Acute Coronary Syndrome, Diabetes Mellitus, Type 2
Conditions
Keywords
Diabetes Mellitus - Type 2, Diabetes Mellitus, cardiovascular outcomes, heart attack, stroke, dipeptidyl-peptidase IV inhibitors, metabolic disorders, metabolic diseases, glucose metabolism disorders
Brief summary
The purpose of this study is to evaluate the cardiovascular outcomes of alogliptin, once daily (QD), compared with placebo, in addition to standard of care, in patients with type 2 diabetes mellitus and acute coronary syndrome.
Detailed description
Alogliptin is a selective and potent dipeptidyl peptidase-4 inhibitor developed by Takeda for use in patients with type 2 diabetes mellitus. Cardiovascular outcomes is of special interest in the type 2 diabetes mellitus population, particularly in type 2 diabetes mellitus patients who have cardiovascular disease and are at high risk for major adverse cardiac events, such as those patients who have had recent acute coronary syndrome. This study has been designed to evaluate the cardiovascular safety of alogliptin versus placebo in addition to Standard of Care in adults with type 2 diabetes mellitus and acute coronary syndrome.
Interventions
DRUGAlogliptin
Alogliptin tablets
DRUGPlacebo
Alogliptin placebo matching tablets
Sponsors
Takeda
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of type 2 diabetes mellitus * Is receiving monotherapy or combination antidiabetic therapy with a glycosylated hemoglobin level between 6.5% and 11.0%, inclusive, at Screening (between 7.0 and 11.0%, inclusive, if the participant's antidiabetic regimen includes insulin) * Diagnosis of acute coronary syndrome within 15 to 90 days prior to randomization.
Exclusion criteria
* Signs of type 1 diabetes mellitus * Currently receiving a glucagon-like peptide-1 analogue for glycemic control of type 2 diabetes mellitus at Screening * Received a dipeptidyl peptidase-4 inhibitor for either more than 14 days total or within the 3 months prior to Screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Primary Major Adverse Cardiac Events (MACE) | From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months). | Primary Major Adverse Cardiac Events were defined as a composite of cardiovascular death, nonfatal myocardial infarction and nonfatal stroke; these events were adjudicated by an independent cardiovascular endpoints committee. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Secondary Major Adverse Cardiac Events (MACE) | From randomization until the adjudication cut-of date of May 31 2013 (maximum time on study was 41 months). | Secondary MACE composite consisted of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or urgent revascularization due to unstable angina; these events were adjudicated by an independent cardiovascular endpoint committee. |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Croatia, Czechia, Denmark, Egypt, Finland, France, Germany, Greece, Guatemala, Hong Kong, Hungary, India, Israel, Italy, Japan, Kuwait, Latvia, Lithuania, Malaysia, Mexico, New Zealand, Peru, Philippines, Poland, Portugal, Puerto Rico, Romania, Russia, Serbia, Slovakia, South Africa, South Korea, Spain, Sweden, Taiwan, Thailand, Turkey (Türkiye), Ukraine, United Arab Emirates, United Kingdom, United States
Participant flow
Recruitment details
Participants took part in the study at 898 investigative sites worldwide from 24 September 2009 to 18 June 2013.
