A Study of LY2189265 Compared to Sitagliptin in Participants With Type 2 Diabetes Mellitus on Metformin

A Phase 2/3, Placebo-Controlled, Efficacy and Safety Study of Once-Weekly, Subcutaneous LY2189265 Compared to Sitagliptin in Patients With Type 2 Diabetes Mellitus on Metformin

This is an adaptive dose finding study and a Phase 3 efficacy study to evaluate the effects of once weekly injection of LY2189265 compared to Sitagliptin on glucose by measuring glycosylated hemoglobin (HbA1c) change from baseline after 52 weeks in participants with type 2 diabetes mellitus on Metformin.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2
• Intervention / Treatment: Drug: LY2189265; Drug: Metformin; Drug: Placebo tablet; Drug: Sitagliptin; Drug: Placebo solution

Detailed Description

This is a double blind study designed to select 1 or 2 LY2189265 doses for evaluation in Phase 3 studies (dose-finding portion) and to evaluate efficacy and safety of selected doses of LY2189265 in comparison to Sitagliptin (100 milligrams) up to 104 weeks and Placebo up to 26 weeks in participants with type 2 diabetes mellitus on Metformin (confirmatory, Phase 3 portion). The primary objective is to show non-inferiority of the higher LY2189265 dose (if 2 doses are selected) to Sitagliptin with respect to change in glycosylated hemoglobin (HbA1c) at 52 weeks. The final endpoint is 104 weeks.

Participants are randomized to receive Placebo, Sitagliptin, or 1 of 7 initial LY2189265 doses until a dose decision is made based on quantitative analysis of the benefits and risks of each LY2189265 dose. A clinical utility index (CUI) that applies predicted values for change from baseline in HbA1c at 12 months and change from baseline in weight, diastolic blood pressure, and pulse rate at 6 months for each LY2189265 dose will be used toward this end. After the dose decision, participants in the selected LY2189265 arms and the comparator arms (Sitagliptin and Placebo/Sitagliptin arms) will continue the study, and additional participants will be randomized to the selected and comparator arms. Regardless of the timing of randomization relative to the dose decision point, all participants in the selected and comparator arms are planned to receive treatment for 104 weeks; participants in the Placebo/Sitagliptin arm will receive Placebo treatment for 26 weeks followed by Sitagliptin 100 mg for 78 weeks for blinding purposes only, and participants in the selected and Sitagliptin arms will receive the same treatment for 104 weeks. All participants will remain blinded to their study treatment throughout the study. Participants in the non-selected arms will discontinue from the study after the dose decision

