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

• Sponsor: Sanofi (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT03684642
• Collaborator: Hanmi Pharmaceutical Company Limited (Industry)
• Enrollment: 908
• Locations: 45
• Arms: 3
• Actual Duration (Months): 25.7
• Patients Per Site: 20.2
• Patients Per Site Per Month: 0.8

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Type 2 Diabetes Mellitus	Drug: Efpeglenatide; Drug: Dulaglutide; Drug: Background therapy Metformin	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 908 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Masking Description: The study was open-label for the tested versus comparator drug and double blind for the doses.
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Sep 26, 2018
• Actual Primary Completion Date: Oct 13, 2020
• Actual Study Completion Date: Nov 17, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Efpeglenatide 4 mg 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; Pharmaceutical form: solution for injection; Route of administration: SC; Other Names: SAR439977 ; Drug: Background therapy Metformin; Pharmaceutical form: tablet; Route of administration: oral; Dose to be kept stable throughout the study.
Experimental: 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.	Drug: Efpeglenatide; Pharmaceutical form: solution for injection; Route of administration: SC; Other Names: SAR439977 ; Drug: Background therapy Metformin; Pharmaceutical form: tablet; Route of administration: oral; Dose to be kept stable throughout the study.
Active Comparator: 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.	Drug: Dulaglutide; Pharmaceutical form: solution for injection; Route of administration: SC; Other Names: Trulicity™ ; Drug: Background therapy Metformin; Pharmaceutical form: tablet; Route of administration: oral; Dose to be kept stable throughout the study.

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Investigational Site Number 8400038	Birmingham	Alabama	United States	35211
2	Investigational Site Number 8400035	Chandler	Arizona	United States	85224
3	Investigational Site Number 8400005	Glendale	Arizona	United States	85306
4	Investigational Site Number 8400054	Peoria	Arizona	United States	85381
5	Investigational Site Number 8400057	Huntington Park	California	United States	90255
6	Investigational Site Number 8400009	Los Angeles	California	United States	90057
7	Investigational Site Number 8400007	San Diego	California	United States	92120
8	Investigational Site Number 8400045	Spring Valley	California	United States	91978
9	Investigational Site Number 8400040	Tustin	California	United States	92780
10	Investigational Site Number 8400026	Van Nuys	California	United States	91405
11	Investigational Site Number 8400050	Waterbury	Connecticut	United States	06708
12	Investigational Site Number 8400055	Orlando	Florida	United States	32825
13	Investigational Site Number 8400041	Pembroke Pines	Florida	United States	33026
14	Investigational Site Number 8400025	Lawrenceville	Georgia	United States	30044
15	Investigational Site Number 8400060	Meridian	Idaho	United States	83642
16	Investigational Site Number 8400059	Skokie	Illinois	United States	60077
17	Investigational Site Number 8400044	Lexington	Kentucky	United States	40503
18	Investigational Site Number 8400061	Boston	Massachusetts	United States	02115
19	Investigational Site Number 8400001	Bridgeton	New Jersey	United States	08302
20	Investigational Site Number 8400039	New Windsor	New York	United States	12553
21	Investigational Site Number 8400028	Burlington	North Carolina	United States	27215
22	Investigational Site Number 8400036	Morehead City	North Carolina	United States	28557
23	Investigational Site Number 8400013	Maumee	Ohio	United States	43537
24	Investigational Site Number 8400014	Goose Creek	South Carolina	United States	29445
25	Investigational Site Number 8400030	Dallas	Texas	United States	75230
26	Investigational Site Number 8400020	San Antonio	Texas	United States	78218
27	Investigational Site Number 8400043	San Antonio	Texas	United States	78229
28	Investigational Site Number 8400053	San Antonio	Texas	United States	78258
29	Investigational Site Number 8400037	Layton	Utah	United States	84041
30	Investigational Site Number 8400049	Manassas	Virginia	United States	20110
31	Investigational Site Number 3480004	Budapest		Hungary	1036
32	Investigational Site Number 3480003	Debrecen		Hungary	4025
33	Investigational Site Number 3480001	Gyula		Hungary	5700
34	Investigational Site Number 3480005	Hatvan		Hungary	3000
35	Investigational Site Number 3480002	Nyíregyháza		Hungary	4400
36	Investigational Site Number 6160008	Gdansk		Poland	80-382
37	Investigational Site Number 6160004	Gdynia		Poland	81-537
38	Investigational Site Number 6160010	Katowice		Poland	40-040
39	Investigational Site Number 6160009	Poznan		Poland	60-702
40	Investigational Site Number 6160003	Warszawa		Poland	01-192
41	Investigational Site Number 6160001	Wroclaw		Poland	50-381
42	Investigational Site Number 8040003	Kyiv		Ukraine	02002
43	Investigational Site Number 8040001	Kyiv		Ukraine	03037
44	Investigational Site Number 8040002	Kyiv		Ukraine	03049
45	Investigational Site Number 8040004	Vinnytsia		Ukraine	21050

