.00%)  1/268 (0.37%)  1/697 (0.14%) 
Varicose vein  1  0/257 (0.00%)  0/274 (0.00%)  1/268 (0.37%)  2/697 (0.29%) 
Vasculitis  1  1/257 (0.39%)  0/274 (0.00%)  0/268 (0.00%)  0/697 (0.00%) 
Venous thrombosis  1  0/257 (0.00%)  0/274 (0.00%)  0/268 (0.00%)  1/697 (0.14%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 14.1
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Methotrexate Adalimumab Adalimumab + Methotrexate Any Adalimumab
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   227/257 (88.33%)   227/274 (82.85%)   241/268 (89.93%)   634/697 (90.96%) 
Blood and lymphatic system disorders         
Anaemia  1  8/257 (3.11%)  13/274 (4.74%)  4/268 (1.49%)  43/697 (6.17%) 
Lymphadenopathy  1  12/257 (4.67%)  15/274 (5.47%)  0/268 (0.00%)  28/697 (4.02%) 
Ear and labyrinth disorders         
Vertigo  1  9/257 (3.50%)  14/274 (5.11%)  5/268 (1.87%)  42/697 (6.03%) 
Eye disorders         
Cataract  1  5/257 (1.95%)  5/274 (1.82%)  6/268 (2.24%)  39/697 (5.60%) 
Conjunctivitis  1  3/257 (1.17%)  6/274 (2.19%)  10/268 (3.73%)  36/697 (5.16%) 
Gastrointestinal disorders         
Abdominal pain  1  9/257 (3.50%)  11/274 (4.01%)  12/268 (4.48%)  46/697 (6.60%) 
Nausea  1  53/257 (20.62%)  48/274 (17.52%)  46/268 (17.16%)  131/697 (18.79%) 
Dyspepsia  1  26/257 (10.12%)  20/274 (7.30%)  25/268 (9.33%)  74/697 (10.62%) 
Diarrhoea  1  42/257 (16.34%)  32/274 (11.68%)  28/268 (10.45%)  105/697 (15.06%) 
Abdominal pain upper  1  22/257 (8.56%)  19/274 (6.93%)  24/268 (8.96%)  77/697 (11.05%) 
Vomiting  1  12/257 (4.67%)  12/274 (4.38%)  14/268 (5.22%)  44/697 (6.31%) 
Mouth ulceration  1  15/257 (5.84%)  7/274 (2.55%)  12/268 (4.48%)  25/697 (3.59%) 
Constipation  1  17/257 (6.61%)  3/274 (1.09%)  11/268 (4.10%)  33/697 (4.73%) 
Gastrooesophageal reflux disease  1  6/257 (2.33%)  9/274 (3.28%)  8/268 (2.99%)  48/697 (6.89%) 
General disorders         
Chest pain  1  8/257 (3.11%)  13/274 (4.74%)  12/268 (4.48%)  42/697 (6.03%) 
Fatigue  1  27/257 (10.51%)  28/274 (10.22%)  33/268 (12.31%)  98/697 (14.06%) 
Oedema peripheral  1  16/257 (6.23%)  16/274 (5.84%)  18/268 (6.72%)  68/697 (9.76%) 
Pyrexia  1  9/257 (3.50%)  11/274 (4.01%)  4/268 (1.49%)  35/697 (5.02%) 
Infections and infestations         
Nasopharyngitis  1  63/257 (24.51%)  62/274 (22.63%)  81/268 (30.22%)  219/697 (31.42%) 
Gastroenteritis  1  11/257 (4.28%)  6/274 (2.19%)  9/268 (3.36%)  38/697 (5.45%) 
Herpes zoster  1  2/257 (0.78%)  8/274 (2.92%)  4/268 (1.49%)  50/697 (7.17%) 
Upper respiratory tract infection  1  47/257 (18.29%)  24/274 (8.76%)  50/268 (18.66%)  176/697 (25.25%) 
Pharyngitis  1  11/257 (4.28%)  9/274 (3.28%)  10/268 (3.73%)  43/697 (6.17%) 
Respiratory tract infection  1  3/257 (1.17%)  10/274 (3.65%)  8/268 (2.99%)  38/697 (5.45%) 
Rhinitis  1  11/257 (4.28%)  14/274 (5.11%)  15/268 (5.60%)  48/697 (6.89%) 
Sinusitis  1  17/257 (6.61%)  23/274 (8.39%)  29/268 (10.82%)  111/697 (15.93%) 
Oral herpes  1  10/257 (3.89%)  5/274 (1.82%)  16/268 (5.97%)  43/697 (6.17%) 
Urinary tract infection  1  22/257 (8.56%)  30/274 (10.95%)  21/268 (7.84%)  132/697 (18.94%) 
Bronchitis  1  28/257 (10.89%)  18/274 (6.57%)  21/268 (7.84%)  109/697 (15.64%) 
Influenza  1  18/257 (7.00%)  21/274 (7.66%)  15/268 (5.60%)  77/697 (11.05%) 
Injury, poisoning and procedural complications         
Contusion  1  8/257 (3.11%)  5/274 (1.82%)  19/268 (7.09%)  48/697 (6.89%) 
Fall  1  5/257 (1.95%)  5/274 (1.82%)  10/268 (3.73%)  42/697 (6.03%) 
Investigations         
Alanine aminotransferase increased  1  17/257 (6.61%)  7/274 (2.55%)  29/268 (10.82%)  52/697 (7.46%) 
