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A Study of Tocilizumab in Comparison to Etanercept in Participants With Rheumatoid Arthritis and Cardiovascular Disease Risk Factors

Sponsor
Hoffmann-La Roche (Industry)
Overall Status
Completed
CT.gov ID
NCT01331837
Collaborator
(none)
3,080
Enrollment
428
Locations
2
Arms
55.8
Actual Duration (Months)
7.2
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This randomized, open-label, parallel-group, multicenter study will evaluate the rate of cardiovascular events with tocilizumab in comparison to etanercept in participants with rheumatoid arthritis (RA). Participants will be randomized to receive intravenous (IV) 8 milligrams per kilogram (mg/kg) tocilizumab every 4 weeks or subcutaneous 50 milligrams (mg) etanercept weekly, with or without non-biologic disease-modifying anti-rheumatic drug (DMARD).

Condition or Disease Intervention/Treatment Phase
Phase 4

Study Design

Study Type:
Interventional
Actual Enrollment :
3080 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Clinical Outcomes Study to Evaluate the Effects of IL-6 Receptor Blockade With Tocilizumab (TCZ) in Comparison With Etanercept (ETA) on the Rate of Cardiovascular Events in Patients With Moderate to Severe Rheumatoid Arthritis (RA)
Actual Study Start Date :
Aug 2, 2011
Actual Primary Completion Date :
Mar 25, 2016
Actual Study Completion Date :
Mar 25, 2016

Arms and Interventions

Arm Intervention/Treatment
Active Comparator: Etanercept

Drug: Etanercept
Participants will receive 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
Experimental: Tocilizumab

Drug: Tocilizumab
Participants will receive 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years.
Other Names:
  • Actemra

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Time to First Cardiovascular (CV) Events Adjudication Committee (EAC) (CV-EAC) Adjudicated Event [From baseline up to 4.9 years]

      Prospective comparison of time to first occurrence of any component of the composite of CV death (including events adjudicated as 'Undetermined Cause of Death'), non-fatal myocardial infarction, or non-fatal stroke.

    2. Percentage of Patients Reporting a Cardiovascular (CV) Events Adjudication Committee (EAC) (CV-EAC) Adjudicated Event [From baseline up to 4.9 years]

      Percentage of patients reporting any component of the composite of CV death (including events adjudicated as 'Undetermined Cause of Death'), non-fatal myocardial infarction, or non-fatal stroke

    3. Time to First CV-EAC Adjudicated Event - Sensitivity Analysis [From Baseline up to 4.9 years]

      Prospective comparison of time to first occurrence of any component of the composite of CV death (including events adjudicated as 'Undetermined Cause of Death'), non-fatal myocardial infarction, or non-fatal stroke - Sensitivity Analysis

    4. Percentage of Patients With a CV-EAC Adjudicated Event - Sensitivity Analysis [From Baseline up to 4.9 years]

      Percentage of patients with any component of the composite of CV death (including events adjudicated as 'Undetermined Cause of Death'), non-fatal myocardial infarction, or non-fatal stroke - Sensitivity Analysis

    5. Time to First CV-EAC Adjudicated Event Excluding Undetermined Cause of Death - Sensitivity Analysis [From baseline up to 4.9 years]

      Prospective comparison of time to first occurrence of any component of the composite of CV death (excluding events adjudicated as 'Undetermined Cause of Death'), non-fatal myocardial infarction, or non-fatal stroke - Sensitivity Analyses

    6. Percentage of Patients With a CV-EAC Adjudicated Event Excluding Undetermined Cause of Death - Sensitivity Analysis [From baseline up to 4.9 years]

      Percentage of patients with any component of the composite of CV death (excluding events adjudicated as 'Undetermined Cause of Death'), non-fatal myocardial infarction, or non-fatal stroke - Sensitivity Analyses

    7. Time to First CV-EAC Adjudicated Event Before Last Direct Contact Date [From Baseline up to 4.9 years]

      Prospective comparison of time to first occurrence of any component of the composite of CV death (including events adjudicated as 'Undetermined Cause of Death'), non-fatal myocardial infarction, or non-fatal stroke before last direct contact date (i.e., latest date of visit, IVRS call, or site call).

    8. Percentage of Participants With a CV-EAC Adjudicated Event Before Last Direct Contact Date [From Baseline up to 4.9 years]

      Percentage of participants with any component of the composite of CV death (including events adjudicated as 'Undetermined Cause of Death'), non-fatal myocardial infarction, or non-fatal stroke before last direct contact date (i.e., latest date of visit, IVRS call, or site call).

    Secondary Outcome Measures

    1. The Time to First Occurrence of an Expanded CV Composite Endpoint [From baseline up to 4.9 years]

      Prospective comparison of the time to first ccurrence of the expanded composite endpoint. The expanded composite endpoint is defined as the CV composite of the primary endpoint with the addition of non-elective coronary revascularization procedures and hospitalization for unstable angina.

    2. Percentages of Participants With an Expanded CV Composite Endpoint [From baseline up to 4.9 years]

      Percentages of participants with the expanded CV composite endpoint. The expanded composite endpoint is defined as the CV composite of the primary endpoint with the addition of non-elective coronary revascularization procedures and hospitalization for unstable angina.

    3. Time to First Occurrence of Individual Component of Primary Endpoint: Non-fatal Myocardial Infarction [From baseline up to 4.9 years]

      Prospective comparison of time to first occurrence of Individual component of primary endpoint: non-fatal Myocardial Infarction

    4. Percentage of Patients With Individual Component of Primary Endpoint: Non-fatal Myocardial Infarction [From baseline up to 4.9 years]

      Percentage of patients reporting Individual component of primary endpoint: non-fatal Myocardial Infarction

    5. Time to First Occurrence of Individual Component of Primary Endpoint: Cardiovascular Death [From baseline up to 4.9 years]

      Prospective comparison of time to first occurrence of Individual component of primary endpoint: cardiovascular death

    6. Percentage of Patients With Individual Component of Primary Endpoint: Cardiovascular Death [From baseline up to 4.9 years]

      Percentage of patients reporting Individual component of primary endpoint: cardiovascular death

    7. Time to First Occurrence of Individual Component of Primary Endpoint: Non-fatal Stroke [From baseline up to 4.9 years]

      Prospective comparison of time to first occurrence of Individual component of primary endpoint: non-fatal stroke

    8. Percentage of Patients With Individual Component of Primary Endpoint: Non-fatal Stroke [From baseline up to 4.9 years]

    9. Time to First Occurrence of Individual Component of Primary Endpoint: All-cause Mortality [From baseline up to 4.9 years]

      Prospective comparison of time to first occurrence of Individual component of primary endpoint: All-cause mortality

    10. Percentage of Patients With Individual Component of Primary Endpoint: All-cause Mortality [From baseline up to 4.9 years]

      Percentage of patients reporting Individual component of primary endpoint: All-cause mortality

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    50 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • Participants with moderate to severe RA of greater than or equal to (>=6) months duration

    • Inadequate response to at least one non-biologic DMARD

    • Positive for Rheumatoid Factor (RF) and/or anti-cyclic citrullinated peptide (CCP) antibodies at screening

    • Have C-reactive protein (CRP) greater than (>) 0.3 milligrams per deciliter (mg/dL) at screening or at the baseline visit

    • Swollen joint count (SJC) >=8 (66 joint count) and tender joint count (TJC) >= 8 (68 joint count) during screening or at the baseline visit

    • History of Coronary Heart Disease (CHD) or presence of one or more additional CHD risk factors, including current cigarette smoking, hypertension, low High Density Lipoprotein (HDL) cholesterol, family history of premature CHD, diabetes, presence of extra-articular disease associated with rheumatoid arthritis

    • At the time of randomization, will have discontinued infliximab, adalimumab, golimumab, or certolizumab for >= 4 weeks

    Exclusion Criteria:

    • Major surgery (including joint surgery or coronary revascularization) within 8 weeks prior to screening or planned major surgery within 1 year of study start

    • Rheumatic autoimmune disease other than RA

    • History of or current inflammatory joint disease other than RA

    • Current or recent (within past 3 months) evidence of serious uncontrolled concomitant cardiovascular or cerebrovascular disease (myocardial infarction, revascularization, stroke, transient ischemic attack, or acute coronary syndrome)

    • Current or previous (within the past 2 years) evidence of serious uncontrolled concomitant pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine (including uncontrolled diabetes mellitus) or gastrointestinal disease

    • Uncontrolled disease states, such as asthma or inflammatory bowel disease where flares are commonly treated with oral or parenteral corticosteroids

    • Pre-existing central nervous system demyelinating or seizure disorders

    • History of diverticulitis, diverticulosis requiring treatment or other lower gastrointestinal tract conditions that might predispose to perforations

    • Current liver disease as determined by the investigator; a history of asymptomatic elevations in liver function tests (LFTs) is not considered an exclusion

    • Active current infection or history of recurrent bacterial, viral, fungal, mycobacterial or other infections, including but not limited to tuberculosis and atypical mycobacterial disease, hepatitis B and C, and herpes zoster, but excluding fungal infections of nail beds

    • Any major episode of infection requiring hospitalization or treatment with IV antibiotics within four weeks of screening or oral antibiotics within two weeks prior to screening visit

    • Active tuberculosis (TB) requiring treatment within 3 years prior to baseline

    • Latent TB diagnosed during screening that has not been appropriately treated

    • Primary or secondary immunodeficiency (history of or currently active)

    • Moderate to severe heart failure

    • Evidence of active malignant disease, malignancies diagnosed within the previous 10 years (including hematologic malignancies and solid tumors, except basal cell carcinoma of the skin that has been excised and cured), or breast cancer diagnosed within the previous 20 years

    • Breast feeding mothers

    • History of alcohol, drug or chemical abuse within the 6 months prior to screening

    • Participants with lack of peripheral venous access

    • Participants with a history of allergic reactions to latex

    • Previous treatment with non-tumor necrosis factor (non-TNF)-inhibitor biologic therapy

    • Treatment with any investigational agent within 4 weeks of screening visit

    • Treatment with any cell depleting therapies within 1 year of baseline

    • Treatment with IV gamma globulin, plasmapheresis or Prosorba column within 6 months of baseline visit

    • Immunization with a live/attenuated vaccine within 4 weeks prior to baseline visit

    • Any previous treatment with alkylating agents, such as cyclophosphamide or chlorambucil, or with total lymphoid irradiation

