A Study of Investigational Dulaglutide Doses in Participants With Type 2 Diabetes on Metformin Monotherapy

• Sponsor: Eli Lilly and Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02973100
• Collaborator: (none)
• Enrollment: 318
• Locations: 66
• Arms: 4
• Duration (Months): 8.4
• Patients Per Site: 4.8
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the efficacy and safety of investigational doses of dulaglutide in participants with type 2 diabetes on metformin monotherapy.

Condition or Disease	Intervention/Treatment	Phase
Type 2 Diabetes	Drug: Dulaglutide; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 318 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Double-Blind, Placebo-Controlled, 18-Week Trial of Investigational Dulaglutide Doses Versus Placebo in Patients With Type 2 Diabetes on Metformin Monotherapy
• Study Start Date: Dec 1, 2016
• Actual Primary Completion Date: Jul 15, 2017
• Actual Study Completion Date: Aug 14, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dulaglutide 4.5mg 4.5mg of Dulaglutide administered subcutaneously (SC)	Drug: Dulaglutide; Administered SC; Other Names: LY2189265
Experimental: Dulaglutide 3.0mg 3.0mg of Dulaglutide administered SC	Drug: Dulaglutide; Administered SC; Other Names: LY2189265
Active Comparator: Dulaglutide 1.5mg 1.5mg of Dulaglutide administered SC	Drug: Dulaglutide; Administered SC; Other Names: LY2189265
Placebo Comparator: Placebo Placebo administered SC	Drug: Placebo; Administered SC

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Hemoglobin A1c (HbA1c) [Baseline, Week 18]

   HbA1c is the glycosylated fraction of hemoglobin A. HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time. Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with baseline as a covariate, pooled country, treatment, time, treatment*time as fixed effects.

Secondary Outcome Measures

1. Percentage of Participants With HbA1c of <7.0% [Week 18]

   Hemoglobin A1c (HbA1c) is the glycosylated fraction of hemoglobin A. HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time.

2. Change From Baseline in Fasting Serum Glucose (FSG) [Baseline, Week 18]

   Fasting serum glucose (FSG) is a test to determine how much glucose (sugar) is in a serum sample after an overnight fast. Least Squares (LS) means was determined by MMRM methodology with baseline as a covariate, pooled country, baseline HbA1c strata using >=8% as cutoff, treatment, time, treatment*time as fixed effects.

3. Change From Baseline in Body Weight [Baseline, Week 18]

   Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with baseline as a covariate, pooled country, baseline HbA1c strata using >=8% as cutoff, treatment, time, treatment*time as fixed effects.

4. Percentage of Participants Discontinuing Study Drug Due to Adverse Events [Baseline through Week 18]

   Adverse event (AE) defined as any unfavorable medical event, newly emerged or a deterioration of a preexisting condition, in other words any untoward medical occurrence in a patient administered a pharmaceutical product, without regard to the possibility of a causal relationship, that occurred after the visit for informed consent and up to the visit for completion of administration, or discontinuation.

5. Rate of Documented Symptomatic Hypoglycemia [Week 18]

   Hypoglycemic events (HE) were classified as severe, documented symptomatic (defined as an HE with typical symptoms of hypoglycemia and a blood glucose level of ≤3.9 millimoles per liter [mmol/L]). Hypoglycemia rate per 30 days was summarized at each visit by treatment group. The rate of hypoglycemia was analyzed using a generalized estimation equations model with a negative binomial distribution and a Log link. LS mean was determined by MMRM methodology with baseline hypoglycemia rate, pooled country, HbA1c at Baseline, treatment, with log of exposure in days divided by 365.25 as the offset.

6. Pharmacokinetics (PK): The Maximum Drug Concentration at Steady State (Cmax,ss) of Dulaglutide [0, 2, 4, 6, 10, 18, 22 weeks and early termination]

   Plasma samples for PK analysis were combined measure obtained from 0, 2, 4, 6, 10, 18, 22 weeks and until early termination of the visit. Cmax takes all time points post dose into account and one value was reported.