• Study Type: Interventional
• Enrollment (Actual): 1202
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2H 2G4
      • 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.
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3P 3P4
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  • Ontario
    • Oakville, Ontario, Canada, L6H 3P1
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  • Quebec
    • Sherbrooke, Quebec, Canada, J1G 5K2
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• France
  • Corbeil-Essonnes, France, 91106
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  • La Rochelle, France, 17019
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  • Mantes La Jolie, France, 78200
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  • Montpellier, France, F-34295
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  • Narbonne, France, 11108
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  • Saint Mande, France, 94160
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  • Strasbourg, France, 67000
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  • Toul, France, 54201
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  • Venissieux, France, 69200
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• Germany
  • Aschaffenburg, Germany, 63739
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  • Bad Lauterberg, Germany, D-37431
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  • Bad Staffelstein, Germany, D-96231
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  • Bochum, Germany, D-44791
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  • Essen, Germany, 45355
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  • Hamburg, Germany, 21073
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  • Hirschhorn, Germany, 69434
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  • Mainz, Germany, D-55116
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  • Muenster, Germany, 48145
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  • Neuwied, Germany, 56564
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  • Pohlheim, Germany, D-35415
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  • Rotenburg-Fulda, Germany, 36199
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• India
  • Ahmedabad, India, 380006
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  • Bangalore, India, 560038
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  • Ghaziabad, India, 201 002
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  • Kochin, India, 682026
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  • Pune, India, 411005
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• Korea, Republic of
  • Goyang-Si, Korea, Republic of, 410-719
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  • Incheon, Korea, Republic of, 400-711
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  • Seongnam-Si, Korea, Republic of, 463-707
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  • Seoul, Korea, Republic of, 139-872
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  • Sungnam-Si, Korea, Republic of, 463-712
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• Mexico
  • Aguascalientes, Mexico, 20129
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  • Chihuahua, Mexico, 31238
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  • Guadalajara, Mexico, 44600
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  • Monterrey, Mexico, 64461
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• Poland
  • Gdynia, Poland, 81-557
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  • Lodz, Poland, 93-319
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  • Lublin, Poland, 20-954
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  • Szczecin, Poland, 70-506
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  • Wroclaw, Poland, 50-403
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• Puerto Rico
  • Manati, Puerto Rico, 00674
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  • San Juan, Puerto Rico, 00907
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• Romania
  • Baia Mare, Romania, 430123
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  • Cluj-Napoca, Romania, 400006
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  • Timisoara, Romania, 300736
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• Russian Federation
  • Arkhangelsk, Russian Federation, 163045
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  • Rostov-On-Don, Russian Federation, 344022
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  • Saint Petersburg, Russian Federation, 193257
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• Spain
  • Dos Hermanas, Spain, 41014
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  • Lleida, Spain, 25198
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  • Malaga, Spain, 29010
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  • Palma De Mallorca, Spain, 07010
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  • Pozuelo De Alarcon, Spain, 28223
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• Taiwan
  • Chiayi City, Taiwan, 600
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  • Kaohsiung, Taiwan, 807
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  • Taichung, Taiwan, 407
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  • Taichung City, Taiwan, 40201
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  • Tainan, Taiwan, 70403
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  • Taipei, Taiwan, 100
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  • Yung-Kang, Tainan, Taiwan, 710
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• United States
  • Arizona
    • Peoria, Arizona, United States, 85381
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    • Phoenix, Arizona, United States, 85050
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    • Tucson, Arizona, United States, 85741
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  • California
    • Fresno, California, United States, 93726
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    • Mission Hills, California, United States, 91345
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  • Colorado
    • Longmont, Colorado, United States, 80501
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  • Connecticut
    • Waterbury, Connecticut, United States, 06708
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  • Florida
    • Hollywood, Florida, United States, 33021
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    • West Palm Beach, Florida, United States, 33401
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  • Georgia
    • Athens, Georgia, United States, 30606
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    • Atlanta, Georgia, United States, 30303
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  • Idaho
    • Idaho Falls, Idaho, United States, 83404
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  • Illinois
    • Springfield, Illinois, United States, 62704
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  • Kansas
    • Topeka, Kansas, United States, 66606
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  • Louisiana
    • Metairie, Louisiana, United States, 70006
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  • Maine
    • Biddeford, Maine, United States, 04005
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  • Michigan
    • Ann Arbor, Michigan, United States, 48106
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    • Southfield, Michigan, United States, 48075
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    • St Clair Shores, Michigan, United States, 48081
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  • Missouri
    • St Louis, Missouri, United States, 63141
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  • Montana
    • Billings, Montana, United States, 59101
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  • Nevada
    • Las Vegas, Nevada, United States, 89101
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  • New York
    • Rochester, New York, United States, 14607
      • 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.
    • Syracuse, New York, United States, 13210
      • 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.
  • North Carolina
    • Greensboro, North Carolina, United States, 27401
      • 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.
    • Morehead City, North Carolina, United States, 28557
      • 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.
    • Winston-Salem, North Carolina, United States, 27103
      • 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.
  • Oregon
    • Corvallis, Oregon, United States, 97330
      • 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.
  • South Carolina
    • Charleston, South Carolina, United States, 29412
      • 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.
  • Texas
    • Dallas, Texas, United States, 75230
      • 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.
    • Georgetown, Texas, United States, 78626
      • 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.
    • Houston, Texas, United States, 77030
      • 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.
    • San Antonio, Texas, United States, 78229
      • 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.
  • Washington
    • Federal Way, Washington, United States, 98003
      • 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.
    • Tacoma, Washington, United States, 98405
      • 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.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diabetes mellitus, type 2, for at least 6 months
• Treatment regimens: diet and exercise, metformin as monotherapy or in combination with another oral antihyperglycemic medication (OAM), or another OAM as monotherapy. Must be able to tolerate metformin at a dose of at least 1500 milligrams (mg) daily for 6 weeks prior to randomization.
• Glycosylated hemoglobin (HbA1c) value of ≥7.0% to ≤9.5%, except participants on diet and exercise therapy who must have had HbA1c value of >8.0% to ≤9.5%
• Body mass index (BMI) between 25 and 40 kilograms per meter squared (kg/m^2), inclusive
• Stable weight for 3 months prior to screening
• Females of childbearing potential must test negative for pregnancy and agree to use a reliable birth control method

