Type 2 Diabetes Mellitus
Conditions
Brief summary
Primary Objective: To demonstrate the non-inferiority of once weekly injection of efpeglenatide in comparison to once weekly injection of dulaglutide on glycated hemoglobin (HbA1c) change in participants with Type 2 diabetes mellitus (T2DM) inadequately controlled with metformin. Secondary Objectives: * To demonstrate the superiority of once weekly injection of efpeglenatide with once weekly injection of dulaglutide on glycemic control. * To demonstrate the superiority of once weekly injection of efpeglenatide with once weekly injection of dulaglutide on body weight. * To evaluate the safety of once weekly injection of efpeglenatide and once weekly injection of dulaglutide.
Detailed description
Study duration per participant was approximately 65 weeks including an up to 3-week Screening Period, a 56-week Treatment Period and a 6-week safety Follow-up Period.
Interventions
DRUGEfpeglenatide
Pharmaceutical form: solution for injection; Route of administration: SC
DRUGDulaglutide
Pharmaceutical form: solution for injection; Route of administration: SC
DRUGBackground therapy Metformin
Pharmaceutical form: tablet; Route of administration: oral; Dose to be kept stable throughout the study.
Sponsors
Hanmi Pharmaceutical Company Limited
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
The study was open-label for the tested versus comparator drug and double blind for the doses.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participant must be greater than or equal to (\>=) 18 years of age at the time of signing the informed consent. * Participants with T2DM. * Diabetes diagnosed at least 1 year before screening. * Participants on stable dose of at least 1500 milligram per day (mg/day) of metformin, or tolerated maximum dose, or as per country regulation if less, for at least 3 months prior to screening. * HbA1c between 7.0 percent (%) and 10.0% (inclusive) measured by the central laboratory at screening.
Exclusion criteria
* Retinopathy or maculopathy with one of the following treatments, either recent (within 3 months prior to screening) or planned: intravitreal injections or laser or vitrectomy surgery. * Clinically relevant history of gastrointestinal (GI) disease associated with prolonged nausea and vomiting, including (but not limited to) gastroparesis, unstable and not controlled gastroesophageal reflux disease requiring medical treatment within 6 months prior to screening or history of surgery affecting gastric emptying. * History of pancreatitis (unless pancreatitis was related to gallstones and cholecystectomy had been performed), pancreatitis during previous treatment with incretin therapies, chronic pancreatitis, pancreatectomy. * Personal or family history of medullary thyroid cancer (MTC) or genetic conditions that predisposes to MTC (e.g., multiple endocrine neoplasia syndromes). * Body weight change of greater than or equal to (\>=) 5 kilogram within the last 3 months prior to screening. * Systolic blood pressure greater than (\>)180 millimeter of mercury (mmHg) and/or diastolic blood pressure \>100 mmHg at randomization. * Severe renal disease as defined by estimated glomerular filtration rate (eGFR), by Modification of Diet in Renal Disease (MDRD)\] of less than (\<)30 mL/min/1.73 m\^2. * Laboratory findings at the screening visit: * Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \>3 \* upper limit of normal (ULN) or total bilirubin \>1.5 \* ULN (except in case of documented Gilbert's syndrome); * Amylase and/or lipase: \>3 \* ULN; * Calcitonin \>=5.9 picomoles per liter (pmol/L) (20 picograms per milliliter). * Gastric surgery or other gastric procedures intended for weight loss within 2 years prior to screening, or planned during study period. * Pregnant (confirmed by serum pregnancy test at screening) or breast-feeding women. * Women of childbearing potential (WOCBP) not willing to use highly effective method(s) of birth control or who are unwilling to be tested for pregnancy during the study period and for at least 5 weeks after the last dose of study intervention. 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 |
|---|---|---|
| Change From Baseline to Week 56 in HbA1c | Baseline to Week 56 | Adjusted Least square (LS) means and Standard errors (SE) were obtained from analysis of covariance (ANCOVA) model to account for missing data. Missing values were imputed by baseline observation carried forward (BOCF)-like multiple imputation method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 56 in Body Weight | Baseline to Week 56 | Adjusted LS means and SE were obtained from ANCOVA model to account for missing data. Missing values were imputed by BOCF-like multiple imputation method. |
| Number of Participants With HbA1c < 7.0 % | Week 56 | Participants who had no available assessment for HbA1c at Week 56 were considered as non-responders. |
| Change From Baseline to Week 56 in Fasting Plasma Glucose (FPG) | Baseline to Week 56 | Adjusted LS means and SE were obtained from ANCOVA model to account for missing data. Missing values were imputed by BOCF-like multiple imputation method. |
