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Cardiovascular and Renal Microvascular Outcome Study With Linagliptin in Patients With Type 2 Diabetes Mellitus (CARMELINA)

Sponsor
Boehringer Ingelheim (Industry)
Overall Status
Completed
CT.gov ID
NCT01897532
Collaborator
Eli Lilly and Company (Industry)
6,991
Enrollment
649
Locations
2
Arms
54.3
Actual Duration (Months)
10.8
Patients Per Site
0.2
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The aim of the study is to investigate the longterm impact on cardiovascular morbidity, mortality and renal function of treatment with linagliptin in a selected population of patients with Type 2 diabetes mellitus (T2DM) and to compare outcomes against placebo, on a background of standard of care.

Condition or Disease Intervention/Treatment Phase
Phase 4

Study Design

Study Type:
Interventional
Actual Enrollment :
6991 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Double (Participant, Investigator)
Primary Purpose:
Treatment
Official Title:
CARMELINA: A Multicenter, International, Randomized, Parallel Group, Double-blind, Placebo-controlled, Cardiovascular Safety and Renal Microvascular Outcome Study With Linagliptin, 5 mg Once Daily in Patients With Type 2 Diabetes Mellitus at High Vascular Risk
Actual Study Start Date :
Jul 10, 2013
Actual Primary Completion Date :
Jan 18, 2018
Actual Study Completion Date :
Jan 18, 2018

Arms and Interventions

Arm Intervention/Treatment
Experimental: Linagliptin

Drug: Linagliptin
Placebo Comparator: Placebo

Drug: Placebo
placebo matching tablets

Outcome Measures

Primary Outcome Measures

  1. Time to the First Occurrence of Any of the Following Adjudication-confirmed Components of the Primary Composite Endpoint 3-point Major Adverse Cardiovascular (CV) Events (3-point MACE): CV Death, Non-fatal Myocardial Infarction (MI) or Non-fatal Stroke. [From randomization to individual end of observation; up to 4.3 years]

    Time to event analysis of patients with first occurrence of any of the following adjudication-confirmed components of the primary composite endpoint (3-point MACE): CV death, non-fatal MI or non-fatal stroke. The percentage of observed patients with first occurrence of any of the following adjudication-confirmed components of the primary composite endpoint (3-point MACE) was reported.

Secondary Outcome Measures

  1. Time to the First Occurrence of Any of the Following Adjudication-confirmed Components: Renal Death, Sustained End Stage Renal Disease (ESRD), or Sustained Decrease of 40% or More in Estimated Glomerular Filtration Rate (eGFR). [From randomization to individual end of observation; up to 4.3 years]

    Time to the first occurrence of any of the following adjudication-confirmed components: renal death, sustained ESRD, or sustained decrease of 40% or more in eGFR. The percentage of observed patients with first occurrence of any of the following adjudication-confirmed components: renal death, sustained ESRD, or sustained decrease of 40% or more in eGFR was reported.

Eligibility Criteria

Criteria

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

  1. Documented diagnosis of T2DM before visit 1(screening).

  2. Male or female patients who are drug-naïve or pre-treated with any antidiabetic background medication, excluding treatment with Glucagon-like Peptide 1 (GLP-1) receptor agonists, Dipeptidyl-peptidase 4 (DPP-4) inhibitors or Sodium Glucose Linked Transporter 2 (SGLT-2) inhibitors if => consecutive 7 days.

  3. Stable antidiabetic background medication (unchanged daily dose) for at least 8 weeks prior to randomization. If insulin is part of the background therapy, the average daily insulin dose should not have changed by more than 10% within the 8 weeks prior to randomization compared with the daily insulin dose at randomization.

  4. HbA1c of => 6.5% and <= 10.0% at Visit 1 (screening)

  5. Age => 18 years at Visit 1(screening). For Japan only: Age => 20 years at Visit 1

  6. Body Mass Index (BMI) <= 45 kg/m2 at Visit 1 (screening)

  7. Signed and dated written informed consent by date of Visit 1(screening) in accordance with Good Clinical Practice (GCP) and local legislation prior to any study related procedure

  8. High risk of cardiovascular (CV) events defined by: 1) albuminuria (micro or macro) and previous macrovascular disease and/or 2) impaired renal function with predefined Urine Albumin Creatinine Ratio (UACR)

Exclusion criteria:

  1. Type 1 diabetes mellitus.

  2. Treatment (=> 7 consecutive days) with GLP-1 receptor agonists, other DPP-4 inhibitors or SGLT-2 inhibitors prior to informed consent. Note: This also includes clinical trials where these antidiabetic drugs have been provided to the patient.

  3. Active liver disease or impaired hepatic function, defined by serum levels of either Alanine Transaminase (ALT) (SGPT), Aspartate transaminase (AST) (SGOT), or alkaline phosphatase (AP) => 3 x upper limit of normal (ULN) as determined at Visit 1.

  4. Estimated Glomerular filtration Rate (eGFR) <15 ml/min/1.73 m2 (severe renal impairment or End Stage Renal Disease (ESRD), Modification of Diet in Renal Disease (MDRD) formula), as determined during screening at Visit 1 and/or the need for maintenance dialysis.

  5. Any previous (or planned within next 12 months) bariatric surgery (open or laparoscopic) or intervention (gastric sleeve).

  6. Pre-planned coronary artery re-vascularisation (PCI, CABG) or any previous PCI and/or CABG <= 2 months prior informed consent.

  7. Known hypersensitivity or allergy to the investigational products or its excipients.

  8. Any previous or current alcohol or drug abuse that would interfere with trial participation in the opinion of the investigator.

  9. Participation in another trial with an investigational drug ongoing or within 2 months prior to visit 1 (screening).

  10. Pre-menopausal women (last menstruation = 1 year prior to informed consent) who are nursing or pregnant, are of child-bearing potential and are not practicing an acceptable method of birth control (acceptable methods of birth control include tubal ligation, transdermal patch, intra uterine devices/systems (IUDs/IUSs), oral, implantable or injectable contraceptives, sexual abstinence (if allowed by local authorities), double barrier method and vasectomised partner) or do not plan to continue using acceptable method of birth control throughout the study and do not agree to submit to periodic pregnancy testing during participation in the trial.

  11. Patients considered unreliable by the investigator concerning the requirements for follow up during the study and/or compliance with study drug administration, have a life expectancy less than 5 years for non-CV causes, or have cancer other than non-melanoma skin cancer within last 3 years, or has any other condition than mentioned which in the opinion of the investigator, would not allow safe participation in the study.