Exclusion Criteria:

• Diabetes mellitus, type 1
• Use of a glucagon-like peptide-1 (GLP-1) analog (for example, exenatide) within 6 months prior to screening or are being treated with insulin
• Gastric emptying abnormality, history of bariatric surgery, or chronic use of drugs that affect gastrointestinal motility
• Use of medications to promote weight loss
• Clinically-relevant cardiovascular event within 6 months prior to screening
• Poorly controlled hypertension
• Electrocardiogram (ECG) reading considered outside the normal limits or indicating cardiac disease
• Liver disease, hepatitis, chronic pancreatitis, idiopathic acute pancreatitis, or alanine transaminase (ALT) levels >3.0 times the upper limit of normal
• Serum creatinine ≥1.5 milligrams per deciliter (mg/dL) or a creatinine clearance <60 milliliters per minute (mL/minute)
• Uncontrolled diabetes, defined as >2 episodes of ketoacidosis or hyperosmolar state requiring hospitalization in the 6 months prior to study entry.
• Uncontrolled endocrine or autoimmune abnormality
• History of a transplanted organ
• Chronic use of systemic glucocorticoid therapy
• Active or untreated malignancy
• Use of central nervous system (CNS) stimulants

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

9

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: 3.0 mg LY2189265; LY2189265 (Dulaglutide): 3.0 milligrams (mg), subcutaneous (SC) injection, once weekly for up to 104 weeks Placebo: tablet, administered orally, once daily for up to 104 weeks Metformin: at least 1500 milligrams per day (mg/day), administered orally for up to 104 weeks	Drug: LY2189265; Other Names: Dulaglutide; Trulicity; Drug: Metformin; Drug: Placebo tablet
EXPERIMENTAL: 2.0 mg LY2189265; LY2189265 (Dulaglutide): 2.0 milligrams (mg), subcutaneous (SC) injection, once weekly for up to 104 weeks Placebo: tablet, administered orally, once daily for up to 104 weeks Metformin: at least 1500 milligrams per day (mg/day), administered orally for up to 104 weeks	Drug: LY2189265; Other Names: Dulaglutide; Trulicity; Drug: Metformin; Drug: Placebo tablet
EXPERIMENTAL: 1.5 mg LY2189265; LY2189265 (Dulaglutide): 1.5 milligrams (mg), subcutaneous (SC) injection, once weekly for up to 104 weeks Placebo: tablet, administered orally, once daily for up to 104 weeks Metformin: at least 1500 milligrams per day (mg/day), administered orally for up to 104 weeks	Drug: LY2189265; Other Names: Dulaglutide; Trulicity; Drug: Metformin; Drug: Placebo tablet
EXPERIMENTAL: 1.0 mg LY2189265; LY2189265 (Dulaglutide): 1.0 milligrams (mg), subcutaneous (SC) injection, once weekly for up to 104 weeks Placebo: tablet, administered orally, once daily for up to 104 weeks Metformin: at least 1500 milligrams per day (mg/day), administered orally for up to 104 weeks	Drug: LY2189265; Other Names: Dulaglutide; Trulicity; Drug: Metformin; Drug: Placebo tablet
EXPERIMENTAL: 0.75 mg LY2189265; LY2189265 (Dulaglutide): 0.75 milligrams (mg), subcutaneous (SC) injection, once weekly for up to 104 weeks Placebo: tablet, administered orally, once daily for up to 104 weeks Metformin: at least 1500 milligrams per day (mg/day), administered orally for up to 104 weeks	Drug: LY2189265; Other Names: Dulaglutide; Trulicity; Drug: Metformin; Drug: Placebo tablet
EXPERIMENTAL: 0.5 mg LY2189265; LY2189265 (Dulaglutide): 0.5 milligrams (mg), subcutaneous (SC) injection, once weekly for up to 104 weeks Placebo: tablet, administered orally, once daily for up to 104 weeks Metformin: at least 1500 milligrams per day (mg/day), administered orally for up to 104 weeks	Drug: LY2189265; Other Names: Dulaglutide; Trulicity; Drug: Metformin; Drug: Placebo tablet
EXPERIMENTAL: 0.25 mg LY2189265; LY2189265 (Dulaglutide): 0.25 milligrams (mg), subcutaneous (SC) injection, once weekly for up to 104 weeks Placebo: tablet, administered orally, once daily for up to 104 weeks Metformin: at least 1500 milligrams per day (mg/day), administered orally for up to 104 weeks	Drug: LY2189265; Other Names: Dulaglutide; Trulicity; Drug: Metformin; Drug: Placebo tablet
ACTIVE_COMPARATOR: Sitagliptin; Sitagliptin: 100-milligrams (mg) tablet, administered orally, once daily for 104 weeks Placebo: solution, subcutaneous (SC) injection, once weekly for 104 weeks Metformin: at least 1500 milligrams per day (mg/day), administered orally for 104 weeks	Drug: Metformin; Drug: Sitagliptin; Drug: Placebo solution
PLACEBO_COMPARATOR: Placebo/Sitagliptin (Baseline Through 104 Weeks); Placebo: solution, subcutaneous (SC) injection, once weekly for 104 weeks Placebo: tablet, administered orally, once daily for 26 weeks Sitagliptin: after 26 weeks, 100-milligrams (mg) tablet, administered orally, once daily for 78 weeks Metformin: at least 1500 milligrams per day (mg/day), administered orally for 104 weeks	Drug: Metformin; Drug: Placebo tablet; Drug: Placebo solution