Pre-assignment details
Participants with a diagnosis of type 2 diabetes mellitus and acute coronary syndrome were enrolled equally in 1 of 2 treatment groups, once a day placebo or alogliptin, in addition to receiving standard of care for cardiovascular disease and diabetes.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Alogliptin placebo matching tablets, orally, once daily. | 2,679 |
| Alogliptin Alogliptin 25 mg, tablets, orally, once daily for participants with normal or mildly impaired renal function as defined by estimated glomerular filtration rate (eGFR) ≥ 60 mL/min). Alogliptin 12.5 mg, tablets, orally, once daily for participants with moderately impaired renal function (eGFR ≥30 and \<60 mL/min). Alogliptin 6.25 mg, tablets, orally, once daily for participants with severely impaired renal function or end stage renal disease (eGFR \<30 mL/min). | 2,701 |
| Total | 5,380 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 169 | 150 |
| Overall Study | Investigator Discretion | 0 | 1 |
| Overall Study | Lost to Follow-up | 19 | 11 |
| Overall Study | Major Protocol Deviation | 0 | 1 |
| Overall Study | Other | 26 | 34 |
| Overall Study | Voluntary Withdrawal | 104 | 101 |
Baseline characteristics
| Characteristic | Total | Alogliptin | Placebo |
|---|---|---|---|
| Age, Continuous | 60.9 years STANDARD_DEVIATION 9.92 | 61.0 years STANDARD_DEVIATION 9.96 | 60.7 years STANDARD_DEVIATION 9.88 |
| Body Mass Index | 29.48 kg/m^2 STANDARD_DEVIATION 5.591 | 29.42 kg/m^2 STANDARD_DEVIATION 5.422 | 29.53 kg/m^2 STANDARD_DEVIATION 5.758 |
| Duration of Type 2 Diabetes Mellitus | 9.16 years STANDARD_DEVIATION 8.159 | 9.13 years STANDARD_DEVIATION 8.198 | 9.18 years STANDARD_DEVIATION 8.121 |
| Estimated Glomerular Filtration Rate (eGFR) | 70.93 mL/min/1.73 m^2 STANDARD_DEVIATION 21.417 | 70.86 mL/min/1.73 m^2 STANDARD_DEVIATION 21.297 | 71.01 mL/min/1.73 m^2 STANDARD_DEVIATION 21.541 |
| Index Acute Coronary Syndrome (ACS) Event Type Myocardial Infarction | 4152 participants | 2084 participants | 2068 participants |
| Index Acute Coronary Syndrome (ACS) Event Type Unstable Angina | 1214 participants | 609 participants | 605 participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 110 participants | 56 participants | 54 participants |
| Race/Ethnicity, Customized Asian | 1089 participants | 547 participants | 542 participants |
| Race/Ethnicity, Customized Black or African American | 216 participants | 101 participants | 115 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 1537 participants | 773 participants | 764 participants |
| Race/Ethnicity, Customized More than one race | 45 participants | 25 participants | 20 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 11 participants | 6 participants | 5 participants |
| Race/Ethnicity, Customized Non-Hispanic or Latino | 3843 participants | 1928 participants | 1915 participants |
| Race/Ethnicity, Customized White | 3909 participants | 1966 participants | 1943 participants |
| Region of Enrollment Argentina | 272 participants | 136 participants | 136 participants |
| Region of Enrollment Australia | 15 participants | 8 participants | 7 participants |
| Region of Enrollment Austria | 16 participants | 8 participants | 8 participants |
| Region of Enrollment Belgium | 23 participants | 12 participants | 11 participants |
| Region of Enrollment Brazil | 360 participants | 181 participants | 179 participants |
| Region of Enrollment Bulgaria | 82 participants | 41 participants | 41 participants |
| Region of Enrollment Canada | 109 participants | 55 participants | 54 participants |
| Region of Enrollment Chile | 106 participants | 55 participants | 51 participants |
| Region of Enrollment Colombia | 28 participants | 13 participants | 15 participants |
| Region of Enrollment Croatia | 77 participants | 39 participants | 38 participants |
| Region of Enrollment Czech Republic | 26 participants | 13 participants | 13 participants |
| Region of Enrollment Denmark | 6 participants | 3 participants | 3 participants |
| Region of Enrollment Egypt | 14 participants | 7 participants | 7 participants |
| Region of Enrollment Finland | 22 participants | 10 participants | 12 participants |
| Region of Enrollment France | 22 participants | 11 participants | 11 participants |
| Region of Enrollment Germany | 53 participants | 27 participants | 26 participants |
| Region of Enrollment Greece | 1 participants | 1 participants | 0 participants |
| Region of Enrollment Guatemala | 49 participants | 24 participants | 25 participants |
| Region of Enrollment Hong Kong | 23 participants | 12 participants | 11 participants |
| Region of Enrollment Hungary | 119 participants | 59 participants | 60 participants |
| Region of Enrollment India | 330 participants | 165 participants | 165 participants |
| Region of Enrollment Israel | 201 participants | 101 participants | 100 participants |
| Region of Enrollment Italy | 50 participants | 25 participants | 25 participants |
| Region of Enrollment Japan | 209 participants | 104 participants | 105 participants |
| Region of Enrollment Korea, Republic Of | 123 participants | 62 participants | 61 participants |
| Region of Enrollment Kuwait | 5 participants | 3 participants | 2 participants |
| Region of Enrollment Latvia | 12 participants | 6 participants | 6 participants |