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Uni Of Alabama,Birmingham; Medicine - Rheumatology Birmingham Alabama United States 35294
    2 Rheumatology Associates of North Alabama Huntsville Alabama United States 35801
    3 Clinical and Translational Research Center of Alabama, PC Tuscaloosa Alabama United States 35406
    4 Arizona Arthritis & Rheumatology Associates, P.C. Glendale Arizona United States 85306
    5 Arizona Arthritis & Rheumatology Research, Pllc Paradise Valley Arizona United States 85253
    6 Sun Valley Arthritis Center Peoria Arizona United States 85381
    7 Valley Arthritis Care Phoenix Arizona United States 85027
    8 Advanced Arthritis Care & Research Scottsdale Arizona United States 85258
    9 Camp Lowell Medical Specialists Tucson Arizona United States 85715
    10 The University of Arizona Tucson Arizona United States 85724
    11 NEA Baptist Clinic Jonesboro Arkansas United States 72401
    12 OrthoArkansas; Orthopedics & Sports Medicine Little Rock Arkansas United States 72205
    13 Samy Metyas, MD, Inc Covina California United States 91723
    14 Talbert Medical Group Huntington Beach California United States 92646
    15 Allergy & Rheumatology Medical Clinic, Inc La Jolla California United States 92037
    16 Valerius Medical Group Los Alamitos California United States 90720
    17 Clinical Interventions Research Institute Mission Viejo California United States 92692
    18 Dr. Brigid Freyne, MD Murrieta California United States 92563
    19 Sharp Rees-Stealy Medical Group Poway California United States 92064
    20 San Diego Arthritis Med Clnc San Diego California United States 92108
    21 Purushotham & Akther Kotha Inc San Diego California United States 92120
    22 C Michael Neuwelt MD Inc San Leandro California United States 94578
    23 Pacific Arthritis Ctr Med Grp Santa Maria California United States 93454
    24 Orrin M. Troum, Md Santa Monica California United States 90404
    25 Harbor UCLA Medical Center Torrance California United States 90509
    26 Inland Rheumatology; Clinical Trials, Inc. Upland California United States 91786
    27 Medvin Clinical Research Whittier California United States 90606
    28 Arthritis Assoc & Osteoporosis; Ctr of Colorado Springs Colorado Springs Colorado United States 80920
    29 Joao Nascimento Bridgeport Connecticut United States 06606
    30 University of Connecticut Health Center Farmington Connecticut United States 06030
    31 Arthritis & Osteoporosis Center Pc Hamden Connecticut United States 06518
    32 ZASA Clinical Research Boynton Beach Florida United States 33472
    33 DC Health Clinic Coral Gables Florida United States 33134
    34 Tsai, Yong Daytona Beach Florida United States 32117
    35 Jacksonville Center For Clinical Research Jacksonville Florida United States 32216
    36 Pharmax Research Clinic Inc. Miami Florida United States 33126
    37 Arthritis/Osteoporosis Treatment Center Orange Park Florida United States 32073
    38 Arthritis Rsrch of Florida, Inc. Palm Harbor Florida United States 34684
    39 Baptist Hospital Clinical Research Pensacola Florida United States 32501
    40 Pinellas Medical Research, LLC Saint Petersburg Florida United States 33708
    41 Lovelace Scientific Resources Sarasota Florida United States 34292
    42 Centre for Arthritis and Rheumatic Diseases South Miami Florida United States 33143
    43 SW Florida Clinical Research Tampa Florida United States 33609
    44 Healthpoint Medical group, Inc Tampa Florida United States 33614
    45 Emory Uni ; Division of Rheumatology Atlanta Georgia United States 30303
    46 Arthritis & Rheumatology of Georgia Atlanta Georgia United States 30342
    47 North Georgia Rheumatology Duluth Georgia United States 30096
    48 Harbin Clinic Rome Georgia United States 30165
    49 St. Joseph'S/Candler Health System, Inc.; Office of Research Savannah Georgia United States 31405
    50 Sonora Clinical Research Boise Idaho United States 83702
    51 St. Luke's Intermountain Research Center Boise Idaho United States 83702
    52 Selah Medical Ctr Boise Idaho United States 83704
    53 Coeur D'Alene Arthritis Clinic Coeur d'Alene Idaho United States 83814
    54 Idaho Arthritis Center Meridian Idaho United States 83642
    55 University of Illinois at Chicago Chicago Illinois United States 60612
    56 Apex Medical Research, AMR, Inc. Chicago Illinois United States 60616
    57 Methodist Medical Center of Ilinois Peoria Illinois United States 61602
    58 Northern Indiana Research Alliance Fort Wayne Indiana United States 46804
    59 Diagnostic Rheumatology & Research Indianapolis Indiana United States 46227
    60 Memorial Medical Group Clinical Research South Bend Indiana United States 46601
    61 Graves Gilbert Clinic Bowling Green Kentucky United States 42101
    62 Research Integrity Owensboro Kentucky United States 42303
    63 Arthritis & Diabetes Clinic, Inc Monroe Louisiana United States 71203
    64 Ochsner Health System New Orleans Louisiana United States 70121
    65 Rheumatology Associates of Baltimore Baltimore Maryland United States 21286
    66 Osteoporosis & Clinical Trials Center Hagerstown Maryland United States 21740
    67 Center For Rheumatology & Bone Research Wheaton Maryland United States 20902
    68 Phase Iii Clinical Research Fall River Massachusetts United States 02720
    69 UMass Memorial Medical Center Worcester Massachusetts United States 01605
    70 Clinical Pharmacology Study Group Worcester Massachusetts United States 01610
    71 Hurley Research Center Flint Michigan United States 48503
    72 Rheumatology, P.C.; Medical Arts Building Kalamazoo Michigan United States 49009
    73 Advanced Rheumatology, PC Lansing Michigan United States 48910
    74 Northern Michigan Regional Hospital Petoskey Michigan United States 49770
    75 St. Paul Rheumatology Eagan Minnesota United States 55121
    76 Va Medical Center Minneapolis Minnesota United States 55417
    77 Mayo Clinic Rochester Rochester Minnesota United States 55905
    78 Jackson Arthritis Clinic Flowood Mississippi United States 39232
    79 North Mississippi Med Clinics, Inc. Tupelo Mississippi United States 38801
    80 Glacier View Research Institute Kalispell Montana United States 59901
    81 Univ of Nebraska Medical Ctr Omaha Nebraska United States 68198
    82 Advanced Biomedical Research of America Las Vegas Nevada United States 89123
    83 Innovative Health Research Las Vegas Nevada United States 89128
    84 Dartmouth-Hitchcock Medical Center, Rheumatology 5C Lebanon New Hampshire United States 03756
    85 Nashua Rheumatology - Foundation Medical Partners Nashua New Hampshire United States 03060
    86 Summit Medical Group Berkeley Heights New Jersey United States 07922
    87 Rheumatology Associates Of New Jersey Teaneck New Jersey United States 07666
    88 Arthritis Rheumatic & Back Disease Associates Voorhees New Jersey United States 08043
    89 Albuquerque Center For Rheumatology Albuquerque New Mexico United States 87102
    90 Arthritis and Osteoporosis Associates of New Mexico Las Cruces New Mexico United States 88011
    91 Arthritis & Osteoporosis Medical Associates, Pllc Brooklyn New York United States 11201
    92 SUNY Downstate Medical Center. Brooklyn New York United States 11203
    93 DiGiovanna Inst for Med Ed&Res North Massapequa New York United States 11758
    94 Southern Tier Arthritis & Rheumatism Olean New York United States 14760
    95 Arthritis Health Associates; Clinical Research Syracuse New York United States 13210
    96 Asheville Arthritis & Osteoporosis Center, PA Asheville North Carolina United States 28803
    97 Joint & Muscle Research Institute Charlotte North Carolina United States 28204
    98 Carolina Bone & Joint P.A. Charlotte North Carolina United States 28210
    99 Durham Rheumatology Durham North Carolina United States 27704
    100 PMG Research of Hickory LLC Hickory North Carolina United States 28602
    101 Shanahan Rheumatology & Immunology, PLLC Raleigh North Carolina United States 27617
    102 Specialty Medical Clinic and Research Center Sanford North Carolina United States 27330
    103 Carolina Arthritis Associates, Pa Wilmington North Carolina United States 28401
    104 Trinity Health Center Minot North Dakota United States 58701
    105 Cincinnati Rheumatic Disease Study Group Cincinnati Ohio United States 45219
    106 University Hospitals Case Medical Center Cleveland Ohio United States 44109
    107 Ohio State Univ Med Center Columbus Ohio United States 43210
    108 Columbus Arthritis Center Columbus Ohio United States 43215
    109 Clinical Research Source, Inc. Toledo Ohio United States 43606
    110 Toledo Clinic Toledo Ohio United States 43623
    111 Lynn Health Science Institute Oklahoma City Oklahoma United States 73112
    112 Altoona Center For Clinical Research Duncansville Pennsylvania United States 16635
    113 Penn State Milton S. Hershey Medical Center Hershey Pennsylvania United States 17033
    114 Ilumina Clinical Associates Indiana Pennsylvania United States 15701
    115 PMA Medical Specialists Limerick Pennsylvania United States 19468
    116 Pivotal Clinical Research, Llc Perkasie Pennsylvania United States 18944
    117 Arthritis Group Philadelphia Pennsylvania United States 19152
    118 University of Pittsburgh Medical Center Health System; Infectious Disease Pittsburgh Pennsylvania United States 15213-2582
    119 Allegheny Rheumatology Wexford Pennsylvania United States 15090
    120 Clinical Research Center of Reading Wyomissing Pennsylvania United States 19610
    121 Pennsylvania Regional Center for Arthritis and Osteoporosis Research Wyomissing Pennsylvania United States 19610
    122 Columbia Arthritis Center (Partnership Practice) Columbia South Carolina United States 29204
    123 South Carolina Research Center Myrtle Beach South Carolina United States 29572
    124 Brown Clinic Watertown South Dakota United States 57201
    125 Ramesh Gupta - PP Memphis Tennessee United States 38119
    126 Amarillo Center For Clinical Research Amarillo Texas United States 79124
    127 Adriana Pop-Moody MD Clinic PA Corpus Christi Texas United States 78404
    128 Metroplex Clinical Research Dallas Texas United States 75231
    129 Leading Edge Research, PA; Office of Dr. Burbano Fort Worth Texas United States 76109
    130 Rheumatic Disease Clin Res Ctr Houston Texas United States 77004
    131 Houston Inst. For Clinical Research Houston Texas United States 77074
    132 Southwest Rheumatology Mesquite Texas United States 75150
    133 Leading Edge Research, PA; Office of Dr. Burbano Richardson Texas United States 75080
    134 Texas Arthritis Research Center San Antonio Texas United States 78217
    135 Arthritis & Osteoporosis Clinic Waco Texas United States 76710
    136 Arthritis and Rheumatic Disease Associates Burke Virginia United States 22015
    137 Sentara Medical Group Norfolk Virginia United States 23510
    138 Apex Clinical Research Kennewick Washington United States 99336
    139 Seattle Rheumatology Associates Seattle Washington United States 98104
    140 Office of George Krick, Md Tacoma Washington United States 98405
    141 Rheum & Pulmonary Clinic Beckley West Virginia United States 25801
    142 Mountain State Clinical Research Clarksburg West Virginia United States 26301
    143 Arthritis Centre; Suite 103 Racine Wisconsin United States 53406
    144 Organizacion Medica de Investigacion Buenos Aires Argentina C1015ABO
    145 CEIM Consultorios Especializados en Investigaciones Médicas Buenos Aires Argentina C1117ABK
    146 APRILLUS Buenos Aires Argentina C1194AAO
    147 Instituto centenario Buenos Aires Argentina C1204AAD
    148 Fundación CIDEA Buenos Aires Argentina C1425DTG
    149 Atencion Integral En Reumatologia Buenos Aires Buenos Aires Argentina C1426AAL
    150 CEMIC Buenos Aires Argentina C1431FWO
    151 Hospital General de Agudos Dr. J. M. Ramos Mejia Ciudad Autonoma Buenos Aires Argentina C1221ADC
    152 Hospital Britanico de Buenos Aires Ciudad Autonoma Buenos Aires Argentina C1284AEB
    153 Centro de Investigaciones Reumatologicas y Osteologicas Ciudad Autonoma de Buenos Aires Argentina 1111
    154 Hospital Privado Cordoba Cordoba Pcia Argentina 5016
    155 Instituto Reumatológico Strusberg Cordoba Argentina 5000
    156 Hospital Italiano de Cordoba Cordoba Argentina X5004BAL
    157 Centro de Investigaciones Médicas - CIM Florencio Varela Argentina 1888
    158 Hospital Municipal Nuestra Sra. de Lujan Lujan Argentina 6700
    159 Centro de Investigacion Pergamino SA Pergamino Argentina B2700CPM
    160 Instituto Centralizado de Asistencia e Investigaci Rosario, Santa Fe Argentina S2000PBJ
    161 Sanatorio Parque de Rosario Rosario Argentina S2000DSV
    162 CER San Juan Centro Polivalente de Asistencia e Investigacion Clinica San Juan Argentina 5400
    163 Centro Médico Privado de Reumatología San Miguel de Tucuman Argentina T4000AXL
    164 Centro de Investigaciones Reumatologicas Tucuman Tucuman Argentina 4000
    165 Lkh-Univ. Klinikum Graz Graz Austria 8036
    166 Landesklinikum Weinviertel Stockerau; Rheumatologie Stockerau Austria 2000
    167 Medizinische Universität Wien Wien Austria 1090
    168 Rheuma-Zentrum Favoriten Wien Wien Austria 1100
    169 Krankenhaus Hietzing; 2.Med.Abteilung, Pav.3A Wien Austria 1130
    170 CHU St Pierre (St Pierre) Brussels Belgium 1000
    171 Cliniques Universitaires St-Luc Bruxelles Belgium 1200
    172 AZ Groeninge (Vercruysselaan) Kortrijk Belgium 8500
    173 CHU Sart-Tilman Liège Belgium 4000
    174 ZNA Jan Palfijn Merksem Belgium 2170
    175 University Clinical Center of the Republic of Srpska Banja Luka Bosnia and Herzegovina 78000
    176 University Clinic Ctr Sarajevo Sarajevo Bosnia and Herzegovina 71 000
    177 General Hospital Prim.dr.Abdulah Nakas Sarajevo Bosnia and Herzegovina 71000
    178 Uni Hospital Center Tuzla Tuzla Bosnia and Herzegovina 75000
    179 Royal Alexandra Hospital Edmonton Alberta Canada T5H 3V9
    180 The Medical Arts Health Research Group Powell River British Columbia Canada V8A 3B6
    181 Baker, Milton F. Victoria British Columbia Canada V8P 5P6
    182 Nexus Clinical Research Centre St John's Newfoundland and Labrador Canada A1A 5E8
    183 St. Clare'S Mercy Hospital St John's Newfoundland and Labrador Canada A1C 5B8
    184 Arthur Karasik, MD Etobicoke Ontario Canada M9C 5N2
    185 Charlton Medical Center Hamilton Ontario Canada L8N 1Y2
    186 K-W Musculoskeletal Research Kitchener Ontario Canada N2M 5N6
    187 St. Joseph's Hospital London Ontario Canada N6A 4V2
    188 Credit Valley, Rheumatology Mississauga Ontario Canada L5M 2V8
    189 Niagara Peninsula Arthritis Centre St. Catharines Ontario Canada L2N 7E4
    190 Mount Sinai Hospital Toronto Ontario Canada M5G 1Z5
    191 Institut de Rhumatologie de Montreal Montreal Quebec Canada H2L 1S6
    192 Groupe de Recherche En Rhumatologie Et Maladies Osseuses Quebec City Quebec Canada G1V 3M7
    193 Chus Hopital Fleurimont Sherbrooke Quebec Canada J1H 5N4
    194 Centre de Recherche Musculo-Squelettique Trois-rivieres Quebec Canada G8Z 1Y2
    195 Centre Re Recherche Saint-Louis Quebec Canada G1W 4R4
    196 Hospital San Juan de Dios La Serena La Serena Chile 1700000
    197 Centro Medico Prosalud Santiago Chile 7500000
    198 Interin Santiago Chile 7500035
    199 Centro de Estudios Reumatológicos Santiago Chile 7501126
    200 Hospital Clinico Pontificia Universidad Catolica de Chile Santiago Chile 8320112
    201 Centro de Investigacion Clinica del Sur Temuco Chile 4780000
    202 Clinica Alemana de Temuco Temuco Chile 4780000
    203 Hospital Clinico Viña del Mar- Oncovida Viña del Mar Chile 2520612
    204 Centro de Estudios Clinicos V Region Limitada Viña del Mar Chile
    205 General Hospital Karlovac Karlovac Croatia 47000
    206 Special Hospital for Medical Rehabilitation Krapinske Toplice Croatia 49217
    207 Clinical Hospital Centre Rijeka; Department of Rheumatology and Clinical Immunology Rijeka Croatia 51000
    208 Clinical Hospital Centre Zagreb Zagreb Croatia 10000
