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A Study of the Effect of Tocilizumab on Markers of Atherogenic Risk in Patients With Moderate to Severe Rheumatoid Arthritis

Sponsor
Hoffmann-La Roche (Industry)
Overall Status
Completed
CT.gov ID
NCT00535782
Collaborator
(none)
132
Enrollment
40
Locations
2
Arms
39
Actual Duration (Months)
3.3
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This 2 arm study will investigate the effects of tocilizumab on lipids, arterial stiffness, and markers of atherogenic risk in patients with moderate to severe active rheumatoid arthritis. In Part 1 of the study, patients will be randomized to receive either tocilizumab 8mg/kg intravenously or placebo every 4 weeks, in combination with methotrexate 7.5-25 mg weekly. In Part 2, all patients will receive open-label treatment with tocilizumab plus methotrexate.

Condition or Disease Intervention/Treatment Phase
Phase 3

Study Design

Study Type:
Interventional
Actual Enrollment :
132 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Double (Participant, Investigator)
Primary Purpose:
Treatment
Official Title:
A Mechanism of Action Study to Evaluate the Effects of IL-6 Receptor Blockade With Tocilizumab (TCZ) on Lipids, Arterial Stiffness, and Markers of Atherogenic Risk in Patients With Moderate to Severe Active Rheumatoid Arthritis (RA).
Actual Study Start Date :
Oct 31, 2007
Actual Primary Completion Date :
Sep 30, 2008
Actual Study Completion Date :
Jan 31, 2011

Arms and Interventions

Arm Intervention/Treatment
Experimental: TCZ + MTX

Participants received 8 mg/kg tocilizumab (TCZ) by intravenous infusion (IV) every 4 weeks plus methotrexate (MTX) 7.5-25 mg (oral or parenteral) weekly for the first 24 weeks. From Week 24 to Week 104, participants received open-label TCZ 8 mg/kg every 4 weeks plus 7.5-25 mg MTX weekly.

Drug: Tocilizumab
Administered by intravenous infusion, 8 mg/kg every 4 weeks.
Other Names:
  • RoActemra
  • Actemra

    • Drug: Methotrexate
    Administered orally or parenterally, 7.5-25 mg weekly.
    Placebo Comparator: Placebo + MTX

    Participants received placebo intravenous infusion (IV) every 4 weeks plus methotrexate (MTX) 7.5-25 mg (oral or parenteral) weekly for the first 24 weeks. From Week 24 to 104, participants received open-label tocilizumab (TCZ) 8 mg/kg every 4 weeks plus 7.5-25 mg MTX.

    Drug: Tocilizumab
    Administered by intravenous infusion, 8 mg/kg every 4 weeks.
    Other Names:
  • RoActemra
  • Actemra

    • Drug: Placebo
    Placebo to tocilizumab administered by intravenous infusion every 4 weeks.

    Drug: Methotrexate
    Administered orally or parenterally, 7.5-25 mg weekly.

    Outcome Measures

    Primary Outcome Measures

    1. Change From Baseline in Small Low Density Lipoprotein (sLDL) Particle Numbers [Baseline and Week 12]

      Small LDL particles are associated with an increased risk of cardiovascular disease: more of these small particles lead to a greater risk. The concentration of fasting small LDL particles was determined using the Nuclear Magnetic Resonance (NMR) methodology.

    2. Change From Baseline to Week 12 in Aortic Pulse Wave Velocity (PWV) [Baseline and Week 12]

      Aortic (central) arterial stiffness was assessed with Pulse Wave Analysis (PWA) of the radial artery and carotid-femoral PWV using applanation tonometry after the patient had rested in a supine position for at least 10 minutes.

    Secondary Outcome Measures

    1. Change From Baseline to Week 24 in Small Low Density Lipoprotein (sLDL) Particle Numbers [Baseline and Week 24]

      Small LDL particles are associated with an increased risk of cardiovascular disease: more of these small particles lead to a greater risk. The concentration of fasting small LDL particles was determined using the Nuclear Magnetic Resonance (NMR) methodology.

    2. Change From Baseline to Week 24 in Aortic Pulse Wave Velocity (PWV) [Baseline and Week 24]

      Aortic (central) arterial stiffness was assessed with Pulse Wave Analysis (PWA) of the radial artery and carotid-femoral PWV using applanation tonometry after the patient had rested in a supine position for at least 10 minutes.

    3. Number of Participants Experiencing Adverse Events (AEs) [Up to Week 24]

      A severe AE is an event in which the intensity of the event results in an inability to work or perform normal daily activity. A Serious AE is fatal, life-threatening, requires in-patient hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant or requires intervention to prevent one of the above outcomes. AEs of special interest include infection, gastrointestinal, infusion reaction (occurring during or within 24 hours of infusion), hepatic disorder, myocardial infarction and stroke.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 75 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • adult patients, 18-75 years of age

    • rheumatoid arthritis (RA) of >6 months duration

    • able to receive outpatient treatment

    • on methotrexate for at least 12 weeks before entering study, at a stable dose of 7.5-25 mg/week for the last 8 weeks

    • oral corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDS) permitted, if at a stable dose for 4 weeks before study start

    Exclusion Criteria

    • major surgery (including joint surgery) within 8 weeks prior to screening, or planned surgery within 6 months after entering study

    • history of, or current inflammatory joint disease or rheumatic autoimmune disease other than RA

    • inadequate response to anti-tumor necrosis factor (TNF) agent during the 6 months prior to baseline, or inadequate response to >2 anti-TNF agents

    • initiation of treatment with lipid lowering agents within 12 weeks prior to baseline