  12. Acute coronary syndrome (ACS), diagnosed <= 2 months prior to visit 1 (screening).

  13. Stroke or Transient Ischemic Attack (TIA) <= 3 months prior to visit 1 (screening).

Contacts and Locations

Locations

Site City State Country Postal Code
1 Longwood Research Huntsville Alabama United States 35801
2 Scottsboro Quick Care Clinic Scottsboro Alabama United States 35768
3 Office of Dr. Terence T. Hart MD Tuscumbia Alabama United States 35674
4 Arrowhead Health Centers Glendale Arizona United States 85306
5 Precision Trials, LLC Phoenix Arizona United States 85032
6 Harrisburg Family Medical Center Harrisburg Arkansas United States 72432
7 Cardiology and Medicine Clinic Little Rock Arkansas United States 72204
8 Little Rock Diagnostic Clinic Little Rock Arkansas United States 72205
9 Kaiser Permanente - San Diego, Bonita Bonita California United States 91902
10 John Muir Physician Network Clinical Research Center Concord California United States 94520
11 Valley Research Fresno California United States 93720
12 VA Loma Linda Healthcare System Loma Linda California United States 92357
13 Long Beach Center for Clinical Research Long Beach California United States 90807
14 Clearview Medical Research, LLC Los Angeles California United States 90019
15 National Research Institute Los Angeles California United States 90057
16 Office of Dr. Richard S. Cherlin Los Gatos California United States 95032
17 Coastal Medical Research Group Los Osos California United States 93402
18 Novo Research, Incorporated Modesto California United States 95350
19 Providence Clinical Research North Hollywood California United States 91606
20 Northridge Clinical Research Inc. Northridge California United States 91324
21 Carr Cardiology Oceanside California United States 92056
22 Center for Clinical Trials of Sacramento, Incorporated Sacramento California United States 95823
23 North America Research Institute San Dimas California United States 91773
24 Trinitas Research, Incorporated San Jose California United States 95116
25 Metabolic Institute of America Tarzana California United States 91356
26 Center for Clinical Trials of San Gabriel West Covina California United States 91790
27 Western Nephrology & Metabolic Arvada Colorado United States 80002
28 South Denver Nephrology Denver Colorado United States 80210
29 Colorado Center for Bone Research, P.C. Golden Colorado United States 80401
30 Helix Biomedics LLC Boynton Beach Florida United States 33435
31 Orthopedic Research Institute Boynton Beach Florida United States 33437
32 Nova Clinical Research, LLC Bradenton Florida United States 34209
33 PAB Clinical Research Brandon Florida United States 33511
34 Meridien Research Brooksville Florida United States 34601
35 Southeast Clinical Research, LLC Chiefland Florida United States 32626
36 BayCare Medical Group Clearwater Florida United States 33756
37 Cohen Medical Research Associates, LLC Delray Beach Florida United States 33446
38 Innovation Medical Research Center, Inc Doral Florida United States 33166
39 Integrative Research Associates Fort Lauderdale Florida United States 33312
40 Jellinger and Lerman, MD, PA dba The Center for Diabetes and Endocrine Care Fort Lauderdale Florida United States 33312
41 Direct Helpers Medical Center, Inc Hialeah Florida United States 33012
42 Universal Clinical Research Hialeah Florida United States 33012
43 Homestead Associates in Research Homestead Florida United States 33032
44 St. Vincent's Cardiology Jacksonville Florida United States 32216
45 Care Partners Clinical Research LLC Jacksonville Florida United States 32277
46 Altus Research, Inc. Lake Clarke Shores Florida United States 33406
47 Meridien Research Lakeland Florida United States 33805
48 Precision Research Organization Miami Lakes Florida United States 33016
49 Clinical Research of Miami Miami Florida United States 33126
50 Prestige Clinical Research Center, Inc. Miami Florida United States 33133
51 Jesscan Medical Research, Internal Medicine Miami Florida United States 33134
52 Clintex Research Group, Inc. Research Miami Florida United States 33135
53 University of Miami Miami Florida United States 33136
54 Florida Medical Center & Research Inc Miami Florida United States 33142
55 A+ Research Incorporated Miami Florida United States 33144
56 Unlimited Medical Research, LLC Miami Florida United States 33144
57 Regenerate Clinical Trials Miami Florida United States 33155
58 Sanitas Research Miami Florida United States 33155
59 Future Care Solution, LLC Miami Florida United States 33165
60 Research Institute of South Florida Inc Miami Florida United States 33173
61 Tellus Clinical Research, Incorporated Miami Florida United States 33173
62 New Horizon Research Center Miami Florida United States 33175
63 Kendall South Medical Center, Inc Miami Florida United States 33185
64 Coral Research Clinic Corp Miami Florida United States 33186
65 School of Clinical Research North Miami Beach Florida United States 33144
66 Harmony Clinical Research, Incorporated North Miami Beach Florida United States 33162
67 Magnolia Research Group Ocala Florida United States 34471
68 Family Medical Center Orlando Florida United States 32806
69 Peninsula Research, Inc. Ormond Beach Florida United States 32174
70 Infinity Clinical Research, LLC Plantation Florida United States 33317
71 Meridien Research Saint Petersburg Florida United States 33709
72 Professional Health Care of Pinellas, Inc. Saint Petersburg Florida United States 33713
73 Intercoastal Medical Group, Endocrinology Sarasota Florida United States 34232
74 Meridien Research Tampa Florida United States 33634
75 Metabolic Research Institute West Palm Beach Florida United States 33401
76 Emory University Atlanta Georgia United States 30303
77 Laureate Clinical Research Group, LLC Atlanta Georgia United States 30308
78 Bainbridge Medical Associates Bainbridge Georgia United States 39819
79 Atlanta Heart Specialists, LLC Cumming Georgia United States 30041
80 McGarity, Jr., William C. Decatur Georgia United States 30035-4000
81 Atlanta Heart Specialists, LLC Tucker Georgia United States 30084
82 Belleville Family Medical Associates, Ltd Belleville Illinois United States 62220
83 Cedar-Crosse Research Center Chicago Illinois United States 60607
84 Chicago Clinical Research Institute, Inc. Chicago Illinois United States 60607
85 Associates in Endocrinology, Incorporated Elgin Illinois United States 60124
86 Kidney Care Center, Nephrology Joliet Illinois United States 60435
87 American Health Network Avon Indiana United States 46123
88 American Health Network of Indiana, LLC Franklin Indiana United States 46131
89 American Health Network of Indiana, LLC Greenfield Indiana United States 46140
90 American Health Network of Indiana, LLC Muncie Indiana United States 47304
91 Buynak Clinical Research Valparaiso Indiana United States 46383
92 Northeast Iowa Medical Education Foundation Waterloo Iowa United States 50702
93 Iowa Diabetes and Endocrinology Research Center West Des Moines Iowa United States 50265
94 Cotton-O'Neil Clinical Research Center Topeka Kansas United States 66606
95 Professional Research Network of Kansas, LLC Wichita Kansas United States 67203
96 Heartland Research Associates, LLC Wichita Kansas United States 67205
97 The Research Group of Lexington, LLC Lexington Kentucky United States 40503
98 Diabetes and Metabolism Associates APMC Metairie Louisiana United States 70006
99 Tulane University Hospital and Clinic New Orleans Louisiana United States 70112
100 Maryland Cardiovascular Specialists Baltimore Maryland United States 21229
101 Overlea Personal Physicians Baltimore Maryland United States 21236
102 Johns Hopkins University Baltimore Maryland United States 21287
103 Delmarva Heart Research Foundation, Inc Salisbury Maryland United States 21804
104 Endeavor Medical Research Alpena Michigan United States 49707
105 University of Michigan Health System Ann Arbor Michigan United States 48105
106 Aa Mrc Llc Flint Michigan United States 48504
107 McLaren Northern Michigan Hospital Petoskey Michigan United States 49770
108 Remedica LLC Rochester Michigan United States 48307
109 Tri-County Research, Inc Sterling Heights Michigan United States 48310-3503
110 Oakland Medical Research Center Troy Michigan United States 48085
111 HealthEast St. Joseph's Hospital Saint Paul Minnesota United States 55102
112 Mississippi Medical Research, LLC Carriere Mississippi United States 39426
113 Truman Medical Centers, Inc. Kansas City Missouri United States 64108
114 Kansas City Veterans Administration Medical Center Kansas City Missouri United States 64128
115 Glacier View Cardiology, PC Kalispell Montana United States 59901
116 Platte River Nephrology North Platte Nebraska United States 69101
117 Omaha Veterans Affairs Medical Center Omaha Nebraska United States 68131
118 Alas Science Clinical Research Las Vegas Nevada United States 89120
119 USMA Clin. Research/Union Square Med. Associates Elizabeth New Jersey United States 07201
120 Mount Sinai - PRIME Linden New Jersey United States 07036
121 New Mexico Clinical Research and Osteoporosis Center, Inc. Albuquerque New Mexico United States 87106
122 Jacobi Medical Center Bronx New York United States 10461
123 Life Medi-Research and Management Brooklyn New York United States 11206
124 United Medical Associates Johnson City New York United States 13901
125 Saratoga Clinical Research, LLC Saratoga Springs New York United States 12866
126 Kernodle Clinic West Burlington North Carolina United States 27215
127 Main Street Physicians Care Calabash North Carolina United States 28467
128 Box Arthritis & Rheumatology of the Carolinas Charlotte North Carolina United States 28210
129 Clinical Research of Gastonia Gastonia North Carolina United States 28054
130 Medication Management, LLC Greensboro North Carolina United States 27408
131 PMG Research of Bristol, LLC Hickory North Carolina United States 28601
132 Novant Health Southern Piedmont Primary Care Monroe North Carolina United States 28110
133 Research Institute of the Carolinas, PLC Mooresville North Carolina United States 28117
134 Down East Medical Associates Morehead City North Carolina United States 28557
135 Burke Primary Care Morganton North Carolina United States 28655
136 PMG Research of Salisbury, LLC Salisbury North Carolina United States 28144
137 Natalie A Doyle, M.D., P.A. Wilson North Carolina United States 27893
138 Summa Health System Akron Ohio United States 44304
139 Medical Frontiers, LLC Carlisle Ohio United States 45005
140 Dayton VA Medical Center Dayton Ohio United States 45428
141 Norton Community Care Norton Ohio United States 44203
142 Apex Medical Research, AMR, Incorporated Springfield Ohio United States 45505
143 ProMedica Health Education & Research Corp. Toledo Ohio United States 43606
144 COR Clinical Research, LLC Oklahoma City Oklahoma United States 73103
145 Lynn Health Science Institute Oklahoma City Oklahoma United States 73112
146 The Corvallis Clinic, PC Corvallis Oregon United States 97330
147 Blair Medical Associates Altoona Pennsylvania United States 16602
148 Clinical Research Associates of Central Pennsylvania Altoona Pennsylvania United States 16602
149 Central Bucks Cardiology Doylestown Pennsylvania United States 18901
150 Doylestown Health Cardiology Doylestown Pennsylvania United States 18901
151 Lycoming Internal Medicine, Inc Jersey Shore Pennsylvania United States 17740
152 Montgomery Medical Incorporated Smithfield Pennsylvania United States 15478
153 Clinical Trials of South Carolina Charleston South Carolina United States 29406
154 Medical University of South Carolina Charleston South Carolina United States 29425
155 Spectrum Medical Research, LLC Gaffney South Carolina United States 29341
156 VitaLink Research Greenville South Carolina United States 29615
157 Mountain View Clinical Research Greer South Carolina United States 29651
158 Vita Link Research- Rock Hill Rock Hill South Carolina United States 29732
159 Health Concepts Rapid City South Dakota United States 57702
160 Holston Medical Group Bristol Tennessee United States 37620
161 State of Franklin Healthcare Associates, PLLC Johnson City Tennessee United States 37604
162 DCT- AACT, LLC dba Discovery Clinical Trials Austin Texas United States 78758
163 Rockwood Medical Clinic Bedford Texas United States 76022
164 Texas Health Physicians Group Dallas Texas United States 75218
165 Research Institute of Dallas Dallas Texas United States 75231
166 Ben Taub General Hospital Houston Texas United States 77030
167 Southwest Clinical Trials Houston Texas United States 77074
168 The Endocrine Center Houston Texas United States 77079
169 Texas Family Geriatrics Clinic Houston Texas United States 77082
170 Memorial Clinical Associates Research Houston Texas United States 77084
171 Break Through Medical Research Irving Texas United States 75039
172 Medical & Surgical Clinic Irving Texas United States 75061
173 West Memorial Family Practice Katy Texas United States 77450
174 Hill Country Medical Associates New Braunfels Texas United States 78130
175 Permian Research Foundation Odessa Texas United States 79761
176 Methodist Hospital Research Institute, Internal Medicine Pearland Texas United States 77584
177 Health Texas Research Institute San Antonio Texas United States 78228-6205
178 Covenant Clinical Research, PA San Antonio Texas United States 78229
179 DM Clinical Research San Antonio Texas United States 78249
180 DCT-Stone Oak, LLC dba Discovery Clinical Trials San Antonio Texas United States 78258
181 Sealy Urgent Care Center and Medical Clinic Sealy Texas United States 77474
182 Pioneer Research Solutions, Inc. Sugar Land Texas United States 77479
183 DM Clinical Research Tomball Texas United States 77375
184 Crossroads Clinical Research, LLC Victoria Texas United States 77901
185 Ericksen Research & Development, LLC Clinton Utah United States 84015
186 Focus Clinical Research Draper Utah United States 84020
187 Advanced Research Institute Ogden Utah United States 84405
188 Paramount Medical Care Ogden Utah United States 84405
189 Burke Internal Medicine and Research Burke Virginia United States 22015
190 Nova Health Management & Research Group, PC Herndon Virginia United States 20170
191 Manassas Clinical Research Center Manassas Virginia United States 20110
192 Dominion Medical Associates, Inc. Richmond Virginia United States 23219
193 Hunter Holmes McGuire Veterans Administration Medical Center Richmond Virginia United States 23249
194 Roanoke Heart Institute PLC Roanoke Virginia United States 24014
195 Salem Veterans Affairs Medical Center Salem Virginia United States 24153
196 Sound Medical Research Port Orchard Washington United States 98366
197 Zablocki VA Medical Center Milwaukee Wisconsin United States 53295
198 Instituto Médico Adrogué Adrogue Argentina B1846DSK
199 Hospital Interzonal General de Agudos Dr Jose Penna Bahia Blanca Argentina 8000
200 Inst de Inv Clinicas-Bahia Blanca Bahia Blanca Argentina B8000FTD
201 Hospital Italiano Regional del Sur, Bahia Blanca Bahia Blanca Argentina B8001HXM
202 Hospital Sirio-Libanés Caba Argentina C1419GEP
203 Centro de Investigaciones Metabólicas Ciudad Autonoma Buenos Aires Argentina C1056ABJ
204 CIPREC Ciudad Autonoma Buenos Aires Argentina C1119ACN
205 Hospital Italiano Ciudad Autonoma Buenos Aires Argentina C1181ACH
206 Consultorios Asociados de Endocrinología e Invest Clínica Ciudad Autonoma Buenos Aires Argentina C1425AGC
207 CEDIC - Centro de Investigacion Clinica Ciudad Autonoma Buenos Aires Argentina C1425DES
208 Instituto Cardiovascular de Buenos Aires Ciudad Autonoma Buenos Aires Argentina C1428ART
209 CCBR - Buenos Aires - AR Ciudad Autonoma Buenos Aires Argentina C1430CKE
210 Centro Médico Viamonte Ciudad Autonoma de Bs As Argentina C1120AAC
211 Centro Médico Colon Cordoba Argentina 5000
212 CEMAIC - Centro Medico Especializado Cordoba Argentina 5008
213 Inst. Privado de Inv. Clínicas de Córdoba Cordoba Argentina X5000AAW
214 Clínica Colombo Cordoba Argentina X5002AOQ
215 Instituto DAMIC - Fundacion Rusculleda Cordoba Argentina X5003DCE
216 Hospital Cordoba Cordoba Argentina X5004CDT
217 IPAC - Clínica Privada Caraffa SRL Cordoba Argentina X5008KKF
218 Clinica Privada del Prado Cordoba Argentina X5020AAA
219 Centro Universitario de Investigacion Corrientes Corrientes Argentina W3400
220 Sanatorio Allende S.A. Córdoba Argentina X5000JHQ
221 CIPADI Godoy Cruz Argentina 5501
222 Centro Medico Dr. Javier Marino Haedo Argentina B1706CZA
223 Hospital Italiano de La Plata La Plata Argentina B1900AXI
224 Unidad de Cardiologia Clinica Mar del Plata Argentina B7600FEN
225 Hospital Privado de Comunidad Mar del Plata Argentina B7602CBM
226 Hospital Central de Mendoza, Mendoza Mendoza Argentina 5500
227 Hospital San Martin Parana Argentina E3100BBJ
228 Sanatorio San Martin S.A., Venado Tuerto Pellegrini 661 Argentina S2600KUE
229 CER Instituto Médico Quilmes Argentina B1878DVB
230 Instituto de Investigaciones Clínicas de Quilmes Quilmes Argentina B1878GEG
231 Instituto de Investigaciones Clinicas de Rosario Rosario Argentina 2000
232 Instituto Medico de la Fundacion Estudios Clinicos, Rosario Rosario Argentina 2000
233 Instituto Medico Fundación Grupo Colaborativo Rosario Rosario Argentina 2000
234 Sanatorio Británico Rosario Argentina 2000
235 Sanatorio Norte Rosario Argentina 2000
236 Instituto de Hematologia y Medicina Clinica Ruben Davoli Rosario Argentina CP2000
237 Sanatorio Delta Rosario Argentina S2000BIF
238 Centro Medico CIR Rosario Argentina S2000DEJ
239 CEDyN Rosario Argentina S2000DNM
240 Instituto CAICI Rosario Argentina S2000PBJ
241 Instituto Medico CENICLAR-C de Investigaciones Clinicas Rosario Argentina S2000QID
242 Centro Cardiovascular Salta Salta Argentina 4406
243 CORDIS S.A., Salta Salta Argentina A4400ANW
244 Prevencion Cardiovascular Salta, Salta Salta Argentina A4400CRC
245 CCBR Tucuman San Miguel de Tucuman Argentina T4000
246 Investigaciones Clinicas Tucuman San Miguel de Tucumán Argentina T4000ICL
247 Instituto de Investigaciones Clinicas San Nicolas San Nicolas Argentina B2900DMH
248 Centro Medico Luquez San Vicente Argentina X5006CBI
249 Centro de Investigaciones Clínicas del Litoral Santa Fe Argentina S3000FWO
250 Hospital "Dr. José Maria Cullen " Santa Fé Argentina S3000EOZ
251 Clinica Privada Fusavim SRL Villa Maria Argentina X5900JKA
252 Instituto de Investigaciones Clínicas Zárate Zarate Argentina 2800
253 Hospital Felício Rocho Belo Horizonte Brazil 30110-060
254 Hospital Lifecenter Belo Horizonte Brazil 30110-921
255 Hospital Vera Cruz Belo Horizonte Brazil 30140-062
256 Hospital Universitário João de Barros Barreto Belém Brazil 66073-000
257 Hospital Angelina Caron Campina Grande do Sul Brazil 83430-000
258 HMCP - Hospital e Maternidade Celso Pierro - PUC-Campinas Campinas Brazil 13060-904
259 CAEP - Centro Avançado de Estudos e Pesquisas Ltda.,Campinas Campinas Brazil 13087-567
260 Hospital Universitário Canoas Brazil 92425-900
261 Universidade de Caxias do Sul - IPCEM - Inst. de Pesq.clilni Caxias do Sul Brazil 95070-560
262 Hospital de Caridade Santa Casa de Misericordia de Curitiba Curitiba Brazil 80010-030
263 HC UFPR Curitiba Brazil 80030-110
264 Cruz Vermelha Brasileira - Filial do Estado do Paraná Curitiba Brazil 80030-480
265 Centro de Estudos em Diabetes e Hipertensão Fortaleza Brazil 60115-282
266 Centro de Pesquisas em Diabetes e Doenças Fortaleza Brazil 60430-350
267 ICE-HUWC - Instituto Cearense de Endocrinologia Fortaleza Brazil 60430-370
268 Via Médica Goiania Brazil 74223-130
269 Hospital Bruno Born Lajeado Brazil 95900-000
270 ICM - Instituto do Coração de Marília Marília Brazil 17515-000
271 Hospital São Vicente de Paulo Passo Fundo Brazil 99010-080
272 Irmandade da Santa Casa de Misericórdia de Porto Alegre Porto Alegre Brazil 90035-074
273 Centro de Pesquisas em Diabetes Porto Alegre Brazil 90035-170
274 Instituto de Cardiologia Rio Grande do Sul Porto Alegre Brazil 90620-001
275 Centro de Pesquisas Médicas Básica e Clínica Ltda Recife Brazil 52020-010
276 CCBR - Rio de Janeiro - BR Rio de Janeiro Brazil 22271-100
277 Centro de Pesquisa Clínica Santa Maria Santa Maria Brazil 97015-530
278 CCBR Brasil - São Paulo Santo Andre Brazil 09190510
279 Instituto Domingo Braile Sao Jose do Rio Preto Brazil 15015-750
280 Fundacao Faculdade Regional de Medicina, Sao Jose Sao Jose do Rio Preto Brazil 15090-000
281 Centro de Pesquisa Clinica - CPCLIN Sao Paulo Brazil 01244-030
282 FGM Clínica Paulista de Doenças Cardiovasculares LTDA Sao Paulo Brazil 01327-010
283 Hospital Sao Paulo - UNIFESP Sao Paulo Brazil 04022-001
284 Cpquali Pesquisa Clinica Ltda São Paulo Brazil 01228-000
285 Hospital Alemao Oswaldo Cruz São Paulo Brazil 01323-903
286 Hospital do Servidor Público Estadual São Paulo Brazil 04039-901
287 Dr. Consulta São Paulo Brazil 04254-020
288 Hospital das Clinicas da FMUSP São Paulo Brazil 05403-000
289 Incor - Instituto do Coração - HCFMUSP São Paulo Brazil 05403-000
290 IMC - Instituto de Moléstias Cardiovasculares Tatuí Tatui Brazil 18270-170
291 ICT - Instituto do Coração do Triângulo Uberlândia Brazil 38400-368
292 MHAT - Blagoevgrad, EOOD Blagoevgrad Bulgaria 2700
293 MHAT "Yuliya Vrevska" EOOD, Byala Byala Bulgaria 7100
294 MHAT "Dr.Stambolski", Cardiology&Intensiv Care Dept,Kazanlak Kazanlak Bulgaria 6100
295 UMHAT "Kaspela", EOOD, Plovdiv Plovdiv Bulgaria 4002
296 DCC 1 - Ruse, EOOD Ruse Bulgaria 7002
297 Fifth MHAT - Sofia EAD, Sofia Sofia Bulgaria 1233
298 MHAT Lyulin Sofia Bulgaria 1336
299 MHAT 'Tokuda Hospital Sofia', EAD Sofia Bulgaria 1407
300 USHATE Hospital 'Academy Ivan Penchev', Sofia Sofia Bulgaria 1431
301 DCC "Equita" EOOD Varna Bulgaria 9000
302 ALTA Clinical Research Inc. Edmonton Alberta Canada T5A 4L8
303 The Bailey Clinic Red Deer Alberta Canada T4N 6V7
304 Dr. Ronald Collette Burnaby British Columbia Canada V5G 1T4
305 The Medical Arts Health Research Group Penticton British Columbia Canada V2A5G8
306 LMC Clinical Research dba Manna Research Inc. Vancouver Vancouver British Columbia Canada V6J 1S3
307 Fraser Clinical Trials Inc. Victoria British Columbia Canada V8R 4R2
308 Discovery Clinical Services Ltd. Victoria British Columbia Canada V8T 5G4