| Region of Enrollment Lithuania | 36 participants | 20 participants | 16 participants |
| Region of Enrollment Malaysia | 81 participants | 42 participants | 39 participants |
| Region of Enrollment Mexico | 383 participants | 191 participants | 192 participants |
| Region of Enrollment New Zealand | 26 participants | 13 participants | 13 participants |
| Region of Enrollment Peru | 160 participants | 81 participants | 79 participants |
| Region of Enrollment Philippines | 102 participants | 50 participants | 52 participants |
| Region of Enrollment Poland | 239 participants | 118 participants | 121 participants |
| Region of Enrollment Portugal | 29 participants | 16 participants | 13 participants |
| Region of Enrollment Puerto Rico | 35 participants | 19 participants | 16 participants |
| Region of Enrollment Romania | 78 participants | 38 participants | 40 participants |
| Region of Enrollment Russian Federation | 304 participants | 151 participants | 153 participants |
| Region of Enrollment Serbia | 70 participants | 35 participants | 35 participants |
| Region of Enrollment Slovakia | 95 participants | 49 participants | 46 participants |
| Region of Enrollment South Africa | 80 participants | 41 participants | 39 participants |
| Region of Enrollment Spain | 43 participants | 22 participants | 21 participants |
| Region of Enrollment Sweden | 32 participants | 16 participants | 16 participants |
| Region of Enrollment Taiwan, Province Of China | 27 participants | 13 participants | 14 participants |
| Region of Enrollment Thailand | 115 participants | 58 participants | 57 participants |
| Region of Enrollment Ukraine | 276 participants | 138 participants | 138 participants |
| Region of Enrollment United Arab Emirates | 6 participants | 3 participants | 3 participants |
| Region of Enrollment United Kingdom | 66 participants | 34 participants | 32 participants |
| Region of Enrollment United States | 744 participants | 372 participants | 372 participants |
| Renal Impairment Category Mild Renal Impairment | 2976 participants | 1530 participants | 1446 participants |
| Renal Impairment Category Moderate Renal Impairment | 1408 participants | 694 participants | 714 participants |
| Renal Impairment Category Normal Renal Function | 839 participants | 399 participants | 440 participants |
| Renal Impairment Category Severe Renal Impairment/End-Stage Renal Disease | 157 participants | 78 participants | 79 participants |
| Sex: Female, Male Female | 1729 Participants | 873 Participants | 856 Participants |
| Sex: Female, Male Male | 3651 Participants | 1828 Participants | 1823 Participants |
| Smoking History Current smoker | 734 participants | 351 participants | 383 participants |
| Smoking History Ex-smoker | 2344 participants | 1192 participants | 1152 participants |
| Smoking History Never smoked | 2302 participants | 1158 participants | 1144 participants |
| Time From Index ACS Event to Randomization | 47.8 days STANDARD_DEVIATION 22 | 47.6 days STANDARD_DEVIATION 22.04 | 48.0 days STANDARD_DEVIATION 21.95 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1,493 / 2,679 | 1,523 / 2,701 |
| serious Total, serious adverse events | 952 / 2,679 | 907 / 2,701 |
Outcome results
Primary
Percentage of Participants With Primary Major Adverse Cardiac Events (MACE)
Primary Major Adverse Cardiac Events were defined as a composite of cardiovascular death, nonfatal myocardial infarction and nonfatal stroke; these events were adjudicated by an independent cardiovascular endpoints committee.
Time frame: From randomization until the adjudication cut-off date of May 31 2013 (maximum time on study was 41 months).
Population: Full analysis set (all randomized participants)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Primary Major Adverse Cardiac Events (MACE) | 11.8 percentage of participants |
| Alogliptin | Percentage of Participants With Primary Major Adverse Cardiac Events (MACE) | 11.3 percentage of participants |
Comparison: Statistical analyses of the primary MACE composite endpoint was based on sequences of 1-sided repeated confidence intervals (CIs) to assess non-inferiority or statistical superiority with respect to the null hypotheses. Each sequence of repeated CIs was constructed using critical values from a 1-sided stopping boundary for a group sequential design (GSD), to preserve an overall false-rejection rate of 2.5%. Each sequence of 1-sided repeated CIs had a simultaneous coverage probability of 97.5%.p-value: 0.315Cox proportional hazards
Comparison: Stratified by endpoint renal function and geographic regionp-value: 0.332Cox proportional hazards
Secondary
Percentage of Participants With Secondary Major Adverse Cardiac Events (MACE)
Secondary MACE composite consisted of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or urgent revascularization due to unstable angina; these events were adjudicated by an independent cardiovascular endpoint committee.
Time frame: From randomization until the adjudication cut-of date of May 31 2013 (maximum time on study was 41 months).
Population: Full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Secondary Major Adverse Cardiac Events (MACE) | 13.4 percentage of participants |
| Alogliptin | Percentage of Participants With Secondary Major Adverse Cardiac Events (MACE) | 12.7 percentage of participants |