7. Pharmacokinetics: Area Under the Concentration-Time Curve at Steady State From Time Zero to 168 Hours (AUC[0-168], ss) of Dulaglutide [0, 2, 4, 6, 10, 18, 22 weeks and early termination]

   AUC[0-168h] is a combined measure obtained from 0, 2, 4, 6, 10, 18, 22 weeks and until early termination of the visit.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Have had type 2 diabetes (T2D) for ≥6 months according to the World Health Organization (WHO) classification

• Have HbA1c of 7.0% to 10.0%, inclusive, as assessed by the central laboratory

• Have been treated with stable doses of metformin for at least 3 months

• Have a body mass index (BMI) ≥25 kilograms per square meter

Exclusion Criteria:

• Have type 1 diabetes (T1D)

• Have used any glucose-lowering medication other than metformin 3 months prior to study entry or during screening/lead-in period or have used any glucagon-like peptide-1 receptor agonists (GLP-1 RAs) at any time in the past

• Have had any of the following cardiovascular conditions: acute myocardial infarction (MI), New York Heart Association Class III or Class IV heart failure, or cerebrovascular accident (stroke)

• Have acute or chronic hepatitis, signs and symptoms of any other liver disease other than nonalcoholic fatty liver disease (NAFLD), or alanine aminotransferase (ALT) level

2.5 times the upper limit of the reference range, as determined by the central laboratory at study entry; participants with NAFLD are eligible for participation in this trial

• Have had chronic or acute pancreatitis any time prior to study entry

• Have an estimated glomerular filtration rate (eGFR) <45 milliliters/minute/1.73 square meter, calculated by the Chronic Kidney Disease-Epidemiology (CKD-EPI) equation

• Have serum calcitonin ≥20 picograms per milliliter, as determined by the central laboratory at study entry

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Parexel Early Phase Unit at Glendale	Glendale	California	United States	91206-4140
2	Marin Endocrine Associates	Greenbrae	California	United States	94904
3	National Research Institute	Huntington Park	California	United States	90255
4	National Research Institute	Los Angeles	California	United States	90057
5	Catalina Research Institute, LLC	Montclair	California	United States	91763
6	Artemis Institute for Clinical Research	San Diego	California	United States	92103
7	Encompass Clinical Research	Spring Valley Lake	California	United States	91978
8	University Clinical Investigators, Inc.	Tustin	California	United States	92780
9	Infosphere	Van Nuys	California	United States	91405
10	Diablo Clinical Research	Walnut Creek	California	United States	94598
11	Chase Medical Research, LLC	Waterbury	Connecticut	United States	06708
12	Axes Medical Research, LLC	Cooper City	Florida	United States	33024
13	Clinical Research of South Florida	Coral Gables	Florida	United States	33134
14	East Coast Institute For Research	Jacksonville	Florida	United States	32204
15	Suncoast Research Group, LLC	Miami Lakes	Florida	United States	33135
16	New Horizon Research Center	Miami	Florida	United States	33175
17	Palm Harbor Medical Associates	Palm Harbor	Florida	United States	34684
18	In-Quest Medical Research, LLC - Norcross	Norcross	Georgia	United States	30071
19	East West Medical Institute	Honolulu	Hawaii	United States	96814
20	Elite Cilnical Trials LLLP	Blackfoot	Idaho	United States	83221
21	Solaris Clinical Research	Meridian	Idaho	United States	83646
22	HSHS Medical Group Diabetes Research	Springfield	Illinois	United States	62711
23	American Health Network	Indianapolis	Indiana	United States	46254
24	Iderc, P.L.C.	Des Moines	Iowa	United States	50314
25	Cotton O'Neil Diabetes and Endocrinology Center	Topeka	Kansas	United States	66606
26	ActivMed Practices & Research, Inc	Methuen	Massachusetts	United States	01844
27	StudyMetrix Research, LLC	Saint Peters	Missouri	United States	63303
28	Manhattan Medical Research	New York Mills	New York	United States	10016
29	High Point Clinical Trials Center	High Point	North Carolina	United States	27265
30	Aventiv Research	Columbus	Ohio	United States	43213
31	The Corvallis Clinic P.C.	Corvallis	Oregon	United States	97330
32	Heritage Valley Medical Group, Inc.	Beaver	Pennsylvania	United States	15009
33	New Phase Research & Development	Knoxville	Tennessee	United States	37909
34	Dallas Diabetes Endocrine Center	Dallas	Texas	United States	75230
35	Consano Clinical Research	San Antonio	Texas	United States	78231
36	Clinpoint Trial, LLC	Waxahachie	Texas	United States	75165
37	Chrysalis Clinical Research	Saint George	Utah	United States	84790
38	Rainier Clinical Research Center	Renton	Washington	United States	98057
39	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Brandýs Nad Labem-Stará Boleslav		Czechia	25001
40	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Krnov		Czechia	79401
41	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Praha 1		Czechia	11000
42	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Praha 4 - Krc		Czechia	140 59
43	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Praha 4		Czechia	149 00
44	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Praha 8		Czechia	181 00
45	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Chihuahua		Mexico	31217
46	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Cuernavaca		Mexico	62250
47	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Guadalajara		Mexico	04460
48	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Monterrey		Mexico	64460
49	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Tampico		Mexico	89000
50	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Bialystok		Poland	15-404
51	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Bialystok		Poland	15-445
52	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Gdansk		Poland	80-546
53	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Lodz		Poland	90-242
54	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Lublin		Poland	20-333
55	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Lublin		Poland	20-538
56	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Poznan		Poland	61-655
57	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Poznan		Poland	61-853
58	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Ruda Slaska		Poland	41-709
59	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Szczecin		Poland	70-506
60	Marginal Doctor's Center	Manati		Puerto Rico	00674
61	American Telemedicine Center	San Juan		Puerto Rico	00917
62	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Alba Iulia		Romania	510053
63	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Baia Mare		Romania	430222
64	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Iasi		Romania	700547
65	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Oradea		Romania	410159
66	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Satu-Mare		Romania	440055