    209 Universtiy Hospital Dubrava Zagreb Croatia 10000
    210 Fakultni nemocnice u sv. Anny v Brne Brno Czechia 656 91
    211 Revmatologicka ambulance Bruntal Czechia 792 01
    212 Revmatologicka Ambulance Hlucin Czechia 748 01
    213 Interni a revmatologicka ordinace Hostivice Czechia 253 01
    214 Revmatologicka a-interni ambulance Kladno Czechia 272 01
    215 Revmatologie MUDr. Klara Sirova s.r.o. Ostrava - Moravska Ostrava Czechia 702 00
    216 Revmatologicka ambulance Praha 4 Czechia 140 00
    217 Revmatologicky Ustav Praha Czechia 128 50
    218 Fakultni Thomayerova nemocnice s poliklinikou Praha Czechia 140 59
    219 Artroscan s.r.o. Sokolov Czechia 356 01
    220 Revmatologicka Ambulance-Terezin Terezin Czechia 411 55
    221 PV - Medical, s.r.o. Zlin Czechia 748 01
    222 Hospital Clínica Santa Inés Cuenca Ecuador 101168
    223 Centro de Reumatología y Rehabilitación Guayaquil Ecuador 593
    224 OMNI Hospital Guayaquil Ecuador 593
    225 Centro Medico Alcivar 4 Guayaquil Ecuador EC090114
    226 Centro Medico Picasso Quito Ecuador 005932
    227 Novaclinica Santa Cecilia; Reumatology Quito Ecuador EC170517
    228 CHU d'Amiens Hôpital Nord; Pharmacie Clinique Amiens France 80054
    229 Groupe Hospitalier Pellegrin Bordeaux France 33000
    230 CHU Hopital Gabriel Montpied Clermont Ferrand France 63003
    231 Centre Hospitalier Sud Francilien Corbeil Essonnes France 91106
    232 CHU Grenoble Sud Echirolles France 38434
    233 Hôpital Edouard Herriot; Service de Rhumatologie Lyon France 69003
    234 CHR Orleans, Hopital Madeleine Orléans France 45067
    235 Hôpital Saint-Antoine; Service de Psychiatrie Paris France 75571
    236 Groupe Hospitalier Pitie-Salpetriere Paris France 75651
    237 Hopital Cochin; Gastro Enterologie Paris France 75679
    238 Hôpital Sud - CHU de Rennes Rennes France 35033
    239 Hôpital Victor Provo Roubaix France 59056
    240 CHU de Rouen, Hopital de Bois Guillaume; Service de Rhumatologie Rouen France 76031
    241 CHU Saint-Etienne, Hopital Bellevue Saint-Etienne France 42055
    242 Hôpital General - CHRU de Dijon Strasbourg France 67098
    243 Institut Universitaire du Cancer - Oncopole Toulouse (IUCT-O) Toulouse France 31059
    244 Charité Universitaetsmedizin Berlin, Campus Charité Mitte Berlin Germany 10117
    245 Schlosspark-Klinik Berlin Germany 14059
    246 Universitätsklinikum "Carl Gustav Carus" der Technischen Universität Dresden Dresden Germany 01307
    247 Universitätsklinikum Erlangen; Augenklinik Erlangen Germany 91054
    248 Praxisgemeinschaft Rheumatologie-Nephrologie Erlangen PGRN Erlangen Germany 91056
    249 Universitaetsklinikum Frankfurt Frankfurt Germany 60528
    250 Universitaetsklinikum Hamburg-Eppendorf; Medizinische Klinik Nephrologie/Rheumatologie Hamburg Germany 20251
    251 Schön Klinik Hamburg-Eilbek Klinik für Rheumatologie Hamburg Germany 22081
    252 Rheumazentrum Ruhrgebiet; St. Josefs-Krankenhaus Herne Germany 44649
    253 Gemeinschaftspraxis Dr. Von Hinueber/Dr. Demary; Rheumatologie Hildesheim Germany 31134
    254 Universitätsklinikum Köln, Klinik I für Innere Medizin Koeln Germany 50937
    255 Universitaetsklinikum Leipzig Leipzig Germany 04103
    256 Praxiszentrum St. Bonifatius Muenchen Germany 81541
    257 Ludwig Maximilians; Universitaet München Germany 80337
    258 Rheumatologische Gemeinschaftspraxis Osnabrueck Germany 49074
    259 Evangelisches Fachkrankenhaus Ratingen Germany 40882
    260 Laiko General Hospital Athen Athens Greece 115 27
    261 Euroclinic of Athens; Internal Medicine & Immunology Dept. Athens Greece 15121
    262 University General Hospital of Heraklion Crete Greece 71110
    263 University General Hospital of Larissa; Rheumatology Unit Larissa Greece 411 10
    264 General Hospital of Thessaloniki Hippokration Thessaloniki Greece 54 642
    265 Euromedica Kyanous Stavros General Hospital Thessaloniki Greece 546 36
    266 424 Military Training Hospital-Egnatia Thessaloniki Greece
    267 Országos Fizioterápiás És Reumatológiai Intézet; I. Reumatológiai És Metabolikus Osteológiai Osztály Budapest Hungary 1027
    268 Clinexpert Egeszsegugyi Szolgaltato es Kereskedelmi Kft Budapest Hungary 1033
    269 Obudai Egeszsegugyi Centrum Kft. Budapest Hungary 1036
    270 Synexus Magyarorszag Kft Budapest Hungary 1036
    271 Debreceni Egyetem, Klinikai Kozpont, Tudogyogyaszati Klinika Debrecen Hungary 4032
    272 Markhot Ferenc Eu. Szolg. Nonprofit Kiem. Kozh. Kft. Eger Hungary 3300
    273 Bekes Megyei Kepviselotestulet Pandy Kalman Korhaza Gyula Hungary 5700
    274 Varosi Korhaz-Rendelointezet Mor Hungary 8060
    275 Fejer Megyei Szent Gyorgy Korhaz Szekesfehervar Hungary 8000
    276 Clinfan Szolgaltato Kft. Szekszard Hungary 7100
    277 Zala Megyei Korhaz; Reumatologia Zalaegerszeg Hungary 8901
    278 Shalby Hospital Limited Ahmedabad Gujarat India 380015
    279 Vedanta Institute; Medical Sciences Ahmedabad India 380009
    280 Manipal Hospital Bangalore India 560017
    281 St.John's Medical College Hospital Banglore India 560034
    282 Arthritis Super Speciality Centre Hubli India 580020
    283 Care Institute of Medical Sciences Hyderabad India 500034
    284 Jasleen Hospital Nagpur India 440010
    285 Barzilai Medical Center Ashkelon Israel 78278
    286 Assaf Harofeh Medical Center Beer Yaacov Israel 6093000
    287 The Lady Davis Carmel Medical Center Haifa Israel 34362
    288 Chaim Sheba Medical Center; Rheumatology Ramat Gan Israel 5262000
    289 Tel-Aviv Sourasky Medical Center Tel Aviv Israel 64239
    290 Azienda Ospedaliera A. Cardarelli Napoli Campania Italy 80131
    291 Ospedale San Giovanni Bosco; Divisione di Reumatologia Napoli Campania Italy 80144
    292 Fondazione Salvatore Maugeri IRCCS; Istituto Scientifico di Riabilitazione di Telese Telese Terme Campania Italy 82037
    293 Ospedale La Colletta Arenzano Liguria Italy 16011
    294 Azienda Ospedaliero Universitaria San Martino Genova Liguria Italy 16132
    295 Ospedali Riuniti di Bergamo Bergamo Lombardia Italy 24128
    296 Asst Grande Ospedale Metropolitano Niguarda; Dipartimento Di Ematologia Ed Oncologia Milano Lombardia Italy 20162
    297 Ospedale Di Circolo E Fondazione Macchi Varese Lombardia Italy 21100
    298 Presidio Ospedaliero Vittorio Emanuele Catania Sicilia Italy 95124
    299 Azienda Ospedaliera Universitaria Careggi Firenze Toscana Italy 50141
    300 Ospedale Misericordia e Dolce Prato Toscana Italy 59100
    301 L.Krumina GP practice Bauska Latvia 3901
    302 Daugavpils Regional Hospital Daugavpils Latvia 5417
    303 D.Saulite-Kandevica Private Practice Liepaja Latvia 3400
    304 Clinic ORTO Riga Latvia 1005
    305 Private Practice EHOKG Riga Latvia 1021
    306 Riga East Clinical University Hospital; Clinic Gailezers Riga Latvia LV 1002
    307 P. Stradins Clinical University Hospital Riga Latvia LV-1002
    308 Alytus Regional S. Kudirkos Hospital, Public Institution Alytus Lithuania 62114
    309 Klaipeda Seamen's Hospital, Public Institution Klaipeda Lithuania 92288
    310 Klaipeda University Hospital; Public Institution Klaipeda Lithuania 92288
    311 Siauliai Republican Hospital Public Institution Siauliai Lithuania 76231
    312 Vilnius District Central Outpatient Clinic, Public Institution Vilnius Lithuania 06122
    313 Hospital Raja Permaisuri Bainun Ipoh Perak Malaysia 30990
    314 Hospital Selayang Kuala Lumpur Malaysia 68100
    315 Hospital Umum Sarawak Kuching Malaysia 93586
    316 Hospital Pulau Pinang Penang Malaysia 10990
    317 Sunway Medical Centre Selangor Malaysia 46150
    318 Sime Darby Medical Centre Selangor Malaysia 47500
    319 Centro de Investigacion del Noroeste SC Tijuana Baja California Mexico 22010
    320 Centro de Investigación de Tratamientos Innovadores de Sinaloa (CITI) Culiacán Rosales Sinaloa Mexico 80000
    321 Unidad de Atencion Medica e Investigacion en Salud S.C. Mérida Yucatan Mexico 97000
    322 Hospital Christus Muguerza del Parque; Reumatologia Chihuahua Mexico 31000
    323 Hospital CIMA Chihuahua; Reumatologia Chihuahua Mexico 31238
    324 Hospital Privado San Jose de Ciudad Obregon SA de CV Ciudad Obregon Mexico 85000
    325 Private Practice Dr. Cortes Cuernavaca Mexico 62270
    326 RM pharma specialist SA de CV Delegacion Benito Juarez Mexico 03100
    327 Mentrials S.A. de C.V Distrito Federal Mexico 06600
    328 Centro de Investigacion y Atencion Integral Durango CIAID Durango Mexico 34080
    329 Mundo Fisico Guadalajara Mexico 44500
    330 Clinica Hospital Angeles Chapalita Guadalajara Mexico 45040
    331 Centro de Investigacion en Enfermedades Reumaticas y Osteoporosis Mexicali Mexico 21100
    332 Inst. Mexicano de Investigacion Clinica Mexico City Mexico 06700
    333 Instituto Nacional de Cardiologia Ignacio Chavez Mexico City Mexico 14080
    334 Hospital Mocel Mexico Df Mexico 11850
    335 Mexico Centre for Clinical Research Mexico Mexico 03100
    336 Comite Mexicano Para la Prevencion de Osteoporosis AC Mexico Mexico 06100
    337 Cliditer SA de CV Miexico City Mexico 06700
    338 Hospital Universitario de Saltillo Saltillo Mexico 25000
    339 Hospital Central Dr. Ignacio Morones Prieto San Luis Potosi S.L.P. Mexico 78240
    340 Centro de Alta Especialidad en Reumatología e Investigación del Potosí, S.C. San Luis Potosí Mexico 78200
    341 Unidad de Enfermedades Reumaticas y Cronicodegenerativas Torreon Mexico 27000
    342 Jan Van Breemen Instituut Amsterdam Netherlands 1056 AB
    343 Albert Schweitzer Ziekenhuis ; Dordwijk Dordrecht Netherlands 3318AT
    344 Franciscus Ziekenhuis Roosendaal Netherlands 4708 AE
    345 Vlietland Hospital Schiedam Netherlands 3118 JH
    346 Cebu Doctors' University Hospital- North General Hospital Cebu City Philippines 6000
    347 Chong Hua Hospital, Cebu City Cebu City Philippines 6000
    348 St. Paul Hospital; Arthritis Center Iloilo City Philippines 5000
    349 Mary Mediatrix Medical Center Lipa City Philippines 4217
    350 Makati Medical Center Makati City Philippines 1229
    351 Szpital Uniwersytecki; nr 2 im. Dr J. Biziela Bydgoszcz Poland 85-168
    352 Wojewodzki Szpital Zespolony w Elblagu Elblag Poland 82-300
    353 Szpital Specjalistyczny Im J. Dietla Malopolskie Centrum Reumat; Oddzial Rumatologii Krakow Poland 30-119
    354 Szpital Specjalistyczny im. J. Dietla Krakow Poland 31-121
    355 NZOZ REUMED Sp. z o.o. Lublin Poland 20-607
    356 Lecznica MAK-MED NZOZ Nadarzyn Poland 05-830
    357 SP Szpital Kliniczny nr 1 Pomorskiej Akademii Medycznej im. prof. Tadeusza Sokolowskiego Szczecin Poland 71-252
    358 Slaski Szpital Reumatologiczno; Rehabilitacyjny; Iii Oddzial Reumatologiczny Ustron Poland 43-450
    359 Rheuma Medicus Zaklad Opieki Zdrowotnej Warszawa Poland 02-118
    360 ARS Rheumatica Sp.z o. o Warszawa Poland 02-653
    361 Akademicki Szpital Kliniczny im. Jana Mikulicza Radeckiego Wroclaw Poland 50-556
    362 Spitalul Clinic Judetean de Urgenta Brasov Brasov Romania 500365
    363 Spitalul Clinic Dr. I Cantacuzino Bucharest Romania 020475
    364 Spitalul Clinic Sf. Maria; Dept Interna si Reumatologie Bucuresti Romania 011172
    365 Centrul de Boli Reumatismale Dr. Ioan Stoia Bucuresti Romania 020983
    366 Medex SRL Cluj-Napoca Romania 400130
    367 Spitalul Clinic Judetean de Urgenta Cluj-Napoca, Clinica de Medicina Muncii Cluj-Napoca Romania 400349
    368 CMI Dr.Ciornohuz Adriana Iasi Romania 700127
    369 Spitalul Clinic de Recuperare Iasi Iasi Romania 700656
    370 Spitalul Municipal Ploiesti Ploiesti Romania 100337
    371 Spitalul Clinic Colentina Sector 2 Romania 020125
    372 Spitalul Judetean de Urgenta Targoviste Targoviste Romania 130083
    373 Mediab SRL Targu Mures Romania 540142
    374 Spitalul Clinic Municipal de Urgenta Timisoara Timisoara Romania 300194
    375 State institution of health care - Territorial Clinical Hospital Barnaul Russian Federation 656024
    376 SEI of HPE "Altay State Medical University of Roszdrav" Barnaul Russian Federation 656038
    377 Scientific and research medical complex Your Health Kazan Russian Federation 420097
    378 SIH Kemerovo Regional Clinical Hospital Kemerovo Russian Federation 650002
    379 City Hospital No.4 Moscow Russian Federation 115093
    380 Scient Res Inst Rheumat RAMS Moscow Russian Federation 115522
    381 Moscow State Medical Stomatological University Moscow Russian Federation 121374
    382 Head Clinical Hospital of Internal Affair Ministry of Russia Moscow Russian Federation 123060
    383 MHI City Clinical Hospital#19 Novosibirsk Russian Federation 630068
    384 FSBI Scientific Research Institute of Clinical Immunology of SB of RAMS Novosibirsk Russian Federation 630099
    385 Ryazan Regional Clinincal Cardiology Dispensary Ryazan Russian Federation 390026
    386 State institution of healthcare "Regional hospital for war veterans" Saratov Russian Federation 410002
    387 Leningradskaya Regional Clinical Hospital; Rheumatology Dept St Petersburg Russian Federation 194291
    388 Stavropol State Medical Academy Stavropol Russian Federation 355017
    389 Tomsk Regional Clinical Hospital Tomsk Russian Federation 634063
    390 Voronezh Regional Clinical Hospital #1 Voronezh Russian Federation 394066
    391 MCHI Medical Sanitary Unit of Yaroslavl Diesel Apparatus Plant Yaroslavl Russian Federation 150007
    392 Institute of Rheumatology Belgrade Serbia 11000
    393 Military Medical Academy Belgrade Serbia 11040
    394 Clinical Center Bezanijska Kosa Belgrade Serbia 11070
    395 Institute of Rheumatology and Cardiovascular Diseases; Rheumatology Niska Banja Serbia 18205
    396 Groote Schuur Hospital; Rheumatology Unit Cape Town South Africa 7925
    397 Chris Hani Baragwanath Hospital; Rheumatology Department Diepkloof South Africa 1862
    398 Charlotte Maxeke Academic Hospital Johannesburg South Africa 2193
    399 University of Pretoria; Clinical Trial Unit Pretoria South Africa 0002
    400 Hospital de Merida ;Servicio de Reumatologia Merida Badajoz Spain 06800
    401 Corporacio Sanitaria Parc Tauli Sabadell Barcelona Spain 08208
    402 Hospital Sierrallana Torrelavega Cantabria Spain 39300
    403 Hospital Clinico Universitario de Santiago Santiago de Compostela La Coruña Spain 15706
    404 Hospital Infanta Sofia; Servicio de Reumatologia San Sebastian de los Reyes Madrid Spain 28702
    405 Hospital Regional Universitario Carlos Haya Málaga Malaga Spain 29009
    406 Hospital Universitario Virgen Macarena Seville Sevilla Spain 41071
    407 Hospital Universitario de Canarias S. Cristobal de la Laguna Tenerife Spain 38320
    408 Hospital de Cruces; Servicio de Reumatologia Barakaldo Vizcaya Spain 48903
    409 Hospital Universitario Basurto Bilbao Vizcaya Spain 48013
    410 Hospital General de Castellon; Servicio de Reumatologia Castellon Spain 12004
    411 Hospital Gregorio Marañon Madrid Spain 28007
    412 Akdeniz Univesity Medical Faculty Antalya Turkey 07058
    413 Trakya University Medical Faculty Edirne Turkey 22030
    414 Ataturk University Med Faculty Erzurum Turkey 25050
    415 Karadeniz Tecnical Uni. Med. Fac. Trabzon Turkey 61100
    416 Selly Oak Hospital; Rheumatology Dept Birmingham United Kingdom B29 6JD
    417 Addenbrooke's NHS Trust Cambridge United Kingdom CB2 0QQ
    418 Cannock Chase Hospital; Rheumatology Cannock United Kingdom WS11 5XY
    419 Russells Hall Hospital; Rheumatology Department Dudley United Kingdom DY1 2HQ
    420 Leicester Royal Infirmary NHS Trust Leicester United Kingdom LE1 5WW
    421 Royal London Hospital Outpatients Department London United Kingdom E1 1BB
    422 Whipps Cross Hospital; Rheumatology Dept London United Kingdom E11 1NR
    423 King'S College Hospital London United Kingdom SE5 9RS
    424 Royal Victoria Infirmary Newcastle upon Tyne United Kingdom NE1 4LP
    425 Salford Royal NHS Foundation Trust Salford United Kingdom M6 8HD
    426 Southampton General Hospital; Rheumatology Southampton United Kingdom SO16 6YD
    427 Southend Hospital; Rheumatology Department Westcliffe-on-sea United Kingdom SS0 0RY
    428 Wrightington Hospital Wrightington United Kingdom WN6 9EP

