AMPLITUDE-S: Efficacy and Safety of Efpeglenatide Versus Placebo in Patients With Type 2 Diabetes Mellitus Inadequately Controlled With Metformin Alone or in Combination With Sulfonylurea

• Sponsor: Sanofi (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT03770728
• Collaborator: Hanmi Pharmaceutical Company Limited (Industry)
• Enrollment: 312
• Locations: 48
• Arms: 4
• Actual Duration (Months): 16.9
• Patients Per Site: 6.5
• Patients Per Site Per Month: 0.4

Study Details

Study Description

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 metformin alone or in combination with sulfonylurea (SU).

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.

Condition or Disease	Intervention/Treatment	Phase
Type 2 Diabetes Mellitus	Drug: Efpeglenatide SAR439977; Drug: Placebo; Drug: Background therapy: Metformin alone or in combination with SU	Phase 3

Detailed Description

Study duration per participant was approximately 39 weeks including an up to 3-week Screening Period, a 30-week Treatment Period, and a 6-week safety Follow-up Period.

Study Design

• Study Type: Interventional
• Actual Enrollment: 312 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A 30-week, Multicenter, Double-blind, Placebo-controlled, Randomized Study to Evaluate the Efficacy and Safety of Efpeglenatide Once Weekly in Patients With Type 2 Diabetes Mellitus Inadequately Controlled With Metformin Alone or in Combination With Sulfonylurea
• Actual Study Start Date: Aug 1, 2019
• Actual Primary Completion Date: Nov 28, 2020
• Actual Study Completion Date: Dec 27, 2020

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Participants received placebo (matched to Efpeglenatide) subcutaneous (SC) injection once weekly up to Week 30 on top of metformin alone or in combination with SU.	Drug: Placebo; Pharmaceutical form: solution for injection Route of administration: subcutaneous; Drug: Background therapy: Metformin alone or in combination with SU; Pharmaceutical form: tablet Route of administration: oral, administered as per investigator and in accordance with local labeling.
Experimental: Efpeglenatide 2 mg Participants received Efpeglenatide 2 milligrams (mg) SC injection once weekly up to Week 30 on top of metformin alone or in combination with SU.	Drug: Efpeglenatide SAR439977; Pharmaceutical form: solution for injection Route of administration: subcutaneous; Drug: Background therapy: Metformin alone or in combination with SU; Pharmaceutical form: tablet Route of administration: oral, administered as per investigator and in accordance with local labeling.
Experimental: Efpeglenatide 4 mg Participants received Efpeglenatide 4 mg SC injection once weekly up to Week 30 on top of metformin alone or in combination with SU. Participants initiated dosing at 2 mg once weekly up to Week 1; which was up titrated to 4 mg and was maintained at the 4 mg dose through-out the treatment duration, up to Week 30.	Drug: Efpeglenatide SAR439977; Pharmaceutical form: solution for injection Route of administration: subcutaneous; Drug: Background therapy: Metformin alone or in combination with SU; Pharmaceutical form: tablet Route of administration: oral, administered as per investigator and in accordance with local labeling.
Experimental: Efpeglenatide 6 mg Participants received Efpeglenatide 6 mg SC injection once weekly up to Week 30 on top of metformin alone or in combination with SU. Participants initiated dosing at 2 mg once weekly up to Week 1; which was up titrated to 4 mg until Week 3 and later up-titrated to 6 mg and was maintained at the 6 mg dose through-out the treatment duration, up to Week 30.	Drug: Efpeglenatide SAR439977; Pharmaceutical form: solution for injection Route of administration: subcutaneous; Drug: Background therapy: Metformin alone or in combination with SU; Pharmaceutical form: tablet Route of administration: oral, administered as per investigator and in accordance with local labeling.

Outcome Measures

Primary Outcome Measures

1. Change From Baseline to Week 30 in HbA1c [Baseline to Week 30]

   This analysis included all Week 30 assessment values available.

Secondary Outcome Measures

1. Number of Participants With HbA1c <7.0% [Week 30]

   Participants who had no available assessment for HbA1c <7% at Week 30 were considered as non-responders.

