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A Study in Participants With Type 2 Diabetes Mellitus (AWARD-2) (AWARD-2)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01075282
Recruitment Status : Completed
First Posted : February 25, 2010
Results First Posted : January 16, 2015
Last Update Posted : January 16, 2015
Sponsor:
Information provided by (Responsible Party):
Eli Lilly and Company

Study Description
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Brief Summary:
The purpose of this study is to determine if LY2189265 is effective in reducing hemoglobin A1c (HbA1c) and safe, as compared to Insulin Glargine in participants with Type 2 Diabetes. Participants must also be taking metformin and glimepiride.

Condition or disease Intervention/treatment Phase
Diabetes Mellitus, Type 2 Drug: Insulin Glargine Drug: LY2189265 Drug: Metformin Drug: Glimepiride Phase 3

Detailed Description:
Rescue therapy refers to 1 of 2 types of additional therapy, each given for a different reason: any additional therapeutic intervention in participants who developed persistent, severe hyperglycemia despite full compliance with the assigned therapeutic regimen, or initiation of an alternative antihyperglycemic medication following study drug discontinuation. Participants who received rescue therapy were included in the analysis population, but only measurements obtained prior to the beginning of rescue therapy were included in specified efficacy analyses.
Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 810 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized, Open-Label, Parallel-Arm, Noninferiority Comparison of the Effects of Two Doses of LY2189265 and Insulin Glargine on Glycemic Control in Patients With Type 2 Diabetes on Stable Doses of Metformin and Glimepiride
Study Start Date : February 2010
Actual Primary Completion Date : May 2012
Actual Study Completion Date : November 2012

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: LY2189265 1.5 mg

LY2189265 (Dulaglutide): 1.5 milligrams (mg), subcutaneous (SC), once weekly for 78 weeks

Metformin: at least 1500 milligrams per day (mg/day), oral, for 78 weeks

Glimepiride: at least 4 mg/day, oral, for 78 weeks

 Drug: LY2189265
Other Name: Dulaglutide

Drug: Metformin
Drug: Glimepiride
Experimental: LY2189265 0.75 mg

LY2189265 (Dulaglutide): 0.75 milligrams (mg), subcutaneous (SC), once weekly for 78 weeks

Metformin: at least 1500 milligrams per day (mg/day), oral, for 78 weeks

Glimepiride: at least 4 mg/day, oral, for 78 weeks

 Drug: LY2189265
Other Name: Dulaglutide

Drug: Metformin
Drug: Glimepiride
Active Comparator: Insulin Glargine

Insulin Glargine: dose titration based on blood glucose measures, subcutaneous (SC), once daily for 78 weeks

Metformin: at least 1500 milligrams per day (mg/day), oral, for 78 weeks

Glimepiride: at least 4 mg/day, oral, for 78 weeks

 Drug: Insulin Glargine
Drug: Metformin
Drug: Glimepiride


Outcome Measures
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Primary Outcome Measures :
  1. Change From Baseline to 52 Weeks Endpoint in Glycosylated Hemoglobin (HbA1c) [ Time Frame: Baseline, 52 weeks ]
    Least Squares (LS) means were calculated using analysis of covariance (ANCOVA) with country and treatment as fixed effects and baseline HbA1c as a covariate.


Secondary Outcome Measures :
  1. Change From Baseline to 26 Weeks and 78 Weeks Endpoint in Glycosylated Hemoglobin (HbA1c) [ Time Frame: Baseline, 26 weeks, and 78 weeks ]
    Least Squares (LS) means were calculated using analysis of covariance (ANCOVA) with country and treatment as fixed effects and baseline HbA1c as a covariate.

  2. Number of Participants Achieving Glycosylated Hemoglobin (HbA1c) Less Than 7% at 26, 52 and 78 Weeks [ Time Frame: 26, 52, and 78 weeks ]
    Number of participants achieving HbA1c levels less than 7.0% was analyzed with a logistic regression model with baseline, country, and treatment as factors included in the model.

  3. Number of Participants Achieving Glycosylated Hemoglobin (HbA1c) Less Than or Equal to 6.5% at 26, 52 and 78 Weeks [ Time Frame: 26, 52, and 78 weeks ]
    Number of participants achieving HbA1c levels less than or equal to 6.5% was analyzed with a logistic regression model with baseline, country, and treatment as factors included in the model.

