SURPASS-4: A Study of Tirzepatide (LY3298176) Once a Week Versus Insulin Glargine Once a Day in Participants With Type 2 Diabetes and Increased Cardiovascular Risk
Sponsor
Eli Lilly and Company (Industry)
Overall Status
Completed
CT.gov ID
NCT03730662
Collaborator
(none)
2,002
216
4
29
9.3
0.3
Study Details
Study Description
Brief Summary
The purpose of the trial is to assess the efficacy and safety of tirzepatide taken once a week to insulin glargine taken once daily in participants with type 2 diabetes and increased cardiovascular risk. The study will last about 108 weeks and may include up to 30 visits.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Study Design
Study Type:
Interventional
Actual Enrollment
:
2002 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Efficacy and Safety of LY3298176 Once Weekly Versus Insulin Glargine in Patients With Type 2 Diabetes and Increased Cardiovascular Risk (SURPASS-4)
Actual Study Start Date
:
Nov 20, 2018
Actual Primary Completion Date
:
Jan 22, 2021
Actual Study Completion Date
:
Apr 22, 2021
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: 5 mg Tirzepatide 5 milligrams (mg) tirzepatide administered subcutaneously (SC) once a week. |
Drug: Tirzepatide
Administered SC.
Other Names:
|
| Experimental: 10 mg Tirzepatide 10 mg tirzepatide administered SC once a week. |
Drug: Tirzepatide
Administered SC.
Other Names:
|
| Experimental: 15 mg Tirzepatide 15 mg tirzepatide administered SC once a week. |
Drug: Tirzepatide
Administered SC.
Other Names:
|
| Active Comparator: Insulin Glargine Insulin glargine administered SC once a day. Doses were individualized and titrated according to protocol-defined targets. The starting dose of insulin glargine was 10 IU/day at bedtime, titrated to a FBG <100 mg/dL, following a treat-to-target (TTT) algorithm. |
Drug: Insulin Glargine
Administered SC
|
Outcome Measures
Primary Outcome Measures
- Change From Baseline in Hemoglobin A1c (HbA1c) (10 mg and 15 mg) [Baseline, Week 52]
HbA1c is the glycosylated fraction of hemoglobin A. HbA1c is measured primarily to identify average plasma glucose concentration over prolonged periods of time. Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model for post-baseline measures: Variable = Baseline + Pooled Country + Baseline sodium-glucose co-transporter-2 inhibitor (SGLT-2i) use Flag (Yes, No) + Treatment + Time + Treatment*Time (Type III sum of squares).
Secondary Outcome Measures
- Change From Baseline in HbA1c (5 mg) [Baseline, Week 52]
HbA1c is the glycosylated fraction of hemoglobin A. HbA1c is measured primarily to identify average plasma glucose concentration over prolonged periods of time. LS mean was determined by MMRM model for post-baseline measures: Variable = Baseline + Pooled Country + Baseline SGLT-2i use Flag (Yes, No) + Treatment + Time + Treatment*Time (Type III sum of squares).
- Change From Baseline in Body Weight [Baseline, Week 52]
LS mean was determined by MMRM model for post-baseline measures: Variable = Baseline + Pooled Country + Baseline HbA1c Group (<=8.5%, >8.5%) + Baseline SGLT-2i use Flag (Yes, No) + Treatment + Time + Treatment*Time (Type III sum of squares).
- Percentage of Participants With HbA1c of <7.0% [Week 52]
HbA1c is the glycosylated fraction of hemoglobin A. HbA1c is measured primarily to identify average plasma glucose concentration over prolonged periods of time. Imputed data includes observed value and imputed value if endpoint measure is missing.
- Change From Baseline in Fasting Serum Glucose [Baseline, Week 52]
LS mean was determined by MMRM model for post-baseline measures: Variable = Baseline + Pooled Country + Baseline HbA1c Group (<=8.5%, >8.5%) + Baseline SGLT-2i use Flag (Yes, No) + Treatment + Time + Treatment*Time (Type III sum of squares).
- Mean Change From Baseline in Daily Average 7-Point Self-Monitored Blood Glucose (SMBG) Values [Baseline, Week 52]
The self-monitored plasma glucose (SMBG) data were collected at the following 7 time points: Morning Premeal - Fasting, Morning 2-hour Postmeal, Midday Premeal, Midday 2-hour Postmeal, Evening Premeal, Evening 2-hour Postmeal and Bedtime. LS mean was determined by mixed-model repeated measures (MMRM) model with variables Baseline + Pooled Country + Baseline HbA1c Group (<=8.5%, >8.5%) + Baseline SGLT-2i use Flag (Yes, No) + Treatment + Time + Treatment*Time (Type III sum of squares).
- Pharmacokinetics (PK): Steady State Area Under the Concentration Time Curve From Zero to Tau (AUC 0-Tau) of Tirzepatide [1 to 24 hours, 24 to 96 hours, or 120 to 168 hours post dose of Week 7, 15, 23, 35]
Pharmacokinetics (PK): Steady State Area Under the Concentration Time Curve From Zero to Tau (AUC 0-Tau) of Tirzepatide
- Rate of Hypoglycemia With Blood Glucose <54 Milligram/Deciliter (mg/dL) [<3.0 (Millimole/Liter (mmol/L))] or Severe Hypoglycemia [Baseline through Week 52]
The hypoglycemia events were defined by participant reported events with blood glucose <54mg/dL (<3.0 mmol/L) or severe hypoglycemia. Severe hypoglycemia is defined as an episode with severe cognitive impairment requiring the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. These episodes may be associated with sufficient neuroglycopenia to induce seizure or coma. Post-baseline comparisons between treatment and control group was evaluated using negative binomial model with variables : Number of episodes = Baseline HbA1c Group (<=8.5%, >8.5%) + Pooled Country + Baseline SGLT-2i use Flag (Yes, No) + Treatment, with log (exposure in days/365.25) as an offset variable
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
Participants must:
-
Have been diagnosed with type 2 diabetes mellitus (T2DM)
-
Have HbA1c between ≥7.5% and ≤10.5%
-
Be on stable treatment with unchanged dose of at least 1 and no more than 3 types of oral antihyperglycemic drugs, which may only include metformin, SGLT-2 inhibitors, and/or sulfonylureas for at least 3 months before screening
-
Have increased risk for cardiovascular (CV) events
-
Be of stable weight (± 5%)
-
Have a BMI ≥25 kilograms per meter squared (kg/m2) at screening
Exclusion Criteria
Participants must not:
-
Have type 1 diabetes mellitus
-
Have had chronic or acute pancreatitis any time prior to study entry
-
Have proliferative diabetic retinopathy or diabetic maculopathy or nonproliferative diabetic retinopathy requiring immediate or urgent treatment
-
Have disorders associated with slowed emptying of the stomach, or have had any stomach surgeries for the purpose of weight loss
-
Have acute or chronic hepatitis, signs and symptoms of any other liver disease, or blood alanine transaminase (ALT) enzyme level >3.0 times the upper limit of normal (ULN) for the reference range, as determined by the central laboratory. Participants with nonalcoholic fatty liver disease (NAFLD) are eligible for participation in this trial only if there ALT level is ≤3.0 the ULN for the reference range
-
Have had a heart attack, stroke, or hospitalization for congestive heart failure in the past 2 months
-
Have a personal or family history of medullary thyroid carcinoma or personal history of multiple endocrine neoplasia syndrome type 2
-
Have been taking any other diabetes medicines other than metformin, SGLT-2 inhibitors, and/or sulfonylureas during the last 3 months
-
Have been taking weight loss drugs, including over-the-counter medications during the last 3 months
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Advanced Research Center | Anaheim | California | United States | 92805 |
| 2 | Valley Clinical Trials, Inc. | Covina | California | United States | 91723 |
| 3 | Marin Endocrine Associates | Greenbrae | California | United States | 94904 |
| 4 | National Research Institute | Huntington Park | California | United States | 90255 |
| 5 | Scripps Whittier Diabetes Institute | La Jolla | California | United States | 92037 |
| 6 | First Valley Medical Group | Lancaster | California | United States | 93534 |
| 7 | National Research Institute | Los Angeles | California | United States | 90057 |
| 8 | Catalina Research Institute, LLC | Montclair | California | United States | 91763 |
| 9 | Monterey Endocrine & Diabetes Institute, Inc. | Monterey | California | United States | 93940 |
| 10 | Valley Clinical Trials, Inc. | Northridge | California | United States | 91325 |
| 11 | Desert Medical Group Inc | Palm Springs | California | United States | 92262 |
| 12 | Havana Research Institute | Pasadena | California | United States | 91105 |
| 13 | Western University of Health Sciences | Pomona | California | United States | 91766 |
| 14 | LCGK Research | San Carlos | California | United States | 94070 |
| 15 | Olive View Medical Center | Sylmar | California | United States | 91342 |
| 16 | University Clinical Investigators, Inc. | Tustin | California | United States | 92780 |
| 17 | Touro University | Vallejo | California | United States | 94592 |
| 18 | Coastal Metabolic Research Centre | Ventura | California | United States | 93003 |