2. Change From Baseline to Week 30 in Fasting Plasma Glucose (FPG) [Baseline to Week 30]

   This analysis included all Week 30 assessment values available.

3. Change From Baseline to Week 30 in Body Weight [Baseline to Week 30]

   This analysis included all Week 30 assessment values available.

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 30]

   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 30]

   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 metformin alone or in combination with SU, for at least 3 months prior to screening.

• Glycated hemoglobin between 7.0% 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 or history of surgery affecting gastric emptying.

• 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 millimeters of mercury (mmHg) and/or diastolic blood pressure >100 mmHg at randomization.

• Severe renal disease as defined by estimated glomerular filtration rate (eGFR) of <30 milliliters per minute per 1.73 square meter.

• Laboratory findings at the screening visit:

• Alanine aminotransferase or aspartate aminotransferase >3upper limit of the normal (ULN) or total bilirubin >1.5ULN (except in case of documented Gilbert's syndrome);

• Amylase and/or lipase: >3*ULN laboratory range;

• Calcitonin >=5.9 picomoles per liter (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 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 8400042	Mesa	Arizona	United States	85206
5	Investigational Site Number 8400051	Phoenix	Arizona	United States	85020
6	Investigational Site Number 8400056	Tucson	Arizona	United States	85741
7	Investigational Site Number 8400057	Huntington Park	California	United States	90255
8	Investigational Site Number 8400009	Los Angeles	California	United States	90057
9	Investigational Site Number 8400045	Spring Valley	California	United States	91978
10	Investigational Site Number 8400040	Tustin	California	United States	92780
11	Investigational Site Number 8400047	Colorado Springs	Colorado	United States	80909
12	Investigational Site Number 8400046	Coral Gables	Florida	United States	33134
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 8400044	Lexington	Kentucky	United States	40503
16	Investigational Site Number 8400001	Bridgeton	New Jersey	United States	08302
17	Investigational Site Number 8400039	New Windsor	New York	United States	12553
18	Investigational Site Number 8400036	Morehead City	North Carolina	United States	28557
19	Investigational Site Number 8400013	Maumee	Ohio	United States	43537
20	Investigational Site Number 8400048	Oklahoma City	Oklahoma	United States	73111
21	Investigational Site Number 8400030	Dallas	Texas	United States	75230
22	Investigational Site Number 8400043	San Antonio	Texas	United States	78229
23	Investigational Site Number 8400037	Layton	Utah	United States	84041
24	Investigational Site Number 1560005	Baotou		China	014010
25	Investigational Site Number 1560042	Beijing		China	101199
26	Investigational Site Number 1560053	Hangzhou		China	310009
27	Investigational Site Number 1560051	Hefei		China	210011
28	Investigational Site Number 1560011	Hunan		China	411100
29	Investigational Site Number 1560025	Meihekou		China	135000
30	Investigational Site Number 1560055	Nanchang		China	330006
31	Investigational Site Number 1560024	Nanjing		China	210011
32	Investigational Site Number 1560020	Pingxiang		China	337055
33	Investigational Site Number 1560031	Shandong		China	250013
34	Investigational Site Number 1560030	Shandong		China	250031
35	Investigational Site Number 1560012	Shanghai		China	200040
36	Investigational Site Number 1560013	Shanghai		China	200040
37	Investigational Site Number 1560004	Shanghai		China	200065
38	Investigational Site Number 1560022	Shanghai		China	200090
39	Investigational Site Number 1560041	Tianjin		China	300052
40	Investigational Site Number 1560010	Wenzhou		China	325027
41	Investigational Site Number 1560052	Wuhu		China	241001
42	Investigational Site Number 1560034	Wuxi		China	214000
43	Investigational Site Number 1560026	Xuzhou		China	221006
44	Investigational Site Number 1560044	Yichun		China	336000
45	Investigational Site Number 1560003	Zhengzhou		China	450003
46	Investigational Site Number 1580006	Kaohsiung		Taiwan	83301
47	Investigational Site Number 1580003	Taichung		Taiwan	40705
48	Investigational Site Number 1580002	Taipei		Taiwan	11217

Sponsors and Collaborators

• Sanofi
• Hanmi Pharmaceutical Company Limited

Investigators

• Study Director: Clinical Sciences & Operations, Sanofi

Study Documents (Full-Text)

• Study Protocol - Jun 20, 2018
• Statistical Analysis Plan - Oct 28, 2020

More Information

Publications

None provided.