    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:
    NCT01331837
    Other Study ID Numbers:
    • WA25204
    • 2010-020065-24
    First Posted:
    Apr 8, 2011
    Last Update Posted:
    Jul 13, 2017
    Last Verified:
    Jun 1, 2017
    Additional relevant MeSH terms:
    Arthritis
    Arthritis, Rheumatoid
    Etanercept

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail A total of 3080 patients were enrolled from 353 sites, across 31 countries
    Arm/Group Title Tocilizumab Etanercept
    Arm/Group Description Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years. Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
    Period Title: Overall Study
    STARTED 1538 1542
    COMPLETED 1482 1475
    NOT COMPLETED 56 67

    Baseline Characteristics

    Arm/Group Title Tocilizumab Etanercept Total
    Arm/Group Description Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years. Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years. Total of all reporting groups
    Overall Participants 1538 1542 3080
    Age (Years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Years]
    60.7
    (7.4)
    60.7
    (7.6)
    60.7
    (7.5)
    Sex: Female, Male (Count of Participants)
    Female
    1193
    77.6%
    1202
    78%
    2395
    77.8%
    Male
    345
    22.4%
    340
    22%
    685
    22.2%

    Outcome Measures

    1. Primary Outcome
    Title Time to First Cardiovascular (CV) Events Adjudication Committee (EAC) (CV-EAC) Adjudicated Event
    Description Prospective comparison of time to first occurrence of any component of the composite of CV death (including events adjudicated as 'Undetermined Cause of Death'), non-fatal myocardial infarction, or non-fatal stroke.
    Time Frame From baseline up to 4.9 years

    Outcome Measure Data

    Analysis Population Description
    Analysis was conducted on the Intention to treat (ITT) population, i.e. all patients randomized who have taken at least one dose of study medication
    Arm/Group Title Tocilizumab Etanercept
    Arm/Group Description Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years. Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
    Measure Participants 1538 1542
    Median (95% Confidence Interval) [Months]
    NA
    NA
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Tocilizumab, Etanercept
    Comments The analysis assessed in the ITT population the hazard ratio of the primary endpoint in TCZ compared to ETA patients. This was done through a comparison of the hazard functions between TCZ and ETA patients. A stratified Cox proportional hazards regression model was used in evaluating the relative CV event rate of TCZ over ETA, with the following randomization factors used as strata: Previous exposure to anti-TNF (Yes/No) History of CV events (Yes/No)
    Type of Statistical Test Non-Inferiority or Equivalence
    Comments In order to reject the null hypothesis and claim non-inferiority of TCZ compared to ETA, a HR point estimate of ≤ 1.278 and upper limit of 95% CI <1.8 was required.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.05
    Confidence Interval (2-Sided) 95%
    0.77 to 1.43
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    2. Primary Outcome
    Title Percentage of Patients Reporting a Cardiovascular (CV) Events Adjudication Committee (EAC) (CV-EAC) Adjudicated Event
    Description Percentage of patients reporting any component of the composite of CV death (including events adjudicated as 'Undetermined Cause of Death'), non-fatal myocardial infarction, or non-fatal stroke
    Time Frame From baseline up to 4.9 years

    Outcome Measure Data

    Analysis Population Description
    Analysis was conducted on the Intention to treat (ITT) population, i.e. all patients randomized who have taken at least one dose of study medication
    Arm/Group Title Tocilizumab Etanercept
    Arm/Group Description Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years. Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
    Measure Participants 1538 1542
    Number [Percentage of patients with event]
    5.4
    5.1
    3. Primary Outcome
    Title Time to First CV-EAC Adjudicated Event - Sensitivity Analysis
    Description Prospective comparison of time to first occurrence of any component of the composite of CV death (including events adjudicated as 'Undetermined Cause of Death'), non-fatal myocardial infarction, or non-fatal stroke - Sensitivity Analysis
    Time Frame From Baseline up to 4.9 years

    Outcome Measure Data

    Analysis Population Description
    Analyses was conducted on the On-treatment (OT) population, i.e. patients who switched from randomized treatment were censored at the time of treatment switching.
    Arm/Group Title Tocilizumab Etanercept
    Arm/Group Description Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years. Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
    Measure Participants 1538 1542
    Median (95% Confidence Interval) [Months]
    NA
    NA
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Tocilizumab, Etanercept
    Comments The analysis assessed in the OT population the hazard ratio of the primary endpoint in TCZ compared to ETA patients. This was done through a comparison of the hazard functions between TCZ and ETA patients. A stratified Cox proportional hazards regression model was used in evaluating the relative CV event rate of TCZ over ETA, with the following randomization factors used as strata: Previous exposure to anti-TNF (Yes/No) History of CV events (Yes/No)
    Type of Statistical Test Non-Inferiority or Equivalence
    Comments The non-inferiority margin was only formally tested for the primary ITT analysis'
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.11
    Confidence Interval (2-Sided) 95%
    0.76 to 1.62
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    4. Primary Outcome
    Title Percentage of Patients With a CV-EAC Adjudicated Event - Sensitivity Analysis
    Description Percentage of patients with any component of the composite of CV death (including events adjudicated as 'Undetermined Cause of Death'), non-fatal myocardial infarction, or non-fatal stroke - Sensitivity Analysis
    Time Frame From Baseline up to 4.9 years

    Outcome Measure Data

    Analysis Population Description
    Analyses was conducted on the On-treatment (OT) population, i.e. patients who switched from randomized treatment were censored at the time of treatment switching.
    Arm/Group Title Tocilizumab Etanercept
    Arm/Group Description Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years. Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
    Measure Participants 1538 1542
    Number [Percentage of patients with event]
    3.7
    3.4
    5. Primary Outcome
    Title Time to First CV-EAC Adjudicated Event Excluding Undetermined Cause of Death - Sensitivity Analysis
    Description Prospective comparison of time to first occurrence of any component of the composite of CV death (excluding events adjudicated as 'Undetermined Cause of Death'), non-fatal myocardial infarction, or non-fatal stroke - Sensitivity Analyses
    Time Frame From baseline up to 4.9 years

    Outcome Measure Data

    Analysis Population Description
    Analysis was conducted on the ITT population
    Arm/Group Title Tocilizumab Etanercept
    Arm/Group Description Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years. Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
    Measure Participants 1538 1542
    Median (95% Confidence Interval) [Months]
    NA
    (NA)
    NA
    (NA)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Tocilizumab, Etanercept
    Comments The analysis assessed in the ITT population the hazard ratio of the primary endpoint in TCZ compared to ETA patients. This was done through a comparison of the hazard functions between TCZ and ETA patients. A stratified Cox proportional hazards regression model was used in evaluating the relative CV event rate of TCZ over ETA, with the following randomization factors used as strata: Previous exposure to anti-TNF (Yes/No) History of CV events (Yes/No)
    Type of Statistical Test Non-Inferiority or Equivalence
    Comments The non-inferiority margin was only formally tested for the primary ITT analysis and not for the sensitivity analysis.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.01
    Confidence Interval (2-Sided) 95%
    0.73 to 1.40
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    6. Primary Outcome
    Title Percentage of Patients With a CV-EAC Adjudicated Event Excluding Undetermined Cause of Death - Sensitivity Analysis
    Description Percentage of patients with any component of the composite of CV death (excluding events adjudicated as 'Undetermined Cause of Death'), non-fatal myocardial infarction, or non-fatal stroke - Sensitivity Analyses
    Time Frame From baseline up to 4.9 years

    Outcome Measure Data

    Analysis Population Description
    Analysis was conducted on the ITT population
    Arm/Group Title Tocilizumab Etanercept
    Arm/Group Description Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years. Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
    Measure Participants 1538 1542
    Number [Percentage of patients with event]
    4.8
    4.7
    7. Primary Outcome
    Title Time to First CV-EAC Adjudicated Event Before Last Direct Contact Date
    Description Prospective comparison of time to first occurrence of any component of the composite of CV death (including events adjudicated as 'Undetermined Cause of Death'), non-fatal myocardial infarction, or non-fatal stroke before last direct contact date (i.e., latest date of visit, IVRS call, or site call).
    Time Frame From Baseline up to 4.9 years

    Outcome Measure Data

    Analysis Population Description
    Analysis was conducted on the ITT population
    Arm/Group Title Tocilizumab Etanercept
    Arm/Group Description Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years. Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
    Measure Participants 1538 1542
    Median (95% Confidence Interval) [Months]
    NA
    (NA)
    NA
    (NA)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Tocilizumab, Etanercept
    Comments The analysis assessed in the ITT population the hazard ratio of the primary endpoint in TCZ compared to ETA patients. This was done through a comparison of the hazard functions between TCZ and ETA patients. A stratified Cox proportional hazards regression model was used in evaluating the relative CV event rate of TCZ over ETA, with the following randomization factors used as strata: Previous exposure to anti-TNF (Yes/No) History of CV events (Yes/No)
    Type of Statistical Test Non-Inferiority or Equivalence
    Comments The non-inferiority margin was only formally tested for the primary ITT analysis and not for the sensitivity analysis.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.04
    Confidence Interval (2-Sided) 95%
    0.70 to 1.56
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    8. Primary Outcome
    Title Percentage of Participants With a CV-EAC Adjudicated Event Before Last Direct Contact Date
    Description Percentage of participants with any component of the composite of CV death (including events adjudicated as 'Undetermined Cause of Death'), non-fatal myocardial infarction, or non-fatal stroke before last direct contact date (i.e., latest date of visit, IVRS call, or site call).
    Time Frame From Baseline up to 4.9 years

    Outcome Measure Data

    Analysis Population Description
    Analysis was conducted on the ITT population
    Arm/Group Title Tocilizumab Etanercept
    Arm/Group Description Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years. Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
    Measure Participants 1538 1542
    Number [Percentage of participants with event]
    3.2
    0.2%
    3.0
    0.2%
    9. Secondary Outcome
    Title The Time to First Occurrence of an Expanded CV Composite Endpoint
    Description Prospective comparison of the time to first ccurrence of the expanded composite endpoint. The expanded composite endpoint is defined as the CV composite of the primary endpoint with the addition of non-elective coronary revascularization procedures and hospitalization for unstable angina.
    Time Frame From baseline up to 4.9 years

    Outcome Measure Data

    Analysis Population Description
    Analysis was conducted on the ITT population.
    Arm/Group Title Tocilizumab Etanercept
    Arm/Group Description Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years. Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
    Measure Participants 1538 1542
    Median (95% Confidence Interval) [Months]
    NA
    (NA)
    NA
    (NA)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Tocilizumab, Etanercept
    Comments The analysis assessed in the ITT population the hazard ratio of the secondary endpoint in TCZ compared to ETA patients. This was done through a comparison of the hazard functions between TCZ and ETA patients. A stratified Cox proportional hazards regression model was used in evaluating the relative CV event rate of TCZ over ETA, with the following randomization factors used as strata: Previous exposure to anti-TNF (Yes/No) History of CV events (Yes/No)
    Type of Statistical Test Non-Inferiority or Equivalence
    Comments The non-inferiority margin was only formally tested for the primary ITT analysis.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.99
    Confidence Interval (2-Sided) 95%
    0.73 to 1.34
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    10. Secondary Outcome
    Title Percentages of Participants With an Expanded CV Composite Endpoint
    Description Percentages of participants with the expanded CV composite endpoint. The expanded composite endpoint is defined as the CV composite of the primary endpoint with the addition of non-elective coronary revascularization procedures and hospitalization for unstable angina.
    Time Frame From baseline up to 4.9 years

    Outcome Measure Data

    Analysis Population Description
    Analysis was conducted on the ITT population.
    Arm/Group Title Tocilizumab Etanercept
    Arm/Group Description Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years. Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
    Measure Participants 1538 1542
    Number [Percentages of participants]
    5.5
    0.4%
    5.4
    0.4%
    11. Secondary Outcome
    Title Time to First Occurrence of Individual Component of Primary Endpoint: Non-fatal Myocardial Infarction
    Description Prospective comparison of time to first occurrence of Individual component of primary endpoint: non-fatal Myocardial Infarction
    Time Frame From baseline up to 4.9 years

    Outcome Measure Data

    Analysis Population Description
    Anlysis was conducted on the ITT population.
    Arm/Group Title Tocilizumab Etanercept
    Arm/Group Description Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years. Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
    Measure Participants 1538 1542
    Median (95% Confidence Interval) [Months]
    NA
    (NA)
    NA
    (NA)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Tocilizumab, Etanercept
    Comments The analysis assessed in the ITT population the hazard ratio of the secondary endpoint in TCZ compared to ETA patients. This was done through a comparison of the hazard functions between TCZ and ETA patients. A stratified Cox proportional hazards regression model was used in evaluating the relative CV event rate of TCZ over ETA, with the following randomization factors used as strata: Previous exposure to anti-TNF (Yes/No) History of CV events (Yes/No)
    Type of Statistical Test Non-Inferiority or Equivalence
    Comments 'The non-inferiority margin was only formally tested for the primary ITT analysis'
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.89
    Confidence Interval (2-Sided) 95%
    0.54 to 1.49
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    12. Secondary Outcome
    Title Percentage of Patients With Individual Component of Primary Endpoint: Non-fatal Myocardial Infarction
    Description Percentage of patients reporting Individual component of primary endpoint: non-fatal Myocardial Infarction
    Time Frame From baseline up to 4.9 years

    Outcome Measure Data

    Analysis Population Description
    Anlysis was conducted on the ITT population
    Arm/Group Title Tocilizumab Etanercept
    Arm/Group Description Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years. Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
    Measure Participants 1538 1542
    Number [Percentage of patients]
    1.8
    2.0
    13. Secondary Outcome
    Title Time to First Occurrence of Individual Component of Primary Endpoint: Cardiovascular Death
    Description Prospective comparison of time to first occurrence of Individual component of primary endpoint: cardiovascular death
    Time Frame From baseline up to 4.9 years

    Outcome Measure Data

    Analysis Population Description
    Analysis was conducted on the ITT population
    Arm/Group Title Tocilizumab Etanercept
    Arm/Group Description Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years. Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
    Measure Participants 1538 1542
    Median (95% Confidence Interval) [Months]
    NA
    (NA)
    NA
    (NA)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Tocilizumab, Etanercept
    Comments The analysis assessed in the ITT population the hazard ratio of the secondary endpoint in TCZ compared to ETA patients. This was done through a comparison of the hazard functions between TCZ and ETA patients. A stratified Cox proportional hazards regression model was used in evaluating the relative CV event rate of TCZ over ETA, with the following randomization factors used as strata: Previous exposure to anti-TNF (Yes/No) History of CV events (Yes/No)
    Type of Statistical Test Non-Inferiority or Equivalence
    Comments The non-inferiority margin was only formally tested for the primary ITT analysis.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.03
    Confidence Interval (2-Sided) 95%
    0.64 to 1.63
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    14. Secondary Outcome
    Title Percentage of Patients With Individual Component of Primary Endpoint: Cardiovascular Death
    Description Percentage of patients reporting Individual component of primary endpoint: cardiovascular death
    Time Frame From baseline up to 4.9 years

    Outcome Measure Data

    Analysis Population Description
    Analysis was conducted on the ITT population
    Arm/Group Title Tocilizumab Etanercept
    Arm/Group Description Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years. Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
    Measure Participants 1538 1542
    Number [Percentage of patients]
    2.3
    2.3
    15. Secondary Outcome
    Title Time to First Occurrence of Individual Component of Primary Endpoint: Non-fatal Stroke
    Description Prospective comparison of time to first occurrence of Individual component of primary endpoint: non-fatal stroke
    Time Frame From baseline up to 4.9 years