| Number of Participants With At Least One Hypoglycemic Events (Documented Symptomatic Hypoglycemia <3.0 mmol/L [<54 mg/dL], Severe Hypoglycemia) | Baseline up to Week 56 | Documented symptomatic hypoglycemia was an event during which typical symptoms of hypoglycemia were accompanied by a measured plasma glucose concentration of \<54 milligrams per deciliter (mg/dL) (\<3.0 mmol/L). Severe hypoglycemia was an event requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. |
| Number of Hypoglycemic Events (Documented Symptomatic Hypoglycemia <3.0 mmol/L [<54 mg/dL] and Severe Hypoglycemia) Per Participant-Year | Baseline up to Week 56 | Documented symptomatic hypoglycemia was an event during which typical symptoms of hypoglycemia were accompanied by a measured plasma glucose concentration of \<54 mg/dL (\<3.0 mmol/L). Severe hypoglycemia was an event requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. |
Countries
Hungary, Poland, Ukraine, United States
Participant flow
Recruitment details
The study was conducted at 45 active sites in 4 countries. A total of 1608 participants were screened between 26 September 2018 and 17 December 2019, out of which 700 were screen failures. Screen failures were mainly due to inclusion criteria not met.
Pre-assignment details
A total of 908 participants were randomized in 1:1:1 ratio to either efpeglenatide 4 milligram (mg), efpeglenatide 6 mg, or dulaglutide 1.5 mg treatment arms, stratified by screening glycated hemoglobin (HbA1c) values (less than \[\<\]8%, greater than or equal to \[\>=\]8 percent \[%\]) and by body mass index (BMI) (\<30 kg/m\^2 and \>=30 kg/m\^2) on Day 1.
Participants by arm
| Arm | Count |
|---|---|
| Efpeglenatide 4 mg Participants received Efpeglenatide SC injection once weekly up to Week 56 on top of metformin. Participants initiated dosing at 2 mg once weekly and increased every 2 weeks to the maximum of 4 mg once weekly for the treatment duration. | 303 |
| Efpeglenatide 6 mg Participants received Efpeglenatide SC injection once weekly up to Week 56 on top of metformin. Participants initiated dosing at 2 mg once weekly and increased every 2 weeks to the maximum of 6 mg once weekly for the treatment duration. | 302 |
| Dulaglutide 1.5 mg Participants received Dulaglutide SC injection once weekly up to Week 56 on top of metformin. Participants initiated dosing at 0.75 mg once weekly and increased after 2 weeks to 1.5 mg once weekly for the treatment duration. | 303 |
| Total | 908 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 6 | 15 | 11 |
| Overall Study | Lack of Efficacy | 0 | 0 | 1 |
| Overall Study | Missing completion status but alive at last contact | 0 | 1 | 2 |
| Overall Study | Other than specified | 62 | 60 | 67 |
| Overall Study | Poor compliance to protocol | 0 | 4 | 1 |
| Overall Study | Randomized and not treated | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 35 | 53 | 23 |
Baseline characteristics
| Characteristic | Efpeglenatide 4 mg | Efpeglenatide 6 mg | Dulaglutide 1.5 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 60.3 years STANDARD_DEVIATION 9.6 | 60.0 years STANDARD_DEVIATION 10.1 | 59.4 years STANDARD_DEVIATION 10.1 | 59.9 years STANDARD_DEVIATION 9.9 |
| Baseline Glycated Hemoglobin (HbA1c %) | 8.12 percentage of HbA1c STANDARD_DEVIATION 0.82 | 8.07 percentage of HbA1c STANDARD_DEVIATION 0.78 | 8.11 percentage of HbA1c STANDARD_DEVIATION 0.81 | 8.10 percentage of HbA1c STANDARD_DEVIATION 0.81 |
| Body Mass Index (BMI) | 33.4 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 6.1 | 33.4 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 6.2 | 33.4 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 6.4 | 33.4 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 6.2 |
| Race/Ethnicity, Customized Asian | 5 Participants | 3 Participants | 6 Participants | 14 Participants |
| Race/Ethnicity, Customized Black or African American | 24 Participants | 30 Participants | 18 Participants | 72 Participants |
| Race/Ethnicity, Customized Not reported | 0 Participants | 2 Participants | 2 Participants | 4 Participants |
| Race/Ethnicity, Customized Other | 3 Participants | 4 Participants | 2 Participants | 9 Participants |
| Race/Ethnicity, Customized White | 271 Participants | 263 Participants | 275 Participants | 809 Participants |
| Sex: Female, Male Female | 142 Participants | 157 Participants | 153 Participants | 452 Participants |
| Sex: Female, Male Male | 161 Participants | 145 Participants | 150 Participants | 456 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 313 | 0 / 292 | 1 / 302 |
| other Total, other adverse events | 202 / 313 | 180 / 292 | 178 / 302 |
| serious Total, serious adverse events | 20 / 313 | 23 / 292 | 20 / 302 |
Outcome results
Primary
Change From Baseline to Week 56 in HbA1c
Adjusted Least square (LS) means and Standard errors (SE) were obtained from analysis of covariance (ANCOVA) model to account for missing data. Missing values were imputed by baseline observation carried forward (BOCF)-like multiple imputation method.