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Pinnacle Research Group; Llc, Central Anniston Alabama United States 36207
    2 Rheumatology Associates of North Alabama Huntsville Alabama United States 35801
    3 Advanced Arthritis Care & Research Scottsdale Arizona United States 85258
    4 Catalina Pointe Clinical Research, Inc. Tucson Arizona United States 85704
    5 Pacific Arthritis Care Center Los Angeles California United States 90045
    6 Arthritis & Rheumatism; Disease Specialities Aventura Florida United States 33180
    7 Science and Research Institute, Inc. Jupiter Florida United States 33458
    8 Arthritis Center Palm Harbor Palm Harbor Florida United States 34684
    9 Arthritis Rsrch of Florida, Inc. Palm Harbor Florida United States 34684
    10 Sarasota Arthritis Center; Research Dept Sarasota Florida United States 34239
    11 Burnette & Silverfield, MDS Tampa Florida United States 33614
    12 Arthritis & Rheumatology of Georgia Atlanta Georgia United States 30342
    13 Deerbrook Medical Associates Vernon Hills Illinois United States 60061
    14 Johns Hopkins Uni Baltimore Maryland United States 21224
    15 Borgess Research Institute Kalamazoo Michigan United States 49048
    16 Jackson Arthritis Clinic Flowood Mississippi United States 39232
    17 Physicians Group, LC DBA Rheumatology & Internal Medicine Associates Saint Louis Missouri United States 63131
    18 NJP Clinical Research Clifton New Jersey United States 07012
    19 Asheville Arthritis & Osteoporosis Center, PA Asheville North Carolina United States 28803
    20 Health Research of Oklahoma, Llc Oklahoma City Oklahoma United States 73103
    21 Lehigh Valley Hospital; Dept of Medicine Allentown Pennsylvania United States 18103
    22 Altoona Center For Clinical Research Duncansville Pennsylvania United States 16635
    23 Clinical Research Center of Reading Wyomissing Pennsylvania United States 19610
    24 Houston Inst. For Clinical Research Houston Texas United States 77074
    25 Texas Research Center Sugar Land Texas United States 77479
    26 South Puget Sound Clinical Research Olympia Washington United States 98502
    27 The Governors of the Uni of Alberta; Heritage Medical Research Centre Edmonton Alberta Canada T6G 2S2
    28 Laurel Medical Clinic Vancouver British Columbia Canada V5Z 3Y1
    29 Manitoba Clinic Winnipeg Manitoba Canada R3A 1M3
    30 Nexus Clinical Research Centre St John's Newfoundland and Labrador Canada A1A 5E8
    31 Dr. William G. Bensen Medicine Professional Corporation Hamilton Ontario Canada L8N 1Y2
    32 Credit Valley, Rheumatology Mississauga Ontario Canada L5M 2V8
    33 Rheumatology Research Associates Ottawa Ontario Canada K1H 1A2
    34 Private Practice Toronto Ontario Canada M4K 1N2
    35 Chus Hopital Fleurimont Sherbrooke Quebec Canada J1H 5N4
    36 Centre Re Recherche Saint-Louis Quebec Canada G1W 4R4
    37 Ponce School of Medicine; Caimed Center Ponce Puerto Rico 00716
    38 Glasgow Royal Infirmary; Centre For Rheumatic Diseases Glasgow United Kingdom G4 0SF
    39 Trafford General Hospital; Rheumatology Manchester United Kingdom M41 5SL
    40 Royal Victoria Infirmary; Clinical Research Facility Newcastle Upon Tyne United Kingdom NE1 4LP

    Sponsors and Collaborators

    • Hoffmann-La Roche

    Investigators

    • Study Director: Clinical Trials, Hoffmann-La Roche

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Hoffmann-La Roche
    ClinicalTrials.gov Identifier:
    NCT00535782
    Other Study ID Numbers:
    • WA19923
    • 2007-001114-17
    First Posted:
    Sep 26, 2007
    Last Update Posted:
    Jul 26, 2017
    Last Verified:
    Jun 1, 2017
    Additional relevant MeSH terms:
    Arthritis
    Arthritis, Rheumatoid
    Methotrexate

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Part 1: TCZ + MTX Part 1: Placebo + MTX Part 2: TCZ + MTX
    Arm/Group Description During Part 1 of the study participants in this group received 8 mg/kg tocilizumab (TCZ) by intravenous infusion (IV) every 4 weeks plus methotrexate (MTX) 7.5-25 mg (oral or parenteral) weekly for 24 weeks. During Part 1 of the study participants in this group received placebo intravenous infusion (IV) every 4 weeks plus methotrexate (MTX) 7.5-25 mg (oral or parenteral) weekly for 24 weeks. During Part 2 of the study, from Week 24 to Week 104, all participants received 8 mg/kg tocilizumab (TCZ) by intravenous infusion (IV) every 4 weeks plus methotrexate (MTX) 7.5-25 mg (oral or parenteral) weekly.
    Period Title: Part 1: 24-Week Double-blind Period
    STARTED 69 63 0
    Treated With TCZ + MTX 69 2 0
    Treated With Placebo + MTX 0 62 0
    COMPLETED 65 59 0
    NOT COMPLETED 4 4 0
    Period Title: Part 1: 24-Week Double-blind Period
    STARTED 0 0 124
    COMPLETED 0 0 98
    NOT COMPLETED 0 0 26

    Baseline Characteristics

    Arm/Group Title TCZ + MTX Placebo + MTX Total
    Arm/Group Description During Part 1 of the study participants received 8 mg/kg tocilizumab (TCZ) by intravenous (IV) infusion every 4 weeks plus methotrexate (MTX) 7.5-25 mg (oral or parenteral) weekly for 24 weeks. During Part 2, from Week 24 to Week 104, participants received open-label 8 mg/kg TCZ every 4 weeks plus 7.5-25 mg MTX weekly. During Part 1 of the study participants received placebo intravenous (IV) infusion every 4 weeks plus methotrexate (MTX) 7.5-25 mg (oral or parenteral) weekly for 24 weeks. During Part 2, from Week 24 to Week 104, participants received 8 mg/kg TCZ IV every 4 weeks plus 7.5-25 mg MTX weekly. Total of all reporting groups
    Overall Participants 69 63 132
    Age, Customized (participants) [Number]
    <52 years
    23
    33.3%
    20
    31.7%
    43
    32.6%
    ≥52 years
    46
    66.7%
    43
    68.3%
    89
    67.4%
    Sex: Female, Male (Count of Participants)
    Female
    57
    82.6%
    47
    74.6%
    104
    78.8%
    Male
    12
    17.4%
    16
    25.4%
    28
    21.2%
    Race/Ethnicity, Customized (participants) [Number]
    Asian
    1
    1.4%
    3
    4.8%
    4
    3%
    Black
    2
    2.9%
    4
    6.3%
    6
    4.5%
    Other
    3
    4.3%
    1
    1.6%
    4
    3%
    White
    63
    91.3%
    55
    87.3%
    118
    89.4%
    Region of Enrollment (participants) [Number]
    United States
    41
    59.4%
    46
    73%
    87
    65.9%
    Canada
    23
    33.3%
    16
    25.4%
    39
    29.5%
    United Kingdom
    5
    7.2%
    1
    1.6%
    6
    4.5%