Sponsors and Collaborators

• Eli Lilly and Company

Investigators

• Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST), Eli Lilly and Company

Study Documents (Full-Text)

• Statistical Analysis Plan - Dec 8, 2016
• Study Protocol - Nov 7, 2016

More Information

Additional Information:

• A Study of Investigational Dulaglutide Doses in Participants With Type 2 Diabetes on Metformin Monotherapy

Publications

None provided.

• Responsible Party: Eli Lilly and Company
• ClinicalTrials.gov Identifier: NCT02973100
• Other Study ID Numbers: 16568; H9X-MC-GBGJ; 2016-002494-34
• First Posted: Nov 25, 2016
• Last Update Posted: Sep 23, 2019
• Last Verified: Sep 1, 2019

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Dulaglutide

Study Results

Participant Flow

Recruitment Details	The study consisted of 3 periods: an approximately 2-week lead-in period, followed by an 18-week treatment period, and a 4-week safety follow-up period.

Arm/Group Title	Placebo	Dulaglutide 1.5 Milligrams (mg)	Dulaglutide 3.0mg	Dulaglutide 4.5mg
Arm/Group Description	Participants received placebo once weekly (QW) by subcutaneous (SC) injection.	Participants received 1.5mg of dulaglutide QW by SC injection.	Participants received 3.0mg of dulaglutide QW by SC injection.	Participants received 4.5mg of dulaglutide QW by SC injection.
Period Title: Overall Study
STARTED	82	81	79	76
Received at Least 1 Dose of Study Drug	81	81	79	76
COMPLETED	75	73	75	69
NOT COMPLETED	7	8	4	7