    Outcome Measure Data

    Analysis Population Description
    Analysis was conducted on the ITT population
    Arm/Group Title Tocilizumab Etanercept
    Arm/Group Description Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years. Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
    Measure Participants 1538 1542
    Median (95% Confidence Interval) [Months]
    NA
    (NA)
    NA
    (NA)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Tocilizumab, Etanercept
    Comments The analysis assessed in the ITT population the hazard ratio of the secondary endpoint in TCZ compared to ETA patients. This was done through a comparison of the hazard functions between TCZ and ETA patients. A stratified Cox proportional hazards regression model was used in evaluating the relative CV event rate of TCZ over ETA, with the following randomization factors used as strata: Previous exposure to anti-TNF (Yes/No) History of CV events (Yes/No)
    Type of Statistical Test Non-Inferiority or Equivalence
    Comments The non-inferiority margin was only formally tested for the primary ITT analysis.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.53
    Confidence Interval (2-Sided) 95%
    0.80 to 2.92
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    16. Secondary Outcome
    Title Percentage of Patients With Individual Component of Primary Endpoint: Non-fatal Stroke
    Description
    Time Frame From baseline up to 4.9 years

    Outcome Measure Data

    Analysis Population Description
    Analysis was conducted on the ITT population
    Arm/Group Title Tocilizumab Etanercept
    Arm/Group Description Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years. Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
    Measure Participants 1538 1542
    Number [Percentage of patients]
    1.6
    1.0
    17. Secondary Outcome
    Title Time to First Occurrence of Individual Component of Primary Endpoint: All-cause Mortality
    Description Prospective comparison of time to first occurrence of Individual component of primary endpoint: All-cause mortality
    Time Frame From baseline up to 4.9 years

    Outcome Measure Data

    Analysis Population Description
    Analysis was conducted on the ITT population.
    Arm/Group Title Tocilizumab Etanercept
    Arm/Group Description Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years. Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
    Measure Participants 1538 1542
    Median (95% Confidence Interval) [Months]
    NA
    (NA)
    NA
    (NA)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Tocilizumab, Etanercept
    Comments The analysis assessed in the ITT population the hazard ratio of the secondary endpoint in TCZ compared to ETA patients. This was done through a comparison of the hazard functions between TCZ and ETA patients. A stratified Cox proportional hazards regression model was used in evaluating the relative CV event rate of TCZ over ETA, with the following randomization factors used as strata: Previous exposure to anti-TNF (Yes/No) History of CV events (Yes/No)
    Type of Statistical Test Non-Inferiority or Equivalence
    Comments The non-inferiority margin was only formally tested for the primary ITT analysis.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.99
    Confidence Interval (2-Sided) 95%
    0.70 to 1.41
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    18. Secondary Outcome
    Title Percentage of Patients With Individual Component of Primary Endpoint: All-cause Mortality
    Description Percentage of patients reporting Individual component of primary endpoint: All-cause mortality
    Time Frame From baseline up to 4.9 years

    Outcome Measure Data

    Analysis Population Description
    Analysis was conducted on the ITT population.
    Arm/Group Title Tocilizumab Etanercept
    Arm/Group Description Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years. Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years.
    Measure Participants 1538 1542
    Number [Percentage of patients]
    4.2
    4.2