Time frame: Baseline to Week 56
Population: Analysis was performed on modified intent-to-treat (mITT) population which included participants who completed study treatment; or who discontinued study treatment and completed/discontinued study before early termination; or who discontinued treatment before early termination and discontinued study due to early termination; or who discontinued treatment due to early termination within 30 days of target Week 56 visit.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Efpeglenatide 4 mg | Change From Baseline to Week 56 in HbA1c | -1.12 percentage of HbA1c | Standard Error 0.06 |
| Efpeglenatide 6 mg | Change From Baseline to Week 56 in HbA1c | -1.17 percentage of HbA1c | Standard Error 0.06 |
| Dulaglutide 1.5 mg | Change From Baseline to Week 56 in HbA1c | -1.09 percentage of HbA1c | Standard Error 0.06 |
Comparison: A hierarchical step-down testing procedure was used to control type 1 error. Analysis was performed using ANCOVA model with the treatment groups, randomization strata, and geographical region as fixed classification effects, and baseline HbA1c value as a continuous covariate.95% CI: [-0.2, 0.14]
Comparison: A hierarchical step-down testing procedure was used to control type 1 error. Analysis was performed using ANCOVA model with the treatment groups, randomization strata, and geographical region as fixed classification effects, and baseline HbA1c value as a continuous covariate.95% CI: [-0.25, 0.09]
p-value: 0.7064ANCOVA
p-value: 0.3427ANCOVA
Secondary
Change From Baseline to Week 56 in Body Weight
Adjusted LS means and SE were obtained from ANCOVA model to account for missing data. Missing values were imputed by BOCF-like multiple imputation method.
Time frame: Baseline to Week 56
Population: Analysis was performed on mITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Efpeglenatide 4 mg | Change From Baseline to Week 56 in Body Weight | -2.87 kilogram | Standard Error 0.64 |
| Efpeglenatide 6 mg | Change From Baseline to Week 56 in Body Weight | -3.04 kilogram | Standard Error 0.67 |
| Dulaglutide 1.5 mg | Change From Baseline to Week 56 in Body Weight | -2.81 kilogram | Standard Error 0.66 |
Secondary
Change From Baseline to Week 56 in Fasting Plasma Glucose (FPG)
Adjusted LS means and SE were obtained from ANCOVA model to account for missing data. Missing values were imputed by BOCF-like multiple imputation method.
Time frame: Baseline to Week 56
Population: Analysis was performed on mITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Efpeglenatide 4 mg | Change From Baseline to Week 56 in Fasting Plasma Glucose (FPG) | -1.81 millimoles per liter (mmol/L) | Standard Error 0.15 |
| Efpeglenatide 6 mg | Change From Baseline to Week 56 in Fasting Plasma Glucose (FPG) | -1.57 millimoles per liter (mmol/L) | Standard Error 0.15 |
| Dulaglutide 1.5 mg | Change From Baseline to Week 56 in Fasting Plasma Glucose (FPG) | -1.71 millimoles per liter (mmol/L) | Standard Error 0.15 |
Secondary
Number of Hypoglycemic Events (Documented Symptomatic Hypoglycemia <3.0 mmol/L [<54 mg/dL] and Severe Hypoglycemia) Per Participant-Year
Documented symptomatic hypoglycemia was an event during which typical symptoms of hypoglycemia were accompanied by a measured plasma glucose concentration of \<54 mg/dL (\<3.0 mmol/L). Severe hypoglycemia was an event requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions.