| 19 | Diablo Clinical Research | Walnut Creek | California | United States | 94598 |
| 20 | Chase Medical Research, LLC | Waterbury | Connecticut | United States | 06708 |
| 21 | ALL Medical Research, LLC | Cooper City | Florida | United States | 33024 |
| 22 | Advanced Pharma Research | Cutler Bay | Florida | United States | 33189 |
| 23 | South Florida Wellness & Clinical Research Institute | Margate | Florida | United States | 33063 |
| 24 | Suncoast Research Group, LLC | Miami | Florida | United States | 33135 |
| 25 | New Horizon Research Center | Miami | Florida | United States | 33165 |
| 26 | Clinical Neuroscience Solutions Inc | Orlando | Florida | United States | 32801 |
| 27 | Progressive Medical Research | Port Orange | Florida | United States | 32127 |
| 28 | Primary Care Specialists, LLC | Atlanta | Georgia | United States | 30312 |
| 29 | Rocky Mountain Diabetes and Osteoporosis Center | Idaho Falls | Idaho | United States | 83404 |
| 30 | Solaris Clinical Research | Meridian | Idaho | United States | 83646 |
| 31 | Saltzer Medical Group. P.A. | Nampa | Idaho | United States | 83686 |
| 32 | Northwestern Feinberg School of Medicine | Chicago | Illinois | United States | 60611 |
| 33 | NorthShore University HealthSystem | Skokie | Illinois | United States | 60077 |
| 34 | University of Iowa Hospital & Clinic | Iowa City | Iowa | United States | 52242 |
| 35 | Iowa Diabetes Research | West Des Moines | Iowa | United States | 50265 |
| 36 | Cotton O'Neil Diabetes and Endocrinology Center | Topeka | Kansas | United States | 66606 |
| 37 | Robley Rex VAMC | Louisville | Kentucky | United States | 40206 |
| 38 | NECCR PrimaCare Research, LLC | Fall River | Massachusetts | United States | 02721 |
| 39 | AA Medical Research Center | Flint | Michigan | United States | 48504 |
| 40 | Troy Internal Medicine, PC | Troy | Michigan | United States | 48098 |
| 41 | Clinical Research Professionals | Chesterfield | Missouri | United States | 63005 |
| 42 | Glacier View Research Institute | Kalispell | Montana | United States | 59901 |
| 43 | Montana Medical Research, Inc | Missoula | Montana | United States | 59808 |
| 44 | Palm Research Center | Las Vegas | Nevada | United States | 89128 |
| 45 | Palm Research Center | Las Vegas | Nevada | United States | 89148 |
| 46 | Southern New Hampshire Diabetes and Endocrinology | Nashua | New Hampshire | United States | 03063 |
| 47 | PharmQuest | Greensboro | North Carolina | United States | 27408 |
| 48 | Lillestol Research LLC | Fargo | North Dakota | United States | 58104 |
| 49 | Rapid Medical Research Inc | Cleveland | Ohio | United States | 44122 |
| 50 | Ohio State Univ College Of Medicine | Columbus | Ohio | United States | 43210 |
| 51 | Aventiv Research | Columbus | Ohio | United States | 43213 |
| 52 | Intend Research | Norman | Oklahoma | United States | 73069 |
| 53 | The Corvallis Clinic P.C. | Corvallis | Oregon | United States | 97330 |
| 54 | Oregon Health and Science University | Portland | Oregon | United States | 97239 |
| 55 | Heritage Valley Medical Group, Inc. | Beaver | Pennsylvania | United States | 15009 |
| 56 | Capital Area Research | Camp Hill | Pennsylvania | United States | 17011 |
| 57 | Detweiler Family Medicine | Lansdale | Pennsylvania | United States | 19446 |
| 58 | Capital Area Research | Newport | Pennsylvania | United States | 17074 |
| 59 | Parkside Family Medical | Philadelphia | Pennsylvania | United States | 19144 |
| 60 | Preferred Primary Care Physicians- Bower Hill | Pittsburgh | Pennsylvania | United States | 15243 |
| 61 | Mountain View Clinical Research, Inc. | Greer | South Carolina | United States | 29651 |
| 62 | The Research Center of the Upstate | Mauldin | South Carolina | United States | 29662 |
| 63 | Holston Medical Group Clinical Research | Kingsport | Tennessee | United States | 37660 |
| 64 | New Phase Research & Development | Knoxville | Tennessee | United States | 37909 |
| 65 | Dallas Diabetes Endocrine Center | Dallas | Texas | United States | 75230 |
| 66 | PCP for Life | Houston | Texas | United States | 77070 |
| 67 | BFHC Research | San Antonio | Texas | United States | 78249 |
| 68 | Consano Clinical Research | Shavano Park | Texas | United States | 78231 |
| 69 | Martin Diagnostic Clinic | Tomball | Texas | United States | 77375 |
| 70 | Alpine Research Organization | Farmington | Utah | United States | 84025 |
| 71 | Burke Internal Medicine & Research | Burke | Virginia | United States | 22015 |
| 72 | Private: Dr. Larry Stonesifer | Federal Way | Washington | United States | 98003 |
| 73 | Capital Clinical Research Center | Olympia | Washington | United States | 98502 |
| 74 | Walla Walla Clinic | Walla Walla | Washington | United States | 99362 |
| 75 | Centro de Investigaciones Metabólicas (CINME) | Caba | Buenos Aires | Argentina | C1056ABJ |
| 76 | Mautalen Salud e Investigación - Servicio de Endocrinología | Caba | Buenos Aires | Argentina | C1128AAF |
| 77 | Investigaciones Medicas IMOBA S.R.L. | Caba | Buenos Aires | Argentina | C1179AAB |
| 78 | CEDIC-Centro de Investigaciones Clinicas | Caba | Buenos Aires | Argentina | C1425DES |
| 79 | CEMEDIC | Caba | Buenos Aires | Argentina | C1440CFD |
| 80 | Centro Medico Dr Laura Maffei Investigacion Clinica Aplicada | Ciudad Autonoma de Buenos Aire | Buenos Aires | Argentina | C1425AGC |
| 81 | Centro de Investigacion y Prevencion Cardiovascular (CIPREC) | Ciudad Autonoma de | Buenos Aires | Argentina | C1119ACN |
| 82 | CIPADI | Godoy Cruz | Mendoza | Argentina | M5501ARP |
| 83 | AXISMED SRL - Bioclinica Research Network | Buenos Aires | Argentina | C1430CKE | |
| 84 | Centro Médico Viamonte | Ciudad Autonoma de Buenos Aire | Argentina | C1120AAC | |
| 85 | Instituto Centenario | Ciudad Autonoma de Buenos Aire | Argentina | C1204AAD | |
| 86 | Cemediab - Centro Médico Diabetológico Dr. Alejandro Chertkoff | Ciudad Autonoma de Buenos Aire | Argentina | C1205AAO | |
| 87 | Centro Diabetologico Dr Waitman | Cordoba | Argentina | 5000 | |
| 88 | Centro Medico Privado San Vicente Diabetes | Cordoba | Argentina | X5006CBI | |
| 89 | Cent Priva Especiali Médicas Ambulatorias Inve Clin CEMAIC | Cordoba | Argentina | X5008HHW | |
| 90 | Paratus Clinical Blacktown Clinic | Blacktown | New South Wales | Australia | 2148 |
| 91 | Campbelltown Medical & Dental Centre | Campbelltown | New South Wales | Australia | 2560 |
| 92 | Paratus Clinical Kanwal Clinic | Kanwal | New South Wales | Australia | 2259 |
| 93 | The AIM Centre | Merewether | New South Wales | Australia | 2291 |
| 94 | Royal North Shore Hospital | St. Leonards | New South Wales | Australia | 2065 |
| 95 | CORE Research Group Pty Ltd | Brisbane | Queensland | Australia | 4064 |
| 96 | Morayfield Medical and Dental Centre | Morayfield | Queensland | Australia | 4506 |
| 97 | AusTrials Pty Ltd | Sherwood | Queensland | Australia | 4075 |
| 98 | Victoria Point Medical and Dental Centre | Victoria Point | Queensland | Australia | 4165 |
| 99 | GP Plus Marion | Oaklands Park | South Australia | Australia | 5046 |
| 100 | Eastern Clinical Research Unit | Box Hill | Victoria | Australia | 3128 |
| 101 | Forest Hill Medical and Dental Centre | Forest Hill | Victoria | Australia | 3131 |
| 102 | Barwon Health - The Geelong Hospital | Geelong | Victoria | Australia | 3220 |
| 103 | Royal Melbourne Hospital | Parkville | Victoria | Australia | 3050 |
| 104 | Fremantle Hospital | Fremantle | Western Australia | Australia | 6160 |
| 105 | Instituto de Ensino e Pesquisa Clinica do Ceara | Fortaleza | Ceara | Brazil | 60170-195 |
| 106 | Centro de Pesquisa Clinica do Brasil | Brasilia | Distrito Federal | Brazil | 71625-009 |
| 107 | Cedoes Centro Diagnostico Pequisa Osteoporose E Santo Ltd | Vitoria | ES | Brazil | 29055-450 |
| 108 | Centro de Diabetes Curitiba | Curitiba | Parana | Brazil | 80810-040 |
| 109 | CCBR Brasil Centro de Analises e Pesquisas Clínicas LTDA | Rio de Janeiro | RJ | Brazil | 22271-100 |
| 110 | CPQuali Pesquisa Clínica Ltda. | São Paulo | SP | Brazil | 01228-000 |
| 111 | Cpclin Centro de Pesquisas Clinicas | São Paulo | SP | Brazil | 01228-200 |
| 112 | Centro de Pesq. em Diabetes e Doencas Endocrino Metabol. | Fortaleza | Brazil | 60430-350 | |
| 113 | Dr. Consulta Clínica Médica LTDA | São Paulo | Brazil | 01141-020 | |
| 114 | LMC Manna Research | Calgary | Alberta | Canada | T2H 2G4 |
| 115 | C-Health Diabetes and Endocrinology Clinic Calgary | Calgary | Alberta | Canada | T2V 4J2 |
| 116 | Synergy Medical Research | Sherwood Park | Alberta | Canada | T8H 0N2 |
| 117 | LMC Endocrinology Centres Ltd. | Barrie | Ontario | Canada | L4N 7L3 |
| 118 | LMC Endocrinology Centers Brampton | Brampton | Ontario | Canada | L6S 0C6 |
| 119 | Aggarwal and Associates Ltd | Brampton | Ontario | Canada | L6T 0G1 |
| 120 | LMC Endocrinology Centres Ltd. | Concord | Ontario | Canada | L4K 4M2 |
| 121 | Milestone Research Inc. | London | Ontario | Canada | N5W6A2 |
| 122 | LMC Endocrinology Centres Ltd. | Nepean | Ontario | Canada | K2J 0V2 |