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Glycosylated Hemoglobin (HbA1c) Change From Baseline	Least squares (LS) means were calculated using analysis of covariance (ANCOVA) and last observation carried forward (LOCF) imputation with country and treatment as fixed effects and baseline HbA1c as a covariate.	Baseline, 52 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Glycosylated Hemoglobin (HbA1c) at the Dose Decision Point	Change from baseline in HbA1c was 1 of the 4 measures included in the clinical utility index (CUI) used to evaluate the dose decision. The maximum duration of exposure to LY2189265, Sitagliptin, or Placebo (across all treatment arms) at the decision point was 27.4 weeks.	Baseline up to 27.4 weeks
Glycosylated Hemoglobin (HbA1c) Change From Baseline	Least squares (LS) means were calculated using analysis of covariance (ANCOVA) and last observation carried forward (LOCF) imputation with country and treatment as fixed effects and baseline HbA1c as a covariate.	Baseline, 26 weeks, 104 weeks
Durability of Change From Baseline in Glycosylated Hemoglobin (HbA1c)	Durability of effect on HbA1c was assessed by comparing the differences in mean change from baseline in HbA1c at 1 time point versus an earlier time point. Least squares (LS) means of change from baseline HbA1c data were calculated using a mixed-effects model for repeated measures (MMRM) analysis with treatment, country, visit, and treatment-by-visit interaction as fixed effects and baseline as a covariate.	Baseline, 13, 26, 52, and 104 weeks
Fasting Blood Glucose Change From Baseline	Least squares (LS) means of change from baseline were calculated using mixed-effects model for repeated measures (MMRM) with treatment, country, visit, and treatment-by-visit interaction as fixed effects and baseline as a covariate.	Baseline, 26, 52, and 104 weeks
Fasting Insulin Change From Baseline	Least squares (LS) means of change from baseline fasting insulin data were calculated using a mixed-effects model for repeated measures (MMRM) analysis with treatment, country, visit, and treatment-by-visit interaction as fixed effects and baseline as a covariate.	Baseline, 26, 52, and 104 weeks
Change From Baseline in Body Weight at Dose Decision Point	Change from baseline in body weight was 1 of the 4 measures included in the clinical utility index (CUI) used to evaluate the dose decision. The maximum duration of exposure to LY2189265, Sitagliptin, or Placebo (across all treatment arms) at the decision point was 27.4 weeks.	Baseline up to 27.4 weeks
Body Weight Change From Baseline	Least squares (LS) means of change from baseline body weight were calculated using analysis of covariance (ANCOVA) and last observation carried forward (LOCF) imputation with country and treatment as fixed effects and baseline as a covariate.	Baseline, 26, 52, and 104 weeks
Durability of Change From Baseline Body Weight	Durability of effect on body weight was assessed by comparing the differences in mean change from baseline in body weight at 1 time point versus an earlier time point. Least squares (LS) means of change from baseline body weight data were calculated using a mixed-effects model for repeated measures (MMRM) analysis with treatment, country, visit, and treatment-by-visit interaction as fixed effects and baseline as a covariate.	Baseline, 13, 26, 52, and 104 weeks
Waist Circumference Change From Baseline	Least squares (LS) means of change from baseline were calculated using a mixed-effects model for repeated measures (MMRM) with treatment, country, visit, and treatment-by-visit interaction as fixed effects and baseline as a covariate.	Baseline, 26, 52, and 104 weeks
Percentage of Participants Who Achieve Glycosylated Hemoglobin (HbA1c) <7% or ≤6.5%	The percentage of participants achieving HbA1c levels <7.0% and ≤6.5% was analyzed using a logistic regression model and last observation carried forward (LOCF) imputation with baseline, country, and treatment as factors included in the model.	Baseline, 26, 52, and 104 weeks