• Responsible Party: Sanofi
• ClinicalTrials.gov Identifier: NCT03770728
• Other Study ID Numbers: EFC15337; U1111-1205-1291
• First Posted: Dec 10, 2018
• Last Update Posted: Dec 2, 2021
• Last Verified: Nov 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
• Product Manufactured in and Exported from the U.S.: No
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Metformin; Efpeglenatide

Study Results

Participant Flow

Recruitment Details	The study was conducted at 48 active sites in 3 countries. A total of 560 participants were screened between 01 August 2019 and 09 August 2020, out of which 248 were screen failures. Screen failures were mainly due to inclusion criteria not met.
Pre-assignment Detail	A total of 312 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).

Arm/Group Title	Placebo	Efpeglenatide 2 mg	Efpeglenatide 4 mg	Efpeglenatide 6 mg
Arm/Group Description	Participants received placebo (matched to Efpeglenatide) subcutaneous (SC) injection once weekly up to Week 30 on top of metformin alone or in combination with SU.	Participants received Efpeglenatide 2 mg SC injection once weekly up to Week 30 on top of metformin alone or in combination with SU.	Participants received Efpeglenatide 4 mg SC injection once weekly up to Week 30 on top of metformin alone or in combination with SU. Participants initiated dosing at 2 mg once weekly up to Week 1; which was up titrated to 4 mg and was maintained at the 4 mg dose through-out the treatment duration, up to Week 30.	Participants received Efpeglenatide 6 mg SC injection once weekly up to Week 30 on top of metformin alone or in combination with SU. Participants initiated dosing at 2 mg once weekly up to Week 1; which was up titrated to 4 mg until Week 3 and later up-titrated to 6 mg and was maintained at the 6 mg dose through-out the treatment duration, up to Week 30.
Period Title: Overall Study
STARTED	79	78	77	78
Safety Population	79	78	80	75
COMPLETED	41	47	45	43
NOT COMPLETED	38	31	32	35

Baseline Characteristics

Arm/Group Title	Placebo	Efpeglenatide 2 mg	Efpeglenatide 4 mg	Efpeglenatide 6 mg	Total
Arm/Group Description	Participants received placebo (matched to Efpeglenatide) SC injection once weekly up to Week 30 on top of metformin alone or in combination with SU.	Participants received Efpeglenatide 2 mg SC injection once weekly up to Week 30 on top of metformin alone or in combination with SU.	Participants received Efpeglenatide 4 mg SC injection once weekly up to Week 30 on top of metformin alone or in combination with SU. Participants initiated dosing at 2 mg once weekly up to Week 1; which was up titrated to 4 mg and was maintained at the 4 mg dose through-out the treatment duration, up to Week 30.	Participants received Efpeglenatide 6 mg SC injection once weekly up to Week 30 on top of metformin alone or in combination with SU. Participants initiated dosing at 2 mg once weekly up to Week 1; which was up titrated to 4 mg until Week 3 and later up-titrated to 6 mg and was maintained at the 6 mg dose through-out the treatment duration, up to Week 30.	Total of all reporting groups
Overall Participants	79	78	77	78	312
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	58.9 (10.6)	60.1 (10.9)	57.9 (10.5)	58.8 (11.5)	58.9 (10.9)
Sex: Female, Male (Count of Participants)
Female	34 43%	34 43.6%	33 42.9%	39 50%	140 44.9%
Male	45 57%	44 56.4%	44 57.1%	39 50%	172 55.1%
Race/Ethnicity, Customized (Count of Participants)
White	42 53.2%	43 55.1%	46 59.7%	48 61.5%	179 57.4%
Black or African American	11 13.9%	10 12.8%	4 5.2%	7 9%	32 10.3%
Asian	24 30.4%	24 30.8%	26 33.8%	22 28.2%	96 30.8%
Other	2 2.5%	1 1.3%	1 1.3%	0 0%	4 1.3%
Not reported	0 0%	0 0%	0 0%	1 1.3%	1 0.3%
Baseline Glycated Hemoglobin (HbA1c %) (percentage of HbA1c) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percentage of HbA1c]	8.09 (0.79)	8.07 (0.76)	8.15 (0.69)	8.09 (0.79)	8.10 (0.76)
Body Mass Index (BMI) (kilogram per square meter (kg/m^2)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram per square meter (kg/m^2)]	32.2 (7.1)	31.8 (7.7)	32.0 (6.3)	32.4 (7.4)	32.1 (7.1)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline to Week 30 in HbA1c
Description	This analysis included all Week 30 assessment values available.
Time Frame	Baseline to Week 30