Baseline Characteristics

Arm/Group Title	Placebo	Dulaglutide 1.5mg	Dulaglutide 3.0mg	Dulaglutide 4.5mg	Total
Arm/Group Description	Participants received placebo once weekly (QW) by subcutaneous (SC) injection.	Participants received 1.5mg of dulaglutide QW by SC injection.	Participants received 3.0mg of dulaglutide QW by SC injection.	Participants received 4.5mg of dulaglutide QW by SC injection.	Total of all reporting groups
Overall Participants	81	81	79	76	317
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	56.52 (8.93)	57.65 (9.79)	55.90 (10.74)	57.13 (9.63)	56.80 (9.77)
Sex: Female, Male (Count of Participants)
Female	33 40.7%	42 51.9%	44 55.7%	40 52.6%	159 50.2%
Male	48 59.3%	39 48.1%	35 44.3%	36 47.4%	158 49.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	35 43.2%	32 39.5%	38 48.1%	30 39.5%	135 42.6%
Not Hispanic or Latino	46 56.8%	49 60.5%	40 50.6%	45 59.2%	180 56.8%
Unknown or Not Reported	0 0%	0 0%	1 1.3%	1 1.3%	2 0.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	10 12.3%	6 7.4%	9 11.4%	6 7.9%	31 9.8%
Asian	0 0%	0 0%	1 1.3%	3 3.9%	4 1.3%
Native Hawaiian or Other Pacific Islander	1 1.2%	0 0%	0 0%	0 0%	1 0.3%
Black or African American	6 7.4%	6 7.4%	6 7.6%	6 7.9%	24 7.6%
White	59 72.8%	68 84%	58 73.4%	59 77.6%	244 77%
More than one race	5 6.2%	1 1.2%	4 5.1%	2 2.6%	12 3.8%
Unknown or Not Reported	0 0%	0 0%	1 1.3%	0 0%	1 0.3%
Region of Enrollment (Count of Participants)
Romania	6 7.4%	6 7.4%	5 6.3%	4 5.3%	21 6.6%
United States	42 51.9%	45 55.6%	44 55.7%	43 56.6%	174 54.9%
Czechia	10 12.3%	9 11.1%	10 12.7%	8 10.5%	37 11.7%
Poland	13 16%	11 13.6%	10 12.7%	10 13.2%	44 13.9%
Mexico	10 12.3%	10 12.3%	10 12.7%	11 14.5%	41 12.9%
Baseline Hemoglobin A1c (HbA1c) (Percentage of glycosylated hemoglobin) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Percentage of glycosylated hemoglobin]	8.08 (0.79)	8.02 (0.80)	8.16 (0.92)	8.12 (0.81)	8.09 (0.83)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Hemoglobin A1c (HbA1c)
Description	HbA1c is the glycosylated fraction of hemoglobin A. HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time. Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with baseline as a covariate, pooled country, treatment, time, treatment*time as fixed effects.
Time Frame	Baseline, Week 18

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least one dose of study drug and had postbaseline values, excluding post rescue data for Hemoglobin A1c.

Arm/Group Title	Placebo	Dulaglutide 1.5mg	Dulaglutide 3.0mg	Dulaglutide 4.5mg
Arm/Group Description	Participants received placebo once weekly (QW) by subcutaneous (SC) injection.	Participants received 1.5mg of dulaglutide QW by SC injection.	Participants received 3.0mg of dulaglutide QW by SC injection.	Participants received 4.5mg of dulaglutide QW by SC injection.
Measure Participants	70	73	73	66
Least Squares Mean (Standard Error) [Percentage of glycosylated hemoglobin]	-0.44 (0.101)	-1.23 (0.099)	-1.31 (0.099)	-1.40 (0.103)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dulaglutide 1.5mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.80
	Confidence Interval	(2-Sided) 95%; -1.07 to -0.53
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dulaglutide 3.0mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.87
	Confidence Interval	(2-Sided) 95%; -1.14 to -0.60
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dulaglutide 4.5mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.96
	Confidence Interval	(2-Sided) 95%; -1.24 to -0.69
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Percentage of Participants With HbA1c of <7.0%
Description	Hemoglobin A1c (HbA1c) is the glycosylated fraction of hemoglobin A. HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time.
Time Frame	Week 18

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least one dose of study drug and had postbaseline values, excluding post rescue data for Hemoglobin A1c.

