Diabetes Mellitus, Type 2
Conditions
Keywords
Diabetes, Coronary artery disease, Outcome, Prevention, Antiplatelet
Brief summary
The purpose of this study is to compare the effect of ticagrelor versus placebo in patients with Type 2 Diabetes Mellitus.
Detailed description
A multinational, randomised, double-blind, placebo-controlled phase IIIb trial to evaluate the effect of ticagrelor twice daily on the incidence of cardiovascular death, myocardial infarction or stroke in patients with type 2 diabetes mellitus
Interventions
DRUGTicagrelor 60 mg
Ticagrelor 60 mg bd taken orally as tablets
Ticagrelor placebo bd taken orally as tablets
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
50 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
Men or women ≥50 years of age with type 2 diabetes mellitus on treatment with a glucose lowering medication since at least 6 months, and either documented coronary artery occlusive disease or previous revascularization of a coronary artery. Key
Exclusion criteria
History of myocardial infarction or any stroke; planned treatment with agents inhibiting blood clotting; planned use of ASA/Aspirin at doses above 150 mg daily; planned coronary, cerebrovascular, or peripheral arterial revascularization; patients with known bleeding disorders and patients who need chronic oral anticoagulant therapy or chronic low-molecular-weight heparin; history of intracranial bleeding at any time, or a history of bleeding from the gastrointestinal tract within the last 6 months or a major surgery within the last 30 days; patients with known severe liver disease or with kidney failure requiring dialysis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Composite of Cardiovascular (CV) Death, MI or Stroke | From randomisation to primary analysis censoring date (PACD). Median time in study until PACD was 40 months. | Participants with Cardiovascular (CV) death, myocardial infarction (MI) or stroke. If no event, censoring occurs at the earliest of PACD, last endpoint assessment date and non-CV death date. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| CV Death | From randomisation to primary analysis censoring date (PACD). Median time in study until PACD was 40 months. | Participants with Cardiovascular (CV) death. If no event, censoring occurs at the earliest of PACD, last endpoint assessment date and non-CV death date. |
| MI | From randomisation to primary analysis censoring date (PACD). Median time in study until PACD was 40 months. | Participants with myocardial infarction. If no event, censoring occurs at the earliest of primary analysis censoring date (PACD), last endpoint assessment date and death date |
| Ischaemic Stroke | From randomisation to primary analysis censoring date (PACD). Median time in study until PACD was 40 months. | Participants with ischaemic stroke. If no event, censoring occurs at the earliest of PACD, last endpoint assessment date and death date. |
| All-cause Death | From randomisation to primary analysis censoring date (PACD). Median time in study until PACD was 40 months. | Participants with all-cause death. If no event, censoring occurs at the earliest of PACD and last endpoint assessment date. Includes deaths based on publically available vital status data in patients who have withdrawn consent. |
Other
| Measure | Time frame | Description |
|---|---|---|
| TIMI Major or Minor Bleeding Event | From randomisation to 7 days following the date of last dose of study medication. Maximum duration of exposure was 59 months. | Participants with TIMI major or minor bleeding event. If no event, censoring occurs at the earliest of last endpoint assessment date, death date and 7 days following the date of last dose of study medication |
| PLATO Major Bleeding Event | From randomisation to 7 days following the date of last dose of study medication. Maximum duration of exposure was 59 months. | Participants with PLATO major bleeding event. If no event, censoring occurs at the earliest of last endpoint assessment date, death date and 7 days following the date of last dose of study medication |
| Permanent Discontinuation of Study Medication Due to Any Bleeding Event | From randomisation to 7 days following the date of last dose of study medication. Maximum duration of exposure was 59 months. | Participants with permanent discontinuation of study medication due to any bleeding event. If no event, censoring occurs at the earliest of last endpoint assessment date, death date and the date of last dose of study medication |
| TIMI Major Bleeding Event (Primary Safety Objective) | From randomisation to 7 days following the date of last dose of study medication. Maximum duration of exposure was 59 months. | Participants with TIMI major bleeding event. If no event, censoring occurs at the earliest of last endpoint assessment date, death date and 7 days following the date of last dose of study medication |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Chile, China, Colombia, Czechia, Denmark, Finland, France, Germany, Hong Kong, Hungary, India, Israel, Italy, Japan, Mexico, Netherlands, Norway, Peru, Philippines, Poland, Puerto Rico, Romania, Russia, Saudi Arabia, Slovakia, South Africa, South Korea, Spain, Sweden, Taiwan, Thailand, Turkey (Türkiye), Ukraine, United Kingdom, United States, Vietnam
Participant flow
Recruitment details
1315 study sites in 42 countries enrolled patients. The first patient was enrolled on 10 February 2014. The last patient visit took place on 25 January 2019.
