Type 2 Diabetes Mellitus
Conditions
Brief summary
Primary Objective: To demonstrate the superiority of once weekly injection of efpeglenatide in comparison to placebo in glycated hemoglobin (HbA1c) change in participants with type 2 diabetes mellitus (T2DM) inadequately controlled with basal insulin alone or in combination with oral antidiabetic drugs (OADs). Secondary Objectives: * To demonstrate the superiority of once weekly injection of efpeglenatide in comparison to placebo on glycemic control. * To demonstrate the superiority of once weekly injection of efpeglenatide in comparison to placebo on body weight. * To evaluate the safety of once weekly injection of efpeglenatide.
Detailed description
Study duration per participant was approximately 64 weeks including an up to 2-week Screening Period, a 30-week Core Treatment Period, a 26-week Safety Extension Period, and a 6-week safety Follow-up Period.
Interventions
Pharmaceutical form: solution for injection Route of administration: subcutaneous
DRUGPlacebo
Pharmaceutical form: solution for injection Route of administration: subcutaneous
Lantus (Insulin Glargine), SC, once daily; OADs, administered as per investigator prescription and in accordance with local labeling.
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
* 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 basal insulin regimen alone or in combination with OADs for at least 6 months prior to screening. * HbA1c between 7.0 percent (%) and 10.0% (inclusive) measured by the central laboratory at screening.
Exclusion criteria
* History of severe hypoglycemia requiring emergency room admission or hospitalization within 3 months prior to screening. * 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 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. * History of pancreatitis (unless pancreatitis was related to gallstones and cholecystectomy has 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 predispose to MTC (e.g., multiple endocrine neoplasia syndromes). * Body weight change of \>=5 kilograms within the last 3 months prior to screening. * Systolic blood pressure greater than (\>)180 millimetres of mercury (mmHg) and/or diastolic blood pressure \>100 mmHg at randomization. * End-stage renal disease as defined by estimated glomerular filtration rate (by Modification of Diet in Renal Disease) of less than 15 mL/min/1.73 m\^2. * Laboratory findings at the screening Visit: * Alanine aminotransferase or aspartate aminotransferase \>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 \[pg/mL\]). * 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 not willing to use highly effective method(s) of birth control or who were 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 |
|---|---|
| Change From Baseline to Week 30 in HbA1c | Baseline to Week 30 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 56 in HbA1c | Baseline to Week 56 | This analysis included Week 56 assessment performed per protocol as well as premature end of treatment/study visit recorded as Week 56 due to early termination. |
| Change From Baseline to Week 30 in Fasting Plasma Glucose (FPG) | Baseline to Week 30 | — |
| Number of Participants With HbA1c <7.0% at Week 30 | Week 30 | Participants who had no available assessment for HbA1c at Week 30 were considered as non-responders. |
| Number of Participants With At Least One Hypoglycemic Events (Documented Symptomatic Hypoglycemia <3.0 mmol/L [<54 mg/dL], and 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 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. |
| Change From Baseline to Week 30 and Week 56 in Body Weight | Baseline to Week 30 and Week 56 | This analysis included Week 56 assessment performed per protocol as well as premature end of treatment/study visit recorded as Week 56 due to early termination. |
Countries
China, South Korea, United States
Participant flow
Recruitment details
The study was conducted at 47 active sites in 3 countries. A total of 540 participants were screened between 09 November 2018 and 02 September 2020, out of which 170 were screen failures. Screen failures were mainly due to inclusion criteria not met.
Pre-assignment details
A total of 370 participants were randomized in 1:1:1:1 ratio to either placebo, efpeglenatide 2 milligrams (mg), efpeglenatide 4 mg, or efpeglenatide 6 mg treatment arms, stratified by screening glycated hemoglobin (HbA1c) values (less than \[\<\]8%, greater than or equal to \[\>=\]8%) and sulfonylurea (SU) use at screening (Yes/No).