Arm/Group Title	Placebo	Dulaglutide 1.5mg	Dulaglutide 3.0mg	Dulaglutide 4.5mg
Arm/Group Description	Participants received placebo once weekly (QW) by subcutaneous (SC) injection.	Participants received 1.5mg of dulaglutide QW by SC injection.	Participants received 3.0mg of dulaglutide QW by SC injection.	Participants received 4.5mg of dulaglutide QW by SC injection.
Measure Participants	70	73	73	66
Number [Percentage of Participants]	20 24.7%	71.2 87.9%	71.2 90.1%	68.2 89.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dulaglutide 1.5mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<.001
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	24.489
	Confidence Interval	(2-Sided) 95%; 8.368 to 71.667
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dulaglutide 3.0mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<.001
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	27.906
	Confidence Interval	(2-Sided) 95%; 9.238 to 84.300
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dulaglutide 4.5mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<.001
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	21.852
	Confidence Interval	(2-Sided) 95%; 7.672 to 62.242
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline in Fasting Serum Glucose (FSG)
Description	Fasting serum glucose (FSG) is a test to determine how much glucose (sugar) is in a serum sample after an overnight fast. Least Squares (LS) means was determined by MMRM methodology with baseline as a covariate, pooled country, baseline HbA1c strata using >=8% as cutoff, treatment, time, treatment*time as fixed effects.
Time Frame	Baseline, Week 18

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least one dose of study drug and had postbaseline values, excluding post rescue data for FSG.

Arm/Group Title	Placebo	Dulaglutide 1.5mg	Dulaglutide 3.0mg	Dulaglutide 4.5mg
Arm/Group Description	Participants received placebo once weekly (QW) by subcutaneous (SC) injection.	Participants received 1.5mg of dulaglutide QW by SC injection.	Participants received 3.0mg of dulaglutide QW by SC injection.	Participants received 4.5mg of dulaglutide QW by SC injection.
Measure Participants	63	62	67	61
Least Squares Mean (Standard Error) [millimole/liter (mmol/L)]	-0.69 (0.257)	-2.01 (0.261)	-1.92 (0.250)	-2.11 (0.263)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dulaglutide 1.5mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.32
	Confidence Interval	(2-Sided) 95%; -2.02 to -0.62
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dulaglutide 3.0mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.23
	Confidence Interval	(2-Sided) 95%; -1.91 to -0.54
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dulaglutide 4.5mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.42
	Confidence Interval	(2-Sided) 95%; -2.12 to -0.72
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline in Body Weight
Description	Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with baseline as a covariate, pooled country, baseline HbA1c strata using >=8% as cutoff, treatment, time, treatment*time as fixed effects.
Time Frame	Baseline, Week 18

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least one dose of study drug and had postbaseline values, excluding post rescue data for body weight.

Arm/Group Title	Placebo	Dulaglutide 1.5mg	Dulaglutide 3.0mg	Dulaglutide 4.5mg
Arm/Group Description	Participants received placebo once weekly (QW) by subcutaneous (SC) injection.	Participants received 1.5mg of dulaglutide QW by SC injection.	Participants received 3.0mg of dulaglutide QW by SC injection.	Participants received 4.5mg of dulaglutide QW by SC injection.
Measure Participants	70	72	74	67
Least Squares Mean (Standard Error) [Kilograms (Kg)]	-1.6 (0.39)	-2.8 (0.39)	-3.9 (0.39)	-4.1 (0.41)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dulaglutide 1.5mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.025
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.2
	Confidence Interval	(2-Sided) 95%; -2.3 to -0.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dulaglutide 3.0mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.4
	Confidence Interval	(2-Sided) 95%; -3.4 to -1.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dulaglutide 4.5mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.6
	Confidence Interval	(2-Sided) 95%; -3.7 to -1.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Percentage of Participants Discontinuing Study Drug Due to Adverse Events
Description	Adverse event (AE) defined as any unfavorable medical event, newly emerged or a deterioration of a preexisting condition, in other words any untoward medical occurrence in a patient administered a pharmaceutical product, without regard to the possibility of a causal relationship, that occurred after the visit for informed consent and up to the visit for completion of administration, or discontinuation.
Time Frame	Baseline through Week 18

Outcome Measure Data

Analysis Population Description

All randomized participants who received study drug and had postbaseline data for safety analyses.