Sponsors and Collaborators

• Sanofi
• Hanmi Pharmaceutical Company Limited

Investigators

• Study Director: Clinical Sciences & Operations, Sanofi

Study Documents (Full-Text)

• Study Protocol - Jul 31, 2019
• Statistical Analysis Plan - Oct 2, 2020

More Information

Publications

None provided.

• Responsible Party: Sanofi
• ClinicalTrials.gov Identifier: NCT03684642
• Other Study ID Numbers: EFC14829; 2017-002956-10; U1111-1205-3150
• First Posted: Sep 26, 2018
• Last Update Posted: Nov 1, 2021
• Last Verified: Oct 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Metformin; Dulaglutide; Efpeglenatide

Study Results

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 Detail	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.

Arm/Group Title	Efpeglenatide 4 mg	Efpeglenatide 6 mg	Dulaglutide 1.5 mg
Arm/Group Description	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.	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.	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.
Period Title: Overall Study
STARTED	303	302	303
Treated	303	302	302
Safety Population	313	292	302
COMPLETED	200	169	197
NOT COMPLETED	103	133	106

Baseline Characteristics

Arm/Group Title	Efpeglenatide 4 mg	Efpeglenatide 6 mg	Dulaglutide 1.5 mg	Total
Arm/Group Description	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.	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.	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.	Total of all reporting groups
Overall Participants	303	302	303	908
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60.3 (9.6)	60.0 (10.1)	59.4 (10.1)	59.9 (9.9)
Sex: Female, Male (Count of Participants)
Female	142 46.9%	157 52%	153 50.5%	452 49.8%
Male	161 53.1%	145 48%	150 49.5%	456 50.2%
Race/Ethnicity, Customized (Count of Participants)
White	271 89.4%	263 87.1%	275 90.8%	809 89.1%
Black or African American	24 7.9%	30 9.9%	18 5.9%	72 7.9%
Asian	5 1.7%	3 1%	6 2%	14 1.5%
Other	3 1%	4 1.3%	2 0.7%	9 1%
Not reported	0 0%	2 0.7%	2 0.7%	4 0.4%
Body Mass Index (BMI) (kilogram per square meter (kg/m^2)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram per square meter (kg/m^2)]	33.4 (6.1)	33.4 (6.2)	33.4 (6.4)	33.4 (6.2)
Baseline Glycated Hemoglobin (HbA1c %) (percentage of HbA1c) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percentage of HbA1c]	8.12 (0.82)	8.07 (0.78)	8.11 (0.81)	8.10 (0.81)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline to Week 56 in HbA1c
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Efpeglenatide 4 mg	Efpeglenatide 6 mg	Dulaglutide 1.5 mg
Arm/Group Description	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.	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.	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.
Measure Participants	257	254	250
Least Squares Mean (Standard Error) [percentage of HbA1c]	-1.12 (0.06)	-1.17 (0.06)	-1.09 (0.06)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Efpeglenatide 4 mg, Dulaglutide 1.5 mg
	Comments	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.
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority of Efpeglenatide vs. Dulaglutide was demonstrated if the upper bound of the two-sided 95% confidence interval (CI) for the difference between groups was <=0.3%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square (LS) Mean difference
	Estimated Value	-0.03
	Confidence Interval	(2-Sided) 95%; -0.20 to 0.14
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.09
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Efpeglenatide 6 mg, Dulaglutide 1.5 mg
	Comments	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.
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority of Efpeglenatide vs. Dulaglutide was demonstrated if the upper bound of the two-sided 95% CI for the difference between groups was <=0.3%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.08
	Confidence Interval	(2-Sided) 95%; -0.25 to 0.09
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.09
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Efpeglenatide 4 mg, Dulaglutide 1.5 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7064
	Comments	Threshold for significance at the level of 0.05.
	Method	ANCOVA
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Efpeglenatide 6 mg, Dulaglutide 1.5 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3427
	Comments	Threshold for significance at the level of 0.05.
	Method	ANCOVA
	Comments

2. Secondary Outcome

Title	Change From Baseline to Week 56 in Body Weight
Description	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

Outcome Measure Data

Analysis Population Description

Analysis was performed on mITT population.

