Type 2 Diabetes Mellitus
Conditions
Brief summary
Primary Objective: To demonstrate that efpeglenatide 4 and 6 mg was noninferior to placebo on 3-point major adverse cardiac events (MACE) in Type 2 diabetes mellitus (T2DM) participants at high cardiovascular (CV) risk. Secondary Objectives: To demonstrate that efpeglenatide 4 and 6 mg was superior to placebo in T2DM participants with high CV risk on the following parameters: * 3-point MACE. * Expanded CV outcome. * Composite outcome of new or worsening nephropathy. To assess the safety and tolerability of efpeglenatide 4 and 6 mg, both added to standard of care in T2DM participants at high CV risk.
Detailed description
The study duration per participant was up to approximately 36 months.
Interventions
Pharmaceutical form: Solution for injection, Route of administration: SC
DRUGPlacebo
Pharmaceutical form: Solution for injection Route of administration: SC
Sponsors
Hanmi Pharmaceutical Company Limited
Sanofi
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
* T2DM with glycosylated hemoglobin (HbA1c) greater than (\>) 7 percentage. * Age 18 years or older who met at least one of the cardiovascular disease criteria or age 50 years (male), 55 years (female) or older with glomerular filtration rate greater than or equal to 25 and less than 60 milliliters per minute and at least had one cardiovascular risk factor. * Female participants agreed to follow contraceptive guidance. * Signed written informed consent.
Exclusion criteria
* Clinically relevant history of gastrointestinal disease associated with prolonged nausea and vomiting. * History of chronic pancreatitis or acute idiopathic pancreatitis or diagnosis of any type of acute pancreatitis within 3 months prior to screening. * Personal or family history of medullary thyroid cancer. * Hypertension (with a systolic blood pressure \>180 millimeters of Mercury \[mmHg\] and/or diastolic blood pressure \>100 mmHg). * Hospitalization for hypertensive emergency within 3 months prior to randomization. * Planned coronary procedure or surgery after randomization. * No documented ophthalmologic exam with fundoscopy within 6 months prior to randomization. * Retinopathy or maculopathy with treatment, either recent (3 months prior to randomization) or planned during the study. * Treated with any glucagon-like peptide-1 receptor agonist product alone (eg, exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, semaglutide) or in combination within 3 months prior to screening. * Use of any Dipeptidyl peptidase 4 inhibitor within 3 months prior to screening. * Antihyperglycemic treatment had not been stable within 3 months prior to screening. The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to First Occurrence of Major Adverse Cardiovascular Events (MACE): Event Rate Per 100 Participant-years for First Occurrence of Major Cardiovascular (CV) Event - Non-Inferiority Analysis | From Day 1 until the date of first adjudicated and confirmed occurrence of major CV event (maximum duration: up to 31.5 months) | All MACE positively adjudicated by the clinical endpoint committee (CEC) were used in the analysis of the composite outcome of first occurrence to CV death, non-fatal myocardial infarction (MI), and non-fatal stroke. Kaplan-Meier curves of the cumulative event rate by treatment groups were used to depict the first occurrence of MACE over time. The event rate per 100 participant-years (calculated by 100\*number of participants with events/sum of time at risk (days) over all participants/365.25) measured in terms of number of events per 100 participant-years was reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to First Occurrence of Major Adverse Cardiovascular Events: Event Rate Per 100 Participant-years for First Occurrence of Major Cardiovascular Event - Superiority Analysis | From Day 1 until the date of first adjudicated and confirmed occurrence of major CV event (maximum duration: up to 31.5 months) | All MACE positively adjudicated by the CEC were used in the analysis of the composite outcome of first occurrence to CV death, non-fatal MI, and non-fatal stroke. Kaplan-Meier curves of the cumulative event rate by treatment groups were used to depict the first occurrence of MACE over time. The event rate per 100 participant-years (calculated by 100\*number of participants with events/sum of time at risk (days) over all participants/365.25) measured in terms of number of events per 100 participant-years was reported. |