Arm/Group Title	Placebo	Dulaglutide 1.5mg	Dulaglutide 3.0mg	Dulaglutide 4.5mg
Arm/Group Description	Participants received placebo once weekly (QW) by subcutaneous (SC) injection.	Participants received 1.5mg of dulaglutide QW by SC injection.	Participants received 3.0mg of dulaglutide QW by SC injection.	Participants received 4.5mg of dulaglutide QW by SC injection.
Measure Participants	82	81	79	76
Number [Percentage of Participants]	4.9 6%	6.2 7.7%	10.1 12.8%	13.2 17.4%

6. Secondary Outcome

Title	Rate of Documented Symptomatic Hypoglycemia
Description	Hypoglycemic events (HE) were classified as severe, documented symptomatic (defined as an HE with typical symptoms of hypoglycemia and a blood glucose level of ≤3.9 millimoles per liter [mmol/L]). Hypoglycemia rate per 30 days was summarized at each visit by treatment group. The rate of hypoglycemia was analyzed using a generalized estimation equations model with a negative binomial distribution and a Log link. LS mean was determined by MMRM methodology with baseline hypoglycemia rate, pooled country, HbA1c at Baseline, treatment, with log of exposure in days divided by 365.25 as the offset.
Time Frame	Week 18

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least one dose of study drug and had postbaseline values, excluding post rescue values for hypoglycemic episodes.

Arm/Group Title	Placebo	Dulaglutide 1.5mg	Dulaglutide 3.0mg	Dulaglutide 4.5mg
Arm/Group Description	Participants received placebo once weekly (QW) by subcutaneous (SC) injection.	Participants received 1.5mg of dulaglutide QW by SC injection.	Participants received 3.0mg of dulaglutide QW by SC injection.	Participants received 4.5mg of dulaglutide QW by SC injection.
Measure Participants	81	81	79	76
Least Squares Mean (Standard Error) [Episodes/participant/365.25 days]	0.00 (0.000)	0.00 (0.000)	0.00 (0.000)	0.00 (0.001)

7. Secondary Outcome

Title	Pharmacokinetics (PK): The Maximum Drug Concentration at Steady State (Cmax,ss) of Dulaglutide
Description	Plasma samples for PK analysis were combined measure obtained from 0, 2, 4, 6, 10, 18, 22 weeks and until early termination of the visit. Cmax takes all time points post dose into account and one value was reported.
Time Frame	0, 2, 4, 6, 10, 18, 22 weeks and early termination

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least one dose of the study drug and have evaluable PK data.

Arm/Group Title	Dulaglutide 1.5mg	Dulaglutide 3.0mg	Dulaglutide 4.5mg
Arm/Group Description	Participants received 1.5mg of dulaglutide QW by SC injection.	Participants received 3.0mg of dulaglutide QW by SC injection.	Participants received 4.5mg of dulaglutide QW by SC injection.
Measure Participants	81	79	76
Mean (90% Confidence Interval) [nanogram per milliliter (ng/mL)]	90.4	151	204

8. Secondary Outcome

Title	Pharmacokinetics: Area Under the Concentration-Time Curve at Steady State From Time Zero to 168 Hours (AUC[0-168], ss) of Dulaglutide
Description	AUC[0-168h] is a combined measure obtained from 0, 2, 4, 6, 10, 18, 22 weeks and until early termination of the visit.
Time Frame	0, 2, 4, 6, 10, 18, 22 weeks and early termination

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least one dose of the study drug and have evaluable PK data.