Pre-assignment details
Enrolled patients randomised to study drug 95.8%; n =19271, of which 51 patients were randomised to study drug at a site prematurely closed by sponsor and excluded from the study results. Patients who were not randomised 4.2%; n=837. Patient did not meet inclusion/exclusion criteria n=454, Patient decision n=256, Death n=1, Other reason n=131.
Participants by arm
| Arm | Count |
|---|---|
| Ticagrelor 60 mg Initially ticagrelor 90 mg or corresponding placebo was the selected dose, but reduced to ticagrelor 60 mg or corresponding placebo in Clinical Study Protocol Amendment No 1. | 9,619 |
| Ticagrelor Placebo Initially ticagrelor 90 mg or corresponding placebo was the selected dose, but reduced to ticagrelor 60 mg or corresponding placebo in Clinical Study Protocol Amendment No 1. | 9,601 |
| Total | 19,220 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 6 | 4 |
| Overall Study | Site prematurely closed by sponsor | 26 | 25 |
| Overall Study | Withdrawal by Subject | 117 | 94 |
Baseline characteristics
| Characteristic | Ticagrelor Placebo | Total | Ticagrelor 60 mg |
|---|---|---|---|
| Age, Continuous | 66.3 Years STANDARD_DEVIATION 7.7 | 66.3 Years STANDARD_DEVIATION 7.8 | 66.3 Years STANDARD_DEVIATION 7.8 |
| Race/Ethnicity, Customized American indian or alaska native | 152 Participants | 313 Participants | 161 Participants |
| Race/Ethnicity, Customized Asian | 2195 Participants | 4406 Participants | 2211 Participants |
| Race/Ethnicity, Customized Black or african american | 198 Participants | 403 Participants | 205 Participants |
| Race/Ethnicity, Customized Native hawaiian or other pacific islander | 7 Participants | 14 Participants | 7 Participants |
| Race/Ethnicity, Customized Other | 191 Participants | 388 Participants | 197 Participants |
| Race/Ethnicity, Customized White | 6858 Participants | 13696 Participants | 6838 Participants |
| Region of Enrollment Argentina | 199 Participants | 394 Participants | 195 Participants |
| Region of Enrollment Australia | 94 Participants | 188 Participants | 94 Participants |
| Region of Enrollment Austria | 45 Participants | 87 Participants | 42 Participants |
| Region of Enrollment Belgium | 108 Participants | 217 Participants | 109 Participants |
| Region of Enrollment Brazil | 399 Participants | 811 Participants | 412 Participants |
| Region of Enrollment Bulgaria | 443 Participants | 878 Participants | 435 Participants |
| Region of Enrollment Canada | 365 Participants | 729 Participants | 364 Participants |
| Region of Enrollment Chile | 148 Participants | 300 Participants | 152 Participants |
| Region of Enrollment China | 454 Participants | 910 Participants | 456 Participants |
| Region of Enrollment Colombia | 68 Participants | 136 Participants | 68 Participants |
| Region of Enrollment Czech Republic | 298 Participants | 602 Participants | 304 Participants |
| Region of Enrollment Denmark | 120 Participants | 243 Participants | 123 Participants |
| Region of Enrollment Finland | 58 Participants | 118 Participants | 60 Participants |
| Region of Enrollment France | 87 Participants | 172 Participants | 85 Participants |
| Region of Enrollment Germany | 270 Participants | 547 Participants | 277 Participants |
| Region of Enrollment Hong Kong | 76 Participants | 152 Participants | 76 Participants |
| Region of Enrollment Hungary | 310 Participants | 616 Participants | 306 Participants |
| Region of Enrollment India | 145 Participants | 292 Participants | 147 Participants |
| Region of Enrollment Israel | 57 Participants | 117 Participants | 60 Participants |
| Region of Enrollment Italy | 63 Participants | 130 Participants | 67 Participants |
| Region of Enrollment Japan | 250 Participants | 496 Participants | 246 Participants |
| Region of Enrollment Korea, Republic Of | 437 Participants | 870 Participants | 433 Participants |
| Region of Enrollment Mexico | 182 Participants | 364 Participants | 182 Participants |
| Region of Enrollment Netherlands | 237 Participants | 479 Participants | 242 Participants |
| Region of Enrollment Norway | 96 Participants | 191 Participants | 95 Participants |
| Region of Enrollment Peru | 82 Participants | 173 Participants | 91 Participants |
| Region of Enrollment Philippines | 45 Participants | 92 Participants | 47 Participants |
