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CAROLINA: Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients With Type 2 Diabetes

Sponsor
Boehringer Ingelheim (Industry)
Overall Status
Completed
CT.gov ID
NCT01243424
Collaborator
Eli Lilly and Company (Industry)
6,103
Enrollment
613
Locations
2
Arms
93.3
Actual Duration (Months)
10
Patients Per Site
0.1
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 and mortality, relevant efficacy parameters (e.g., glycaemic parameters) and safety (e.g., weight and hypoglycaemia) of treatment with linagliptin in patients with type 2 diabetes at elevated cardiovascular risk receiving usual care, and compare outcome against glimepiride.

Condition or Disease Intervention/Treatment Phase
Phase 3

Study Design

Study Type:
Interventional
Actual Enrollment :
6103 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Double (Participant, Investigator)
Primary Purpose:
Treatment
Official Title:
A Multicentre, International, Randomised, Parallel Group, Double Blind Study to Evaluate Cardiovascular Safety of Linagliptin Versus Glimepiride in Patients With Type 2 Diabetes Mellitus at High Cardiovascular Risk.
Actual Study Start Date :
Nov 11, 2010
Actual Primary Completion Date :
Aug 21, 2018
Actual Study Completion Date :
Aug 21, 2018

Arms and Interventions

Arm Intervention/Treatment
Experimental: linagliptin

patient to receive linagliptin or glimepiride placebo over encapsulated tablet Quaque die (QD)

Drug: linagliptin
linagliptin tablets 5mg QD

Drug: glimepiride placebo
glimepiride placebo
Active Comparator: glimepiride 1-4 mg QD

patient to receive glimepiride 1-4 mg or linagliptin placebo tablet Quaque die (QD)

Drug: glimepiride
glimepiride over-encapsulated tablet 1-4 mg QD

Drug: linagliptin placebo
linagliptin placebo

Outcome Measures

Primary Outcome Measures

  1. The First 3-point Major Adverse Cardiovascular Events (3P-MACE) [From randomization until individual day of trial completion, up to 432 weeks]

    The first occurrence of any of the following Clinical Event Committee (CEC) confirmed adjudicated components of the primary composite endpoint: CV death (including fatal stroke and fatal myocardial infarction (MI)), non-fatal MI (excluding silent MI), or nonfatal stroke is presented.

Secondary Outcome Measures

  1. The First 4-point (4P)- MACE [From randomization until individual day of trial completion, up to 432 weeks]

    The first key secondary endpoint was time to first occurrence of any of the following adjudicated components of the composite endpoint: CV death (including fatal stroke and fatal MI), non-fatal stroke, non-fatal MI (excluding silent MI), or hospitalisation for unstable angina pectoris.

  2. Percentage of Participants Taking Trial Medication at Trial End, Maintained Glycaemic Control (HbA1c ≤7.0%) Without Need for Rescue Medication, Without >2% Weight Gain, and Without Moderate/Severe Hypoglycaemic Episodes During Maintenance Phase [From Visit 6 (Week 16) to Final visit (Week 432) (Maintenance Phase)]

    The second key secondary endpoint was a composite endpoint of treatment sustainability, defined as the percentage of patients taking trial medication at trial end, maintained glycaemic control (HbA1c ≤7.0%) without need for rescue medication, without >2% weight gain, and without moderate/severe hypoglycaemic episodes during maintenance phase.

  3. Percentage of Participants Who Were on Trial Medication at Trial End, Maintained Glycaemic Control (HbA1c ≤7.0%) Without Need for Rescue Medication, and Without >2% Weight Gain During Maintenance Phase [From Visit 6 (Week 16) to Final visit (Week 432) (Maintenance Phase)]

    The third key secondary endpoint was a composite endpoint of treatment sustainability, defined as percentage of patients who were on trial medication at trial end, maintained glycaemic control (HbA1c ≤7.0%) without need for rescue medication, and without >2% weight gain during maintenance phase.

  4. Percentage of Participants With the Occurrence of at Least One Event of 3P-MACE [From randomization until individual day of trial completion, up to 432 weeks]

    Percentage of participants occurrence of at least one of the following adjudicated components of CV death (including fatal stroke and fatal MI), non-fatal MI (excluding silent MI) and non-fatal stroke is presented as secondary CV endpoint.

  5. Percentage of Participants With the Occurrence of at Least One Event of 4P -MACE [From randomization until individual day of trial completion, up to 432 weeks]

    Percentage of participants occurrence of at least one of the following adjudicated components of CV death (including fatal stroke and fatal MI), non-fatal MI (excluding silent MI), non-fatal stroke, and hospitalisation for unstable angina pectoris is presented as secondary CV endpoint.

  6. Percentage of Participants With Occurrence of Any of the Components of the Composite Endpoint of All Adjudication-confirmed Events [From start of the treatment until 7 days after the end of treatment, up to 433 weeks]

    Percentage of participants with occurrence of any of the following components of the composite endpoint of all adjudication-confirmed events of: CV death (including fatal stroke and fatal MI) non-fatal MI non-fatal stroke hospitalisation for unstable angina pectoris TIA hospitalisation for heart failure hospitalisation for coronary revascularisation procedures (CABG, PCI)

  7. Time to First Occurrence of Any of the Components of the Composite Endpoint of All Adjudication-confirmed Events [From start of the treatment until 7 days after the end of treatment, up to 433 weeks]

    Time to first occurrence of any of the following components of the composite endpoint of all adjudication-confirmed events of: CV death (including fatal stroke and fatal MI) non-fatal MI non-fatal stroke hospitalisation for unstable angina pectoris Transient ischaemic attack (TIA) hospitalisation for heart failure hospitalisation for coronary revascularisation procedures (CABG, PCI)

  8. Change From Baseline to Final Visit in Hemoglobin A1c (HbA1c) [Baseline and week 432]

    Change from baseline to final visit in HbA1c is presented as secondary diabetes-related endpoint. Least square mean is adjusted mean. The Final Visit value referred to the last value obtained on-treatment.

  9. Change From Baseline to Final Visit in Fasting Plasma Glucose (FPG) [Baseline and week 432]

    Change from baseline to final visit in fasting plasma glucose (FPG) is presented as secondary diabetes-related endpoint. Least square mean is adjusted mean. The Final Visit value referred to the last value obtained on-treatment.

  10. Change From Baseline to Final Visit Fasting Total Cholesterol, Low-density Lipoprotein (LDL) Cholesterol and High-density Lipoprotein (HDL) Cholesterol [Baseline and week 432]

    Change from baseline to final visit in total cholesterol, low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol is presented as secondary diabetes-related endpoint. Least square mean is adjusted mean. The Final Visit value referred to the last value obtained on-treatment.

  11. Change From Baseline to Final Visit in Triglycerides [Baseline and week 432]

    Change from baseline to final visit in triglycerides is presented as secondary diabetes-related endpoint. Least square mean is adjusted mean. The Final Visit value referred to the last value obtained on-treatment.

  12. Change From Baseline to Final Visit in Creatinine [Baseline and week 432]

    Change from baseline to final visit in creatinine is presented as secondary diabetes-related endpoint. Least square mean is adjusted mean. The Final Visit value referred to the last value obtained on-treatment.

  13. Change From Baseline to Final Visit in Estimated Glomerular Filtration Rate (eGFR) [Baseline and week 432]

    Change from baseline to final visit in eGFR is presented as secondary diabetes-related endpoint. Least square mean is adjusted mean. The Final Visit value referred to the last value obtained on-treatment.

  14. Change From Baseline to Final Visit in Urine Albumin Creatinine Ratio (UACR) [Baseline and week 432]

    Change from baseline to final visit in UACR is presented as secondary diabetes-related endpoint. Least square mean is adjusted geometric mean (gMean) ratio. The Final Visit value referred to the last value obtained on-treatment.

  15. Percentage of Participants With Transition in Albuminuria Classes [Baseline and week 432]

    Percentage of patients with transition in albuminuria classes is presented as secondary endpoint. Data for last value on treatment (LVOT) to baseline (base) is presented.

  16. Change From Baseline of Insulin Secretion Rate (ISR) at Fixed Glucose Concentration at 208 Weeks [Baseline and week 208]

    The endpoint change from baseline of ISR at fixed glucose concentration at 208 weeks as derived from a 3-hour meal tolerance test is Beta-cell function sub-study endpoint.

  17. Percentage of Participants With Occurrence of Accelerated Cognitive Decline at End of Follow-up [433 weeks]

    Occurrence of accelerated cognitive decline based on regression based index (RBI) score at end of follow-up (a dichotomous outcome measure; presence or absence of accelerated cognitive decline) is Cognition sub-study endpoint.

  18. Continuous Glucose Monitoring (CGM) Sub-study: Change From Baseline in the Inter-quartile Range of Diurnal Glucose Variability (Milligrams/ Deciliter) to End of Study [Baseline]

    Baseline data for the continuous glucose monitoring sub-study was collected and analyzed. However, the participant number was far less than original planned. The study was stopped early around week 64 (V9) due to recruitment issues and data were not pre-specified to be analyzed and reported at week 64 time point as target was with an estimated time point of 432 weeks for primary or secondary end points. Thus this endpoint was not analysed and only the baseline data collected were analysed and the results are reported in this CGM substudy endpoint.

  19. CGM Sub-study : Change From Baseline in the Inter-quartile Range of Diurnal Glucose Variability (Millimoles/ Litre) to End of Study [Baseline]

    Baseline data for the continuous glucose monitoring sub-study was collected and analyzed. However, the participant number was far less than original planned. The study was stopped early around week 64 (V9) due to recruitment issues and data were not pre-specified to be analyzed and reported at week 64 time point as target was with an estimated time point of 432 weeks for primary or secondary end points. Thus this endpoint was not analysed and only the baseline data collected were analysed and the results are reported in this CGM substudy endpoint.

Eligibility Criteria

Criteria

Ages Eligible for Study:
40 Years to 85 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion criteria:

  1. Type 2 diabetes

  2. Elevated glycosylated haemoglobin (HbA1c): 6.5 - 8.5%, inclusive, if treatment naïve or mono-/dual therapy with metformin and/or an alpha-glucosidase inhibitor; 6.5 - 7.5%, inclusive, if treatment with sulphonylurea/glinide in mono- or dual (with metformin OR an alpha-glucosidase inhibitor) therapy)

  3. Pre-existing cardiovascular disease OR specified diabetes end-organ damage OR age => 70 years OR two or more specified cardiovascular risk factor

  4. BMI =< 45kg/m²

  5. age between >= 40 and =< 85 years

  6. signed and dated written International Conference of Harmonisation( ICF)

  7. stable anti-diabetic background for at least 8 wks before study start

Exclusion criteria:

  1. Type 1 diabetes

  2. Treatment with other antidiabetic drugs (e.g. rosiglitazone, pioglitazone, Glucagon-like peptide 1 (GLP-1) analogue/agonists, Dipeptidyl-peptidase IV (DPP-IV) inhibitors or any insulin) prior to informed consent (previous short term use of insulin (up to two weeks) is allowed if taken at least 8 weeks prior informed consent)

  3. treatment with any anti-obesity drug less than 3 months before ICF

  4. uncontrolled hyperglycemia

  5. previous or planned bariatric surgery or intervention

  6. current or planned system corticoid treatment

  7. change in thyroid hormones treatment

  8. acute liver disease or impaired hepatic function

  9. pre-planned coronary artery revascularization within 6 months of ICF

  10. known hypersensitivity to any of the components

  11. Inappropriateness of glimepiride treatment for renal safety issues according to local prescribing information

  12. congestive heart failure class III or IV

  13. acute or chronic metabolic acidosis

  14. hereditary galactose intolerance

  15. alcohol or drug abuse

  16. participation in another trail with IMP given 2 months before Investigational Medicinal/Medical Product (IMP) start

  17. pre-menopausal women who are nursing or pregnant or of child-bearing potential and not willing to use acceptable method of birth control