309 CookMed Research Victoria British Columbia Canada V8V 4A1
310 Winnipeg Regional Health Authority, Winnipeg Winnipeg Manitoba Canada R3E 3P4
311 True North Clinical Research Halifax, Inc. Halifax Nova Scotia Canada B3S 1M7
312 LMC Endocrinology Centres (Barrie) Ltd. Barrie Ontario Canada L4N 7L3
313 JBN Medical Diagnostic Services Inc. Burlington Ontario Canada L7M 4Y1
314 LMC Endocrinology Centres (Etobicoke) Ltd. Etobicoke Ontario Canada M9R 4E1
315 LMC Endocrinology Centres (Markham) Ltd. Markham Ontario Canada L6B 0P9
316 SKDS Research Incorporated Newmarket Ontario Canada L3Y 5G8
317 Medicor Research Sudbury Ontario Canada P3E 1H5
318 Sudbury Cardiac Research Sudbury Ontario Canada P3E 2N8
319 Dr. R. Labonte Prof. Med. Corp Sudbury Ontario Canada P3E 3B8
320 ViaCar Recherche Clinique Inc Brossard Quebec Canada J4Z 2K9
321 Hopital Charles - LeMoyne Greenfield Park Quebec Canada J4V 2G9
322 Centre De Recherche Clinique Laval Quebec Canada H7T 2P5
323 Recherche Invascor Inc. Longueuil Quebec Canada J4N 1C2
324 Centre Hospitalier de l'Universite de Montreal (CHUM) Montreal Quebec Canada H2X 0A9
325 McGill University Health Centre (MUHC) Montreal Quebec Canada H4A 3J1
326 St Jerome Medical Research Inc. St-Jerome Quebec Canada J7Z 5T3
327 LMC Endocrinology Centres (Montreal) Ville Saint-Laurent Quebec Canada H4T 1Z9
328 Recherche Clinique Sigma Inc. Quebec Canada G1G 3Y8
329 Clinique des maladies Lipidiques de Quebec Quebec Canada G1V 4M6
330 Hospital Regional de Punta Arenas Dr. Lautaro Navarro Avaria Punta Arenas Chile 6200000
331 Hospital El Pino Santiago Chile 0
332 Sociedad Medica Cardiologica El Llano Santiago Chile 0
333 Hospital Militar de Santiago Santiago Chile 7850000
334 Hospital Sotero del Rio Santiago Chile 8150000
335 CeCim - Centro de Estudios Clinicos e Investigacion Medica Santiago Chile 8331143
336 Hospital Padre Alberto Hurtado Santiago Chile 8880465
337 Hospital Base Valdivia Valdivia Chile 5090000
338 Hospital Naval Almirante Nef Viña del Mar Chile 2520000
339 Beijing Jishuitan Hospital Beijing China 100035
340 Third Affiliated Hospital of Guangzhou Medical University Guangzhou China 510150
341 Zhejiang University School of Medicine SIR RUN RUN SHAW Hospital Hangzhou China 310016
342 Center Hospital of Jinan Jinan China 250013
343 People's Hospital of Guangxi Zhuang Autonomous Region Nanning China 530021
344 Tongji Hospital, Tongji University Shanghai China 200065
345 First Affiliated Hospital of Xi'an JiaoTong University Xi'an China 710061
346 General Hospital of Ningxia Medical University Yinchuan China 750004
347 CEQUIN Armenia Colombia 55860
348 Corazon IPS S.A.S. Barranquilla Colombia 0000
349 Clínica de la Costa Ltda. Barranquilla Colombia 0
350 IPS Centro Cientifico Asistencia Barranquilla Colombia 80020
351 Centro de Atencion e Investigacion Medica S.A. - CAIMED Bogota Colombia 0
352 CAFESALUD Medicina Prepagada S.A. Bogota Colombia 110221
353 Solano y Terront Servicios Médicos Ltda. Bogota Colombia 110221
354 Dexa Diabetes Servicios Médicos Ltda Bogotá Colombia 110221
355 Fundacion Reina Isabel Cali Colombia 0
356 IPS Centro Medico Julián Coronel S.A. Cali Colombia 0
357 Fundación Centro de Investigaciones Biomédicas Riescard Espinal Colombia 0
358 Centro de Investigacion Clínica Avanzada Medellin Colombia 0
359 Fundacion Centro de Investigacion Clinica CIC, Medellin Medellin Colombia 50021
360 Fundacion Centro de Obesidad y Metabolismo - COMETA Pasto Colombia 52002
361 Healthy Medical CenterS.A.S, Zipaquirá Zipaquirá Colombia 0
362 General Hospital Karlovac Karlovac Croatia 47000
363 Hospital for Medical Rehabilitation, Krapinske Toplice Krapinske Toplice Croatia 49217
364 General Hospital Slavonski Brod Slavonski Brod Croatia 35000
365 General Hospital Varazdin Varazdin Croatia 42000
366 General Hosp. Zadar, Dept. of Internal Medicine-Pulmonology Zadar Croatia 23000
367 Clinical Hospital Sveti Duh Zagreb Croatia 10000
368 University hospital center Zagreb Zagreb Croatia 10000
369 Fakultni nemocnice u sv. Anny v Brne Brno Czechia 656 91
370 Fakultni nemocnice u sv. Anny v Brne Brno Czechia 65691
371 Revmatologie Bruntal, s.r.o. Bruntal Czechia 792 01
372 Poliklinika Chocen, a.s. Chocen Czechia 56501
373 Aesculap Ambulance Sro Dolni Brezany Czechia 252 41
374 OKELI s.r.o. Hodonin Czechia 695 01
375 Nemocnice Jindrichuv Hradec a.s. Jindrichuv Hradec Czechia 377 01
376 Regional Hospital Liberec Liberec Czechia 460 63
377 InterKardioML s.r.o. Marianske Lazne Czechia 353 01
378 Interna a diabetologicka ordinace s.r.o. Nachod Czechia 547 01
379 PreventaMed, s.r.o. Olomouc Czechia 77900
380 Univ. Hospital Kralovske Vinohrady Praha 10 Czechia 100 34
381 Vseobecna fakultni nemocnice V Praze Praha 2 Czechia 128 08
382 Thomayer Hospital Praha 4 - Krc Czechia 140 59
383 ResTrial s.r.o. Praha 8 Czechia 181 00
384 Hospital Slany, Internal Department Slany Czechia 274 01
385 Krajska zdravotni, a.s. - Nemocnice Teplice, o.z. Teplice Czechia 41501
386 Studienzentrum Aschaffenburg Aschaffenburg Germany 63739
387 Zentrum für klinische Forschung Dr. med. Irma Schöll & Kollegen Bad Homburg Germany 61348
388 Universitätsklinikum Carl Gustav Carus Dresden Dresden Germany 1307
389 IKF Pneumologie GmbH & Co. KG Frankfurt am Main Germany 60596
390 ClinPhenomics GmbH & Co KG, Frankfurt Frankfurt Germany 60594
391 Diabetologische Schwerpunktpraxis, Hohenmölsen Hohenmölsen Germany 6679
392 EUGASTRO GmbH, Leipzig Leipzig Germany 4103
393 Gemeinschaftspraxis Dr. Taeschner / Dr. Bonigut, Leipzig Leipzig Germany 4249
394 Lausmed Kft. Outpatient Unit of Internal Medicine Baja Hungary 6500
395 Dr. Kenessey Albert Kórház-Rendelõintézet, Balassagyarmat Balassagyarmat Hungary 2660
396 DRC Gyogyszervizsgalo Kozpont Kft., Balatonfured Balatonfured Hungary 8230
397 Clinexpert Kft. Budapest Hungary 1033
398 Obudai Egeszsegugyi Centrum Budapest Hungary 1036
399 QUALICLINIC Kft Budapest Hungary 1036
400 Semmelweis Egyetem, Budapest Budapest Hungary 1083
401 Semmelweis Egyetem, Budapest Budapest Hungary 1088
402 Semmelweis Egyetem, Budapest Budapest Hungary 1125
403 University Debrecen Hospital Debrecen Hungary 4032
404 Markhot Ferenc Hospital, Eger Eger Hungary 3300
405 Csongrad Megyei Eu. Ellato Kozp. Hodmezovasarhely-Mako Hodmezovasarhely Hungary 6800
406 Somogy Megyei Kaposi Mor Oktato Korhaz, Kaposvar Kaposvar Hungary 7400
407 Selye Janos Hospital Komarom Komarom Hungary 2900
408 Ermellek Egeszsegcentrum Letavertes Hungary 4281
409 Borsod-Abauj-Zemplen Megyei Korhaz es Egyetemi Oktato Korhaz Miskolc Hungary 3526
410 Pecsi Tudomanyegyetem Pecs Hungary 7624
411 Szegedi Tudomanyegyetem Szent-Gyorgyi Albert Klin. Kozpont Szeged Hungary 6725
412 Zala Megyei Szent Rafael Korhaz Zalaegerszeg Hungary 8900
413 Haemek Medical Center Afula Israel 18101
414 Bnei Zion Medical Center, Haifa Haifa Israel 31048
415 Rambam Medical Center Haifa Israel 3109601
416 Herzliya Medical Center Herzliya Israel 4685107
417 Wolfson Medical Center Holon Israel 58100
418 Hadassah Medical Center, Ein-Karem Jerusalem Israel 9112001
419 Meir Medical Center Kfar-Saba Israel 4428164
420 Galilee Medical Center Nahariya Israel 2210001
421 Ziv Medical Center Safed Israel 13100
422 Sourasky Medical Center Tel Aviv Israel 6423906
423 Daishinkai Medical Corporation Ookuma Hospital Aichi, Nagoya Japan 462-0825
424 Seikeikai New Tokyo Heart Clinic Chiba, Matsudo Japan 271-0077
425 Saiseikai Matsuyama Hospital Ehime, Matsuyama Japan 791-8026
426 Aso Co.,Ltd Iizuka Hospital Fukuoka, Iizuka Japan 820-8505
427 Kitakyushubyoin Kitakyushu General Hospital Fukuoka, Kitakyushu Japan 800-0295
428 The Veritas Hospital Hyogo, Kawanishi Japan 666-0125
429 Ibaraki Seinan Medical Center Hospital Ibaraki, Sashima-gun Japan 306-0433
430 Kokan Clinic Kanagawa, Kawasaki Japan 210-0852
431 Nagano Red Cross Hospital Nagano, Nagano Japan 380-8582
432 Josuikai Olive Takamatsu Medical Clinic Takamatsu-shi Japan 760-0076
433 Hallym University Sacred Heart Hospital Anyang-si Korea, Republic of 431-070
434 Inje University Busan Paik Hospital Busan Korea, Republic of 47392
435 Dong-A University Hospital Busan Korea, Republic of 602-715
436 Pusan National Univ. Hosp Busan Korea, Republic of 602-739
437 Myongji Hospital Goyang-si Korea, Republic of 412-270
438 Gachon University Gil Medical Center Incheon Korea, Republic of 21565
439 The Catholic University of Korea, Seoul St.Mary's Hospital Seoul Korea, Republic of 06591
440 Seoul National University Hospital Seoul Korea, Republic of 110744
441 Asan Medical Center Seoul Korea, Republic of 138736
442 Korea University Anam Hospital Seoul Korea, Republic of 2841
443 Korea University Guro Hospital Seoul Korea, Republic of 8308
444 Wonju Severance Christian Hosp Wonju Korea, Republic of 26426
445 Hospital Sultanah Bahiyah Alor Setar Malaysia 5460
446 Hospital Tengku Ampuan Rahimah Klang Malaysia 41200
447 University Malaya Medical Centre Kuala Lumpur Malaysia 59100
448 Hospital Tengku Ampuan Afzan Kuantan Malaysia 25100
449 Monash University(Sunway Campus) Petaling Jaya Malaysia 46150
450 Hospital Pulau Pinang Pulau Pinang Malaysia 10450
451 Universiti Putra Malaysia Serdang Malaysia 43400
452 Hospital Seri Manjung Seri Manjung Malaysia 32040
453 Hospital Taiping Taiping Malaysia 34000
454 Klinik Kesihatan Tampin Tampin Malaysia 73009
455 Investigación en Salud y Metabolismo S.C. Chihuahua Mexico 31237
456 Phylasis Clinicas Research S de RL de CV Cuautitlan Izcalli Mexico 54769
457 Centro para el Desarrollo de la Medicina y de Asist Med Espe Culiacan Mexico CP80020
458 Centro de Investigacion Biomedica y Farmaceutica, S.C. Distrito Federal Mexico 03100
459 Servicios Medicos de la Pena SC Guadalajara Mexico 44690
460 Medical Care & Research SA de CV Merida Mexico 97070
461 Sociedad de Cirugia Vascular Plastica Reconstructiva Merida Mexico 97129
462 Phytomedicamenta S.A. de C.V. Mexico Mexico 03100
463 Comite Mexicano Para la Prevencion de Osteoporosis AC Mexico Mexico 06100
464 Centro de Atención e Investigación en Factores de Riesgo Mexico Mexico 06700
465 Clinstile S.A. de C.V. Mexico Mexico 06700
466 Ultimate Medica SA de CV Mexico Mexico 11850
467 Health Pharma Professional Research S.A. de C.V. Mexico Mexico 3810
468 Centro de Estudios Clinicos y Especialidades Medicas, S.C. Monterrey Mexico 64620
469 AVIX Investigación Clínica S.C Monterrey Mexico 64710
470 Global Trial Research Center S.A. de C.V. Monterrey Mexico 64718
471 Centro de Investigacion Clinica Chapultepec S. A. de C. V. Morelia Mexico 58260
472 Centro de Estudios Clínicos de Queretaro S.C., CECLIQ Queretaro Mexico 76000
473 Centro de Investigacion Cardiovascular y Metabolica Tijuana Mexico 22500
474 Centro de Investigación Médica de Ocidente, S.C. Zapopan Mexico 45116
475 Hospital Dr Angel Leano Zapopan Mexico 45200
476 Rijnstate Hospital Arnhem Netherlands 6815 AD
477 Albert SchweitzerZiekenhuis Dordrecht Netherlands 3318 AT
478 Universitair Medisch Centrum Groningen Groningen Netherlands 9713 GZ
479 Martini Ziekenhuis Groningen Netherlands 9728 NT
480 Bethesda Cardiology Group, Hoogeveen Hoogeveen Netherlands 7909 AA
481 Maastricht Universitair Medisch Centrum Maastricht Netherlands 6229 HX
482 Rotterdam Research Institute Rotterdam Netherlands 3039 BD
483 Universitair Medisch Centrum Utrecht Utrecht Netherlands 3584 CX
484 TweeSteden Ziekenhuis Waalwijk Netherlands 5141 BM
485 Gelre Ziekenhuis Zutphen Zutphen Netherlands 7207 BA
486 B_Serwis Popenda Sp.Jawna Chorzow Poland 41-500
487 Poradnia Kardiologiczna Jaroslaw Jurowiecki Gdansk Poland 80-286
488 University Clinical Center, Gdansk Gdansk Poland 80-952
489 Indywidualna Specjalistyczna Praktyka Lekarska Gdynia Poland 81-157
490 MCBK Iwona Czajkowska Anna Podrazka- Szczepaniak S.C. Grodzisk Mazowiecki Poland 05-825
491 Centrum Medyczne Pratia Katowice II Katowice Poland 40-084
492 Polimedica Centrum Bada?, Profilaktyki I Leczenia Kielce Poland 25-364
493 NZOZ Centrum Medyczne ProMiMed Sp. z o.o., Sp.k., Krakow Krakow Poland 31-637
494 Centrum Terapii Wspolczesnej J.M. Lodz Poland 90-242
495 CCBR - Lodz - PL, Lodz Lodz Poland 90-368
496 Individual Specialized Practice Lodz Poland 94-255
497 Centrum Medyczne "Luxmed" Sp. z o.o. Lublin Poland 20-109
498 KO-MED Centra Kliniczne Lublin II Lublin Poland 20-362
499 NZOZ Specialized Ambulance "MEDICA" Lublin Poland 20-538
500 RCMed- Regionalne Centrum Medyczne Nowy Duninow Poland 09-505
501 Medicome Sp. z o.o. Oswiecim Poland 32-600
502 Prywatny Gabinet Lekarski Lech Lazuka Parczew Poland 21-200
503 Clin.Hosp.Med.Univ.Marcinkowski in Poznan Poznan Poland 60-569
504 Praktyka Lekarska Ewa Krzyzagorska Poznan Poland 61-655
505 KOMED Marek Konieczny Pulawy Poland 24-100
506 Indywidualna Specjalistyczna Praktyka Lekarska Dr N Med Andrzej Wittek Ruda Slaska Poland 41-709
507 Centrum Medyczne Medyk Rzeszow Poland 35-055
508 RCMed- Regionalne Centrum Medyczne Sochaczew Poland 96-500
509 NSZOZ Medicus Sroda Wielkopolska Poland 63-000
510 KO-MED Centra Kliniczne Staszow Staszow Poland 28-200
511 Lecznice Citomed Sp. z o.o. Torun Poland 87-100
512 NZOZ Nasz Lekarz Torun Poland 87-100
513 NBR Polska Warsaw Poland 00-465
514 CCBR/Somed - Warszaw - PL Warszaw Poland 04-730
515 Regionalna Poradnia Diabetoloiczna Zytkiewicz-Jaruga Wroclaw Poland 50-127
516 KO-MED Centra Kliniczne Zamosc Zamosc Poland 22-400
517 Polimedica Centrum Bada?, Profilaktyki I Leczenia Zgierz Poland 95-100
518 Hospital de Braga-Escala Braga Braga Portugal 4710-243
519 CHUC - Centro Hospitalar e Universitário de Coimbra, EPE Coimbra Portugal 3000-075
520 APDP - Associação Protectora dos Diabéticos de Portugal Lisboa Portugal 1250-203
521 CHLO, EPE - Hospital S. Francisco Xavier Lisboa Portugal 1449-005
522 Hospital da Luz Lisboa Portugal 1500-650
523 Hospital CUF Porto Porto Portugal 4100-180
524 Centro Hospitalar de Vila Nova de Gaia V. N. Gaia Portugal 4434-502
525 SC Diana Barbonta SRL, Alba Iulia Alba Iulia Romania 510053
526 Spitalul Universitar de Urgenta, Bucuresti Bucuresti Romania 010825
527 I.N.D.N.B.M. "Prof. Dr. N.C. Paulescu" - Sediul Central Bucuresti Romania 011234
528 I.N.D.N.B.M. "Prof. Dr. N.C. Paulescu" - Sediul Central Bucuresti Romania 020475
529 CMI Dr. Stolea T. Violeta Bucuresti Romania 061072
530 Clinica Medicala Data Plus SRL Bucuresti Romania 10192
531 I.N.D.N.B.M. "Prof. Dr. N.C. Paulescu" - Sediul "I.L. Caragiale" Bucuresti Romania 20045
532 S.C Centrul Medical "Sanatatea Ta" S.R.L Bucuresti Romania 20614
533 S.C. Policlinica CCBR SRL, Bucuresti Bucuresti Romania 30463
534 Medcon SRL Buzau Romania 120203
535 Spitalul Clinic Judetean de Urgenta ¿Sf. Apostol Andrei¿ Galati Romania 800578
536 Spitalul Clinic, Iasi Iasi Romania 700503
537 Consultmed SRL, Iasi Iasi Romania 700547
538 SC Diaconu-Sotropa Michaela, Cabinet de Diabet Iasi Romania 700613
539 S.C Grandmed S.R.L, Oradea Oradea Romania 410159
540 Pelican Impex SRL, Cabinet Nr. 15 Oradea Romania 410469
541 S.C Anamed S.R.L Oradea Romania 410491
542 S.C. Diabmed Dr. Popescu Alexandrina S.R.L Ploiesti Romania 100163
543 Gensan SRL Sibiu Romania 550371
544 Centrul Medical Dr Negrisanu SRL Timisoara Romania 300456
545 Mediab SRL Tirgu Mures Romania 540142
546 SBEI HPE Altay State Medical University of MoH and SD Barnaul Russian Federation 656038
547 Res.Inst.-Compl.Iss.Cardi.Dis. Kemerovo Russian Federation 650002
548 NSIH "Departmental Hospital on Station Kemerovo of OJSC "Russian Railways" Kemerovo Russian Federation 650055
549 First Moscow State Medical University n.a. I.M. Sechenov Moscow Russian Federation 119435
550 Moscow 1st State Med.Univ.n.a.I.M.Sechenov Moscow Russian Federation 119992
551 SBEI HPE "Moscow State Medical and Dentistry University Moscow Russian Federation 127473
552 Moscow State Medical Dentistry University Moscow Russian Federation 129301
553 SBIH of Novosibirsk Region "Clinical Emergency Hospital #2" Novosibirsk Russian Federation 630008
554 Novosibirsk Regional Clinical Cardiological Dispansary Novosibirsk Russian Federation 630047
555 FSBSI "Scientific Research Institute", Novosibirsk Novosibirsk Russian Federation 630089
556 FSBSI "Scientific and Research Institute of Physiology and Basic Medicine" Novosibirsk Russian Federation 630117
557 BIH of OR "City Hospital # 2", Omsk Omsk Russian Federation 644021
558 SBIH of Perm territory " City Clinical Hospital # 2 n.a. Perm Russian Federation 614068
559 SBI of Ryazan region "Regional Clinical Cardiological Dis. Ryazan Russian Federation 390026
560 FSBMEI HPE "Military Medical Academy n.a. S.M. Kirov" Saint-Petersburg Russian Federation 194044
561 1stPavlov St.Med.Univ.St.-Petersburg Res.Inst. Saint-Petersburg Russian Federation 197022
562 Federal North-West Medical Research Centre Saint-Petersburg Russian Federation 197341
563 SPb SBHI "City Policlinic #74" Saint-Petersburg Russian Federation 197762
564 SPb SBIH "City Pokrovskaya Hospital" Saint-Petersburg Russian Federation 199106
565 GUZ "City Clinical Hospital #40, 197706 Saint-Petersburg Sestroretsk Russian Federation 197706
566 Medical Research Institute LLC, St. Petersburg St. Petersburg Russian Federation 196084
567 FSBI "Research Institute for Cardiology" Tomsk Russian Federation 634012
568 Cardiology Clinical Research Alberton South Africa 1449
569 Iatros International Bloemfontein South Africa 9301
570 Limaro Research Bloemfontein South Africa 9301
571 Dr JM Engelbrecht Practice Cape Town South Africa 7129
572 Dr Dawood, Mohamed and Pillay Cape Town South Africa 7405
573 TREAD Research Cape Town South Africa 7500
574 Langeberg Clinical Trials Cape Town South Africa 7570
575 Cape Town Medical Research Centre Cape Town South Africa 7580
576 Ismail, SM Cape Town South Africa 7764
577 Groote Schuur Hospital Cape Town South Africa 7925
578 Latiff, GHVM Durban South Africa 4001
579 Londisizwe Research Centre, Durban Durban South Africa 4001
580 Diabetes Care Centre Johannesburg South Africa 1501
581 Wits Clinical Research Chris Hani Baragwanath Hospital Johannesburg South Africa 2013
582 WCR CMJAH Clinical Trial Site Johannesburg South Africa 2193
583 DJW Navorsing Krugersdorp South Africa 1739
584 Emmed Research Pretoria South Africa 0002
585 University of Pretoria Pretoria South Africa 0002
586 Syzygy Clinical Research Services Pretoria South Africa 0087
587 Into Research Pretoria South Africa 181
588 Seeber, M Pretoria South Africa 2
589 Dr M Duki Research and Trial Site, Verulam Verulam South Africa 4339
590 Clinical Projects Research Worcester South Africa 6850
591 Hospital Virgen del Mar Almeria Spain 04120
592 Hospital de la Ribera Alzira Spain 46600
593 Hospital Germans Trias i Pujol Badalona Spain 08916
594 Specialist Barcelona Spain 08006
595 CAP Sarria Barcelona Spain 08017
596 Hospital Quiron. I.C.U. Barcelona Spain 08023
597 EBA Centelles Centelles Spain 08540
598 Fundación Jiménez Díaz Madrid Spain 28040
599 Hospital Regional Universitario de Málaga Malaga Spain 29010
600 Hospital General de Segovia Segovia Spain 40002
601 Hospital Quironsalud Infanta Luisa Sevilla Spain 41010
602 Hospital Virgen Macarena Sevilla Spain 41071
603 Hospital General Universitario de Valencia Valencia Spain 46014
604 Hospital Dr. Peset Valencia Spain 46017
605 Hospital Virgen de las Montañas, Villamartin Villamartin Spain 11650
606 Kaohsiung Medical University Chung-Ho Memorial Hospital Kaohsiung Taiwan 807
607 Kaohsiung Veterans General Hospital Kaohsiung Taiwan 81362
608 Far Eastern Memorial Hospital New Taipei City Taiwan 220
609 China Medical University Hospital Taichung Taiwan 404
610 NCKUH Tainan Taiwan 704
611 National Taiwan University Hospital Taipei Taiwan 100
612 Taipe Veterans General Hospital Taipei Taiwan 11217
613 Chang-Gung Memorial Hospital, Linkou Taoyuan County Taiwan 333
614 Chernivtsi Regional Endocrinology Dispensary Chernivtsi Ukraine 58022
615 Regional CH Dept of Endocrinology SHEI Ivano-Frankivsk NMU Ivano-Frankivsk Ukraine 76008
616 CI Ivano-Frankivsk Reg Cl Card Center Ivano-Frankivsk Ukraine 76018
617 L.T. Malaya Institute of Therapy AMS of Ukraine Kharkiv Ukraine 61039
618 CIPH Prof. O.I. Meshchaninov Kharkiv CCH of A&E Kharkiv Ukraine 61103
619 CI of Healthcare Kharkiv CCH #8, Kharkiv Kharkiv Ukraine 61176
620 KCCC of Endocr Dept of General Endocrine Pathology Kyiv Ukraine 01004
621 City Clinical Hospital No. 1, Kiev Kyiv Ukraine 02091
622 V.P. Komisarenko Inst. of Endocrinology and Metabolism Kyiv Ukraine 04114
623 Kjiv City Oleksandrivska Clinical Hospital Kyiv Ukraine 1601
624 LLC Treatment and Diagnostic Center Adonis Plus, Kyiv Kyiv Ukraine 2002
625 SI National Scientific Centre of Radiation Medicine of NAMSU Kyiv Ukraine 3115
626 P.L. Shupyk NMA of PGE Ch of D H for S-ts of NASU Kyiv Ukraine 4050
627 SI V.P.Komisarenko Institute of Endocrinology and Metabolism Kyiv Ukraine 4114
628 Lviv Regional Endocrinology Dispensary Lviv Ukraine 79010
629 M.V. Sklifosovskyi Poltava RCH, Poltava Poltava Ukraine 36011
630 CI Sumy City Clinical Hospital #1 Dept of Therapy Sumy SU Sumy Ukraine 40021
631 CI of TRC Ternopil UH Ternopli Ukraine 46002
632 Private Small Enterprise Medical Center Pulse Vinnytsia Ukraine 21001
633 Vinnytsia RC Highly Special.Endocr.Center Dept of Therapy Vinnytsia Ukraine 21010
634 M.I. Pyrogov VRCH, Vinnytsia Vinnytsia Ukraine 21018
635 CCH #1 M.I. Pyrogov VNMU Ch of Propaedeutics of IM Vinnytsia Ukraine 21021
636 CI Zapor CCH#10 SI ZMA PGE Ch of therapy clin pharmacol & endocrin Zaporizhzhia Ukraine 69001
637 University Hospital Monklands Airdrie United Kingdom ML6 0JS
638 Queen Elizabeth Hospital Birmingham United Kingdom B15 2TH
639 Bradford on Avon Health Centre Bradford on Avon United Kingdom BA15 1DQ
640 Ashgate Medical Practice Chesterfield United Kingdom S40 4AA
641 Dumfries and Galloway Royal Infirmary Dumfries United Kingdom DG1 4AP
642 Ninewells Hospital & Medical School Dundee United Kingdom DD1 9SY
643 Royal Devon and Exeter Hospital Exeter United Kingdom EX2 5DW
644 Glasgow Royal Infirmary Glasgow United Kingdom G4 0SF
645 Leicester General Hospital Leicester United Kingdom LE5 4PW
646 Barts and The London School of Medicine and Dentistry London United Kingdom EC1M 6BQ
647 Morriston Hospital Swansea United Kingdom SA6 6NL
648 Queen Elizabeth II Hospital Welwyn Garden City United Kingdom AL7 4HQ
649 New Cross Hospital Wolverhampton United Kingdom WV10 0QP