Incidence of Hypoglycemic Episodes	Hypoglycemic episodes (HE) were classified as severe (defined as episodes requiring assistance from another person to actively administer resuscitative actions), documented symptomatic (defined as any time a participant feels that he/she is experiencing symptoms and/or signs associated with hypoglycemia and has a plasma glucose level of ≤3.9 millimoles per liter [mmol/L]), asymptomatic (defined as episodes not accompanied by typical symptoms of hypoglycemia but with a measured plasma glucose of ≤3.9 mmol/L), nocturnal (defined as any episode that occurred between bedtime and waking), or probable symptomatic (defined as episodes during which symptoms of hypoglycemia were not accompanied by a plasma glucose determination). The number of participants with self-reported hypoglycemic events is summarized cumulatively.	Baseline through 26 and 104 weeks
Rate of Hypoglycemic Episodes	Hypoglycemic episodes (HE) were classified as severe (defined as episodes requiring assistance from another person to actively administer resuscitative actions), documented symptomatic (defined as any time a participant feels that he/she is experiencing symptoms and/or signs associated with hypoglycemia and has a plasma glucose level of ≤3.9 millimoles per liter [mmol/L]), asymptomatic (defined as episodes not accompanied by typical symptoms of hypoglycemia but with a measured plasma glucose of ≤3.9 mmol/L), nocturnal (defined as any episode that occurred between bedtime and waking), or probable symptomatic (defined as episodes during which symptoms of hypoglycemia were not accompanied by a plasma glucose determination). The 1-year adjusted rate of HE is summarized cumulatively.	Baseline through 26 and 104 weeks
Beta Cell Function and Insulin Sensitivity (HOMA2)	The homeostatic model assessment (HOMA) is a method used to quantify insulin resistance and beta (β)-cell function. HOMA2-%B is a computer model that uses fasting plasma insulin and glucose concentrations to estimate steady state beta cell function (%B) as a percentage of a normal reference population (normal young adults). HOMA2-%S is a computer model that uses fasting plasma insulin and glucose concentrations to estimate insulin sensitivity (%S), as percentages of a normal reference population (normal young adults). The normal reference population for both HOMA2-%B and HOMA2-%S were set at 100%. Least squares (LS) means of change from baseline of C-peptide based HOMA2-%B and HOMA2-%S were calculated using a mixed-effects model for repeated measures (MMRM) with treatment, country, visit, and treatment-by-visit interaction as fixed effects and baseline as a covariate.	Baseline, 26, 52, and 104 weeks
Number of Participants With Treatment-emergent Adverse Events at 26 Weeks	A treatment-emergent adverse event (TEAE) was defined as an event that first occurs or worsens (increases in severity) after baseline regardless of causality or severity. The number of participants with 1 or more TEAEs is summarized cumulatively. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module.	Baseline through 26 weeks
Number of Participants With Treatment-emergent Adverse Events at 52 Weeks	A treatment-emergent adverse event (TEAE) was defined as an event that first occurs or worsens (increases in severity) after baseline regardless of causality or severity. The number of participants with 1 or more TEAEs is summarized cumulatively. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module.	Baseline through 52 weeks
Number of Participants With Treatment-emergent Adverse Events at 104 Weeks	A treatment-emergent adverse event (TEAE) was defined as an event that first occurs or worsens (increases in severity) after baseline regardless of causality or severity. The number of participants with 1 or more TEAEs is summarized cumulatively. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module.	Baseline through 104 weeks
Number of Participants With Treatment-emergent Abnormal Laboratory Tests at 26 Weeks	The number of participants with treatment-emergent abnormal laboratory results (defined as abnormalities that first occur after baseline) was summarized cumulatively for alkaline phosphatase, alanine aminotransferase or serum glutamic pyruvic transaminase (ALT/SGPT), amylase (pancreatic and total), aspartate aminotransferase or serum glutamic oxaloacetic transaminase (AST/SGOT), basophils, bilirubin (direct and total), calcitonin, chloride, creatine phosphokinase (CPK), creatinine, creatinine clearance, eosinophils, erythrocytes, gamma glutamyltransferase (GGT), hematocrit, hemoglobin, leukocytes, lipase, lymphocytes, mean cell hemoglobin concentration (MCHC), mean cell volume (MCV), monocytes, neutrophils, platelets, potassium, sodium, urea nitrogen, and urine microalbumin-to-creatinine ratio (UMCR).	Baseline through 26 weeks