| 123 | Bluewater Clinical Research Group Inc | Sarnia | Ontario | Canada | N7T 4X3 |
| 124 | Canadian Centre for Research on Diabetes | Smiths Falls | Ontario | Canada | K7A 4W8 |
| 125 | Manna Research, Inc. | Stoney Creek | Ontario | Canada | L8J 3W2 |
| 126 | Medicor Research Inc | Sudbury | Ontario | Canada | P3A 1W8 |
| 127 | LMC Endocrinology Centres Ltd. | Toronto | Ontario | Canada | M4G 3E8 |
| 128 | Sameh Fikry Medicine Professional Corporation | Waterloo | Ontario | Canada | N2J 1C4 |
| 129 | Q & T Research Outaouais | Gatineau | Quebec | Canada | J8Y 6S8 |
| 130 | Centre De Recherche Clinique De Laval | Laval | Quebec | Canada | H7T 2P5 |
| 131 | Manna Research (Quebec) | Levis | Quebec | Canada | G6W 0M5 |
| 132 | LMC Endocrinology Centres Ltd. | Ville St-Laurent | Quebec | Canada | H4T 1Z9 |
| 133 | Iatriko Palaiou Falirou, Medical Center | Palaio Faliro | Athens | Greece | 17562 |
| 134 | Thermi Clinic | Thermi | Thessaloniki | Greece | 57001 |
| 135 | University General Hospital of Larissa | Larissa | Greece | 41110 | |
| 136 | AHEPA Hospital | Thessaloniki | Greece | 54636 | |
| 137 | Euromedica - General Clinic of Thessaloniki | Thessaloniki | Greece | 54645 | |
| 138 | Ha'Emek Medical Center | Afula | Israel | 1834111 | |
| 139 | Soroka Medical Center | Beer Sheva | Israel | 8410101 | |
| 140 | Rambam Medical Center | Haifa | Israel | 3109601 | |
| 141 | Wolfson Medical Center | Holon | Israel | 5822012 | |
| 142 | Hadassah Medical Center | Jerusalem | Israel | 911201 | |
| 143 | Rabin Medical Center | Petach Tikva | Israel | 4941492 | |
| 144 | Sheba Medical Center | Ramat Gan | Israel | 5266202 | |
| 145 | Sakhnin Community Clinic, Clalit Health Services | Sakhnin | Israel | 3081000 | |
| 146 | Tel Aviv Sourasky Medical Center | Tel Aviv Jaffa | Israel | 6423906 | |
| 147 | Instituto Jalisciense de Investigacion en Diabetes y Obesida | Guadalajara | Jalisco | Mexico | 04460 |
| 148 | Diseno y Planeacion en Investigacion Medica S.C. | Guadalajara | Jalisco | Mexico | 44130 |
| 149 | St. Lucas Clinical Research Center | Merida | Mexico State | Mexico | 97217 |
| 150 | Unidad Medica para la Salud Integral (UMSI) | Monterrey | Nuevo León | Mexico | 66465 |
| 151 | Centro de Estudios de Investigacion Metabolicos y Cardiovasc | Tampico | Tamaulipas | Mexico | 89000 |
| 152 | Investigacion en Salud y Metabolismo S.C | Chihuahua | Mexico | 31217 | |
| 153 | Centralny Szpital Kliniczny MSWiA Klinika Dermatologiczna | Warszawa | Mazowieckie | Poland | 02-507 |
| 154 | Poradnia Diabetologiczna SN ZOZ Lege Artis | Bialystok | Poland | 15-404 | |
| 155 | NZOZ Diab-Endo-Met | Krakow | Poland | 31-261 | |
| 156 | Centrum Terapii Wspolczesnej J.M. Jasnorzewska S.K.A. | Lodz | Poland | 90-242 | |
| 157 | NZOZ CenterMed Lublin | Lublin | Poland | 20-044 | |
| 158 | Gabinety Terpa | Lublin | Poland | 20-333 | |
| 159 | NZOZ Przychodnia Specjalistyczna MEDICA | Lublin | Poland | 20-538 | |
| 160 | Praktyka Lekarska | Poznan | Poland | 61-655 | |
| 161 | Nzoz Neuro - Kard | Poznan | Poland | 61-853 | |
| 162 | NZOZ Przychodnia Specjalistyczna Henryk RudzkiAndrzej Wittek | Ruda Slaska | Poland | 41-709 | |
| 163 | Woj. Zesp. Spec. Opieki Zdrowotnej | Wroclaw | Poland | 50-403 | |
| 164 | Emanuelli Research & Development Center, LLC | Arecibo | Puerto Rico | 00612 | |
| 165 | Manati Center for Clinical Research Inc | Manati | Puerto Rico | 00674 | |
| 166 | Ponce School of Medicine CAIMED Center | Ponce | Puerto Rico | 00716 | |
| 167 | Research and Cardiovascular Corp. | Ponce | Puerto Rico | 00717 | |
| 168 | University Of Puerto Rico | Rio Pedras | Puerto Rico | 00936 | |
| 169 | GCM Medical Group PSC | San Juan | Puerto Rico | 00909 | |
| 170 | Consultorio Medico | San Juan | Puerto Rico | 00921 | |
| 171 | SC Gama Diamed SRL | Mangalia | Constanta | Romania | 905500 |
| 172 | Spitalul Judetean de Urgenta Satu Mare | Satu-Mare | Jud Satu-Mare | Romania | 440055 |
| 173 | CMI DNBM Dr. Pop Lavinia | Baia Mare | Maramures | Romania | 430222 |
| 174 | Cosamext SRL | Targu Mures | Mures | Romania | 540098 |
| 175 | Centrul Medical Dr. Negrisanu | Timisoara | Timis | Romania | 300456 |
| 176 | Centrul Medical de Diagnostic si Tratament Ambulatoriu Neomed SRL | Brasov | Romania | 500283 | |
| 177 | Cabinetul Medical Nicodiab SRL | Bucharest | Romania | 010507 | |
| 178 | SC Nutrilife SRL | Bucuresti | Romania | 013671 | |
| 179 | Milena Sante SRL | Galati | Romania | 800001 | |
| 180 | Arkhangelsk the first city clinical hospital | Arkhangelsk | Russian Federation | 163045 | |
| 181 | FSBI Endocrinological Research Center of the MOH of the ROF | Moscow | Russian Federation | 117036 | |
| 182 | Novosibirsk Regional Clinical Hospital | Novosibirsk | Russian Federation | 630087 | |
| 183 | Ryazan Regional Clinincal Cardiology Dispensary | Ryazan | Russian Federation | 390026 | |
| 184 | City Hospital of Saint Martyr Elizabeth | Saint Petersburg | Russian Federation | 193257 | |
| 185 | Medical Military Academy | Saint Petersburg | Russian Federation | 194044 | |
| 186 | SPb GUZ "Diagnostic Center #85" | Saint Petersburg | Russian Federation | 198255 | |
| 187 | City Consultative and Diagnostic Center | Saint-Petersburg | Russian Federation | 194354 | |
| 188 | Regional Clinical Hospital | Saratov | Russian Federation | 410053 | |
| 189 | Research & Practice Ltd | Yaroslavl | Russian Federation | 150003 | |
| 190 | Human care s.r.o. | Kosice | Slovak Republic | Slovakia | 04012 |
| 191 | MediVet s.r.o. | Malacky | Slovak Republic | Slovakia | 90101 |
| 192 | Areteus s.r.o. | Trebisov | Slovak Republic | Slovakia | 07501 |
| 193 | DIA-MED CENTRUM s.r.o. | Puchov | Slovakia | 02001 | |
| 194 | Tatratrial s.r.o. | Roznava | Slovakia | 04801 | |
| 195 | MEDI-DIA s.r.o. | Sabinov | Slovakia | 08301 | |
| 196 | Hospital Universitario Marques De Valdecilla | Santander | Cantabria | Spain | 39011 |
| 197 | Hospital Universitario Quiron Madrid | Pozuelo de Alarcon | Madrid | Spain | 28223 |
| 198 | Hospital de la Ribera | Alcira | Valencia | Spain | 46600 |
| 199 | Instituto de Ciencias medicas | Alicante | Spain | 03004 | |
| 200 | Centro Periférico de Especialidades Bola Azul | Almeria | Spain | 04009 | |
| 201 | Hospital Quironsalud Barcelona- END | Barcelona | Spain | 08023 | |
| 202 | Hospital Clinico Universitario San Cecilio | Granada | Spain | 18016 | |
| 203 | Complexo Hospitalario Universitario A Coruña, CHUAC | La Coruña | Spain | 15006 | |
| 204 | Centro Especialidades San Jose Obrero (Barbarela) | Malaga | Spain | 29006 | |
| 205 | Clinica Juaneda | Palma de Mallorca | Spain | 07014 | |
| 206 | Hospital Universitario Virgen Macarena | Sevilla | Spain | 41009 | |
| 207 | Clinica Nuevas Tecnologias en Diabetes y Endocrinologia | Seville | Spain | 41003 | |
| 208 | Cardinal Tien Hospital | Sindian City | Taipei County | Taiwan | 23148 |
| 209 | Chang Gung Memorial Hospital - Kaohsiung | Kaohsiung City | Taiwan | 833 | |
| 210 | Chung Shan Medical University Hospital | Taichung City | Taiwan | 40201 | |
| 211 | Kuang Tien General Hospital | Taichung County | Taiwan | 433 | |
| 212 | China Medical University Hospital | Taichung | Taiwan | 40447 | |
| 213 | Chi-Mei Medical Center | Tainan City | Taiwan | 71004 | |
| 214 | National Cheng Kung University Hospital | Tainan | Taiwan | 70403 | |
| 215 | National Taiwan University Hospital | Taipei City | Taiwan | 10048 | |
| 216 | Taipei Veterans General Hospital | Taipei | Taiwan | 11217 |
Sponsors and Collaborators
- Eli Lilly and Company
Investigators
- Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST), Eli Lilly and Company
Study Documents (Full-Text)
More Information
Additional Information:
Publications
None provided.Responsible Party:
Eli Lilly and Company
ClinicalTrials.gov Identifier:
NCT03730662
Other Study ID Numbers:
- 17072
- I8F-MC-GPGM
- 2018-002618-11
First Posted:
Nov 5, 2018
Last Update Posted:
Feb 14, 2022
Last Verified:
Jan 1, 2022
Individual Participant Data (IPD) Sharing Statement:
Yes
Plan to Share IPD:
Yes
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by Eli Lilly and Company
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | 5 mg Tirzepatide | 10 mg Tirzepatide | 15 mg Tirzepatide | Insulin Glargine |
|---|---|---|---|---|
| Arm/Group Description | 5 milligrams (mg) tirzepatide administered subcutaneously (SC) once a week. | 10 mg tirzepatide administered SC once a week. | 15 mg tirzepatide administered SC once a week. | Insulin glargine administered SC once a day. Doses were individualized and titrated according to protocol-defined targets. The starting dose of insulin glargine was 10 IU/day at bedtime, titrated to a FBG <100 mg/dL, following a treat-to-target (TTT) algorithm. |
| Period Title: Treatment Period (52 Weeks) | ||||
| STARTED | 329 | 330 | 338 | 1005 |
| Received at Least One Dose of Study Drug | 329 | 328 | 338 | 1000 |
| COMPLETED | 308 | 319 | 329 | 953 |
| NOT COMPLETED | 21 | 11 | 9 | 52 |
| Period Title: Treatment Period (52 Weeks) | ||||
| STARTED | 308 | 319 | 329 | 953 |
| COMPLETED | 294 | 312 | 313 | 882 |