    Outcome Measures

    1. Primary Outcome
    Title Change From Baseline in Small Low Density Lipoprotein (sLDL) Particle Numbers
    Description Small LDL particles are associated with an increased risk of cardiovascular disease: more of these small particles lead to a greater risk. The concentration of fasting small LDL particles was determined using the Nuclear Magnetic Resonance (NMR) methodology.
    Time Frame Baseline and Week 12

    Outcome Measure Data

    Analysis Population Description
    Intent to treat (ITT) population. All randomized patients who received any part of an infusion of study medication are included. Patients who received an incorrect therapy from that intended are summarized in the group according to the intended randomized treatment group. Last observation carried forward (LOCF) imputation was used.
    Arm/Group Title TCZ + MTX Placebo + MTX
    Arm/Group Description Participants received 8 mg/kg tocilizumab (TCZ) by intravenous infusion (IV) every 4 weeks plus 7.5-25 mg of methotrexate (MTX) weekly for the first 24 weeks. Participants received placebo intravenous infusion (IV) every 4 weeks plus methotrexate (MTX) 7.5-25 mg (oral or parenteral) weekly for the first 24 weeks.
    Measure Participants 69 63
    Baseline (n=63, 59)
    737.79
    (467.097)
    792.78
    (392.051)
    Week 12 (n=69, 63)
    768.04
    (628.281)
    777.71
    (394.527)
    Change from Baseline at Week 12 (n=63, 59)
    23.73
    (368.273)
    22.41
    (237.476)
    2. Secondary Outcome
    Title Change From Baseline to Week 24 in Small Low Density Lipoprotein (sLDL) Particle Numbers
    Description Small LDL particles are associated with an increased risk of cardiovascular disease: more of these small particles lead to a greater risk. The concentration of fasting small LDL particles was determined using the Nuclear Magnetic Resonance (NMR) methodology.
    Time Frame Baseline and Week 24

    Outcome Measure Data

    Analysis Population Description
    Intent to treat (ITT) population. All randomized patients who received any part of an infusion of study medication are included. Patients who received an incorrect therapy from that intended are summarized in the group according to the intended randomized treatment group. Last observation carried forward (LOCF) imputation was used.
    Arm/Group Title TCZ + MTX Placebo + MTX
    Arm/Group Description Participants received 8 mg/kg tocilizumab (TCZ) by intravenous infusion (IV) every 4 weeks plus 7.5-25 mg of methotrexate (MTX) weekly for the first 24 weeks. Participants received placebo intravenous infusion (IV) every 4 weeks plus methotrexate (MTX) 7.5-25 mg (oral or parenteral) weekly for the first 24 weeks.
    Measure Participants 69 63
    Baseline (n=63, 59)
    737.79
    (467.097)
    792.78
    (392.051)
    Week 24 (n=69, 63)
    792.78
    (605.485)
    801.78
    (398.910)
    Change from Baseline at Week 24 (n=63, 59)
    39.03
    (367.786)
    32.41
    (250.576)
    3. Secondary Outcome
    Title Change From Baseline to Week 24 in Aortic Pulse Wave Velocity (PWV)
    Description Aortic (central) arterial stiffness was assessed with Pulse Wave Analysis (PWA) of the radial artery and carotid-femoral PWV using applanation tonometry after the patient had rested in a supine position for at least 10 minutes.
    Time Frame Baseline and Week 24

    Outcome Measure Data

    Analysis Population Description
    Intent to treat (ITT) population. All randomized patients who received any part of an infusion of study medication are included. Patients who received an incorrect therapy from that intended are summarized in the group according to the intended randomized treatment group. Last observation carried forward (LOCF) imputation was used.
    Arm/Group Title TCZ + MTX Placebo + MTX
    Arm/Group Description Participants received 8 mg/kg tocilizumab (TCZ) by intravenous infusion (IV) every 4 weeks plus 7.5-25 mg of methotrexate (MTX) weekly for the first 24 weeks. Participants received placebo intravenous infusion (IV) every 4 weeks plus methotrexate (MTX) 7.5-25 mg (oral or parenteral) weekly for the first 24 weeks.
    Measure Participants 69 63
    Baseline (n=69, 59)
    8.97
    (1.970)
    9.01
    (2.519)
    Week 24 (n=69, 62)
    8.98
    (2.337)
    8.85
    (2.014)
    Change from Baseline at Week 24 (n=69, 59)
    0.01
    (1.946)
    -0.20
    (1.792)
    4. Secondary Outcome
    Title Number of Participants Experiencing Adverse Events (AEs)
    Description A severe AE is an event in which the intensity of the event results in an inability to work or perform normal daily activity. A Serious AE is fatal, life-threatening, requires in-patient hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant or requires intervention to prevent one of the above outcomes. AEs of special interest include infection, gastrointestinal, infusion reaction (occurring during or within 24 hours of infusion), hepatic disorder, myocardial infarction and stroke.
    Time Frame Up to Week 24