Sponsors and Collaborators

  • Boehringer Ingelheim
  • Eli Lilly and Company

Investigators

  • Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

More Information

Additional Information:

Publications

None provided.
Responsible Party:
Boehringer Ingelheim
ClinicalTrials.gov Identifier:
NCT01897532
Other Study ID Numbers:
  • 1218.22
  • 2011-004148-23
First Posted:
Jul 12, 2013
Last Update Posted:
Apr 4, 2019
Last Verified:
Mar 1, 2019
Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Linagliptin

Study Results

Participant Flow

Recruitment Details Prior to initiation of any trial-related procedure, all patients were informed about the trial verbally and in writing by the investigator. The patients signed and dated the informed consent before any study related procedures.
Pre-assignment Detail Patients with documented diagnosis of Type 2 Diabetes Mellitus (T2DM) at high risk of cardiovascular (CV) events and who met all the inclusion criteria and did not meet any of the exclusion criteria could be enrolled in the trial.
Arm/Group Title Placebo Linagliptin
Arm/Group Description Patients were administered Placebo matching Linagliptin 5 mg film-coated tablet orally once daily. At Visit 2, patients received one treatment box sufficient for 12 weeks treatment (plus 1 week reserve). At Visit 3 (until trial end) patients received 2 medication boxes sufficient for 24 weeks treatment (plus 2 weeks reserve). Patients were administered Linagliptin 5 milligram (mg) film-coated tablet orally once daily. At Visit 2, patients received one treatment box sufficient for 12 weeks treatment (plus 1 week reserve). At Visit 3 (until trial end) patients received 2 medication boxes sufficient for 24 weeks treatment (plus 2 weeks reserve).
Period Title: Discontinuation From Treatment
STARTED 3492 3499
Treated 3485 3494
COMPLETED 2530 2660
NOT COMPLETED 962 839
Period Title: Discontinuation From Treatment
STARTED 3492 3499
Treated 3485 3494
COMPLETED 3430 3458
NOT COMPLETED 62 41

Baseline Characteristics

Arm/Group Title Placebo Linagliptin Total
Arm/Group Description Patients were administered Placebo matching Linagliptin 5 mg film-coated tablet orally once daily. At Visit 2, patients received one treatment box sufficient for 12 weeks treatment (plus 1 week reserve). At Visit 3 (until trial end) patients received 2 medication boxes sufficient for 24 weeks treatment (plus 2 weeks reserve). Patients were administered Linagliptin 5 milligram (mg) film-coated tablet orally once daily. At Visit 2, patients received one treatment box sufficient for 12 weeks treatment (plus 1 week reserve). At Visit 3 (until trial end) patients received 2 medication boxes sufficient for 24 weeks treatment (plus 2 weeks reserve). Total of all reporting groups
Overall Participants 3485 3494 6979
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]
65.6
(9.14)
66.1
(9.05)
65.9
(9.10)
Sex: Female, Male (Count of Participants)
Female
1243
35.7%
1346
38.5%
2589
37.1%
Male
2242
64.3%
2148
61.5%
4390
62.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino
1274
36.6%
1227
35.1%
2501
35.8%
Not Hispanic or Latino
2211
63.4%
2267
64.9%
4478
64.2%
Unknown or Not Reported
0
0%
0
0%
0
0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native
156
4.5%
159
4.6%
315
4.5%
Asian
333
9.6%
307
8.8%
640
9.2%
Native Hawaiian or Other Pacific Islander
10
0.3%
7
0.2%
17
0.2%
Black or African American
217
6.2%
194
5.6%
411
5.9%
White
2769
79.5%
2827
80.9%
5596
80.2%
More than one race
0
0%
0
0%
0
0%
Unknown or Not Reported
0
0%
0
0%
0
0%

Outcome Measures

1. Primary Outcome
Title Time to the First Occurrence of Any of the Following Adjudication-confirmed Components of the Primary Composite Endpoint 3-point Major Adverse Cardiovascular (CV) Events (3-point MACE): CV Death, Non-fatal Myocardial Infarction (MI) or Non-fatal Stroke.
Description Time to event analysis of patients with first occurrence of any of the following adjudication-confirmed components of the primary composite endpoint (3-point MACE): CV death, non-fatal MI or non-fatal stroke. The percentage of observed patients with first occurrence of any of the following adjudication-confirmed components of the primary composite endpoint (3-point MACE) was reported.
Time Frame From randomization to individual end of observation; up to 4.3 years

Outcome Measure Data

Analysis Population Description
Treated set (TS): All patients treated with at least one dose of trial medication. If no trial medication was taken at site during the visit, but the medication kit was dispensed to the patient and not all trial medication was returned, the patient was included in the TS.
Arm/Group Title Placebo Linagliptin
Arm/Group Description Patients were administered Placebo matching Linagliptin 5 mg film-coated tablet orally once daily. At Visit 2, patients received one treatment box sufficient for 12 weeks treatment (plus 1 week reserve). At Visit 3 (until trial end) patients received 2 medication boxes sufficient for 24 weeks treatment (plus 2 weeks reserve). Patients were administered Linagliptin 5 milligram (mg) film-coated tablet orally once daily. At Visit 2, patients received one treatment box sufficient for 12 weeks treatment (plus 1 week reserve). At Visit 3 (until trial end) patients received 2 medication boxes sufficient for 24 weeks treatment (plus 2 weeks reserve).
Measure Participants 3485 3494
Number [percentage of participants]
12.1
0.3%
12.4
0.4%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Linagliptin
Comments Cox proportional hazard regression model was performed to compare the effect of linagliptin versus placebo. Model included randomised treatment and geographical region as factors. Breslow's method was used for dealing with ties. First hypothesis (non-inferiority of the primary endpoint) was to be tested at the one-sided alpha-level of 2.5%. In case of significance the next set of hypotheses (two separate hypothesis tests) were to be tested with a sequentially rejective multiple test procedure.
Type of Statistical Test Non-Inferiority
Comments The non-inferiority margin was chosen as 1.3 (FDA Guidance for Industry - Diabetes Mellitus - Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes).
Statistical Test of Hypothesis p-Value 0.0002
Comments p-value for Hazard ratio (HR) ≥1.3 (1-sided)
Method Regression, Cox
Comments Based on a Cox regression model with terms for treatment group and region.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.02
Confidence Interval (2-Sided) 95%
0.89 to 1.17
Parameter Dispersion Type:
Value:
Estimation Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Linagliptin
Comments Cox proportional hazard regression model was performed to compare the effect of linagliptin versus placebo. Model included randomised treatment and geographical region as factors. Breslow's method was used for dealing with ties. First hypothesis (non-inferiority of the primary endpoint) was to be tested at the one-sided alpha-level of 2.5%. In case of significance the next set of hypotheses (two separate hypothesis tests) were to be tested with a sequentially rejective multiple test procedure.
Type of Statistical Test Other
Comments
Statistical Test of Hypothesis p-Value 0.6301
Comments p-value for HR ≥1.0 (1-sided).
Method Regression, Cox
Comments Based on a Cox regression model with terms for treatment group and region.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.02
Confidence Interval (2-Sided) 95%
0.89 to 1.17
Parameter Dispersion Type:
Value:
Estimation Comments
2. Secondary Outcome
Title Time to the First Occurrence of Any of the Following Adjudication-confirmed Components: Renal Death, Sustained End Stage Renal Disease (ESRD), or Sustained Decrease of 40% or More in Estimated Glomerular Filtration Rate (eGFR).
Description Time to the first occurrence of any of the following adjudication-confirmed components: renal death, sustained ESRD, or sustained decrease of 40% or more in eGFR. The percentage of observed patients with first occurrence of any of the following adjudication-confirmed components: renal death, sustained ESRD, or sustained decrease of 40% or more in eGFR was reported.
Time Frame From randomization to individual end of observation; up to 4.3 years

Outcome Measure Data

Analysis Population Description
TS
Arm/Group Title Placebo Linagliptin
Arm/Group Description Patients were administered Placebo matching Linagliptin 5 mg film-coated tablet orally once daily. At Visit 2, patients received one treatment box sufficient for 12 weeks treatment (plus 1 week reserve). At Visit 3 (until trial end) patients received 2 medication boxes sufficient for 24 weeks treatment (plus 2 weeks reserve). Patients were administered Linagliptin 5 milligram (mg) film-coated tablet orally once daily. At Visit 2, patients received one treatment box sufficient for 12 weeks treatment (plus 1 week reserve). At Visit 3 (until trial end) patients received 2 medication boxes sufficient for 24 weeks treatment (plus 2 weeks reserve).
Measure Participants 3485 3494
Number [percentage of participants]
8.8
0.3%
9.4
0.3%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Linagliptin
Comments Cox proportional hazard regression model was performed to compare the effect of linagliptin versus placebo. Model included randomised treatment and geographical region as factors. Breslow's method was used for dealing with ties. First hypothesis (non-inferiority of the primary endpoint) was to be tested at the one-sided alpha-level of 2.5%. In case of significance the next set of hypotheses (two separate hypothesis tests) were to be tested with a sequentially rejective multiple test procedure.
Type of Statistical Test Other
Comments
Statistical Test of Hypothesis p-Value 0.6918
Comments p-value for HR ≥1.0 (1-sided)
Method Regression, Cox
Comments Based on a Cox regression model with terms for treatment group and region.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.04
Confidence Interval (2-Sided) 95%
0.89 to 1.22
Parameter Dispersion Type:
Value:
Estimation Comments