| NOT COMPLETED | 14 | 7 | 16 | 71 |
Baseline Characteristics
| Arm/Group Title | 5 mg Tirzepatide | 10 mg Tirzepatide | 15 mg Tirzepatide | Insulin Glargine | Total |
|---|---|---|---|---|---|
| Arm/Group Description | 5 milligrams (mg) tirzepatide administered subcutaneously (SC) once a week. | 10 mg tirzepatide administered SC once a week. | 15 mg tirzepatide administered SC once a week. | Insulin glargine administered SC once a day. Doses were individualized and titrated according to protocol-defined targets. The starting dose of insulin glargine was 10 IU/day at bedtime, titrated to a FBG <100 mg/dL, following a treat-to-target (TTT) algorithm. | Total of all reporting groups |
| Overall Participants | 329 | 330 | 338 | 1005 | 2002 |
| Age (years) [Mean (Standard Deviation) ] | |||||
| Mean (Standard Deviation) [years] |
62.90
(8.56)
|
63.70
(8.68)
|
63.70
(8.60)
|
63.80
(8.51)
|
63.60
(8.56)
|
| Sex: Female, Male (Count of Participants) | |||||
| Female |
131
39.8%
|
121
36.7%
|
135
39.9%
|
364
36.2%
|
751
37.5%
|
| Male |
198
60.2%
|
209
63.3%
|
203
60.1%
|
641
63.8%
|
1251
62.5%
|
| Ethnicity (NIH/OMB) (Count of Participants) | |||||
| Hispanic or Latino |
154
46.8%
|
164
49.7%
|
155
45.9%
|
478
47.6%
|
951
47.5%
|
| Not Hispanic or Latino |
172
52.3%
|
164
49.7%
|
179
53%
|
521
51.8%
|
1036
51.7%
|
| Unknown or Not Reported |
3
0.9%
|
2
0.6%
|
4
1.2%
|
6
0.6%
|
15
0.7%
|
| Race (NIH/OMB) (Count of Participants) | |||||
| American Indian or Alaska Native |
32
9.7%
|
30
9.1%
|
26
7.7%
|
86
8.6%
|
174
8.7%
|
| Asian |
15
4.6%
|
16
4.8%
|
8
2.4%
|
31
3.1%
|
70
3.5%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
2
0.6%
|
1
0.1%
|
3
0.1%
|
| Black or African American |
13
4%
|
18
5.5%
|
11
3.3%
|
34
3.4%
|
76
3.8%
|
| White |
260
79%
|
260
78.8%
|
285
84.3%
|
827
82.3%
|
1632
81.5%
|
| More than one race |
8
2.4%
|
6
1.8%
|
5
1.5%
|
24
2.4%
|
43
2.1%
|
| Unknown or Not Reported |
1
0.3%
|
0
0%
|
1
0.3%
|
2
0.2%
|
4
0.2%
|
| Region of Enrollment (Count of Participants) | |||||
| Argentina |
80
24.3%
|
80
24.2%
|
82
24.3%
|
242
24.1%
|
484
24.2%
|
| Australia |
3
0.9%
|
3
0.9%
|
4
1.2%
|
9
0.9%
|
19
0.9%
|
| Brazil |
42
12.8%
|
41
12.4%
|
42
12.4%
|
125
12.4%
|
250
12.5%
|
| Canada |
8
2.4%
|
9
2.7%
|
7
2.1%
|
27
2.7%
|
51
2.5%
|
| Greece |
7
2.1%
|
5
1.5%
|
7
2.1%
|
19
1.9%
|
38
1.9%
|
| Israel |
4
1.2%
|
5
1.5%
|
5
1.5%
|
15
1.5%
|
29
1.4%
|
| Mexico |
27
8.2%
|
27
8.2%
|
26
7.7%
|
80
8%
|
160
8%
|
| Poland |
27
8.2%
|
25
7.6%
|
26
7.7%
|
78
7.8%
|
156
7.8%
|
| Romania |
13
4%
|
14
4.2%
|
14
4.1%
|
41
4.1%
|
82
4.1%
|
| Russia |
14
4.3%
|
14
4.2%
|
15
4.4%
|
45
4.5%
|
88
4.4%
|
| Slovakia |
33
10%
|
32
9.7%
|
34
10.1%
|
100
10%
|
199
9.9%
|
| Spain |
11
3.3%
|
14
4.2%
|
14
4.1%
|
38
3.8%
|
77
3.8%
|
| Taiwan |
5
1.5%
|
5
1.5%
|
5
1.5%
|
15
1.5%
|
30
1.5%
|
| United States |
55
16.7%
|
56
17%
|
57
16.9%
|
171
17%
|
339
16.9%
|
| Hemoglobin A1c (Percentage of HbA1c) [Mean (Standard Deviation) ] | |||||
| Mean (Standard Deviation) [Percentage of HbA1c] |
8.52
(0.84)
|
8.59
(0.91)
|
8.52
(0.98)
|
8.50
(0.85)
|
8.52
(0.88)
|
Outcome Measures
| Title | Change From Baseline in Hemoglobin A1c (HbA1c) (10 mg and 15 mg) |
|---|---|
| Description | HbA1c is the glycosylated fraction of hemoglobin A. HbA1c is measured primarily to identify average plasma glucose concentration over prolonged periods of time. Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model for post-baseline measures: Variable = Baseline + Pooled Country + Baseline sodium-glucose co-transporter-2 inhibitor (SGLT-2i) use Flag (Yes, No) + Treatment + Time + Treatment*Time (Type III sum of squares). |
| Time Frame | Baseline, Week 52 |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants who received at least one dose of study drug and had a baseline and at least 1 post-baseline value, excluding participants discontinuing study drug due to inadvertent enrollment |
| Arm/Group Title | 10 mg Tirzepatide | 15 mg Tirzepatide | Insulin Glargine |
|---|---|---|---|
| Arm/Group Description | 10 mg tirzepatide administered SC once a week. | 15 mg tirzepatide administered SC once a week. | Insulin glargine administered SC once a day. Doses were individualized and titrated according to protocol-defined targets. The starting dose of insulin glargine was 10 IU/day at bedtime, titrated to a FBG <100 mg/dL, following a treat-to-target (TTT) algorithm. |
| Measure Participants | 289 | 291 | 887 |
| Least Squares Mean (Standard Error) [Percentage of HbA1c] |
-2.43
(0.053)
|
-2.58
(0.053)
|
-1.44
(0.030)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | 10 mg Tirzepatide, Insulin Glargine |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Non-Inferiority | |
| Comments | Although the primary objective is to establish noninferiority, sample size selection is guided by the objective of establishing superiority. The chosen sample size and randomization ratio also provides >90% power to establish superiority of 10 mg LY3298176 and 15 mg LY3298176 doses to insulin glargine in absence of confounding effects of rescue therapy for persistent severe hyperglycemia ("efficacy" estimand). | |
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| Method | Mixed Models Analysis | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Net) |
| Estimated Value | -0.99 | |
| Confidence Interval |
(2-Sided) 97.5% -1.13 to -0.86 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | 15 mg Tirzepatide, Insulin Glargine |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Non-Inferiority | |
| Comments | Although the primary objective is to establish noninferiority, sample size selection is guided by the objective of establishing superiority. The chosen sample size and randomization ratio also provides >90% power to establish superiority of 10 mg LY3298176 and 15 mg LY3298176 doses to insulin glargine in absence of confounding effects of rescue therapy for persistent severe hyperglycemia ("efficacy" estimand). | |
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| Method | Mixed Models Analysis | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Net) |
| Estimated Value | -1.14 | |
| Confidence Interval |
(2-Sided) 97.5% -1.28 to -1.00 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Change From Baseline in HbA1c (5 mg) |
|---|---|
| Description | HbA1c is the glycosylated fraction of hemoglobin A. HbA1c is measured primarily to identify average plasma glucose concentration over prolonged periods of time. LS mean was determined by MMRM model for post-baseline measures: Variable = Baseline + Pooled Country + Baseline SGLT-2i use Flag (Yes, No) + Treatment + Time + Treatment*Time (Type III sum of squares). |
| Time Frame | Baseline, Week 52 |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants who received at least one dose of study drug and had a baseline and at least 1 post-baseline value, excluding participants discontinuing study drug due to inadvertent enrollment |
| Arm/Group Title | 5 mg Tirzepatide | Insulin Glargine |
|---|---|---|
| Arm/Group Description | 5 milligrams (mg) tirzepatide administered subcutaneously (SC) once a week. | Insulin glargine administered SC once a day. Doses were individualized and titrated according to protocol-defined targets. The starting dose of insulin glargine was 10 IU/day at bedtime, titrated to a FBG <100 mg/dL, following a treat-to-target (TTT) algorithm. |
| Measure Participants | 283 | 887 |
| Least Squares Mean (Standard Error) [Percentage of HbA1c] |
-2.24
(0.053)
|
-1.44
(0.030)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | 10 mg Tirzepatide, 15 mg Tirzepatide |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Non-Inferiority | |
| Comments | Although the primary objective is to establish noninferiority, sample size selection is guided by the objective of establishing superiority. The chosen sample size and randomization ratio also provides >90% power to establish superiority of 10 mg LY3298176 and 15 mg LY3298176 doses to insulin glargine in absence of confounding effects of rescue therapy for persistent severe hyperglycemia ("efficacy" estimand). | |
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| Method | Mixed Models Analysis | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Net) |
| Estimated Value | -0.80 | |
| Confidence Interval |
(2-Sided) 97.5% -0.93 to -0.66 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Change From Baseline in Body Weight |
|---|---|
| Description | LS mean was determined by MMRM model for post-baseline measures: Variable = Baseline + Pooled Country + Baseline HbA1c Group (<=8.5%, >8.5%) + Baseline SGLT-2i use Flag (Yes, No) + Treatment + Time + Treatment*Time (Type III sum of squares). |
| Time Frame | Baseline, Week 52 |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants who received at least one dose of study drug and had a baseline and at least 1 post-baseline value, excluding participants discontinuing study drug due to inadvertent enrollment |
| Arm/Group Title | 5 mg Tirzepatide | 10 mg Tirzepatide | 15 mg Tirzepatide | Insulin Glargine |