Outcome Measure Data

Analysis Population Description

Analysis was performed on Intent-to-treat (ITT) population, which included all participants randomized irrespective of rescue therapy use and compliance with the study protocol and procedures, and were analyzed according to the treatment group allocated by randomization. Here, "Overall number of participants analyzed"= participants evaluable for this outcome measure.

Arm/Group Title	Placebo	Efpeglenatide 2 mg	Efpeglenatide 4 mg	Efpeglenatide 6 mg
Arm/Group Description	Participants received placebo (matched to Efpeglenatide) SC injection once weekly up to Week 30 on top of metformin alone or in combination with SU.	Participants received Efpeglenatide 2 mg SC injection once weekly up to Week 30 on top of metformin alone or in combination with SU.	Participants received Efpeglenatide 4 mg SC injection once weekly up to Week 30 on top of metformin alone or in combination with SU. Participants initiated dosing at 2 mg once weekly up to Week 1; which was up titrated to 4 mg and was maintained at the 4 mg dose through-out the treatment duration, up to Week 30.	Participants received Efpeglenatide 6 mg SC injection once weekly up to Week 30 on top of metformin alone or in combination with SU. Participants initiated dosing at 2 mg once weekly up to Week 1; which was up titrated to 4 mg until Week 3 and later up-titrated to 6 mg and was maintained at the 6 mg dose through-out the treatment duration, up to Week 30.
Measure Participants	48	48	49	48
Mean (Standard Deviation) [percentage of HbA1c]	-0.27 (0.92)	-1.05 (0.88)	-1.46 (0.90)	-1.36 (1.09)

2. Secondary Outcome

Title	Number of Participants With HbA1c <7.0%
Description	Participants who had no available assessment for HbA1c <7% at Week 30 were considered as non-responders.
Time Frame	Week 30

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT population.

Arm/Group Title	Placebo	Efpeglenatide 2 mg	Efpeglenatide 4 mg	Efpeglenatide 6 mg
Arm/Group Description	Participants received placebo (matched to Efpeglenatide) SC injection once weekly up to Week 30 on top of metformin alone or in combination with SU.	Participants received Efpeglenatide 2 mg SC injection once weekly up to Week 30 on top of metformin alone or in combination with SU.	Participants received Efpeglenatide 4 mg SC injection once weekly up to Week 30 on top of metformin alone or in combination with SU. Participants initiated dosing at 2 mg once weekly up to Week 1; which was up titrated to 4 mg and was maintained at the 4 mg dose through-out the treatment duration, up to Week 30.	Participants received Efpeglenatide 6 mg SC injection once weekly up to Week 30 on top of metformin alone or in combination with SU. Participants initiated dosing at 2 mg once weekly up to Week 1; which was up titrated to 4 mg until Week 3 and later up-titrated to 6 mg and was maintained at the 6 mg dose through-out the treatment duration, up to Week 30.
Measure Participants	79	78	77	78
Count of Participants [Participants]	11 13.9%	27 34.6%	33 42.9%	32 41%

3. Secondary Outcome

Title	Change From Baseline to Week 30 in Fasting Plasma Glucose (FPG)
Description	This analysis included all Week 30 assessment values available.
Time Frame	Baseline to Week 30

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT population. Here, "Overall number of participants analyzed"= participants evaluable for this outcome measure.