    Outcome Measure Data

    Analysis Population Description
    The safety population includes all patients who received any part of an infusion of study drug and who provided at least one assessment of safety. Randomized patients who received the incorrect therapy from that intended are summarized in the group according to the therapy actually received.
    Arm/Group Title TCZ + MTX Placebo + MTX
    Arm/Group Description Participants received 8 mg/kg tocilizumab (TCZ) by intravenous infusion (IV) every 4 weeks plus 7.5-25 mg of methotrexate (MTX) weekly for the first 24 weeks. Participants received placebo intravenous infusion (IV) every 4 weeks plus methotrexate (MTX) 7.5-25 mg (oral or parenteral) weekly for the first 24 weeks.
    Measure Participants 70 62
    Any AE
    59
    85.5%
    45
    71.4%
    Severe AE
    7
    10.1%
    4
    6.3%
    Serious AE
    3
    4.3%
    2
    3.2%
    Deaths
    0
    0%
    0
    0%
    Withdrawals due to AE
    2
    2.9%
    1
    1.6%
    Pregnancy
    0
    0%
    0
    0%
    Infection AEs
    42
    60.9%
    17
    27%
    Gastrointestinal AEs
    22
    31.9%
    10
    15.9%
    Infusion reaction AEs
    12
    17.4%
    7
    11.1%
    Hepatic disorder AEs
    0
    0%
    0
    0%
    Myocardial infarction
    0
    0%
    0
    0%
    Stroke
    0
    0%
    0
    0%
    5. Primary Outcome
    Title Change From Baseline to Week 12 in Aortic Pulse Wave Velocity (PWV)
    Description Aortic (central) arterial stiffness was assessed with Pulse Wave Analysis (PWA) of the radial artery and carotid-femoral PWV using applanation tonometry after the patient had rested in a supine position for at least 10 minutes.
    Time Frame Baseline and Week 12

    Outcome Measure Data

    Analysis Population Description
    Intent to treat (ITT) population. All randomized patients who received any part of an infusion of study medication are included. Patients who received an incorrect therapy from that intended are summarized in the group according to the intended randomized treatment group. Last observation carried forward (LOCF) imputation was used.
    Arm/Group Title TCZ + MTX Placebo + MTX
    Arm/Group Description Participants received 8 mg/kg tocilizumab (TCZ) by intravenous infusion (IV) every 4 weeks plus 7.5-25 mg of methotrexate (MTX) weekly for the first 24 weeks. Participants received placebo intravenous infusion (IV) every 4 weeks plus methotrexate (MTX) 7.5-25 mg (oral or parenteral) weekly for the first 24 weeks.
    Measure Participants 69 63
    Baseline (n=69, 59)
    8.97
    (1.970)
    9.01
    (2.519)
    Week 12 (n=69, 62)
    8.94
    (2.510)
    8.39
    (1.836)
    Change from Baseline at Week 12 (n=69, 59)
    -0.03
    (1.970)
    -0.68
    (1.741)