|---|---|---|---|---|
| Arm/Group Description | 5 milligrams (mg) tirzepatide administered subcutaneously (SC) once a week. | 10 mg tirzepatide administered SC once a week. | 15 mg tirzepatide administered SC once a week. | Insulin glargine administered SC once a day. Doses were individualized and titrated according to protocol-defined targets. The starting dose of insulin glargine was 10 IU/day at bedtime, titrated to a FBG <100 mg/dL, following a treat-to-target (TTT) algorithm. |
| Measure Participants | 285 | 288 | 291 | 891 |
| Least Squares Mean (Standard Error) [Kilograms (kg)] |
-7.1
(0.34)
|
-9.5
(0.34)
|
-11.7
(0.33)
|
1.9
(0.19)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | 10 mg Tirzepatide, Insulin Glargine |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| Method | Mixed Models Analysis | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Net) |
| Estimated Value | -9.0 | |
| Confidence Interval |
(2-Sided) 95% -9.8 to -8.3 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | 15 mg Tirzepatide, Insulin Glargine |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| Method | Mixed Models Analysis | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Net) |
| Estimated Value | -11.4 | |
| Confidence Interval |
(2-Sided) 95% -12.1 to -10.6 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Insulin Glargine, Insulin Glargine |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| Method | Mixed Models Analysis | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Net) |
| Estimated Value | -13.5 | |
| Confidence Interval |
(2-Sided) 95% -14.3 to -12.8 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Percentage of Participants With HbA1c of <7.0% |
|---|---|
| Description | HbA1c is the glycosylated fraction of hemoglobin A. HbA1c is measured primarily to identify average plasma glucose concentration over prolonged periods of time. Imputed data includes observed value and imputed value if endpoint measure is missing. |
| Time Frame | Week 52 |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants who received at least one dose of study drug and had a baseline and at least 1 post-baseline value, excluding participants discontinuing study drug due to inadvertent enrollment |
| Arm/Group Title | 5 mg Tirzepatide | 10 mg Tirzepatide | 15 mg Tirzepatide | Insulin Glargine |
|---|---|---|---|---|
| Arm/Group Description | 5 milligrams (mg) tirzepatide administered subcutaneously (SC) once a week. | 10 mg tirzepatide administered SC once a week. | 15 mg tirzepatide administered SC once a week. | Insulin glargine administered SC once a day. Doses were individualized and titrated according to protocol-defined targets. The starting dose of insulin glargine was 10 IU/day at bedtime, titrated to a FBG <100 mg/dL, following a treat-to-target (TTT) algorithm. |
| Measure Participants | 326 | 321 | 334 | 978 |
| Number [percentage of participants] |
80.98
24.6%
|
88.16
26.7%
|
90.72
26.8%
|
50.72
5%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | 10 mg Tirzepatide, Insulin Glargine |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 4.78 | |
| Confidence Interval |
(2-Sided) 95% 3.47 to 6.58 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | 15 mg Tirzepatide, Insulin Glargine |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 9.23 | |
| Confidence Interval |
(2-Sided) 95% 6.31 to 13.49 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Insulin Glargine, Insulin Glargine |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 11.87 | |
| Confidence Interval |
(2-Sided) 95% 7.88 to 17.89 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Change From Baseline in Fasting Serum Glucose |
|---|---|
| Description | LS mean was determined by MMRM model for post-baseline measures: Variable = Baseline + Pooled Country + Baseline HbA1c Group (<=8.5%, >8.5%) + Baseline SGLT-2i use Flag (Yes, No) + Treatment + Time + Treatment*Time (Type III sum of squares). |
| Time Frame | Baseline, Week 52 |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants who received at least one dose of study drug and had a baseline and at least 1 post-baseline value, excluding participants discontinuing study drug due to inadvertent enrollment |
| Arm/Group Title | 5 mg Tirzepatide | 10 mg Tirzepatide | 15 mg Tirzepatide | Insulin Glargine |
|---|---|---|---|---|
| Arm/Group Description | 5 milligrams (mg) tirzepatide administered subcutaneously (SC) once a week. | 10 mg tirzepatide administered SC once a week. | 15 mg tirzepatide administered SC once a week. | Insulin glargine administered SC once a day. Doses were individualized and titrated according to protocol-defined targets. The starting dose of insulin glargine was 10 IU/day at bedtime, titrated to a FBG <100 mg/dL, following a treat-to-target (TTT) algorithm. |
| Measure Participants | 281 | 283 | 288 | 880 |
| Least Squares Mean (Standard Error) [milligram per Deciliter (mg/dL)] |
-50.4
(2.07)
|
-54.9
(2.06)
|
-59.3
(2.04)
|
-51.4
(1.17)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | 10 mg Tirzepatide, Insulin Glargine |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.672 |
| Comments | ||
| Method | Mixed Models Analysis | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Net) |
| Estimated Value | 1.0 | |
| Confidence Interval |
(2-Sided) 95% -3.7 to 5.7 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | 15 mg Tirzepatide, Insulin Glargine |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.134 |
| Comments | ||
| Method | Mixed Models Analysis | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Net) |
| Estimated Value | -3.6 | |
| Confidence Interval |
(2-Sided) 95% -8.2 to 1.1 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Insulin Glargine, Insulin Glargine |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| Method | Mixed Models Analysis | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Net) |
| Estimated Value | -8.0 | |
| Confidence Interval |
(2-Sided) 95% -12.6 to -3.4 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Mean Change From Baseline in Daily Average 7-Point Self-Monitored Blood Glucose (SMBG) Values |
|---|---|
| Description | The self-monitored plasma glucose (SMBG) data were collected at the following 7 time points: Morning Premeal - Fasting, Morning 2-hour Postmeal, Midday Premeal, Midday 2-hour Postmeal, Evening Premeal, Evening 2-hour Postmeal and Bedtime. LS mean was determined by mixed-model repeated measures (MMRM) model with variables Baseline + Pooled Country + Baseline HbA1c Group (<=8.5%, >8.5%) + Baseline SGLT-2i use Flag (Yes, No) + Treatment + Time + Treatment*Time (Type III sum of squares). |
| Time Frame | Baseline, Week 52 |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants who received at least one dose of study drug, excluding participants discontinuing study drug due to inadvertent enrollment |
| Arm/Group Title | 5 mg Tirzepatide | 10 mg Tirzepatide | 15 mg Tirzepatide | Insulin Glargine |
|---|---|---|---|---|
| Arm/Group Description | 5 milligrams (mg) tirzepatide administered subcutaneously (SC) once a week. | 10 mg tirzepatide administered SC once a week. | 15 mg tirzepatide administered SC once a week. | Insulin glargine administered SC once a day. Doses were individualized and titrated according to protocol-defined targets. The starting dose of insulin glargine was 10 IU/day at bedtime, titrated to a FBG <100 mg/dL, following a treat-to-target (TTT) algorithm. |
| Measure Participants | 265 | 261 | 265 | 784 |
| Least Squares Mean (Standard Error) [mg/dL] |
-58.4
(1.65)
|
-61.1
(1.66)
|
-66.1
(1.66)
|
-46.1
(0.96)
|
| Title | Pharmacokinetics (PK): Steady State Area Under the Concentration Time Curve From Zero to Tau (AUC 0-Tau) of Tirzepatide |
|---|---|
| Description | Pharmacokinetics (PK): Steady State Area Under the Concentration Time Curve From Zero to Tau (AUC 0-Tau) of Tirzepatide |
| Time Frame | 1 to 24 hours, 24 to 96 hours, or 120 to 168 hours post dose of Week 7, 15, 23, 35 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacokinetic samples were collected from atleast the first 150 participants at each Tirzepatide dose, all participants aged ≥70 years, and all participants with severe renal impairment or end-stage renal disease (ESRD) (estimated glomerular filtration rate [eGFR] <30 mL/min) |
| Arm/Group Title | 5 mg Tirzepatide | 10 mg Tirzepatide | 15 mg Tirzepatide |
|---|---|---|---|
| Arm/Group Description | 5 milligrams (mg) tirzepatide administered subcutaneously (SC) once a week. | 10 mg tirzepatide administered SC once a week. | 15 mg tirzepatide administered SC once a week. |
| Measure Participants | 326 | 324 | 334 |
| Geometric Mean (Geometric Coefficient of Variation) [Nanograms per millilitre per hour] |
81800
(23.9)
|
165000
(20.3)
|
246000
(20.6)
|
| Title | Rate of Hypoglycemia With Blood Glucose <54 Milligram/Deciliter (mg/dL) [<3.0 (Millimole/Liter (mmol/L))] or Severe Hypoglycemia |
|---|---|