Adverse Events

Time Frame Adverse events with an onset after the first dose of trial medication up to a period of 7 days after the last permanent study drug stop; up to 4.3 years
Adverse Event Reporting Description
Arm/Group Title Placebo Linagliptin
Arm/Group Description Patients were administered Placebo matching Linagliptin 5 mg film-coated tablet orally once daily. At Visit 2, patients received one treatment box sufficient for 12 weeks treatment (plus 1 week reserve). At Visit 3 (until trial end) patients received 2 medication boxes sufficient for 24 weeks treatment (plus 2 weeks reserve). Patients were administered Linagliptin 5 milligram (mg) film-coated tablet orally once daily. At Visit 2, patients received one treatment box sufficient for 12 weeks treatment (plus 1 week reserve). At Visit 3 (until trial end) patients received 2 medication boxes sufficient for 24 weeks treatment (plus 2 weeks reserve).
All Cause Mortality
Placebo Linagliptin
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 253/3485 (7.3%) 250/3494 (7.2%)
Serious Adverse Events
Placebo Linagliptin
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 1343/3485 (38.5%) 1293/3494 (37%)
Blood and lymphatic system disorders
Anaemia 17/3485 (0.5%) 19/3494 (0.5%)
Lymphadenopathy 1/3485 (0%) 2/3494 (0.1%)
Thrombocytopenia 2/3485 (0.1%) 1/3494 (0%)
Autoimmune haemolytic anaemia 1/3485 (0%) 1/3494 (0%)
Haemorrhagic anaemia 0/3485 (0%) 2/3494 (0.1%)
Immune thrombocytopenic purpura 1/3485 (0%) 1/3494 (0%)
Leukocytosis 1/3485 (0%) 1/3494 (0%)
Pancytopenia 2/3485 (0.1%) 0/3494 (0%)
Anaemia macrocytic 1/3485 (0%) 0/3494 (0%)
Anaemia of malignant disease 1/3485 (0%) 0/3494 (0%)
Eosinophilia 0/3485 (0%) 1/3494 (0%)
Febrile neutropenia 0/3485 (0%) 1/3494 (0%)
Hypochromic anaemia 1/3485 (0%) 0/3494 (0%)
Iron deficiency anaemia 1/3485 (0%) 0/3494 (0%)
Lymphadenitis 0/3485 (0%) 1/3494 (0%)
Nephrogenic anaemia 0/3485 (0%) 1/3494 (0%)
Cardiac disorders
Cardiac failure 104/3485 (3%) 104/3494 (3%)
Cardiac failure congestive 98/3485 (2.8%) 77/3494 (2.2%)
Angina unstable 70/3485 (2%) 77/3494 (2.2%)
Acute myocardial infarction 59/3485 (1.7%) 78/3494 (2.2%)
Myocardial infarction 54/3485 (1.5%) 47/3494 (1.3%)
Angina pectoris 25/3485 (0.7%) 42/3494 (1.2%)
Atrial fibrillation 26/3485 (0.7%) 34/3494 (1%)
Coronary artery disease 21/3485 (0.6%) 26/3494 (0.7%)
Cardiac failure chronic 20/3485 (0.6%) 24/3494 (0.7%)
Cardiac arrest 17/3485 (0.5%) 25/3494 (0.7%)
Myocardial ischaemia 12/3485 (0.3%) 20/3494 (0.6%)
Acute coronary syndrome 18/3485 (0.5%) 12/3494 (0.3%)
Left ventricular failure 12/3485 (0.3%) 13/3494 (0.4%)
Atrial flutter 11/3485 (0.3%) 13/3494 (0.4%)
Cardiogenic shock 12/3485 (0.3%) 8/3494 (0.2%)
Atrioventricular block complete 10/3485 (0.3%) 9/3494 (0.3%)
Cardiac failure acute 7/3485 (0.2%) 10/3494 (0.3%)
Cardio-respiratory arrest 8/3485 (0.2%) 8/3494 (0.2%)
Coronary artery stenosis 8/3485 (0.2%) 5/3494 (0.1%)
Bradycardia 6/3485 (0.2%) 5/3494 (0.1%)
Sinus node dysfunction 4/3485 (0.1%) 7/3494 (0.2%)
Acute left ventricular failure 8/3485 (0.2%) 1/3494 (0%)
Atrioventricular block second degree 4/3485 (0.1%) 5/3494 (0.1%)
Coronary artery occlusion 3/3485 (0.1%) 6/3494 (0.2%)
Arteriosclerosis coronary artery 6/3485 (0.2%) 2/3494 (0.1%)
Atrioventricular block 5/3485 (0.1%) 2/3494 (0.1%)
Ischaemic cardiomyopathy 3/3485 (0.1%) 4/3494 (0.1%)
Ventricular tachycardia 3/3485 (0.1%) 3/3494 (0.1%)
Cardiomyopathy 2/3485 (0.1%) 2/3494 (0.1%)
Cardiopulmonary failure 1/3485 (0%) 3/3494 (0.1%)
Ventricular fibrillation 3/3485 (0.1%) 1/3494 (0%)
Arrhythmia 1/3485 (0%) 2/3494 (0.1%)
Cardiovascular insufficiency 1/3485 (0%) 2/3494 (0.1%)
Sinus bradycardia 1/3485 (0%) 2/3494 (0.1%)
Supraventricular tachycardia 2/3485 (0.1%) 1/3494 (0%)
Ventricular arrhythmia 3/3485 (0.1%) 0/3494 (0%)
Aortic valve incompetence 1/3485 (0%) 1/3494 (0%)
Bundle branch block left 1/3485 (0%) 1/3494 (0%)
Cardiac disorder 0/3485 (0%) 2/3494 (0.1%)
Cardiomegaly 2/3485 (0.1%) 0/3494 (0%)
Diastolic dysfunction 1/3485 (0%) 1/3494 (0%)
Mitral valve incompetence 0/3485 (0%) 2/3494 (0.1%)
Myocardial fibrosis 1/3485 (0%) 1/3494 (0%)
Pericardial effusion 0/3485 (0%) 2/3494 (0.1%)
Silent myocardial infarction 1/3485 (0%) 1/3494 (0%)
Sinus tachycardia 1/3485 (0%) 1/3494 (0%)
Systolic dysfunction 1/3485 (0%) 1/3494 (0%)
Adams-stokes syndrome 1/3485 (0%) 0/3494 (0%)
Aortic valve disease 0/3485 (0%) 1/3494 (0%)
Arrhythmia supraventricular 1/3485 (0%) 0/3494 (0%)
Atrioventricular block first degree 1/3485 (0%) 0/3494 (0%)
Cardiac tamponade 0/3485 (0%) 1/3494 (0%)
Cardiomyopathy acute 1/3485 (0%) 0/3494 (0%)
Cardiorenal syndrome 1/3485 (0%) 0/3494 (0%)
Cardiovascular disorder 1/3485 (0%) 0/3494 (0%)
Chordae tendinae rupture 1/3485 (0%) 0/3494 (0%)
Chronic left ventricular failure 1/3485 (0%) 0/3494 (0%)
Conduction disorder 0/3485 (0%) 1/3494 (0%)
Cyanosis 0/3485 (0%) 1/3494 (0%)
Degenerative mitral valve disease 0/3485 (0%) 1/3494 (0%)
Intracardiac thrombus 1/3485 (0%) 0/3494 (0%)
Left ventricular dysfunction 1/3485 (0%) 0/3494 (0%)
Mitral valve disease 1/3485 (0%) 0/3494 (0%)
Mitral valve stenosis 0/3485 (0%) 1/3494 (0%)
Myocardial necrosis 1/3485 (0%) 0/3494 (0%)
Myocarditis 1/3485 (0%) 0/3494 (0%)
Paroxysmal atrioventricular block 1/3485 (0%) 0/3494 (0%)
Pericarditis 1/3485 (0%) 0/3494 (0%)
Pericarditis constrictive 0/3485 (0%) 1/3494 (0%)
Pulseless electrical activity 0/3485 (0%) 1/3494 (0%)
Sinus arrest 1/3485 (0%) 0/3494 (0%)
Tachyarrhythmia 0/3485 (0%) 1/3494 (0%)
Tachycardia 1/3485 (0%) 0/3494 (0%)
Tricuspid valve incompetence 0/3485 (0%) 1/3494 (0%)
Trifascicular block 0/3485 (0%) 1/3494 (0%)
Ventricular extrasystoles 1/3485 (0%) 0/3494 (0%)
Congenital, familial and genetic disorders
Accessory spleen 0/3485 (0%) 1/3494 (0%)
Atrial septal defect 0/3485 (0%) 1/3494 (0%)
Cystic lymphangioma 1/3485 (0%) 0/3494 (0%)
Dermoid cyst 1/3485 (0%) 0/3494 (0%)
Gastrointestinal arteriovenous malformation 1/3485 (0%) 0/3494 (0%)
Hypertrophic cardiomyopathy 1/3485 (0%) 0/3494 (0%)
Keratosis follicular 1/3485 (0%) 0/3494 (0%)
Myocardial bridging 0/3485 (0%) 1/3494 (0%)
Ear and labyrinth disorders
Deafness neurosensory 3/3485 (0.1%) 4/3494 (0.1%)
Vertigo 4/3485 (0.1%) 3/3494 (0.1%)
Deafness 2/3485 (0.1%) 1/3494 (0%)
Deafness bilateral 2/3485 (0.1%) 1/3494 (0%)
Tinnitus 3/3485 (0.1%) 0/3494 (0%)
Deafness unilateral 0/3485 (0%) 2/3494 (0.1%)
Hypoacusis 0/3485 (0%) 2/3494 (0.1%)
Vertigo positional 1/3485 (0%) 1/3494 (0%)
Conductive deafness 0/3485 (0%) 1/3494 (0%)
Sudden hearing loss 1/3485 (0%) 0/3494 (0%)
Endocrine disorders
Goitre 2/3485 (0.1%) 2/3494 (0.1%)
Adrenal insufficiency 1/3485 (0%) 0/3494 (0%)
Adrenal mass 1/3485 (0%) 0/3494 (0%)
Hyperthyroidism 0/3485 (0%) 1/3494 (0%)
Hypothyroidism 1/3485 (0%) 0/3494 (0%)
Thyroid mass 0/3485 (0%) 1/3494 (0%)
Eye disorders
Cataract 13/3485 (0.4%) 11/3494 (0.3%)
Glaucoma 9/3485 (0.3%) 6/3494 (0.2%)
Vitreous haemorrhage 5/3485 (0.1%) 6/3494 (0.2%)
Retinal detachment 5/3485 (0.1%) 4/3494 (0.1%)
Diabetic retinopathy 4/3485 (0.1%) 3/3494 (0.1%)
Macular hole 2/3485 (0.1%) 4/3494 (0.1%)
Retinal vein occlusion 1/3485 (0%) 3/3494 (0.1%)
Ulcerative keratitis 2/3485 (0.1%) 2/3494 (0.1%)
Diplopia 2/3485 (0.1%) 1/3494 (0%)
Macular degeneration 2/3485 (0.1%) 1/3494 (0%)
Angle closure glaucoma 1/3485 (0%) 1/3494 (0%)
Macular fibrosis 1/3485 (0%) 1/3494 (0%)
Neovascular age-related macular degeneration 2/3485 (0.1%) 0/3494 (0%)
Retinal haemorrhage 2/3485 (0.1%) 0/3494 (0%)
Acquired corneal dystrophy 1/3485 (0%) 0/3494 (0%)
Amaurosis 0/3485 (0%) 1/3494 (0%)
Amaurosis fugax 1/3485 (0%) 0/3494 (0%)
Blindness 0/3485 (0%) 1/3494 (0%)
Blindness unilateral 0/3485 (0%) 1/3494 (0%)
Cataract cortical 0/3485 (0%) 1/3494 (0%)
Corneal decompensation 0/3485 (0%) 1/3494 (0%)
Cystoid macular oedema 0/3485 (0%) 1/3494 (0%)
Diabetic retinal oedema 0/3485 (0%) 1/3494 (0%)
Dry age-related macular degeneration 0/3485 (0%) 1/3494 (0%)
Hyalosis asteroid 1/3485 (0%) 0/3494 (0%)
Macular oedema 0/3485 (0%) 1/3494 (0%)
Open angle glaucoma 1/3485 (0%) 0/3494 (0%)
Optic ischaemic neuropathy 0/3485 (0%) 1/3494 (0%)
Retinal artery embolism 0/3485 (0%) 1/3494 (0%)
Retinal artery occlusion 0/3485 (0%) 1/3494 (0%)
Retinal degeneration 1/3485 (0%) 0/3494 (0%)
Retinopathy 0/3485 (0%) 1/3494 (0%)
Uveitis 1/3485 (0%) 0/3494 (0%)
Vitreous haematoma 1/3485 (0%) 0/3494 (0%)
Gastrointestinal disorders
Gastrointestinal haemorrhage 11/3485 (0.3%) 9/3494 (0.3%)
Gastritis 8/3485 (0.2%) 5/3494 (0.1%)
Upper gastrointestinal haemorrhage 5/3485 (0.1%) 8/3494 (0.2%)
Diarrhoea 2/3485 (0.1%) 9/3494 (0.3%)
Abdominal pain 5/3485 (0.1%) 5/3494 (0.1%)
Pancreatitis acute 3/3485 (0.1%) 7/3494 (0.2%)
Inguinal hernia 5/3485 (0.1%) 4/3494 (0.1%)
Pancreatitis 3/3485 (0.1%) 6/3494 (0.2%)
Vomiting 3/3485 (0.1%) 6/3494 (0.2%)
Constipation 4/3485 (0.1%) 4/3494 (0.1%)
Pancreatitis chronic 6/3485 (0.2%) 2/3494 (0.1%)
Abdominal hernia 5/3485 (0.1%) 2/3494 (0.1%)
Large intestine polyp 3/3485 (0.1%) 4/3494 (0.1%)
Lower gastrointestinal haemorrhage 3/3485 (0.1%) 4/3494 (0.1%)
Intestinal obstruction 3/3485 (0.1%) 3/3494 (0.1%)
Colitis ischaemic 1/3485 (0%) 4/3494 (0.1%)
Gastric ulcer 2/3485 (0.1%) 3/3494 (0.1%)
Chronic gastritis 1/3485 (0%) 3/3494 (0.1%)
Haematochezia 2/3485 (0.1%) 2/3494 (0.1%)
Rectal haemorrhage 2/3485 (0.1%) 2/3494 (0.1%)
Small intestinal obstruction 2/3485 (0.1%) 2/3494 (0.1%)
Duodenal ulcer 3/3485 (0.1%) 0/3494 (0%)
Duodenitis 3/3485 (0.1%) 0/3494 (0%)
Haemorrhoids 1/3485 (0%) 2/3494 (0.1%)
Hiatus hernia 2/3485 (0.1%) 1/3494 (0%)
Melaena 0/3485 (0%) 3/3494 (0.1%)
Pancreatic cyst 3/3485 (0.1%) 0/3494 (0%)
Umbilical hernia 3/3485 (0.1%) 0/3494 (0%)
Abdominal adhesions 0/3485 (0%) 2/3494 (0.1%)
Abdominal wall haematoma 1/3485 (0%) 1/3494 (0%)
Ascites 1/3485 (0%) 1/3494 (0%)
Colitis 0/3485 (0%) 2/3494 (0.1%)
Diverticulum intestinal 1/3485 (0%) 1/3494 (0%)
Diverticulum intestinal haemorrhagic 0/3485 (0%) 2/3494 (0.1%)
Dysphagia 2/3485 (0.1%) 0/3494 (0%)
Enterocolitis 1/3485 (0%) 1/3494 (0%)
Gastric haemorrhage 1/3485 (0%) 1/3494 (0%)
Gastric polyps 1/3485 (0%) 1/3494 (0%)
Gastrointestinal necrosis 1/3485 (0%) 1/3494 (0%)
Gastrooesophageal reflux disease 1/3485 (0%) 1/3494 (0%)
Ileus 1/3485 (0%) 1/3494 (0%)
Incarcerated inguinal hernia 1/3485 (0%) 1/3494 (0%)
Intestinal haemorrhage 1/3485 (0%) 1/3494 (0%)
Intestinal perforation 2/3485 (0.1%) 0/3494 (0%)
Irritable bowel syndrome 1/3485 (0%) 1/3494 (0%)
Mesenteric artery thrombosis 1/3485 (0%) 1/3494 (0%)
Nausea 1/3485 (0%) 1/3494 (0%)
Obstructive pancreatitis 1/3485 (0%) 1/3494 (0%)
Peptic ulcer 2/3485 (0.1%) 0/3494 (0%)
Abdominal hernia obstructive 0/3485 (0%) 1/3494 (0%)
Abdominal pain upper 1/3485 (0%) 0/3494 (0%)
Abdominal tenderness 0/3485 (0%) 1/3494 (0%)
Anal fissure 0/3485 (0%) 1/3494 (0%)
Anal fistula 1/3485 (0%) 0/3494 (0%)
Anal polyp 1/3485 (0%) 0/3494 (0%)
Barrett's oesophagus 0/3485 (0%) 1/3494 (0%)
Diabetic gastroparesis 1/3485 (0%) 0/3494 (0%)
Diverticulum 1/3485 (0%) 0/3494 (0%)
Duodenal perforation 0/3485 (0%) 1/3494 (0%)
Duodenal vascular ectasia 0/3485 (0%) 1/3494 (0%)
Duodenitis haemorrhagic 0/3485 (0%) 1/3494 (0%)
Enteritis 0/3485 (0%) 1/3494 (0%)
Enterocolitis haemorrhagic 0/3485 (0%) 1/3494 (0%)
Enterovesical fistula 0/3485 (0%) 1/3494 (0%)
Faecaloma 0/3485 (0%) 1/3494 (0%)
Gastric antral vascular ectasia 0/3485 (0%) 1/3494 (0%)
Gastric ulcer perforation 1/3485 (0%) 0/3494 (0%)
Gastritis erosive 0/3485 (0%) 1/3494 (0%)
Gastritis haemorrhagic 0/3485 (0%) 1/3494 (0%)
Gastroduodenal ulcer 1/3485 (0%) 0/3494 (0%)
Gastrointestinal obstruction 1/3485 (0%) 0/3494 (0%)
Gastrointestinal perforation 1/3485 (0%) 0/3494 (0%)
Haematemesis 0/3485 (0%) 1/3494 (0%)
Intestinal polyp 1/3485 (0%) 0/3494 (0%)
Large intestinal obstruction 0/3485 (0%) 1/3494 (0%)
Lip ulceration 1/3485 (0%) 0/3494 (0%)
Mechanical ileus 0/3485 (0%) 1/3494 (0%)
Mesenteric haemorrhage 1/3485 (0%) 0/3494 (0%)
Oedema mouth 0/3485 (0%) 1/3494 (0%)
Oesophageal varices haemorrhage 1/3485 (0%) 0/3494 (0%)
Oesophagitis 1/3485 (0%) 0/3494 (0%)
Pancreatic failure 0/3485 (0%) 1/3494 (0%)
Peritoneal adhesions 1/3485 (0%) 0/3494 (0%)
Rectal polyp 1/3485 (0%) 0/3494 (0%)
Retroperitoneal fibrosis 0/3485 (0%) 1/3494 (0%)