    Adverse Events

    Time Frame
    Adverse Event Reporting Description
    Arm/Group Title Part 1: TCZ + MTX Part 1: Placebo + MTX All TCZ + MTX
    Arm/Group Description During Part 1 of the study participants in this group received 8 mg/kg tocilizumab (TCZ) by intravenous infusion (IV) every 4 weeks plus methotrexate (MTX) 7.5-25 mg (oral or parenteral) weekly for 24 weeks. During Part 1 of the study participants in this group received placebo intravenous infusion (IV) every 4 weeks plus methotrexate (MTX) 7.5-25 mg (oral or parenteral) weekly for 24 weeks. Includes patients who received at least one dose of active tocilizumab (TCZ) regardless of when they received it during the study and whether it was double-blind (Part 1) or open-label (Part 2). Participants received 8 mg/kg TCZ by intravenous infusion (IV) every 4 weeks plus methotrexate (MTX) 7.5-25 mg (oral or parenteral) weekly.
    All Cause Mortality
    Part 1: TCZ + MTX Part 1: Placebo + MTX All TCZ + MTX
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    Part 1: TCZ + MTX Part 1: Placebo + MTX All TCZ + MTX
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 3/70 (4.3%) 2/62 (3.2%) 30/130 (23.1%)
    Blood and lymphatic system disorders
    Lymphadenitis 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Lymphadenopathy 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Cardiac disorders
    Coronary artery disease 0/70 (0%) 0/62 (0%) 4/130 (3.1%)
    Stress cardiomyopathy 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Ear and labyrinth disorders
    Vertigo 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Endocrine disorders
    Goitre 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Gastrointestinal disorders
    Constipation 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Gastric ulcer 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Small intestinal obstruction 0/70 (0%) 1/62 (1.6%) 0/130 (0%)
    General disorders
    Non-cardiac chest pain 1/70 (1.4%) 0/62 (0%) 2/130 (1.5%)
    Chest pain 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Hepatobiliary disorders
    Bile duct stone 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Cholelithiasis 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Hepatic artery aneurysm 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Immune system disorders
    Drug hypersensitivity 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Sarcoidosis 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Infections and infestations
    Arthritis bacterial 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Bronchitis 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Device related infection 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Pneumonia 0/70 (0%) 1/62 (1.6%) 1/130 (0.8%)
    Pneumonia streptococcal 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Puncture site abscess 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Staphylococcal abscess 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Staphylococcal sepsis 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Injury, poisoning and procedural complications
    Femur fracture 1/70 (1.4%) 0/62 (0%) 1/130 (0.8%)
    Limb injury 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Multiple drug overdose 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Subdural haematoma 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Wound dehiscence 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Musculoskeletal chest pain 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Non-small cell lung cancer metastatic 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Psychiatric disorders
    Bipolar disorder 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Suicidal ideation 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Renal and urinary disorders
    Urinary incontinence 1/70 (1.4%) 0/62 (0%) 1/130 (0.8%)
    Reproductive system and breast disorders
    Vaginal haemorrhage 1/70 (1.4%) 0/62 (0%) 1/130 (0.8%)
    Respiratory, thoracic and mediastinal disorders
    Hydropneumothorax 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Pneumonitis 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Respiratory failure 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Vascular disorders
    Aortic stenosis 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Shock haemorrhagic 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Other (Not Including Serious) Adverse Events
    Part 1: TCZ + MTX Part 1: Placebo + MTX All TCZ + MTX
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 59/70 (84.3%) 44/62 (71%) 124/130 (95.4%)
    Blood and lymphatic system disorders
    Leukopenia 0/70 (0%) 0/62 (0%) 6/130 (4.6%)
    Anaemia 1/70 (1.4%) 0/62 (0%) 3/130 (2.3%)
    Neutropenia 1/70 (1.4%) 0/62 (0%) 3/130 (2.3%)
    Lymphadenopathy 1/70 (1.4%) 0/62 (0%) 2/130 (1.5%)
    Thrombocytopenia 0/70 (0%) 0/62 (0%) 2/130 (1.5%)
    Lymph node calcification 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Splenic lesion 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Splenomegaly 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Cardiac disorders
    Palpitations 3/70 (4.3%) 0/62 (0%) 4/130 (3.1%)
    Coronary artery disease 0/70 (0%) 0/62 (0%) 2/130 (1.5%)
    Supraventricular extrasystoles 1/70 (1.4%) 0/62 (0%) 2/130 (1.5%)
    Atrial fibrillation 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Pericardial effusion 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Ear and labyrinth disorders
    Vertigo 0/70 (0%) 1/62 (1.6%) 2/130 (1.5%)
    Ear congestion 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Ear pain 2/70 (2.9%) 0/62 (0%) 1/130 (0.8%)
    Middle ear inflammation 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Tinnitus 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Endocrine disorders
    Hypothyroidism 0/70 (0%) 0/62 (0%) 2/130 (1.5%)
    Eye disorders
    Cataract 0/70 (0%) 0/62 (0%) 3/130 (2.3%)
    Dry eye 1/70 (1.4%) 0/62 (0%) 3/130 (2.3%)
    Ocular hyperaemia 0/70 (0%) 0/62 (0%) 2/130 (1.5%)
    Asthenopia 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Conjunctival haemorrhage 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Conjunctivitis 1/70 (1.4%) 1/62 (1.6%) 1/130 (0.8%)
    Conjunctivitis allergic 1/70 (1.4%) 0/62 (0%) 1/130 (0.8%)
    Eye irritation 0/70 (0%) 1/62 (1.6%) 1/130 (0.8%)
    Eye swelling 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Eyelid cyst 1/70 (1.4%) 0/62 (0%) 1/130 (0.8%)
    Glaucoma 1/70 (1.4%) 0/62 (0%) 1/130 (0.8%)
    Macular oedema 1/70 (1.4%) 0/62 (0%) 1/130 (0.8%)
    Posterior capsule opacification 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Retinal tear 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Ulcerative keratitis 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Visual impairment 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Vitreous floaters 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Myodesopsia 1/70 (1.4%) 0/62 (0%) 0/130 (0%)
    Gastrointestinal disorders