  18. patients considered reliable by the investigator

  19. acute coronary syndrome =< 6 wks before ICF

  20. stroke or Transient Ischemic Attack (TIA) =< 3 months prior to ICF

Contacts and Locations

Locations

Site City State Country Postal Code
1 North Alabama Research Center, LLC Athens Alabama United States 35611
2 Alabama Internal Medicine, PC Birmingham Alabama United States 35235
3 Cahaba Research, Inc. Birmingham Alabama United States 35242
4 Internal Medicine Center, LLC Mobile Alabama United States 36608
5 Diagnostic and Medical Clinic Mobile Alabama United States 36695
6 Extended Arm Physicians, Inc. Montgomery Alabama United States 36106
7 Office of Dr. Terence T. Hart MD Tuscumbia Alabama United States 35674
8 Advanced Clinical Research Pell City Alaska United States 35128
9 Clinical Research Advantage, Inc./Rita B. Chuang, MD, LLC Mesa Arizona United States 85203
10 Clinical Research Advantage, Inc./Rita B. Chuang, MD, LLC Mesa Arizona United States 85213
11 Genova Clinical Research Tucson Arizona United States 85704
12 Quality of Life Medical & Research Center Tucson Arizona United States 85712
13 Northeast Arkansas Baptist Clinic Jonesboro Arkansas United States 72404
14 Medical Investigations, Inc Little Rock Arkansas United States 72205
15 Aureus Research, Inc Little Rock Arkansas United States 72211
16 Desert Oasis Healthcare Bermuda Dunes California United States 92203
17 Edinger Medical Group and Research Center Fountain Valley California United States 92708
18 Clinical Trials of St. Jude Heritage Med. Group Fullerton California United States 92835
19 Long Beach Center for Clinical Research Long Beach California United States 90807
20 Office of Dr. Richard S. Cherlin Los Gatos California United States 95032
21 Providence Clinical Research North Hollywood California United States 91606
22 Chaparral Medical Group, Inc Pomona California United States 91767
23 ARI Clinical Trials, Inc Redondo Beach California United States 90277
24 San Diego Sports Medicine and Family Health Center San Diego California United States 92120
25 West Coast Research, LLC San Ramon California United States 94582
26 University of California Los Angeles Sylmar California United States 91342
27 Metabolic Institute of America Tarzana California United States 91356
28 Matrix Research Institute Tustin California United States 92780
29 Orange County Research Center Tustin California United States 92780
30 Westlake Medical Research Westlake Village California United States 91361
31 Clinical Research Advantage, Inc./Rita B. Chuang, MD, LLC Colorado Springs Colorado United States 80909
32 Clinical Research Advantage, Inc./Rita B. Chuang, MD, LLC Colorado Springs Colorado United States 80920
33 East Coast Medical Associates Boca Raton Florida United States 33433
34 Todd Kazdan, DO Family Practice Davie Florida United States 33314
35 Century Clinical Research, Inc Daytona Beach Florida United States 32117
36 Doral Research Center Doral Florida United States 33172
37 Riverside Clinical Research Edgewater Florida United States 32132
38 Alan Graff, MD, PA Fort Lauderdale Florida United States 33309
39 M & O Clinical Research, LLC Fort Lauderdale Florida United States 33316
40 Eastern Research Hialeah Florida United States 33013
41 Research in Miami Inc Hialeah Florida United States 33013
42 Jacksonville Impotence Treatment Center Jacksonville Florida United States 32223
43 East Coast Institute for Research, LLC Jacksonville Florida United States 32258
44 Care Partners Clinical Research LLC Jacksonville Florida United States 32277
45 Precision Clinical Research, LLC Lauderdale Lakes Florida United States 33319
46 Veritas Research Corporation Miami Florida United States 33126
47 APF Research, LLC Miami Florida United States 33134
48 Swiss Medical Research Miami Florida United States 33135
49 University of Miami Miami Florida United States 33136
50 South Miami Clinical Research Miami Florida United States 33143
51 Well Pharma Medical Research Miami Florida United States 33143
52 Advanced Pharma CR, LLC Miami Florida United States 33147
53 AppleMed Research Group, LLC Miami Florida United States 33155
54 Kendall South Medical Center, Inc Miami Florida United States 33185
55 Suncoast Clinical Research, Inc. New Port Richey Florida United States 34652
56 Advanced Research Institute, Inc New Port Richey Florida United States 34653
57 Sunshine Research Center Opa-locka Florida United States 33054
58 Diabetes and Endocrine Center of Orlando Orlando Florida United States 32803
59 Suncoast Clinical Research Palm Harbor Florida United States 34684
60 Misal Khan, MD FRCS, ED, PA Panama City Florida United States 32401
61 Iconic Clinical Trials Pembroke Pines Florida United States 33024
62 Gulf Region Clinical Research Institute Pensacola Florida United States 32514
63 St. John's Center for Clinical Research Ponte Vedra Beach Florida United States 32081
64 Metabolic Research Institute West Palm Beach Florida United States 33401
65 PMI Health Research Group Atlanta Georgia United States 30312
66 Atlanta Diabetes Associates Atlanta Georgia United States 30318
67 Albert F. Johary MD, PC Dunwoody Georgia United States 30338
68 Georgia Clinical Research, LLC Snellville Georgia United States 30078
69 Hayden Lake Family Physicians Hayden Lake Idaho United States 83835
70 Boise Kidney and Hypertension Institute Meridian Idaho United States 83642
71 Suburban Clinical Research Bolingbrook Illinois United States 60490
72 Cedar-Crosse Research Center Chicago Illinois United States 60607
73 John H. Stroger Jr. Hospital of Cook Country Chicago Illinois United States 60612
74 Apex Medical Research Chicago Illinois United States 60616
75 Pharmakon Inc Evergreen Park Illinois United States 60805
76 American Health Network Avon Indiana United States 46123
77 Investigators Research Group, LLC Brownsburg Indiana United States 46112
78 American Health Network of Indiana, LLC Franklin Indiana United States 46131
79 Mapleton Medical Center Indianapolis Indiana United States 46205
80 American Health Network, LLC Indianapolis Indiana United States 46254
81 McKinley Research, LLC Mishawaka Indiana United States 46545
82 American Health Network of Indiana, LLC Muncie Indiana United States 47304
83 MCM Clinical Research, LLC Florence Kentucky United States 41042
84 Kentucky Diabetes Endocrinology Center Lexington Kentucky United States 40503
85 Four Rivers Clinical Research, Inc Paducah Kentucky United States 42003
86 Crescent City Clinical Research Metairie Louisiana United States 70006
87 Acadia Clinical Research, LLC Bangor Maine United States 04401
88 Office of Dr. Stephen R. Smith, MD Baltimore Maryland United States 21234
89 Endocrine and Metabolic Consultants Rockville Maryland United States 20852
90 Tristan Medical Enterprises, PC dba Regeneris North Attleboro Massachusetts United States 02760
91 ClinSite, LLC Canton Michigan United States 48187
92 Apex Medical Research, AMR Inc Flint Michigan United States 48504
93 Westside Family Medical Center, PC Kalamazoo Michigan United States 49009
94 Tri City Medical Centers, PC Livonia Michigan United States 48152
95 KMED Research Saint Clair Shores Michigan United States 48081
96 Tri-County Research, Inc Sterling Heights Michigan United States 48310
97 Medical Research Associates Traverse City Michigan United States 49684
98 Oakland Medical Research Center Troy Michigan United States 48085
99 Park Nicollet Institute Minneapolis Minnesota United States 55416
100 The Center for Clinical Trials, Inc. Biloxi Mississippi United States 39531
101 Mercy Health Research Saint Louis Missouri United States 63141
102 Quality Clinical Research Omaha Nebraska United States 68114
103 Clinical Research Advantage, Inc./Rita B. Chuang, MD, LLC Henderson Nevada United States 89052
104 Clinical Research of South Nevada Las Vegas Nevada United States 89121
105 Palm Medical Research Center Las Vegas Nevada United States 89148
106 Atco Medical Associates, PC Atco New Jersey United States 08004
107 Summit Medical Group Clifton New Jersey United States 07012
108 USMA Clinical Research Elizabeth New Jersey United States 07201
109 Central Jersey Medical Research Elizabeth New Jersey United States 07202
110 Albany Medical Center / Albany Medical College Albany New York United States 12206
111 Endocrine Associates of Long Island, PC Smithtown New York United States 11787
112 Southgate Medical Group/ Southgate Medical Park West Seneca New York United States 14224
113 OnSite Clinical Solutions, LLC Asheville North Carolina United States 28801
114 Kernodle Clinic West Burlington North Carolina United States 27215
115 The University of North Carolina at Chapel Hill Chapel Hill North Carolina United States 27517
116 Internal Medicine Research Charlotte North Carolina United States 28204
117 Gaffney Health Services Charlotte North Carolina United States 28205
118 Durham Internal Medicine Associates Durham North Carolina United States 27704
119 Sentara Family Medicine Elizabeth City North Carolina United States 27909
120 PMG Research of Raleigh, LLC Raleigh North Carolina United States 27609
121 Carolina Research Center, Inc Shelby North Carolina United States 28150
122 Piedmont Healthcare Statesville North Carolina United States 28625
123 PMG Research of Wilmington, LLC Wilmington North Carolina United States 28401
124 Community Health Care of Manchester Akron Ohio United States 44319
125 Community Medical Associates, LLC Austintown Ohio United States 44515
126 Harrison Community Research Center Cadiz Ohio United States 43907
127 Medical Frontiers, LLC Carlisle Ohio United States 45005
128 Genoa Medical Center Genoa Ohio United States 43430
129 Office of Dr. Craig S. Thompson, MD, LLC Marion Ohio United States 43302
130 RAS Health Limited Marion Ohio United States 43302
131 Advanced Medical Research, LLC Maumee Ohio United States 43537
132 Pharmacotherapy Research Associates, Inc Zanesville Ohio United States 43701
133 Infinity Research Group, LLC Oklahoma City Oklahoma United States 73103
134 Castlerock Clinical Research Consultants, LLC Tulsa Oklahoma United States 74136
135 Oregon Medical Group Eugene Oregon United States 97401
136 Harleysville Medical Associates Harleysville Pennsylvania United States 19438
137 Detweiler Family Medicine & Associates, PC Lansdale Pennsylvania United States 19446
138 Temple University School of Medicine Philadelphia Pennsylvania United States 19140
139 Warminster Medical Associates, PC Warminster Pennsylvania United States 18974
140 New England Center for Clinical Research, Inc Cranston Rhode Island United States 02920
141 Hartwell Research Group, LLC Anderson South Carolina United States 29621
142 Paris View Family Practice Greenville South Carolina United States 29601
143 Mountain View Clinical Research Greer South Carolina United States 29651
144 South Carolina Nephrology and Hypertension Center, Inc Orangeburg South Carolina United States 29118
145 Carolina Diabetes & Kidney Center Sumter South Carolina United States 29150
146 PMG Research of Bristol Bristol Tennessee United States 37620
147 University Diabetes and Endocrine Consultants Chattanooga Tennessee United States 37411
148 University of Tennessee Memphis Tennessee United States 38163
149 Trinity Clinical Research, LLC Tullahoma Tennessee United States 37388
150 KRK Medical Research Arlington Texas United States 76012
151 Austin Center for Clinical Research Austin Texas United States 78758
152 Punzi Medical Center Carrollton Texas United States 75006
153 Dallas Diabetes and Endocrine Center Dallas Texas United States 75230
154 Baylor Endocrine Center Dallas Texas United States 75246
155 University of Texas Southwestern Medical Center Dallas Texas United States 75390-8858
156 Jacon Medical Research Associates, LLC Houston Texas United States 77030
157 JVC Family Medicine Houston Texas United States 77040
158 Clinical Trial Network Houston Texas United States 77074
159 Endocrine and Psychiastry Center Houston Texas United States 77095
160 Pioneer Research Solutions, Inc. Houston Texas United States 77099
161 Midland Clinical Research Center Midland Texas United States 79707
162 Hill Country Medical Associates New Braunfels Texas United States 78130
163 Naidu Clinic Odessa Texas United States 79761
164 The Methodist Hospital d/b/a HMRI CCAT at Pearland Pearland Texas United States 77584
165 Village Health Partners Plano Texas United States 75024
166 Sun Research Institute San Antonio Texas United States 78215
167 Northeast Clinical Research of San Antonio, LLC Schertz Texas United States 78154
168 Kenneth Otah and Associates Sugar Land Texas United States 77478
169 PHS Clinical Trials Midvale Utah United States 84047
170 Highland Clinical Research Salt Lake City Utah United States 84124
171 Burke Internal Medicine and Research Burke Virginia United States 22015
172 Ettrick Health Center Ettrick Virginia United States 23803
173 Manassas Clinical Research Center Manassas Virginia United States 20110
174 Clinical Research Partners, LLC Richmond Virginia United States 23220
175 Richmond Family Practice Richmond Virginia United States 23220
176 Larry D Stonesifer, MD Inc., PS Federal Way Washington United States 98003
177 Premier Clinical Research Spokane Washington United States 99204
178 Instituto de Investigaciones Clínicas de Bahía Blanca Bahía Blanca Argentina B8000FTD
179 CIPREC Caba Argentina C1119ACN
180 CENUDIAB Caba Argentina C1440AAD
181 Instituto Médico Especializado Capital Federal Argentina C1405BCH
182 Consultorios Asociados de Endocrinología e Invest Clínica Capital Federal Argentina C1425AGC
183 IPAC - Clínica Privada Caraffa SRL Cordoba Argentina X5008KKF
184 Instituto Cardiovascular de Corrientes Juana Francisca Cabra Corrientes Argentina W3400AMZ
185 Ilaim-Ceom Córdoba Argentina X5000BNB
186 Hospital Italiano de La Plata La Plata Argentina B1900AWT
187 CIPADI Mendoza Argentina M5500EVJ
188 Instituto de Investigaciones Clinicas de Rosario Rosario Argentina S2000CVD
189 Instituto de Hematología y Medicina Clínica Dr. Rubén Davoli Rosario Argentina S2000CXP
190 Hospital San Bernardo Salta Argentina A4406CLA
191 Investigaciones Clinicas Tucuman San Miguel de Tucumán Argentina T4000ICL
192 Instituto de Investigaciones Biomédicas Santa Fe Argentina S3000FNF
193 Centro de Investigaciones Clínicas del Litoral Santa Fe Argentina S3000SWO
194 Royal Brisbane & Women's Hospital-Endocrinology Herston Queensland Australia 4029
195 Logan Hospital Meadowbrook Queensland Australia 4131
196 Royal Adelaide Hospital Adelaide South Australia Australia 5000
197 Eastern Clinical Research Unit East Ringwood Victoria Australia 3135
198 Royal Melbourne Hospital Parkville Victoria Australia 3050
199 Blankenberge - PRAC Vileyn, Geert Blankenberge Belgium 8370
200 Bonheiden - HOSP Imelda Bonheiden Belgium 2820
201 De Pinte - PRAC Hollanders, Geert De Pinte Belgium 9840
202 Retie - PRAC De Vos, Axel Dessel Belgium 2480
203 Deurne - PRAC Heyvaert, Frank Deurne Belgium 2100
204 Deurne - PRAC Verelst, Joost Deurne Belgium 2100
205 Genk - PRAC Vernijns, J. Genk Belgium 3600
206 Gozée - PRAC De Meulemeester, Marc Gozée Belgium 6534
207 Hasselt - PRAC Vantroyen, Daniel Hasselt Belgium 3500
208 Herent - PRAC Denolf, Bart Herent Belgium 3020
209 Linkebeek - PRAC Maury, Olivier Linkebeek Belgium 1630
210 Moorsel - PRAC Van Mulders, N. Moorsel Belgium 9310
211 Natoye - PRAC Balthazar, Y. Natoye Belgium 5360
212 Tremelo - PRAC Vermeersch, Lode Tremelo Belgium 3210
213 Hospital Universitário João de Barros Barreto Belém Brazil 66073-000
214 Universidade Federal do Paraná Curitiba Brazil 80060-900
215 Hospital Geral de Goiânia Alberto Rassi Goiânia Brazil 74043-110
216 Centro de Pesquisas Clínicas Ltda Higienópolis Brazil 01244-030
217 Centro de Estudos em Diabetes e Hipertensão Joaquim Távora Brazil 60115-282
218 Irmandade Santa Casa de Misericordia de Porto Alegre Porto Alegre Brazil 90020-090
219 Centro de Pesquisas em Diabetes Porto Alegre Brazil 90035-170
220 Instituto Estadual de Diabetes e Endocrinologia Río de Janeiro Brazil 20211-340
221 Irmandade da Santa Casa de Misericórdia de São Paulo - IPEC - Instituto de Pesquisa Clínica Santa Cecília Brazil 01221-020
222 Instituto de Molestias Cardiovasculares - IMC São José do Rio Preto Brazil 15015-210
223 Hospital das Clinicas da FMUSP São Paulo Brazil 05403-900
224 Hospital do Rim e Hipertensão - UNIFESP Vila Clementino Brazil 04025-011
225 Univ.Multiprofile Hospital "Dr. Georgy Stranski" EAD, Pleven Pleven Bulgaria 5800
226 Multiprofile Hospital for Active Treatment Sofia Bulgaria 1431
227 Multiprofile Hospital for Active Treatment "Zaritza Johanna" Sofia Bulgaria 1527
228 Military Medical Academy, Clin. Endocrinology & Metab. Dis. Sofia Bulgaria 1606
229 MHAT Prof Stoyan Kirkovich AD Stara Zagora Bulgaria 6000
230 IUCPQ (Laval University) Quebec Migration Data Canada G1V 4G5
231 First Line Medical Services Ltd. St. John's Newfoundland and Labrador Canada A1E 2C2
232 Topsail Road Medical Clinic St. John's Newfoundland and Labrador Canada A1E 2E2
233 Cambridge Cardiac Care Inc. Cambridge Ontario Canada N1R 6V6
234 Hamilton Medical Research Group Hamilton Ontario Canada L8M 1K7
235 SKDS Research Incorporated Newmarket Ontario Canada L3Y 5G8
236 Wilderman Medical Clinic Thornhill Ontario Canada L4J 1W3
237 St. Michael's Hospital Toronto Ontario Canada M5C 2T2
238 Albion Finch Medical Centre Toronto Ontario Canada M9V 4B4
239 Kings County Medical Centre Montague Prince Edward Island Canada C0A 1R0
240 Dynamik Research Pointe Claire Quebec Canada H9R 3J1
241 Consulta Privada Maria Loreto Aguirre Coveña Providencia Chile 7500010
242 Hospital de Servicios Médicos Godoy Ltda Providencia Chile
243 Centro Medico Antulawen Temuco Chile
244 Hospital Naval Almirante Nef Viña del Mar Chile
245 BioMelab Barranquilla Colombia
246 Centro Cientifico Asistencial Jose Luis Accini Barranquilla Colombia
247 Fundacion del Caribe de Investigacion Biomedica Barranquilla Colombia
248 Endocare Research Institute Bogota Colombia
249 Dexa Diabetes Servicios Médicos Ltda Bogotá Colombia
250 UNIENDO Unidad Integral de Endocrinologia Bogotá Colombia
251 Centro cardiovascular Aristides Cartagena Colombia
252 centro de Diagnostico Cardiologico para la Investigacion Bio Cartagena Colombia
253 Fundacion Cardiovascular de Colombia El Bosque Colombia
254 Fundación Oftalmologica de Santander El Bosque Colombia
255 Fundación Centro de Investigaciones Biomédicas Riescard Tolima Colombia
256 Internal & Diabetology Ambulance, Jablonec nad Nisou Jablonec nad Nisou Czechia 466 01
257 Diabetology & Internal Ambulance Olomouc-Lazce Czechia 779 00
258 Internal & Diabetology Ambulance Dr. Vrkoc, Ostrava Ostrava Czechia 702 00
259 Cardiology ambulance, Plzen Plzen Czechia 301 00
260 ResTrial s.r.o. Praha 8 Czechia 181 00
261 Diebetology internal Ambulance Praha Czechia 101 00
262 Internal & Diabetology Ambulance, Prostejov Prostejov Czechia 796 01
263 Hospital Strakonice, Internal Department Strakonice Czechia 386 29
264 Diabetesklinikka, Mehiläinen Töölö Helsinki Finland 00260
265 Lääkärikeskus Ite Joensuu Finland 80100
266 Lääkärikeskus Aava Kerava Kerava Finland 04200
267 Kokkolan Lääkärikeskus Kokkola Finland 67100
268 IteLasaretti Kuopio Finland FI-70100
269 Terveystalo Oulu, Diapolis Oulu Finland FI-90100
270 TYKS Turku Finland FI-20520
271 CAB Hell M, MG, Behren Les Forbach Behren Les Forbach France 57460
272 HOP Haut Levèque, Diabéto, Pessac Bordeaux France 33075
273 CAB Lemarie B, MG, Bourg des Cptes Bourg des Comptes France 35890
274 CAB Cadinot Dr D, Broglie Broglie France 27270
275 CAB Breton Dr Nicolas Béziers France 34500
276 CAB Ferrier R, MG, Cannes Cannes France 06400
277 CAB Jordan E, MG, Carbonne Carbonne France 31390
278 CAB Merlin P, MG Castets Castets France 40260
279 CAB Fonteny R, MG, Chartres Chartres France 28000
280 CAB Fournier P, MG, Chartres Chartres France 28000
281 CAB Martocq G, MG, Cournonterral Cournonterral France 34660
282 HOP, Fort de France, Fort de France Fort De France France 97261
283 CAB Le Mouel S, MG, Hinx Hinx France 40180
284 CAB Pholsena, MG, La Réunion La Reunion France 97410
285 CAB Bismuth M Labarthe sur Leze France 31860
286 CAB Zimmermann D Louvigne De Bie France 35680
287 CAB Mainetti P, MG, Maintenon Maintenon France 28130
288 CAB Barucq F, MG, Orthez Orthez France 64300
289 CAB Mostephai M Orthez France 64300
290 CAB Cassagnes JL, MG, Palau Del Vidre Palau Del Vidre France 66690
291 CAB Mercey Y, MG, St Genies des Fontaines Saint Genies Des Fontaines France 66740
292 Hop St Dié des Vosges, Diabéto, St Dié des Vosges St Dié des Vosges Cedex France 88187
293 CAB Bonneau D, MG, Thouars Thouars France 79100
294 CAB Morel H, MG, Tilly sur Seulles Tilly sur Seulles France 14250
295 Unimed Ajara LLC, Private Practice Batumi Georgia 6004
296 Central Hospital LTD 'Gormedi', Gori Gori Georgia 1400
297 L&J Clinic, Kutaisi Kutaisi Georgia 4600
298 EC Cardiology Clinic,Tbilisi Tbilisi Georgia 0144
299 National Center for Diabetes Research Ltd., Tbilisi Tbilisi Georgia 0159
300 National Institute of Endocrinology, Tbilisi Tbilisi Georgia 0159
301 Zhordania Institute of Human Reproduction, Tbilisi Tbilisi Georgia 0159
302 Medical Centre Medelite Ltd., Tbilisi Tbilisi Georgia 0177
303 Chemotherapy & Immunotherapy Clinic 'Medulla', Tbilisi Tbilisi Georgia 0186
304 JSC 'Curatio' Zugdidi Georgia 2100
305 Universitätsklinikum Aachen, AöR Aachen Germany 52074
306 Studienzentrum Klausmann Aschaffenburg Germany 63739
307 Gemeinschaftspraxis, Asslar Asslar Germany 35614
308 Diabetes Schwerpunktpraxis Bad Nauheim Germany 61231
309 Praxis Dr. Naumburger, Berlin Berlin Germany 10409
310 emovis GmbH Berlin Germany 10629
311 Praxis Dr. Rieker, Berlin Berlin Germany 10789
312 IFG Institut für Gesundheitsförderung GmbH Berlin Germany 12621
313 MVZ DaVita Dormagen GmbH Dormagen- Hackenbroich Germany 41540
314 Praxis Dr. Busch, Dortmund Dortmund Germany 44137
315 GWT-TUD GmbH Dresden Germany 01307
316 Praxis Dr. Schlecht, Eisenach Eisenach Germany 99817
317 ZKS Südbrandenburg GmbH Elsterwerda Germany 04910
318 Praxis Dr. Huptas, Essen Essen Germany 45307
319 Praxis Dr. Schmidt, Flörsheim Flörsheim Germany 65439
320 Institut für Stoffwechselforschung, Frankfurt Frankfurt Germany 60322
321 Praxis Dr. Groeneveld, Furth im Wald Furth im Wald Germany 93437
322 Praxis Dr. Kohlhas, Gebhardshain Gebhardshain Germany 57580
323 Praxis Dr. Samer, Haag Haag Germany 83527
324 Klinische Forschung Management & Services GmbH Hamburg Germany 20253
325 Diabetologische Schwerpunktpraxis Hamburg Germany 21073
326 Praxis Dr. Burkhardt, Hamburg Hamburg Germany 22335
327 Diabeteszentrum Alstertal, Hamburg Hamburg Germany 22391
328 Praxis Dr. Herrmann, Hatten Kirchhatten Germany 26209
329 Dünnwaldpraxis, Köln Köln Germany 51069
330 Praxis Dr. Klein, Künzing Künzing Germany 94550
331 Praxis Dr. Nischik, Leipzig Leipzig Germany 04109
332 Praxis Dr. Kropp, Lübeck Lübeck Germany 23554
333 PFÜTZNER Science & Health Institute GmbH Mainz Germany 55128
334 Diabetologische Schwerpunktpraxis Münster Germany 48153
335 Praxis Dr. Böckmann Neumünster Germany 24534
336 Praxis Dr. Hilgenberg Rehburg-Loccum Germany 31547
337 Praxis Dr. Naudts, Rodgau Rodgau/Dudenhofen Germany 63110
338 Praxis Dr. Hirschhäuser Saarbrücken Germany 66121
339 Praxis Dr. Segner, St. Ingberg Saint Ingbert / Oberwürzbach Germany 66386
340 Praxis Dr. Herrmann Schwabenheim Germany 55270
341 Praxis Dr. Dietlein Stadtbergen Germany 86391
342 Praxis Dr. Sauter Wangen Germany 88239
343 Schwerpunktpraxis Diabetologie Zwenkau Germany 04442
344 General Hospital of Athens Evangelismos Athens Greece 10676
345 General University Hospital "Attikon" Haidari, Athens Greece 12410
346 Univ. Gen. Hosp. of Ioannina Ioannina Greece 45500
347 General Hospital "Amalia Fleming" Melissia, Athens Greece 15127
348 General Hospital of Nikaia Nikaia Greece 18484
349 University General Hospital of Thessaloniki AHEPA Thessaloniki Greece 54636
350 General Hopsital of Thessaloniki "Ippokrateio" Thessaloniki Greece 54642
351 Kliniki Thermi Thessaloniki Greece 57001
352 Alice Ho Miu Ling Nethersole Hospital Hong Kong Hong Kong
353 Prince of Wales Hospital Hong Kong Hong Kong
354 Queen Mary Hospital Hong Kong Hong Kong
355 Imre Magyar Hospital, Ajka Ajka Hungary 8400
356 Lausmed Kft. Outpatient Unit of Internal Medicine Baja Hungary 6500
357 Karolyi Sandor Hospital, Budapest Budapest Hungary 1041
358 Bekes County Pandy Kalman Hospital Gyula Hungary 5700
359 Erzsebet Hospital, Hodmezövasarhely Hódmezövásárhely Hungary 6800
360 Dr. Samuel Diosszilagyi Hospital and Outpatient Clinic, Mako Mako Hungary 6900
361 TaNa Med Kft. Mosonmagyarovar Hungary 9200
362 Grof Esterhazy Hospital and Outpatient Clinic Papa Hungary 8500
363 Tolna County Balassa Janos Hospital Szekszard Hungary 7100
364 Shree Krishna Hospital and Heart Care Centre, Ahmedabad Ahmedabad India 380052
365 CIIGMA Institute of Medical Sciences Pvt Ltd Aurangabad India 431001
366 MS Ramaiah Memorial Hospital, Bangalore, Karnataka India 560054
367 Diabetes care and research centre Bangalore India 560010
368 Manipal Hospital Bangalore India 560017
369 Bangalore Diabetes Centre (BDC)- Medisys Clinical Research Bangalore India 560043
370 Belgaum Diabetes Centre, Belgaum Belgaum India 590001
371 Swamy Diabetes Centre Chennai India 600 028
372 Apollo Hospitals Chennai India 600010
373 M V Hospital For Diabetes and Diabetes Research Centre Chennai India 600013
374 Dr. Mohans Diabetes Speciality Centre Chennai India 600086
375 Kovai Diabetes Speciality Centre & Hospital Coimbatore India 641009
376 TOTALL Diabetes Hormone Institute Indore India 452010
377 Diabetes Thyroid and Endocrine Centre Jaipur India 302 006
378 Diamed Clinical Research Services Pvt. Ltd. Jaipur India 302016
379 Grant Medical Foundation, Ruby Hall Clinic Maharashtra India 411001
380 K.G.N. Diabetes and Endocrine Centre Mumbai, Maharastra India 400008
381 Global Hospital- Superspeciality & Transplant Centre Mumbai India 400012
382 RHIDEM Mumbai India 400014
383 Sunil's Diabetes care and Research Centre Nagpur India 440 010
384 Jahingir Clinical Development Centre Pune India 411001
385 Deshmukh Clinic Pune India 411030
386 Diabetes Care Center Thiruvananthapuram India 695 010
387 Yalamanchi Hospitals & Research Centres Pvt Ltd. Vijayawada India 520 002
388 The Red House Family Practice Co. Cork Ireland CORK
389 Connolly Hospital Blanchardstown Dublin Ireland 15
390 The Palms GP Surgery Gorey Ireland Wexford
391 Fethard-on-Sea Medical Practice Wexford Ireland Wexford
392 Barzilai Medical Center Ashkelon Israel 78278
393 Rambam Medical Center Haifa Israel 31096
394 Edith Wolfson Medical Center, Diabetic Unit, Holon Holon Israel 58100
395 Hadassah Medical Center, Ein-Karem Jerusalem Israel 91120
396 Western Galilee Hospital Nahariya Israel 22100
397 The Chaim Sheba Medical Center Tel Hashomer Tel Hashomer Israel 52621
398 Sourasky Medical Center Tel-Aviv Israel 64239
399 Ospedale "SS. Trinità" Cagliari Italy 09100
400 Policlinico Universitario Mater Domini, Universita di Catanzaro Catanzaro Italy 88100
401 Policlinico San Martino Genova Italy 16132
402 Ospedale di Guastalla Guastalla (RE) Italy 42016
403 A.O.U.Policlinico G.Martino Messina Italy 98125
404 Fondazione Centro San Raffaele del Monte Tabor Milano Italy 20132
405 Ospedale S. Pertini Roma Italy 00100
406 Azienda Ospedaliera Sant'Andrea-Università di Roma La Sapienza Roma Italy 00189
407 IRCCS Gruppo Multimedica Sesto San Giovanni (MI) Italy 20099
408 Daishinkai Medical Corporation Ookuma Hospital Aichi, Nagoya Japan 462-0825
409 Chibanishi General Hospital Chiba, Matsudo Japan 270-2251
410 New Tokyo Heart Clinic Chiba, Matsudo Japan 271-0077
411 Kashinoki I.M. Clinic, Fukushima, I.M. Fukushima, Date Japan 960-0418
412 Japan Community Health care Organization Nihonmatsu Hospital Fukushima, Nihonmatsu Japan 964-8501
413 Iwase General Hospital Fukushima, Sukagawa Japan 962-8503
414 Iryohojinshadan Sasaki Clinic Hyogo, Amagasaki Japan 660-0827
415 Takasagoseibu Hospital Hyogo, Takasago Japan 676-0812
416 Kanagawa Cardiovascular and Respiratory Center Kanagawa, Yokohama Japan 236-0051
417 Jinnouchi Clinic Diabetes Care Center Kumamoto, Kumamoto Japan 862-0976
418 Kumamoto Rosai Hospital Kumamoto, Yatsushiro Japan 866-8533
419 Koga General Hospital Miyazaki, Miyazaki Japan 880-0041
420 Saitama Medical Cooperative Association Hanyu General Hospital Saitama, Hanyu Japan 348-0045
421 Nihon University Itabashi Hospital Tokyo, Itabashi-ku Japan 173-8610
422 Korea University Ansan Hospital Ansan Korea, Republic of 15355
423 Inje University Busan Paik Hospital Busan Korea, Republic of 614-735
424 Keimyung University Dongsan Medical Center Daegu Korea, Republic of 700-712
425 National Health Insurance Service Ilsan Hospital Goyang Korea, Republic of 410-719
426 Dongguk University Ilsan Hospital Goyang Korea, Republic of 410-773
427 Inje University Ilsan Paik Hospital Goyang Korea, Republic of 411-706
428 Chonbuk National University Hospital Jeonju Korea, Republic of 561-712
429 Pusan National Univ. Hosp Pusan Korea, Republic of 602-739
430 Seoul National University Bundang Hospital Seongnam Korea, Republic of 463-707
431 Korea University Anam Hospital Seoul Korea, Republic of 02841
432 Korea University Guro Hospital Seoul Korea, Republic of 08308
433 Kangdong Sacred Heart Hospital Seoul Korea, Republic of 134-701
434 Ajou University Hospital Suwon Korea, Republic of 443-380
435 Wonju Severance Christian Hosp Wonju Korea, Republic of 220-701
436 Pusan National University Yangsan Hospital Yangsan Korea, Republic of 626-770
437 Monash University Johor Bahru, Johor Malaysia 80100
438 Hospital University Sains Malaysia Kota Bharu Malaysia 16150
439 Hospital Kuala Lumpur Kuala Lumpur Malaysia 50586
440 University Malaya Medical Centre Kuala Lumpur Malaysia 59100
441 Hospital Tengku Ampuan Afzan Kuantan Malaysia 25100
442 Hospital Melaka Melaka Malaysia 75400
443 Penang Medical College Penang Malaysia 10450
444 Hospital Taiping Taiping Malaysia 34000
445 Hospital General de Acapulco Acapulco Mexico 39570
446 Centro de Investigacion Cardiometabolica de Aguascalientes Aguascalientes Mexico 20234
447 Instituto Nacional de Cardiologia Ignacio Chavez Distrito Federal Mexico 14080
448 Unidad de Investigacion Clinica Cardiometabolica de Occident Guadalajara Mexico 44150
449 Hospital Universitario Dr Jose Eleuterio Gonzalez Monterrey Mexico 64460
450 Huisartspraktijk Emmers 's-hertogenbosch Netherlands 5235 KG
451 FlevoResearch Almere Netherlands 1311 RL
452 Academisch Medisch Centrum (AMC) Amsterdam Netherlands 1105 AZ
453 Rode Kruis Ziekenhuis Beverwijk Beverwijk Netherlands 1942 LE
454 Andromed Breda Breda Netherlands 4811 SW
455 Noordwest Ziekenhuisgroep, location Den Helder Den Helder Netherlands 1782 GZ
456 Andromed Eindhoven Eindhoven Netherlands 5611 NV
457 Andromed Noord Groningen Netherlands 9711 SG
458 Vasculair Onderzoek Centrum Hoorn Netherlands 1624 NP
459 Maastricht Universitair Medisch Centrum Maastricht Netherlands 6229 HX
460 Andromed Rotterdam Rotterdam Netherlands 3039 BD
461 Rotterdam Research Institute Rotterdam Netherlands 3039 BD
462 Ikazia Ziekenhuis Rotterdam Netherlands 3083 AN
463 Antonius Ziekenhuis Sneek Netherlands 8601 ZK
464 Andromed Oost Velp Netherlands 6883 ES
465 Andromed Leiden-Zoetermeer Zoetermeer Netherlands 2724 EK
466 Christchurch Hospital Christchurch New Zealand 4710
467 RMC Medical Research Ltd Dunedin New Zealand 9012
468 P3 Research, Wellington Newtown Wellington NZ New Zealand 6021
469 P3 Research, Promed House Tauranga New Zealand 3110
470 Bodø Legesenter AS, avd. for med. studier Bodø Norway N-8001
471 Medi 3 Innlandet AS, avd Elverum Elverum Norway N-2408
472 Vestre Viken HF, Bærum sykehus Gjettum Norway N-1346
473 M3 Helse AS Hamar Norway N-2317
474 Bylegene SA Jessheim Norway N-2050
475 Heiaklinikken Lierskogen Norway N-3420
476 Rådhuset Spesialistsenter Oslo Norway N-0160
477 Sandvika Spesialistsenter Sandvika Norway N-1337
478 Grålum Legesenter Sarpsborg Norway N-1727
479 Forusakutten - Kolibri Medical, Avd. Stavanger Stavanger Norway N-4005
480 Medi 3 AS Ålesund Norway N-6002
481 Instituto Delgado de Investigacion Medica Arequipa Peru LIMA 54
482 Clinica San Pedro Huacho Peru
483 Hospital Nacional Dos de Mayo Lima Peru 01
484 Clinica Internacional Lima Peru LIMA 1
485 Centro de Investigaciones Médicas METABOLICARE SAC Lima Peru Lima 27
486 Clinica San Gabriel Lima Peru Lima 32
487 Centro De Especialidades Medicas Santa Maria S.A.C Piura Peru
488 Clinica San Judas Tadeo San Miguel Peru 32
489 Center for Diabetes Care Iloilo Philippines 5000
490 Mary Mediatrix Medical Center Lipa City, Batangas Philippines 4217
491 Philippine General Hospital Manila Philippines 1000
492 University of Santo Tomas Hospital Manila Philippines 1008
493 Manila Doctors Hospital Manila Philippines 1011
494 Asian Hospital & Medical Center Muntinlupa Philippines 1781
495 St. Luke's Medical Center Quezon City Philippines 1102
496 Quirino Memorial Medical Center Quezon City Philippines 1109
497 Cardinal Santos Medical Center San Juan Philippines 1503
498 Surigao Health Specialists Surigao Philippines 8400
499 Hospital Fernando Fonseca, EPE Amadora Portugal 2700-276
500 CHLO, EPE - Hospital de Santa Cruz Carnaxide Portugal 2799-523
501 CHUC - Centro Hospitalar e Universitário de Coimbra, EPE Coimbra Portugal 3000-075
502 Centro Hospitalar da Cova da Beira Hospital Pêro da Covilhã Covilhã Portugal 6200-251
503 Hospital Distrital Figueira da Foz, EPE Figueira da Foz Portugal 3094-001
504 Hospital da Luz Lisboa Portugal 1500-650
505 Centro Hospitalar São João,EPE Porto Portugal 4202-451
506 Centro Hospitalar de Entre o Douro e Vouga, E.P.E. - Hospital de São Sebastião Santa Maria da Feira Portugal 4520-211
507 SC Diabol SRL, Brasov Brasov Romania 500365
508 Nicodiab SRL, Bucharest Bucharest Romania 010507
509 SC Medical Centre "Sanatatea Ta" SRL, Bucharest Bucharest Romania 020614
510 Consultmed SRL, Iasi Iasi Romania 700547
511 Emergency County Clinical Hospital, Sibiu Sibiu Romania 550245
512 Private Practice Dr. Remus Gagiu Tirgoviste Romania 130083
513 LLC Clinic of new technologies of medicine Dzerzhinsky Russian Federation 140091
514 City Clinical Hospital No. 6 of MoH of Udmurt Republic Izhevsk Russian Federation 436000
515 City Clinical Hospital No. 4, Moscow Moscow Russian Federation 115093
516 City Clinical Hospital No. 13, Moscow Moscow Russian Federation 115280
517 State Institution "Central Clinical Hospital of RAS", Moscow Moscow Russian Federation 117333
518 City Clinical Hospital No. 61, Moscow Moscow Russian Federation 119048
519 State Healthcare Institution, Regional hospital #2 Rostov-na-Donu Russian Federation 344029
520 Limited Liability Company "CENTER DIABET", Samara Samara Russian Federation 443067
521 MMU City Outpatient Clinic no. 20, Saratov Saratov Russian Federation 410018
522 Clinical Medical Center Zvezdara, Belgrade Belgrade Serbia 11000
523 Clinical Centre Nis Nis Serbia 18000
524 General Hospital Pancevo Pancevo Serbia 26000
525 General Hospital Subotica, Internal Medicine Subotica Serbia 24000
526 Clinical Hospital Center Zemun Zemun Serbia 11080
527 DIASTYLE s.r.o., Diabetology Outpatient Department Banska Bystrica Slovakia 974 01
528 ENDIAMED s.r.o., Dolny Kubin Dolny Kubin Slovakia 026 01
529 CELL B s.r.o. Levice Slovakia 934 01
530 DIA-KONTROL s.r.o. Levice Slovakia 934 01
531 Funkystuff s.r.o., Nove Zamky Nove Zamky Slovakia 940 01
532 Diabetologicka ambulancia MUDr. Lucia Gajdosikova s.r.o. Povazska Bystrica Slovakia 017 01
533 MEDIVASA s.r.o., Outpatient Clinic, Zilina Zilina Slovakia 010 01
534 Dr. P. Patel Cape Town South Africa 7764
535 Dr. E. L. Janari Cape Town South Africa 7965
536 Dr. Vawda Durban South Africa 4091
537 Parklands Medical Centre Durban South Africa 4091
538 Dr. Jurgens Krugersdorp South Africa 1739
539 Dr. H. Makan Lenasia South Africa 1827
540 Dr. D. R. Lakha, Johannesburg Lenasia South Africa 2033
541 Greenacres Hospital Port Elizabeth South Africa 6045
542 Dr. M. Seeber Pretoria South Africa 0083
543 Vergelegen Medi-Clinic Somerset West South Africa 7130
544 C.A.P. Sardenya Barcelona Spain 08025
545 CAP Les Corts Barcelona Spain 08028
546 CAP Casanova Barcelona Spain 08036
547 CAP Burjassot 1 Burjassot Spain 46100
548 C.S. Natahoyo Gijon Spain 33212
549 Hospital Universitari de Girona Doctor Josep Trueta Girona Spain 17007
550 CAP Florida L'Hospitalet de Llobregat Spain 08905
551 Hospital de Bellvitge L'Hospitalet de Llobregat Spain 08907
552 CAP La Roca La Roca Del Vallés (Barcelona) Spain 08430
553 Hospital General Universitario Gregorio Marañón Madrid Spain 28007
554 C.S. El Cristo Oviedo Spain 33006
555 C.S. Colloto Oviedo Spain 33010
556 C.S. Vallobin-La Florida Oviedo Spain 33012
557 ABS Pineda de Mar Pineda de Mar Spain 08397
558 Hospital de l'Esperit Sant Santa Coloma De Gramanet Spain 08923
559 CAP Tàrrega Tàrrega Spain 25300
560 CS Ingeniero Joaquin Benlloch Valencia Spain 46006
561 Hospital Clínico de Valencia Valencia Spain 46010
562 CTC Sahlgrenska Universitetssjukhuset Göteborg Sweden 413 45
563 Sjukhuset, Härnösand Härnösand Sweden 87182
564 Avonova Hälsa AB Järfälla Sweden 177 30
565 Skånes universitetssjukhus, Malmö Malmö Sweden 20502
566 Dalecarlia Clinical Research Center Rättvik Sweden 795 30
567 Södra Dalarnas vårdcentral, Hedemora Rättvik Sweden 79530
568 Näsets Läkargrupp Skanör Sweden 239 33
569 Vårdcentralen Silentzvägen Uddevalla Sweden 451 50
570 S3 Clinical Research Centers Vällingby Sweden 162 68
571 Allgemeine Medizin Basel Switzerland 4057
572 FMH endocrinologia diabetologia Bellinzona Switzerland 6500
573 Inselspital Bern Bern Switzerland 3010
574 Dr. Pietro Gerber Lugano Switzerland 6900
575 Chang-Hua Christian Hospital Changhua Taiwan 500
576 Kaohsiung Medical University Chung-Ho Memorial Hospital Kaohsiung Taiwan 807
577 E-Da Hospital Kaohsiung Taiwan 824
578 Far Eastern Memorial Hospital New Taipei City Taiwan 220
579 Taichung Veterans General Hospital Taichung, Taiwan 40705
580 China Medical University Hospital Taichung Taiwan 40447
581 NCKUH Tainan Taiwan 704
582 National Taiwan University Hospital Taipei Taiwan 100
583 Shih-Kong Wu Ho-Shu Memorial Hospital Taipei Taiwan 111
584 Taipe Veterans General Hospital Taipei Taiwan 11217
585 Cheng Hsin General Hospital Taipei Taiwan 112
586 Tri-Service General Hospital Taipei Taiwan 114
587 Cardinal Tien Hospital Taipei Taiwan 23137
588 Taipei Medical University-Shuang Ho Hospital Taipei Taiwan 235
589 Mackay Memorial Hospital Taipei Taiwan 25160
590 HOP Fattouma Bourguiba, Mint, Monastir Monastir Tunisia 5000
591 HOP Hédi Chaker, Endo, Sfax Sfax Tunisia 3029
592 HOP Farhat Hached, Mint, Sousse Sousse Tunisia 4000
593 HOP Habib Thameur, Mint, Tunis Tunis Tunisia 1008
594 Donetsk Regional Clinical Hosp, Therapy Department Donetsk Ukraine 83003
595 Ivano-Frankivsk City Central Clinical Hospital Ivano-Frankivsk Ukraine 76000
596 City Clinical Hospital No. 17, Kharkov Kharkiv Ukraine 61037
597 City Clinical Hospital No. 27, Kharkiv Kharkov Ukraine 61002
598 Clinic for Cardiology "Sertse i sudyny", Kiev Kiev Ukraine 01032
599 City Clinical Hospital No. 1, Kiev Kiev Ukraine 02091
600 Poliklinika #2, Kyiv Kyiv Ukraine 02002
601 City Hospital No. 5, Lvov Lvov Ukraine 73013
602 Odeska zaliznichna likarnya, Odessa Odesa Ukraine 65039
603 Vinnitsia Regional Endocrinology Dispensary Vinnitsa Ukraine 21010
604 Crouch Oak Family Practice Addlestone United Kingdom KT15 2BH
605 Ash Vale Health Centre, Aldershot Ash Vale, Aldershot United Kingdom GU12 5BA
606 Birmingham Heartlands Hospital Birmingham United Kingdom B9 5SS
607 Hathaway Medical Centre Chippenham United Kingdom SN14 6GT
608 University Hospital of North Durham Durham United Kingdom DH1 5TW
609 St Mary's Surgery Ely United Kingdom CB7 4HF
610 Gloucestershire Royal Hospital Gloucester United Kingdom GL1 3NN
611 James Paget University Hospital Great Yarmouth United Kingdom NR31 6LA
612 Morriston Hospital Swansea United Kingdom SA6 6NL
613 Royal Cornwall Hospital Truro United Kingdom TR1 3LJ