Strangulated umbilical hernia 1/3485 (0%) 0/3494 (0%)
Tongue oedema 0/3485 (0%) 1/3494 (0%)
Vomiting projectile 1/3485 (0%) 0/3494 (0%)
General disorders
Death 23/3485 (0.7%) 16/3494 (0.5%)
Non-cardiac chest pain 15/3485 (0.4%) 15/3494 (0.4%)
Sudden death 20/3485 (0.6%) 10/3494 (0.3%)
Cardiac death 5/3485 (0.1%) 7/3494 (0.2%)
Asthenia 8/3485 (0.2%) 2/3494 (0.1%)
Chest pain 4/3485 (0.1%) 3/3494 (0.1%)
Pyrexia 2/3485 (0.1%) 5/3494 (0.1%)
Multiple organ dysfunction syndrome 2/3485 (0.1%) 3/3494 (0.1%)
Generalised oedema 1/3485 (0%) 3/3494 (0.1%)
Oedema peripheral 3/3485 (0.1%) 1/3494 (0%)
Sudden cardiac death 3/3485 (0.1%) 1/3494 (0%)
Chest discomfort 1/3485 (0%) 2/3494 (0.1%)
Vascular stent restenosis 1/3485 (0%) 2/3494 (0.1%)
Catheter site haemorrhage 0/3485 (0%) 2/3494 (0.1%)
Chills 0/3485 (0%) 2/3494 (0.1%)
Complication associated with device 0/3485 (0%) 2/3494 (0.1%)
General physical health deterioration 0/3485 (0%) 2/3494 (0.1%)
Necrobiosis 0/3485 (0%) 2/3494 (0.1%)
Application site haemorrhage 0/3485 (0%) 1/3494 (0%)
Chronic fatigue syndrome 1/3485 (0%) 0/3494 (0%)
Fatigue 1/3485 (0%) 0/3494 (0%)
Feeling abnormal 0/3485 (0%) 1/3494 (0%)
Impaired healing 1/3485 (0%) 0/3494 (0%)
Injection site haematoma 1/3485 (0%) 0/3494 (0%)
Malaise 1/3485 (0%) 0/3494 (0%)
Medical device site joint inflammation 0/3485 (0%) 1/3494 (0%)
Peripheral swelling 1/3485 (0%) 0/3494 (0%)
Strangulated hernia 1/3485 (0%) 0/3494 (0%)
Systemic inflammatory response syndrome 0/3485 (0%) 1/3494 (0%)
Ulcer haemorrhage 0/3485 (0%) 1/3494 (0%)
Vascular stent occlusion 0/3485 (0%) 1/3494 (0%)
Hepatobiliary disorders
Cholelithiasis 9/3485 (0.3%) 10/3494 (0.3%)
Cholecystitis acute 7/3485 (0.2%) 10/3494 (0.3%)
Cholecystitis 3/3485 (0.1%) 7/3494 (0.2%)
Hepatic cirrhosis 2/3485 (0.1%) 5/3494 (0.1%)
Hepatic failure 2/3485 (0.1%) 3/3494 (0.1%)
Bile duct stone 2/3485 (0.1%) 2/3494 (0.1%)
Biliary colic 0/3485 (0%) 2/3494 (0.1%)
Cholangitis 2/3485 (0.1%) 0/3494 (0%)
Cholecystitis chronic 1/3485 (0%) 1/3494 (0%)
Hepatic steatosis 0/3485 (0%) 2/3494 (0.1%)
Autoimmune hepatitis 0/3485 (0%) 1/3494 (0%)
Bile duct obstruction 0/3485 (0%) 1/3494 (0%)
Biliary dyspepsia 0/3485 (0%) 1/3494 (0%)
Biliary tract disorder 1/3485 (0%) 0/3494 (0%)
Cholangitis acute 1/3485 (0%) 0/3494 (0%)
Cirrhosis alcoholic 1/3485 (0%) 0/3494 (0%)
Ischaemic hepatitis 1/3485 (0%) 0/3494 (0%)
Jaundice 0/3485 (0%) 1/3494 (0%)
Portal hypertension 0/3485 (0%) 1/3494 (0%)
Portal vein thrombosis 0/3485 (0%) 1/3494 (0%)
Immune system disorders
Hypersensitivity 0/3485 (0%) 2/3494 (0.1%)
Drug hypersensitivity 0/3485 (0%) 1/3494 (0%)
Overlap syndrome 1/3485 (0%) 0/3494 (0%)
Infections and infestations
Pneumonia 121/3485 (3.5%) 99/3494 (2.8%)
Urinary tract infection 41/3485 (1.2%) 30/3494 (0.9%)
Cellulitis 38/3485 (1.1%) 22/3494 (0.6%)
Sepsis 33/3485 (0.9%) 18/3494 (0.5%)
Bronchitis 17/3485 (0.5%) 8/3494 (0.2%)
Osteomyelitis 14/3485 (0.4%) 11/3494 (0.3%)
Septic shock 12/3485 (0.3%) 13/3494 (0.4%)
Gangrene 14/3485 (0.4%) 10/3494 (0.3%)
Gastroenteritis 9/3485 (0.3%) 11/3494 (0.3%)
Localised infection 7/3485 (0.2%) 10/3494 (0.3%)
Pyelonephritis 3/3485 (0.1%) 14/3494 (0.4%)
Urosepsis 7/3485 (0.2%) 5/3494 (0.1%)
Respiratory tract infection 7/3485 (0.2%) 3/3494 (0.1%)
Diabetic foot infection 6/3485 (0.2%) 3/3494 (0.1%)
Influenza 2/3485 (0.1%) 7/3494 (0.2%)
Pyelonephritis acute 3/3485 (0.1%) 6/3494 (0.2%)
Erysipelas 4/3485 (0.1%) 3/3494 (0.1%)
Infected skin ulcer 6/3485 (0.2%) 1/3494 (0%)
Lower respiratory tract infection 4/3485 (0.1%) 3/3494 (0.1%)
Abscess limb 4/3485 (0.1%) 2/3494 (0.1%)
Device related infection 2/3485 (0.1%) 4/3494 (0.1%)
Peritonitis 4/3485 (0.1%) 2/3494 (0.1%)
Upper respiratory tract infection 2/3485 (0.1%) 4/3494 (0.1%)
Bacteraemia 2/3485 (0.1%) 3/3494 (0.1%)
Necrotising fasciitis 3/3485 (0.1%) 2/3494 (0.1%)
Postoperative wound infection 2/3485 (0.1%) 3/3494 (0.1%)
Anal abscess 4/3485 (0.1%) 0/3494 (0%)
Catheter site infection 3/3485 (0.1%) 1/3494 (0%)
Diabetic gangrene 3/3485 (0.1%) 1/3494 (0%)
Diverticulitis 2/3485 (0.1%) 2/3494 (0.1%)
Lung infection 1/3485 (0%) 3/3494 (0.1%)
Post procedural infection 3/3485 (0.1%) 1/3494 (0%)
Subcutaneous abscess 4/3485 (0.1%) 0/3494 (0%)
Appendicitis 3/3485 (0.1%) 0/3494 (0%)
Arthritis bacterial 2/3485 (0.1%) 1/3494 (0%)
Clostridium difficile colitis 1/3485 (0%) 2/3494 (0.1%)
Endocarditis 2/3485 (0.1%) 1/3494 (0%)
Escherichia sepsis 1/3485 (0%) 2/3494 (0.1%)
Infection 1/3485 (0%) 2/3494 (0.1%)
Pneumonia bacterial 1/3485 (0%) 2/3494 (0.1%)
Pulmonary sepsis 1/3485 (0%) 2/3494 (0.1%)
Soft tissue infection 1/3485 (0%) 2/3494 (0.1%)
Bacterial infection 1/3485 (0%) 1/3494 (0%)
Carbuncle 1/3485 (0%) 1/3494 (0%)
Cholecystitis infective 2/3485 (0.1%) 0/3494 (0%)
Device related sepsis 1/3485 (0%) 1/3494 (0%)
Escherichia urinary tract infection 1/3485 (0%) 1/3494 (0%)
Gastroenteritis viral 0/3485 (0%) 2/3494 (0.1%)
Herpes zoster 0/3485 (0%) 2/3494 (0.1%)
Intervertebral discitis 0/3485 (0%) 2/3494 (0.1%)
Osteomyelitis chronic 1/3485 (0%) 1/3494 (0%)
Paronychia 2/3485 (0.1%) 0/3494 (0%)
Periodontitis 2/3485 (0.1%) 0/3494 (0%)
Scrotal abscess 0/3485 (0%) 2/3494 (0.1%)
Staphylococcal infection 1/3485 (0%) 1/3494 (0%)
Staphylococcal sepsis 1/3485 (0%) 1/3494 (0%)
Urinary tract infection fungal 1/3485 (0%) 1/3494 (0%)
Wound infection 2/3485 (0.1%) 0/3494 (0%)
Abdominal abscess 1/3485 (0%) 0/3494 (0%)
Abdominal sepsis 0/3485 (0%) 1/3494 (0%)
Abdominal wall abscess 0/3485 (0%) 1/3494 (0%)
Bacterial pyelonephritis 1/3485 (0%) 0/3494 (0%)
Bacterial sepsis 1/3485 (0%) 0/3494 (0%)
Blebitis 1/3485 (0%) 0/3494 (0%)
Bursitis infective 1/3485 (0%) 0/3494 (0%)
Chikungunya virus infection 1/3485 (0%) 0/3494 (0%)
Chronic sinusitis 1/3485 (0%) 0/3494 (0%)
Clostridium colitis 1/3485 (0%) 0/3494 (0%)
Clostridium difficile infection 0/3485 (0%) 1/3494 (0%)
Cytomegalovirus infection 1/3485 (0%) 0/3494 (0%)
Dengue fever 1/3485 (0%) 0/3494 (0%)
Disseminated tuberculosis 0/3485 (0%) 1/3494 (0%)
Endocarditis bacterial 0/3485 (0%) 1/3494 (0%)
Enteritis infectious 0/3485 (0%) 1/3494 (0%)
Epididymitis 0/3485 (0%) 1/3494 (0%)
Escherichia bacteraemia 0/3485 (0%) 1/3494 (0%)
Fungal peritonitis 0/3485 (0%) 1/3494 (0%)
Gastroenteritis norovirus 0/3485 (0%) 1/3494 (0%)
Gastroenteritis shigella 1/3485 (0%) 0/3494 (0%)
Gastrointestinal bacterial infection 0/3485 (0%) 1/3494 (0%)
Gastrointestinal infection 0/3485 (0%) 1/3494 (0%)
Gastrointestinal viral infection 1/3485 (0%) 0/3494 (0%)
Graft infection 1/3485 (0%) 0/3494 (0%)
Groin abscess 1/3485 (0%) 0/3494 (0%)
H1n1 influenza 0/3485 (0%) 1/3494 (0%)
Hepatitis c 1/3485 (0%) 0/3494 (0%)
Hepatitis infectious mononucleosis 1/3485 (0%) 0/3494 (0%)
Histoplasmosis cutaneous 1/3485 (0%) 0/3494 (0%)
Histoplasmosis disseminated 0/3485 (0%) 1/3494 (0%)
Infected cyst 1/3485 (0%) 0/3494 (0%)
Infected dermal cyst 0/3485 (0%) 1/3494 (0%)
Infectious colitis 0/3485 (0%) 1/3494 (0%)
Infective exacerbation of chronic obstructive airways disease 1/3485 (0%) 0/3494 (0%)
Injection site abscess 0/3485 (0%) 1/3494 (0%)
Intestinal sepsis 1/3485 (0%) 0/3494 (0%)
Klebsiella bacteraemia 0/3485 (0%) 1/3494 (0%)
Klebsiella infection 0/3485 (0%) 1/3494 (0%)
Klebsiella sepsis 0/3485 (0%) 1/3494 (0%)
Laryngitis 1/3485 (0%) 0/3494 (0%)
Leptospirosis 0/3485 (0%) 1/3494 (0%)
Liver abscess 1/3485 (0%) 0/3494 (0%)
Lyme disease 1/3485 (0%) 0/3494 (0%)
Mediastinitis 1/3485 (0%) 0/3494 (0%)
Medical device site cellulitis 1/3485 (0%) 0/3494 (0%)
Meningitis 1/3485 (0%) 0/3494 (0%)
Meningitis viral 0/3485 (0%) 1/3494 (0%)
Mycoplasma infection 0/3485 (0%) 1/3494 (0%)
Myiasis 1/3485 (0%) 0/3494 (0%)
Neutropenic sepsis 1/3485 (0%) 0/3494 (0%)
Nosocomial infection 1/3485 (0%) 0/3494 (0%)
Oral candidiasis 0/3485 (0%) 1/3494 (0%)
Orchitis 0/3485 (0%) 1/3494 (0%)
Osteomyelitis viral 1/3485 (0%) 0/3494 (0%)
Otitis externa 1/3485 (0%) 0/3494 (0%)
Otitis media 1/3485 (0%) 0/3494 (0%)
Pelvic abscess 1/3485 (0%) 0/3494 (0%)
Perineal abscess 1/3485 (0%) 0/3494 (0%)
Peritonitis bacterial 1/3485 (0%) 0/3494 (0%)
Peritonsillar abscess 0/3485 (0%) 1/3494 (0%)
Pneumonia chlamydial 1/3485 (0%) 0/3494 (0%)
Pneumonia klebsiella 0/3485 (0%) 1/3494 (0%)
Pneumonia legionella 0/3485 (0%) 1/3494 (0%)
Pneumonia pneumococcal 0/3485 (0%) 1/3494 (0%)
Pseudomembranous colitis 0/3485 (0%) 1/3494 (0%)
Pseudomonas infection 0/3485 (0%) 1/3494 (0%)
Pulpitis dental 1/3485 (0%) 0/3494 (0%)
Pyelonephritis chronic 1/3485 (0%) 0/3494 (0%)
Renal abscess 1/3485 (0%) 0/3494 (0%)
Respiratory tract infection viral 1/3485 (0%) 0/3494 (0%)
Scrub typhus 0/3485 (0%) 1/3494 (0%)
Sialoadenitis 0/3485 (0%) 1/3494 (0%)
Skin infection 1/3485 (0%) 0/3494 (0%)
Spinal cord abscess 1/3485 (0%) 0/3494 (0%)
Streptococcal bacteraemia 0/3485 (0%) 1/3494 (0%)
Systemic infection 1/3485 (0%) 0/3494 (0%)
Tonsillitis 0/3485 (0%) 1/3494 (0%)
Tooth infection 1/3485 (0%) 0/3494 (0%)
Tracheobronchitis 0/3485 (0%) 1/3494 (0%)
Tuberculosis 1/3485 (0%) 0/3494 (0%)
Urinary tract infection bacterial 1/3485 (0%) 0/3494 (0%)
Urinary tract infection pseudomonal 0/3485 (0%) 1/3494 (0%)
Viraemia 0/3485 (0%) 1/3494 (0%)
Viral tonsillitis 0/3485 (0%) 1/3494 (0%)
Injury, poisoning and procedural complications
Fall 25/3485 (0.7%) 19/3494 (0.5%)
Femur fracture 6/3485 (0.2%) 10/3494 (0.3%)
Hip fracture 7/3485 (0.2%) 3/3494 (0.1%)
Limb injury 5/3485 (0.1%) 5/3494 (0.1%)
Road traffic accident 7/3485 (0.2%) 2/3494 (0.1%)
Contusion 3/3485 (0.1%) 5/3494 (0.1%)
Tibia fracture 3/3485 (0.1%) 4/3494 (0.1%)
Humerus fracture 3/3485 (0.1%) 3/3494 (0.1%)
Rib fracture 1/3485 (0%) 5/3494 (0.1%)
Subdural haematoma 1/3485 (0%) 5/3494 (0.1%)
Ankle fracture 0/3485 (0%) 5/3494 (0.1%)
Femoral neck fracture 3/3485 (0.1%) 2/3494 (0.1%)
Head injury 3/3485 (0.1%) 2/3494 (0.1%)
Facial bones fracture 3/3485 (0.1%) 1/3494 (0%)
Foot fracture 1/3485 (0%) 3/3494 (0.1%)
Lower limb fracture 2/3485 (0.1%) 2/3494 (0.1%)
Patella fracture 1/3485 (0%) 3/3494 (0.1%)
Pelvic fracture 2/3485 (0.1%) 2/3494 (0.1%)
Tendon rupture 2/3485 (0.1%) 2/3494 (0.1%)
Wound dehiscence 3/3485 (0.1%) 1/3494 (0%)
Craniocerebral injury 1/3485 (0%) 2/3494 (0.1%)
Overdose 2/3485 (0.1%) 1/3494 (0%)
Upper limb fracture 3/3485 (0.1%) 0/3494 (0%)
Arteriovenous fistula site complication 1/3485 (0%) 1/3494 (0%)
Back injury 1/3485 (0%) 1/3494 (0%)
Fibula fracture 1/3485 (0%) 1/3494 (0%)
Hyphaema 1/3485 (0%) 1/3494 (0%)
Incisional hernia 0/3485 (0%) 2/3494 (0.1%)
Joint dislocation 1/3485 (0%) 1/3494 (0%)
Post procedural haemorrhage 1/3485 (0%) 1/3494 (0%)
Subarachnoid haemorrhage 1/3485 (0%) 1/3494 (0%)
Anastomotic complication 0/3485 (0%) 1/3494 (0%)
Animal bite 0/3485 (0%) 1/3494 (0%)
Arterial bypass occlusion 0/3485 (0%) 1/3494 (0%)
Arteriovenous fistula thrombosis 0/3485 (0%) 1/3494 (0%)
Bone contusion 1/3485 (0%) 0/3494 (0%)
Brain contusion 1/3485 (0%) 0/3494 (0%)
Burns second degree 1/3485 (0%) 0/3494 (0%)
Carbon monoxide poisoning 1/3485 (0%) 0/3494 (0%)
Cervical vertebral fracture 1/3485 (0%) 0/3494 (0%)
Chest injury 1/3485 (0%) 0/3494 (0%)
Colon injury 0/3485 (0%) 1/3494 (0%)
Coronary artery restenosis 0/3485 (0%) 1/3494 (0%)
Endotracheal intubation complication 0/3485 (0%) 1/3494 (0%)
Fracture displacement 0/3485 (0%) 1/3494 (0%)
Hand fracture 1/3485 (0%) 0/3494 (0%)
Heart injury 1/3485 (0%) 0/3494 (0%)
Incomplete spinal fusion 1/3485 (0%) 0/3494 (0%)
Injury 1/3485 (0%) 0/3494 (0%)
Jaw fracture 1/3485 (0%) 0/3494 (0%)
Joint injury 0/3485 (0%) 1/3494 (0%)
Laceration 1/3485 (0%) 0/3494 (0%)
Limb crushing injury 0/3485 (0%) 1/3494 (0%)
Lumbar vertebral fracture 1/3485 (0%) 0/3494 (0%)
Multiple injuries 1/3485 (0%) 0/3494 (0%)
Muscle injury 1/3485 (0%) 0/3494 (0%)
Muscle strain 1/3485 (0%) 0/3494 (0%)
Periprocedural myocardial infarction 1/3485 (0%) 0/3494 (0%)
Periprosthetic fracture 1/3485 (0%) 0/3494 (0%)
Peritoneal dialysis complication 0/3485 (0%) 1/3494 (0%)
Pneumothorax traumatic 0/3485 (0%) 1/3494 (0%)
Post procedural complication 1/3485 (0%) 0/3494 (0%)
Postoperative delirium 0/3485 (0%) 1/3494 (0%)
Postoperative respiratory distress 0/3485 (0%) 1/3494 (0%)
Procedural hypotension 1/3485 (0%) 0/3494 (0%)
Procedural intestinal perforation 1/3485 (0%) 0/3494 (0%)
Radius fracture 0/3485 (0%) 1/3494 (0%)