    Diarrhoea 9/70 (12.9%) 2/62 (3.2%) 22/130 (16.9%)
    Nausea 1/70 (1.4%) 2/62 (3.2%) 12/130 (9.2%)
    Vomiting 4/70 (5.7%) 1/62 (1.6%) 10/130 (7.7%)
    Gastritis 5/70 (7.1%) 0/62 (0%) 8/130 (6.2%)
    Abdominal pain 2/70 (2.9%) 2/62 (3.2%) 7/130 (5.4%)
    Abdominal pain upper 1/70 (1.4%) 0/62 (0%) 7/130 (5.4%)
    Gastrooesophageal reflux disease 0/70 (0%) 1/62 (1.6%) 7/130 (5.4%)
    Dyspepsia 1/70 (1.4%) 0/62 (0%) 6/130 (4.6%)
    Abdominal discomfort 1/70 (1.4%) 0/62 (0%) 5/130 (3.8%)
    Constipation 1/70 (1.4%) 0/62 (0%) 5/130 (3.8%)
    Mouth ulceration 4/70 (5.7%) 0/62 (0%) 5/130 (3.8%)
    Aphthous stomatitis 1/70 (1.4%) 0/62 (0%) 3/130 (2.3%)
    Dry mouth 0/70 (0%) 0/62 (0%) 3/130 (2.3%)
    Hiatus hernia 0/70 (0%) 1/62 (1.6%) 3/130 (2.3%)
    Cheilitis 1/70 (1.4%) 0/62 (0%) 2/130 (1.5%)
    Dental caries 0/70 (0%) 0/62 (0%) 2/130 (1.5%)
    Flatulence 0/70 (0%) 0/62 (0%) 2/130 (1.5%)
    Abdominal distension 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Abdominal pain lower 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Anal fistula 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Barrett's Oesophagus 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Duodenitis 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Faeces discoloured 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Gastrointestinal ulcer 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Gingivitis 1/70 (1.4%) 0/62 (0%) 1/130 (0.8%)
    Haematochezia 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Haemorrhoids 0/70 (0%) 1/62 (1.6%) 1/130 (0.8%)
    Irritable bowel syndrome 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Lip swelling 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Oesophageal irritation 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Oesophagitis 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Parotid gland enlargement 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Peptic ulcer 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Periodontitis 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Rectal haemorrhage 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Stomach discomfort 1/70 (1.4%) 0/62 (0%) 0/130 (0%)
    General disorders
    Fatigue 2/70 (2.9%) 7/62 (11.3%) 11/130 (8.5%)
    Oedema peripheral 1/70 (1.4%) 0/62 (0%) 8/130 (6.2%)
    Chest pain 0/70 (0%) 0/62 (0%) 4/130 (3.1%)
    Pyrexia 1/70 (1.4%) 0/62 (0%) 4/130 (3.1%)
    Influenza like illness 0/70 (0%) 1/62 (1.6%) 3/130 (2.3%)
    Cyst 1/70 (1.4%) 0/62 (0%) 2/130 (1.5%)
    Infusion related reaction 1/70 (1.4%) 0/62 (0%) 2/130 (1.5%)
    Non-cardiac chest pain 2/70 (2.9%) 0/62 (0%) 2/130 (1.5%)
    Chills 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Feeling hot 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Impaired healing 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Infusion site rash 1/70 (1.4%) 0/62 (0%) 1/130 (0.8%)
    Metaplasia 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Oedema 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Pain 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Hepatobiliary disorders
    Hepatic steatosis 0/70 (0%) 0/62 (0%) 2/130 (1.5%)
    Cholelithiasis 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Hepatic lesion 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Hyperbilirubinaemia 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Bile duct stone 0/70 (0%) 1/62 (1.6%) 0/130 (0%)
    Immune system disorders
    Seasonal allergy 1/70 (1.4%) 1/62 (1.6%) 5/130 (3.8%)
    Infections and infestations
    Upper respiratory tract infection 8/70 (11.4%) 6/62 (9.7%) 39/130 (30%)
    Urinary tract infection 7/70 (10%) 2/62 (3.2%) 25/130 (19.2%)
    Bronchitis 3/70 (4.3%) 2/62 (3.2%) 23/130 (17.7%)
    Sinusitis 4/70 (5.7%) 1/62 (1.6%) 19/130 (14.6%)
    Nasopharyngitis 5/70 (7.1%) 0/62 (0%) 16/130 (12.3%)
    Gastroenteritis 1/70 (1.4%) 2/62 (3.2%) 9/130 (6.9%)
    Pneumonia 0/70 (0%) 0/62 (0%) 7/130 (5.4%)
    Cellulitis 1/70 (1.4%) 0/62 (0%) 6/130 (4.6%)
    Gastroenteritis viral 1/70 (1.4%) 0/62 (0%) 6/130 (4.6%)
    Lower respiratory tract infection 2/70 (2.9%) 0/62 (0%) 6/130 (4.6%)
    Oral herpes 1/70 (1.4%) 0/62 (0%) 6/130 (4.6%)
    Otitis media 0/70 (0%) 0/62 (0%) 5/130 (3.8%)
    Influenza 1/70 (1.4%) 2/62 (3.2%) 4/130 (3.1%)
    Cystitis 2/70 (2.9%) 0/62 (0%) 3/130 (2.3%)
    Eye infection 0/70 (0%) 0/62 (0%) 3/130 (2.3%)
    Laryngitis 0/70 (0%) 0/62 (0%) 3/130 (2.3%)
    Localised infection 1/70 (1.4%) 1/62 (1.6%) 3/130 (2.3%)
    Paronychia 1/70 (1.4%) 0/62 (0%) 3/130 (2.3%)
    Ear infection 1/70 (1.4%) 0/62 (0%) 2/130 (1.5%)
    Folliculitis 1/70 (1.4%) 0/62 (0%) 2/130 (1.5%)
    Furuncle 1/70 (1.4%) 0/62 (0%) 2/130 (1.5%)
    Herpes zoster 0/70 (0%) 0/62 (0%) 2/130 (1.5%)
    Infected bites 1/70 (1.4%) 0/62 (0%) 2/130 (1.5%)
    Labyrinthitis 1/70 (1.4%) 0/62 (0%) 2/130 (1.5%)
    Tinea pedis 0/70 (0%) 1/62 (1.6%) 2/130 (1.5%)
    Tooth abscess 0/70 (0%) 1/62 (1.6%) 2/130 (1.5%)
    Viral infection 0/70 (0%) 1/62 (1.6%) 2/130 (1.5%)
    Alveolar osteitis 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Blister infected 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Bronchiectasis 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Burn infection 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Clostridial infection 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Clostridium difficile colitis 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Fungal infection 0/70 (0%) 1/62 (1.6%) 1/130 (0.8%)
    Fungal skin infection 1/70 (1.4%) 0/62 (0%) 1/130 (0.8%)
    Gastrointestinal infection 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Gingival infection 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Helicobacter gastritis 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Helicobacter infection 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Hordeolum 1/70 (1.4%) 1/62 (1.6%) 1/130 (0.8%)
    Impetigo 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Infected cyst 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Kidney infection 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Nail infection 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Onychomycosis 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Oral candidiasis 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Osteomyelitis 1/70 (1.4%) 0/62 (0%) 1/130 (0.8%)
    Papilloma viral infection 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Pharyngitis 1/70 (1.4%) 0/62 (0%) 1/130 (0.8%)
    Postoperative wound infection 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Respiratory tract infection 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Rhinitis 1/70 (1.4%) 0/62 (0%) 1/130 (0.8%)
    Sinobronchitis 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Staphylococcal infection 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Tinea cruris 1/70 (1.4%) 0/62 (0%) 1/130 (0.8%)
    Tooth infection 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Vulvovaginal candidiasis 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Vulvovaginal mycotic infection 1/70 (1.4%) 0/62 (0%) 1/130 (0.8%)