Arm/Group Title	Efpeglenatide 4 mg	Efpeglenatide 6 mg	Dulaglutide 1.5 mg
Arm/Group Description	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.	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.	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.
Measure Participants	257	254	250
Least Squares Mean (Standard Error) [kilogram]	-2.87 (0.64)	-3.04 (0.67)	-2.81 (0.66)

3. Secondary Outcome

Title	Number of Participants With HbA1c < 7.0 %
Description	Participants who had no available assessment for HbA1c at Week 56 were considered as non-responders.
Time Frame	Week 56

Outcome Measure Data

Analysis Population Description

Analysis was performed on mITT population.

Arm/Group Title	Efpeglenatide 4 mg	Efpeglenatide 6 mg	Dulaglutide 1.5 mg
Arm/Group Description	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.	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.	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.
Measure Participants	257	254	250
Count of Participants [Participants]	155 51.2%	157 52%	150 49.5%

4. Secondary Outcome

Title	Change From Baseline to Week 56 in Fasting Plasma Glucose (FPG)
Description	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

Outcome Measure Data

Analysis Population Description

Analysis was performed on mITT population.

Arm/Group Title	Efpeglenatide 4 mg	Efpeglenatide 6 mg	Dulaglutide 1.5 mg
Arm/Group Description	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.	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.	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.
Measure Participants	257	254	250
Least Squares Mean (Standard Error) [millimoles per liter (mmol/L)]	-1.81 (0.15)	-1.57 (0.15)	-1.71 (0.15)

5. Secondary Outcome

Title	Number of Participants With At Least One Hypoglycemic Events (Documented Symptomatic Hypoglycemia <3.0 mmol/L [<54 mg/dL], Severe Hypoglycemia)
Description	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

Outcome Measure Data

Analysis Population Description

Analysis was performed on safety population.

Arm/Group Title	Efpeglenatide 4 mg	Efpeglenatide 6 mg	Dulaglutide 1.5 mg
Arm/Group Description	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.	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.	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.
Measure Participants	313	292	302
Documented symptomatic hypoglycemia (<54 mg/dL)	3 1%	1 0.3%	0 0%
Severe hypoglycemia	0 0%	0 0%	0 0%

6. Secondary Outcome

Title	Number of Hypoglycemic Events (Documented Symptomatic Hypoglycemia <3.0 mmol/L [<54 mg/dL] and Severe Hypoglycemia) Per Participant-Year
Description	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

Outcome Measure Data

Analysis Population Description

Analysis was performed on safety population.

Arm/Group Title	Efpeglenatide 4 mg	Efpeglenatide 6 mg	Dulaglutide 1.5 mg
Arm/Group Description	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.	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.	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.
Measure Participants	313	292	302
Documented symptomatic hypoglycemia (<54 mg/dL)	0.01	0.01	0
Severe hypoglycemia	0	0	0