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:
NCT01243424
Other Study ID Numbers:
  • 1218.74
  • 2009-013157-15
First Posted:
Nov 18, 2010
Last Update Posted:
Jan 7, 2020
Last Verified:
Dec 1, 2019
Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glimepiride
Linagliptin

Study Results

Participant Flow

Recruitment Details This multicentre, multinational, randomised, double-blind, double-dummy, parallel group,comparator-controlled trial compared Linagliptin versus (vs.) Glimepiride, predominantly on metformin background treatment in participants with type 2 diabetes mellitus (T2DM) at elevated cardiovascular (CV) risk receiving usual care.
Pre-assignment Detail All participants were screened for eligibility to participate in the trial. Participants attended specialist sites which would then ensure that all participants met all inclusion/exclusion criteria. Participants were not to be randomised to trial treatment if any one of the specific entry criteria were not met.
Arm/Group Title Linagliptin Glimepiride
Arm/Group Description After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period. After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
Period Title: Discontinuation From Study (Treated Set)
STARTED 3028 3014
Patient Died (Other Cause Than CV Death) 123 146
Treated 3023 3010
COMPLETED 2899 2895
NOT COMPLETED 129 119
Period Title: Discontinuation From Study (Treated Set)
STARTED 3028 3014
Treated 3023 3010
COMPLETED 1896 1832
NOT COMPLETED 1132 1182

Baseline Characteristics

Arm/Group Title Linagliptin Glimepiride Total
Arm/Group Description After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period. After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period. Total of all reporting groups
Overall Participants 3023 3010 6033
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]
63.9
(9.5)
64.2
(9.5)
64.0
(9.5)
Sex: Female, Male (Count of Participants)
Female
1185
39.2%
1229
40.8%
2414
40%
Male
1838
60.8%
1781
59.2%
3619
60%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino
519
17.2%
513
17%
1032
17.1%
Not Hispanic or Latino
2495
82.5%
2487
82.6%
4982
82.6%
Unknown or Not Reported
9
0.3%
10
0.3%
19
0.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native
106
3.5%
108
3.6%
214
3.5%
Asian
531
17.6%
530
17.6%
1061
17.6%
Native Hawaiian or Other Pacific Islander
5
0.2%
3
0.1%
8
0.1%
Black or African American
155
5.1%
169
5.6%
324
5.4%
White
2217
73.3%
2190
72.8%
4407
73%
More than one race
0
0%
0
0%
0
0%
Unknown or Not Reported
9
0.3%
10
0.3%
19
0.3%

Outcome Measures

1. Primary Outcome
Title The First 3-point Major Adverse Cardiovascular Events (3P-MACE)
Description The first occurrence of any of the following Clinical Event Committee (CEC) confirmed adjudicated components of the primary composite endpoint: CV death (including fatal stroke and fatal myocardial infarction (MI)), non-fatal MI (excluding silent MI), or nonfatal stroke is presented.
Time Frame From randomization until individual day of trial completion, up to 432 weeks

Outcome Measure Data

Analysis Population Description
Treated set (TS): All patients treated with at least one dose of trial drug.
Arm/Group Title Linagliptin Glimepiride
Arm/Group Description After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period. After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
Measure Participants 3023 3010
Number [Events/ 1000 patients-years]
20.7
21.2
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Linagliptin, Glimepiride
Comments
Type of Statistical Test Non-Inferiority
Comments This was the first step in a pre-defined hierarchical testing approach. The upper bound of the confidence interval (CI) of the Hazard ratio (HR) of linagliptin vs. glimepiride was compared with this noninferiority margin for the testing of non-inferiority. All non-inferiority tests were based on a margin of 1.3.
Statistical Test of Hypothesis p-Value <0.0001
Comments P-values derived from Wald´s Chi-square test for non-inferiority were calculated.
Method Regression, Cox
Comments Cox proportional-hazard model with factor treatment was applied to compare linagliptin with glimepiride
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.98
Confidence Interval (2-Sided) 95.47%
0.84 to 1.14
Parameter Dispersion Type:
Value:
Estimation Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Linagliptin, Glimepiride
Comments
Type of Statistical Test Superiority
Comments This was the second step in a pre-defined hierarchical testing approach.
Statistical Test of Hypothesis p-Value 0.3813
Comments P-values derived from Wald´s Chi-square test.
Method Regression, Cox
Comments Cox proportional-hazard model with factor treatment was applied to compare linagliptin with glimepiride.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.98
Confidence Interval (2-Sided) 95.47%
0.84 to 1.14
Parameter Dispersion Type:
Value:
Estimation Comments
2. Secondary Outcome
Title The First 4-point (4P)- MACE
Description The first key secondary endpoint was time to first occurrence of any of the following adjudicated components of the composite endpoint: CV death (including fatal stroke and fatal MI), non-fatal stroke, non-fatal MI (excluding silent MI), or hospitalisation for unstable angina pectoris.
Time Frame From randomization until individual day of trial completion, up to 432 weeks

Outcome Measure Data

Analysis Population Description
TS
Arm/Group Title Linagliptin Glimepiride
Arm/Group Description After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period. After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
Measure Participants 3023 3010
Number [Events/ 1000 patients-years]
23.4
23.7
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Linagliptin, Glimepiride
Comments
Type of Statistical Test Superiority
Comments This was the third step in a pre-defined hierarchical testing approach.
Statistical Test of Hypothesis p-Value 0.4334
Comments P-values derived from Wald´s Chi-square test for non-inferiority.
Method Regression, Cox
Comments Cox proportional-hazard model with factor treatment was applied to compare linagliptin with glimepiride.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.99
Confidence Interval (2-Sided) 95.47%
0.86 to 1.14
Parameter Dispersion Type:
Value:
Estimation Comments
3. Secondary Outcome
Title Percentage of Participants Taking Trial Medication at Trial End, Maintained Glycaemic Control (HbA1c ≤7.0%) Without Need for Rescue Medication, Without >2% Weight Gain, and Without Moderate/Severe Hypoglycaemic Episodes During Maintenance Phase
Description The second key secondary endpoint was a composite endpoint of treatment sustainability, defined as the percentage of patients taking trial medication at trial end, maintained glycaemic control (HbA1c ≤7.0%) without need for rescue medication, without >2% weight gain, and without moderate/severe hypoglycaemic episodes during maintenance phase.
Time Frame From Visit 6 (Week 16) to Final visit (Week 432) (Maintenance Phase)

Outcome Measure Data

Analysis Population Description
TS without duplicates (TS w/o duplicates), patients who are off-drug or died prior to regular study stop were handled as non-completers considered failure (NCF).
Arm/Group Title Linagliptin Glimepiride
Arm/Group Description After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period. After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
Measure Participants 3014 3000
Number (95% Confidence Interval) [Percentage of participants (%)]
16.0
0.5%
10.2
0.3%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Linagliptin, Glimepiride
Comments
Type of Statistical Test Other
Comments
Statistical Test of Hypothesis p-Value <0.0001
Comments p-value derived from logistic regression.
Method Regression, Logistic
Comments
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.68
Confidence Interval (2-Sided) 95.47%
1.43 to 1.96
Parameter Dispersion Type:
Value:
Estimation Comments Odds ratio and confidence interval are based on logistic regression with factor for treatment.
4. Secondary Outcome
Title Percentage of Participants Who Were on Trial Medication at Trial End, Maintained Glycaemic Control (HbA1c ≤7.0%) Without Need for Rescue Medication, and Without >2% Weight Gain During Maintenance Phase
Description The third key secondary endpoint was a composite endpoint of treatment sustainability, defined as percentage of patients who were on trial medication at trial end, maintained glycaemic control (HbA1c ≤7.0%) without need for rescue medication, and without >2% weight gain during maintenance phase.
Time Frame From Visit 6 (Week 16) to Final visit (Week 432) (Maintenance Phase)

Outcome Measure Data

Analysis Population Description
TS w/o duplicates (NCF)
Arm/Group Title Linagliptin Glimepiride
Arm/Group Description After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period. After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
Measure Participants 3014 3000
Number (95% Confidence Interval) [Percentage of participants (%)]
17.4
0.6%
14.1
0.5%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Linagliptin, Glimepiride
Comments This was the fifth step in a pre-defined hierarchical testing approach.
Type of Statistical Test Other
Comments
Statistical Test of Hypothesis p-Value 0.0004
Comments p-value derived from logistic regression.
Method Regression, Logistic
Comments
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.29
Confidence Interval (2-Sided) 95.47%
1.11 to 1.48
Parameter Dispersion Type:
Value:
Estimation Comments Odds ratio and confidence interval are based on logistic regression with factor for treatment.
5. Secondary Outcome
Title Percentage of Participants With the Occurrence of at Least One Event of 3P-MACE
Description Percentage of participants occurrence of at least one of the following adjudicated components of CV death (including fatal stroke and fatal MI), non-fatal MI (excluding silent MI) and non-fatal stroke is presented as secondary CV endpoint.
Time Frame From randomization until individual day of trial completion, up to 432 weeks

Outcome Measure Data

Analysis Population Description
TS
Arm/Group Title Linagliptin Glimepiride
Arm/Group Description After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period. After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
Measure Participants 3023 3010
Number (95% Confidence Interval) [Percentage of participants (%)]
11.8
0.4%
12.0
0.4%
6. Secondary Outcome
Title Percentage of Participants With the Occurrence of at Least One Event of 4P -MACE
Description Percentage of participants occurrence of at least one of the following adjudicated components of CV death (including fatal stroke and fatal MI), non-fatal MI (excluding silent MI), non-fatal stroke, and hospitalisation for unstable angina pectoris is presented as secondary CV endpoint.
Time Frame From randomization until individual day of trial completion, up to 432 weeks

Outcome Measure Data

Analysis Population Description
TS
Arm/Group Title Linagliptin Glimepiride
Arm/Group Description After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period. After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
Measure Participants 3023 3010
Number (95% Confidence Interval) [Percentage of participants (%)]
13.2
0.4%
13.3
0.4%
7. Secondary Outcome
Title Percentage of Participants With Occurrence of Any of the Components of the Composite Endpoint of All Adjudication-confirmed Events
Description Percentage of participants with occurrence of any of the following components of the composite endpoint of all adjudication-confirmed events of: CV death (including fatal stroke and fatal MI) non-fatal MI non-fatal stroke hospitalisation for unstable angina pectoris TIA hospitalisation for heart failure hospitalisation for coronary revascularisation procedures (CABG, PCI)
Time Frame From start of the treatment until 7 days after the end of treatment, up to 433 weeks

Outcome Measure Data

Analysis Population Description
TS
Arm/Group Title Linagliptin Glimepiride
Arm/Group Description After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period. After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
Measure Participants 3023 3010
Number (95% Confidence Interval) [Percentage of participants (%)]
17.1
0.6%
17.8
0.6%
8. Secondary Outcome
Title Time to First Occurrence of Any of the Components of the Composite Endpoint of All Adjudication-confirmed Events
Description Time to first occurrence of any of the following components of the composite endpoint of all adjudication-confirmed events of: CV death (including fatal stroke and fatal MI) non-fatal MI non-fatal stroke hospitalisation for unstable angina pectoris Transient ischaemic attack (TIA) hospitalisation for heart failure hospitalisation for coronary revascularisation procedures (CABG, PCI)
Time Frame From start of the treatment until 7 days after the end of treatment, up to 433 weeks

Outcome Measure Data

Analysis Population Description
TS
Arm/Group Title Linagliptin Glimepiride
Arm/Group Description After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period. After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
Measure Participants 3023 3010
Number [Events/ 1000 patients-years]
31.1
32.4
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Linagliptin, Glimepiride
Comments This was the fifth step in a pre-defined hierarchical testing approach.
Type of Statistical Test Other
Comments
Statistical Test of Hypothesis p-Value 0.5249
Comments p-value derived from Wald´s chi-square test.
Method Regression, Cox
Comments
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.96
Confidence Interval (2-Sided) 95%
0.85 to 1.09
Parameter Dispersion Type:
Value:
Estimation Comments Hazard ratio and confidence interval derived from Cox regression with factor treatment.
9. Secondary Outcome
Title Change From Baseline to Final Visit in Hemoglobin A1c (HbA1c)
Description Change from baseline to final visit in HbA1c is presented as secondary diabetes-related endpoint. Least square mean is adjusted mean. The Final Visit value referred to the last value obtained on-treatment.
Time Frame Baseline and week 432