| Time to First Occurrence of the Expanded Major Adverse Cardiovascular Events Composite Events: Event Rate Per 100 Participant-years for First Occurrence of Expanded Major Cardiovascular Event | From Day 1 until the date of first adjudicated and confirmed occurrence of major CV event (maximum duration: up to 31.5 months) | All MACE positively adjudicated by the CEC were used in the analysis of the expanded outcome of first occurrence to CV death (including fatal MI and fatal stroke), non-fatal MI, non-fatal stroke, coronary revascularization or hospitalization for unstable angina. Kaplan-Meier curves of the cumulative event rate by treatment groups were used to depict the first occurrence of MACE over time. The event rate per 100 participant-years (calculated by 100\*number of participants with events/sum of time at risk (days) over all participants/365.25) measured in terms of number of events per 100 participant-years was reported. Data analysis was also performed independently by external steering committee for the publication. |
| Time to First Occurrence of Composite Renal Endpoint: Event Rate Per 100 Participant-years for First Occurrence of Composite Renal Endpoint | From Day 1 until the confirmed occurrence of composite renal endpoint (maximum duration: up to 31.5 months) | Composite renal endpoint included the following: incident macroalbuminuria (defined as urinary albumin-to-creatinine ratio of greater than (\>) 300, as measured in mg of albumin to grams of creatinine, or \>33.9, as measured in mg of albumin to millimoles of creatinine), plus an increase in urinary albumin-to-creatinine ratio of at least 30% from baseline, a sustained decrease in estimated glomerular filtration rate (eGFR) of at least 40% for 30 days or more, renal-replacement therapy for 90 days or more, and a sustained eGFR of less than 15 ml per minute per 1.73 m\^2 for 30 days or more. Kaplan-Meier curves of the cumulative event rate by treatment groups were used to depict the first occurrence of renal endpoint over time. The event rate per 100 participant-years (calculated by 100\*number of participants with events/sum of time at risk (days) over all participants/365.25) measured in terms of number of events per 100 participant-years was reported. |
Countries
Argentina, Bulgaria, Canada, Chile, Denmark, Estonia, Finland, Germany, Hungary, India, Italy, Latvia, Lithuania, Mexico, Norway, Peru, Poland, Romania, Russia, Serbia, Slovakia, South Africa, South Korea, Spain, Sweden, Turkey (Türkiye), Ukraine, United States
Participant flow
Recruitment details
The study was conducted at 344 active sites in 28 countries. Overall, 5732 participants were screened between 27 April 2018 and 25 April 2019; of whom 4076 participants were randomized by interactive response technology (1:1:1 ratio) to receive placebo, efpeglenatide 4 milligrams (mg) or efpeglenatide 6 mg. Screen failures were mainly due to inclusion criteria not met.
Pre-assignment details
Randomization was stratified by the current or potential future use of a sodium-glucose co-transporter-2 (SGLT2) inhibitor: current use; potential future use; neither current nor potential future use.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received placebo (matched to Efpeglenatide) as SC injection once weekly up to end of treatment (median duration: 19.8 months). | 1,359 |
| Efpeglenatide 4 mg Participants received Efpeglenatide as SC injection 2 mg per week for 4 weeks then 4 mg per week up to end of treatment (median duration: 19.9 months). | 1,359 |
| Efpeglenatide 6 mg Participants received Efpeglenatide as SC injection 2 mg per week for 4 weeks, then 4 mg per week for 4 weeks and then 6 mg per week up to end of treatment (median duration: 20 months). | 1,358 |
| Total | 4,076 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 49 | 68 | 79 |
| Overall Study | Other | 29 | 20 | 23 |
| Overall Study | Physician decision (other than Adverse event) | 12 | 17 | 10 |
| Overall Study | Randomized and not treated | 1 | 1 | 1 |
| Overall Study | Study terminated by Sponsor | 1,050 | 1,063 | 1,071 |
| Overall Study | Withdrawal by Subject | 176 | 154 | 151 |
Baseline characteristics
| Characteristic | Placebo | Total | Efpeglenatide 6 mg | Efpeglenatide 4 mg |
|---|---|---|---|---|
| Age, Continuous | 64.4 years STANDARD_DEVIATION 8.3 | 64.5 years STANDARD_DEVIATION 8.2 | 64.7 years STANDARD_DEVIATION 8.2 | 64.6 years STANDARD_DEVIATION 8.2 |
| Body Mass Index (BMI) | 32.40 kilogram meter per square (kg/m^2) STANDARD_DEVIATION 6.01 | 32.70 kilogram meter per square (kg/m^2) STANDARD_DEVIATION 6.15 | 32.90 kilogram meter per square (kg/m^2) STANDARD_DEVIATION 6.21 | 32.81 kilogram meter per square (kg/m^2) STANDARD_DEVIATION 6.22 |