Scar 1/3485 (0%) 0/3494 (0%)
Skeletal injury 1/3485 (0%) 0/3494 (0%)
Skull fractured base 0/3485 (0%) 1/3494 (0%)
Spinal compression fracture 0/3485 (0%) 1/3494 (0%)
Spinal fracture 1/3485 (0%) 0/3494 (0%)
Splenic rupture 1/3485 (0%) 0/3494 (0%)
Sternal fracture 0/3485 (0%) 1/3494 (0%)
Stoma site polyp 1/3485 (0%) 0/3494 (0%)
Stomal hernia 0/3485 (0%) 1/3494 (0%)
Subdural haemorrhage 1/3485 (0%) 0/3494 (0%)
Thoracic vertebral fracture 0/3485 (0%) 1/3494 (0%)
Traumatic intracranial haemorrhage 0/3485 (0%) 1/3494 (0%)
Traumatic liver injury 1/3485 (0%) 0/3494 (0%)
Ulna fracture 1/3485 (0%) 0/3494 (0%)
Vascular pseudoaneurysm 0/3485 (0%) 1/3494 (0%)
Vith nerve injury 1/3485 (0%) 0/3494 (0%)
Wound 1/3485 (0%) 0/3494 (0%)
Wound necrosis 1/3485 (0%) 0/3494 (0%)
Wrist fracture 0/3485 (0%) 1/3494 (0%)
Investigations
Glomerular filtration rate decreased 30/3485 (0.9%) 36/3494 (1%)
Lipase increased 5/3485 (0.1%) 4/3494 (0.1%)
Blood creatinine increased 3/3485 (0.1%) 1/3494 (0%)
Blood pressure increased 1/3485 (0%) 2/3494 (0.1%)
Arteriogram coronary 0/3485 (0%) 2/3494 (0.1%)
Blood glucose increased 0/3485 (0%) 2/3494 (0.1%)
Glycosylated haemoglobin increased 2/3485 (0.1%) 0/3494 (0%)
Troponin increased 1/3485 (0%) 1/3494 (0%)
Alanine aminotransferase increased 1/3485 (0%) 0/3494 (0%)
Aspartate aminotransferase increased 1/3485 (0%) 0/3494 (0%)
Aspiration bronchial 1/3485 (0%) 0/3494 (0%)
Catheterisation cardiac 0/3485 (0%) 1/3494 (0%)
Creatinine renal clearance decreased 1/3485 (0%) 0/3494 (0%)
Echocardiogram 0/3485 (0%) 1/3494 (0%)
Ejection fraction decreased 0/3485 (0%) 1/3494 (0%)
Electrocardiogram qt prolonged 1/3485 (0%) 0/3494 (0%)
Electrocardiogram t wave inversion 0/3485 (0%) 1/3494 (0%)
Influenza a virus test positive 0/3485 (0%) 1/3494 (0%)
International normalised ratio increased 1/3485 (0%) 0/3494 (0%)
Intracardiac pressure increased 0/3485 (0%) 1/3494 (0%)
Liver function test abnormal 1/3485 (0%) 0/3494 (0%)
Liver function test increased 0/3485 (0%) 1/3494 (0%)
Prostatic specific antigen increased 1/3485 (0%) 0/3494 (0%)
Staphylococcus test positive 1/3485 (0%) 0/3494 (0%)
Urine output decreased 1/3485 (0%) 0/3494 (0%)
Metabolism and nutrition disorders
Hypoglycaemia 38/3485 (1.1%) 28/3494 (0.8%)
Hyperkalaemia 19/3485 (0.5%) 16/3494 (0.5%)
Hyperglycaemia 22/3485 (0.6%) 12/3494 (0.3%)
Dehydration 6/3485 (0.2%) 11/3494 (0.3%)
Diabetes mellitus inadequate control 10/3485 (0.3%) 7/3494 (0.2%)
Diabetes mellitus 7/3485 (0.2%) 9/3494 (0.3%)
Fluid overload 11/3485 (0.3%) 5/3494 (0.1%)
Diabetic metabolic decompensation 5/3485 (0.1%) 10/3494 (0.3%)
Hyponatraemia 5/3485 (0.1%) 6/3494 (0.2%)
Metabolic acidosis 1/3485 (0%) 7/3494 (0.2%)
Diabetic ketoacidosis 4/3485 (0.1%) 3/3494 (0.1%)
Electrolyte imbalance 3/3485 (0.1%) 3/3494 (0.1%)
Hypokalaemia 1/3485 (0%) 3/3494 (0.1%)
Type 2 diabetes mellitus 0/3485 (0%) 4/3494 (0.1%)
Gout 1/3485 (0%) 2/3494 (0.1%)
Hyperlipasaemia 1/3485 (0%) 2/3494 (0.1%)
Hypovolaemia 3/3485 (0.1%) 0/3494 (0%)
Lactic acidosis 1/3485 (0%) 2/3494 (0.1%)
Fluid retention 1/3485 (0%) 1/3494 (0%)
Hypercalcaemia 1/3485 (0%) 1/3494 (0%)
Hypocalcaemia 0/3485 (0%) 2/3494 (0.1%)
Abnormal loss of weight 0/3485 (0%) 1/3494 (0%)
Acquired mixed hyperlipidaemia 1/3485 (0%) 0/3494 (0%)
Decreased appetite 0/3485 (0%) 1/3494 (0%)
Diabetes with hyperosmolarity 1/3485 (0%) 0/3494 (0%)
Failure to thrive 0/3485 (0%) 1/3494 (0%)
Fluid imbalance 0/3485 (0%) 1/3494 (0%)
Hypernatraemia 1/3485 (0%) 0/3494 (0%)
Hyperosmolar state 1/3485 (0%) 0/3494 (0%)
Hyperphosphataemia 0/3485 (0%) 1/3494 (0%)
Hypertriglyceridaemia 0/3485 (0%) 1/3494 (0%)
Hyperuricaemia 1/3485 (0%) 0/3494 (0%)
Hypophagia 1/3485 (0%) 0/3494 (0%)
Obesity 1/3485 (0%) 0/3494 (0%)
Vitamin d deficiency 0/3485 (0%) 1/3494 (0%)
Musculoskeletal and connective tissue disorders
Osteoarthritis 17/3485 (0.5%) 15/3494 (0.4%)
Musculoskeletal chest pain 6/3485 (0.2%) 3/3494 (0.1%)
Intervertebral disc protrusion 2/3485 (0.1%) 3/3494 (0.1%)
Lumbar spinal stenosis 4/3485 (0.1%) 1/3494 (0%)
Rhabdomyolysis 2/3485 (0.1%) 3/3494 (0.1%)
Spinal osteoarthritis 2/3485 (0.1%) 3/3494 (0.1%)
Arthritis 1/3485 (0%) 3/3494 (0.1%)
Back pain 1/3485 (0%) 3/3494 (0.1%)
Spinal column stenosis 2/3485 (0.1%) 2/3494 (0.1%)
Intervertebral disc disorder 1/3485 (0%) 2/3494 (0.1%)
Musculoskeletal pain 1/3485 (0%) 2/3494 (0.1%)
Pain in extremity 2/3485 (0.1%) 1/3494 (0%)
Polymyalgia rheumatica 1/3485 (0%) 2/3494 (0.1%)
Spinal pain 1/3485 (0%) 2/3494 (0.1%)
Spondylolisthesis 1/3485 (0%) 2/3494 (0.1%)
Arthralgia 1/3485 (0%) 1/3494 (0%)
Diabetic arthropathy 2/3485 (0.1%) 0/3494 (0%)
Osteitis 2/3485 (0.1%) 0/3494 (0%)
Plantar fasciitis 1/3485 (0%) 1/3494 (0%)
Rotator cuff syndrome 0/3485 (0%) 2/3494 (0.1%)
Ankylosing spondylitis 1/3485 (0%) 0/3494 (0%)
Arthritis reactive 1/3485 (0%) 0/3494 (0%)
Bone pain 1/3485 (0%) 0/3494 (0%)
Bursitis 0/3485 (0%) 1/3494 (0%)
Exostosis 1/3485 (0%) 0/3494 (0%)
Fibromyalgia 0/3485 (0%) 1/3494 (0%)
Gouty arthritis 0/3485 (0%) 1/3494 (0%)
Intervertebral disc degeneration 1/3485 (0%) 0/3494 (0%)
Joint range of motion decreased 0/3485 (0%) 1/3494 (0%)
Limb discomfort 0/3485 (0%) 1/3494 (0%)
Muscle haemorrhage 1/3485 (0%) 0/3494 (0%)
Muscle spasms 1/3485 (0%) 0/3494 (0%)
Myopathy 0/3485 (0%) 1/3494 (0%)
Myopathy toxic 1/3485 (0%) 0/3494 (0%)
Neck pain 1/3485 (0%) 0/3494 (0%)
Neuropathic arthropathy 0/3485 (0%) 1/3494 (0%)
Osteochondrosis 1/3485 (0%) 0/3494 (0%)
Osteonecrosis 0/3485 (0%) 1/3494 (0%)
Pathological fracture 0/3485 (0%) 1/3494 (0%)
Periostitis 0/3485 (0%) 1/3494 (0%)
Rheumatoid arthritis 0/3485 (0%) 1/3494 (0%)
Synovial cyst 1/3485 (0%) 0/3494 (0%)
Systemic lupus erythematosus 1/3485 (0%) 0/3494 (0%)
Vertebral osteophyte 0/3485 (0%) 1/3494 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma 14/3485 (0.4%) 14/3494 (0.4%)
Prostate cancer 8/3485 (0.2%) 9/3494 (0.3%)
Squamous cell carcinoma of skin 9/3485 (0.3%) 8/3494 (0.2%)
Lung neoplasm malignant 5/3485 (0.1%) 7/3494 (0.2%)
Colon cancer 7/3485 (0.2%) 2/3494 (0.1%)
Breast cancer 4/3485 (0.1%) 2/3494 (0.1%)
Adenocarcinoma of colon 4/3485 (0.1%) 1/3494 (0%)
Bladder cancer 3/3485 (0.1%) 2/3494 (0.1%)
Bladder transitional cell carcinoma 2/3485 (0.1%) 2/3494 (0.1%)
Hepatic cancer 3/3485 (0.1%) 1/3494 (0%)
Invasive ductal breast carcinoma 3/3485 (0.1%) 1/3494 (0%)
Lung adenocarcinoma 1/3485 (0%) 3/3494 (0.1%)
Myelodysplastic syndrome 3/3485 (0.1%) 1/3494 (0%)
Plasma cell myeloma 2/3485 (0.1%) 2/3494 (0.1%)
Renal cancer 1/3485 (0%) 3/3494 (0.1%)
Transitional cell carcinoma 3/3485 (0.1%) 1/3494 (0%)
Bowen's disease 2/3485 (0.1%) 1/3494 (0%)
Colon adenoma 2/3485 (0.1%) 1/3494 (0%)
Hepatocellular carcinoma 1/3485 (0%) 2/3494 (0.1%)
Metastases to bone 2/3485 (0.1%) 1/3494 (0%)
Metastases to liver 3/3485 (0.1%) 0/3494 (0%)
Non-hodgkin's lymphoma 3/3485 (0.1%) 0/3494 (0%)
Rectal adenocarcinoma 2/3485 (0.1%) 1/3494 (0%)
Adenocarcinoma gastric 1/3485 (0%) 1/3494 (0%)
Adenocarcinoma pancreas 2/3485 (0.1%) 0/3494 (0%)
Benign breast neoplasm 1/3485 (0%) 1/3494 (0%)
Benign ovarian tumour 2/3485 (0.1%) 0/3494 (0%)
Lung neoplasm 0/3485 (0%) 2/3494 (0.1%)
Malignant melanoma 1/3485 (0%) 1/3494 (0%)
Mediastinum neoplasm 1/3485 (0%) 1/3494 (0%)
Meningioma 0/3485 (0%) 2/3494 (0.1%)
Pancreatic carcinoma 0/3485 (0%) 2/3494 (0.1%)
Plasmacytoma 1/3485 (0%) 1/3494 (0%)
Prostate cancer metastatic 0/3485 (0%) 2/3494 (0.1%)
Rectal cancer 1/3485 (0%) 1/3494 (0%)
Renal neoplasm 1/3485 (0%) 1/3494 (0%)
Small cell lung cancer 1/3485 (0%) 1/3494 (0%)
Squamous cell carcinoma of lung 1/3485 (0%) 1/3494 (0%)
Acute monocytic leukaemia 1/3485 (0%) 0/3494 (0%)
Acute myeloid leukaemia 1/3485 (0%) 0/3494 (0%)
Acute promyelocytic leukaemia 1/3485 (0%) 0/3494 (0%)
Basosquamous carcinoma 1/3485 (0%) 0/3494 (0%)
Basosquamous carcinoma of skin 0/3485 (0%) 1/3494 (0%)
Bladder neoplasm 1/3485 (0%) 0/3494 (0%)
Brain neoplasm 0/3485 (0%) 1/3494 (0%)
Bronchial carcinoma 1/3485 (0%) 0/3494 (0%)
Cancer pain 1/3485 (0%) 0/3494 (0%)
Carcinoma in situ of penis 1/3485 (0%) 0/3494 (0%)
Cardiac myxoma 1/3485 (0%) 0/3494 (0%)
Cardiac neoplasm unspecified 0/3485 (0%) 1/3494 (0%)
Cervix carcinoma 1/3485 (0%) 0/3494 (0%)
Chest wall tumour 1/3485 (0%) 0/3494 (0%)
Cholesteatoma 1/3485 (0%) 0/3494 (0%)
Chronic lymphocytic leukaemia 1/3485 (0%) 0/3494 (0%)
Colon neoplasm 1/3485 (0%) 0/3494 (0%)
Diffuse large b-cell lymphoma 0/3485 (0%) 1/3494 (0%)
Endometrial adenocarcinoma 1/3485 (0%) 0/3494 (0%)
Endometrial cancer 0/3485 (0%) 1/3494 (0%)
Gallbladder cancer 0/3485 (0%) 1/3494 (0%)
Gastric adenoma 0/3485 (0%) 1/3494 (0%)
Gastric cancer 1/3485 (0%) 0/3494 (0%)
Gastrointestinal cancer metastatic 1/3485 (0%) 0/3494 (0%)
Gastrointestinal neoplasm 1/3485 (0%) 0/3494 (0%)
Hepatic neoplasm 1/3485 (0%) 0/3494 (0%)
Hodgkin's disease 1/3485 (0%) 0/3494 (0%)
Intraductal proliferative breast lesion 0/3485 (0%) 1/3494 (0%)
Laryngeal cancer 0/3485 (0%) 1/3494 (0%)
Leiomyosarcoma 1/3485 (0%) 0/3494 (0%)
Lip neoplasm malignant stage unspecified 1/3485 (0%) 0/3494 (0%)
Lung adenocarcinoma stage 0 1/3485 (0%) 0/3494 (0%)
Lung cancer metastatic 0/3485 (0%) 1/3494 (0%)
Lymphoma 1/3485 (0%) 0/3494 (0%)
Malignant anorectal neoplasm 1/3485 (0%) 0/3494 (0%)
Malignant melanoma in situ 1/3485 (0%) 0/3494 (0%)
Malignant pleural effusion 1/3485 (0%) 0/3494 (0%)
Metastases to lung 0/3485 (0%) 1/3494 (0%)
Metastases to spine 0/3485 (0%) 1/3494 (0%)
Metastatic carcinoma of the bladder 1/3485 (0%) 0/3494 (0%)
Metastatic malignant melanoma 0/3485 (0%) 1/3494 (0%)
Mucinous cystadenocarcinoma of pancreas 1/3485 (0%) 0/3494 (0%)
Myeloproliferative neoplasm 0/3485 (0%) 1/3494 (0%)
Naevoid melanoma 1/3485 (0%) 0/3494 (0%)
Neoplasm skin 1/3485 (0%) 0/3494 (0%)
Neuroendocrine tumour 0/3485 (0%) 1/3494 (0%)
Non-small cell lung cancer 0/3485 (0%) 1/3494 (0%)
Oesophageal adenocarcinoma 0/3485 (0%) 1/3494 (0%)
Oesophageal carcinoma 0/3485 (0%) 1/3494 (0%)
Oesophageal carcinoma recurrent 1/3485 (0%) 0/3494 (0%)
Pancreatic carcinoma metastatic 0/3485 (0%) 1/3494 (0%)
Pancreatic neoplasm 0/3485 (0%) 1/3494 (0%)
Papillary renal cell carcinoma 1/3485 (0%) 0/3494 (0%)
Papillary thyroid cancer 1/3485 (0%) 0/3494 (0%)
Penile squamous cell carcinoma 0/3485 (0%) 1/3494 (0%)
Prostatic adenoma 0/3485 (0%) 1/3494 (0%)
Rectal adenoma 1/3485 (0%) 0/3494 (0%)
Renal cell carcinoma 1/3485 (0%) 0/3494 (0%)
Schwannoma 0/3485 (0%) 1/3494 (0%)
Sebaceous adenoma 0/3485 (0%) 1/3494 (0%)
Testis cancer 0/3485 (0%) 1/3494 (0%)
Tongue cancer recurrent 0/3485 (0%) 1/3494 (0%)
Tongue neoplasm malignant stage unspecified 0/3485 (0%) 1/3494 (0%)
Transitional cell cancer of the renal pelvis and ureter 0/3485 (0%) 1/3494 (0%)
Tumour of ampulla of vater 0/3485 (0%) 1/3494 (0%)
Uterine leiomyoma 1/3485 (0%) 0/3494 (0%)
Vulval cancer 0/3485 (0%) 1/3494 (0%)
Vulval cancer stage 0 1/3485 (0%) 0/3494 (0%)
Nervous system disorders
Ischaemic stroke 49/3485 (1.4%) 61/3494 (1.7%)
Syncope 25/3485 (0.7%) 15/3494 (0.4%)
Transient ischaemic attack 9/3485 (0.3%) 27/3494 (0.8%)
Cerebrovascular accident 12/3485 (0.3%) 10/3494 (0.3%)
Haemorrhagic stroke 8/3485 (0.2%) 10/3494 (0.3%)
Dementia 6/3485 (0.2%) 8/3494 (0.2%)
Diabetic neuropathy 5/3485 (0.1%) 7/3494 (0.2%)
Seizure 6/3485 (0.2%) 5/3494 (0.1%)
Cerebral infarction 8/3485 (0.2%) 2/3494 (0.1%)
Presyncope 7/3485 (0.2%) 2/3494 (0.1%)
Carotid artery stenosis 6/3485 (0.2%) 2/3494 (0.1%)
Cerebral ischaemia 4/3485 (0.1%) 2/3494 (0.1%)
Facial paralysis 3/3485 (0.1%) 2/3494 (0.1%)
Headache 4/3485 (0.1%) 1/3494 (0%)
Loss of consciousness 3/3485 (0.1%) 2/3494 (0.1%)
Dizziness 0/3485 (0%) 4/3494 (0.1%)
Encephalopathy 2/3485 (0.1%) 2/3494 (0.1%)
Haemorrhage intracranial 1/3485 (0%) 3/3494 (0.1%)
Hemiparesis 4/3485 (0.1%) 0/3494 (0%)
Myelopathy 3/3485 (0.1%) 1/3494 (0%)
Altered state of consciousness 1/3485 (0%) 2/3494 (0.1%)
Cerebral haemorrhage 1/3485 (0%) 2/3494 (0.1%)
Diabetic coma 1/3485 (0%) 2/3494 (0.1%)
Epilepsy 2/3485 (0.1%) 1/3494 (0%)
Hypertensive encephalopathy 1/3485 (0%) 2/3494 (0.1%)
Lacunar infarction 2/3485 (0.1%) 1/3494 (0%)
Basal ganglia infarction 2/3485 (0.1%) 0/3494 (0%)
Brain oedema 1/3485 (0%) 1/3494 (0%)
Brain stem infarction 1/3485 (0%) 1/3494 (0%)
Carotid artery occlusion 2/3485 (0.1%) 0/3494 (0%)