| Description | The hypoglycemia events were defined by participant reported events with blood glucose <54mg/dL (<3.0 mmol/L) or severe hypoglycemia. Severe hypoglycemia is defined as an episode with severe cognitive impairment requiring the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. These episodes may be associated with sufficient neuroglycopenia to induce seizure or coma. Post-baseline comparisons between treatment and control group was evaluated using negative binomial model with variables : Number of episodes = Baseline HbA1c Group (<=8.5%, >8.5%) + Pooled Country + Baseline SGLT-2i use Flag (Yes, No) + Treatment, with log (exposure in days/365.25) as an offset variable |
| Time Frame | Baseline through Week 52 |
Outcome Measure Data
| Analysis Population Description |
|---|
| All randomized participants who received at least one dose of study drug, excluding participants hypoglycemic events occurring after initiation of a new antihyperglycemic therapy |
| Arm/Group Title | 5 mg Tirzepatide | 10 mg Tirzepatide | 15 mg Tirzepatide | Insulin Glargine |
|---|---|---|---|---|
| Arm/Group Description | 5 milligrams (mg) tirzepatide administered subcutaneously (SC) once a week. | 10 mg tirzepatide administered SC once a week. | 15 mg tirzepatide administered SC once a week. | Insulin glargine administered SC once a day. Doses were individualized and titrated according to protocol-defined targets. The starting dose of insulin glargine was 10 IU/day at bedtime, titrated to a FBG <100 mg/dL, following a treat-to-target (TTT) algorithm. |
| Measure Participants | 329 | 328 | 338 | 1000 |
| Mean (Standard Error) [Episodes/participant/365.25 days] |
0.10
(0.023)
|
0.09
(0.025)
|
0.11
(0.030)
|
0.35
(0.044)
|
Adverse Events
| Time Frame | Baseline Up To 2 Years | |||||||
|---|---|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | All participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants at risk adjusted accordingly. | |||||||
| Arm/Group Title | 5 mg Tirzepatide | 10 mg Tirzepatide | 15 mg Tirzepatide | Insulin Glargine | ||||
| Arm/Group Description | 5 milligrams (mg) tirzepatide administered subcutaneously (SC) once a week. | 10 mg tirzepatide administered SC once a week. | 15 mg tirzepatide administered SC once a week. | Insulin glargine administered SC once a day. Doses were individualized and titrated according to protocol-defined targets. The starting dose of insulin glargine was 10 IU/day at bedtime, titrated to a FBG <100 mg/dL, following a treat-to-target (TTT) algorithm. | ||||
All Cause Mortality |
||||||||
| 5 mg Tirzepatide | 10 mg Tirzepatide | 15 mg Tirzepatide | Insulin Glargine | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 15/329 (4.6%) | 2/328 (0.6%) | 8/338 (2.4%) | 35/1000 (3.5%) | ||||
Serious Adverse Events |
||||||||
| 5 mg Tirzepatide | 10 mg Tirzepatide | 15 mg Tirzepatide | Insulin Glargine | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 48/329 (14.6%) | 54/328 (16.5%) | 41/338 (12.1%) | 193/1000 (19.3%) | ||||
| Blood and lymphatic system disorders | ||||||||
| Anaemia | 0/329 (0%) | 0 | 1/328 (0.3%) | 1 | 0/338 (0%) | 0 | 3/1000 (0.3%) | 3 |
| Bicytopenia | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Hypochromic anaemia | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Cardiac disorders | ||||||||
| Acute coronary syndrome | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 1/338 (0.3%) | 1 | 1/1000 (0.1%) | 1 |
| Acute left ventricular failure | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Acute myocardial infarction | 3/329 (0.9%) | 3 | 7/328 (2.1%) | 7 | 3/338 (0.9%) | 3 | 18/1000 (1.8%) | 19 |
| Angina pectoris | 1/329 (0.3%) | 1 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 3/1000 (0.3%) | 3 |
| Angina unstable | 1/329 (0.3%) | 1 | 2/328 (0.6%) | 2 | 1/338 (0.3%) | 1 | 6/1000 (0.6%) | 6 |
| Aortic valve sclerosis | 0/329 (0%) | 0 | 1/328 (0.3%) | 1 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Arteriosclerosis coronary artery | 1/329 (0.3%) | 1 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Atrial fibrillation | 1/329 (0.3%) | 1 | 2/328 (0.6%) | 2 | 1/338 (0.3%) | 1 | 2/1000 (0.2%) | 3 |
| Atrial flutter | 1/329 (0.3%) | 1 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Atrial tachycardia | 0/329 (0%) | 0 | 1/328 (0.3%) | 1 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Atrioventricular block | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Atrioventricular block second degree | 1/329 (0.3%) | 1 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Cardiac arrest | 1/329 (0.3%) | 1 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Cardiac disorder | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Cardiac failure | 2/329 (0.6%) | 2 | 0/328 (0%) | 0 | 2/338 (0.6%) | 2 | 2/1000 (0.2%) | 2 |
| Cardiac failure acute | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 1/338 (0.3%) | 1 | 2/1000 (0.2%) | 2 |
| Cardiac failure chronic | 0/329 (0%) | 0 | 1/328 (0.3%) | 1 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Cardiac failure congestive | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 5/1000 (0.5%) | 6 |
| Cardio-respiratory arrest | 1/329 (0.3%) | 1 | 0/328 (0%) | 0 | 1/338 (0.3%) | 1 | 0/1000 (0%) | 0 |
| Cardiogenic shock | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 2/1000 (0.2%) | 2 |
| Cardiomyopathy | 1/329 (0.3%) | 1 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Coronary artery disease | 5/329 (1.5%) | 5 | 4/328 (1.2%) | 4 | 2/338 (0.6%) | 3 | 15/1000 (1.5%) | 16 |
| Coronary artery stenosis | 1/329 (0.3%) | 1 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Ischaemic cardiomyopathy | 1/329 (0.3%) | 1 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Left ventricular failure | 1/329 (0.3%) | 1 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Myocardial infarction | 3/329 (0.9%) | 3 | 0/328 (0%) | 0 | 1/338 (0.3%) | 1 | 4/1000 (0.4%) | 4 |
| Myocardial ischaemia | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 1/338 (0.3%) | 1 | 2/1000 (0.2%) | 2 |
| Myocarditis | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 1/338 (0.3%) | 1 | 0/1000 (0%) | 0 |
| Supraventricular extrasystoles | 0/329 (0%) | 0 | 1/328 (0.3%) | 1 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Supraventricular tachycardia | 0/329 (0%) | 0 | 1/328 (0.3%) | 1 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Ventricular dysfunction | 1/329 (0.3%) | 1 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Ventricular extrasystoles | 0/329 (0%) | 0 | 1/328 (0.3%) | 1 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Congenital, familial and genetic disorders | ||||||||
| Phimosis | 1/198 (0.5%) | 1 | 0/209 (0%) | 0 | 0/203 (0%) | 0 | 0/636 (0%) | 0 |
| Ear and labyrinth disorders | ||||||||
| Vertigo | 0/329 (0%) | 0 | 1/328 (0.3%) | 1 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Eye disorders | ||||||||
| Retinal vein occlusion | 1/329 (0.3%) | 1 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Vitreous haemorrhage | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Gastrointestinal disorders | ||||||||
| Abdominal hernia | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Abdominal pain upper | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Abdominal wall haematoma | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Duodenal ulcer | 0/329 (0%) | 0 | 1/328 (0.3%) | 1 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Dysphagia | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Gastric polyps | 0/329 (0%) | 0 | 1/328 (0.3%) | 1 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Gastric ulcer | 0/329 (0%) | 0 | 1/328 (0.3%) | 1 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Gastritis | 0/329 (0%) | 0 | 1/328 (0.3%) | 1 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Inguinal hernia | 1/329 (0.3%) | 1 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Obstructive pancreatitis | 1/329 (0.3%) | 1 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Pancreatitis | 2/329 (0.6%) | 2 | 1/328 (0.3%) | 1 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Pancreatitis acute | 0/329 (0%) | 0 | 1/328 (0.3%) | 1 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Peptic ulcer | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Vomiting | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| General disorders | ||||||||
| Asthenia | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 2/338 (0.6%) | 2 | 0/1000 (0%) | 0 |
| Chest pain | 1/329 (0.3%) | 1 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 2/1000 (0.2%) | 2 |
| Death | 1/329 (0.3%) | 1 | 0/328 (0%) | 0 | 1/338 (0.3%) | 1 | 2/1000 (0.2%) | 2 |
| Necrosis | 0/329 (0%) | 0 | 1/328 (0.3%) | 1 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Non-cardiac chest pain | 1/329 (0.3%) | 1 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Pyrexia | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 1/338 (0.3%) | 1 | 0/1000 (0%) | 0 |
| Sudden cardiac death | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 1/338 (0.3%) | 1 | 1/1000 (0.1%) | 1 |