    Adverse Events

    Time Frame Adverse events were collected throughout the entire course of the study.
    Adverse Event Reporting Description Analyses were conducted on the On treatment safety (OTS) population, i.e. all patients randomized who have taken at lease one dose of study medication, with patients censored at time of treatment switch. Patients are presented according to treatment received.
    Arm/Group Title Etanercept Tocilizumab
    Arm/Group Description Participants received 50 mg etanercept subcutaneously weekly until switch to another RA therapy or up to 4.9 years. Participants received 8 mg/kg tocilizumab IV every 4 weeks until switch to another RA therapy or up to 4.9 years.
    All Cause Mortality
    Etanercept Tocilizumab
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN)
    Serious Adverse Events
    Etanercept Tocilizumab
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 422/1542 (27.4%) 479/1538 (31.1%)
    Blood and lymphatic system disorders
    ANAEMIA 9/1542 (0.6%) 5/1538 (0.3%)
    AUTOIMMUNE HAEMOLYTIC ANAEMIA 0/1542 (0%) 1/1538 (0.1%)
    COAGULOPATHY 1/1542 (0.1%) 0/1538 (0%)
    GRANULOCYTOPENIA 0/1542 (0%) 1/1538 (0.1%)
    LEUKOCYTOSIS 0/1542 (0%) 1/1538 (0.1%)
    MICROCYTIC ANAEMIA 2/1542 (0.1%) 0/1538 (0%)
    PANCYTOPENIA 4/1542 (0.3%) 1/1538 (0.1%)
    THROMBOCYTOPENIA 0/1542 (0%) 2/1538 (0.1%)
    LEUKOPENIA 0/1542 (0%) 1/1538 (0.1%)
    Cardiac disorders
    ACUTE CORONARY SYNDROME 1/1542 (0.1%) 1/1538 (0.1%)
    ACUTE MYOCARDIAL INFARCTION 9/1542 (0.6%) 7/1538 (0.5%)
    ADAMS-STOKES SYNDROME 1/1542 (0.1%) 0/1538 (0%)
    ANGINA PECTORIS 2/1542 (0.1%) 8/1538 (0.5%)
    ANGINA UNSTABLE 7/1542 (0.5%) 4/1538 (0.3%)
    ATRIAL FIBRILLATION 18/1542 (1.2%) 14/1538 (0.9%)
    ATRIAL FLUTTER 0/1542 (0%) 2/1538 (0.1%)
    ATRIOVENTRICULAR BLOCK SECOND DEGREE 2/1542 (0.1%) 0/1538 (0%)
    BRADYARRHYTHMIA 1/1542 (0.1%) 0/1538 (0%)
    BRADYCARDIA 2/1542 (0.1%) 1/1538 (0.1%)
    BUNDLE BRANCH BLOCK LEFT 0/1542 (0%) 1/1538 (0.1%)
    CARDIAC ARREST 4/1542 (0.3%) 1/1538 (0.1%)
    CARDIAC FAILURE 3/1542 (0.2%) 11/1538 (0.7%)
    CARDIAC FAILURE CHRONIC 1/1542 (0.1%) 0/1538 (0%)
    CARDIAC FAILURE CONGESTIVE 8/1542 (0.5%) 7/1538 (0.5%)
    CARDIAC FIBRILLATION 0/1542 (0%) 1/1538 (0.1%)
    CARDIAC TAMPONADE 1/1542 (0.1%) 0/1538 (0%)
    CARDIOGENIC SHOCK 1/1542 (0.1%) 0/1538 (0%)
    CARDIOMYOPATHY 1/1542 (0.1%) 0/1538 (0%)
    CARDIOPULMONARY FAILURE 1/1542 (0.1%) 4/1538 (0.3%)
    CORONARY ARTERY DISEASE 3/1542 (0.2%) 9/1538 (0.6%)
    CORONARY ARTERY OCCLUSION 1/1542 (0.1%) 1/1538 (0.1%)
    CORONARY ARTERY STENOSIS 2/1542 (0.1%) 0/1538 (0%)
    HYPERTENSIVE HEART DISEASE 0/1542 (0%) 3/1538 (0.2%)
    ISCHAEMIC CARDIOMYOPATHY 2/1542 (0.1%) 0/1538 (0%)
    LEFT VENTRICULAR FAILURE 2/1542 (0.1%) 0/1538 (0%)
    MITRAL VALVE INCOMPETENCE 1/1542 (0.1%) 0/1538 (0%)
    MITRAL VALVE STENOSIS 0/1542 (0%) 1/1538 (0.1%)
    MYOCARDIAL INFARCTION 15/1542 (1%) 10/1538 (0.7%)
    MYOCARDIAL ISCHAEMIA 3/1542 (0.2%) 1/1538 (0.1%)
    PALPITATIONS 1/1542 (0.1%) 1/1538 (0.1%)
    POSTINFARCTION ANGINA 0/1542 (0%) 1/1538 (0.1%)
    SILENT MYOCARDIAL INFARCTION 2/1542 (0.1%) 0/1538 (0%)
    SINOATRIAL BLOCK 1/1542 (0.1%) 0/1538 (0%)
    SINUS BRADYCARDIA 1/1542 (0.1%) 1/1538 (0.1%)
    SINUS NODE DYSFUNCTION 1/1542 (0.1%) 0/1538 (0%)
    SUPRAVENTRICULAR TACHYCARDIA 1/1542 (0.1%) 1/1538 (0.1%)
    TACHYCARDIA 1/1542 (0.1%) 1/1538 (0.1%)
    VENTRICULAR DYSFUNCTION 1/1542 (0.1%) 0/1538 (0%)
    VENTRICULAR FIBRILLATION 1/1542 (0.1%) 0/1538 (0%)
    VENTRICULAR TACHYCARDIA 2/1542 (0.1%) 0/1538 (0%)
    CARDIO-RESPIRATORY ARREST 3/1542 (0.2%) 1/1538 (0.1%)
    Congenital, familial and genetic disorders
    ATRIAL SEPTAL DEFECT 0/1542 (0%) 1/1538 (0.1%)
    HYDROCELE 1/1542 (0.1%) 0/1538 (0%)
    Ear and labyrinth disorders
    DEAFNESS UNILATERAL 1/1542 (0.1%) 1/1538 (0.1%)
    VERTIGO 1/1542 (0.1%) 1/1538 (0.1%)
    Endocrine disorders
    GOITRE 1/1542 (0.1%) 0/1538 (0%)
    HYPERTHYROIDISM 0/1542 (0%) 1/1538 (0.1%)
    HYPOTHYROIDISM 0/1542 (0%) 1/1538 (0.1%)
    Eye disorders
    CATARACT 2/1542 (0.1%) 2/1538 (0.1%)
    CORNEAL PERFORATION 0/1542 (0%) 1/1538 (0.1%)
    KERATITIS 0/1542 (0%) 1/1538 (0.1%)
    RETINAL ARTERY OCCLUSION 1/1542 (0.1%) 1/1538 (0.1%)
    RETINAL DETACHMENT 1/1542 (0.1%) 0/1538 (0%)
    SCLERITIS 1/1542 (0.1%) 0/1538 (0%)
    ULCERATIVE KERATITIS 1/1542 (0.1%) 2/1538 (0.1%)
    Gastrointestinal disorders
    ABDOMINAL ADHESIONS 0/1542 (0%) 1/1538 (0.1%)
    ABDOMINAL HERNIA 1/1542 (0.1%) 0/1538 (0%)
    ABDOMINAL PAIN 4/1542 (0.3%) 3/1538 (0.2%)
    ABDOMINAL PAIN UPPER 0/1542 (0%) 2/1538 (0.1%)
    ACID PEPTIC DISEASE 1/1542 (0.1%) 0/1538 (0%)
    ACUTE ABDOMEN 0/1542 (0%) 1/1538 (0.1%)
    ASCITES 0/1542 (0%) 1/1538 (0.1%)
    COLITIS 1/1542 (0.1%) 1/1538 (0.1%)
    COLITIS ISCHAEMIC 1/1542 (0.1%) 0/1538 (0%)
    COLITIS ULCERATIVE 0/1542 (0%) 1/1538 (0.1%)
    CONSTIPATION 0/1542 (0%) 1/1538 (0.1%)
    CROHN'S DISEASE 1/1542 (0.1%) 0/1538 (0%)
    DIAPHRAGMATIC HERNIA 1/1542 (0.1%) 0/1538 (0%)
    DIARRHOEA 4/1542 (0.3%) 2/1538 (0.1%)
    DIVERTICULAR PERFORATION 1/1542 (0.1%) 6/1538 (0.4%)
    DIVERTICULUM 0/1542 (0%) 1/1538 (0.1%)
    DIVERTICULUM INTESTINAL 2/1542 (0.1%) 1/1538 (0.1%)
    DIVERTICULUM INTESTINAL HAEMORRHAGIC 0/1542 (0%) 1/1538 (0.1%)
    DUODENAL ULCER 1/1542 (0.1%) 0/1538 (0%)
    ENTERITIS 0/1542 (0%) 1/1538 (0.1%)
    ENTEROCOLITIS 0/1542 (0%) 2/1538 (0.1%)
    FEMORAL HERNIA 0/1542 (0%) 1/1538 (0.1%)
    GASTRIC ULCER 1/1542 (0.1%) 2/1538 (0.1%)
    GASTRIC ULCER HAEMORRHAGE 0/1542 (0%) 1/1538 (0.1%)
    GASTRIC ULCER PERFORATION 1/1542 (0.1%) 0/1538 (0%)
    GASTRITIS 2/1542 (0.1%) 4/1538 (0.3%)
    GASTRITIS HAEMORRHAGIC 1/1542 (0.1%) 0/1538 (0%)
    GASTROINTESTINAL HAEMORRHAGE 4/1542 (0.3%) 4/1538 (0.3%)
    GASTROINTESTINAL INFLAMMATION 1/1542 (0.1%) 0/1538 (0%)
    GASTROINTESTINAL ULCER HAEMORRHAGE 0/1542 (0%) 1/1538 (0.1%)
    GASTROOESOPHAGEAL REFLUX DISEASE 1/1542 (0.1%) 1/1538 (0.1%)
    HAEMATEMESIS 0/1542 (0%) 2/1538 (0.1%)
    HAEMATOCHEZIA 1/1542 (0.1%) 0/1538 (0%)
    HAEMORRHOIDS 0/1542 (0%) 1/1538 (0.1%)
    INCARCERATED HIATUS HERNIA 1/1542 (0.1%) 0/1538 (0%)
    INCARCERATED UMBILICAL HERNIA 0/1542 (0%) 1/1538 (0.1%)
    INGUINAL HERNIA 1/1542 (0.1%) 1/1538 (0.1%)
    INTESTINAL OBSTRUCTION 1/1542 (0.1%) 1/1538 (0.1%)
    LARGE INTESTINAL STENOSIS 0/1542 (0%) 1/1538 (0.1%)
    LARGE INTESTINE PERFORATION 0/1542 (0%) 4/1538 (0.3%)
    LARGE INTESTINE POLYP 2/1542 (0.1%) 0/1538 (0%)
    LOWER GASTROINTESTINAL HAEMORRHAGE 2/1542 (0.1%) 0/1538 (0%)
    MALLORY-WEISS SYNDROME 0/1542 (0%) 1/1538 (0.1%)
    MELAENA 1/1542 (0.1%) 0/1538 (0%)
    NAUSEA 0/1542 (0%) 2/1538 (0.1%)
    OESOPHAGITIS 0/1542 (0%) 1/1538 (0.1%)
    PALATAL DISORDER 1/1542 (0.1%) 0/1538 (0%)
    PANCREATITIS 1/1542 (0.1%) 4/1538 (0.3%)
    PANCREATITIS ACUTE 3/1542 (0.2%) 5/1538 (0.3%)
    PEPTIC ULCER 1/1542 (0.1%) 1/1538 (0.1%)
    PEPTIC ULCER HAEMORRHAGE 0/1542 (0%) 1/1538 (0.1%)
    RETROPERITONEAL FIBROSIS 1/1542 (0.1%) 1/1538 (0.1%)
    UPPER GASTROINTESTINAL HAEMORRHAGE 2/1542 (0.1%) 2/1538 (0.1%)
    VOMITING 0/1542 (0%) 1/1538 (0.1%)
    General disorders
    CHEST PAIN 10/1542 (0.6%) 3/1538 (0.2%)
    COMPLICATION ASSOCIATED WITH DEVICE 0/1542 (0%) 1/1538 (0.1%)
    DEATH 4/1542 (0.3%) 3/1538 (0.2%)
    GENERAL PHYSICAL HEALTH DETERIORATION 0/1542 (0%) 1/1538 (0.1%)
    IMPAIRED HEALING 0/1542 (0%) 1/1538 (0.1%)
    LOCAL SWELLING 0/1542 (0%) 1/1538 (0.1%)
    MULTIPLE ORGAN DYSFUNCTION SYNDROME 0/1542 (0%) 2/1538 (0.1%)
    NON-CARDIAC CHEST PAIN 1/1542 (0.1%) 5/1538 (0.3%)
    OEDEMA PERIPHERAL 1/1542 (0.1%) 0/1538 (0%)
    PAIN 0/1542 (0%) 1/1538 (0.1%)
    PYREXIA 3/1542 (0.2%) 3/1538 (0.2%)
    SUDDEN DEATH 1/1542 (0.1%) 3/1538 (0.2%)
    SWELLING 0/1542 (0%) 1/1538 (0.1%)
    Hepatobiliary disorders
    BILE DUCT OBSTRUCTION 0/1542 (0%) 1/1538 (0.1%)
    CHOLANGITIS ACUTE 0/1542 (0%) 1/1538 (0.1%)
    CHOLECYSTITIS 0/1542 (0%) 3/1538 (0.2%)
    CHOLECYSTITIS ACUTE 2/1542 (0.1%) 1/1538 (0.1%)
    CHOLECYSTITIS CHRONIC 1/1542 (0.1%) 1/1538 (0.1%)
    CHOLELITHIASIS 6/1542 (0.4%) 14/1538 (0.9%)
    HEPATIC VEIN THROMBOSIS 1/1542 (0.1%) 0/1538 (0%)
    HEPATITIS 0/1542 (0%) 2/1538 (0.1%)
    HEPATITIS ACUTE 1/1542 (0.1%) 0/1538 (0%)
    POST CHOLECYSTECTOMY SYNDROME 0/1542 (0%) 1/1538 (0.1%)
    Immune system disorders
    DRUG HYPERSENSITIVITY 0/1542 (0%) 1/1538 (0.1%)
    HYPERSENSITIVITY 0/1542 (0%) 1/1538 (0.1%)
    OVERLAP SYNDROME 1/1542 (0.1%) 0/1538 (0%)
    SARCOIDOSIS 1/1542 (0.1%) 0/1538 (0%)
    Infections and infestations
    ABSCESS 1/1542 (0.1%) 1/1538 (0.1%)
    ABSCESS LIMB 0/1542 (0%) 6/1538 (0.4%)
    ABSCESS ORAL 0/1542 (0%) 1/1538 (0.1%)
    ABSCESS RUPTURE 1/1542 (0.1%) 0/1538 (0%)
    ACUTE SINUSITIS 1/1542 (0.1%) 0/1538 (0%)
    ANAL ABSCESS 1/1542 (0.1%) 0/1538 (0%)
    APPENDICITIS 0/1542 (0%) 3/1538 (0.2%)
    ARTHRITIS BACTERIAL 6/1542 (0.4%) 9/1538 (0.6%)
    ARTHRITIS INFECTIVE 1/1542 (0.1%) 2/1538 (0.1%)
    ASPERGILLUS INFECTION 0/1542 (0%) 1/1538 (0.1%)
    ATYPICAL PNEUMONIA 2/1542 (0.1%) 0/1538 (0%)
    BILIARY SEPSIS 0/1542 (0%) 1/1538 (0.1%)
    BRONCHITIS 4/1542 (0.3%) 5/1538 (0.3%)
    BRONCHITIS VIRAL 1/1542 (0.1%) 0/1538 (0%)
    BRONCHOPULMONARY ASPERGILLOSIS 1/1542 (0.1%) 0/1538 (0%)
    BURSITIS INFECTIVE 0/1542 (0%) 2/1538 (0.1%)
    CELLULITIS 8/1542 (0.5%) 24/1538 (1.6%)
    CELLULITIS STAPHYLOCOCCAL 1/1542 (0.1%) 0/1538 (0%)
    CELLULITIS STREPTOCOCCAL 0/1542 (0%) 1/1538 (0.1%)
    CERVICITIS 0/1542 (0%) 1/1538 (0.1%)
    CHRONIC TONSILLITIS 0/1542 (0%) 1/1538 (0.1%)
    CLOSTRIDIUM DIFFICILE COLITIS 1/1542 (0.1%) 0/1538 (0%)
    CLOSTRIDIUM DIFFICILE INFECTION 1/1542 (0.1%) 0/1538 (0%)
    COLONIC ABSCESS 0/1542 (0%) 1/1538 (0.1%)
    DENGUE FEVER 0/1542 (0%) 1/1538 (0.1%)
    DEVICE RELATED INFECTION 1/1542 (0.1%) 1/1538 (0.1%)
    DEVICE RELATED SEPSIS 0/1542 (0%) 1/1538 (0.1%)
    DISSEMINATED TUBERCULOSIS 1/1542 (0.1%) 1/1538 (0.1%)
    DIVERTICULITIS 1/1542 (0.1%) 10/1538 (0.7%)
    EMPYEMA 1/1542 (0.1%) 1/1538 (0.1%)
    ENDOPHTHALMITIS 1/1542 (0.1%) 0/1538 (0%)
    ENTERITIS INFECTIOUS 2/1542 (0.1%) 0/1538 (0%)
    EPIDIDYMITIS 1/1542 (0.1%) 1/1538 (0.1%)
    EPIGLOTTITIS 0/1542 (0%) 2/1538 (0.1%)
    ERYSIPELAS 2/1542 (0.1%) 11/1538 (0.7%)
    ESCHERICHIA PYELONEPHRITIS 0/1542 (0%) 1/1538 (0.1%)
    ESCHERICHIA SEPSIS 0/1542 (0%) 1/1538 (0.1%)
    ESCHERICHIA URINARY TRACT INFECTION 1/1542 (0.1%) 0/1538 (0%)
    FUNGAL SKIN INFECTION 0/1542 (0%) 1/1538 (0.1%)
    GASTROENTERITIS 6/1542 (0.4%) 3/1538 (0.2%)
    GASTROENTERITIS NOROVIRUS 0/1542 (0%) 1/1538 (0.1%)
    GASTROENTERITIS VIRAL 1/1542 (0.1%) 1/1538 (0.1%)
    GROIN ABSCESS 1/1542 (0.1%) 0/1538 (0%)
    HAEMATOMA INFECTION 0/1542 (0%) 1/1538 (0.1%)
    HAEMOPHILUS SEPSIS 0/1542 (0%) 1/1538 (0.1%)
    HERPANGINA 0/1542 (0%) 1/1538 (0.1%)
    HERPES ZOSTER 4/1542 (0.3%) 2/1538 (0.1%)
    INFECTED DERMAL CYST 1/1542 (0.1%) 1/1538 (0.1%)
    INFECTION 1/1542 (0.1%) 0/1538 (0%)
    INFECTIOUS COLITIS 2/1542 (0.1%) 0/1538 (0%)
    INFECTIOUS PLEURAL EFFUSION 1/1542 (0.1%) 3/1538 (0.2%)
    INFECTIVE ANEURYSM 0/1542 (0%) 1/1538 (0.1%)