Arm/Group Title	Placebo	Efpeglenatide 2 mg	Efpeglenatide 4 mg	Efpeglenatide 6 mg
Arm/Group Description	Participants received placebo (matched to Efpeglenatide) SC injection once weekly up to Week 30 on top of metformin alone or in combination with SU.	Participants received Efpeglenatide 2 mg SC injection once weekly up to Week 30 on top of metformin alone or in combination with SU.	Participants received Efpeglenatide 4 mg SC injection once weekly up to Week 30 on top of metformin alone or in combination with SU. Participants initiated dosing at 2 mg once weekly up to Week 1; which was up titrated to 4 mg and was maintained at the 4 mg dose through-out the treatment duration, up to Week 30.	Participants received Efpeglenatide 6 mg SC injection once weekly up to Week 30 on top of metformin alone or in combination with SU. Participants initiated dosing at 2 mg once weekly up to Week 1; which was up titrated to 4 mg until Week 3 and later up-titrated to 6 mg and was maintained at the 6 mg dose through-out the treatment duration, up to Week 30.
Measure Participants	45	45	47	43
Mean (Standard Deviation) [millimoles per liter (mmol/L)]	0.12 (2.37)	-0.97 (2.43)	-1.75 (2.43)	-1.20 (4.68)

4. Secondary Outcome

Title	Change From Baseline to Week 30 in Body Weight
Description	This analysis included all Week 30 assessment values available.
Time Frame	Baseline to Week 30

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT population. Here, "Overall number of participants analyzed"= participants evaluable for this outcome measure.

Arm/Group Title	Placebo	Efpeglenatide 2 mg	Efpeglenatide 4 mg	Efpeglenatide 6 mg
Arm/Group Description	Participants received placebo (matched to Efpeglenatide) SC injection once weekly up to Week 30 on top of metformin alone or in combination with SU.	Participants received Efpeglenatide 2 mg SC injection once weekly up to Week 30 on top of metformin alone or in combination with SU.	Participants received Efpeglenatide 4 mg SC injection once weekly up to Week 30 on top of metformin alone or in combination with SU. Participants initiated dosing at 2 mg once weekly up to Week 1; which was up titrated to 4 mg and was maintained at the 4 mg dose through-out the treatment duration, up to Week 30.	Participants received Efpeglenatide 6 mg SC injection once weekly up to Week 30 on top of metformin alone or in combination with SU. Participants initiated dosing at 2 mg once weekly up to Week 1; which was up titrated to 4 mg until Week 3 and later up-titrated to 6 mg and was maintained at the 6 mg dose through-out the treatment duration, up to Week 30.
Measure Participants	47	46	47	47
Mean (Standard Deviation) [kilograms]	-1.89 (5.53)	-2.49 (3.93)	-2.72 (6.49)	-3.87 (4.62)

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 30

Outcome Measure Data

Analysis Population Description

Analysis was performed on safety population.

Arm/Group Title	Placebo	Efpeglenatide 2 mg	Efpeglenatide 4 mg	Efpeglenatide 6 mg
Arm/Group Description	Participants received placebo (matched to Efpeglenatide) SC injection once weekly up to Week 30 on top of metformin alone or in combination with SU.	Participants received Efpeglenatide 2 mg SC injection once weekly up to Week 30 on top of metformin alone or in combination with SU.	Participants received Efpeglenatide 4 mg SC injection once weekly up to Week 30 on top of metformin alone or in combination with SU. 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 30.	Participants received Efpeglenatide 6 mg SC injection once weekly up to Week 30 on top of metformin alone or in combination with SU. Participants initiated dosing at 2 mg once weekly up to Week 1; which was up titrated to 4 mg until Week 3 and later up-titrated to 6 mg and maintained at the 6 mg dose through-out the treatment duration, up to Week 30.
Measure Participants	79	78	80	75
Documented symptomatic hypoglycemia (<54 mg/dL)	1 1.3%	0 0%	2 2.6%	3 3.8%
Severe hypoglycemia	0 0%	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 30

Outcome Measure Data

Analysis Population Description

Analysis was performed on safety population.