Number of Participants With Treatment-emergent Abnormal Laboratory Tests at 52 Weeks	The number of participants with treatment-emergent abnormal laboratory results (defined as abnormalities that first occur after baseline) was summarized cumulatively for alkaline phosphatase, alanine aminotransferase or serum glutamic pyruvic transaminase (ALT/SGPT), amylase (pancreatic and total), aspartate aminotransferase or serum glutamic oxaloacetic transaminase (AST/SGOT), basophils, bilirubin (direct and total), calcitonin, chloride, creatine phosphokinase (CPK), creatinine, creatinine clearance, eosinophils, erythrocytes, gamma glutamyltransferase (GGT), hematocrit, hemoglobin, leukocytes, lipase, lymphocytes, mean cell hemoglobin concentration (MCHC), mean cell volume (MCV), monocytes, neutrophils, platelets, potassium, sodium, urea nitrogen, and urine microalbumin-to-creatinine ratio (UMCR) .	Baseline through 52 weeks
Number of Participants With Treatment-emergent Abnormal Laboratory Tests at 104 Weeks	The number of participants with treatment-emergent abnormal laboratory results (defined as abnormalities that first occur after baseline) was summarized cumulatively for alkaline phosphatase, alanine aminotransferase or serum glutamic pyruvic transaminase (ALT/SGPT), amylase (pancreatic and total), aspartate aminotransferase or serum glutamic oxaloacetic transaminase (AST/SGOT), basophils, bilirubin (direct and total), calcitonin, chloride, creatine phosphokinase (CPK), creatinine, creatinine clearance, eosinophils, erythrocytes, gamma glutamyltransferase (GGT), hematocrit, hemoglobin, leukocytes, lipase, lymphocytes, mean cell hemoglobin concentration (MCHC), mean cell volume (MCV), monocytes, neutrophils, platelets, potassium, sodium, urea nitrogen, and urine microalbumin-to-creatinine ratio (UMCR).	Baseline through 104 weeks
Number of Participants With Treatment-emergent Abnormal Lipid Tests	The number of participants with treatment-emergent abnormal lipid test (cholesterol, high density lipoprotein cholesterol [HDL-C], low density lipoprotein cholesterol [LDL-C], and triglycerides [TG]) results (defined as lipid test abnormalities that first occurred after baseline) is summarized cumulatively.	Baseline through 26 and 104 weeks
Change From Baseline in Pulse Rate at Dose Decision Point	Sitting pulse rate was measured at the time that the dose decision was made (dose decision point). Change from baseline in pulse rate was 1 of the 4 measures included in the clinical utility index (CUI) used to evaluate the dose decision. The maximum duration of exposure to LY2189265, Sitagliptin, or Placebo (across all treatment arms) at the decision point was 27.4 weeks.	Baseline up to 27.4 weeks
Change From Baseline in Blood Pressure at Dose Decision Point	Sitting systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured at the dose decision point. Change from baseline in DBP was 1 of the 4 measures included in the clinical utility index (CUI) used to evaluate the dose decision. The maximum duration of exposure to LY2189265, Sitagliptin, or Placebo (across all treatment arms) at the time of the decision point was 27.4 weeks.	Baseline up to 27.4 weeks
Change From Baseline in Pulse Rate	Sitting and standing pulse rate were measured. Least squares (LS) means of change from baseline were calculated using a mixed-effects model for repeated measures (MMRM) with treatment, country, visit, and treatment-by-visit interaction as fixed effects and baseline as covariate.	Baseline, 26 weeks, 104 weeks
Change From Baseline in Blood Pressure	Sitting and standing systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured. Least squares (LS) means of change from baseline were calculated using a mixed-effects model for repeated measures (MMRM) with treatment, country, visit, and treatment-by-visit interaction as fixed effects and baseline as a covariate.	Baseline, 26 weeks, 104 weeks