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received placebo (matched to efpeglenatide) SC injection once weekly up to Week 56 on top of basal insulin alone or in combination with OADs. | 92 |
| Efpeglenatide 2 mg Participants received Efpeglenatide 2 mg SC injection once weekly up to Week 56 on top of basal insulin alone or in combination with OADs. | 92 |
| Efpeglenatide 4 mg Participants received Efpeglenatide 4 mg SC injection once weekly up to Week 56 on top of basal insulin alone or in combination with OADs. Participants initiated dosing at 2 mg once weekly up to Week 1; which was up titrated to 4 mg and maintained at the 4 mg dose through-out the treatment duration up to Week 56. | 93 |
| Efpeglenatide 6 mg Participants received Efpeglenatide 6 mg SC injection once weekly up to Week 56 on top of basal insulin alone or in combination with OADs. Participants initiated dosing at 2 mg once weekly up to Week 1; which was up titrated to 4 mg until Week 4 and later up-titrated to 6 mg and maintained at the 6 mg dose through-out the treatment duration up to Week 56. | 93 |
| Total | 370 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 3 | 1 | 0 |
| Overall Study | Other than specified | 69 | 77 | 73 | 70 |
| Overall Study | Poor compliance to protocol | 2 | 1 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 14 | 6 | 14 | 16 |
Baseline characteristics
| Characteristic | Placebo | Efpeglenatide 2 mg | Efpeglenatide 4 mg | Efpeglenatide 6 mg | Total |
|---|---|---|---|---|---|
| Age, Continuous | 58.9 years STANDARD_DEVIATION 10.7 | 59.1 years STANDARD_DEVIATION 10.7 | 60.6 years STANDARD_DEVIATION 11.5 | 61.6 years STANDARD_DEVIATION 10.3 | 60.1 years STANDARD_DEVIATION 10.8 |
| Baseline Glycated Hemoglobin (HbA1c %) | 8.54 percentage of HbA1c STANDARD_DEVIATION 0.83 | 8.42 percentage of HbA1c STANDARD_DEVIATION 0.79 | 8.46 percentage of HbA1c STANDARD_DEVIATION 0.79 | 8.40 percentage of HbA1c STANDARD_DEVIATION 0.72 | 8.46 percentage of HbA1c STANDARD_DEVIATION 0.78 |
| Body Mass Index (BMI) | 30.1 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 5.6 | 31.1 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 6.1 | 30.0 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 6.6 | 31.0 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 7.1 | 30.6 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 6.4 |
| Race/Ethnicity, Customized Asian | 36 Participants | 33 Participants | 30 Participants | 34 Participants | 133 Participants |
| Race/Ethnicity, Customized Black or African American | 9 Participants | 9 Participants | 10 Participants | 8 Participants | 36 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 1 Participants | 1 Participants | 1 Participants | 5 Participants |
| Race/Ethnicity, Customized Unknown | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 45 Participants | 49 Participants | 51 Participants | 50 Participants | 195 Participants |
| Sex: Female, Male Female | 49 Participants | 42 Participants | 42 Participants | 40 Participants | 173 Participants |
| Sex: Female, Male Male | 43 Participants | 50 Participants | 51 Participants | 53 Participants | 197 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 92 | 0 / 92 | 0 / 96 | 0 / 90 |
| other Total, other adverse events | 25 / 92 | 33 / 92 | 42 / 96 | 46 / 90 |
| serious Total, serious adverse events | 9 / 92 | 7 / 92 | 5 / 96 | 10 / 90 |
Outcome results
Primary
Change From Baseline to Week 30 in HbA1c
Time frame: Baseline to Week 30
Population: Analysis was performed on intent to treat (ITT) population which included all randomized participants, irrespective of compliance with the study protocol and procedures analyzed, according to the treatment group allocated by randomization. Here, Overall number of participants analyzed= participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 30 in HbA1c | -0.33 percentage of HbA1c | Standard Deviation 1.09 |
| Efpeglenatide 2 mg | Change From Baseline to Week 30 in HbA1c | -1.27 percentage of HbA1c | Standard Deviation 0.95 |
| Efpeglenatide 4 mg | Change From Baseline to Week 30 in HbA1c | -1.24 percentage of HbA1c | Standard Deviation 0.96 |
| Efpeglenatide 6 mg | Change From Baseline to Week 30 in HbA1c | -1.43 percentage of HbA1c | Standard Deviation 0.94 |
Secondary
Change From Baseline to Week 30 and Week 56 in Body Weight
This analysis included Week 56 assessment performed per protocol as well as premature end of treatment/study visit recorded as Week 56 due to early termination.