Outcome Measure Data

Analysis Population Description
TS w/o duplicates considering all available data
Arm/Group Title Linagliptin Glimepiride
Arm/Group Description After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period. After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
Measure Participants 2951 2949
Least Squares Mean (Standard Error) [Percentage glycosylated hemoglobin (%)]
0.06
(0.02)
0.15
(0.02)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Linagliptin, Glimepiride
Comments This was the fifth step in a pre-defined hierarchical testing approach.
Type of Statistical Test Other
Comments
Statistical Test of Hypothesis p-Value 0.0023
Comments
Method ANCOVA
Comments The Analysis of Covariance (ANCOVA) model includes the fixed categorical effect of treatment and the continuous covariate of baseline HbA1c.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.09
Confidence Interval (2-Sided) 95%
-0.15 to -0.03
Parameter Dispersion Type: Standard Error of the Mean
Value: 0.03
Estimation Comments Mean difference = Linagliptin mean - Glimepiride mean
10. Secondary Outcome
Title Change From Baseline to Final Visit in Fasting Plasma Glucose (FPG)
Description Change from baseline to final visit in fasting plasma glucose (FPG) is presented as secondary diabetes-related endpoint. Least square mean is adjusted mean. The Final Visit value referred to the last value obtained on-treatment.
Time Frame Baseline and week 432

Outcome Measure Data

Analysis Population Description
TS w/o duplicates considering all available data
Arm/Group Title Linagliptin Glimepiride
Arm/Group Description After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period. After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
Measure Participants 2996 2949
Least Squares Mean (Standard Error) [Milligram/ deciliter (mg/dL)]
12.4
(0.9)
19.7
(0.9)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Linagliptin, Glimepiride
Comments This was the fifth step in a pre-defined hierarchical testing approach.
Type of Statistical Test Other
Comments
Statistical Test of Hypothesis p-Value <0.0001
Comments
Method ANCOVA
Comments The ANCOVA model includes the fixed categorical effect of treatment and the continuous covariate of baseline FPG.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -7.3
Confidence Interval (2-Sided) 95%
-9.7 to -4.8
Parameter Dispersion Type: Standard Error of the Mean
Value: 1.2
Estimation Comments Mean difference = Linagliptin mean - Glimepiride mean
11. Secondary Outcome
Title Change From Baseline to Final Visit Fasting Total Cholesterol, Low-density Lipoprotein (LDL) Cholesterol and High-density Lipoprotein (HDL) Cholesterol
Description Change from baseline to final visit in total cholesterol, low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol is presented as secondary diabetes-related endpoint. Least square mean is adjusted mean. The Final Visit value referred to the last value obtained on-treatment.
Time Frame Baseline and week 432

Outcome Measure Data

Analysis Population Description
TS w/o duplicates, participants on treatment
Arm/Group Title Linagliptin Glimepiride
Arm/Group Description After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period. After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
Measure Participants 3014 3000
LDL cholesterol
-6.1
(0.6)
-6.5
(0.6)
HDL cholesterol
0.7
(0.2)
0.3
(0.2)
Total cholesterol
-5.4
(0.7)
-0.5
(0.7)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Linagliptin, Glimepiride
Comments LDL cholesterol, this was the fifth step in a pre-defined hierarchical testing approach.
Type of Statistical Test Other
Comments
Statistical Test of Hypothesis p-Value 0.6400
Comments
Method ANCOVA
Comments The ANCOVA model includes the fixed categorical effect of treatment and the continuous covariate of baseline LDL cholesterol.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.4
Confidence Interval (2-Sided) 95.47%
-1.3 to 2.1
Parameter Dispersion Type: Standard Error of the Mean
Value: 0.9
Estimation Comments Mean difference = Linagliptin mean - Glimepiride mean
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Linagliptin, Glimepiride
Comments HDL cholesterol, this was the fifth step in a pre-defined hierarchical testing approach.
Type of Statistical Test Other
Comments
Statistical Test of Hypothesis p-Value 0.0497
Comments
Method ANCOVA
Comments The ANCOVA model includes the fixed categorical effect of treatment and the continuous covariate of baseline HDL cholesterol.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.5
Confidence Interval (2-Sided) 95%
0.0 to 1.0
Parameter Dispersion Type: Standard Error of the Mean
Value: 0.2
Estimation Comments Mean difference = Linagliptin mean - Glimepiride mean
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Linagliptin, Glimepiride
Comments Total cholesterol, this was the fifth step in a pre-defined hierarchical testing approach.
Type of Statistical Test Other
Comments
Statistical Test of Hypothesis p-Value 0.6823
Comments
Method ANCOVA
Comments The ANCOVA model includes the fixed categorical effect of treatment and the continuous covariate of baseline total cholesterol.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.4
Confidence Interval (2-Sided) 95%
-2.4 to 1.6
Parameter Dispersion Type: Standard Error of the Mean
Value: 1.0
Estimation Comments Mean difference = Linagliptin mean - Glimepiride mean
12. Secondary Outcome
Title Change From Baseline to Final Visit in Triglycerides
Description Change from baseline to final visit in triglycerides is presented as secondary diabetes-related endpoint. Least square mean is adjusted mean. The Final Visit value referred to the last value obtained on-treatment.
Time Frame Baseline and week 432

Outcome Measure Data

Analysis Population Description
TS w/o duplicates, participants on treatment
Arm/Group Title Linagliptin Glimepiride
Arm/Group Description After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period. After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
Measure Participants 2788 2762
Least Squares Mean (Standard Error) [mg/dL]
1.7
(2.2)
5.2
(2.2)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Linagliptin, Glimepiride
Comments This was the fifth step in a pre-defined hierarchical testing approach.
Type of Statistical Test Other
Comments
Statistical Test of Hypothesis p-Value 0.2678
Comments
Method ANCOVA
Comments The ANCOVA model includes the fixed categorical effect of treatment and the continuous covariate of baseline FPG.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -3.5
Confidence Interval (2-Sided) 95%
-9.6 to 2.7
Parameter Dispersion Type: Standard Error of the Mean
Value: 3.1
Estimation Comments Mean difference = Linagliptin mean - Glimepiride mean
13. Secondary Outcome
Title Change From Baseline to Final Visit in Creatinine
Description Change from baseline to final visit in creatinine is presented as secondary diabetes-related endpoint. Least square mean is adjusted mean. The Final Visit value referred to the last value obtained on-treatment.
Time Frame Baseline and week 432

Outcome Measure Data

Analysis Population Description
TS w/o duplicates, participants on treatment
Arm/Group Title Linagliptin Glimepiride
Arm/Group Description After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period. After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
Measure Participants 2917 2898
Least Squares Mean (Standard Error) [mg/dL]
0.08
(0.01)
0.09
(0.01)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Linagliptin, Glimepiride
Comments This was the fifth step in a pre-defined hierarchical testing approach.
Type of Statistical Test Other
Comments
Statistical Test of Hypothesis p-Value 0.5165
Comments
Method ANCOVA
Comments The ANCOVA model includes the fixed categorical effect of treatment and the continuous covariate of baseline creatinine.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.01
Confidence Interval (2-Sided) 95%
-0.03 to 0.01
Parameter Dispersion Type: Standard Error of the Mean
Value: 0.01
Estimation Comments Mean difference = Linagliptin mean - Glimepiride mean
14. Secondary Outcome
Title Change From Baseline to Final Visit in Estimated Glomerular Filtration Rate (eGFR)
Description Change from baseline to final visit in eGFR is presented as secondary diabetes-related endpoint. Least square mean is adjusted mean. The Final Visit value referred to the last value obtained on-treatment.
Time Frame Baseline and week 432

Outcome Measure Data

Analysis Population Description
TS w/o duplicates, participants on treatment
Arm/Group Title Linagliptin Glimepiride
Arm/Group Description After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period. After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
Measure Participants 2917 2898
Least Squares Mean (Standard Error) [mL/minute/1.73 meter^2]
-4.0
(0.3)
-5.0
(0.3)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Linagliptin, Glimepiride
Comments This was the fifth step in a pre-defined hierarchical testing approach.
Type of Statistical Test Other
Comments
Statistical Test of Hypothesis p-Value 0.5165
Comments
Method ANCOVA
Comments The ANCOVA model includes the fixed categorical effect of treatment and the continuous covariate of baseline eGFR.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 1.0
Confidence Interval (2-Sided) 95%
0.2 to 1.8
Parameter Dispersion Type: Standard Error of the Mean
Value: 0.4
Estimation Comments Mean difference = Linagliptin mean - Glimepiride mean
15. Secondary Outcome
Title Change From Baseline to Final Visit in Urine Albumin Creatinine Ratio (UACR)
Description Change from baseline to final visit in UACR is presented as secondary diabetes-related endpoint. Least square mean is adjusted geometric mean (gMean) ratio. The Final Visit value referred to the last value obtained on-treatment.
Time Frame Baseline and week 432

Outcome Measure Data

Analysis Population Description
TS w/o duplicates, participants on treatment
Arm/Group Title Linagliptin Glimepiride
Arm/Group Description After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period. After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
Measure Participants 2904 2880
Geometric Mean (Geometric Coefficient of Variation) [mg/ gcrea]
1.52
(1.83)
1.57
(1.83)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Linagliptin, Glimepiride
Comments This was the fifth step in a pre-defined hierarchical testing approach.
Type of Statistical Test Other
Comments
Statistical Test of Hypothesis p-Value 0.2921
Comments
Method ANCOVA
Comments The ANCOVA model includes the fixed categorical effect of treatment and the continuous covariate of baseline UACR.
Method of Estimation Estimation Parameter geometric mean (gMean) ratio (%)
Estimated Value 0.97
Confidence Interval (2-Sided) 95%
0.91 to 1.03
Parameter Dispersion Type:
Value:
Estimation Comments gMean ration= Linagliptin mean/ Glimepiride mean
16. Secondary Outcome
Title Percentage of Participants With Transition in Albuminuria Classes
Description Percentage of patients with transition in albuminuria classes is presented as secondary endpoint. Data for last value on treatment (LVOT) to baseline (base) is presented.
Time Frame Baseline and week 432

Outcome Measure Data

Analysis Population Description
TS w/o duplicates, participants on treatment
Arm/Group Title Linagliptin Glimepiride
Arm/Group Description After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period. After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
Measure Participants 3014 3000
Base (<30mg/gcrea) LVOT (<30mg/gcrea)
58.4
1.9%
57.7
1.9%
Base(<30mg/gcrea)LVOT(>=30 to<=300mg/gcrea)
14.1
0.5%
16.0
0.5%
Base (<30 mg/gcrea) LVOT (>300 mg/gcrea)
1.4
0%
1.4
0%
Base (>=30 to <=300 mg/gcrea) LVOT(<30mg/gcrea)
5.4
0.2%
5.1
0.2%
Base(>=30to<=300mg/gcrea)LVOT(>=30to<=300mg/gcrea)
12.7
0.4%
12.1
0.4%
Base (>=30 to <=300 mg/gcrea) LVOT(>300 mg/gcrea)
3.5
0.1%
3.7
0.1%
Base (>300 mg/gcrea) LVOT (<30 mg/gcrea)
0.1
0%
0.3
0%
Base (>300 mg/gcrea) LVOT(>=30 to<=300mg/gcrea)
0.8
0%
0.9
0%
Base (>300 mg/gcrea) LVOT(>300 mg/gcrea)
3.4
0.1%
2.7
0.1%
17. Secondary Outcome
Title Change From Baseline of Insulin Secretion Rate (ISR) at Fixed Glucose Concentration at 208 Weeks
Description The endpoint change from baseline of ISR at fixed glucose concentration at 208 weeks as derived from a 3-hour meal tolerance test is Beta-cell function sub-study endpoint.
Time Frame Baseline and week 208

Outcome Measure Data

Analysis Population Description
Meal tolerance test(MTT) last observation carried forward(LOCF) set: Randomised and treated patients with one dose of study drug and signed the sub-study Informed Consent with valid baseline and on-treatment MTT. If values taken after rescue medication intake will be set to missing, last observed on-treatment value was carry forwarded.
Arm/Group Title Linagliptin Glimepiride
Arm/Group Description After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period. After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
Measure Participants 40 48
Mean (Standard Error) [Picomol/ minute/meter^2 (pmol/min/m²)]
11.07
(15.07)
6.95
(13.76)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Linagliptin, Glimepiride
Comments
Type of Statistical Test Equivalence
Comments This was the fifth step in a pre-defined hierarchical testing approach.
Statistical Test of Hypothesis p-Value 0.8402
Comments
Method ANCOVA
Comments The ANCOVA model includes the fixed categorical effects of treatment and the continuous covariate of baseline ISR.
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value 4.13
Confidence Interval (2-Sided) 95%
-36.46 to 44.71
Parameter Dispersion Type:
Value:
Estimation Comments Mean difference= Linagliptin mean- Glimepiride mean
18. Secondary Outcome
Title Percentage of Participants With Occurrence of Accelerated Cognitive Decline at End of Follow-up
Description Occurrence of accelerated cognitive decline based on regression based index (RBI) score at end of follow-up (a dichotomous outcome measure; presence or absence of accelerated cognitive decline) is Cognition sub-study endpoint.
Time Frame 433 weeks

Outcome Measure Data

Analysis Population Description
Full analysis set cognition(FAS-COG): Randomised and treated patients with one dose of study drug, baseline assessment (the z-scores, A&E or Mini-mental state examination(MMSE) can be calculated), years of formal education with baseline MMSE≥24 and at least one on-treatment assessment (of which at least one of the RBI scores can be calculated).
Arm/Group Title Linagliptin Glimepiride
Arm/Group Description After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period. After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
Measure Participants 1618 1545
Number (95% Confidence Interval) [Percentage of participants (%)]
27.8
0.9%
27.6
0.9%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Linagliptin, Glimepiride
Comments This was the fifth step in a pre-defined hierarchical testing approach.
Type of Statistical Test Other
Comments
Statistical Test of Hypothesis p-Value 0.9112
Comments
Method Regression, Logistic
Comments Logistic regression model with terms for treatment as a fixed effect with Wald confidence Interval was used.
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.01
Confidence Interval (2-Sided) 95%
0.86 to 1.18
Parameter Dispersion Type:
Value:
Estimation Comments Linagliptin vs. Glimepiride odds is presented.
19. Secondary Outcome
Title Continuous Glucose Monitoring (CGM) Sub-study: Change From Baseline in the Inter-quartile Range of Diurnal Glucose Variability (Milligrams/ Deciliter) to End of Study
Description Baseline data for the continuous glucose monitoring sub-study was collected and analyzed. However, the participant number was far less than original planned. The study was stopped early around week 64 (V9) due to recruitment issues and data were not pre-specified to be analyzed and reported at week 64 time point as target was with an estimated time point of 432 weeks for primary or secondary end points. Thus this endpoint was not analysed and only the baseline data collected were analysed and the results are reported in this CGM substudy endpoint.
Time Frame Baseline

Outcome Measure Data

Analysis Population Description
The sub-study was stopped early and required target with an estimated time point of 432 weeks was not achieved for this endpoint. Thus the data were not unblinded and only the baseline data collected were reported overall and not by treatment arm for this endpoint.
Arm/Group Title All Participants
Arm/Group Description After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose or 1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. All doses were administered once daily orally up to an estimated 432 weeks treatment period.
Measure Participants 44
Mean (Standard Deviation) [Milligrams/ deciliter (mg/ dL)]
44.2
(12.6)
20. Secondary Outcome
Title CGM Sub-study : Change From Baseline in the Inter-quartile Range of Diurnal Glucose Variability (Millimoles/ Litre) to End of Study
Description Baseline data for the continuous glucose monitoring sub-study was collected and analyzed. However, the participant number was far less than original planned. The study was stopped early around week 64 (V9) due to recruitment issues and data were not pre-specified to be analyzed and reported at week 64 time point as target was with an estimated time point of 432 weeks for primary or secondary end points. Thus this endpoint was not analysed and only the baseline data collected were analysed and the results are reported in this CGM substudy endpoint.
Time Frame Baseline

Outcome Measure Data

Analysis Population Description
The sub-study was stopped early and required target with an estimated time point of 432 weeks was not achieved for this endpoint. Thus the data were not unblinded and only the baseline data collected were reported overall and not by treatment arm for this endpoint.
Arm/Group Title All Participants
Arm/Group Description After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose or 1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. All doses were administered once daily orally up to an estimated 432 weeks treatment period.
Measure Participants 44
Mean (Standard Deviation) [Millimoles/ Litre (mmol/L)]
2.45
(0.7)