| Region of Enrollment Poland | 821 Participants | 1636 Participants | 815 Participants |
| Region of Enrollment Romania | 43 Participants | 80 Participants | 37 Participants |
| Region of Enrollment Russia | 560 Participants | 1121 Participants | 561 Participants |
| Region of Enrollment Saudi Arabia | 76 Participants | 155 Participants | 79 Participants |
| Region of Enrollment Slovakia | 122 Participants | 244 Participants | 122 Participants |
| Region of Enrollment South Africa | 149 Participants | 299 Participants | 150 Participants |
| Region of Enrollment Spain | 170 Participants | 340 Participants | 170 Participants |
| Region of Enrollment Sweden | 114 Participants | 224 Participants | 110 Participants |
| Region of Enrollment Taiwan, Province Of China | 401 Participants | 803 Participants | 402 Participants |
| Region of Enrollment Thailand | 116 Participants | 231 Participants | 115 Participants |
| Region of Enrollment Turkey | 112 Participants | 225 Participants | 113 Participants |
| Region of Enrollment Ukraine | 393 Participants | 792 Participants | 399 Participants |
| Region of Enrollment United Kingdom | 123 Participants | 246 Participants | 123 Participants |
| Region of Enrollment USA | 1140 Participants | 2266 Participants | 1126 Participants |
| Region of Enrollment Viet Nam | 125 Participants | 254 Participants | 129 Participants |
| Sex: Female, Male Female | 2988 Participants | 6031 Participants | 3043 Participants |
| Sex: Female, Male Male | 6613 Participants | 13189 Participants | 6576 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 589 / 9,619 | 602 / 9,601 |
| other Total, other adverse events | 1,951 / 9,562 | 610 / 9,531 |
| serious Total, serious adverse events | 3,049 / 9,562 | 3,210 / 9,531 |
Outcome results
Primary
Composite of Cardiovascular (CV) Death, MI or Stroke
Participants with Cardiovascular (CV) death, myocardial infarction (MI) or stroke. If no event, censoring occurs at the earliest of PACD, last endpoint assessment date and non-CV death date.
Time frame: From randomisation to primary analysis censoring date (PACD). Median time in study until PACD was 40 months.
Population: The population was the full analysis set, which included all randomised patients except the 51 patients who were randomised to study drug at a site prematurely closed by sponsor.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ticagrelor 60 mg | Composite of Cardiovascular (CV) Death, MI or Stroke | 736 Number of participants with event |
| Ticagrelor Placebo | Composite of Cardiovascular (CV) Death, MI or Stroke | 818 Number of participants with event |
p-value: 0.037895% CI: [0.81, 0.99]Regression, Cox
Secondary
All-cause Death
Participants with all-cause death. If no event, censoring occurs at the earliest of PACD and last endpoint assessment date. Includes deaths based on publically available vital status data in patients who have withdrawn consent.
Time frame: From randomisation to primary analysis censoring date (PACD). Median time in study until PACD was 40 months.
Population: The population was the full analysis set, which included all randomised patients except the 51 patients who were randomised to study drug at a site prematurely closed by sponsor.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ticagrelor 60 mg | All-cause Death | 579 Number of participants with event |
| Ticagrelor Placebo | All-cause Death | 592 Number of participants with event |
p-value: 0.684695% CI: [0.87, 1.1]Regression, Cox
Secondary
CV Death
Participants with Cardiovascular (CV) death. If no event, censoring occurs at the earliest of PACD, last endpoint assessment date and non-CV death date.
Time frame: From randomisation to primary analysis censoring date (PACD). Median time in study until PACD was 40 months.
Population: The population was the full analysis set, which included all randomised patients except the 51 patients who were randomised to study drug at a site prematurely closed by sponsor.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ticagrelor 60 mg | CV Death | 364 Number of participants with event |
| Ticagrelor Placebo | CV Death | 357 Number of participants with event |
p-value: 0.788395% CI: [0.88, 1.18]Regression, Cox
Secondary
Ischaemic Stroke
Participants with ischaemic stroke. If no event, censoring occurs at the earliest of PACD, last endpoint assessment date and death date.