Adverse Events

Time Frame	All Adverse Events (AEs) were collected from signature of the informed consent up to end of study. Time frame for reporting of treatment emergent adverse events (TEAEs) was from first dose up to 30 days after the last injection of the Investigational Medicinal Product (IMP) (Week 60).
Adverse Event Reporting Description	TEAEs were defined as AEs that developed or worsened during the treatment-emergent period. Analysis was performed on safety population.
Arm/Group Title	Efpeglenatide 4 mg		Efpeglenatide 6 mg		Dulaglutide 1.5 mg
Arm/Group Description	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.		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.		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.
All Cause Mortality
	Efpeglenatide 4 mg		Efpeglenatide 6 mg		Dulaglutide 1.5 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/313 (0%)		0/292 (0%)		1/302 (0.3%)
Serious Adverse Events
	Efpeglenatide 4 mg		Efpeglenatide 6 mg		Dulaglutide 1.5 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	20/313 (6.4%)		23/292 (7.9%)		20/302 (6.6%)
Blood and lymphatic system disorders
Iron Deficiency Anaemia	0/313 (0%)	0	1/292 (0.3%)	1	1/302 (0.3%)	1
Cardiac disorders
Acute Myocardial Infarction	1/313 (0.3%)	1	2/292 (0.7%)	2	0/302 (0%)	0
Angina Pectoris	1/313 (0.3%)	1	0/292 (0%)	0	0/302 (0%)	0
Angina Unstable	0/313 (0%)	0	1/292 (0.3%)	1	1/302 (0.3%)	1
Atrial Fibrillation	1/313 (0.3%)	1	1/292 (0.3%)	1	2/302 (0.7%)	3
Atrioventricular Block Complete	0/313 (0%)	0	2/292 (0.7%)	2	0/302 (0%)	0
Cardiac Failure	0/313 (0%)	0	0/292 (0%)	0	1/302 (0.3%)	1
Coronary Artery Disease	2/313 (0.6%)	2	0/292 (0%)	0	0/302 (0%)	0
Myocardial Ischaemia	0/313 (0%)	0	0/292 (0%)	0	1/302 (0.3%)	1
Sinus Node Dysfunction	0/313 (0%)	0	1/292 (0.3%)	1	0/302 (0%)	0
Supraventricular Tachycardia	0/313 (0%)	0	1/292 (0.3%)	1	0/302 (0%)	0
Ear and labyrinth disorders
Vertigo	0/313 (0%)	0	1/292 (0.3%)	1	0/302 (0%)	0
Gastrointestinal disorders
Colitis Ulcerative	1/313 (0.3%)	1	0/292 (0%)	0	0/302 (0%)	0
Diverticulum Intestinal Haemorrhagic	0/313 (0%)	0	1/292 (0.3%)	1	0/302 (0%)	0
Enteritis	1/313 (0.3%)	1	0/292 (0%)	0	0/302 (0%)	0
Inguinal Hernia	1/313 (0.3%)	1	0/292 (0%)	0	0/302 (0%)	0
Omental Necrosis	0/313 (0%)	0	1/292 (0.3%)	1	0/302 (0%)	0
Pancreatitis	0/313 (0%)	0	0/292 (0%)	0	1/302 (0.3%)	1
Pancreatitis Chronic	0/313 (0%)	0	1/292 (0.3%)	1	0/302 (0%)	0
Hepatobiliary disorders
Cholecystitis	0/313 (0%)	0	0/292 (0%)	0	1/302 (0.3%)	1
Cholelithiasis	1/313 (0.3%)	1	2/292 (0.7%)	2	0/302 (0%)	0
Infections and infestations
Covid-19 Pneumonia	0/313 (0%)	0	0/292 (0%)	0	1/302 (0.3%)	1
Cholecystitis Infective	0/313 (0%)	0	0/292 (0%)	0	1/302 (0.3%)	1
Diverticulitis	1/313 (0.3%)	1	1/292 (0.3%)	1	0/302 (0%)	0
Escherichia Urinary Tract Infection	0/313 (0%)	0	0/292 (0%)	0	1/302 (0.3%)	1
Gangrene	0/313 (0%)	0	0/292 (0%)	0	1/302 (0.3%)	1
Gastroenteritis	1/313 (0.3%)	1	1/292 (0.3%)	1	0/302 (0%)	0
Pneumonia	1/313 (0.3%)	1	0/292 (0%)	0	1/302 (0.3%)	1
Sepsis	0/313 (0%)	0	1/292 (0.3%)	1	1/302 (0.3%)	1
Sialoadenitis	0/313 (0%)	0	0/292 (0%)	0	1/302 (0.3%)	1
Staphylococcal Infection	1/313 (0.3%)	1	0/292 (0%)	0	0/302 (0%)	0
Injury, poisoning and procedural complications
Concussion	0/313 (0%)	0	0/292 (0%)	0	1/302 (0.3%)	1
Ligament Sprain	0/313 (0%)	0	0/292 (0%)	0	1/302 (0.3%)	1
Vascular Graft Occlusion	0/313 (0%)	0	0/292 (0%)	0	1/302 (0.3%)	1
Metabolism and nutrition disorders
Dehydration	0/313 (0%)	0	1/292 (0.3%)	1	0/302 (0%)	0
Musculoskeletal and connective tissue disorders
Back Pain	0/313 (0%)	0	1/292 (0.3%)	1	0/302 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Benign Salivary Gland Neoplasm	0/313 (0%)	0	1/292 (0.3%)	1	0/302 (0%)	0