Aspartate aminotransferase increased  1  11/257 (4.28%)  4/274 (1.46%)  14/268 (5.22%)  28/697 (4.02%) 
Metabolism and nutrition disorders         
Hypercholesterolaemia  1  8/257 (3.11%)  12/274 (4.38%)  2/268 (0.75%)  61/697 (8.75%) 
Musculoskeletal and connective tissue disorders         
Arthralgia  1  29/257 (11.28%)  34/274 (12.41%)  30/268 (11.19%)  129/697 (18.51%) 
Back pain  1  29/257 (11.28%)  31/274 (11.31%)  23/268 (8.58%)  108/697 (15.49%) 
Bursitis  1  6/257 (2.33%)  11/274 (4.01%)  10/268 (3.73%)  58/697 (8.32%) 
Muscle spasms  1  7/257 (2.72%)  9/274 (3.28%)  12/268 (4.48%)  40/697 (5.74%) 
Musculoskeletal pain  1  10/257 (3.89%)  9/274 (3.28%)  5/268 (1.87%)  46/697 (6.60%) 
Myalgia  1  6/257 (2.33%)  6/274 (2.19%)  4/268 (1.49%)  39/697 (5.60%) 
Osteoarthritis  1  4/257 (1.56%)  9/274 (3.28%)  2/268 (0.75%)  50/697 (7.17%) 
Pain in extremity  1  11/257 (4.28%)  11/274 (4.01%)  18/268 (6.72%)  74/697 (10.62%) 
Rheumatoid arthritis  1  38/257 (14.79%)  43/274 (15.69%)  26/268 (9.70%)  189/697 (27.12%) 
Joint swelling  1  13/257 (5.06%)  15/274 (5.47%)  5/268 (1.87%)  39/697 (5.60%) 
Tendonitis  1  5/257 (1.95%)  5/274 (1.82%)  5/268 (1.87%)  41/697 (5.88%) 
Nervous system disorders         
Headache  1  42/257 (16.34%)  59/274 (21.53%)  55/268 (20.52%)  155/697 (22.24%) 
Dizziness  1  15/257 (5.84%)  26/274 (9.49%)  20/268 (7.46%)  67/697 (9.61%) 
Paraesthesia  1  8/257 (3.11%)  13/274 (4.74%)  8/268 (2.99%)  46/697 (6.60%) 
Psychiatric disorders         
Depression  1  19/257 (7.39%)  13/274 (4.74%)  19/268 (7.09%)  69/697 (9.90%) 
Insomnia  1  7/257 (2.72%)  17/274 (6.20%)  8/268 (2.99%)  48/697 (6.89%) 
Respiratory, thoracic and mediastinal disorders         
Cough  1  25/257 (9.73%)  34/274 (12.41%)  30/268 (11.19%)  107/697 (15.35%) 
Dyspnoea  1  8/257 (3.11%)  16/274 (5.84%)  10/268 (3.73%)  43/697 (6.17%) 
Oropharyngeal pain  1  19/257 (7.39%)  24/274 (8.76%)  22/268 (8.21%)  65/697 (9.33%) 
Skin and subcutaneous tissue disorders         
Alopecia  1  13/257 (5.06%)  11/274 (4.01%)  18/268 (6.72%)  38/697 (5.45%) 
Rash  1  22/257 (8.56%)  25/274 (9.12%)  17/268 (6.34%)  98/697 (14.06%) 
Eczema  1  6/257 (2.33%)  12/274 (4.38%)  9/268 (3.36%)  43/697 (6.17%) 
Erythema  1  3/257 (1.17%)  9/274 (3.28%)  5/268 (1.87%)  36/697 (5.16%) 
Vascular disorders         
Hypertension  1  32/257 (12.45%)  25/274 (9.12%)  29/268 (10.82%)  153/697 (21.95%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 14.1
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
AbbVie requests that any investigator or institution that plans on presenting/publishing results disclosure, provide written notification of their request 60 days prior to their presentation/publication. AbbVie requests that no presentation/publication will be instituted until 12 months after a study is completed, or after the first presentation/publication whichever occurs first. A delay may be proposed of a presentation/publication if AbbVie needs to secure patent or proprietary protection.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Global Medical Services
Organization: AbbVie (prior sponsor, Abbott)
Phone: 800-633-9110
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: AbbVie ( AbbVie (prior sponsor, Abbott) )
ClinicalTrials.gov Identifier: NCT00195663    
Other Study ID Numbers: DE013
First Submitted: September 13, 2005
First Posted: September 20, 2005
Results First Submitted: December 8, 2009
Results First Posted: February 25, 2010
Last Update Posted: July 12, 2013