Arm/Group Title	Placebo	Efpeglenatide 2 mg	Efpeglenatide 4 mg	Efpeglenatide 6 mg
Arm/Group Description	Participants received placebo (matched to Efpeglenatide) SC injection once weekly up to Week 30 on top of metformin alone or in combination with SU.	Participants received Efpeglenatide 2 mg SC injection once weekly up to Week 30 on top of metformin alone or in combination with SU.	Participants received Efpeglenatide 4 mg SC injection once weekly up to Week 30 on top of metformin alone or in combination with SU. Participants initiated dosing at 2 mg once weekly up to Week 1; which was up titrated to 4 mg and was maintained at the 4 mg dose through-out the treatment duration, up to Week 30.	Participants received Efpeglenatide 6 mg SC injection once weekly up to Week 30 on top of metformin alone or in combination with SU. Participants initiated dosing at 2 mg once weekly up to Week 1; which was up titrated to 4 mg until Week 3 and later up-titrated to 6 mg and was maintained at the 6 mg dose through-out the treatment duration, up to Week 30.
Measure Participants	79	78	80	75
Documented symptomatic hypoglycemia (<54 mg/dL)	0.03	0	0.06	0.14
Severe hypoglycemia	0	0	0	0

Adverse Events

Time Frame	All Adverse Events (AEs) were collected from signature of the informed consent up to end of study (up to Week 36). Time frame for reporting of treatment emergent adverse events (TEAEs) was from first injection of investigational medicinal product (IMP) up to 30 days after the last injection of the IMP (i.e. up to Week 34).
Adverse Event Reporting Description	TEAEs were defined as AEs that developed or worsened or became serious during the treatment-emergent period. Analysis was performed on safety population.
Arm/Group Title	Placebo		Efpeglenatide 2 mg		Efpeglenatide 4 mg		Efpeglenatide 6 mg
Arm/Group Description	Participants received placebo (matched to Efpeglenatide) SC injection once weekly up to Week 30 on top of metformin alone or in combination with SU.		Participants received Efpeglenatide 2 mg SC injection once weekly up to Week 30 on top of metformin alone or in combination with SU.		Participants received Efpeglenatide 4 mg SC injection once weekly up to Week 30 on top of metformin alone or in combination with SU. Participants initiated dosing at 2 mg once weekly up to Week 1; which was up titrated to 4 mg and was maintained at the 4 mg dose through-out the treatment duration, up to Week 30.		Participants received Efpeglenatide 6 mg SC injection once weekly up to Week 30 on top of metformin alone or in combination with SU. Participants initiated dosing at 2 mg once weekly up to Week 1; which was up titrated to 4 mg until Week 3 and later up-titrated to 6 mg and was maintained at the 6 mg dose through-out the treatment duration, up to Week 30.
All Cause Mortality
	Placebo		Efpeglenatide 2 mg		Efpeglenatide 4 mg		Efpeglenatide 6 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/79 (0%)		0/78 (0%)		0/80 (0%)		0/75 (0%)
Serious Adverse Events
	Placebo		Efpeglenatide 2 mg		Efpeglenatide 4 mg		Efpeglenatide 6 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/79 (3.8%)		4/78 (5.1%)		5/80 (6.3%)		2/75 (2.7%)