Time frame: Baseline up to Week 56
Population: Analysis was performed on safety population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Efpeglenatide 4 mg | Number of Hypoglycemic Events (Documented Symptomatic Hypoglycemia <3.0 mmol/L [<54 mg/dL] and Severe Hypoglycemia) Per Participant-Year | Documented symptomatic hypoglycemia (<54 mg/dL) | 0.01 events per participant-year |
| Efpeglenatide 4 mg | Number of Hypoglycemic Events (Documented Symptomatic Hypoglycemia <3.0 mmol/L [<54 mg/dL] and Severe Hypoglycemia) Per Participant-Year | Severe hypoglycemia | 0 events per participant-year |
| Efpeglenatide 6 mg | Number of Hypoglycemic Events (Documented Symptomatic Hypoglycemia <3.0 mmol/L [<54 mg/dL] and Severe Hypoglycemia) Per Participant-Year | Documented symptomatic hypoglycemia (<54 mg/dL) | 0.01 events per participant-year |
| Efpeglenatide 6 mg | Number of Hypoglycemic Events (Documented Symptomatic Hypoglycemia <3.0 mmol/L [<54 mg/dL] and Severe Hypoglycemia) Per Participant-Year | Severe hypoglycemia | 0 events per participant-year |
| Dulaglutide 1.5 mg | Number of Hypoglycemic Events (Documented Symptomatic Hypoglycemia <3.0 mmol/L [<54 mg/dL] and Severe Hypoglycemia) Per Participant-Year | Documented symptomatic hypoglycemia (<54 mg/dL) | 0 events per participant-year |
| Dulaglutide 1.5 mg | Number of Hypoglycemic Events (Documented Symptomatic Hypoglycemia <3.0 mmol/L [<54 mg/dL] and Severe Hypoglycemia) Per Participant-Year | Severe hypoglycemia | 0 events per participant-year |
Secondary
Number of Participants With At Least One Hypoglycemic Events (Documented Symptomatic Hypoglycemia <3.0 mmol/L [<54 mg/dL], Severe Hypoglycemia)
Documented symptomatic hypoglycemia was an event during which typical symptoms of hypoglycemia were accompanied by a measured plasma glucose concentration of \<54 milligrams per deciliter (mg/dL) (\<3.0 mmol/L). Severe hypoglycemia was an event requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions.
Time frame: Baseline up to Week 56
Population: Analysis was performed on safety population.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Efpeglenatide 4 mg | Number of Participants With At Least One Hypoglycemic Events (Documented Symptomatic Hypoglycemia <3.0 mmol/L [<54 mg/dL], Severe Hypoglycemia) | Documented symptomatic hypoglycemia (<54 mg/dL) | 3 Participants |
| Efpeglenatide 4 mg | Number of Participants With At Least One Hypoglycemic Events (Documented Symptomatic Hypoglycemia <3.0 mmol/L [<54 mg/dL], Severe Hypoglycemia) | Severe hypoglycemia | 0 Participants |
| Efpeglenatide 6 mg | Number of Participants With At Least One Hypoglycemic Events (Documented Symptomatic Hypoglycemia <3.0 mmol/L [<54 mg/dL], Severe Hypoglycemia) | Documented symptomatic hypoglycemia (<54 mg/dL) | 1 Participants |
| Efpeglenatide 6 mg | Number of Participants With At Least One Hypoglycemic Events (Documented Symptomatic Hypoglycemia <3.0 mmol/L [<54 mg/dL], Severe Hypoglycemia) | Severe hypoglycemia | 0 Participants |
| Dulaglutide 1.5 mg | Number of Participants With At Least One Hypoglycemic Events (Documented Symptomatic Hypoglycemia <3.0 mmol/L [<54 mg/dL], Severe Hypoglycemia) | Documented symptomatic hypoglycemia (<54 mg/dL) | 0 Participants |
| Dulaglutide 1.5 mg | Number of Participants With At Least One Hypoglycemic Events (Documented Symptomatic Hypoglycemia <3.0 mmol/L [<54 mg/dL], Severe Hypoglycemia) | Severe hypoglycemia | 0 Participants |
Secondary
Number of Participants With HbA1c < 7.0 %
Participants who had no available assessment for HbA1c at Week 56 were considered as non-responders.
Time frame: Week 56
Population: Analysis was performed on mITT population.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Efpeglenatide 4 mg | Number of Participants With HbA1c < 7.0 % | 155 Participants |
| Efpeglenatide 6 mg | Number of Participants With HbA1c < 7.0 % | 157 Participants |
| Dulaglutide 1.5 mg | Number of Participants With HbA1c < 7.0 % | 150 Participants |