Arm/Group Title	Dulaglutide 1.5mg	Dulaglutide 3.0mg	Dulaglutide 4.5mg
Arm/Group Description	Participants received 1.5mg of dulaglutide QW by SC injection.	Participants received 3.0mg of dulaglutide QW by SC injection.	Participants received 4.5mg of dulaglutide QW by SC injection.
Measure Participants	81	79	76
Mean (90% Confidence Interval) [nanogram*hour per milliliter (ng*h/mL)]	11800	26700	36600

Adverse Events

Time Frame	Up to 22 weeks
Adverse Event Reporting Description	All participants who received at least one dose of study drug.
Arm/Group Title	Placebo		Dulaglutide 1.5mg		Dulaglutide 3.0mg		Dulaglutide 4.5mg
Arm/Group Description	Participants received placebo once weekly (QW) by subcutaneous (SC) injection.		Participants received 1.5mg of dulaglutide QW by SC injection.		Participants received 3.0mg of dulaglutide QW by SC injection.		Participants received 4.5mg of dulaglutide QW by SC injection.
All Cause Mortality
	Placebo		Dulaglutide 1.5mg		Dulaglutide 3.0mg		Dulaglutide 4.5mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/81 (0%)		0/81 (0%)		0/79 (0%)		0/76 (0%)
Serious Adverse Events
	Placebo		Dulaglutide 1.5mg		Dulaglutide 3.0mg		Dulaglutide 4.5mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/81 (4.9%)		3/81 (3.7%)		7/79 (8.9%)		3/76 (3.9%)
Cardiac disorders
Acute myocardial infarction	1/81 (1.2%)	1	0/81 (0%)	0	0/79 (0%)	0	0/76 (0%)	0
Atrioventricular block second degree	0/81 (0%)	0	0/81 (0%)	0	1/79 (1.3%)	1	0/76 (0%)	0
Myocardial infarction	0/81 (0%)	0	1/81 (1.2%)	1	0/79 (0%)	0	0/76 (0%)	0
Pericarditis	0/81 (0%)	0	1/81 (1.2%)	1	0/79 (0%)	0	0/76 (0%)	0
Gastrointestinal disorders
Abdominal pain upper	0/81 (0%)	0	0/81 (0%)	0	0/79 (0%)	0	1/76 (1.3%)	1
Pancreatitis	0/81 (0%)	0	0/81 (0%)	0	0/79 (0%)	0	1/76 (1.3%)	1
Vomiting	0/81 (0%)	0	0/81 (0%)	0	1/79 (1.3%)	1	0/76 (0%)	0
Hepatobiliary disorders
Cholecystitis	0/81 (0%)	0	0/81 (0%)	0	0/79 (0%)	0	1/76 (1.3%)	1
Cholecystitis acute	0/81 (0%)	0	0/81 (0%)	0	0/79 (0%)	0	1/76 (1.3%)	1
Cholelithiasis	0/81 (0%)	0	1/81 (1.2%)	1	0/79 (0%)	0	0/76 (0%)	0
Infections and infestations
Bronchitis	0/81 (0%)	0	0/81 (0%)	0	0/79 (0%)	0	1/76 (1.3%)	1
Cholecystitis infective	0/81 (0%)	0	0/81 (0%)	0	1/79 (1.3%)	1	0/76 (0%)	0
Fungal oesophagitis	0/81 (0%)	0	0/81 (0%)	0	1/79 (1.3%)	1	0/76 (0%)	0
Peritonsillar abscess	0/81 (0%)	0	0/81 (0%)	0	1/79 (1.3%)	1	0/76 (0%)	0
Injury, poisoning and procedural complications
Traumatic intracranial haemorrhage	1/81 (1.2%)	1	0/81 (0%)	0	0/79 (0%)	0	0/76 (0%)	0
Metabolism and nutrition disorders