Cardiac disorders
Acute Myocardial Infarction	0/79 (0%)	0	0/78 (0%)	0	0/80 (0%)	0	1/75 (1.3%)	1
Gastrointestinal disorders
Enterovesical Fistula	1/79 (1.3%)	1	0/78 (0%)	0	0/80 (0%)	0	0/75 (0%)	0
General disorders
Non-Cardiac Chest Pain	0/79 (0%)	0	0/78 (0%)	0	1/80 (1.3%)	1	0/75 (0%)	0
Infections and infestations
Cellulitis	0/79 (0%)	0	0/78 (0%)	0	1/80 (1.3%)	1	0/75 (0%)	0
Diverticulitis	1/79 (1.3%)	3	0/78 (0%)	0	1/80 (1.3%)	1	0/75 (0%)	0
Osteomyelitis	0/79 (0%)	0	0/78 (0%)	0	1/80 (1.3%)	1	0/75 (0%)	0
Pneumonia	0/79 (0%)	0	1/78 (1.3%)	1	0/80 (0%)	0	0/75 (0%)	0
Upper Respiratory Tract Infection	1/79 (1.3%)	1	0/78 (0%)	0	0/80 (0%)	0	0/75 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Intraductal Proliferative Breast Lesion	0/79 (0%)	0	1/78 (1.3%)	1	0/80 (0%)	0	0/75 (0%)	0
Ovarian Cancer	1/79 (1.3%)	1	0/78 (0%)	0	0/80 (0%)	0	0/75 (0%)	0
Pancreatic Carcinoma Metastatic	0/79 (0%)	0	0/78 (0%)	0	1/80 (1.3%)	1	0/75 (0%)	0
Nervous system disorders
Carotid Artery Stenosis	0/79 (0%)	0	1/78 (1.3%)	1	0/80 (0%)	0	0/75 (0%)	0
Cerebral Ischaemia	0/79 (0%)	0	0/78 (0%)	0	0/80 (0%)	0	1/75 (1.3%)	1
Transient Ischaemic Attack	0/79 (0%)	0	2/78 (2.6%)	2	0/80 (0%)	0	0/75 (0%)	0
Psychiatric disorders
Mental Status Changes	0/79 (0%)	0	0/78 (0%)	0	1/80 (1.3%)	1	0/75 (0%)	0
Respiratory, thoracic and mediastinal disorders
Acute Respiratory Failure	1/79 (1.3%)	1	0/78 (0%)	0	0/80 (0%)	0	0/75 (0%)	0
Chronic Obstructive Pulmonary Disease	1/79 (1.3%)	1	0/78 (0%)	0	0/80 (0%)	0	0/75 (0%)	0
Respiratory Failure	0/79 (0%)	0	1/78 (1.3%)	1	0/80 (0%)	0	0/75 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo		Efpeglenatide 2 mg		Efpeglenatide 4 mg		Efpeglenatide 6 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	21/79 (26.6%)		30/78 (38.5%)		36/80 (45%)		32/75 (42.7%)
Gastrointestinal disorders
Abdominal Pain	0/79 (0%)	0	0/78 (0%)	0	1/80 (1.3%)	1	4/75 (5.3%)	4
Diarrhoea	4/79 (5.1%)	4	8/78 (10.3%)	9	13/80 (16.3%)	16	12/75 (16%)	17
Nausea	5/79 (6.3%)	6	10/78 (12.8%)	10	16/80 (20%)	17	8/75 (10.7%)	9
Vomiting	1/79 (1.3%)	1	5/78 (6.4%)	5	6/80 (7.5%)	6	10/75 (13.3%)	16
General disorders
Fatigue	1/79 (1.3%)	1	4/78 (5.1%)	5	5/80 (6.3%)	5	0/75 (0%)	0
Injection Site Pain	4/79 (5.1%)	5	2/78 (2.6%)	4	2/80 (2.5%)	2	2/75 (2.7%)	2
Infections and infestations
Nasopharyngitis	1/79 (1.3%)	1	3/78 (3.8%)	4	1/80 (1.3%)	1	5/75 (6.7%)	5
Upper Respiratory Tract Infection	9/79 (11.4%)	10	5/78 (6.4%)	5	2/80 (2.5%)	2	5/75 (6.7%)	5
Urinary Tract Infection	0/79 (0%)	0	3/78 (3.8%)	3	6/80 (7.5%)	7	2/75 (2.7%)	2
Investigations
Lipase Increased	1/79 (1.3%)	2	4/78 (5.1%)	5	6/80 (7.5%)	7	3/75 (4%)	3
Metabolism and nutrition disorders
Decreased Appetite	0/79 (0%)	0	2/78 (2.6%)	2	4/80 (5%)	4	4/75 (5.3%)	5

Limitations/Caveats

The study was terminated early by the Sponsor on 09 September 2020. Due to early termination of the study, few efficacy evaluations and analyses originally planned in the protocol were no longer considered to be applicable and were not performed. Primary, and secondary efficacy data were descriptively summarized.

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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.