Adverse Events

Time Frame From start of the treatment until 7 days after the end of treatment, up to 433 weeks.
Adverse Event Reporting Description
Arm/Group Title Linagliptin Glimepiride
Arm/Group Description After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period. After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.
All Cause Mortality
Linagliptin Glimepiride
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 308/3023 (10.2%) 336/3010 (11.2%)
Serious Adverse Events
Linagliptin Glimepiride
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 1403/3023 (46.4%) 1448/3010 (48.1%)
Blood and lymphatic system disorders
Anaemia 14/3023 (0.5%) 18/3010 (0.6%)
Anaemia macrocytic 0/3023 (0%) 1/3010 (0%)
Coagulopathy 1/3023 (0%) 0/3010 (0%)
Febrile neutropenia 2/3023 (0.1%) 0/3010 (0%)
Haemorrhagic anaemia 6/3023 (0.2%) 1/3010 (0%)
Haemorrhagic diathesis 1/3023 (0%) 0/3010 (0%)
Increased tendency to bruise 1/3023 (0%) 0/3010 (0%)
Iron deficiency anaemia 1/3023 (0%) 3/3010 (0.1%)
Leukocytosis 1/3023 (0%) 1/3010 (0%)
Lymphadenopathy 0/3023 (0%) 1/3010 (0%)
Normocytic anaemia 1/3023 (0%) 0/3010 (0%)
Pancytopenia 5/3023 (0.2%) 1/3010 (0%)
Splenic haematoma 1/3023 (0%) 0/3010 (0%)
Splenic vein thrombosis 0/3023 (0%) 1/3010 (0%)
Cardiac disorders
Acute coronary syndrome 18/3023 (0.6%) 12/3010 (0.4%)
Acute left ventricular failure 2/3023 (0.1%) 1/3010 (0%)
Acute myocardial infarction 52/3023 (1.7%) 56/3010 (1.9%)
Adams-Stokes syndrome 0/3023 (0%) 1/3010 (0%)
Angina pectoris 37/3023 (1.2%) 40/3010 (1.3%)
Angina unstable 54/3023 (1.8%) 65/3010 (2.2%)
Aortic valve disease 1/3023 (0%) 2/3010 (0.1%)
Aortic valve incompetence 1/3023 (0%) 1/3010 (0%)
Aortic valve stenosis 5/3023 (0.2%) 4/3010 (0.1%)
Arrhythmia 4/3023 (0.1%) 5/3010 (0.2%)
Arteriosclerosis coronary artery 4/3023 (0.1%) 4/3010 (0.1%)
Atrial fibrillation 39/3023 (1.3%) 48/3010 (1.6%)
Atrial flutter 23/3023 (0.8%) 14/3010 (0.5%)
Atrial tachycardia 2/3023 (0.1%) 2/3010 (0.1%)
Atrioventricular block 1/3023 (0%) 1/3010 (0%)
Atrioventricular block complete 10/3023 (0.3%) 8/3010 (0.3%)
Atrioventricular block first degree 1/3023 (0%) 0/3010 (0%)
Atrioventricular block second degree 3/3023 (0.1%) 3/3010 (0.1%)
Bradyarrhythmia 0/3023 (0%) 1/3010 (0%)
Bradycardia 6/3023 (0.2%) 7/3010 (0.2%)
Bundle branch block 1/3023 (0%) 0/3010 (0%)
Bundle branch block left 1/3023 (0%) 3/3010 (0.1%)
Cardiac aneurysm 1/3023 (0%) 0/3010 (0%)
Cardiac arrest 4/3023 (0.1%) 8/3010 (0.3%)
Cardiac asthma 1/3023 (0%) 0/3010 (0%)
Cardiac disorder 3/3023 (0.1%) 1/3010 (0%)
Cardiac failure 58/3023 (1.9%) 53/3010 (1.8%)
Cardiac failure acute 7/3023 (0.2%) 6/3010 (0.2%)
Cardiac failure chronic 9/3023 (0.3%) 12/3010 (0.4%)
Cardiac failure congestive 37/3023 (1.2%) 45/3010 (1.5%)
Cardiac perforation 1/3023 (0%) 0/3010 (0%)
Cardiac valve disease 1/3023 (0%) 0/3010 (0%)
Cardio-respiratory arrest 4/3023 (0.1%) 2/3010 (0.1%)
Cardiogenic shock 2/3023 (0.1%) 4/3010 (0.1%)
Cardiomegaly 0/3023 (0%) 1/3010 (0%)
Cardiomyopathy 1/3023 (0%) 2/3010 (0.1%)
Cardiopulmonary failure 1/3023 (0%) 1/3010 (0%)
Cardiovascular disorder 1/3023 (0%) 0/3010 (0%)
Cardiovascular insufficiency 1/3023 (0%) 0/3010 (0%)
Conduction disorder 0/3023 (0%) 1/3010 (0%)
Congestive cardiomyopathy 1/3023 (0%) 2/3010 (0.1%)
Cor pulmonale 0/3023 (0%) 3/3010 (0.1%)
Coronary artery disease 43/3023 (1.4%) 42/3010 (1.4%)
Coronary artery dissection 1/3023 (0%) 0/3010 (0%)
Coronary artery insufficiency 2/3023 (0.1%) 1/3010 (0%)
Coronary artery occlusion 3/3023 (0.1%) 2/3010 (0.1%)
Coronary artery stenosis 4/3023 (0.1%) 12/3010 (0.4%)
Diastolic dysfunction 1/3023 (0%) 0/3010 (0%)
Extrasystoles 0/3023 (0%) 1/3010 (0%)
Heart valve incompetence 1/3023 (0%) 0/3010 (0%)
Ischaemic cardiomyopathy 4/3023 (0.1%) 2/3010 (0.1%)
Left ventricular dysfunction 2/3023 (0.1%) 0/3010 (0%)
Left ventricular failure 2/3023 (0.1%) 4/3010 (0.1%)
Left ventricular hypertrophy 1/3023 (0%) 0/3010 (0%)
Long QT syndrome 0/3023 (0%) 1/3010 (0%)
Mitral valve incompetence 1/3023 (0%) 2/3010 (0.1%)
Mitral valve stenosis 0/3023 (0%) 1/3010 (0%)
Myocardial infarction 49/3023 (1.6%) 64/3010 (2.1%)
Myocardial ischaemia 14/3023 (0.5%) 9/3010 (0.3%)
Myocardial rupture 0/3023 (0%) 1/3010 (0%)
Palpitations 2/3023 (0.1%) 2/3010 (0.1%)
Pericardial effusion 1/3023 (0%) 0/3010 (0%)
Pericarditis 1/3023 (0%) 3/3010 (0.1%)
Postinfarction angina 1/3023 (0%) 1/3010 (0%)
Prinzmetal angina 1/3023 (0%) 1/3010 (0%)
Pulmonary valve stenosis 0/3023 (0%) 1/3010 (0%)
Right ventricular dysfunction 0/3023 (0%) 1/3010 (0%)
Right ventricular failure 1/3023 (0%) 1/3010 (0%)
Silent myocardial infarction 5/3023 (0.2%) 5/3010 (0.2%)
Sinoatrial block 1/3023 (0%) 0/3010 (0%)
Sinus arrest 0/3023 (0%) 1/3010 (0%)
Sinus arrhythmia 0/3023 (0%) 1/3010 (0%)
Sinus bradycardia 1/3023 (0%) 1/3010 (0%)
Sinus node dysfunction 4/3023 (0.1%) 5/3010 (0.2%)
Sinus tachycardia 2/3023 (0.1%) 1/3010 (0%)
Stress cardiomyopathy 0/3023 (0%) 1/3010 (0%)
Supraventricular tachyarrhythmia 0/3023 (0%) 1/3010 (0%)
Supraventricular tachycardia 1/3023 (0%) 7/3010 (0.2%)
Tachyarrhythmia 2/3023 (0.1%) 1/3010 (0%)
Tachycardia 5/3023 (0.2%) 2/3010 (0.1%)
Tachycardia paroxysmal 0/3023 (0%) 2/3010 (0.1%)
Thyrotoxic cardiomyopathy 0/3023 (0%) 1/3010 (0%)
Tricuspid valve incompetence 0/3023 (0%) 1/3010 (0%)
Trifascicular block 1/3023 (0%) 0/3010 (0%)
Ventricular arrhythmia 1/3023 (0%) 0/3010 (0%)
Ventricular extrasystoles 4/3023 (0.1%) 2/3010 (0.1%)
Ventricular fibrillation 0/3023 (0%) 2/3010 (0.1%)
Ventricular hypokinesia 0/3023 (0%) 1/3010 (0%)
Ventricular tachycardia 4/3023 (0.1%) 1/3010 (0%)
Wolff-Parkinson-White syndrome 1/3023 (0%) 0/3010 (0%)
Congenital, familial and genetic disorders
Adenomatous polyposis coli 0/3023 (0%) 1/3010 (0%)
Arteriovenous malformation 1/3023 (0%) 0/3010 (0%)
Choledochal cyst 1/3023 (0%) 0/3010 (0%)
Congenital cystic kidney disease 1/3023 (0%) 0/3010 (0%)
Corneal dystrophy 1/3023 (0%) 0/3010 (0%)
Developmental hip dysplasia 0/3023 (0%) 1/3010 (0%)
Exomphalos 1/3023 (0%) 0/3010 (0%)
Fibrous dysplasia of bone 1/3023 (0%) 0/3010 (0%)
Hereditary haemochromatosis 0/3023 (0%) 1/3010 (0%)
Hydrocele 2/3023 (0.1%) 3/3010 (0.1%)
Hypertrophic cardiomyopathy 1/3023 (0%) 0/3010 (0%)
Ichthyosis 0/3023 (0%) 1/3010 (0%)
Left ventricle outflow tract obstruction 0/3023 (0%) 1/3010 (0%)
Phimosis 3/3023 (0.1%) 6/3010 (0.2%)
Porokeratosis 1/3023 (0%) 2/3010 (0.1%)
Stargardt's disease 1/3023 (0%) 0/3010 (0%)
Urachal abnormality 0/3023 (0%) 1/3010 (0%)
Ear and labyrinth disorders
Acute vestibular syndrome 1/3023 (0%) 0/3010 (0%)
Aural polyp 1/3023 (0%) 0/3010 (0%)
Conductive deafness 1/3023 (0%) 0/3010 (0%)
Deafness 7/3023 (0.2%) 2/3010 (0.1%)
Deafness neurosensory 3/3023 (0.1%) 6/3010 (0.2%)
Deafness unilateral 0/3023 (0%) 4/3010 (0.1%)
Ear canal stenosis 1/3023 (0%) 0/3010 (0%)
Hypoacusis 0/3023 (0%) 1/3010 (0%)
Inner ear disorder 1/3023 (0%) 0/3010 (0%)
Meniere's disease 1/3023 (0%) 0/3010 (0%)
Mixed deafness 0/3023 (0%) 1/3010 (0%)
Sudden hearing loss 0/3023 (0%) 1/3010 (0%)
Tympanic membrane perforation 1/3023 (0%) 1/3010 (0%)
Vertigo 9/3023 (0.3%) 12/3010 (0.4%)
Vestibular disorder 0/3023 (0%) 1/3010 (0%)
Endocrine disorders
Adrenal insufficiency 0/3023 (0%) 1/3010 (0%)
Basedow's disease 1/3023 (0%) 0/3010 (0%)
Goitre 3/3023 (0.1%) 4/3010 (0.1%)
Hyperparathyroidism 0/3023 (0%) 1/3010 (0%)
Hyperthyroidism 0/3023 (0%) 1/3010 (0%)
Hypoparathyroidism 0/3023 (0%) 1/3010 (0%)
Inappropriate antidiuretic hormone secretion 1/3023 (0%) 1/3010 (0%)
Thyroid mass 1/3023 (0%) 0/3010 (0%)
Eye disorders
Age-related macular degeneration 0/3023 (0%) 1/3010 (0%)
Amaurosis 0/3023 (0%) 1/3010 (0%)
Amaurosis fugax 2/3023 (0.1%) 3/3010 (0.1%)
Angle closure glaucoma 4/3023 (0.1%) 1/3010 (0%)
Aphakia 1/3023 (0%) 0/3010 (0%)
Blepharitis 0/3023 (0%) 1/3010 (0%)
Blindness 1/3023 (0%) 0/3010 (0%)
Blindness transient 0/3023 (0%) 1/3010 (0%)
Blindness unilateral 1/3023 (0%) 0/3010 (0%)
Cataract 16/3023 (0.5%) 21/3010 (0.7%)
Chalazion 0/3023 (0%) 1/3010 (0%)
Detachment of retinal pigment epithelium 0/3023 (0%) 1/3010 (0%)
Diabetic retinopathy 1/3023 (0%) 2/3010 (0.1%)
Diplopia 0/3023 (0%) 1/3010 (0%)
Dry age-related macular degeneration 0/3023 (0%) 2/3010 (0.1%)
Endocrine ophthalmopathy 0/3023 (0%) 1/3010 (0%)
Eye haemorrhage 1/3023 (0%) 0/3010 (0%)
Eye swelling 1/3023 (0%) 0/3010 (0%)
Eyelid ptosis 1/3023 (0%) 2/3010 (0.1%)
Eyelid rash 1/3023 (0%) 0/3010 (0%)
Glaucoma 29/3023 (1%) 31/3010 (1%)
Iris neovascularisation 1/3023 (0%) 0/3010 (0%)
Keratitis 0/3023 (0%) 1/3010 (0%)
Lens dislocation 1/3023 (0%) 0/3010 (0%)
Macular degeneration 12/3023 (0.4%) 11/3010 (0.4%)
Macular fibrosis 5/3023 (0.2%) 6/3010 (0.2%)
Macular hole 2/3023 (0.1%) 0/3010 (0%)
Neovascular age-related macular degeneration 0/3023 (0%) 1/3010 (0%)
Open angle glaucoma 0/3023 (0%) 1/3010 (0%)
Panophthalmitis 2/3023 (0.1%) 0/3010 (0%)
Pterygium 0/3023 (0%) 1/3010 (0%)
Retinal artery embolism 2/3023 (0.1%) 1/3010 (0%)
Retinal artery occlusion 3/3023 (0.1%) 0/3010 (0%)
Retinal degeneration 2/3023 (0.1%) 0/3010 (0%)
Retinal detachment 6/3023 (0.2%) 7/3010 (0.2%)
Retinal tear 2/3023 (0.1%) 2/3010 (0.1%)
Retinal vein occlusion 2/3023 (0.1%) 2/3010 (0.1%)
Retinopathy 0/3023 (0%) 1/3010 (0%)
Ulcerative keratitis 1/3023 (0%) 3/3010 (0.1%)
Uveitic glaucoma 0/3023 (0%) 1/3010 (0%)
Vision blurred 1/3023 (0%) 0/3010 (0%)
Visual impairment 1/3023 (0%) 1/3010 (0%)
Vitreous adhesions 1/3023 (0%) 0/3010 (0%)
Vitreous degeneration 0/3023 (0%) 1/3010 (0%)
Vitreous detachment 0/3023 (0%) 1/3010 (0%)
Vitreous haemorrhage 1/3023 (0%) 0/3010 (0%)
Gastrointestinal disorders
Abdominal adhesions 0/3023 (0%) 1/3010 (0%)
Abdominal discomfort 0/3023 (0%) 1/3010 (0%)
Abdominal distension 0/3023 (0%) 1/3010 (0%)
Abdominal hernia 2/3023 (0.1%) 2/3010 (0.1%)
Abdominal incarcerated hernia 0/3023 (0%) 1/3010 (0%)
Abdominal pain 7/3023 (0.2%) 7/3010 (0.2%)
Abdominal pain lower 1/3023 (0%) 1/3010 (0%)
Abdominal pain upper 1/3023 (0%) 1/3010 (0%)
Abdominal tenderness 0/3023 (0%) 1/3010 (0%)
Abdominal wall haematoma 1/3023 (0%) 1/3010 (0%)
Acute abdomen 1/3023 (0%) 0/3010 (0%)
Anal fissure 0/3023 (0%) 1/3010 (0%)
Anal fistula 1/3023 (0%) 2/3010 (0.1%)
Appendiceal mucocoele 0/3023 (0%) 1/3010 (0%)
Ascites 1/3023 (0%) 3/3010 (0.1%)
Barrett's oesophagus 0/3023 (0%) 1/3010 (0%)
Bezoar 1/3023 (0%) 0/3010 (0%)
Colitis 6/3023 (0.2%) 2/3010 (0.1%)
Colitis ischaemic 2/3023 (0.1%) 1/3010 (0%)
Colon dysplasia 1/3023 (0%) 0/3010 (0%)
Constipation 4/3023 (0.1%) 3/3010 (0.1%)
Crohn's disease 1/3023 (0%) 0/3010 (0%)
Dental necrosis 1/3023 (0%) 0/3010 (0%)
Diarrhoea 5/3023 (0.2%) 5/3010 (0.2%)
Diverticulum 1/3023 (0%) 2/3010 (0.1%)
Diverticulum intestinal 1/3023 (0%) 2/3010 (0.1%)
Diverticulum intestinal haemorrhagic 2/3023 (0.1%) 0/3010 (0%)
Duodenal polyp 1/3023 (0%) 0/3010 (0%)
Duodenal ulcer 3/3023 (0.1%) 2/3010 (0.1%)
Duodenal ulcer haemorrhage 2/3023 (0.1%) 4/3010 (0.1%)
Duodenitis 0/3023 (0%) 1/3010 (0%)
Dyspepsia 1/3023 (0%) 1/3010 (0%)
Dysphagia 0/3023 (0%) 2/3010 (0.1%)
Enteritis 3/3023 (0.1%) 0/3010 (0%)
Enterovesical fistula 0/3023 (0%) 1/3010 (0%)
Erosive duodenitis 0/3023 (0%) 1/3010 (0%)
Faecaloma 0/3023 (0%) 1/3010 (0%)
Food poisoning 1/3023 (0%) 1/3010 (0%)
Gastric haemorrhage 0/3023 (0%) 1/3010 (0%)
Gastric polyps 1/3023 (0%) 1/3010 (0%)
Gastric ulcer 4/3023 (0.1%) 3/3010 (0.1%)
Gastric ulcer haemorrhage 3/3023 (0.1%) 0/3010 (0%)
Gastric ulcer perforation 1/3023 (0%) 0/3010 (0%)
Gastritis 5/3023 (0.2%) 6/3010 (0.2%)
Gastritis erosive 0/3023 (0%) 3/3010 (0.1%)
Gastritis haemorrhagic 1/3023 (0%) 1/3010 (0%)
Gastroduodenal haemorrhage 1/3023 (0%) 0/3010 (0%)
Gastroduodenitis 1/3023 (0%) 0/3010 (0%)
Gastrointestinal disorder 1/3023 (0%) 1/3010 (0%)
Gastrointestinal haemorrhage 16/3023 (0.5%) 10/3010 (0.3%)
Gastrointestinal obstruction 0/3023 (0%) 1/3010 (0%)
Gastrointestinal ulcer 0/3023 (0%) 1/3010 (0%)
Gastrointestinal ulcer haemorrhage 1/3023 (0%) 0/3010 (0%)
Gastrooesophageal reflux disease 1/3023 (0%) 2/3010 (0.1%)
Gingival bleeding 0/3023 (0%) 1/3010 (0%)
Haematemesis 1/3023 (0%) 3/3010 (0.1%)
Haematochezia 1/3023 (0%) 1/3010 (0%)
Haemorrhoidal haemorrhage 2/3023 (0.1%) 1/3010 (0%)
Haemorrhoids 3/3023 (0.1%) 2/3010 (0.1%)
Hiatus hernia 1/3023 (0%) 2/3010 (0.1%)
Ileus 3/3023 (0.1%) 1/3010 (0%)
Ileus paralytic 0/3023 (0%) 4/3010 (0.1%)
Impaired gastric emptying 0/3023 (0%) 1/3010 (0%)
Incarcerated inguinal hernia 0/3023 (0%) 2/3010 (0.1%)
Inguinal hernia 18/3023 (0.6%) 14/3010 (0.5%)
Intestinal haematoma 1/3023 (0%) 0/3010 (0%)
Intestinal haemorrhage 2/3023 (0.1%) 0/3010 (0%)
Intestinal mass 1/3023 (0%) 0/3010 (0%)
Intestinal obstruction 3/3023 (0.1%) 4/3010 (0.1%)
Intestinal perforation 0/3023 (0%) 1/3010 (0%)
Intra-abdominal haematoma 0/3023 (0%) 1/3010 (0%)
Irritable bowel syndrome 1/3023 (0%) 0/3010 (0%)
Jejunal perforation 0/3023 (0%) 1/3010 (0%)
Large intestinal haemorrhage 1/3023 (0%) 0/3010 (0%)
Large intestine perforation 0/3023 (0%) 1/3010 (0%)
Large intestine polyp 6/3023 (0.2%) 9/3010 (0.3%)
Lip swelling 0/3023 (0%) 1/3010 (0%)
Lower gastrointestinal haemorrhage 2/3023 (0.1%) 3/3010 (0.1%)
Lumbar hernia 1/3023 (0%) 0/3010 (0%)
Malignant bowel obstruction 1/3023 (0%) 0/3010 (0%)
Melaena 3/3023 (0.1%) 4/3010 (0.1%)
Mesenteric artery thrombosis 0/3023 (0%) 1/3010 (0%)
Nausea 1/3023 (0%) 5/3010 (0.2%)
Obstructive pancreatitis 1/3023 (0%) 0/3010 (0%)
Oesophageal fistula 1/3023 (0%) 0/3010 (0%)
Oesophageal obstruction 1/3023 (0%) 0/3010 (0%)
Oesophageal ulcer 1/3023 (0%) 0/3010 (0%)
Oesophageal varices haemorrhage 0/3023 (0%) 1/3010 (0%)
Oesophagitis 1/3023 (0%) 1/3010 (0%)
Pancreatic failure 1/3023 (0%) 0/3010 (0%)
Pancreatic mass 0/3023 (0%) 1/3010 (0%)
Pancreatitis 10/3023 (0.3%) 11/3010 (0.4%)
Pancreatitis acute 8/3023 (0.3%) 8/3010 (0.3%)
Pancreatitis chronic 5/3023 (0.2%) 2/3010 (0.1%)
Pancreatitis necrotising 1/3023 (0%) 0/3010 (0%)
Paraesthesia oral 0/3023 (0%) 1/3010 (0%)
Peptic ulcer perforation 0/3023 (0%) 1/3010 (0%)
Proctitis 0/3023 (0%) 1/3010 (0%)
Rectal haemorrhage 3/3023 (0.1%) 2/3010 (0.1%)
Rectal polyp 1/3023 (0%) 0/3010 (0%)
Retroperitoneal fibrosis 1/3023 (0%) 0/3010 (0%)
Salivary gland calculus 1/3023 (0%) 0/3010 (0%)
Salivary gland mass 1/3023 (0%) 0/3010 (0%)
Small intestinal haemorrhage 1/3023 (0%) 1/3010 (0%)
Small intestinal obstruction 5/3023 (0.2%) 1/3010 (0%)
Subileus 1/3023 (0%) 0/3010 (0%)
Swollen tongue 0/3023 (0%) 1/3010 (0%)
Tongue oedema 0/3023 (0%) 1/3010 (0%)
Tongue ulceration 0/3023 (0%) 1/3010 (0%)
Umbilical hernia 4/3023 (0.1%) 3/3010 (0.1%)
Upper gastrointestinal haemorrhage 7/3023 (0.2%) 4/3010 (0.1%)
Vomiting 3/3023 (0.1%) 4/3010 (0.1%)
General disorders
Adhesion 1/3023 (0%) 0/3010 (0%)
Adverse drug reaction 1/3023 (0%) 0/3010 (0%)
Asthenia 3/3023 (0.1%) 7/3010 (0.2%)
Cardiac death 7/3023 (0.2%) 3/3010 (0.1%)
Chest discomfort 3/3023 (0.1%) 6/3010 (0.2%)
Chest pain 50/3023 (1.7%) 52/3010 (1.7%)
Chills 0/3023 (0%) 1/3010 (0%)
Condition aggravated 0/3023 (0%) 1/3010 (0%)
Death 20/3023 (0.7%) 20/3010 (0.7%)
Discomfort 1/3023 (0%) 0/3010 (0%)
Exercise tolerance decreased 1/3023 (0%) 0/3010 (0%)
Fatigue 0/3023 (0%) 3/3010 (0.1%)
Fibrosis 1/3023 (0%) 0/3010 (0%)
General physical health deterioration 3/3023 (0.1%) 4/3010 (0.1%)
Hernia 1/3023 (0%) 0/3010 (0%)
Hyperthermia 1/3023 (0%) 0/3010 (0%)
Impaired healing 0/3023 (0%) 1/3010 (0%)
Implant site extravasation 1/3023 (0%) 0/3010 (0%)
Implant site haematoma 0/3023 (0%) 1/3010 (0%)
Malaise 3/3023 (0.1%) 2/3010 (0.1%)
Mass 1/3023 (0%) 0/3010 (0%)
Multi-organ disorder 1/3023 (0%) 0/3010 (0%)
Multiple organ dysfunction syndrome 1/3023 (0%) 7/3010 (0.2%)
Non-cardiac chest pain 8/3023 (0.3%) 8/3010 (0.3%)
Oedema peripheral 2/3023 (0.1%) 1/3010 (0%)
Puncture site haemorrhage 1/3023 (0%) 0/3010 (0%)
Pyrexia 7/3023 (0.2%) 8/3010 (0.3%)
Retention cyst 0/3023 (0%) 1/3010 (0%)
Sudden cardiac death 3/3023 (0.1%) 1/3010 (0%)
Sudden death 9/3023 (0.3%) 4/3010 (0.1%)