Time frame: Baseline to Week 30 and Week 56
Population: Analysis was performed on ITT population. Here, Overall number of participants analyzed= participants evaluable for this outcome measure and 'number analyzed' = participants with available data for each specified row.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline to Week 30 and Week 56 in Body Weight | Week 30 | 0.29 kilograms | Standard Deviation 3.23 |
| Placebo | Change From Baseline to Week 30 and Week 56 in Body Weight | Week 56 | 0.66 kilograms | Standard Deviation 3.22 |
| Efpeglenatide 2 mg | Change From Baseline to Week 30 and Week 56 in Body Weight | Week 56 | -2.39 kilograms | Standard Deviation 10.69 |
| Efpeglenatide 2 mg | Change From Baseline to Week 30 and Week 56 in Body Weight | Week 30 | -0.68 kilograms | Standard Deviation 3.63 |
| Efpeglenatide 4 mg | Change From Baseline to Week 30 and Week 56 in Body Weight | Week 56 | -1.77 kilograms | Standard Deviation 5.36 |
| Efpeglenatide 4 mg | Change From Baseline to Week 30 and Week 56 in Body Weight | Week 30 | -1.99 kilograms | Standard Deviation 3.13 |
| Efpeglenatide 6 mg | Change From Baseline to Week 30 and Week 56 in Body Weight | Week 56 | -2.85 kilograms | Standard Deviation 4.8 |
| Efpeglenatide 6 mg | Change From Baseline to Week 30 and Week 56 in Body Weight | Week 30 | -3.14 kilograms | Standard Deviation 3.19 |
Secondary
Change From Baseline to Week 30 in Fasting Plasma Glucose (FPG)
Time frame: Baseline to Week 30
Population: Analysis was performed on ITT population. Here, Overall number of participants analyzed= participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 30 in Fasting Plasma Glucose (FPG) | -0.41 millimoles per liter (mmol/L) | Standard Deviation 3 |
| Efpeglenatide 2 mg | Change From Baseline to Week 30 in Fasting Plasma Glucose (FPG) | -1.34 millimoles per liter (mmol/L) | Standard Deviation 2.8 |
| Efpeglenatide 4 mg | Change From Baseline to Week 30 in Fasting Plasma Glucose (FPG) | -1.33 millimoles per liter (mmol/L) | Standard Deviation 3.52 |
| Efpeglenatide 6 mg | Change From Baseline to Week 30 in Fasting Plasma Glucose (FPG) | -2.22 millimoles per liter (mmol/L) | Standard Deviation 1.89 |
Secondary
Change From Baseline to Week 56 in HbA1c
This analysis included Week 56 assessment performed per protocol as well as premature end of treatment/study visit recorded as Week 56 due to early termination.