Change From Baseline in Electrocardiogram (ECG) Parameters, Fridericia-corrected QT (QTcF) and PR Interval	The QT interval is a measure of the time between the start of the Q wave and the end of the T wave and was calculated from electrocardiogram (ECG) data using Fridericia's formula: QTc = QT/RR^0.33. Corrected QT (QTc) is the QT interval corrected for heart rate and RR, which is the interval between two R waves. PR is the interval between the P wave and the QRS complex. Least Squares (LS) means of change from baseline were calculated using a mixed-effects model for repeated measures (MMRM) with treatment, country, visit, and treatment-by-visit interaction as fixed effects and baseline as a covariate.	Baseline, 26 weeks, 104 weeks
Participant-reported Outcomes, Impact of Weight on Quality of Life-Lite (IWQoL-Lite)	The Impact of Weight on Quality of Life-Lite (IWQoL-Lite questionnaire) is an obesity-specific, 31-item questionnaire designed to measure the impact of weight on participants' quality of life. Items are scored on a 5-point numeric rating scale where 5 = "always true" and 1 = "never true". Items are summed into 6 scales (physical function [11 items], self-esteem [7 items], sexual life [4 items], public distress [5 items], work [4 items], and total score [31 items]) based on the average for the valid responses on that scale multiplied by the number of items on that scale (rounded to the nearest whole integer). Higher scores indicate lower levels of functioning (negative effects). Scores are linearly transformed to a 0 to 100 scale.	Baseline, 52 weeks, and 104 weeks
Participant-reported Outcomes, EQ-5D	The EQ-5D questionnaire is a generic, multidimensional, health-related, quality-of-life instrument. It consists of 2 parts. The first part allows participants to rate their health state in 5 health domains: mobility, self-care, usual activities, pain/discomfort, and mood using a three level scale of 1-3 (no problem, some problems, and major problems). These combinations of attributes were converted into a weighted health-state Index Score according to the United Kingdom (UK) population-based algorithm. The possible values for the Index Score ranged from -0.59 (severe problems in all 5 dimensions) to 1.0 (no problem in any dimension). The second part of the questionnaire consists of a 100-millimeter visual analog scale (VAS) on which the participants rated their perceived health state on that day from 0 (worst imaginable health state) to 100 (best imaginable health state).	Baseline, 52 weeks, and 104 weeks
Resource Utilization	The number of visits to the emergency room (ER) is summarized cumulatively.	Baseline through 52 and 104 weeks
Pharmacokinetics of LY2189265: Area Under the Concentration-Time Curve	Pharmacokinetic (PK) parameter estimates from LY2189265 concentration data were obtained using a 2-compartment population PK model with first order absorption. Area under the plasma-concentration curve from 0 to 168 hours, steady state (AUC0-168h, ss) of LY2189265 is summarized.	Baseline through 52 weeks
Antibodies to LY2189265	The number of participants with postbaseline detection of treatment-emergent antidrug LY2189265 antibodies (ADA) is summarized.	Baseline through 104 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Adjudicated Pancreatitis at 104 Weeks	The number of participants with pancreatitis confirmed by adjudication is summarized cumulatively. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module.	Baseline through 104 weeks
Number of Participants With Adjudicated Cardiovascular Events at 104 Weeks	Data on any new cardiovascular (CV) event was prospectively collected using a CV event electronic case report form. At prespecified visits, participants were asked about any new CV event. Deaths and nonfatal cardiovascular adverse events (AEs) were adjudicated by a committee of physicians with cardiology expertise external to the Sponsor. The nonfatal cardiovascular AEs to be adjudicated include myocardial infarction, hospitalization for unstable angina, hospitalization for heart failure, coronary interventions (such as coronary artery bypass graft or percutaneous coronary intervention), and cerebrovascular events including cerebrovascular accident (stroke) and transient ischemic attack. The number of participants with adjudicated CV events is summarized cumulatively. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module.	Baseline through 104 weeks