Time frame: From randomisation to primary analysis censoring date (PACD). Median time in study until PACD was 40 months.
Population: The population was the full analysis set, which included all randomised patients except the 51 patients who were randomised to study drug at a site prematurely closed by sponsor.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ticagrelor 60 mg | Ischaemic Stroke | 152 Number of participants with event |
| Ticagrelor Placebo | Ischaemic Stroke | 191 Number of participants with event |
p-value: 0.037595% CI: [0.64, 0.99]Regression, Cox
Secondary
MI
Participants with myocardial infarction. If no event, censoring occurs at the earliest of primary analysis censoring date (PACD), last endpoint assessment date and death date
Time frame: From randomisation to primary analysis censoring date (PACD). Median time in study until PACD was 40 months.
Population: The population was the full analysis set, which included all randomised patients except the 51 patients who were randomised to study drug at a site prematurely closed by sponsor.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ticagrelor 60 mg | MI | 274 Number of participants with event |
| Ticagrelor Placebo | MI | 328 Number of participants with event |
p-value: 0.029495% CI: [0.71, 0.98]Regression, Cox
Other Pre-specified
Permanent Discontinuation of Study Medication Due to Any Bleeding Event
Participants with permanent discontinuation of study medication due to any bleeding event. If no event, censoring occurs at the earliest of last endpoint assessment date, death date and the date of last dose of study medication
Time frame: From randomisation to 7 days following the date of last dose of study medication. Maximum duration of exposure was 59 months.
Population: The population was the safety analysis set, which included all patients who received at least 1 dose of randomised ticagrelor or placebo
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ticagrelor 60 mg | Permanent Discontinuation of Study Medication Due to Any Bleeding Event | 466 Number of participants with event |
| Ticagrelor Placebo | Permanent Discontinuation of Study Medication Due to Any Bleeding Event | 125 Number of participants with event |
p-value: <0.000195% CI: [3.32, 4.92]Regression, Cox
Other Pre-specified
PLATO Major Bleeding Event
Participants with PLATO major bleeding event. If no event, censoring occurs at the earliest of last endpoint assessment date, death date and 7 days following the date of last dose of study medication
Time frame: From randomisation to 7 days following the date of last dose of study medication. Maximum duration of exposure was 59 months.
Population: The population was the safety analysis set, which included all patients who received at least 1 dose of randomised ticagrelor or placebo
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ticagrelor 60 mg | PLATO Major Bleeding Event | 310 Number of participants with event |
| Ticagrelor Placebo | PLATO Major Bleeding Event | 145 Number of participants with event |
p-value: <0.000195% CI: [1.98, 2.93]Regression, Cox
Other Pre-specified
TIMI Major Bleeding Event (Primary Safety Objective)
Participants with TIMI major bleeding event. If no event, censoring occurs at the earliest of last endpoint assessment date, death date and 7 days following the date of last dose of study medication
Time frame: From randomisation to 7 days following the date of last dose of study medication. Maximum duration of exposure was 59 months.
Population: The population was the safety analysis set, which included all patients who received at least 1 dose of randomised ticagrelor or placebo
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ticagrelor 60 mg | TIMI Major Bleeding Event (Primary Safety Objective) | 206 Number of participants with event |
| Ticagrelor Placebo | TIMI Major Bleeding Event (Primary Safety Objective) | 100 Number of participants with event |
p-value: <0.000195% CI: [1.82, 2.94]Regression, Cox
Other Pre-specified
TIMI Major or Minor Bleeding Event
Participants with TIMI major or minor bleeding event. If no event, censoring occurs at the earliest of last endpoint assessment date, death date and 7 days following the date of last dose of study medication
Time frame: From randomisation to 7 days following the date of last dose of study medication. Maximum duration of exposure was 59 months.
Population: The population was the safety analysis set, which included all patients who received at least 1 dose of randomised ticagrelor or placebo
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ticagrelor 60 mg | TIMI Major or Minor Bleeding Event | 285 Number of participants with event |
| Ticagrelor Placebo | TIMI Major or Minor Bleeding Event | 129 Number of participants with event |
p-value: <0.000195% CI: [2.02, 3.07]Regression, Cox