Colon Cancer Metastatic	1/313 (0.3%)	1	0/292 (0%)	0	0/302 (0%)	0
Malignant Melanoma	1/313 (0.3%)	1	0/292 (0%)	0	0/302 (0%)	0
Meningioma Benign	1/313 (0.3%)	1	0/292 (0%)	0	0/302 (0%)	0
Papillary Renal Cell Carcinoma	1/313 (0.3%)	1	0/292 (0%)	0	0/302 (0%)	0
Renal Neoplasm	0/313 (0%)	0	0/292 (0%)	0	1/302 (0.3%)	1
Spinal Meningioma Benign	0/313 (0%)	0	0/292 (0%)	0	1/302 (0.3%)	1
Nervous system disorders
Carpal Tunnel Syndrome	1/313 (0.3%)	1	0/292 (0%)	0	0/302 (0%)	0
Cerebrovascular Accident	0/313 (0%)	0	1/292 (0.3%)	1	0/302 (0%)	0
Dizziness	1/313 (0.3%)	1	0/292 (0%)	0	0/302 (0%)	0
Sciatica	0/313 (0%)	0	1/292 (0.3%)	1	0/302 (0%)	0
Syncope	0/313 (0%)	0	1/292 (0.3%)	1	0/302 (0%)	0
Transient Ischaemic Attack	0/313 (0%)	0	0/292 (0%)	0	1/302 (0.3%)	1
Vascular Encephalopathy	0/313 (0%)	0	1/292 (0.3%)	1	0/302 (0%)	0
Psychiatric disorders
Mental Status Changes	1/313 (0.3%)	1	0/292 (0%)	0	0/302 (0%)	0
Renal and urinary disorders
Acute Kidney Injury	1/313 (0.3%)	1	1/292 (0.3%)	1	0/302 (0%)	0
Chronic Kidney Disease	0/313 (0%)	0	1/292 (0.3%)	1	0/302 (0%)	0
Nephrolithiasis	0/313 (0%)	0	1/292 (0.3%)	1	0/302 (0%)	0
Subcapsular Renal Haematoma	1/313 (0.3%)	1	0/292 (0%)	0	0/302 (0%)	0
Reproductive system and breast disorders
Benign Prostatic Hyperplasia	1/313 (0.3%)	1	0/292 (0%)	0	0/302 (0%)	0
Respiratory, thoracic and mediastinal disorders
Asthma	1/313 (0.3%)	1	0/292 (0%)	0	0/302 (0%)	0
Chronic Obstructive Pulmonary Disease	0/313 (0%)	0	1/292 (0.3%)	1	0/302 (0%)	0
Pulmonary Embolism	0/313 (0%)	0	0/292 (0%)	0	2/302 (0.7%)	2
Vascular disorders
Hypertension	0/313 (0%)	0	0/292 (0%)	0	1/302 (0.3%)	1
Hypertensive Urgency	0/313 (0%)	0	1/292 (0.3%)	1	0/302 (0%)	0
Peripheral Arterial Occlusive Disease	1/313 (0.3%)	1	0/292 (0%)	0	1/302 (0.3%)	1
Other (Not Including Serious) Adverse Events
	Efpeglenatide 4 mg		Efpeglenatide 6 mg		Dulaglutide 1.5 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	202/313 (64.5%)		180/292 (61.6%)		178/302 (58.9%)
Gastrointestinal disorders
Abdominal Pain	24/313 (7.7%)	32	30/292 (10.3%)	39	16/302 (5.3%)	25
Abdominal Pain Upper	22/313 (7%)	22	16/292 (5.5%)	20	18/302 (6%)	18
Constipation	32/313 (10.2%)	33	34/292 (11.6%)	37	19/302 (6.3%)	21
Diarrhoea	93/313 (29.7%)	128	83/292 (28.4%)	120	90/302 (29.8%)	134
Dyspepsia	26/313 (8.3%)	30	17/292 (5.8%)	18	15/302 (5%)	20
Nausea	85/313 (27.2%)	116	83/292 (28.4%)	109	78/302 (25.8%)	111
Vomiting	41/313 (13.1%)	57	45/292 (15.4%)	65	37/302 (12.3%)	64
Infections and infestations
Upper Respiratory Tract Infection	21/313 (6.7%)	24	18/292 (6.2%)	20	20/302 (6.6%)	22
Investigations
Lipase Increased	27/313 (8.6%)	34	19/292 (6.5%)	22	24/302 (7.9%)	29
Metabolism and nutrition disorders
Decreased Appetite	38/313 (12.1%)	39	50/292 (17.1%)	56	36/302 (11.9%)	40
Nervous system disorders
Dizziness	18/313 (5.8%)	18	10/292 (3.4%)	15	10/302 (3.3%)	11

Limitations/Caveats

The study was terminated early by the Sponsor on 09 September 2020. Due to early termination of the study, model-based efficacy analyses were performed in the mITT population instead of the ITT population originally planned and data was carefully considered given that the study was terminated early.

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Sponsor supports publication of clinical trial results but may request that investigators temporarily delay or alter publications in order to protect proprietary information. The Sponsor may also require that the results of multicenter studies be published only in their entirety and not as individual site data.