    Wound infection 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Genital herpes 1/70 (1.4%) 0/62 (0%) 0/130 (0%)
    Injury, poisoning and procedural complications
    Skin laceration 2/70 (2.9%) 0/62 (0%) 8/130 (6.2%)
    Contusion 1/70 (1.4%) 1/62 (1.6%) 6/130 (4.6%)
    Fall 1/70 (1.4%) 2/62 (3.2%) 6/130 (4.6%)
    Foot fracture 0/70 (0%) 0/62 (0%) 4/130 (3.1%)
    Joint sprain 0/70 (0%) 1/62 (1.6%) 3/130 (2.3%)
    Meniscus lesion 1/70 (1.4%) 0/62 (0%) 3/130 (2.3%)
    Arthropod bite 1/70 (1.4%) 0/62 (0%) 2/130 (1.5%)
    Limb injury 0/70 (0%) 0/62 (0%) 2/130 (1.5%)
    Thermal burn 0/70 (0%) 0/62 (0%) 2/130 (1.5%)
    Anaemia postoperative 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Animal scratch 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Avulsion fracture 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Excoriation 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Hand fracture 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Incision site haematoma 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Joint injury 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Laceration 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Ligament sprain 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Muscle injury 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Muscle strain 0/70 (0%) 2/62 (3.2%) 1/130 (0.8%)
    Post procedural complication 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Procedural headache 1/70 (1.4%) 0/62 (0%) 1/130 (0.8%)
    Rib fracture 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Spinal compression fracture 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Wrist fracture 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Investigations
    Hepatic enzyme increased 1/70 (1.4%) 1/62 (1.6%) 6/130 (4.6%)
    Alanine aminotransferase increased 0/70 (0%) 0/62 (0%) 4/130 (3.1%)
    Cardiac murmur 0/70 (0%) 0/62 (0%) 3/130 (2.3%)
    Transaminases increased 1/70 (1.4%) 0/62 (0%) 3/130 (2.3%)
    Weight increased 0/70 (0%) 0/62 (0%) 3/130 (2.3%)
    Aspartate amniotransferase increased 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Blood cholesterol increased 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Blood thyroid stimulating hormone decreased 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Blood triglycerides increased 1/70 (1.4%) 0/62 (0%) 1/130 (0.8%)
    Haemoglobin decreased 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Helicobacter test positive 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Neutrophil count decreased 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Serum ferritin decreased 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    White blood cell count decreased 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Band neutrophil count increased 0/70 (0%) 1/62 (1.6%) 0/130 (0%)
    Helicobacter pylori identification test positive 1/70 (1.4%) 0/62 (0%) 0/130 (0%)
    Occult blood 0/70 (0%) 1/62 (1.6%) 0/130 (0%)
    Blood pressure increased 1/70 (1.4%) 0/62 (0%) 1/130 (0.8%)
    Metabolism and nutrition disorders
    Dyslipidaemia 0/70 (0%) 0/62 (0%) 5/130 (3.8%)
    Hypercholesterolaemia 1/70 (1.4%) 0/62 (0%) 4/130 (3.1%)
    Hyperlipidaemia 1/70 (1.4%) 1/62 (1.6%) 3/130 (2.3%)
    Decreased appetite 0/70 (0%) 0/62 (0%) 2/130 (1.5%)
    Vitamin D deficiency 0/70 (0%) 0/62 (0%) 2/130 (1.5%)
    Hyperglycaemia 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Hyperuricaemia 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Hypokalaemia 0/70 (0%) 1/62 (1.6%) 0/130 (0%)
    Musculoskeletal and connective tissue disorders
    Rheumatoid arthritis 4/70 (5.7%) 6/62 (9.7%) 16/130 (12.3%)
    Back pain 1/70 (1.4%) 2/62 (3.2%) 13/130 (10%)
    Arthralgia 1/70 (1.4%) 0/62 (0%) 11/130 (8.5%)
    Bursitis 2/70 (2.9%) 0/62 (0%) 9/130 (6.9%)
    Muscle spasms 1/70 (1.4%) 1/62 (1.6%) 8/130 (6.2%)
    Intervertebral disc degeneration 0/70 (0%) 0/62 (0%) 6/130 (4.6%)
    Osteoarthritis 0/70 (0%) 0/62 (0%) 5/130 (3.8%)
    Osteopenia 0/70 (0%) 0/62 (0%) 5/130 (3.8%)
    Musculoskeletal chest pain 1/70 (1.4%) 1/62 (1.6%) 4/130 (3.1%)
    Rheumatoid nodule 2/70 (2.9%) 1/62 (1.6%) 4/130 (3.1%)
    Tendonitis 3/70 (4.3%) 1/62 (1.6%) 4/130 (3.1%)
    Musculoskeletal pain 0/70 (0%) 1/62 (1.6%) 3/130 (2.3%)
    Myalgia 0/70 (0%) 0/62 (0%) 3/130 (2.3%)
    Pain in extremity 0/70 (0%) 1/62 (1.6%) 3/130 (2.3%)
    Rotator cuff syndrome 0/70 (0%) 0/62 (0%) 3/130 (2.3%)
    Fibromyalgia 0/70 (0%) 1/62 (1.6%) 2/130 (1.5%)
    Foot deformity 0/70 (0%) 0/62 (0%) 2/130 (1.5%)
    Joint swelling 0/70 (0%) 0/62 (0%) 2/130 (1.5%)
    Periarthritis 1/70 (1.4%) 0/62 (0%) 2/130 (1.5%)
    Spinal osteoarthritis 0/70 (0%) 0/62 (0%) 2/130 (1.5%)
    Arthritis 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Bunion 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Costochondritis 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Exostosis 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Flank pain 1/70 (1.4%) 0/62 (0%) 1/130 (0.8%)
    Joint effusion 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Ligament disorder 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Muscle twitching 1/70 (1.4%) 0/62 (0%) 1/130 (0.8%)
    Musculoskeletal stiffness 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Osteoporosis 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Plantar fascitis 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Tendon disorder 1/70 (1.4%) 0/62 (0%) 1/130 (0.8%)
    Tendon pain 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Trigger finger 0/70 (0%) 1/62 (1.6%) 1/130 (0.8%)
    Vertebral foraminal stenosis 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Intervertebral disc protrusion 0/70 (0%) 1/62 (1.6%) 0/130 (0%)
    Neck pain 0/70 (0%) 1/62 (1.6%) 0/130 (0%)
    Pain in jaw 0/70 (0%) 1/62 (1.6%) 0/130 (0%)
    Spinal column stenosis 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Melanocytic naevus 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Skin papilloma 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Squamous cell carcinoma of skin 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Lung neoplasm 0/70 (0%) 1/62 (1.6%) 0/130 (0%)
    Nervous system disorders
    Headache 4/70 (5.7%) 0/62 (0%) 15/130 (11.5%)
    Dizziness 2/70 (2.9%) 1/62 (1.6%) 9/130 (6.9%)
    Amnesia 1/70 (1.4%) 0/62 (0%) 2/130 (1.5%)
    Migraine 1/70 (1.4%) 0/62 (0%) 2/130 (1.5%)
    Neuropathy peripheral 0/70 (0%) 0/62 (0%) 2/130 (1.5%)
    Aphasia 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Carotid artery disease 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Carotid artery stenosis 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Carpal tunnel syndrome 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Cauda equina syndrome 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Hypoaesthesia 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Lethargy 1/70 (1.4%) 0/62 (0%) 1/130 (0.8%)