Swelling 1/3023 (0%) 0/3010 (0%)
Vascular stent stenosis 3/3023 (0.1%) 1/3010 (0%)
Hepatobiliary disorders
Acute hepatic failure 0/3023 (0%) 2/3010 (0.1%)
Bile duct obstruction 2/3023 (0.1%) 0/3010 (0%)
Bile duct stenosis 1/3023 (0%) 0/3010 (0%)
Bile duct stone 6/3023 (0.2%) 1/3010 (0%)
Biliary colic 1/3023 (0%) 1/3010 (0%)
Biliary dyskinesia 0/3023 (0%) 1/3010 (0%)
Cholangitis 2/3023 (0.1%) 1/3010 (0%)
Cholangitis acute 1/3023 (0%) 1/3010 (0%)
Cholecystitis 20/3023 (0.7%) 16/3010 (0.5%)
Cholecystitis acute 9/3023 (0.3%) 5/3010 (0.2%)
Cholecystitis chronic 3/3023 (0.1%) 0/3010 (0%)
Cholelithiasis 20/3023 (0.7%) 14/3010 (0.5%)
Cholestasis 0/3023 (0%) 1/3010 (0%)
Cholestatic liver injury 1/3023 (0%) 0/3010 (0%)
Cirrhosis alcoholic 0/3023 (0%) 1/3010 (0%)
Drug-induced liver injury 2/3023 (0.1%) 0/3010 (0%)
Gallbladder disorder 1/3023 (0%) 0/3010 (0%)
Gallbladder necrosis 1/3023 (0%) 0/3010 (0%)
Gallbladder polyp 1/3023 (0%) 0/3010 (0%)
Hepatic cirrhosis 3/3023 (0.1%) 6/3010 (0.2%)
Hepatic cyst 0/3023 (0%) 1/3010 (0%)
Hepatic failure 1/3023 (0%) 1/3010 (0%)
Hepatic fibrosis 0/3023 (0%) 1/3010 (0%)
Hepatic lesion 0/3023 (0%) 1/3010 (0%)
Hepatic mass 0/3023 (0%) 1/3010 (0%)
Hepatic steatosis 6/3023 (0.2%) 5/3010 (0.2%)
Hepatitis acute 2/3023 (0.1%) 0/3010 (0%)
Hepatocellular injury 1/3023 (0%) 0/3010 (0%)
Hydrocholecystis 1/3023 (0%) 1/3010 (0%)
Hypertransaminasaemia 2/3023 (0.1%) 0/3010 (0%)
Ischaemic hepatitis 0/3023 (0%) 1/3010 (0%)
Jaundice 1/3023 (0%) 1/3010 (0%)
Jaundice cholestatic 2/3023 (0.1%) 0/3010 (0%)
Liver disorder 1/3023 (0%) 0/3010 (0%)
Liver injury 0/3023 (0%) 1/3010 (0%)
Portal vein thrombosis 0/3023 (0%) 2/3010 (0.1%)
Immune system disorders
Allergy to vaccine 0/3023 (0%) 1/3010 (0%)
Anaphylactic reaction 1/3023 (0%) 1/3010 (0%)
Hypersensitivity 2/3023 (0.1%) 1/3010 (0%)
Infections and infestations
Abdominal abscess 1/3023 (0%) 0/3010 (0%)
Abdominal infection 0/3023 (0%) 1/3010 (0%)
Abscess 1/3023 (0%) 0/3010 (0%)
Abscess intestinal 1/3023 (0%) 0/3010 (0%)
Abscess jaw 1/3023 (0%) 0/3010 (0%)
Abscess limb 3/3023 (0.1%) 3/3010 (0.1%)
Abscess neck 1/3023 (0%) 0/3010 (0%)
Acarodermatitis 0/3023 (0%) 1/3010 (0%)
Actinomycotic pulmonary infection 1/3023 (0%) 0/3010 (0%)
Acute hepatitis C 0/3023 (0%) 1/3010 (0%)
Administration site cellulitis 0/3023 (0%) 1/3010 (0%)
Anal abscess 1/3023 (0%) 2/3010 (0.1%)
Appendiceal abscess 1/3023 (0%) 0/3010 (0%)
Appendicitis 5/3023 (0.2%) 5/3010 (0.2%)
Appendicitis perforated 1/3023 (0%) 0/3010 (0%)
Arthritis bacterial 1/3023 (0%) 4/3010 (0.1%)
Arthritis infective 1/3023 (0%) 1/3010 (0%)
Atypical pneumonia 1/3023 (0%) 0/3010 (0%)
Bacteraemia 4/3023 (0.1%) 1/3010 (0%)
Bacterial sepsis 1/3023 (0%) 2/3010 (0.1%)
Biliary sepsis 0/3023 (0%) 1/3010 (0%)
Body tinea 0/3023 (0%) 1/3010 (0%)
Bronchitis 15/3023 (0.5%) 11/3010 (0.4%)
Campylobacter gastroenteritis 1/3023 (0%) 1/3010 (0%)
Candida sepsis 0/3023 (0%) 1/3010 (0%)
Cellulitis 17/3023 (0.6%) 18/3010 (0.6%)
Cellulitis staphylococcal 0/3023 (0%) 1/3010 (0%)
Cholecystitis infective 1/3023 (0%) 1/3010 (0%)
Chronic tonsillitis 0/3023 (0%) 1/3010 (0%)
Clostridium difficile infection 1/3023 (0%) 0/3010 (0%)
Colon gangrene 1/3023 (0%) 1/3010 (0%)
Conjunctivitis 0/3023 (0%) 1/3010 (0%)
Creutzfeldt-Jakob disease 0/3023 (0%) 2/3010 (0.1%)
Cystitis 0/3023 (0%) 3/3010 (0.1%)
Cystitis escherichia 0/3023 (0%) 1/3010 (0%)
Dengue fever 0/3023 (0%) 3/3010 (0.1%)
Device related infection 0/3023 (0%) 1/3010 (0%)
Device related sepsis 0/3023 (0%) 1/3010 (0%)
Diabetic foot infection 2/3023 (0.1%) 0/3010 (0%)
Diabetic gangrene 1/3023 (0%) 1/3010 (0%)
Diarrhoea infectious 1/3023 (0%) 1/3010 (0%)
Diverticulitis 6/3023 (0.2%) 6/3010 (0.2%)
Empyema 0/3023 (0%) 2/3010 (0.1%)
Encephalitis 0/3023 (0%) 2/3010 (0.1%)
Endocarditis 1/3023 (0%) 1/3010 (0%)
Endocarditis bacterial 1/3023 (0%) 0/3010 (0%)
Enteritis infectious 2/3023 (0.1%) 0/3010 (0%)
Enterococcal sepsis 0/3023 (0%) 1/3010 (0%)
Epididymitis 2/3023 (0.1%) 2/3010 (0.1%)
Epiglottitis 0/3023 (0%) 1/3010 (0%)
Erysipelas 3/3023 (0.1%) 11/3010 (0.4%)
Escherichia sepsis 1/3023 (0%) 0/3010 (0%)
External ear cellulitis 0/3023 (0%) 1/3010 (0%)
Febrile infection 1/3023 (0%) 1/3010 (0%)
Fungal infection 1/3023 (0%) 0/3010 (0%)
Gallbladder abscess 2/3023 (0.1%) 1/3010 (0%)
Gangrene 3/3023 (0.1%) 4/3010 (0.1%)
Gastric ulcer helicobacter 1/3023 (0%) 0/3010 (0%)
Gastroenteritis 17/3023 (0.6%) 17/3010 (0.6%)
Gastroenteritis clostridial 1/3023 (0%) 0/3010 (0%)
Gastroenteritis norovirus 2/3023 (0.1%) 0/3010 (0%)
Gastroenteritis viral 3/3023 (0.1%) 2/3010 (0.1%)
Gastrointestinal infection 1/3023 (0%) 0/3010 (0%)
Gingival abscess 1/3023 (0%) 0/3010 (0%)
Graft infection 0/3023 (0%) 1/3010 (0%)
Groin abscess 2/3023 (0.1%) 0/3010 (0%)
Haematoma infection 1/3023 (0%) 1/3010 (0%)
Haemophilus infection 0/3023 (0%) 1/3010 (0%)
Helicobacter gastritis 2/3023 (0.1%) 1/3010 (0%)
Hepatitis A 1/3023 (0%) 0/3010 (0%)
Hepatitis C 1/3023 (0%) 1/3010 (0%)
Herpes simplex 1/3023 (0%) 0/3010 (0%)
Herpes zoster 1/3023 (0%) 9/3010 (0.3%)
Infected bite 1/3023 (0%) 0/3010 (0%)
Infected dermal cyst 0/3023 (0%) 1/3010 (0%)
Infected skin ulcer 2/3023 (0.1%) 0/3010 (0%)
Infection 1/3023 (0%) 3/3010 (0.1%)
Infectious colitis 0/3023 (0%) 1/3010 (0%)
Infectious pleural effusion 0/3023 (0%) 2/3010 (0.1%)
Infective exacerbation of chronic obstructive airways disease 2/3023 (0.1%) 1/3010 (0%)
Infective spondylitis 1/3023 (0%) 0/3010 (0%)
Influenza 2/3023 (0.1%) 8/3010 (0.3%)
Intervertebral discitis 0/3023 (0%) 1/3010 (0%)
Kidney infection 1/3023 (0%) 0/3010 (0%)
Klebsiella bacteraemia 1/3023 (0%) 0/3010 (0%)
Labyrinthitis 0/3023 (0%) 1/3010 (0%)
Liver abscess 1/3023 (0%) 2/3010 (0.1%)
Localised infection 2/3023 (0.1%) 1/3010 (0%)
Lower respiratory tract infection 4/3023 (0.1%) 4/3010 (0.1%)
Lung infection 1/3023 (0%) 2/3010 (0.1%)
Lymphangitis 0/3023 (0%) 1/3010 (0%)
Mediastinitis 0/3023 (0%) 1/3010 (0%)
Medical device site infection 0/3023 (0%) 1/3010 (0%)
Meningitis 0/3023 (0%) 1/3010 (0%)
Meningitis aseptic 0/3023 (0%) 1/3010 (0%)
Meningitis bacterial 1/3023 (0%) 1/3010 (0%)
Meningitis viral 1/3023 (0%) 0/3010 (0%)
Meningoencephalitis viral 0/3023 (0%) 1/3010 (0%)
Morganella infection 1/3023 (0%) 0/3010 (0%)
Nasopharyngitis 0/3023 (0%) 2/3010 (0.1%)
Necrotising fasciitis 0/3023 (0%) 1/3010 (0%)
Nosocomial infection 1/3023 (0%) 0/3010 (0%)
Oesophageal candidiasis 1/3023 (0%) 0/3010 (0%)
Orchitis 0/3023 (0%) 2/3010 (0.1%)
Osteomyelitis 8/3023 (0.3%) 3/3010 (0.1%)
Osteomyelitis chronic 1/3023 (0%) 0/3010 (0%)
Osteomyelitis fungal 1/3023 (0%) 0/3010 (0%)
Otitis media 1/3023 (0%) 0/3010 (0%)
Otitis media chronic 0/3023 (0%) 1/3010 (0%)
Parotitis 0/3023 (0%) 1/3010 (0%)
Pelvic abscess 1/3023 (0%) 0/3010 (0%)
Perichondritis 0/3023 (0%) 1/3010 (0%)
Periodontitis 0/3023 (0%) 1/3010 (0%)
Peritonitis 1/3023 (0%) 1/3010 (0%)
Peritonsillar abscess 0/3023 (0%) 2/3010 (0.1%)
Pneumonia 83/3023 (2.7%) 83/3010 (2.8%)
Pneumonia bacterial 3/3023 (0.1%) 0/3010 (0%)
Pneumonia necrotising 1/3023 (0%) 0/3010 (0%)
Pneumonia pneumococcal 2/3023 (0.1%) 0/3010 (0%)
Pneumonia viral 0/3023 (0%) 1/3010 (0%)
Post procedural cellulitis 0/3023 (0%) 1/3010 (0%)
Post procedural infection 1/3023 (0%) 3/3010 (0.1%)
Postoperative abscess 1/3023 (0%) 0/3010 (0%)
Postoperative wound infection 3/3023 (0.1%) 4/3010 (0.1%)
Pseudomembranous colitis 1/3023 (0%) 0/3010 (0%)
Purulence 0/3023 (0%) 1/3010 (0%)
Pyelitis 1/3023 (0%) 0/3010 (0%)
Pyelonephritis 8/3023 (0.3%) 4/3010 (0.1%)
Pyelonephritis acute 4/3023 (0.1%) 2/3010 (0.1%)
Pyelonephritis fungal 1/3023 (0%) 0/3010 (0%)
Pyonephrosis 0/3023 (0%) 1/3010 (0%)
Respiratory tract infection 2/3023 (0.1%) 7/3010 (0.2%)
Respiratory tract infection viral 0/3023 (0%) 1/3010 (0%)
Retroperitoneal abscess 0/3023 (0%) 1/3010 (0%)
Rotavirus infection 0/3023 (0%) 1/3010 (0%)
Salmonellosis 0/3023 (0%) 1/3010 (0%)
Scrotal abscess 0/3023 (0%) 1/3010 (0%)
Scrub typhus 1/3023 (0%) 0/3010 (0%)
Sepsis 17/3023 (0.6%) 24/3010 (0.8%)
Septic arthritis streptococcal 1/3023 (0%) 0/3010 (0%)
Septic shock 6/3023 (0.2%) 7/3010 (0.2%)
Sialoadenitis 1/3023 (0%) 0/3010 (0%)
Sinusitis 1/3023 (0%) 1/3010 (0%)
Small intestine gangrene 0/3023 (0%) 1/3010 (0%)
Soft tissue infection 1/3023 (0%) 1/3010 (0%)
Staphylococcal bacteraemia 0/3023 (0%) 2/3010 (0.1%)
Staphylococcal infection 1/3023 (0%) 1/3010 (0%)
Subcutaneous abscess 0/3023 (0%) 1/3010 (0%)
Tooth abscess 1/3023 (0%) 2/3010 (0.1%)
Tooth infection 0/3023 (0%) 1/3010 (0%)
Tracheobronchitis 1/3023 (0%) 0/3010 (0%)
Tuberculosis 1/3023 (0%) 0/3010 (0%)
Upper respiratory tract infection 5/3023 (0.2%) 3/3010 (0.1%)
Ureteritis 2/3023 (0.1%) 0/3010 (0%)
Urethritis 0/3023 (0%) 1/3010 (0%)
Urinary tract infection 30/3023 (1%) 31/3010 (1%)
Urinary tract infection bacterial 1/3023 (0%) 0/3010 (0%)
Urinary tract infection enterococcal 0/3023 (0%) 1/3010 (0%)
Urinary tract infection fungal 1/3023 (0%) 0/3010 (0%)
Urosepsis 7/3023 (0.2%) 6/3010 (0.2%)
Varicella 0/3023 (0%) 1/3010 (0%)
Vestibular neuronitis 1/3023 (0%) 1/3010 (0%)
Viral infection 1/3023 (0%) 2/3010 (0.1%)
Vulval abscess 1/3023 (0%) 0/3010 (0%)
Wound infection 2/3023 (0.1%) 4/3010 (0.1%)
Injury, poisoning and procedural complications
Accident 1/3023 (0%) 3/3010 (0.1%)
Anaemia postoperative 0/3023 (0%) 1/3010 (0%)
Anaesthetic complication cardiac 0/3023 (0%) 1/3010 (0%)
Anastomotic leak 1/3023 (0%) 0/3010 (0%)
Ankle fracture 6/3023 (0.2%) 11/3010 (0.4%)
Arterial restenosis 1/3023 (0%) 0/3010 (0%)
Arthropod sting 0/3023 (0%) 1/3010 (0%)
Back injury 0/3023 (0%) 1/3010 (0%)
Bladder injury 1/3023 (0%) 0/3010 (0%)
Bone contusion 0/3023 (0%) 1/3010 (0%)
Bone fragmentation 1/3023 (0%) 0/3010 (0%)
Brain contusion 2/3023 (0.1%) 1/3010 (0%)
Brain herniation 0/3023 (0%) 1/3010 (0%)
Burns second degree 0/3023 (0%) 1/3010 (0%)
Carbon monoxide poisoning 0/3023 (0%) 1/3010 (0%)
Cardiac valve replacement complication 0/3023 (0%) 1/3010 (0%)
Carotid artery restenosis 0/3023 (0%) 1/3010 (0%)
Cartilage injury 1/3023 (0%) 0/3010 (0%)
Cervical vertebral fracture 2/3023 (0.1%) 0/3010 (0%)
Chemical burn 0/3023 (0%) 1/3010 (0%)
Chest injury 1/3023 (0%) 0/3010 (0%)
Comminuted fracture 0/3023 (0%) 1/3010 (0%)
Concussion 1/3023 (0%) 3/3010 (0.1%)
Conjunctival laceration 0/3023 (0%) 1/3010 (0%)
Contusion 4/3023 (0.1%) 5/3010 (0.2%)
Coronary artery reocclusion 0/3023 (0%) 1/3010 (0%)
Coronary artery restenosis 0/3023 (0%) 3/3010 (0.1%)
Craniocerebral injury 5/3023 (0.2%) 1/3010 (0%)
Crush injury 0/3023 (0%) 1/3010 (0%)
Extradural haematoma 1/3023 (0%) 0/3010 (0%)
Eye contusion 1/3023 (0%) 0/3010 (0%)
Face injury 0/3023 (0%) 1/3010 (0%)
Facial bones fracture 1/3023 (0%) 2/3010 (0.1%)
Fall 31/3023 (1%) 44/3010 (1.5%)
Femoral neck fracture 4/3023 (0.1%) 4/3010 (0.1%)
Femur fracture 9/3023 (0.3%) 6/3010 (0.2%)
Fibula fracture 1/3023 (0%) 2/3010 (0.1%)
Foot fracture 1/3023 (0%) 4/3010 (0.1%)
Forearm fracture 1/3023 (0%) 1/3010 (0%)
Fracture 0/3023 (0%) 1/3010 (0%)
Fracture displacement 0/3023 (0%) 3/3010 (0.1%)
Fracture of penis 1/3023 (0%) 0/3010 (0%)
Graft thrombosis 0/3023 (0%) 1/3010 (0%)
Hand fracture 2/3023 (0.1%) 2/3010 (0.1%)
Head injury 5/3023 (0.2%) 4/3010 (0.1%)
Hip fracture 7/3023 (0.2%) 16/3010 (0.5%)
Humerus fracture 1/3023 (0%) 6/3010 (0.2%)
Ilium fracture 1/3023 (0%) 0/3010 (0%)
Impacted fracture 1/3023 (0%) 1/3010 (0%)
Incarcerated incisional hernia 1/3023 (0%) 0/3010 (0%)
Incisional hernia 3/3023 (0.1%) 1/3010 (0%)
Inflammation of wound 0/3023 (0%) 1/3010 (0%)
Injury 0/3023 (0%) 1/3010 (0%)
Injury corneal 0/3023 (0%) 1/3010 (0%)
Intentional overdose 1/3023 (0%) 0/3010 (0%)
Jaw fracture 0/3023 (0%) 1/3010 (0%)
Joint dislocation 6/3023 (0.2%) 6/3010 (0.2%)
Laceration 1/3023 (0%) 0/3010 (0%)
Ligament rupture 5/3023 (0.2%) 0/3010 (0%)
Ligament sprain 1/3023 (0%) 4/3010 (0.1%)
Limb injury 2/3023 (0.1%) 3/3010 (0.1%)
Limb traumatic amputation 1/3023 (0%) 1/3010 (0%)
Lower limb fracture 7/3023 (0.2%) 5/3010 (0.2%)
Lumbar vertebral fracture 3/3023 (0.1%) 2/3010 (0.1%)
Meniscus injury 6/3023 (0.2%) 4/3010 (0.1%)
Multiple fractures 1/3023 (0%) 1/3010 (0%)
Multiple injuries 1/3023 (0%) 0/3010 (0%)
Muscle rupture 1/3023 (0%) 2/3010 (0.1%)
Muscle strain 0/3023 (0%) 1/3010 (0%)
Overdose 4/3023 (0.1%) 1/3010 (0%)
Patella fracture 2/3023 (0.1%) 0/3010 (0%)
Pelvic fracture 0/3023 (0%) 1/3010 (0%)
Pneumoconiosis 0/3023 (0%) 1/3010 (0%)
Post procedural bile leak 1/3023 (0%) 0/3010 (0%)
Post procedural fistula 0/3023 (0%) 1/3010 (0%)
Post procedural haemorrhage 1/3023 (0%) 0/3010 (0%)
Post procedural inflammation 1/3023 (0%) 1/3010 (0%)
Post procedural urine leak 0/3023 (0%) 1/3010 (0%)
Postoperative ileus 1/3023 (0%) 0/3010 (0%)
Postoperative renal failure 0/3023 (0%) 1/3010 (0%)
Postpericardiotomy syndrome 1/3023 (0%) 0/3010 (0%)
Procedural haemorrhage 1/3023 (0%) 0/3010 (0%)
Procedural pain 0/3023 (0%) 1/3010 (0%)
Procedural pneumothorax 0/3023 (0%) 1/3010 (0%)
Pubis fracture 2/3023 (0.1%) 1/3010 (0%)
Pulmonary contusion 1/3023 (0%) 0/3010 (0%)
Radius fracture 2/3023 (0.1%) 6/3010 (0.2%)
Rib fracture 5/3023 (0.2%) 4/3010 (0.1%)
Road traffic accident 13/3023 (0.4%) 7/3010 (0.2%)
Scar 0/3023 (0%) 1/3010 (0%)
Shunt occlusion 1/3023 (0%) 0/3010 (0%)
Skin abrasion 0/3023 (0%) 1/3010 (0%)
Skull fracture 0/3023 (0%) 1/3010 (0%)
Soft tissue injury 0/3023 (0%) 2/3010 (0.1%)
Spinal compression fracture 8/3023 (0.3%) 1/3010 (0%)
Spinal cord injury cervical 1/3023 (0%) 0/3010 (0%)
Spinal fracture 2/3023 (0.1%) 4/3010 (0.1%)
Splenic injury 1/3023 (0%) 0/3010 (0%)
Stab wound 1/3023 (0%) 0/3010 (0%)
Sternal fracture 0/3023 (0%) 1/3010 (0%)
Subarachnoid haemorrhage 5/3023 (0.2%) 5/3010 (0.2%)
Subdural haematoma 5/3023 (0.2%) 7/3010 (0.2%)
Subdural haemorrhage 5/3023 (0.2%) 1/3010 (0%)
Tendon injury 0/3023 (0%) 1/3010 (0%)
Tendon rupture 6/3023 (0.2%) 3/3010 (0.1%)
Thoracic vertebral fracture 2/3023 (0.1%) 0/3010 (0%)
Tibia fracture 3/3023 (0.1%) 1/3010 (0%)
Toxicity to various agents 0/3023 (0%) 2/3010 (0.1%)
Transplant dysfunction 0/3023 (0%) 1/3010 (0%)
Traumatic arthritis 1/3023 (0%) 0/3010 (0%)
Traumatic intracranial haemorrhage 2/3023 (0.1%) 0/3010 (0%)
Ulna fracture 1/3023 (0%) 3/3010 (0.1%)
Upper limb fracture 2/3023 (0.1%) 2/3010 (0.1%)
Urethral injury 1/3023 (0%) 0/3010 (0%)
Vascular graft occlusion 1/3023 (0%) 1/3010 (0%)
Vascular pseudoaneurysm 1/3023 (0%) 0/3010 (0%)
Wound 2/3023 (0.1%) 2/3010 (0.1%)
Wound dehiscence 2/3023 (0.1%) 0/3010 (0%)
Wound necrosis 1/3023 (0%) 0/3010 (0%)
Wrist fracture 1/3023 (0%) 1/3010 (0%)
Investigations
Alanine aminotransferase increased 6/3023 (0.2%) 7/3010 (0.2%)
Amylase increased 3/3023 (0.1%) 0/3010 (0%)
Anticoagulation drug level below therapeutic 0/3023 (0%) 1/3010 (0%)
Arteriogram coronary 1/3023 (0%) 0/3010 (0%)
Aspartate aminotransferase increased 6/3023 (0.2%) 7/3010 (0.2%)
Blood alkaline phosphatase increased 0/3023 (0%) 2/3010 (0.1%)
Blood bilirubin increased 0/3023 (0%) 1/3010 (0%)
Blood creatine phosphokinase MB increased 0/3023 (0%) 1/3010 (0%)
Blood creatinine increased 12/3023 (0.4%) 11/3010 (0.4%)
Blood pressure decreased 1/3023 (0%) 0/3010 (0%)
Blood pressure increased 1/3023 (0%) 0/3010 (0%)
Body temperature increased 1/3023 (0%) 0/3010 (0%)
Cardiac stress test abnormal 1/3023 (0%) 0/3010 (0%)
Computerised tomogram head abnormal 1/3023 (0%) 0/3010 (0%)
Electrocardiogram QT prolonged 2/3023 (0.1%) 0/3010 (0%)
Electrocardiogram ST segment depression 1/3023 (0%) 0/3010 (0%)
Electrocardiogram T wave inversion 2/3023 (0.1%) 2/3010 (0.1%)
Electrocardiogram abnormal 1/3023 (0%) 0/3010 (0%)
Electrocardiogram ambulatory abnormal 1/3023 (0%) 0/3010 (0%)
Full blood count decreased 1/3023 (0%) 0/3010 (0%)
Gamma-glutamyltransferase increased 7/3023 (0.2%) 7/3010 (0.2%)
Glomerular filtration rate decreased 0/3023 (0%) 1/3010 (0%)
Haemoglobin decreased 0/3023 (0%) 2/3010 (0.1%)
Heart rate decreased 0/3023 (0%) 1/3010 (0%)
Hepatic enzyme increased 2/3023 (0.1%) 1/3010 (0%)