    INFLUENZA 1/1542 (0.1%) 1/1538 (0.1%)
    INJECTION SITE ABSCESS 0/1542 (0%) 1/1538 (0.1%)
    INTERVERTEBRAL DISCITIS 0/1542 (0%) 1/1538 (0.1%)
    LOCALISED INFECTION 0/1542 (0%) 1/1538 (0.1%)
    LOWER RESPIRATORY TRACT INFECTION 2/1542 (0.1%) 1/1538 (0.1%)
    LUDWIG ANGINA 0/1542 (0%) 1/1538 (0.1%)
    LUNG ABSCESS 0/1542 (0%) 1/1538 (0.1%)
    LUNG INFECTION 1/1542 (0.1%) 0/1538 (0%)
    LUNG INFECTION PSEUDOMONAL 0/1542 (0%) 1/1538 (0.1%)
    MASTOIDITIS 0/1542 (0%) 1/1538 (0.1%)
    MENINGITIS 0/1542 (0%) 2/1538 (0.1%)
    MUSCLE ABSCESS 1/1542 (0.1%) 1/1538 (0.1%)
    NASAL ABSCESS 1/1542 (0.1%) 0/1538 (0%)
    NEUROSYPHILIS 0/1542 (0%) 1/1538 (0.1%)
    OESOPHAGEAL CANDIDIASIS 2/1542 (0.1%) 0/1538 (0%)
    OPHTHALMIC HERPES SIMPLEX 1/1542 (0.1%) 0/1538 (0%)
    OPHTHALMIC HERPES ZOSTER 1/1542 (0.1%) 2/1538 (0.1%)
    OSTEOMYELITIS 2/1542 (0.1%) 2/1538 (0.1%)
    OSTEOMYELITIS CHRONIC 1/1542 (0.1%) 0/1538 (0%)
    OTITIS EXTERNA 0/1542 (0%) 1/1538 (0.1%)
    PAPILLOMA VIRAL INFECTION 0/1542 (0%) 1/1538 (0.1%)
    PERIHEPATIC ABSCESS 1/1542 (0.1%) 0/1538 (0%)
    PERITONITIS 0/1542 (0%) 3/1538 (0.2%)
    PERITONSILLAR ABSCESS 1/1542 (0.1%) 0/1538 (0%)
    PHARYNGITIS 1/1542 (0.1%) 0/1538 (0%)
    PNEUMOCYSTIS JIROVECII PNEUMONIA 1/1542 (0.1%) 0/1538 (0%)
    PNEUMONIA 41/1542 (2.7%) 47/1538 (3.1%)
    PNEUMONIA BACTERIAL 1/1542 (0.1%) 1/1538 (0.1%)
    PNEUMONIA INFLUENZAL 1/1542 (0.1%) 0/1538 (0%)
    PNEUMONIA MYCOPLASMAL 1/1542 (0.1%) 0/1538 (0%)
    PNEUMONIA PNEUMOCOCCAL 0/1542 (0%) 1/1538 (0.1%)
    PNEUMONIA STAPHYLOCOCCAL 1/1542 (0.1%) 0/1538 (0%)
    PNEUMONIA VIRAL 1/1542 (0.1%) 0/1538 (0%)
    POST PROCEDURAL INFECTION 0/1542 (0%) 2/1538 (0.1%)
    POSTOPERATIVE WOUND INFECTION 4/1542 (0.3%) 1/1538 (0.1%)
    PSEUDOMONAS INFECTION 0/1542 (0%) 1/1538 (0.1%)
    PULMONARY TUBERCULOMA 1/1542 (0.1%) 0/1538 (0%)
    PULMONARY TUBERCULOSIS 1/1542 (0.1%) 1/1538 (0.1%)
    PYELONEPHRITIS 1/1542 (0.1%) 5/1538 (0.3%)
    RECTAL ABSCESS 0/1542 (0%) 1/1538 (0.1%)
    RESPIRATORY TRACT INFECTION 2/1542 (0.1%) 2/1538 (0.1%)
    SALPINGITIS 0/1542 (0%) 1/1538 (0.1%)
    SCROTAL ABSCESS 0/1542 (0%) 1/1538 (0.1%)
    SEPSIS 7/1542 (0.5%) 6/1538 (0.4%)
    SEPTIC SHOCK 3/1542 (0.2%) 3/1538 (0.2%)
    SINUSITIS 2/1542 (0.1%) 0/1538 (0%)
    SOFT TISSUE INFECTION 0/1542 (0%) 1/1538 (0.1%)
    STAPHYLOCOCCAL INFECTION 1/1542 (0.1%) 1/1538 (0.1%)
    STAPHYLOCOCCAL SEPSIS 0/1542 (0%) 2/1538 (0.1%)
    STREPTOCOCCAL BACTERAEMIA 1/1542 (0.1%) 0/1538 (0%)
    SUBCUTANEOUS ABSCESS 3/1542 (0.2%) 2/1538 (0.1%)
    TONGUE ABSCESS 1/1542 (0.1%) 0/1538 (0%)
    TONSILLITIS 0/1542 (0%) 1/1538 (0.1%)
    TOXIC SHOCK SYNDROME STREPTOCOCCAL 0/1542 (0%) 1/1538 (0.1%)
    TRACHEITIS 1/1542 (0.1%) 0/1538 (0%)
    TUBERCULOSIS 0/1542 (0%) 1/1538 (0.1%)
    UPPER RESPIRATORY TRACT INFECTION 1/1542 (0.1%) 1/1538 (0.1%)
    URINARY TRACT INFECTION 12/1542 (0.8%) 7/1538 (0.5%)
    URINARY TRACT INFECTION BACTERIAL 0/1542 (0%) 1/1538 (0.1%)
    UROSEPSIS 2/1542 (0.1%) 1/1538 (0.1%)
    VIRAL INFECTION 0/1542 (0%) 1/1538 (0.1%)
    VIRAL PHARYNGITIS 1/1542 (0.1%) 0/1538 (0%)
    WEST NILE VIRAL INFECTION 1/1542 (0.1%) 0/1538 (0%)
    WOUND INFECTION 1/1542 (0.1%) 1/1538 (0.1%)
    Injury, poisoning and procedural complications
    ACCIDENT AT WORK 0/1542 (0%) 1/1538 (0.1%)
    ANAEMIA POSTOPERATIVE 0/1542 (0%) 1/1538 (0.1%)
    ANKLE FRACTURE 0/1542 (0%) 1/1538 (0.1%)
    ARTHROPOD STING 1/1542 (0.1%) 0/1538 (0%)
    COMMINUTED FRACTURE 1/1542 (0.1%) 0/1538 (0%)
    CONTUSION 1/1542 (0.1%) 1/1538 (0.1%)
    DISLOCATION OF VERTEBRA 2/1542 (0.1%) 0/1538 (0%)
    FALL 1/1542 (0.1%) 2/1538 (0.1%)
    FEMORAL NECK FRACTURE 3/1542 (0.2%) 0/1538 (0%)
    FEMUR FRACTURE 6/1542 (0.4%) 5/1538 (0.3%)
    FOOT FRACTURE 0/1542 (0%) 1/1538 (0.1%)
    FRACTURE DISPLACEMENT 1/1542 (0.1%) 0/1538 (0%)
    GUN SHOT WOUND 1/1542 (0.1%) 0/1538 (0%)
    HAND FRACTURE 1/1542 (0.1%) 0/1538 (0%)
    HIP FRACTURE 12/1542 (0.8%) 4/1538 (0.3%)
    HUMERUS FRACTURE 4/1542 (0.3%) 3/1538 (0.2%)
    INFUSION RELATED REACTION 0/1542 (0%) 2/1538 (0.1%)
    JOINT DISLOCATION 2/1542 (0.1%) 3/1538 (0.2%)
    JOINT INJURY 1/1542 (0.1%) 0/1538 (0%)
    LIGAMENT INJURY 1/1542 (0.1%) 0/1538 (0%)
    LOWER LIMB FRACTURE 1/1542 (0.1%) 0/1538 (0%)
    OVERDOSE 1/1542 (0.1%) 0/1538 (0%)
    PATELLA FRACTURE 1/1542 (0.1%) 0/1538 (0%)
    PNEUMOTHORAX TRAUMATIC 0/1542 (0%) 1/1538 (0.1%)
    POST PROCEDURAL FISTULA 0/1542 (0%) 1/1538 (0.1%)
    POST PROCEDURAL HAEMATOMA 0/1542 (0%) 1/1538 (0.1%)
    RADIUS FRACTURE 0/1542 (0%) 2/1538 (0.1%)
    RESPIRATORY FUME INHALATION DISORDER 0/1542 (0%) 1/1538 (0.1%)
    RIB FRACTURE 4/1542 (0.3%) 1/1538 (0.1%)
    SPINAL COMPRESSION FRACTURE 1/1542 (0.1%) 1/1538 (0.1%)
    SPINAL FRACTURE 0/1542 (0%) 1/1538 (0.1%)
    STOMAL HERNIA 0/1542 (0%) 1/1538 (0.1%)
    STRESS FRACTURE 1/1542 (0.1%) 0/1538 (0%)
    SUBCUTANEOUS HAEMATOMA 0/1542 (0%) 1/1538 (0.1%)
    SUBDURAL HAEMATOMA 0/1542 (0%) 2/1538 (0.1%)
    SYNOVIAL RUPTURE 1/1542 (0.1%) 0/1538 (0%)
    TENDON RUPTURE 2/1542 (0.1%) 1/1538 (0.1%)
    THORACIC VERTEBRAL FRACTURE 2/1542 (0.1%) 0/1538 (0%)
    ULNA FRACTURE 1/1542 (0.1%) 2/1538 (0.1%)
    UPPER LIMB FRACTURE 0/1542 (0%) 2/1538 (0.1%)
    WOUND 0/1542 (0%) 1/1538 (0.1%)
    WOUND DEHISCENCE 0/1542 (0%) 1/1538 (0.1%)
    WRIST FRACTURE 2/1542 (0.1%) 0/1538 (0%)
    Investigations
    EOSINOPHIL COUNT INCREASED 1/1542 (0.1%) 0/1538 (0%)
    HAEMATOCRIT ABNORMAL 0/1542 (0%) 1/1538 (0.1%)
    HAEMOGLOBIN ABNORMAL 0/1542 (0%) 1/1538 (0.1%)
    LIVER FUNCTION TEST INCREASED 1/1542 (0.1%) 0/1538 (0%)
    STAPHYLOCOCCUS TEST POSITIVE 1/1542 (0.1%) 0/1538 (0%)
    SYNOVIAL FLUID WHITE BLOOD CELLS POSITIVE 0/1542 (0%) 1/1538 (0.1%)
    TRANSAMINASES INCREASED 1/1542 (0.1%) 0/1538 (0%)
    TROPONIN INCREASED 2/1542 (0.1%) 0/1538 (0%)
    Metabolism and nutrition disorders
    DEHYDRATION 4/1542 (0.3%) 5/1538 (0.3%)
    DIABETES MELLITUS 0/1542 (0%) 1/1538 (0.1%)
    DIABETIC COMPLICATION 1/1542 (0.1%) 0/1538 (0%)
    ELECTROLYTE IMBALANCE 1/1542 (0.1%) 0/1538 (0%)
    HYPERGLYCAEMIA 1/1542 (0.1%) 0/1538 (0%)
    HYPERKALAEMIA 3/1542 (0.2%) 0/1538 (0%)
    HYPOKALAEMIA 1/1542 (0.1%) 0/1538 (0%)
    HYPONATRAEMIA 3/1542 (0.2%) 1/1538 (0.1%)
    METABOLIC ACIDOSIS 1/1542 (0.1%) 0/1538 (0%)
    TYPE 2 DIABETES MELLITUS 1/1542 (0.1%) 0/1538 (0%)
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA 1/1542 (0.1%) 1/1538 (0.1%)
    ARTHRITIS 1/1542 (0.1%) 1/1538 (0.1%)
    BACK PAIN 6/1542 (0.4%) 0/1538 (0%)
    BURSITIS 2/1542 (0.1%) 2/1538 (0.1%)
    COSTOCHONDRITIS 1/1542 (0.1%) 0/1538 (0%)
    FASCIITIS 1/1542 (0.1%) 0/1538 (0%)
    FINGER DEFORMITY 0/1542 (0%) 1/1538 (0.1%)
    FISTULA 0/1542 (0%) 1/1538 (0.1%)
    FOOT DEFORMITY 3/1542 (0.2%) 2/1538 (0.1%)
    HAEMARTHROSIS 1/1542 (0.1%) 0/1538 (0%)
    INTERVERTEBRAL DISC DISORDER 0/1542 (0%) 3/1538 (0.2%)
    INTERVERTEBRAL DISC PROTRUSION 6/1542 (0.4%) 5/1538 (0.3%)
    KNEE DEFORMITY 0/1542 (0%) 1/1538 (0.1%)
    LIMB DEFORMITY 1/1542 (0.1%) 0/1538 (0%)
    LUMBAR SPINAL STENOSIS 1/1542 (0.1%) 0/1538 (0%)
    MORPHOEA 1/1542 (0.1%) 0/1538 (0%)
    MUSCLE SPASMS 1/1542 (0.1%) 0/1538 (0%)
    MUSCULOSKELETAL CHEST PAIN 1/1542 (0.1%) 0/1538 (0%)
    MYALGIA 0/1542 (0%) 1/1538 (0.1%)
    NECK PAIN 0/1542 (0%) 1/1538 (0.1%)
    OSTEOARTHRITIS 22/1542 (1.4%) 14/1538 (0.9%)
    OSTEONECROSIS 4/1542 (0.3%) 2/1538 (0.1%)
    OSTEONECROSIS OF JAW 1/1542 (0.1%) 0/1538 (0%)
    OSTEOPOROSIS 0/1542 (0%) 1/1538 (0.1%)
    OSTEOPOROTIC FRACTURE 2/1542 (0.1%) 1/1538 (0.1%)
    PAIN IN EXTREMITY 1/1542 (0.1%) 1/1538 (0.1%)
    PERIARTHRITIS 0/1542 (0%) 1/1538 (0.1%)
    RHEUMATOID ARTHRITIS 15/1542 (1%) 12/1538 (0.8%)
    RHEUMATOID NODULE 0/1542 (0%) 1/1538 (0.1%)
    ROTATOR CUFF SYNDROME 1/1542 (0.1%) 0/1538 (0%)
    SPINAL OSTEOARTHRITIS 1/1542 (0.1%) 0/1538 (0%)
    SPONDYLOLISTHESIS 1/1542 (0.1%) 0/1538 (0%)
    SYNOVIAL CYST 0/1542 (0%) 1/1538 (0.1%)
    SYNOVITIS 1/1542 (0.1%) 1/1538 (0.1%)
    TENOSYNOVITIS 1/1542 (0.1%) 0/1538 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    ADENOCARCINOMA 1/1542 (0.1%) 0/1538 (0%)
    ADENOCARCINOMA OF COLON 2/1542 (0.1%) 0/1538 (0%)
    ANAL SQUAMOUS CELL CARCINOMA 1/1542 (0.1%) 0/1538 (0%)
    BASAL CELL CARCINOMA 3/1542 (0.2%) 1/1538 (0.1%)
    BENIGN ANORECTAL NEOPLASM 0/1542 (0%) 1/1538 (0.1%)
    BENIGN NEOPLASM OF CERVIX UTERI 0/1542 (0%) 1/1538 (0.1%)
    BLADDER CANCER 1/1542 (0.1%) 0/1538 (0%)
    BLADDER TRANSITIONAL CELL CARCINOMA 0/1542 (0%) 1/1538 (0.1%)
    BRAIN NEOPLASM 0/1542 (0%) 1/1538 (0.1%)
    BREAST CANCER 3/1542 (0.2%) 3/1538 (0.2%)
    CARCINOID TUMOUR OF THE GASTROINTESTINAL TRACT 0/1542 (0%) 1/1538 (0.1%)
    CARCINOID TUMOUR PULMONARY 1/1542 (0.1%) 0/1538 (0%)
    CARDIAC MYXOMA 0/1542 (0%) 1/1538 (0.1%)
    CENTRAL NERVOUS SYSTEM LYMPHOMA 0/1542 (0%) 1/1538 (0.1%)
    CEREBRAL HAEMANGIOMA 0/1542 (0%) 1/1538 (0.1%)
    CHOLANGIOCARCINOMA 1/1542 (0.1%) 0/1538 (0%)
    COLON ADENOMA 1/1542 (0.1%) 0/1538 (0%)
    COLON CANCER 1/1542 (0.1%) 0/1538 (0%)
    COLON CANCER METASTATIC 1/1542 (0.1%) 0/1538 (0%)
    COLORECTAL CANCER 1/1542 (0.1%) 0/1538 (0%)
    DIFFUSE LARGE B-CELL LYMPHOMA 0/1542 (0%) 1/1538 (0.1%)
    ENDOMETRIAL ADENOCARCINOMA 0/1542 (0%) 1/1538 (0.1%)
    GLIOBLASTOMA 0/1542 (0%) 1/1538 (0.1%)
    HAEMANGIOMA 0/1542 (0%) 1/1538 (0.1%)
    INTESTINAL ADENOCARCINOMA 0/1542 (0%) 1/1538 (0.1%)
    INTRADUCTAL PROLIFERATIVE BREAST LESION 1/1542 (0.1%) 0/1538 (0%)
    LARYNGEAL CANCER 0/1542 (0%) 1/1538 (0.1%)
    LUNG ADENOCARCINOMA 1/1542 (0.1%) 3/1538 (0.2%)
    LUNG ADENOCARCINOMA STAGE IV 1/1542 (0.1%) 0/1538 (0%)
    LUNG CANCER METASTATIC 2/1542 (0.1%) 2/1538 (0.1%)
    LUNG NEOPLASM 1/1542 (0.1%) 1/1538 (0.1%)
    LUNG NEOPLASM MALIGNANT 4/1542 (0.3%) 3/1538 (0.2%)
    MALIGNANT MELANOMA STAGE II 1/1542 (0.1%) 0/1538 (0%)
    MARJOLIN'S ULCER 1/1542 (0.1%) 0/1538 (0%)
    METASTASES TO BONE 1/1542 (0.1%) 0/1538 (0%)
    METASTATIC GASTRIC CANCER 1/1542 (0.1%) 0/1538 (0%)
    METASTATIC NEOPLASM 1/1542 (0.1%) 0/1538 (0%)
    NEOPLASM MALIGNANT 0/1542 (0%) 1/1538 (0.1%)
    NON-HODGKIN'S LYMPHOMA 0/1542 (0%) 1/1538 (0.1%)
    OVARIAN ADENOMA 0/1542 (0%) 1/1538 (0.1%)
    OVARIAN CANCER 0/1542 (0%) 2/1538 (0.1%)
    PANCREATIC CARCINOMA METASTATIC 0/1542 (0%) 1/1538 (0.1%)
    PANCREATIC NEOPLASM 1/1542 (0.1%) 0/1538 (0%)
    PAPILLARY THYROID CANCER 0/1542 (0%) 1/1538 (0.1%)
    PARAPROTEINAEMIA 1/1542 (0.1%) 0/1538 (0%)
    PARATHYROID TUMOUR BENIGN 0/1542 (0%) 1/1538 (0.1%)
    PHARYNGEAL NEOPLASM BENIGN 1/1542 (0.1%) 0/1538 (0%)
    PITUITARY TUMOUR BENIGN 1/1542 (0.1%) 0/1538 (0%)
    PLASMA CELL MYELOMA 1/1542 (0.1%) 0/1538 (0%)
    PROSTATE CANCER 1/1542 (0.1%) 3/1538 (0.2%)
    RENAL CANCER 0/1542 (0%) 1/1538 (0.1%)
    RENAL CELL CARCINOMA 1/1542 (0.1%) 0/1538 (0%)
    SMALL CELL LUNG CANCER 1/1542 (0.1%) 0/1538 (0%)
    SQUAMOUS CELL CARCINOMA OF LUNG 1/1542 (0.1%) 0/1538 (0%)
    SQUAMOUS CELL CARCINOMA OF THE TONGUE 0/1542 (0%) 1/1538 (0.1%)
    SQUAMOUS ENDOMETRIAL CARCINOMA 0/1542 (0%) 1/1538 (0.1%)
    THYROID ADENOMA 0/1542 (0%) 1/1538 (0.1%)
    TONGUE NEOPLASM MALIGNANT STAGE UNSPECIFIED 1/1542 (0.1%) 1/1538 (0.1%)