Time frame: Baseline to Week 56
Population: Analysis was performed on ITT population. Here, Overall number of participants analyzed= participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 56 in HbA1c | -0.32 percentage of HbA1c | Standard Deviation 0.86 |
| Efpeglenatide 2 mg | Change From Baseline to Week 56 in HbA1c | -1.08 percentage of HbA1c | Standard Deviation 0.77 |
| Efpeglenatide 4 mg | Change From Baseline to Week 56 in HbA1c | -1.23 percentage of HbA1c | Standard Deviation 0.88 |
| Efpeglenatide 6 mg | Change From Baseline to Week 56 in HbA1c | -1.16 percentage of HbA1c | Standard Deviation 1.34 |
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) |
|---|---|---|---|
| Placebo | 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) | 0.07 events per participant-year |
| Placebo | Number of Hypoglycemic Events (Documented Symptomatic Hypoglycemia <3.0 mmol/L [<54 mg/dL] and Severe Hypoglycemia) Per Participant-Year | Severe hypoglycemia | 0.09 events per participant-year |
| Efpeglenatide 2 mg | Number of Hypoglycemic Events (Documented Symptomatic Hypoglycemia <3.0 mmol/L [<54 mg/dL] and Severe Hypoglycemia) Per Participant-Year | Severe hypoglycemia | 0.05 events per participant-year |
| Efpeglenatide 2 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) | 0.27 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 | Documented symptomatic hypoglycemia (<54 mg/dL) | 0.45 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 | 0.05 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) | 0.46 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 | 0.04 events per participant-year |
Secondary
Number of Participants With At Least One Hypoglycemic Events (Documented Symptomatic Hypoglycemia <3.0 mmol/L [<54 mg/dL], and Severe Hypoglycemia)
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 (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With At Least One Hypoglycemic Events (Documented Symptomatic Hypoglycemia <3.0 mmol/L [<54 mg/dL], and Severe Hypoglycemia) | Documented symptomatic hypoglycemia (<54 mg/dL) | 4 Participants |
| Placebo | Number of Participants With At Least One Hypoglycemic Events (Documented Symptomatic Hypoglycemia <3.0 mmol/L [<54 mg/dL], and Severe Hypoglycemia) | Severe hypoglycemia | 1 Participants |
| Efpeglenatide 2 mg | Number of Participants With At Least One Hypoglycemic Events (Documented Symptomatic Hypoglycemia <3.0 mmol/L [<54 mg/dL], and Severe Hypoglycemia) | Severe hypoglycemia | 2 Participants |
| Efpeglenatide 2 mg | Number of Participants With At Least One Hypoglycemic Events (Documented Symptomatic Hypoglycemia <3.0 mmol/L [<54 mg/dL], and Severe Hypoglycemia) | Documented symptomatic hypoglycemia (<54 mg/dL) | 8 Participants |
| Efpeglenatide 4 mg | Number of Participants With At Least One Hypoglycemic Events (Documented Symptomatic Hypoglycemia <3.0 mmol/L [<54 mg/dL], and Severe Hypoglycemia) | Documented symptomatic hypoglycemia (<54 mg/dL) | 10 Participants |
| Efpeglenatide 4 mg | Number of Participants With At Least One Hypoglycemic Events (Documented Symptomatic Hypoglycemia <3.0 mmol/L [<54 mg/dL], and Severe Hypoglycemia) | Severe hypoglycemia | 1 Participants |
| Efpeglenatide 6 mg | Number of Participants With At Least One Hypoglycemic Events (Documented Symptomatic Hypoglycemia <3.0 mmol/L [<54 mg/dL], and Severe Hypoglycemia) | Documented symptomatic hypoglycemia (<54 mg/dL) | 9 Participants |
| Efpeglenatide 6 mg | Number of Participants With At Least One Hypoglycemic Events (Documented Symptomatic Hypoglycemia <3.0 mmol/L [<54 mg/dL], and Severe Hypoglycemia) | Severe hypoglycemia | 2 Participants |
Secondary
Number of Participants With HbA1c <7.0% at Week 30
Participants who had no available assessment for HbA1c at Week 30 were considered as non-responders.
Time frame: Week 30
Population: Analysis was performed on ITT population.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With HbA1c <7.0% at Week 30 | 10 Participants |
| Efpeglenatide 2 mg | Number of Participants With HbA1c <7.0% at Week 30 | 32 Participants |
| Efpeglenatide 4 mg | Number of Participants With HbA1c <7.0% at Week 30 | 28 Participants |
| Efpeglenatide 6 mg | Number of Participants With HbA1c <7.0% at Week 30 | 40 Participants |