Cerebrovascular disorder 2/3485 (0.1%) 0/3494 (0%)
Dementia with lewy bodies 2/3485 (0.1%) 0/3494 (0%)
Embolic stroke 1/3485 (0%) 1/3494 (0%)
Facial nerve disorder 1/3485 (0%) 1/3494 (0%)
Hemiplegia 0/3485 (0%) 2/3494 (0.1%)
Hypoglycaemic coma 1/3485 (0%) 1/3494 (0%)
Hypoxic-ischaemic encephalopathy 1/3485 (0%) 1/3494 (0%)
Intracranial aneurysm 0/3485 (0%) 2/3494 (0.1%)
Ischaemic cerebral infarction 1/3485 (0%) 1/3494 (0%)
Lumbar radiculopathy 1/3485 (0%) 1/3494 (0%)
Neuropathy peripheral 0/3485 (0%) 2/3494 (0.1%)
Parkinson's disease 1/3485 (0%) 1/3494 (0%)
Partial seizures 0/3485 (0%) 2/3494 (0.1%)
Sciatica 0/3485 (0%) 2/3494 (0.1%)
Thrombotic stroke 1/3485 (0%) 1/3494 (0%)
Vertebrobasilar insufficiency 1/3485 (0%) 1/3494 (0%)
Brain injury 1/3485 (0%) 0/3494 (0%)
Carotid arteriosclerosis 1/3485 (0%) 0/3494 (0%)
Carotid artery dissection 1/3485 (0%) 0/3494 (0%)
Carotid sinus syndrome 0/3485 (0%) 1/3494 (0%)
Carpal tunnel syndrome 0/3485 (0%) 1/3494 (0%)
Central nervous system lesion 1/3485 (0%) 0/3494 (0%)
Cerebral haematoma 1/3485 (0%) 0/3494 (0%)
Cerebral small vessel ischaemic disease 1/3485 (0%) 0/3494 (0%)
Cerebrospinal fluid leakage 1/3485 (0%) 0/3494 (0%)
Cervical radiculopathy 0/3485 (0%) 1/3494 (0%)
Cervicobrachial syndrome 1/3485 (0%) 0/3494 (0%)
Coma 1/3485 (0%) 0/3494 (0%)
Complex regional pain syndrome 1/3485 (0%) 0/3494 (0%)
Dyskinesia 0/3485 (0%) 1/3494 (0%)
Generalised tonic-clonic seizure 1/3485 (0%) 0/3494 (0%)
Hepatic encephalopathy 1/3485 (0%) 0/3494 (0%)
Incoherent 1/3485 (0%) 0/3494 (0%)
Intracranial pressure increased 0/3485 (0%) 1/3494 (0%)
Intraventricular haemorrhage 1/3485 (0%) 0/3494 (0%)
Lacunar stroke 0/3485 (0%) 1/3494 (0%)
Metabolic encephalopathy 0/3485 (0%) 1/3494 (0%)
Multiple sclerosis 0/3485 (0%) 1/3494 (0%)
Myasthenia gravis 1/3485 (0%) 0/3494 (0%)
Neuritis cranial 0/3485 (0%) 1/3494 (0%)
Neuroglycopenia 0/3485 (0%) 1/3494 (0%)
Paraesthesia 0/3485 (0%) 1/3494 (0%)
Parkinsonism 1/3485 (0%) 0/3494 (0%)
Peripheral sensory neuropathy 1/3485 (0%) 0/3494 (0%)
Polyneuropathy 1/3485 (0%) 0/3494 (0%)
Post stroke seizure 0/3485 (0%) 1/3494 (0%)
Spinal claudication 1/3485 (0%) 0/3494 (0%)
Spinal cord compression 0/3485 (0%) 1/3494 (0%)
Spinal epidural haematoma 0/3485 (0%) 1/3494 (0%)
Thalamic infarction 1/3485 (0%) 0/3494 (0%)
Tremor 1/3485 (0%) 0/3494 (0%)
Uraemic encephalopathy 1/3485 (0%) 0/3494 (0%)
Vascular headache 1/3485 (0%) 0/3494 (0%)
Vith nerve paralysis 1/3485 (0%) 0/3494 (0%)
Wernicke's encephalopathy 1/3485 (0%) 0/3494 (0%)
Product Issues
Device malfunction 2/3485 (0.1%) 2/3494 (0.1%)
Device failure 1/3485 (0%) 0/3494 (0%)
Psychiatric disorders
Delirium 4/3485 (0.1%) 4/3494 (0.1%)
Major depression 3/3485 (0.1%) 2/3494 (0.1%)
Mental status changes 3/3485 (0.1%) 2/3494 (0.1%)
Depression 3/3485 (0.1%) 1/3494 (0%)
Anxiety 2/3485 (0.1%) 1/3494 (0%)
Confusional state 1/3485 (0%) 1/3494 (0%)
Hallucination, visual 2/3485 (0.1%) 0/3494 (0%)
Acute stress disorder 1/3485 (0%) 0/3494 (0%)
Adjustment disorder 0/3485 (0%) 1/3494 (0%)
Affect lability 0/3485 (0%) 1/3494 (0%)
Completed suicide 1/3485 (0%) 0/3494 (0%)
Drug use disorder 1/3485 (0%) 0/3494 (0%)
Insomnia 1/3485 (0%) 0/3494 (0%)
Irritability 1/3485 (0%) 0/3494 (0%)
Mood disorder due to a general medical condition 1/3485 (0%) 0/3494 (0%)
Psychotic disorder 1/3485 (0%) 0/3494 (0%)
Suicidal ideation 1/3485 (0%) 0/3494 (0%)
Renal and urinary disorders
Acute kidney injury 100/3485 (2.9%) 96/3494 (2.7%)
End stage renal disease 45/3485 (1.3%) 38/3494 (1.1%)
Chronic kidney disease 32/3485 (0.9%) 49/3494 (1.4%)
Renal failure 31/3485 (0.9%) 32/3494 (0.9%)
Renal impairment 27/3485 (0.8%) 24/3494 (0.7%)
Diabetic nephropathy 7/3485 (0.2%) 9/3494 (0.3%)
Nephrolithiasis 7/3485 (0.2%) 5/3494 (0.1%)
Urinary retention 6/3485 (0.2%) 5/3494 (0.1%)
Haematuria 4/3485 (0.1%) 5/3494 (0.1%)
Nephrotic syndrome 2/3485 (0.1%) 7/3494 (0.2%)
Azotaemia 6/3485 (0.2%) 1/3494 (0%)
Nephropathy 4/3485 (0.1%) 3/3494 (0.1%)
Hydronephrosis 1/3485 (0%) 4/3494 (0.1%)
Ureterolithiasis 1/3485 (0%) 4/3494 (0.1%)
Urinary tract obstruction 2/3485 (0.1%) 2/3494 (0.1%)
Calculus bladder 0/3485 (0%) 2/3494 (0.1%)
Nephropathy toxic 1/3485 (0%) 1/3494 (0%)
Renal artery stenosis 1/3485 (0%) 1/3494 (0%)
Renal colic 1/3485 (0%) 1/3494 (0%)
Renal mass 1/3485 (0%) 1/3494 (0%)
Acute prerenal failure 0/3485 (0%) 1/3494 (0%)
Anuria 1/3485 (0%) 0/3494 (0%)
Bladder prolapse 1/3485 (0%) 0/3494 (0%)
Dysuria 1/3485 (0%) 0/3494 (0%)
Glomerulonephritis membranous 0/3485 (0%) 1/3494 (0%)
Hypertensive nephropathy 1/3485 (0%) 0/3494 (0%)
Mesangioproliferative glomerulonephritis 1/3485 (0%) 0/3494 (0%)
Oliguria 1/3485 (0%) 0/3494 (0%)
Proteinuria 1/3485 (0%) 0/3494 (0%)
Renal disorder 1/3485 (0%) 0/3494 (0%)
Renal pain 0/3485 (0%) 1/3494 (0%)
Renal tubular necrosis 1/3485 (0%) 0/3494 (0%)
Tubulointerstitial nephritis 1/3485 (0%) 0/3494 (0%)
Urethral haemorrhage 0/3485 (0%) 1/3494 (0%)
Urinary incontinence 1/3485 (0%) 0/3494 (0%)
Reproductive system and breast disorders
Benign prostatic hyperplasia 8/3485 (0.2%) 4/3494 (0.1%)
Acquired hydrocele 0/3485 (0%) 2/3494 (0.1%)
Uterine polyp 2/3485 (0.1%) 0/3494 (0%)
Acquired phimosis 0/3485 (0%) 1/3494 (0%)
Cervical polyp 1/3485 (0%) 0/3494 (0%)
Cystocele 1/3485 (0%) 0/3494 (0%)
Endometrial hypertrophy 1/3485 (0%) 0/3494 (0%)
Haemorrhagic ovarian cyst 0/3485 (0%) 1/3494 (0%)
Vaginal haemorrhage 1/3485 (0%) 0/3494 (0%)
Vaginal leukoplakia 1/3485 (0%) 0/3494 (0%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease 28/3485 (0.8%) 21/3494 (0.6%)
Dyspnoea 16/3485 (0.5%) 16/3494 (0.5%)
Pulmonary oedema 13/3485 (0.4%) 16/3494 (0.5%)
Acute pulmonary oedema 15/3485 (0.4%) 13/3494 (0.4%)
Respiratory failure 14/3485 (0.4%) 13/3494 (0.4%)
Pulmonary hypertension 14/3485 (0.4%) 12/3494 (0.3%)
Pulmonary embolism 12/3485 (0.3%) 9/3494 (0.3%)
Acute respiratory failure 11/3485 (0.3%) 9/3494 (0.3%)
Pleural effusion 11/3485 (0.3%) 5/3494 (0.1%)
Asthma 3/3485 (0.1%) 3/3494 (0.1%)
Dyspnoea exertional 5/3485 (0.1%) 1/3494 (0%)
Pulmonary fibrosis 5/3485 (0.1%) 1/3494 (0%)
Hypoxia 1/3485 (0%) 4/3494 (0.1%)
Epistaxis 2/3485 (0.1%) 2/3494 (0.1%)
Pulmonary mass 1/3485 (0%) 3/3494 (0.1%)
Respiratory arrest 2/3485 (0.1%) 2/3494 (0.1%)
Haemoptysis 1/3485 (0%) 2/3494 (0.1%)
Pneumonia aspiration 1/3485 (0%) 2/3494 (0.1%)
Respiratory distress 1/3485 (0%) 2/3494 (0.1%)
Sleep apnoea syndrome 2/3485 (0.1%) 1/3494 (0%)
Asphyxia 0/3485 (0%) 2/3494 (0.1%)
Chronic respiratory failure 1/3485 (0%) 1/3494 (0%)
Cough 1/3485 (0%) 1/3494 (0%)
Emphysema 0/3485 (0%) 2/3494 (0.1%)
Lung disorder 2/3485 (0.1%) 0/3494 (0%)
Pneumothorax 2/3485 (0.1%) 0/3494 (0%)
Pulmonary congestion 1/3485 (0%) 1/3494 (0%)
Wheezing 0/3485 (0%) 2/3494 (0.1%)
Acute respiratory distress syndrome 0/3485 (0%) 1/3494 (0%)
Aspiration 0/3485 (0%) 1/3494 (0%)
Atelectasis 0/3485 (0%) 1/3494 (0%)
Bronchitis chronic 1/3485 (0%) 0/3494 (0%)
Bronchospasm 1/3485 (0%) 0/3494 (0%)
Eosinophilic pneumonia 0/3485 (0%) 1/3494 (0%)
Haemothorax 0/3485 (0%) 1/3494 (0%)
Interstitial lung disease 0/3485 (0%) 1/3494 (0%)
Laryngeal oedema 0/3485 (0%) 1/3494 (0%)
Mediastinal mass 0/3485 (0%) 1/3494 (0%)
Mendelson's syndrome 0/3485 (0%) 1/3494 (0%)
Paraneoplastic pleural effusion 1/3485 (0%) 0/3494 (0%)
Pleural thickening 1/3485 (0%) 0/3494 (0%)
Pneumonitis 0/3485 (0%) 1/3494 (0%)
Portopulmonary hypertension 0/3485 (0%) 1/3494 (0%)
Restrictive pulmonary disease 1/3485 (0%) 0/3494 (0%)
Sinus polyp 1/3485 (0%) 0/3494 (0%)
Vocal cord cyst 1/3485 (0%) 0/3494 (0%)
Vocal cord disorder 1/3485 (0%) 0/3494 (0%)
Vocal cord polyp 0/3485 (0%) 1/3494 (0%)
Skin and subcutaneous tissue disorders
Diabetic foot 24/3485 (0.7%) 21/3494 (0.6%)
Skin ulcer 10/3485 (0.3%) 7/3494 (0.2%)
Angioedema 1/3485 (0%) 2/3494 (0.1%)
Ischaemic skin ulcer 2/3485 (0.1%) 1/3494 (0%)
Pemphigoid 0/3485 (0%) 3/3494 (0.1%)
Pruritus 0/3485 (0%) 2/3494 (0.1%)
Stasis dermatitis 2/3485 (0.1%) 0/3494 (0%)
Decubitus ulcer 0/3485 (0%) 1/3494 (0%)
Dermal cyst 0/3485 (0%) 1/3494 (0%)
Dermatitis bullous 0/3485 (0%) 1/3494 (0%)
Dermatitis exfoliative generalised 0/3485 (0%) 1/3494 (0%)
Ecchymosis 1/3485 (0%) 0/3494 (0%)
Ichthyosis acquired 0/3485 (0%) 1/3494 (0%)
Lentigo 0/3485 (0%) 1/3494 (0%)
Necrobiosis lipoidica diabeticorum 1/3485 (0%) 0/3494 (0%)
Neurodermatitis 1/3485 (0%) 0/3494 (0%)
Rash 0/3485 (0%) 1/3494 (0%)
Rash maculo-papular 1/3485 (0%) 0/3494 (0%)
Skin necrosis 0/3485 (0%) 1/3494 (0%)
Skin ulcer haemorrhage 0/3485 (0%) 1/3494 (0%)
Swelling face 0/3485 (0%) 1/3494 (0%)
Toxic epidermal necrolysis 0/3485 (0%) 1/3494 (0%)
Social circumstances
Homicide 0/3485 (0%) 1/3494 (0%)
Limb prosthesis user 0/3485 (0%) 1/3494 (0%)
Surgical and medical procedures
Coronary revascularisation 1/3485 (0%) 2/3494 (0.1%)
Hospitalisation 0/3485 (0%) 1/3494 (0%)
Peripheral endarterectomy 1/3485 (0%) 0/3494 (0%)
Vascular disorders
Hypertension 18/3485 (0.5%) 32/3494 (0.9%)
Hypertensive crisis 20/3485 (0.6%) 16/3494 (0.5%)
Peripheral arterial occlusive disease 17/3485 (0.5%) 18/3494 (0.5%)
Deep vein thrombosis 14/3485 (0.4%) 12/3494 (0.3%)
Peripheral artery occlusion 12/3485 (0.3%) 5/3494 (0.1%)
Peripheral ischaemia 11/3485 (0.3%) 5/3494 (0.1%)
Aortic stenosis 5/3485 (0.1%) 8/3494 (0.2%)
Peripheral vascular disorder 7/3485 (0.2%) 6/3494 (0.2%)
Extremity necrosis 9/3485 (0.3%) 3/3494 (0.1%)
Hypotension 7/3485 (0.2%) 5/3494 (0.1%)
Peripheral artery stenosis 4/3485 (0.1%) 3/3494 (0.1%)
Orthostatic hypotension 0/3485 (0%) 6/3494 (0.2%)
Aortic aneurysm 1/3485 (0%) 4/3494 (0.1%)
Hypovolaemic shock 1/3485 (0%) 4/3494 (0.1%)
Venous thrombosis limb 2/3485 (0.1%) 3/3494 (0.1%)
Arteriosclerosis 3/3485 (0.1%) 1/3494 (0%)
Hypertensive emergency 2/3485 (0.1%) 2/3494 (0.1%)
Circulatory collapse 1/3485 (0%) 2/3494 (0.1%)
Accelerated hypertension 1/3485 (0%) 1/3494 (0%)
Angiopathy 1/3485 (0%) 1/3494 (0%)
Diabetic macroangiopathy 2/3485 (0.1%) 0/3494 (0%)
Dry gangrene 1/3485 (0%) 1/3494 (0%)
Haematoma 2/3485 (0.1%) 0/3494 (0%)
Intermittent claudication 0/3485 (0%) 2/3494 (0.1%)
Peripheral embolism 2/3485 (0.1%) 0/3494 (0%)
Thrombophlebitis 1/3485 (0%) 1/3494 (0%)
Thrombophlebitis superficial 0/3485 (0%) 2/3494 (0.1%)
Varicose ulceration 0/3485 (0%) 2/3494 (0.1%)
Aortic aneurysm rupture 1/3485 (0%) 0/3494 (0%)
Aortic thrombosis 1/3485 (0%) 0/3494 (0%)
Arterial insufficiency 0/3485 (0%) 1/3494 (0%)
Arterial rupture 0/3485 (0%) 1/3494 (0%)
Arteriovenous fistula 1/3485 (0%) 0/3494 (0%)
Blood pressure inadequately controlled 0/3485 (0%) 1/3494 (0%)
Diabetic vascular disorder 0/3485 (0%) 1/3494 (0%)
Distributive shock 1/3485 (0%) 0/3494 (0%)
Embolism 1/3485 (0%) 0/3494 (0%)
Embolism arterial 0/3485 (0%) 1/3494 (0%)
Embolism venous 0/3485 (0%) 1/3494 (0%)
Femoral artery aneurysm 0/3485 (0%) 1/3494 (0%)
Iliac artery occlusion 0/3485 (0%) 1/3494 (0%)
Orthostatic hypertension 1/3485 (0%) 0/3494 (0%)
Peripheral artery thrombosis 0/3485 (0%) 1/3494 (0%)
Peripheral venous disease 0/3485 (0%) 1/3494 (0%)
Shock 1/3485 (0%) 0/3494 (0%)
Subclavian artery stenosis 0/3485 (0%) 1/3494 (0%)
Systolic hypertension 1/3485 (0%) 0/3494 (0%)
Thrombosis 0/3485 (0%) 1/3494 (0%)
Vascular insufficiency 1/3485 (0%) 0/3494 (0%)
Vein rupture 1/3485 (0%) 0/3494 (0%)
Other (Not Including Serious) Adverse Events
Placebo Linagliptin
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 1422/3485 (40.8%) 1434/3494 (41%)
Infections and infestations
Urinary tract infection 162/3485 (4.6%) 196/3494 (5.6%)
Investigations
Glomerular filtration rate decreased 200/3485 (5.7%) 202/3494 (5.8%)
Metabolism and nutrition disorders
Hypoglycaemia 1003/3485 (28.8%) 1022/3494 (29.3%)
Hyperglycaemia 240/3485 (6.9%) 208/3494 (6%)
Vascular disorders
Hypertension 232/3485 (6.7%) 216/3494 (6.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.

Results Point of Contact

Name/Title Boehringer Ingelheim, Call Center
Organization Boehringer Ingelheim
Phone 1-800-243-0127
Email clintriage.rdg@boehringer-ingelheim.com
Responsible Party:
Boehringer Ingelheim
ClinicalTrials.gov Identifier:
NCT01897532
Other Study ID Numbers:
  • 1218.22
  • 2011-004148-23
First Posted:
Jul 12, 2013
Last Update Posted:
Apr 4, 2019
Last Verified:
Mar 1, 2019