    TUMOUR INVASION 1/1542 (0.1%) 0/1538 (0%)
    UTERINE CANCER 0/1542 (0%) 3/1538 (0.2%)
    Nervous system disorders
    AMYOTROPHIC LATERAL SCLEROSIS 1/1542 (0.1%) 0/1538 (0%)
    BALANCE DISORDER 1/1542 (0.1%) 0/1538 (0%)
    BRAIN STEM INFARCTION 0/1542 (0%) 1/1538 (0.1%)
    CAROTID ARTERY DISEASE 1/1542 (0.1%) 0/1538 (0%)
    CAROTID ARTERY STENOSIS 1/1542 (0.1%) 1/1538 (0.1%)
    CEREBRAL HAEMATOMA 0/1542 (0%) 1/1538 (0.1%)
    CEREBRAL INFARCTION 2/1542 (0.1%) 1/1538 (0.1%)
    CEREBRAL ISCHAEMIA 2/1542 (0.1%) 1/1538 (0.1%)
    CEREBROVASCULAR ACCIDENT 8/1542 (0.5%) 14/1538 (0.9%)
    CEREBROVASCULAR DISORDER 1/1542 (0.1%) 1/1538 (0.1%)
    CERVICAL CORD COMPRESSION 0/1542 (0%) 1/1538 (0.1%)
    CERVICAL RADICULOPATHY 1/1542 (0.1%) 0/1538 (0%)
    COMA 1/1542 (0.1%) 0/1538 (0%)
    DEMENTIA 0/1542 (0%) 1/1538 (0.1%)
    DEMENTIA ALZHEIMER'S TYPE 0/1542 (0%) 1/1538 (0.1%)
    DIABETIC COMA 0/1542 (0%) 1/1538 (0.1%)
    DYSARTHRIA 0/1542 (0%) 1/1538 (0.1%)
    DYSKINESIA 0/1542 (0%) 1/1538 (0.1%)
    EMBOLIC STROKE 1/1542 (0.1%) 0/1538 (0%)
    ENCEPHALOPATHY 1/1542 (0.1%) 0/1538 (0%)
    EPILEPSY 0/1542 (0%) 3/1538 (0.2%)
    FACIAL PARALYSIS 0/1542 (0%) 1/1538 (0.1%)
    GENERALISED TONIC-CLONIC SEIZURE 0/1542 (0%) 1/1538 (0.1%)
    HAEMORRHAGIC STROKE 1/1542 (0.1%) 0/1538 (0%)
    HEMIPARESIS 1/1542 (0.1%) 0/1538 (0%)
    HEPATIC ENCEPHALOPATHY 0/1542 (0%) 1/1538 (0.1%)
    HYPERTENSIVE ENCEPHALOPATHY 0/1542 (0%) 1/1538 (0.1%)
    INTRACRANIAL ANEURYSM 0/1542 (0%) 1/1538 (0.1%)
    ISCHAEMIC STROKE 5/1542 (0.3%) 5/1538 (0.3%)
    LOSS OF CONSCIOUSNESS 1/1542 (0.1%) 0/1538 (0%)
    LUMBAR RADICULOPATHY 2/1542 (0.1%) 0/1538 (0%)
    METABOLIC ENCEPHALOPATHY 1/1542 (0.1%) 0/1538 (0%)
    MIGRAINE 0/1542 (0%) 1/1538 (0.1%)
    MYASTHENIA GRAVIS 1/1542 (0.1%) 0/1538 (0%)
    PARAESTHESIA 1/1542 (0.1%) 1/1538 (0.1%)
    PARKINSON'S DISEASE 1/1542 (0.1%) 0/1538 (0%)
    PRESYNCOPE 2/1542 (0.1%) 0/1538 (0%)
    REVERSIBLE ISCHAEMIC NEUROLOGICAL DEFICIT 1/1542 (0.1%) 0/1538 (0%)
    RUPTURED CEREBRAL ANEURYSM 0/1542 (0%) 1/1538 (0.1%)
    SCIATICA 3/1542 (0.2%) 1/1538 (0.1%)
    SEIZURE 1/1542 (0.1%) 1/1538 (0.1%)
    SPINAL CORD COMPRESSION 0/1542 (0%) 2/1538 (0.1%)
    SUBARACHNOID HAEMORRHAGE 3/1542 (0.2%) 1/1538 (0.1%)
    SYNCOPE 1/1542 (0.1%) 0/1538 (0%)
    TRANSIENT GLOBAL AMNESIA 1/1542 (0.1%) 0/1538 (0%)
    TRANSIENT ISCHAEMIC ATTACK 3/1542 (0.2%) 9/1538 (0.6%)
    VASCULAR DEMENTIA 0/1542 (0%) 1/1538 (0.1%)
    Product Issues
    DEVICE BREAKAGE 1/1542 (0.1%) 0/1538 (0%)
    DEVICE DISLOCATION 0/1542 (0%) 3/1538 (0.2%)
    DEVICE FAILURE 0/1542 (0%) 1/1538 (0.1%)
    DEVICE LOOSENING 0/1542 (0%) 1/1538 (0.1%)
    Psychiatric disorders
    BURNOUT SYNDROME 1/1542 (0.1%) 0/1538 (0%)
    CONFUSIONAL STATE 0/1542 (0%) 1/1538 (0.1%)
    DELIRIUM 0/1542 (0%) 1/1538 (0.1%)
    DELIRIUM TREMENS 1/1542 (0.1%) 0/1538 (0%)
    DEPRESSION 2/1542 (0.1%) 0/1538 (0%)
    MAJOR DEPRESSION 0/1542 (0%) 1/1538 (0.1%)
    MENTAL DISORDER 1/1542 (0.1%) 0/1538 (0%)
    MENTAL STATUS CHANGES 0/1542 (0%) 1/1538 (0.1%)
    PSYCHOTIC DISORDER 0/1542 (0%) 1/1538 (0.1%)
    SCHIZOAFFECTIVE DISORDER BIPOLAR TYPE 0/1542 (0%) 1/1538 (0.1%)
    SUICIDAL IDEATION 0/1542 (0%) 1/1538 (0.1%)
    SUICIDE ATTEMPT 0/1542 (0%) 1/1538 (0.1%)
    MANIA 1/1542 (0.1%) 0/1538 (0%)
    Renal and urinary disorders
    ACUTE KIDNEY INJURY 5/1542 (0.3%) 3/1538 (0.2%)
    CALCULUS BLADDER 0/1542 (0%) 1/1538 (0.1%)
    CALCULUS URINARY 2/1542 (0.1%) 1/1538 (0.1%)
    CHRONIC KIDNEY DISEASE 1/1542 (0.1%) 1/1538 (0.1%)
    CYSTITIS HAEMORRHAGIC 1/1542 (0.1%) 0/1538 (0%)
    END STAGE RENAL DISEASE 1/1542 (0.1%) 0/1538 (0%)
    GLOMERULONEPHRITIS CHRONIC 0/1542 (0%) 1/1538 (0.1%)
    HYDRONEPHROSIS 1/1542 (0.1%) 0/1538 (0%)
    NEPHROLITHIASIS 3/1542 (0.2%) 3/1538 (0.2%)
    OBSTRUCTIVE NEPHROPATHY 0/1542 (0%) 1/1538 (0.1%)
    PELVI-URETERIC OBSTRUCTION 0/1542 (0%) 1/1538 (0.1%)
    RENAL COLIC 0/1542 (0%) 1/1538 (0.1%)
    RENAL FAILURE 3/1542 (0.2%) 2/1538 (0.1%)
    TUBULOINTERSTITIAL NEPHRITIS 1/1542 (0.1%) 0/1538 (0%)
    URETERIC OBSTRUCTION 0/1542 (0%) 1/1538 (0.1%)
    URETEROLITHIASIS 1/1542 (0.1%) 2/1538 (0.1%)
    URETHRAL STENOSIS 0/1542 (0%) 1/1538 (0.1%)
    URINARY RETENTION 0/1542 (0%) 1/1538 (0.1%)
    Reproductive system and breast disorders
    ACQUIRED PHIMOSIS 1/1542 (0.1%) 0/1538 (0%)
    BREAST FIBROSIS 1/1542 (0.1%) 0/1538 (0%)
    CERVICAL DYSPLASIA 0/1542 (0%) 1/1538 (0.1%)
    CERVICAL POLYP 0/1542 (0%) 1/1538 (0.1%)
    CYSTOCELE 0/1542 (0%) 2/1538 (0.1%)
    GENITAL PROLAPSE 0/1542 (0%) 1/1538 (0.1%)
    METRORRHAGIA 0/1542 (0%) 1/1538 (0.1%)
    OVARIAN CYST 0/1542 (0%) 0/1538 (0%)
    OVARIAN CYST TORSION 0/1542 (0%) 1/1538 (0.1%)
    RECTOCELE 1/1542 (0.1%) 0/1538 (0%)
    SPERMATOCELE 0/1542 (0%) 1/1538 (0.1%)
    UTERINE POLYP 1/1542 (0.1%) 0/1538 (0%)
    UTERINE PROLAPSE 1/1542 (0.1%) 1/1538 (0.1%)
    VAGINAL HAEMATOMA 0/1542 (0%) 1/1538 (0.1%)
    Respiratory, thoracic and mediastinal disorders
    ACUTE PULMONARY OEDEMA 0/1542 (0%) 1/1538 (0.1%)
    ACUTE RESPIRATORY DISTRESS SYNDROME 0/1542 (0%) 1/1538 (0.1%)
    ACUTE RESPIRATORY FAILURE 1/1542 (0.1%) 1/1538 (0.1%)
    ALVEOLITIS 0/1542 (0%) 1/1538 (0.1%)
    ASTHMA 5/1542 (0.3%) 2/1538 (0.1%)
    ASTHMATIC CRISIS 1/1542 (0.1%) 0/1538 (0%)
    ATELECTASIS 1/1542 (0.1%) 1/1538 (0.1%)
    BRONCHIAL HYPERREACTIVITY 0/1542 (0%) 1/1538 (0.1%)
    BRONCHIAL OBSTRUCTION 0/1542 (0%) 1/1538 (0.1%)
    BRONCHITIS CHRONIC 0/1542 (0%) 1/1538 (0.1%)
    BRONCHOSPASM 1/1542 (0.1%) 0/1538 (0%)
    BRONCHOSTENOSIS 1/1542 (0.1%) 0/1538 (0%)
    CHRONIC OBSTRUCTIVE PULMONARY DISEASE 7/1542 (0.5%) 10/1538 (0.7%)
    CHRONIC RESPIRATORY FAILURE 1/1542 (0.1%) 0/1538 (0%)
    DYSPNOEA 4/1542 (0.3%) 5/1538 (0.3%)
    EMPHYSEMA 0/1542 (0%) 1/1538 (0.1%)
    EPISTAXIS 1/1542 (0.1%) 0/1538 (0%)
    HYDROTHORAX 0/1542 (0%) 1/1538 (0.1%)
    HYPOXIA 1/1542 (0.1%) 0/1538 (0%)
    INTERSTITIAL LUNG DISEASE 3/1542 (0.2%) 5/1538 (0.3%)
    LUNG DISORDER 0/1542 (0%) 1/1538 (0.1%)
    LUNG INFILTRATION 0/1542 (0%) 1/1538 (0.1%)
    PLEURAL EFFUSION 5/1542 (0.3%) 6/1538 (0.4%)
    PNEUMONIA ASPIRATION 0/1542 (0%) 1/1538 (0.1%)
    PNEUMONITIS 0/1542 (0%) 1/1538 (0.1%)
    PNEUMOTHORAX 2/1542 (0.1%) 1/1538 (0.1%)
    PULMONARY EMBOLISM 11/1542 (0.7%) 1/1538 (0.1%)
    PULMONARY FIBROSIS 1/1542 (0.1%) 1/1538 (0.1%)
    PULMONARY GRANULOMA 0/1542 (0%) 1/1538 (0.1%)
    PULMONARY HYPERTENSION 1/1542 (0.1%) 0/1538 (0%)
    PULMONARY MASS 1/1542 (0.1%) 0/1538 (0%)
    PULMONARY OEDEMA 1/1542 (0.1%) 0/1538 (0%)
    PULMONARY SARCOIDOSIS 1/1542 (0.1%) 0/1538 (0%)
    PULMONARY THROMBOSIS 0/1542 (0%) 1/1538 (0.1%)
    RESPIRATORY DISTRESS 1/1542 (0.1%) 2/1538 (0.1%)
    RESPIRATORY FAILURE 1/1542 (0.1%) 1/1538 (0.1%)
    Skin and subcutaneous tissue disorders
    ANGIOEDEMA 2/1542 (0.1%) 1/1538 (0.1%)
    BLISTER 0/1542 (0%) 1/1538 (0.1%)
    DECUBITUS ULCER 1/1542 (0.1%) 0/1538 (0%)
    DERMAL CYST 1/1542 (0.1%) 1/1538 (0.1%)
    DERMATITIS 1/1542 (0.1%) 0/1538 (0%)
    DIABETIC FOOT 1/1542 (0.1%) 0/1538 (0%)
    HYPERSENSITIVITY VASCULITIS 1/1542 (0.1%) 0/1538 (0%)
    PEMPHIGOID 1/1542 (0.1%) 0/1538 (0%)
    RASH 0/1542 (0%) 1/1538 (0.1%)
    RASH ERYTHEMATOUS 1/1542 (0.1%) 0/1538 (0%)
    SKIN DISORDER 1/1542 (0.1%) 0/1538 (0%)
    SKIN NECROSIS 0/1542 (0%) 2/1538 (0.1%)
    SKIN ULCER 1/1542 (0.1%) 4/1538 (0.3%)
    URTICARIA 2/1542 (0.1%) 0/1538 (0%)
    VASCULITIC ULCER 0/1542 (0%) 1/1538 (0.1%)
    Surgical and medical procedures
    ABDOMINAL HERNIA REPAIR 1/1542 (0.1%) 0/1538 (0%)
    ANAL FISTULA EXCISION 1/1542 (0.1%) 0/1538 (0%)
    ANGIOPLASTY 0/1542 (0%) 1/1538 (0.1%)
    APPENDICECTOMY 0/1542 (0%) 1/1538 (0.1%)
    CARDIAC PACEMAKER REPLACEMENT 0/1542 (0%) 1/1538 (0.1%)
    COLOSTOMY CLOSURE 1/1542 (0.1%) 0/1538 (0%)
    HIP ARTHROPLASTY 1/1542 (0.1%) 1/1538 (0.1%)
    IMPLANTABLE DEFIBRILLATOR INSERTION 1/1542 (0.1%) 0/1538 (0%)
    KNEE ARTHROPLASTY 0/1542 (0%) 1/1538 (0.1%)
    LARGE INTESTINE ANASTOMOSIS 0/1542 (0%) 1/1538 (0.1%)
    MITRAL VALVE REPLACEMENT 1/1542 (0.1%) 0/1538 (0%)
    SEQUESTRECTOMY 0/1542 (0%) 1/1538 (0.1%)
    UMBILICAL HERNIA REPAIR 0/1542 (0%) 1/1538 (0.1%)
    Vascular disorders
    AORTIC ANEURYSM 4/1542 (0.3%) 3/1538 (0.2%)
    AORTIC ANEURYSM RUPTURE 0/1542 (0%) 1/1538 (0.1%)
    AORTIC CALCIFICATION 0/1542 (0%) 1/1538 (0.1%)
    AORTIC DISSECTION 1/1542 (0.1%) 1/1538 (0.1%)
    AORTIC STENOSIS 0/1542 (0%) 1/1538 (0.1%)
    DEEP VEIN THROMBOSIS 8/1542 (0.5%) 6/1538 (0.4%)
    EMBOLISM ARTERIAL 1/1542 (0.1%) 0/1538 (0%)
    FEMORAL ARTERY EMBOLISM 1/1542 (0.1%) 0/1538 (0%)
    HAEMATOMA 1/1542 (0.1%) 0/1538 (0%)
    HYPERTENSION 6/1542 (0.4%) 4/1538 (0.3%)
    HYPERTENSIVE CRISIS 2/1542 (0.1%) 1/1538 (0.1%)
    HYPERTENSIVE EMERGENCY 1/1542 (0.1%) 0/1538 (0%)
    HYPOTENSION 1/1542 (0.1%) 2/1538 (0.1%)
    INFARCTION 1/1542 (0.1%) 0/1538 (0%)
    ORTHOSTATIC HYPOTENSION 0/1542 (0%) 1/1538 (0.1%)
    PERIPHERAL ARTERIAL OCCLUSIVE DISEASE 2/1542 (0.1%) 1/1538 (0.1%)
    PERIPHERAL ISCHAEMIA 2/1542 (0.1%) 3/1538 (0.2%)
    PERIPHERAL VENOUS DISEASE 1/1542 (0.1%) 2/1538 (0.1%)
    RHEUMATOID VASCULITIS 1/1542 (0.1%) 0/1538 (0%)
    SUBCLAVIAN ARTERY OCCLUSION 1/1542 (0.1%) 0/1538 (0%)
    THROMBOSIS 1/1542 (0.1%) 2/1538 (0.1%)
    VARICOSE VEIN 0/1542 (0%) 1/1538 (0.1%)
    VENOUS THROMBOSIS LIMB 1/1542 (0.1%) 1/1538 (0.1%)
    Other (Not Including Serious) Adverse Events
    Etanercept Tocilizumab
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 910/1542 (59%) 1090/1538 (70.9%)
    Blood and lymphatic system disorders
    LEUKOPENIA 21/1542 (1.4%) 85/1538 (5.5%)
    NEUTROPENIA 33/1542 (2.1%) 92/1538 (6%)
    Gastrointestinal disorders
    DIARRHOEA 84/1542 (5.4%) 140/1538 (9.1%)
    Infections and infestations
    BRONCHITIS 185/1542 (12%) 244/1538 (15.9%)
    NASOPHARYNGITIS 141/1542 (9.1%) 239/1538 (15.5%)
    PHARYNGITIS 76/1542 (4.9%) 113/1538 (7.3%)
    SINUSITIS 78/1542 (5.1%) 88/1538 (5.7%)
    UPPER RESPIRATORY TRACT INFECTION 193/1542 (12.5%) 243/1538 (15.8%)
    URINARY TRACT INFECTION 150/1542 (9.7%) 174/1538 (11.3%)
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED 44/1542 (2.9%) 120/1538 (7.8%)
    Metabolism and nutrition disorders
    HYPERCHOLESTEROLAEMIA 52/1542 (3.4%) 143/1538 (9.3%)
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA 106/1542 (6.9%) 143/1538 (9.3%)
    BACK PAIN 92/1542 (6%) 147/1538 (9.6%)
    RHEUMATOID ARTHRITIS 132/1542 (8.6%) 152/1538 (9.9%)
    Nervous system disorders
    HEADACHE 68/1542 (4.4%) 103/1538 (6.7%)
    Respiratory, thoracic and mediastinal disorders
    COUGH 76/1542 (4.9%) 127/1538 (8.3%)
    Vascular disorders
    HYPERTENSION 158/1542 (10.2%) 200/1538 (13%)

    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 Hoffmann-La Roche
    Phone 800-821-8590
    Email genentech@druginfo.com
    Responsible Party:
    Hoffmann-La Roche
    ClinicalTrials.gov Identifier:
    NCT01331837
    Other Study ID Numbers:
    • WA25204
    • 2010-020065-24
    First Posted:
    Apr 8, 2011
    Last Update Posted:
    Jul 13, 2017
    Last Verified:
    Jun 1, 2017