Hyperglycaemic hyperosmolar nonketotic syndrome	1/81 (1.2%)	1	0/81 (0%)	0	0/79 (0%)	0	0/76 (0%)	0
Hyponatraemia	0/81 (0%)	0	0/81 (0%)	0	1/79 (1.3%)	1	0/76 (0%)	0
Hypovolaemia	0/81 (0%)	0	0/81 (0%)	0	1/79 (1.3%)	1	0/76 (0%)	0
Musculoskeletal and connective tissue disorders
Spinal pain	1/81 (1.2%)	1	0/81 (0%)	0	0/79 (0%)	0	0/76 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Invasive ductal breast carcinoma	0/81 (0%)	0	0/81 (0%)	0	1/79 (1.3%)	1	0/76 (0%)	0
Renal and urinary disorders
Renal failure	0/81 (0%)	0	0/81 (0%)	0	1/79 (1.3%)	1	0/76 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pulmonary oedema	0/81 (0%)	0	0/81 (0%)	0	1/79 (1.3%)	1	0/76 (0%)	0
Vascular disorders
Hypotension	0/81 (0%)	0	0/81 (0%)	0	1/79 (1.3%)	1	0/76 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo		Dulaglutide 1.5mg		Dulaglutide 3.0mg		Dulaglutide 4.5mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	29/81 (35.8%)		36/81 (44.4%)		49/79 (62%)		39/76 (51.3%)
Gastrointestinal disorders
Abdominal discomfort	0/81 (0%)	0	0/81 (0%)	0	2/79 (2.5%)	2	4/76 (5.3%)	10
Abdominal pain	1/81 (1.2%)	1	3/81 (3.7%)	4	1/79 (1.3%)	1	7/76 (9.2%)	7
Constipation	0/81 (0%)	0	5/81 (6.2%)	5	4/79 (5.1%)	4	6/76 (7.9%)	6
Diarrhoea	9/81 (11.1%)	10	9/81 (11.1%)	17	18/79 (22.8%)	34	16/76 (21.1%)	32
Dyspepsia	0/81 (0%)	0	6/81 (7.4%)	10	5/79 (6.3%)	5	8/76 (10.5%)	13
Eructation	0/81 (0%)	0	3/81 (3.7%)	3	1/79 (1.3%)	1	6/76 (7.9%)	6
Gastrooesophageal reflux disease	0/81 (0%)	0	5/81 (6.2%)	5	1/79 (1.3%)	1	0/76 (0%)	0
Nausea	4/81 (4.9%)	5	18/81 (22.2%)	45	20/79 (25.3%)	32	23/76 (30.3%)	40
Vomiting	4/81 (4.9%)	6	9/81 (11.1%)	20	9/79 (11.4%)	15	10/76 (13.2%)	16
General disorders
Fatigue	2/81 (2.5%)	3	1/81 (1.2%)	1	4/79 (5.1%)	4	7/76 (9.2%)	7
Infections and infestations
Influenza	0/81 (0%)	0	1/81 (1.2%)	1	4/79 (5.1%)	4	1/76 (1.3%)	1
Upper respiratory tract infection	3/81 (3.7%)	5	1/81 (1.2%)	1	5/79 (6.3%)	5	1/76 (1.3%)	1
Viral upper respiratory tract infection	5/81 (6.2%)	7	2/81 (2.5%)	2	6/79 (7.6%)	6	3/76 (3.9%)	4
Investigations
Weight decreased	0/81 (0%)	0	3/81 (3.7%)	6	5/79 (6.3%)	6	2/76 (2.6%)	2
Metabolism and nutrition disorders
Decreased appetite	1/81 (1.2%)	1	3/81 (3.7%)	3	13/79 (16.5%)	17	6/76 (7.9%)	6
Musculoskeletal and connective tissue disorders
Back pain	1/81 (1.2%)	1	0/81 (0%)	0	1/79 (1.3%)	2	4/76 (5.3%)	4
Nervous system disorders
Dizziness	4/81 (4.9%)	6	4/81 (4.9%)	6	5/79 (6.3%)	6	4/76 (5.3%)	5
Headache	7/81 (8.6%)	11	4/81 (4.9%)	4	10/79 (12.7%)	13	5/76 (6.6%)	8
Vascular disorders
Hypertension	1/81 (1.2%)	1	1/81 (1.2%)	1	4/79 (5.1%)	4	0/76 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.