Hepatitis C virus test 1/3023 (0%) 0/3010 (0%)
International normalised ratio decreased 1/3023 (0%) 1/3010 (0%)
International normalised ratio increased 3/3023 (0.1%) 0/3010 (0%)
Lipase increased 3/3023 (0.1%) 1/3010 (0%)
Liver function test abnormal 0/3023 (0%) 2/3010 (0.1%)
Liver function test increased 1/3023 (0%) 1/3010 (0%)
Myelocyte count increased 0/3023 (0%) 1/3010 (0%)
Positron emission tomogram abnormal 0/3023 (0%) 1/3010 (0%)
Prostatic specific antigen increased 1/3023 (0%) 0/3010 (0%)
Transaminases increased 1/3023 (0%) 0/3010 (0%)
Troponin increased 4/3023 (0.1%) 1/3010 (0%)
Urine albumin/creatinine ratio increased 0/3023 (0%) 1/3010 (0%)
Weight decreased 1/3023 (0%) 1/3010 (0%)
Weight increased 0/3023 (0%) 1/3010 (0%)
White blood cell count increased 0/3023 (0%) 1/3010 (0%)
Metabolism and nutrition disorders
Acidosis 1/3023 (0%) 0/3010 (0%)
Decreased appetite 2/3023 (0.1%) 0/3010 (0%)
Dehydration 13/3023 (0.4%) 10/3010 (0.3%)
Diabetes mellitus 3/3023 (0.1%) 2/3010 (0.1%)
Diabetes mellitus inadequate control 2/3023 (0.1%) 3/3010 (0.1%)
Diabetic metabolic decompensation 0/3023 (0%) 2/3010 (0.1%)
Fluid overload 2/3023 (0.1%) 2/3010 (0.1%)
Gout 4/3023 (0.1%) 1/3010 (0%)
Hypercholesterolaemia 2/3023 (0.1%) 0/3010 (0%)
Hyperglycaemia 6/3023 (0.2%) 8/3010 (0.3%)
Hyperglycaemic hyperosmolar nonketotic syndrome 1/3023 (0%) 1/3010 (0%)
Hyperkalaemia 7/3023 (0.2%) 4/3010 (0.1%)
Hypocalcaemia 0/3023 (0%) 2/3010 (0.1%)
Hypochloraemia 1/3023 (0%) 0/3010 (0%)
Hypoglycaemia 3/3023 (0.1%) 29/3010 (1%)
Hypokalaemia 4/3023 (0.1%) 1/3010 (0%)
Hypomagnesaemia 1/3023 (0%) 0/3010 (0%)
Hyponatraemia 6/3023 (0.2%) 4/3010 (0.1%)
Hypophagia 1/3023 (0%) 0/3010 (0%)
Lactic acidosis 1/3023 (0%) 1/3010 (0%)
Malnutrition 1/3023 (0%) 1/3010 (0%)
Metabolic acidosis 4/3023 (0.1%) 1/3010 (0%)
Metabolic disorder 0/3023 (0%) 1/3010 (0%)
Obesity 0/3023 (0%) 5/3010 (0.2%)
Musculoskeletal and connective tissue disorders
Arthralgia 6/3023 (0.2%) 9/3010 (0.3%)
Arthritis 6/3023 (0.2%) 4/3010 (0.1%)
Arthritis reactive 1/3023 (0%) 0/3010 (0%)
Arthropathy 4/3023 (0.1%) 1/3010 (0%)
Back pain 6/3023 (0.2%) 8/3010 (0.3%)
Bone atrophy 1/3023 (0%) 0/3010 (0%)
Bursitis 1/3023 (0%) 1/3010 (0%)
Cervical spinal stenosis 1/3023 (0%) 0/3010 (0%)
Compartment syndrome 1/3023 (0%) 0/3010 (0%)
Costochondritis 0/3023 (0%) 2/3010 (0.1%)
Dupuytren's contracture 1/3023 (0%) 0/3010 (0%)
Facet joint syndrome 1/3023 (0%) 0/3010 (0%)
Fibromyalgia 0/3023 (0%) 1/3010 (0%)
Flank pain 0/3023 (0%) 1/3010 (0%)
Foot deformity 3/3023 (0.1%) 1/3010 (0%)
Gouty arthritis 4/3023 (0.1%) 0/3010 (0%)
Groin pain 0/3023 (0%) 1/3010 (0%)
Haemarthrosis 1/3023 (0%) 1/3010 (0%)
Intervertebral disc degeneration 1/3023 (0%) 3/3010 (0.1%)
Intervertebral disc disorder 2/3023 (0.1%) 1/3010 (0%)
Intervertebral disc protrusion 8/3023 (0.3%) 12/3010 (0.4%)
Joint effusion 1/3023 (0%) 1/3010 (0%)
Joint swelling 1/3023 (0%) 1/3010 (0%)
Limb deformity 0/3023 (0%) 1/3010 (0%)
Lumbar spinal stenosis 11/3023 (0.4%) 7/3010 (0.2%)
Mobility decreased 1/3023 (0%) 2/3010 (0.1%)
Muscle haemorrhage 0/3023 (0%) 1/3010 (0%)
Muscular weakness 1/3023 (0%) 3/3010 (0.1%)
Musculoskeletal chest pain 2/3023 (0.1%) 1/3010 (0%)
Musculoskeletal pain 4/3023 (0.1%) 1/3010 (0%)
Myalgia 1/3023 (0%) 0/3010 (0%)
Neck pain 0/3023 (0%) 2/3010 (0.1%)
Osteoarthritis 49/3023 (1.6%) 63/3010 (2.1%)
Osteolysis 1/3023 (0%) 1/3010 (0%)
Osteonecrosis 0/3023 (0%) 3/3010 (0.1%)
Osteoporosis 1/3023 (0%) 0/3010 (0%)
Pain in extremity 3/3023 (0.1%) 1/3010 (0%)
Pathological fracture 2/3023 (0.1%) 1/3010 (0%)
Periarthritis 1/3023 (0%) 0/3010 (0%)
Polyarthritis 1/3023 (0%) 0/3010 (0%)
Polymyalgia rheumatica 9/3023 (0.3%) 13/3010 (0.4%)
Pseudarthrosis 0/3023 (0%) 1/3010 (0%)
Psoriatic arthropathy 0/3023 (0%) 1/3010 (0%)
Rhabdomyolysis 4/3023 (0.1%) 3/3010 (0.1%)
Rheumatoid arthritis 0/3023 (0%) 2/3010 (0.1%)
Rotator cuff syndrome 7/3023 (0.2%) 5/3010 (0.2%)
Scoliosis 1/3023 (0%) 1/3010 (0%)
Sjogren's syndrome 1/3023 (0%) 1/3010 (0%)
Spinal column stenosis 4/3023 (0.1%) 12/3010 (0.4%)
Spinal disorder 0/3023 (0%) 1/3010 (0%)
Spinal ligament ossification 1/3023 (0%) 0/3010 (0%)
Spinal osteoarthritis 5/3023 (0.2%) 8/3010 (0.3%)
Spinal pain 2/3023 (0.1%) 2/3010 (0.1%)
Spondylitis 1/3023 (0%) 0/3010 (0%)
Spondylolisthesis 3/3023 (0.1%) 2/3010 (0.1%)
Synovial cyst 1/3023 (0%) 1/3010 (0%)
Systemic lupus erythematosus 1/3023 (0%) 0/3010 (0%)
Tendon disorder 1/3023 (0%) 0/3010 (0%)
Tenosynovitis 1/3023 (0%) 0/3010 (0%)
Trigger finger 1/3023 (0%) 0/3010 (0%)
Vertebral foraminal stenosis 0/3023 (0%) 2/3010 (0.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute leukaemia 0/3023 (0%) 1/3010 (0%)
Acute lymphocytic leukaemia 0/3023 (0%) 1/3010 (0%)
Acute promyelocytic leukaemia 0/3023 (0%) 1/3010 (0%)
Adenocarcinoma 1/3023 (0%) 0/3010 (0%)
Adenocarcinoma gastric 1/3023 (0%) 0/3010 (0%)
Adenocarcinoma of appendix 1/3023 (0%) 0/3010 (0%)
Adenocarcinoma of colon 8/3023 (0.3%) 7/3010 (0.2%)
Adenocarcinoma pancreas 2/3023 (0.1%) 1/3010 (0%)
Adenoma benign 1/3023 (0%) 1/3010 (0%)
Adrenal neoplasm 0/3023 (0%) 1/3010 (0%)
Anal cancer 0/3023 (0%) 1/3010 (0%)
Angiosarcoma 1/3023 (0%) 0/3010 (0%)
B-cell lymphoma 1/3023 (0%) 1/3010 (0%)
Basal cell carcinoma 39/3023 (1.3%) 33/3010 (1.1%)
Basosquamous carcinoma of skin 1/3023 (0%) 0/3010 (0%)
Bile duct cancer 1/3023 (0%) 1/3010 (0%)
Bladder cancer 4/3023 (0.1%) 8/3010 (0.3%)
Bladder cancer recurrent 0/3023 (0%) 2/3010 (0.1%)
Bladder papilloma 0/3023 (0%) 1/3010 (0%)
Bladder transitional cell carcinoma 2/3023 (0.1%) 8/3010 (0.3%)
Bladder transitional cell carcinoma recurrent 0/3023 (0%) 1/3010 (0%)
Bowen's disease 5/3023 (0.2%) 5/3010 (0.2%)
Brain neoplasm 0/3023 (0%) 2/3010 (0.1%)
Brain neoplasm benign 1/3023 (0%) 0/3010 (0%)
Breast cancer 12/3023 (0.4%) 9/3010 (0.3%)
Breast cancer metastatic 1/3023 (0%) 1/3010 (0%)
Breast cancer stage IV 1/3023 (0%) 0/3010 (0%)
Breast neoplasm 1/3023 (0%) 0/3010 (0%)
Bronchial carcinoma 0/3023 (0%) 2/3010 (0.1%)
Carcinoid tumour pulmonary 0/3023 (0%) 1/3010 (0%)
Carcinoma in situ of skin 1/3023 (0%) 0/3010 (0%)
Central nervous system lymphoma 1/3023 (0%) 0/3010 (0%)
Cervix carcinoma 0/3023 (0%) 1/3010 (0%)
Cholangiocarcinoma 2/3023 (0.1%) 1/3010 (0%)
Chronic lymphocytic leukaemia 2/3023 (0.1%) 3/3010 (0.1%)
Chronic myeloid leukaemia 1/3023 (0%) 1/3010 (0%)
Colon adenoma 2/3023 (0.1%) 1/3010 (0%)
Colon cancer 12/3023 (0.4%) 5/3010 (0.2%)
Colon cancer metastatic 0/3023 (0%) 2/3010 (0.1%)
Colon neoplasm 0/3023 (0%) 1/3010 (0%)
Colorectal adenocarcinoma 2/3023 (0.1%) 0/3010 (0%)
Colorectal cancer 1/3023 (0%) 0/3010 (0%)
Conjunctival melanoma 1/3023 (0%) 0/3010 (0%)
Cutaneous lymphoma 0/3023 (0%) 1/3010 (0%)
Diffuse large B-cell lymphoma 1/3023 (0%) 0/3010 (0%)
Dysplastic naevus 2/3023 (0.1%) 0/3010 (0%)
Enchondromatosis 1/3023 (0%) 0/3010 (0%)
Endometrial adenocarcinoma 2/3023 (0.1%) 0/3010 (0%)
Endometrial cancer 2/3023 (0.1%) 2/3010 (0.1%)
Ependymoma benign 1/3023 (0%) 0/3010 (0%)
Essential thrombocythaemia 1/3023 (0%) 0/3010 (0%)
Fibrous histiocytoma 0/3023 (0%) 1/3010 (0%)
Gallbladder adenocarcinoma 1/3023 (0%) 0/3010 (0%)
Gallbladder cancer 0/3023 (0%) 1/3010 (0%)
Gastric adenoma 1/3023 (0%) 0/3010 (0%)
Gastric cancer 6/3023 (0.2%) 3/3010 (0.1%)
Gastrointestinal carcinoma 1/3023 (0%) 0/3010 (0%)
Gastrointestinal melanoma 0/3023 (0%) 1/3010 (0%)
Gastrointestinal stromal tumour 0/3023 (0%) 2/3010 (0.1%)
Gastrointestinal tract adenoma 1/3023 (0%) 0/3010 (0%)
Gastrooesophageal cancer 0/3023 (0%) 1/3010 (0%)
Glioblastoma 1/3023 (0%) 0/3010 (0%)
Haemangioma 1/3023 (0%) 0/3010 (0%)
Hairy cell leukaemia 1/3023 (0%) 0/3010 (0%)
Hepatic cancer 0/3023 (0%) 2/3010 (0.1%)
Hepatocellular carcinoma 1/3023 (0%) 3/3010 (0.1%)
Hodgkin's disease 1/3023 (0%) 0/3010 (0%)
Hypopharyngeal neoplasm 1/3023 (0%) 0/3010 (0%)
Intestinal adenocarcinoma 0/3023 (0%) 1/3010 (0%)
Intraductal papillary mucinous neoplasm 2/3023 (0.1%) 1/3010 (0%)
Intraductal proliferative breast lesion 2/3023 (0.1%) 0/3010 (0%)
Invasive ductal breast carcinoma 1/3023 (0%) 3/3010 (0.1%)
Invasive lobular breast carcinoma 1/3023 (0%) 1/3010 (0%)
Keratoacanthoma 2/3023 (0.1%) 1/3010 (0%)
Laryngeal cancer 3/3023 (0.1%) 0/3010 (0%)
Laryngeal squamous cell carcinoma 1/3023 (0%) 0/3010 (0%)
Leiomyoma 1/3023 (0%) 0/3010 (0%)
Lentigo maligna 2/3023 (0.1%) 1/3010 (0%)
Lentigo maligna recurrent 1/3023 (0%) 0/3010 (0%)
Leukaemia 1/3023 (0%) 0/3010 (0%)
Lipoma 0/3023 (0%) 1/3010 (0%)
Lung adenocarcinoma 4/3023 (0.1%) 8/3010 (0.3%)
Lung adenocarcinoma stage I 0/3023 (0%) 1/3010 (0%)
Lung adenocarcinoma stage II 0/3023 (0%) 1/3010 (0%)
Lung adenocarcinoma stage IV 1/3023 (0%) 0/3010 (0%)
Lung cancer metastatic 2/3023 (0.1%) 1/3010 (0%)
Lung carcinoma cell type unspecified stage III 0/3023 (0%) 1/3010 (0%)
Lung neoplasm 1/3023 (0%) 0/3010 (0%)
Lung neoplasm malignant 10/3023 (0.3%) 6/3010 (0.2%)
Lung squamous cell carcinoma metastatic 0/3023 (0%) 1/3010 (0%)
Lung squamous cell carcinoma stage III 1/3023 (0%) 0/3010 (0%)
Lymphocytic leukaemia 0/3023 (0%) 1/3010 (0%)
Lymphoma 1/3023 (0%) 2/3010 (0.1%)
Malignant ascites 0/3023 (0%) 1/3010 (0%)
Malignant melanoma 7/3023 (0.2%) 2/3010 (0.1%)
Malignant melanoma in situ 0/3023 (0%) 1/3010 (0%)
Malignant neoplasm of unknown primary site 0/3023 (0%) 1/3010 (0%)
Malignant neoplasm progression 0/3023 (0%) 1/3010 (0%)
Malignant polyp 0/3023 (0%) 1/3010 (0%)
Mantle cell lymphoma 0/3023 (0%) 1/3010 (0%)
Meningioma 1/3023 (0%) 3/3010 (0.1%)
Meningioma benign 0/3023 (0%) 1/3010 (0%)
Mesothelioma 0/3023 (0%) 1/3010 (0%)
Metastases to bladder 1/3023 (0%) 0/3010 (0%)
Metastases to bone 2/3023 (0.1%) 2/3010 (0.1%)
Metastases to liver 5/3023 (0.2%) 3/3010 (0.1%)
Metastases to lung 3/3023 (0.1%) 2/3010 (0.1%)
Metastases to lymph nodes 5/3023 (0.2%) 3/3010 (0.1%)
Metastases to peritoneum 0/3023 (0%) 1/3010 (0%)
Metastasis 1/3023 (0%) 0/3010 (0%)
Metastatic gastric cancer 2/3023 (0.1%) 0/3010 (0%)
Metastatic malignant melanoma 0/3023 (0%) 1/3010 (0%)
Metastatic neoplasm 2/3023 (0.1%) 0/3010 (0%)
Mucinous adenocarcinoma of appendix 0/3023 (0%) 1/3010 (0%)
Mycosis fungoides 1/3023 (0%) 0/3010 (0%)
Myelodysplastic syndrome 1/3023 (0%) 1/3010 (0%)
Myxofibrosarcoma 0/3023 (0%) 1/3010 (0%)
Nasopharyngeal cancer 1/3023 (0%) 0/3010 (0%)
Neoplasm malignant 0/3023 (0%) 1/3010 (0%)
Neoplasm prostate 1/3023 (0%) 0/3010 (0%)
Neoplasm skin 0/3023 (0%) 1/3010 (0%)
Neurofibroma 0/3023 (0%) 1/3010 (0%)
Non-Hodgkin's lymphoma 2/3023 (0.1%) 1/3010 (0%)
Non-small cell lung cancer 0/3023 (0%) 3/3010 (0.1%)
Non-small cell lung cancer metastatic 1/3023 (0%) 0/3010 (0%)
Non-small cell lung cancer stage IV 1/3023 (0%) 0/3010 (0%)
Oesophageal carcinoma 0/3023 (0%) 3/3010 (0.1%)
Oesophageal squamous cell carcinoma 0/3023 (0%) 1/3010 (0%)
Oral papilloma 0/3023 (0%) 1/3010 (0%)
Oropharyngeal cancer 0/3023 (0%) 1/3010 (0%)
Ovarian cancer 2/3023 (0.1%) 1/3010 (0%)
Ovarian cancer metastatic 0/3023 (0%) 1/3010 (0%)
Ovarian epithelial cancer 0/3023 (0%) 1/3010 (0%)
Pancreatic carcinoma 9/3023 (0.3%) 9/3010 (0.3%)
Pancreatic carcinoma metastatic 0/3023 (0%) 3/3010 (0.1%)
Pancreatic carcinoma stage IV 0/3023 (0%) 1/3010 (0%)
Pancreatic neoplasm 0/3023 (0%) 1/3010 (0%)
Papillary thyroid cancer 0/3023 (0%) 2/3010 (0.1%)
Paranasal sinus and nasal cavity malignant neoplasm 1/3023 (0%) 0/3010 (0%)
Pituitary tumour 0/3023 (0%) 1/3010 (0%)
Pituitary tumour benign 0/3023 (0%) 2/3010 (0.1%)
Plasma cell myeloma 1/3023 (0%) 6/3010 (0.2%)
Plasmacytoma 0/3023 (0%) 1/3010 (0%)
Pleural sarcoma 1/3023 (0%) 0/3010 (0%)
Porocarcinoma 0/3023 (0%) 1/3010 (0%)
Prolactin-producing pituitary tumour 0/3023 (0%) 1/3010 (0%)
Prostate cancer 28/3023 (0.9%) 29/3010 (1%)
Prostate cancer metastatic 0/3023 (0%) 3/3010 (0.1%)
Prostate cancer recurrent 0/3023 (0%) 3/3010 (0.1%)
Prostate cancer stage 0 1/3023 (0%) 0/3010 (0%)
Prostatic adenoma 1/3023 (0%) 4/3010 (0.1%)
Rectal adenocarcinoma 0/3023 (0%) 1/3010 (0%)
Rectal adenoma 1/3023 (0%) 0/3010 (0%)
Rectal cancer 2/3023 (0.1%) 5/3010 (0.2%)
Rectal cancer metastatic 1/3023 (0%) 0/3010 (0%)
Rectosigmoid cancer 1/3023 (0%) 1/3010 (0%)
Refractory anaemia with ringed sideroblasts 0/3023 (0%) 1/3010 (0%)
Renal cancer 3/3023 (0.1%) 6/3010 (0.2%)
Renal cell carcinoma 6/3023 (0.2%) 2/3010 (0.1%)
Renal neoplasm 1/3023 (0%) 1/3010 (0%)
Salivary gland neoplasm 1/3023 (0%) 0/3010 (0%)
Sebaceous carcinoma 0/3023 (0%) 1/3010 (0%)
Seborrhoeic keratosis 0/3023 (0%) 2/3010 (0.1%)
Skin angiosarcoma 1/3023 (0%) 0/3010 (0%)
Skin cancer 1/3023 (0%) 0/3010 (0%)
Small cell lung cancer 1/3023 (0%) 0/3010 (0%)
Small cell lung cancer metastatic 0/3023 (0%) 1/3010 (0%)
Small intestine adenocarcinoma 0/3023 (0%) 1/3010 (0%)
Small intestine carcinoma 0/3023 (0%) 2/3010 (0.1%)
Soft tissue sarcoma 1/3023 (0%) 0/3010 (0%)
Squamous cell carcinoma 6/3023 (0.2%) 6/3010 (0.2%)
Squamous cell carcinoma of lung 6/3023 (0.2%) 3/3010 (0.1%)
Squamous cell carcinoma of skin 13/3023 (0.4%) 16/3010 (0.5%)
Squamous cell carcinoma of the cervix 0/3023 (0%) 1/3010 (0%)
Squamous cell carcinoma of the hypopharynx 1/3023 (0%) 0/3010 (0%)
Squamous cell carcinoma of the oral cavity 1/3023 (0%) 0/3010 (0%)
Squamous cell carcinoma of the tongue 0/3023 (0%) 1/3010 (0%)
Squamous cell carcinoma of the vulva 1/3023 (0%) 1/3010 (0%)
Thymoma 0/3023 (0%) 1/3010 (0%)
Thyroid cancer 0/3023 (0%) 1/3010 (0%)
Transitional cell cancer of the renal pelvis and ureter 1/3023 (0%) 0/3010 (0%)
Transitional cell carcinoma 2/3023 (0.1%) 2/3010 (0.1%)
Tumour ulceration 0/3023 (0%) 1/3010 (0%)
Uterine cancer 1/3023 (0%) 1/3010 (0%)
Uterine leiomyoma 1/3023 (0%) 2/3010 (0.1%)
Vipoma 0/3023 (0%) 1/3010 (0%)
Waldenstrom's macroglobulinaemia 1/3023 (0%) 0/3010 (0%)
Nervous system disorders
Altered state of consciousness 0/3023 (0%) 1/3010 (0%)
Amyotrophic lateral sclerosis 2/3023 (0.1%) 1/3010 (0%)
Aphasia 1/3023 (0%) 1/3010 (0%)
Balance disorder 0/3023 (0%) 1/3010 (0%)
Basal ganglia haematoma 1/3023 (0%) 0/3010 (0%)
Basal ganglia haemorrhage 2/3023 (0.1%) 0/3010 (0%)
Basal ganglia infarction 2/3023 (0.1%) 1/3010 (0%)
Basilar artery stenosis 0/3023 (0%) 1/3010 (0%)
Basilar artery thrombosis 1/3023 (0%) 0/3010 (0%)
Brain oedema 0/3023 (0%) 1/3010 (0%)
Brain stem stroke 0/3023 (0%) 2/3010 (0.1%)
Carotid artery aneurysm 1/3023 (0%) 1/3010 (0%)
Carotid artery occlusion 5/3023 (0.2%) 3/3010 (0.1%)
Carotid artery stenosis 13/3023 (0.4%) 10/3010 (0.3%)
Carpal tunnel syndrome 1/3023 (0%) 1/3010 (0%)
Central pain syndrome 1/3023 (0%) 0/3010 (0%)
Cerebellar haemorrhage 1/3023 (0%) 0/3010 (0%)
Cerebellar infarction 1/3023 (0%) 0/3010 (0%)
Cerebral haemorrhage 2/3023 (0.1%) 3/3010 (0.1%)
Cerebral infarction 14/3023 (0.5%) 13/3010 (0.4%)
Cerebral ischaemia 3/3023 (0.1%) 1/3010 (0%)
Cerebral small vessel ischaemic disease 1/3023 (0%) 0/3010 (0%)
Cerebrovascular accident 51/3023 (1.7%) 61/3010 (2%)
Cerebrovascular disorder 1/3023 (0%) 0/3010 (0%)
Cervical radiculopathy 1/3023 (0%) 1/3010 (0%)
Cervicobrachial syndrome 1/3023 (0%) 0/3010 (0%)
Cognitive disorder 0/3023 (0%) 2/3010 (0.1%)
Coma 0/3023 (0%) 1/3010 (0%)
Coordination abnormal 0/3023 (0%) 2/3010 (0.1%)
Dementia 13/3023 (0.4%) 19/3010 (0.6%)
Dementia Alzheimer's type 1/3023 (0%) 2/3010 (0.1%)
Diabetic neuropathy 0/3023 (0%) 3/3010 (0.1%)
Dizziness 11/3023 (0.4%) 7/3010 (0.2%)
Drop attacks 0/3023 (0%) 1/3010 (0%)
Dysarthria 1/3023 (0%) 1/3010 (0%)
Encephalomalacia 1/3023 (0%) 0/3010 (0%)
Encephalopathy 0/3023 (0%) 1/3010 (0%)
Epilepsy 4/3023 (0.1%) 11/3010 (0.4%)
Facial paresis 0/3023 (0%) 1/3010 (0%)
Generalised non-convulsive epilepsy 1/3023 (0%) 0/3010 (0%)
Generalised tonic-clonic seizure 0/3023 (0%) 1/3010 (0%)
Haemorrhage intracranial 2/3023 (0.1%) 1/3010 (0%)
Haemorrhagic cerebral infarction 0/3023 (0%) 1/3010 (0%)
Haemorrhagic stroke 6/3023 (0.2%) 3/3010 (0.1%)
Headache 3/3023 (0.1%) 2/3010 (0.1%)
Hemianopia 1/3023 (0%) 0/3010 (0%)
Hemianopia homonymous 0/3023 (0%) 1/3010 (0%)