| Sudden death | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Systemic inflammatory response syndrome | 1/329 (0.3%) | 1 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Hepatobiliary disorders | ||||||||
| Biliary dilatation | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Cholangitis acute | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Cholecystitis | 0/329 (0%) | 0 | 1/328 (0.3%) | 1 | 0/338 (0%) | 0 | 2/1000 (0.2%) | 2 |
| Cholecystitis acute | 0/329 (0%) | 0 | 1/328 (0.3%) | 1 | 0/338 (0%) | 0 | 2/1000 (0.2%) | 2 |
| Hepatic cirrhosis | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 1/338 (0.3%) | 1 | 0/1000 (0%) | 0 |
| Hepatic function abnormal | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Hepatitis acute | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 1/338 (0.3%) | 1 | 0/1000 (0%) | 0 |
| Hepatotoxicity | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 1/338 (0.3%) | 1 | 0/1000 (0%) | 0 |
| Infections and infestations | ||||||||
| Appendicitis | 1/329 (0.3%) | 1 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Asymptomatic covid-19 | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 1/338 (0.3%) | 1 | 0/1000 (0%) | 0 |
| Bronchitis | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Cellulitis | 1/329 (0.3%) | 1 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 2/1000 (0.2%) | 2 |
| Covid-19 | 2/329 (0.6%) | 2 | 2/328 (0.6%) | 2 | 2/338 (0.6%) | 2 | 10/1000 (1%) | 10 |
| Covid-19 pneumonia | 2/329 (0.6%) | 2 | 6/328 (1.8%) | 6 | 3/338 (0.9%) | 3 | 15/1000 (1.5%) | 15 |
| Diabetic foot infection | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Diverticulitis | 0/329 (0%) | 0 | 1/328 (0.3%) | 1 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Erysipelas | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 3/1000 (0.3%) | 3 |
| Fournier's gangrene | 0/329 (0%) | 0 | 1/328 (0.3%) | 1 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Gastroenteritis | 0/329 (0%) | 0 | 1/328 (0.3%) | 1 | 0/338 (0%) | 0 | 2/1000 (0.2%) | 2 |
| Hiv infection | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Infected skin ulcer | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Infection | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Liver abscess | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Nosocomial infection | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Pneumonia | 1/329 (0.3%) | 1 | 1/328 (0.3%) | 1 | 2/338 (0.6%) | 2 | 10/1000 (1%) | 10 |
| Pneumonia bacterial | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Pneumonia klebsiella | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Postoperative wound infection | 0/329 (0%) | 0 | 1/328 (0.3%) | 1 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Pyelonephritis | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Respiratory tract infection | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Sepsis | 1/329 (0.3%) | 1 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 4/1000 (0.4%) | 4 |
| Septic shock | 0/329 (0%) | 0 | 1/328 (0.3%) | 1 | 1/338 (0.3%) | 1 | 0/1000 (0%) | 0 |
| Urinary tract infection | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 1/338 (0.3%) | 1 | 3/1000 (0.3%) | 3 |
| Urosepsis | 2/329 (0.6%) | 2 | 1/328 (0.3%) | 1 | 2/338 (0.6%) | 2 | 1/1000 (0.1%) | 1 |
| Wound infection | 0/329 (0%) | 0 | 1/328 (0.3%) | 1 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Injury, poisoning and procedural complications | ||||||||
| Ankle fracture | 0/329 (0%) | 0 | 1/328 (0.3%) | 1 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Concussion | 1/329 (0.3%) | 1 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Fall | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Femoral neck fracture | 1/329 (0.3%) | 1 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Femur fracture | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Hand fracture | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Hip fracture | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 1/338 (0.3%) | 1 | 1/1000 (0.1%) | 1 |
| Humerus fracture | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Joint dislocation | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Ligament injury | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Limb injury | 0/329 (0%) | 0 | 1/328 (0.3%) | 1 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Meniscus injury | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Nerve injury | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 1/338 (0.3%) | 1 | 0/1000 (0%) | 0 |
| Rib fracture | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Spinal column injury | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Spinal compression fracture | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 1/338 (0.3%) | 1 | 0/1000 (0%) | 0 |
| Subdural haematoma | 1/329 (0.3%) | 1 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Thoracic vertebral fracture | 0/329 (0%) | 0 | 1/328 (0.3%) | 1 | 1/338 (0.3%) | 1 | 0/1000 (0%) | 0 |
| Investigations | ||||||||
| Blood creatinine increased | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Blood lactic acid increased | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Influenza a virus test positive | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Pancreatic enzymes increased | 1/329 (0.3%) | 1 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Metabolism and nutrition disorders | ||||||||
| Dehydration | 2/329 (0.6%) | 2 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Diabetes mellitus inadequate control | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Hyperkalaemia | 1/329 (0.3%) | 1 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Hypoglycaemia | 1/329 (0.3%) | 1 | 0/328 (0%) | 0 | 3/338 (0.9%) | 5 | 12/1000 (1.2%) | 15 |
| Hypokalaemia | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Hyponatraemia | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Iron deficiency | 1/329 (0.3%) | 1 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Musculoskeletal and connective tissue disorders | ||||||||
| Arthropathy | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Intervertebral disc disorder | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Intervertebral disc protrusion | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 1/338 (0.3%) | 1 | 1/1000 (0.1%) | 1 |
| Osteoarthritis | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 2/1000 (0.2%) | 2 |
| Pain in extremity | 0/329 (0%) | 0 | 1/328 (0.3%) | 1 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Spinal osteoarthritis | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Systemic lupus erythematosus | 1/329 (0.3%) | 1 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||||
| Adenocarcinoma of colon | 0/329 (0%) | 0 | 1/328 (0.3%) | 1 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Bile duct adenocarcinoma | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Bladder transitional cell carcinoma | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Breast cancer stage ii | 0/329 (0%) | 0 | 1/328 (0.3%) | 1 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Colon cancer metastatic | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 1/338 (0.3%) | 1 | 1/1000 (0.1%) | 1 |
| Glioblastoma | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Invasive ductal breast carcinoma | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Invasive lobular breast carcinoma | 0/329 (0%) | 0 | 1/328 (0.3%) | 1 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Laryngeal squamous cell carcinoma | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Lung adenocarcinoma | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Lung neoplasm malignant | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Meningioma | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Metastases to liver | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Metastases to lymph nodes | 0/329 (0%) | 0 | 1/328 (0.3%) | 1 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Metastatic squamous cell carcinoma | 0/329 (0%) | 0 | 1/328 (0.3%) | 1 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Nasopharyngeal cancer | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Neoplasm malignant | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 1/338 (0.3%) | 1 | 0/1000 (0%) | 0 |
| Non-hodgkin's lymphoma | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Ovarian cancer | 0/131 (0%) | 0 | 0/119 (0%) | 0 | 1/135 (0.7%) | 1 | 0/364 (0%) | 0 |
| Pancreatic carcinoma | 1/329 (0.3%) | 1 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Pancreatic neoplasm | 0/329 (0%) | 0 | 1/328 (0.3%) | 1 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Papillary renal cell carcinoma | 1/329 (0.3%) | 1 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Prostate cancer | 0/198 (0%) | 0 | 0/209 (0%) | 0 | 1/203 (0.5%) | 1 | 3/636 (0.5%) | 3 |
| Renal cancer recurrent | 1/329 (0.3%) | 1 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Renal cell carcinoma | 1/329 (0.3%) | 1 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Squamous cell carcinoma of lung | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 2/1000 (0.2%) | 2 |