Collaborators and Investigators

• Sponsor: Eli Lilly and Company
• Collaborators: Berry Consultants; United BioSource, LLC; Tessella Inc.

Publications and helpful links

General Publications

• Sherman SI, Kloos RT, Tuttle RM, Pontecorvi A, Volzke H, Harper K, Vance C, Alston JT, Usborne AL, Sloop KW, Lakshmanan M. No calcitonin change in a person taking dulaglutide diagnosed with pre-existing medullary thyroid cancer. Diabet Med. 2018 Mar;35(3):381-385. doi: 10.1111/dme.13437.
• Boustani MA, Pittman I 4th, Yu M, Thieu VT, Varnado OJ, Juneja R. Similar efficacy and safety of once-weekly dulaglutide in patients with type 2 diabetes aged >/=65 and <65 years. Diabetes Obes Metab. 2016 Aug;18(8):820-8. doi: 10.1111/dom.12687. Epub 2016 Jun 7.
• Yu M, Van Brunt K, Varnado OJ, Boye KS. Patient-reported outcome results in patients with type 2 diabetes treated with once-weekly dulaglutide: data from the AWARD phase III clinical trial programme. Diabetes Obes Metab. 2016 Apr;18(4):419-24. doi: 10.1111/dom.12624. Epub 2016 Feb 4.
• Weinstock RS, Guerci B, Umpierrez G, Nauck MA, Skrivanek Z, Milicevic Z. Safety and efficacy of once-weekly dulaglutide versus sitagliptin after 2 years in metformin-treated patients with type 2 diabetes (AWARD-5): a randomized, phase III study. Diabetes Obes Metab. 2015 Sep;17(9):849-58. doi: 10.1111/dom.12479. Epub 2015 May 20.
• Skrivanek Z, Gaydos BL, Chien JY, Geiger MJ, Heathman MA, Berry S, Anderson JH, Forst T, Milicevic Z, Berry D. Dose-finding results in an adaptive, seamless, randomized trial of once-weekly dulaglutide combined with metformin in type 2 diabetes patients (AWARD-5). Diabetes Obes Metab. 2014 Aug;16(8):748-56. doi: 10.1111/dom.12305. Epub 2014 May 22.
• Spencer K, Colvin K, Braunecker B, Brackman M, Ripley J, Hines P, Skrivanek Z, Gaydos B, Geiger MJ. Operational challenges and solutions with implementation of an adaptive seamless phase 2/3 study. J Diabetes Sci Technol. 2012 Nov 1;6(6):1296-304. doi: 10.1177/193229681200600608.

Helpful Links

• (Lilly Clinical Trial Registry)

Study record dates

Study Major Dates

• Study Start: August 1, 2008
• Primary Completion (ACTUAL): June 1, 2011
• Study Completion (ACTUAL): July 1, 2012

Study Registration Dates

• First Submitted: August 12, 2008
• First Submitted That Met QC Criteria: August 12, 2008
• First Posted (ESTIMATE): August 14, 2008

Study Record Updates

• Last Update Posted (ESTIMATE): April 20, 2015
• Last Update Submitted That Met QC Criteria: March 31, 2015
• Last Verified: March 1, 2015

More Information

Terms related to this study

• Keywords: Diabetes, type 2 diabetes
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Incretins; Dipeptidyl-Peptidase IV Inhibitors; Dulaglutide; Metformin; Sitagliptin Phosphate
• Other Study ID Numbers: 11422; H9X-MC-GBCF (OTHER: Eli Lilly and Company); CTRI/2009/091/000969 (REGISTRY: Clinical Trials Registry - India)