| Race (NIH/OMB) American Indian or Alaska Native | 11 Participants | 27 Participants | 8 Participants | 8 Participants |
| Race (NIH/OMB) Asian | 98 Participants | 267 Participants | 82 Participants | 87 Participants |
| Race (NIH/OMB) Black or African American | 50 Participants | 143 Participants | 55 Participants | 38 Participants |
| Race (NIH/OMB) More than one race | 4 Participants | 18 Participants | 5 Participants | 9 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 3 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 34 Participants | 84 Participants | 26 Participants | 24 Participants |
| Race (NIH/OMB) White | 1162 Participants | 3534 Participants | 1180 Participants | 1192 Participants |
| Sex: Female, Male Female | 419 Participants | 1344 Participants | 483 Participants | 442 Participants |
| Sex: Female, Male Male | 940 Participants | 2732 Participants | 875 Participants | 917 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 49 / 1,355 | 40 / 1,360 | 25 / 1,358 |
| other Total, other adverse events | 151 / 1,355 | 348 / 1,360 | 342 / 1,358 |
| serious Total, serious adverse events | 298 / 1,355 | 312 / 1,360 | 275 / 1,358 |
Outcome results
Primary
Time to First Occurrence of Major Adverse Cardiovascular Events (MACE): Event Rate Per 100 Participant-years for First Occurrence of Major Cardiovascular (CV) Event - Non-Inferiority Analysis
All MACE positively adjudicated by the clinical endpoint committee (CEC) were used in the analysis of the composite outcome of first occurrence to CV death, non-fatal myocardial infarction (MI), and non-fatal stroke. Kaplan-Meier curves of the cumulative event rate by treatment groups were used to depict the first occurrence of MACE over time. The event rate per 100 participant-years (calculated by 100\*number of participants with events/sum of time at risk (days) over all participants/365.25) measured in terms of number of events per 100 participant-years was reported.
Time frame: From Day 1 until the date of first adjudicated and confirmed occurrence of major CV event (maximum duration: up to 31.5 months)
Population: Analysis was performed on intent-to-treat (ITT) population. Data for this outcome measure (OM) was planned to be collected and analyzed for pooled population of participants who received Efpeglenatide (at any dose: 4 mg and 6 mg) as pre-specified in the protocol.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Efpeglenatide 4 mg+6 mg | Time to First Occurrence of Major Adverse Cardiovascular Events (MACE): Event Rate Per 100 Participant-years for First Occurrence of Major Cardiovascular (CV) Event - Non-Inferiority Analysis | 3.9 events per 100 participant-years |
| Placebo | Time to First Occurrence of Major Adverse Cardiovascular Events (MACE): Event Rate Per 100 Participant-years for First Occurrence of Major Cardiovascular (CV) Event - Non-Inferiority Analysis | 5.3 events per 100 participant-years |
Comparison: Hazard ratio and 95% Confidence Interval (CI) were obtained from a Cox proportional hazards model with region (North America, Latin America, Europe, other), randomization stratum of SGLT2 inhibitor use (current use, potential future use, neither current nor potential future use) and treatment (efpeglenatide 4 mg, efpeglenatide 6 mg, placebo) as fixed effect factor.p-value: <0.000195% CI: [0.583, 0.918]Log Rank
Secondary
Time to First Occurrence of Composite Renal Endpoint: Event Rate Per 100 Participant-years for First Occurrence of Composite Renal Endpoint
Composite renal endpoint included the following: incident macroalbuminuria (defined as urinary albumin-to-creatinine ratio of greater than (\>) 300, as measured in mg of albumin to grams of creatinine, or \>33.9, as measured in mg of albumin to millimoles of creatinine), plus an increase in urinary albumin-to-creatinine ratio of at least 30% from baseline, a sustained decrease in estimated glomerular filtration rate (eGFR) of at least 40% for 30 days or more, renal-replacement therapy for 90 days or more, and a sustained eGFR of less than 15 ml per minute per 1.73 m\^2 for 30 days or more. Kaplan-Meier curves of the cumulative event rate by treatment groups were used to depict the first occurrence of renal endpoint over time. The event rate per 100 participant-years (calculated by 100\*number of participants with events/sum of time at risk (days) over all participants/365.25) measured in terms of number of events per 100 participant-years was reported.