    Nerve compression 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Tarsal tunnel syndrome 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Tremor 1/70 (1.4%) 0/62 (0%) 1/130 (0.8%)
    Lumbar radiculopathy 0/70 (0%) 1/62 (1.6%) 0/130 (0%)
    Sinus headache 0/70 (0%) 1/62 (1.6%) 0/130 (0%)
    Psychiatric disorders
    Insomnia 1/70 (1.4%) 0/62 (0%) 9/130 (6.9%)
    Depression 0/70 (0%) 4/62 (6.5%) 5/130 (3.8%)
    Anxiety 0/70 (0%) 1/62 (1.6%) 2/130 (1.5%)
    Confusional state 1/70 (1.4%) 0/62 (0%) 1/130 (0.8%)
    Libido increased 1/70 (1.4%) 0/62 (0%) 1/130 (0.8%)
    Restlessness 1/70 (1.4%) 0/62 (0%) 1/130 (0.8%)
    Renal and urinary disorders
    Nephrolithiasis 1/70 (1.4%) 1/62 (1.6%) 3/130 (2.3%)
    Dysuria 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Haematuria 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Pollakiuria 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Renal artery stenosis 0/70 (0%) 1/62 (1.6%) 1/130 (0.8%)
    Renal colic 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Renal cyst 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Reproductive system and breast disorders
    Prostatitis 0/70 (0%) 0/62 (0%) 2/130 (1.5%)
    Benign prostatic hyperplasia 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Breast calcifications 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Breast cyst 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Breast tenderness 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Genital ulceration 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Menstrual disorder 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Pelvic pain 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Menopausal symptoms 0/70 (0%) 1/62 (1.6%) 0/130 (0%)
    Respiratory, thoracic and mediastinal disorders
    Oropharnygeal pain 6/70 (8.6%) 1/62 (1.6%) 17/130 (13.1%)
    Cough 2/70 (2.9%) 1/62 (1.6%) 11/130 (8.5%)
    Epistaxis 0/70 (0%) 2/62 (3.2%) 4/130 (3.1%)
    Asthma 0/70 (0%) 0/62 (0%) 3/130 (2.3%)
    Dyspnoea 0/70 (0%) 0/62 (0%) 3/130 (2.3%)
    Productive cough 1/70 (1.4%) 0/62 (0%) 3/130 (2.3%)
    Chronic obstructive pulmonary disease 0/70 (0%) 0/62 (0%) 2/130 (1.5%)
    Dysphonia 0/70 (0%) 0/62 (0%) 2/130 (1.5%)
    Nasal congestion 1/70 (1.4%) 0/62 (0%) 2/130 (1.5%)
    Respiratory tract congestion 1/70 (1.4%) 0/62 (0%) 2/130 (1.5%)
    Upper respiratory tract congestion 2/70 (2.9%) 0/62 (0%) 2/130 (1.5%)
    Nasal dryness 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Nasal polyps 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Pleural fibrosis 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Pleurisy 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Pulmonary fibrosis 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Pulmonary oedema 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Rhinitis allergic 0/70 (0%) 1/62 (1.6%) 1/130 (0.8%)
    Rhinorrhoea 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Sinus congestion 1/70 (1.4%) 0/62 (0%) 1/130 (0.8%)
    Sneezing 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Throat irritation 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Upper airway obstruction 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Upper-airway cough syndrome 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Wheezing 1/70 (1.4%) 0/62 (0%) 1/130 (0.8%)
    Obstructive airways disorder 1/70 (1.4%) 0/62 (0%) 0/130 (0%)
    Polymenorrhoea 1/70 (1.4%) 0/62 (0%) 1/130 (0.8%)
    Uterine synechiae 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Skin and subcutaneous tissue disorders
    Rash 4/70 (5.7%) 2/62 (3.2%) 14/130 (10.8%)
    Dermatitis contact 1/70 (1.4%) 1/62 (1.6%) 7/130 (5.4%)
    Skin ulcer 0/70 (0%) 0/62 (0%) 4/130 (3.1%)
    Increased tendency to bruise 1/70 (1.4%) 1/62 (1.6%) 3/130 (2.3%)
    Pruritis 1/70 (1.4%) 1/62 (1.6%) 3/130 (2.3%)
    Alopecia 2/70 (2.9%) 0/62 (0%) 2/130 (1.5%)
    Dermal cyst 0/70 (0%) 0/62 (0%) 2/130 (1.5%)
    Dermatitis 1/70 (1.4%) 0/62 (0%) 2/130 (1.5%)
    Eczema 0/70 (0%) 0/62 (0%) 2/130 (1.5%)
    Ingrowing nail 0/70 (0%) 0/62 (0%) 2/130 (1.5%)
    Psoriasis 1/70 (1.4%) 0/62 (0%) 2/130 (1.5%)
    Rash macular 1/70 (1.4%) 0/62 (0%) 2/130 (1.5%)
    Blister 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Drug eruption 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Dry skin 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Eczema nummular 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Erythema 0/70 (0%) 1/62 (1.6%) 1/130 (0.8%)
    Granuloma annulare 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Hyperkeratosis 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Night sweats 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Photosensitivity reaction 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Purpura 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Pustular psoriasis 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Rash erythematous 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Rash pruritic 0/70 (0%) 1/62 (1.6%) 1/130 (0.8%)
    Rosacea 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Skin lesion 0/70 (0%) 1/62 (1.6%) 1/130 (0.8%)
    Skin plaque 1/70 (1.4%) 0/62 (0%) 1/130 (0.8%)
    Urticaria 1/70 (1.4%) 0/62 (0%) 1/130 (0.8%)
    Seborrhoeic dermatitis 0/70 (0%) 1/62 (1.6%) 0/130 (0%)
    Surgical and medical procedures
    Cataract operation 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Hip arthroplasty 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Mole excision 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Retinal operation 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Rhinoplasty 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Tooth extraction 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Vascular disorders
    Hypertension 0/70 (0%) 1/62 (1.6%) 12/130 (9.2%)
    Aortic aneurysm 0/70 (0%) 0/62 (0%) 3/130 (2.3%)
    Arteriosclerosis 0/70 (0%) 1/62 (1.6%) 2/130 (1.5%)
    Accelerated hypertension 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Flushing 1/70 (1.4%) 1/62 (1.6%) 1/130 (0.8%)
    Hot flush 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Hypotension 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Peripheral artery aneurysm 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Peripheral vascular disorder 0/70 (0%) 0/62 (0%) 1/130 (0.8%)
    Iliac artery stenosis 0/70 (0%) 1/62 (1.6%) 0/130 (0%)
    Phlebitis 0/70 (0%) 1/62 (1.6%) 0/130 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

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

    The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.

    Results Point of Contact

    Name/Title Medical Communications
    Organization Hoffman-LaRoche
    Phone 800-821-8590
    Email
    Responsible Party:
    Hoffmann-La Roche
    ClinicalTrials.gov Identifier:
    NCT00535782
    Other Study ID Numbers:
    • WA19923
    • 2007-001114-17
    First Posted:
    Sep 26, 2007
    Last Update Posted:
    Jul 26, 2017
    Last Verified:
    Jun 1, 2017