Hemiparesis 6/3023 (0.2%) 4/3010 (0.1%)
Hemiplegia 1/3023 (0%) 0/3010 (0%)
Hydrocephalus 1/3023 (0%) 0/3010 (0%)
Hypertensive cerebrovascular disease 1/3023 (0%) 0/3010 (0%)
Hypoaesthesia 0/3023 (0%) 2/3010 (0.1%)
IIIrd nerve paralysis 0/3023 (0%) 1/3010 (0%)
Internal carotid artery kinking 0/3023 (0%) 2/3010 (0.1%)
Intracranial aneurysm 1/3023 (0%) 2/3010 (0.1%)
Intracranial haematoma 0/3023 (0%) 1/3010 (0%)
Intracranial mass 0/3023 (0%) 1/3010 (0%)
Ischaemic cerebral infarction 1/3023 (0%) 1/3010 (0%)
Ischaemic stroke 22/3023 (0.7%) 20/3010 (0.7%)
Lacunar infarction 4/3023 (0.1%) 4/3010 (0.1%)
Lacunar stroke 2/3023 (0.1%) 3/3010 (0.1%)
Loss of consciousness 1/3023 (0%) 3/3010 (0.1%)
Lumbar radiculopathy 1/3023 (0%) 2/3010 (0.1%)
Memory impairment 1/3023 (0%) 1/3010 (0%)
Mental impairment 1/3023 (0%) 1/3010 (0%)
Metabolic encephalopathy 1/3023 (0%) 2/3010 (0.1%)
Mononeuritis 0/3023 (0%) 1/3010 (0%)
Monoparesis 0/3023 (0%) 1/3010 (0%)
Myelopathy 1/3023 (0%) 1/3010 (0%)
Neurological symptom 0/3023 (0%) 1/3010 (0%)
Neuropathy peripheral 1/3023 (0%) 1/3010 (0%)
Paraesthesia 0/3023 (0%) 1/3010 (0%)
Paralysis recurrent laryngeal nerve 0/3023 (0%) 1/3010 (0%)
Paraparesis 0/3023 (0%) 1/3010 (0%)
Parkinson's disease 1/3023 (0%) 2/3010 (0.1%)
Parkinsonism 1/3023 (0%) 0/3010 (0%)
Partial seizures 1/3023 (0%) 1/3010 (0%)
Polyneuropathy 1/3023 (0%) 0/3010 (0%)
Presyncope 5/3023 (0.2%) 5/3010 (0.2%)
Quadriplegia 0/3023 (0%) 1/3010 (0%)
Radicular syndrome 1/3023 (0%) 0/3010 (0%)
Radiculopathy 0/3023 (0%) 2/3010 (0.1%)
Retinal migraine 1/3023 (0%) 0/3010 (0%)
Sciatica 7/3023 (0.2%) 7/3010 (0.2%)
Seizure 6/3023 (0.2%) 6/3010 (0.2%)
Sensory disturbance 0/3023 (0%) 1/3010 (0%)
Spinal claudication 1/3023 (0%) 0/3010 (0%)
Spinal cord compression 1/3023 (0%) 1/3010 (0%)
Spinal cord disorder 0/3023 (0%) 1/3010 (0%)
Spondylitic myelopathy 0/3023 (0%) 1/3010 (0%)
Status epilepticus 0/3023 (0%) 1/3010 (0%)
Subdural hygroma 1/3023 (0%) 0/3010 (0%)
Syncope 17/3023 (0.6%) 18/3010 (0.6%)
Tension headache 1/3023 (0%) 1/3010 (0%)
Thrombotic cerebral infarction 2/3023 (0.1%) 0/3010 (0%)
Transient ischaemic attack 31/3023 (1%) 33/3010 (1.1%)
Tunnel vision 1/3023 (0%) 0/3010 (0%)
Vascular dementia 2/3023 (0.1%) 1/3010 (0%)
Vascular encephalopathy 1/3023 (0%) 1/3010 (0%)
Vertebral artery aneurysm 0/3023 (0%) 1/3010 (0%)
Vertebral artery stenosis 0/3023 (0%) 1/3010 (0%)
Vertebrobasilar insufficiency 2/3023 (0.1%) 1/3010 (0%)
Product Issues
Device battery issue 1/3023 (0%) 1/3010 (0%)
Device defective 1/3023 (0%) 0/3010 (0%)
Device dislocation 1/3023 (0%) 3/3010 (0.1%)
Device failure 1/3023 (0%) 0/3010 (0%)
Device fastener issue 1/3023 (0%) 0/3010 (0%)
Device leakage 0/3023 (0%) 1/3010 (0%)
Device loosening 1/3023 (0%) 0/3010 (0%)
Device malfunction 2/3023 (0.1%) 0/3010 (0%)
Device occlusion 1/3023 (0%) 0/3010 (0%)
Psychiatric disorders
Acute psychosis 1/3023 (0%) 0/3010 (0%)
Agitated depression 1/3023 (0%) 0/3010 (0%)
Agitation 1/3023 (0%) 0/3010 (0%)
Anxiety 4/3023 (0.1%) 0/3010 (0%)
Anxiety disorder 0/3023 (0%) 1/3010 (0%)
Burnout syndrome 0/3023 (0%) 1/3010 (0%)
Completed suicide 0/3023 (0%) 3/3010 (0.1%)
Confusional state 1/3023 (0%) 0/3010 (0%)
Delirium 6/3023 (0.2%) 4/3010 (0.1%)
Delirium tremens 0/3023 (0%) 1/3010 (0%)
Depression 3/3023 (0.1%) 6/3010 (0.2%)
Depression suicidal 0/3023 (0%) 1/3010 (0%)
Disorientation 2/3023 (0.1%) 0/3010 (0%)
Encopresis 1/3023 (0%) 0/3010 (0%)
Hallucination 0/3023 (0%) 1/3010 (0%)
Major depression 1/3023 (0%) 5/3010 (0.2%)
Mental disorder 2/3023 (0.1%) 1/3010 (0%)
Mental status changes 2/3023 (0.1%) 5/3010 (0.2%)
Panic attack 0/3023 (0%) 1/3010 (0%)
Panic disorder 1/3023 (0%) 0/3010 (0%)
Post-traumatic stress disorder 0/3023 (0%) 1/3010 (0%)
Psychotic disorder 0/3023 (0%) 1/3010 (0%)
Schizophrenia 1/3023 (0%) 0/3010 (0%)
Somatic symptom disorder 1/3023 (0%) 2/3010 (0.1%)
Substance abuse 0/3023 (0%) 1/3010 (0%)
Suicidal ideation 3/3023 (0.1%) 1/3010 (0%)
Suicide attempt 1/3023 (0%) 1/3010 (0%)
Transient psychosis 1/3023 (0%) 0/3010 (0%)
Renal and urinary disorders
Acute kidney injury 47/3023 (1.6%) 41/3010 (1.4%)
Anuria 0/3023 (0%) 1/3010 (0%)
Atonic urinary bladder 0/3023 (0%) 1/3010 (0%)
Bladder neck obstruction 0/3023 (0%) 1/3010 (0%)
Bladder outlet obstruction 1/3023 (0%) 1/3010 (0%)
Bladder perforation 1/3023 (0%) 0/3010 (0%)
Bladder prolapse 1/3023 (0%) 2/3010 (0.1%)
Calculus bladder 1/3023 (0%) 2/3010 (0.1%)
Calculus urinary 2/3023 (0.1%) 0/3010 (0%)
Chronic kidney disease 15/3023 (0.5%) 6/3010 (0.2%)
Diabetic nephropathy 1/3023 (0%) 1/3010 (0%)
Dysuria 1/3023 (0%) 0/3010 (0%)
End stage renal disease 1/3023 (0%) 3/3010 (0.1%)
Glomerulonephritis 0/3023 (0%) 1/3010 (0%)
Glomerulonephritis membranous 0/3023 (0%) 1/3010 (0%)
Haematuria 7/3023 (0.2%) 4/3010 (0.1%)
Hydronephrosis 7/3023 (0.2%) 6/3010 (0.2%)
Hypertonic bladder 0/3023 (0%) 1/3010 (0%)
Leukocyturia 1/3023 (0%) 0/3010 (0%)
Lower urinary tract symptoms 1/3023 (0%) 1/3010 (0%)
Nephrolithiasis 14/3023 (0.5%) 4/3010 (0.1%)
Nephrotic syndrome 1/3023 (0%) 1/3010 (0%)
Obstructive nephropathy 1/3023 (0%) 0/3010 (0%)
Prerenal failure 1/3023 (0%) 1/3010 (0%)
Proteinuria 1/3023 (0%) 1/3010 (0%)
Renal artery arteriosclerosis 0/3023 (0%) 1/3010 (0%)
Renal artery stenosis 0/3023 (0%) 1/3010 (0%)
Renal colic 3/3023 (0.1%) 1/3010 (0%)
Renal cyst 0/3023 (0%) 2/3010 (0.1%)
Renal failure 20/3023 (0.7%) 13/3010 (0.4%)
Renal impairment 8/3023 (0.3%) 10/3010 (0.3%)
Renal mass 1/3023 (0%) 0/3010 (0%)
Stag horn calculus 0/3023 (0%) 1/3010 (0%)
Stress urinary incontinence 1/3023 (0%) 0/3010 (0%)
Ureteral disorder 1/3023 (0%) 0/3010 (0%)
Ureteral polyp 1/3023 (0%) 0/3010 (0%)
Ureteric obstruction 1/3023 (0%) 0/3010 (0%)
Ureterolithiasis 5/3023 (0.2%) 8/3010 (0.3%)
Urethral meatus stenosis 0/3023 (0%) 1/3010 (0%)
Urethral stenosis 3/3023 (0.1%) 0/3010 (0%)
Urinary bladder polyp 2/3023 (0.1%) 0/3010 (0%)
Urinary incontinence 0/3023 (0%) 1/3010 (0%)
Urinary retention 13/3023 (0.4%) 3/3010 (0.1%)
Urinary tract obstruction 0/3023 (0%) 2/3010 (0.1%)
Reproductive system and breast disorders
Acquired phimosis 0/3023 (0%) 1/3010 (0%)
Adenomyosis 1/3023 (0%) 0/3010 (0%)
Balanoposthitis 0/3023 (0%) 2/3010 (0.1%)
Benign prostatic hyperplasia 5/3023 (0.2%) 19/3010 (0.6%)
Breast pain 0/3023 (0%) 1/3010 (0%)
Cystocele 1/3023 (0%) 0/3010 (0%)
Endometriosis 1/3023 (0%) 0/3010 (0%)
Erectile dysfunction 1/3023 (0%) 1/3010 (0%)
Genital haemorrhage 0/3023 (0%) 1/3010 (0%)
Metrorrhagia 1/3023 (0%) 0/3010 (0%)
Ovarian cyst 0/3023 (0%) 1/3010 (0%)
Ovarian disorder 1/3023 (0%) 0/3010 (0%)
Pelvic prolapse 0/3023 (0%) 1/3010 (0%)
Postmenopausal haemorrhage 1/3023 (0%) 0/3010 (0%)
Prostatic disorder 1/3023 (0%) 0/3010 (0%)
Prostatic obstruction 1/3023 (0%) 0/3010 (0%)
Prostatism 0/3023 (0%) 1/3010 (0%)
Prostatitis 1/3023 (0%) 0/3010 (0%)
Prostatomegaly 0/3023 (0%) 1/3010 (0%)
Rectocele 1/3023 (0%) 1/3010 (0%)
Uterine haemorrhage 0/3023 (0%) 1/3010 (0%)
Uterine polyp 0/3023 (0%) 1/3010 (0%)
Uterine prolapse 4/3023 (0.1%) 4/3010 (0.1%)
Uterovaginal prolapse 1/3023 (0%) 0/3010 (0%)
Vaginal haemorrhage 1/3023 (0%) 1/3010 (0%)
Vaginal prolapse 2/3023 (0.1%) 4/3010 (0.1%)
Vulvar dysplasia 0/3023 (0%) 1/3010 (0%)
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema 9/3023 (0.3%) 3/3010 (0.1%)
Acute respiratory distress syndrome 2/3023 (0.1%) 0/3010 (0%)
Acute respiratory failure 8/3023 (0.3%) 10/3010 (0.3%)
Apnoea 0/3023 (0%) 1/3010 (0%)
Aspiration 1/3023 (0%) 1/3010 (0%)
Asthma 5/3023 (0.2%) 7/3010 (0.2%)
Bronchiectasis 1/3023 (0%) 1/3010 (0%)
Bronchospasm 2/3023 (0.1%) 3/3010 (0.1%)
Chronic obstructive pulmonary disease 23/3023 (0.8%) 26/3010 (0.9%)
Chronic respiratory failure 0/3023 (0%) 1/3010 (0%)
Cough 2/3023 (0.1%) 3/3010 (0.1%)
Diaphragm muscle weakness 1/3023 (0%) 0/3010 (0%)
Diaphragmatic paralysis 1/3023 (0%) 0/3010 (0%)
Dyspnoea 15/3023 (0.5%) 22/3010 (0.7%)
Dyspnoea at rest 1/3023 (0%) 0/3010 (0%)
Dyspnoea exertional 5/3023 (0.2%) 3/3010 (0.1%)
Emphysema 1/3023 (0%) 1/3010 (0%)
Epistaxis 7/3023 (0.2%) 2/3010 (0.1%)
Haemoptysis 1/3023 (0%) 2/3010 (0.1%)
Haemothorax 1/3023 (0%) 0/3010 (0%)
Hypercapnia 1/3023 (0%) 0/3010 (0%)
Hyperventilation 0/3023 (0%) 1/3010 (0%)
Hypoxia 1/3023 (0%) 3/3010 (0.1%)
Idiopathic pulmonary fibrosis 0/3023 (0%) 1/3010 (0%)
Interstitial lung disease 2/3023 (0.1%) 3/3010 (0.1%)
Lung disorder 1/3023 (0%) 2/3010 (0.1%)
Nasal polyps 1/3023 (0%) 2/3010 (0.1%)
Nasal septum deviation 1/3023 (0%) 0/3010 (0%)
Obstructive airways disorder 2/3023 (0.1%) 0/3010 (0%)
Oropharyngeal pain 0/3023 (0%) 1/3010 (0%)
Pharyngeal disorder 1/3023 (0%) 0/3010 (0%)
Pickwickian syndrome 0/3023 (0%) 1/3010 (0%)
Pleural effusion 8/3023 (0.3%) 5/3010 (0.2%)
Pleurisy 1/3023 (0%) 1/3010 (0%)
Pneumonia aspiration 2/3023 (0.1%) 2/3010 (0.1%)
Pneumonitis 1/3023 (0%) 2/3010 (0.1%)
Pneumothorax 3/3023 (0.1%) 5/3010 (0.2%)
Productive cough 1/3023 (0%) 0/3010 (0%)
Pulmonary arterial hypertension 0/3023 (0%) 2/3010 (0.1%)
Pulmonary artery thrombosis 1/3023 (0%) 0/3010 (0%)
Pulmonary congestion 1/3023 (0%) 1/3010 (0%)
Pulmonary embolism 6/3023 (0.2%) 16/3010 (0.5%)
Pulmonary fibrosis 3/3023 (0.1%) 2/3010 (0.1%)
Pulmonary hypertension 6/3023 (0.2%) 11/3010 (0.4%)
Pulmonary mass 0/3023 (0%) 1/3010 (0%)
Pulmonary oedema 5/3023 (0.2%) 7/3010 (0.2%)
Pulmonary toxicity 1/3023 (0%) 0/3010 (0%)
Respiratory acidosis 0/3023 (0%) 1/3010 (0%)
Respiratory disorder 1/3023 (0%) 0/3010 (0%)
Respiratory failure 8/3023 (0.3%) 14/3010 (0.5%)
Sleep apnoea syndrome 3/3023 (0.1%) 5/3010 (0.2%)
Snoring 0/3023 (0%) 1/3010 (0%)
Status asthmaticus 1/3023 (0%) 0/3010 (0%)
Tracheomalacia 1/3023 (0%) 0/3010 (0%)
Vocal cord polyp 1/3023 (0%) 0/3010 (0%)
Skin and subcutaneous tissue disorders
Angioedema 2/3023 (0.1%) 4/3010 (0.1%)
Decubitus ulcer 1/3023 (0%) 0/3010 (0%)
Dermal cyst 0/3023 (0%) 2/3010 (0.1%)
Dermatitis 0/3023 (0%) 2/3010 (0.1%)
Dermatitis allergic 0/3023 (0%) 1/3010 (0%)
Dermatitis bullous 1/3023 (0%) 0/3010 (0%)
Dermatitis exfoliative 2/3023 (0.1%) 0/3010 (0%)
Diabetic foot 4/3023 (0.1%) 3/3010 (0.1%)
Diabetic neuropathic ulcer 0/3023 (0%) 1/3010 (0%)
Diabetic ulcer 1/3023 (0%) 0/3010 (0%)
Drug eruption 3/3023 (0.1%) 0/3010 (0%)
Eczema 2/3023 (0.1%) 2/3010 (0.1%)
Erythema 1/3023 (0%) 0/3010 (0%)
Macule 0/3023 (0%) 1/3010 (0%)
Nail bed inflammation 0/3023 (0%) 1/3010 (0%)
Night sweats 0/3023 (0%) 1/3010 (0%)
Pemphigoid 3/3023 (0.1%) 0/3010 (0%)
Prurigo 1/3023 (0%) 0/3010 (0%)
Pruritus 0/3023 (0%) 1/3010 (0%)
Pruritus generalised 0/3023 (0%) 1/3010 (0%)
Psoriasis 2/3023 (0.1%) 1/3010 (0%)
Rash 2/3023 (0.1%) 4/3010 (0.1%)
Rash macular 0/3023 (0%) 1/3010 (0%)
Rash vesicular 0/3023 (0%) 1/3010 (0%)
Skin lesion 1/3023 (0%) 4/3010 (0.1%)
Skin plaque 0/3023 (0%) 1/3010 (0%)
Skin ulcer 3/3023 (0.1%) 6/3010 (0.2%)
Solar lentigo 1/3023 (0%) 0/3010 (0%)
Swelling face 0/3023 (0%) 1/3010 (0%)
Transient acantholytic dermatosis 1/3023 (0%) 0/3010 (0%)
Umbilical haematoma 1/3023 (0%) 0/3010 (0%)
Urticaria 1/3023 (0%) 1/3010 (0%)
Social circumstances
Loss of personal independence in daily activities 1/3023 (0%) 1/3010 (0%)
Sexual abuse 1/3023 (0%) 0/3010 (0%)
Surgical and medical procedures
Cardiac operation 1/3023 (0%) 0/3010 (0%)
Cardiac pacemaker replacement 1/3023 (0%) 0/3010 (0%)
Cholecystectomy 0/3023 (0%) 1/3010 (0%)
Colostomy 0/3023 (0%) 1/3010 (0%)
Colostomy closure 1/3023 (0%) 0/3010 (0%)
Coronary arterial stent insertion 1/3023 (0%) 0/3010 (0%)
Hip arthroplasty 1/3023 (0%) 0/3010 (0%)
Implantable defibrillator insertion 0/3023 (0%) 1/3010 (0%)
Knee arthroplasty 3/3023 (0.1%) 3/3010 (0.1%)
Mitral valve replacement 1/3023 (0%) 0/3010 (0%)
Prostatic operation 1/3023 (0%) 0/3010 (0%)
Shoulder arthroplasty 1/3023 (0%) 0/3010 (0%)
Spinal decompression 1/3023 (0%) 0/3010 (0%)
Stent placement 1/3023 (0%) 0/3010 (0%)
Thyroidectomy 0/3023 (0%) 1/3010 (0%)
Transurethral prostatectomy 0/3023 (0%) 1/3010 (0%)
Vascular disorders
Accelerated hypertension 1/3023 (0%) 0/3010 (0%)
Aneurysm 0/3023 (0%) 1/3010 (0%)
Aortic aneurysm 5/3023 (0.2%) 7/3010 (0.2%)
Aortic aneurysm rupture 2/3023 (0.1%) 1/3010 (0%)
Aortic arteriosclerosis 0/3023 (0%) 1/3010 (0%)
Aortic dissection 1/3023 (0%) 0/3010 (0%)
Aortic occlusion 0/3023 (0%) 1/3010 (0%)
Aortic stenosis 3/3023 (0.1%) 3/3010 (0.1%)
Arterial occlusive disease 1/3023 (0%) 3/3010 (0.1%)
Arteriosclerosis 0/3023 (0%) 2/3010 (0.1%)
Arteritis 1/3023 (0%) 2/3010 (0.1%)
Atherosclerotic plaque rupture 0/3023 (0%) 1/3010 (0%)
Circulatory collapse 4/3023 (0.1%) 6/3010 (0.2%)
Deep vein thrombosis 9/3023 (0.3%) 17/3010 (0.6%)
Diabetic vascular disorder 1/3023 (0%) 0/3010 (0%)
Embolism 0/3023 (0%) 1/3010 (0%)
Embolism venous 0/3023 (0%) 1/3010 (0%)
Extremity necrosis 1/3023 (0%) 0/3010 (0%)
Femoral artery aneurysm 1/3023 (0%) 0/3010 (0%)
Femoral artery embolism 1/3023 (0%) 0/3010 (0%)
Haematoma 4/3023 (0.1%) 3/3010 (0.1%)
Haemodynamic instability 0/3023 (0%) 1/3010 (0%)
Haemorrhage 2/3023 (0.1%) 0/3010 (0%)
Hypertension 12/3023 (0.4%) 9/3010 (0.3%)
Hypertensive crisis 15/3023 (0.5%) 21/3010 (0.7%)
Hypertensive emergency 1/3023 (0%) 1/3010 (0%)
Hypotension 5/3023 (0.2%) 3/3010 (0.1%)
Hypovolaemic shock 1/3023 (0%) 2/3010 (0.1%)
Infarction 0/3023 (0%) 2/3010 (0.1%)
Intermittent claudication 1/3023 (0%) 4/3010 (0.1%)
Ischaemia 1/3023 (0%) 2/3010 (0.1%)
Ischaemic limb pain 0/3023 (0%) 1/3010 (0%)
Lymphocele 2/3023 (0.1%) 0/3010 (0%)
Orthostatic hypotension 1/3023 (0%) 1/3010 (0%)
Peripheral arterial occlusive disease 6/3023 (0.2%) 12/3010 (0.4%)
Peripheral artery aneurysm 1/3023 (0%) 0/3010 (0%)
Peripheral artery occlusion 10/3023 (0.3%) 0/3010 (0%)
Peripheral artery stenosis 0/3023 (0%) 1/3010 (0%)
Peripheral artery thrombosis 1/3023 (0%) 2/3010 (0.1%)
Peripheral ischaemia 0/3023 (0%) 5/3010 (0.2%)
Peripheral vascular disorder 3/3023 (0.1%) 4/3010 (0.1%)
Shock 3/3023 (0.1%) 2/3010 (0.1%)
Thrombophlebitis 1/3023 (0%) 1/3010 (0%)
Thrombophlebitis superficial 0/3023 (0%) 1/3010 (0%)
Varicose vein 1/3023 (0%) 2/3010 (0.1%)
Venous thrombosis 0/3023 (0%) 1/3010 (0%)
Venous thrombosis limb 0/3023 (0%) 1/3010 (0%)
Other (Not Including Serious) Adverse Events
Linagliptin Glimepiride
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 2376/3023 (78.6%) 2504/3010 (83.2%)
Blood and lymphatic system disorders
Anaemia 208/3023 (6.9%) 178/3010 (5.9%)
Eye disorders
Cataract 219/3023 (7.2%) 203/3010 (6.7%)
Gastrointestinal disorders
Constipation 195/3023 (6.5%) 173/3010 (5.7%)
Diarrhoea 365/3023 (12.1%) 324/3010 (10.8%)
Nausea 157/3023 (5.2%) 164/3010 (5.4%)
General disorders
Fatigue 118/3023 (3.9%) 162/3010 (5.4%)
Oedema peripheral 150/3023 (5%) 194/3010 (6.4%)
Infections and infestations
Bronchitis 315/3023 (10.4%) 340/3010 (11.3%)
Influenza 268/3023 (8.9%) 243/3010 (8.1%)
Nasopharyngitis 530/3023 (17.5%) 517/3010 (17.2%)
Upper respiratory tract infection 313/3023 (10.4%) 319/3010 (10.6%)
Urinary tract infection 318/3023 (10.5%) 312/3010 (10.4%)
Injury, poisoning and procedural complications
Fall 151/3023 (5%) 170/3010 (5.6%)
Investigations
Lipase increased 209/3023 (6.9%) 154/3010 (5.1%)
Metabolism and nutrition disorders
Hyperglycaemia 422/3023 (14%) 483/3010 (16%)
Hypoglycaemia 299/3023 (9.9%) 1067/3010 (35.4%)
Musculoskeletal and connective tissue disorders
Arthralgia 310/3023 (10.3%) 308/3010 (10.2%)
Back pain 388/3023 (12.8%) 368/3010 (12.2%)
Musculoskeletal pain 150/3023 (5%) 181/3010 (6%)
Osteoarthritis 224/3023 (7.4%) 261/3010 (8.7%)
Pain in extremity 215/3023 (7.1%) 224/3010 (7.4%)
Nervous system disorders
Dizziness 283/3023 (9.4%) 358/3010 (11.9%)
Headache 268/3023 (8.9%) 295/3010 (9.8%)
Respiratory, thoracic and mediastinal disorders
Cough 284/3023 (9.4%) 290/3010 (9.6%)
Vascular disorders
Hypertension 430/3023 (14.2%) 452/3010 (15%)

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:
NCT01243424
Other Study ID Numbers:
  • 1218.74
  • 2009-013157-15
First Posted:
Nov 18, 2010
Last Update Posted:
Jan 7, 2020
Last Verified:
Dec 1, 2019