Efficacy and Safety of Efpeglenatide Versus Dulaglutide in Patients With Type 2 Diabetes Mellitus Inadequately Controlled With Metformin

Study Overview
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Brief Summary
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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
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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.

Official Title
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A 56-week, Multicenter, Open-label, Active-controlled, Randomized Study to Evaluate the Efficacy and Safety of Efpeglenatide Once Weekly Compared to Dulaglutide Once Weekly in Patients With Type 2 Diabetes Mellitus Inadequately Controlled With Metformin

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Efpeglenatide
* Drug: Dulaglutide
* Drug: Background therapy Metformin


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Efpeglenatide 4 mg<br>Participants received Efpeglenatide subcutaneous (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. | Drug: Efpeglenatide<br>* Pharmaceutical form: solution for injection; Route of administration: SC<br>* Other names: SAR439977;Drug: Background therapy Metformin<br>* Pharmaceutical form: tablet; Route of administration: oral; Dose to be kept stable throughout the study.<br>|
| Experimental: Efpeglenatide 6 mg<br>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. | Drug: Efpeglenatide<br>* Pharmaceutical form: solution for injection; Route of administration: SC<br>* Other names: SAR439977;Drug: Background therapy Metformin<br>* Pharmaceutical form: tablet; Route of administration: oral; Dose to be kept stable throughout the study.<br>|
| Active Comparator: Dulaglutide 1.5 mg<br>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. | Drug: Dulaglutide<br>* Pharmaceutical form: solution for injection; Route of administration: SC<br>* Other names: Trulicity™;Drug: Background therapy Metformin<br>* Pharmaceutical form: tablet; Route of administration: oral; Dose to be kept stable throughout the study.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline to Week 56 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline to Week 56 | 
| Number of Participants With HbA1c < 7.0 % | Participants who had no available assessment for HbA1c at Week 56 were considered as non-responders. | Week 56 | 
| 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. | Baseline to Week 56 | 
| 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. | Baseline up to Week 56 | 
| 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. | Baseline up to Week 56 |