Time frame: From Day 1 until the confirmed occurrence of composite renal endpoint (maximum duration: up to 31.5 months)
Population: Analysis was performed on ITT population. Data for this OM was planned to be collected and analyzed for pooled population of participants who received Efpeglenatide (at any dose: 4 mg and 6 mg) as pre-specified in the protocol.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Efpeglenatide 4 mg+6 mg | Time to First Occurrence of Composite Renal Endpoint: Event Rate Per 100 Participant-years for First Occurrence of Composite Renal Endpoint | 7.7 events per 100 participant-years |
| Placebo | Time to First Occurrence of Composite Renal Endpoint: Event Rate Per 100 Participant-years for First Occurrence of Composite Renal Endpoint | 11.6 events per 100 participant-years |
Comparison: Hazard ratio and 95% CI were obtained from a Cox proportional hazards model with region (North America, Latin America, Europe, other), randomization stratum of SGLT2 inhibitor use (current use, potential future use, neither current nor potential future use) and treatment (efpeglenatide 4 mg, efpeglenatide 6 mg, placebo) as fixed effect factor.p-value: <0.000195% CI: [0.574, 0.794]Log Rank
Secondary
Time to First Occurrence of Major Adverse Cardiovascular Events: Event Rate Per 100 Participant-years for First Occurrence of Major Cardiovascular Event - Superiority Analysis
All MACE positively adjudicated by the CEC were used in the analysis of the composite outcome of first occurrence to CV death, non-fatal MI, and non-fatal stroke. Kaplan-Meier curves of the cumulative event rate by treatment groups were used to depict the first occurrence of MACE over time. The event rate per 100 participant-years (calculated by 100\*number of participants with events/sum of time at risk (days) over all participants/365.25) measured in terms of number of events per 100 participant-years was reported.
Time frame: From Day 1 until the date of first adjudicated and confirmed occurrence of major CV event (maximum duration: up to 31.5 months)
Population: Analysis was performed on ITT population. Data for this OM was planned to be collected and analyzed for pooled population of participants who received Efpeglenatide (at any dose: 4 mg and 6 mg) as pre-specified in the protocol.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Efpeglenatide 4 mg+6 mg | Time to First Occurrence of Major Adverse Cardiovascular Events: Event Rate Per 100 Participant-years for First Occurrence of Major Cardiovascular Event - Superiority Analysis | 3.9 events per 100 participant-years |
| Placebo | Time to First Occurrence of Major Adverse Cardiovascular Events: Event Rate Per 100 Participant-years for First Occurrence of Major Cardiovascular Event - Superiority Analysis | 5.3 events per 100 participant-years |
Comparison: Hazard ratio and 95% CI were obtained from a Cox proportional hazards model with region (North America, Latin America, Europe, other), randomization stratum of SGLT2 inhibitor use (current use, potential future use, neither current nor potential future use) and treatment (efpeglenatide 4 mg, efpeglenatide 6 mg, placebo) as fixed effect factor.p-value: 0.006995% CI: [0.583, 0.918]Log Rank
Secondary
Time to First Occurrence of the Expanded Major Adverse Cardiovascular Events Composite Events: Event Rate Per 100 Participant-years for First Occurrence of Expanded Major Cardiovascular Event
All MACE positively adjudicated by the CEC were used in the analysis of the expanded outcome of first occurrence to CV death (including fatal MI and fatal stroke), non-fatal MI, non-fatal stroke, coronary revascularization or hospitalization for unstable angina. Kaplan-Meier curves of the cumulative event rate by treatment groups were used to depict the first occurrence of MACE over time. The event rate per 100 participant-years (calculated by 100\*number of participants with events/sum of time at risk (days) over all participants/365.25) measured in terms of number of events per 100 participant-years was reported. Data analysis was also performed independently by external steering committee for the publication.
Time frame: From Day 1 until the date of first adjudicated and confirmed occurrence of major CV event (maximum duration: up to 31.5 months)
Population: Analysis was performed on ITT population. Data for this OM was planned to be collected and analyzed for pooled population of participants who received Efpeglenatide (at any dose: 4 mg and 6 mg) as pre-specified in the protocol.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Efpeglenatide 4 mg+6 mg | Time to First Occurrence of the Expanded Major Adverse Cardiovascular Events Composite Events: Event Rate Per 100 Participant-years for First Occurrence of Expanded Major Cardiovascular Event | 5.4 events per 100 participant-years |
| Placebo | Time to First Occurrence of the Expanded Major Adverse Cardiovascular Events Composite Events: Event Rate Per 100 Participant-years for First Occurrence of Expanded Major Cardiovascular Event | 6.8 events per 100 participant-years |
Comparison: Hazard ratio and 95% CI were obtained from a Cox proportional hazards model with region (North America, Latin America, Europe, other), randomization stratum of SGLT2 inhibitor use (current use, potential future use, neither current nor potential future use) and treatment (efpeglenatide 4 mg, efpeglenatide 6 mg, placebo) as fixed effect factor.p-value: 0.0295% CI: [0.65, 0.96]Log Rank