| Nervous system disorders | ||||||||
| Carpal tunnel syndrome | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Cerebellar stroke | 0/329 (0%) | 0 | 1/328 (0.3%) | 1 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Cerebrovascular accident | 1/329 (0.3%) | 1 | 0/328 (0%) | 0 | 1/338 (0.3%) | 1 | 1/1000 (0.1%) | 1 |
| Cognitive disorder | 1/329 (0.3%) | 1 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Coma | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Cranial nerve disorder | 1/329 (0.3%) | 1 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Dizziness | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Encephalopathy | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Guillain-barre syndrome | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 1/338 (0.3%) | 1 | 0/1000 (0%) | 0 |
| Haemorrhagic stroke | 2/329 (0.6%) | 2 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 2/1000 (0.2%) | 2 |
| Headache | 1/329 (0.3%) | 1 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Hemiplegia | 1/329 (0.3%) | 1 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Hypoxic-ischaemic encephalopathy | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 1/338 (0.3%) | 1 | 2/1000 (0.2%) | 2 |
| Ischaemic stroke | 2/329 (0.6%) | 2 | 4/328 (1.2%) | 4 | 1/338 (0.3%) | 1 | 6/1000 (0.6%) | 6 |
| Lacunar infarction | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Lacunar stroke | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Lumbar radiculopathy | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Metabolic encephalopathy | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Myelopathy | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Neuropathy peripheral | 1/329 (0.3%) | 1 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Presyncope | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Spinal cord compression | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Subarachnoid haemorrhage | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Syncope | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 1/338 (0.3%) | 1 | 2/1000 (0.2%) | 2 |
| Thalamic infarction | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Transient ischaemic attack | 0/329 (0%) | 0 | 2/328 (0.6%) | 2 | 1/338 (0.3%) | 1 | 1/1000 (0.1%) | 1 |
| Psychiatric disorders | ||||||||
| Confusional state | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Disorientation | 0/329 (0%) | 0 | 1/328 (0.3%) | 1 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Renal and urinary disorders | ||||||||
| Acute kidney injury | 2/329 (0.6%) | 2 | 1/328 (0.3%) | 1 | 0/338 (0%) | 0 | 3/1000 (0.3%) | 3 |
| Bladder mass | 1/329 (0.3%) | 1 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Chronic kidney disease | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Haematuria | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 1/338 (0.3%) | 1 | 0/1000 (0%) | 0 |
| Hydronephrosis | 1/329 (0.3%) | 2 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Nephrolithiasis | 1/329 (0.3%) | 1 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Renal cyst | 1/329 (0.3%) | 1 | 0/328 (0%) | 0 | 1/338 (0.3%) | 1 | 1/1000 (0.1%) | 1 |
| Renal failure | 0/329 (0%) | 0 | 1/328 (0.3%) | 1 | 0/338 (0%) | 0 | 2/1000 (0.2%) | 2 |
| Renal impairment | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 2/1000 (0.2%) | 2 |
| Renal infarct | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Renal mass | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Ureterolithiasis | 1/329 (0.3%) | 1 | 1/328 (0.3%) | 1 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Urinary bladder polyp | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Reproductive system and breast disorders | ||||||||
| Ovarian cyst | 0/131 (0%) | 0 | 0/119 (0%) | 0 | 0/135 (0%) | 0 | 1/364 (0.3%) | 1 |
| Respiratory, thoracic and mediastinal disorders | ||||||||
| Acute pulmonary oedema | 1/329 (0.3%) | 1 | 1/328 (0.3%) | 1 | 0/338 (0%) | 0 | 2/1000 (0.2%) | 2 |
| Acute respiratory distress syndrome | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Acute respiratory failure | 1/329 (0.3%) | 1 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 3/1000 (0.3%) | 3 |
| Asthma | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 1/338 (0.3%) | 1 | 0/1000 (0%) | 0 |
| Asthmatic crisis | 1/329 (0.3%) | 1 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Chronic obstructive pulmonary disease | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 3/1000 (0.3%) | 4 |
| Dyspnoea | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 1/338 (0.3%) | 1 | 1/1000 (0.1%) | 1 |
| Epistaxis | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Hypoxia | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 1/338 (0.3%) | 1 | 1/1000 (0.1%) | 1 |
| Interstitial lung disease | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 2/1000 (0.2%) | 2 |
| Pneumothorax | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Pulmonary embolism | 1/329 (0.3%) | 1 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 3/1000 (0.3%) | 3 |
| Pulmonary fibrosis | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Pulmonary mass | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Respiratory failure | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 4/1000 (0.4%) | 4 |
| Skin and subcutaneous tissue disorders | ||||||||
| Diabetic foot | 0/329 (0%) | 0 | 1/328 (0.3%) | 1 | 0/338 (0%) | 0 | 3/1000 (0.3%) | 4 |
| Skin necrosis | 1/329 (0.3%) | 1 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Skin ulcer | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Surgical and medical procedures | ||||||||
| Coronary artery bypass | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 1/338 (0.3%) | 1 | 0/1000 (0%) | 0 |
| Intervertebral disc operation | 0/329 (0%) | 0 | 1/328 (0.3%) | 1 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Spinal fusion surgery | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Vascular disorders | ||||||||
| Aortic aneurysm | 0/329 (0%) | 0 | 1/328 (0.3%) | 1 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Aortic aneurysm rupture | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Arteriosclerosis | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Deep vein thrombosis | 1/329 (0.3%) | 1 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 2/1000 (0.2%) | 2 |
| Hypertension | 0/329 (0%) | 0 | 1/328 (0.3%) | 1 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Hypotension | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Iliac artery stenosis | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Peripheral arterial occlusive disease | 0/329 (0%) | 0 | 2/328 (0.6%) | 2 | 1/338 (0.3%) | 1 | 1/1000 (0.1%) | 1 |
| Peripheral artery occlusion | 1/329 (0.3%) | 1 | 1/328 (0.3%) | 1 | 0/338 (0%) | 0 | 0/1000 (0%) | 0 |
| Peripheral ischaemia | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 1/338 (0.3%) | 1 | 0/1000 (0%) | 0 |
| Peripheral vascular disorder | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
| Thrombophlebitis superficial | 0/329 (0%) | 0 | 0/328 (0%) | 0 | 0/338 (0%) | 0 | 1/1000 (0.1%) | 1 |
Other (Not Including Serious) Adverse Events |
||||||||
| 5 mg Tirzepatide | 10 mg Tirzepatide | 15 mg Tirzepatide | Insulin Glargine | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 112/329 (34%) | 158/328 (48.2%) | 184/338 (54.4%) | 192/1000 (19.2%) | ||||
| Gastrointestinal disorders | ||||||||
| Constipation | 17/329 (5.2%) | 17 | 14/328 (4.3%) | 15 | 14/338 (4.1%) | 14 | 5/1000 (0.5%) | 5 |
| Diarrhoea | 41/329 (12.5%) | 68 | 65/328 (19.8%) | 128 | 74/338 (21.9%) | 118 | 44/1000 (4.4%) | 50 |
| Dyspepsia | 18/329 (5.5%) | 23 | 27/328 (8.2%) | 36 | 26/338 (7.7%) | 36 | 13/1000 (1.3%) | 13 |
| Nausea | 39/329 (11.9%) | 104 | 53/328 (16.2%) | 91 | 76/338 (22.5%) | 157 | 23/1000 (2.3%) | 29 |
| Vomiting | 16/329 (4.9%) | 18 | 27/328 (8.2%) | 43 | 29/338 (8.6%) | 62 | 15/1000 (1.5%) | 16 |
| Infections and infestations | ||||||||
| Covid-19 | 13/329 (4%) | 14 | 12/328 (3.7%) | 12 | 17/338 (5%) | 17 | 49/1000 (4.9%) | 49 |
| Nasopharyngitis | 10/329 (3%) | 11 | 16/328 (4.9%) | 17 | 16/338 (4.7%) | 19 | 65/1000 (6.5%) | 70 |
| Investigations | ||||||||
| Lipase increased | 10/329 (3%) | 11 | 13/328 (4%) | 15 | 21/338 (6.2%) | 25 | 18/1000 (1.8%) | 18 |
| Metabolism and nutrition disorders | ||||||||
| Decreased appetite | 29/329 (8.8%) | 36 | 36/328 (11%) | 46 | 35/338 (10.4%) | 43 | 5/1000 (0.5%) | 5 |
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
Results Point of Contact
| Name/Title | Chief Medical Officer |
|---|---|
| Organization | Eli Lilly and Company |
| Phone | 800-545-5979 |
| ClinicalTrials.gov@lilly.com |
Responsible Party:
Eli Lilly and Company
ClinicalTrials.gov Identifier:
NCT03730662
Other Study ID Numbers:
- 17072
- I8F-MC-GPGM
- 2018-002618-11
First Posted:
Nov 5, 2018
Last Update Posted:
Feb 14, 2022
Last Verified:
Jan 1, 2022