  4. Change From Baseline to 26, 52 and 78 Weeks for Daily Mean Blood Glucose Values From the 8-point Self-monitored Blood Glucose (SMBG) Profiles [ Time Frame: Baseline, 26, 52, and 78 weeks ]
    The self-monitored blood glucose (SMBG) data were collected at the following 8 time points: pre-morning meal; 2 hours post-morning meal; pre-midday meal; 2 hours post-midday meal; pre-evening meal; 2 hours post-evening meal; bedtime; and 3 AM or 5 hours after bedtime. Least Squares (LS) means of the mean of the 8 time points (Daily Mean) 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.

  5. Change From Baseline to 52 and 78 Weeks in Updated Homeostasis Model Assessment of Beta-cell Function (HOMA2-%B) and Updated Homeostasis Model Assessment of Insulin Sensitivity (HOMA2-%S) [ Time Frame: Baseline, 52, and 78 weeks ]
    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 HOMA-2S 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.

  6. Change From Baseline to 52 and 78 Weeks in Glucagon Concentration [ Time Frame: Baseline, 52, and 78 weeks ]
    Least Squares (LS) means of change from baseline were calculated using analysis of covariance (ANCOVA) with country and treatment as fixed effects and baseline as a covariate.

  7. Change From Baseline to 26, 52 and 78 Weeks for Body Weight [ Time Frame: Baseline, 26, 52, and 78 weeks ]
    Least Squares (LS) means of change from baseline were calculated using analysis of covariance (ANCOVA) with country and treatment as fixed effects and baseline as a covariate.

  8. Change From Baseline to 26, 52 and 78 Weeks for Body Mass Index [ Time Frame: Baseline, 26, 52, and 78 weeks ]
    Body mass index (BMI) is an estimate of body fat based on body weight divided by height squared. 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.

  9. Change From Baseline to 26, 52 and 78 Weeks in the EuroQol 5 Dimension [ Time Frame: Baseline, 26, 52, and 78 weeks ]
    The European Quality of Life - 5 dimensions (EQ-5D) questionnaire is a generic, multidimensional, health-related, quality-of-life instrument. It consists of 2 parts: the first part assesses 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) that have 3 possible levels of response (no problem, some problem, or extreme problem). These dimensions are converted into a weighted health-state Index Score. The EQ-5D United Kingdom (UK) score ranges from -0.59 to 1.0, where a score of 1.0 indicates perfect health and negative values are valued as worse than dead. The second part of the questionnaire consists of a 100-mm 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). Least Squares (LS) means of change from baseline were calculated using analysis of covariance (ANCOVA) and adjusted by treatment, country, and baseline.

  10. Change From Baseline to 26, 52 and 78 Weeks in the Impact of Weight on Activities of Daily Living [ Time Frame: Baseline, 26, 52, and 78 weeks ]
    The Impact of Weight on Activities of Daily Living questionnaire (renamed the Ability to Perform Physical Activities of Daily Living Questionnaire [APPADL]) contains 7 items that assess how difficult it is for participants to engage in certain activities considered to be integral to normal daily life, such as walking, standing and climbing stairs. Items are scored on a 5-point numeric rating scale where 5 = "not at all difficult" and 1 = "unable to do". The individual scores from all 7 items are summed and a single total score is calculated and may range between 7 and 35. A higher score indicates better ability to perform activities of daily living. Least Squares (LS) means of change from baseline were calculated using analysis of covariance (ANCOVA) with country and treatment as fixed effects and baseline as a covariate.

  11. Change From Baseline to 26, 52 and 78 Weeks in the Impact of Weight on Self-Perception [ Time Frame: Baseline, 26, 52, and 78 weeks ]
    The Impact of Weight on Self-Perception (IW-SP) questionnaire contains 3 items that assess how often the participants' body weight affects how happy they are with their appearance and how often they feel self-conscious when out in public. Items are scored on a 5-point numeric rating scale where 5 = never and 1 = always. A single total score is calculated by summing the scores for all 3 items. Total score ranges between 3 and 15, where a higher score is indicative of better self-perception. Least Squares (LS) means of change from baseline were calculated using analysis of covariance (ANCOVA) with country and treatment as fixed effects and baseline as a covariate.

  12. Change From Baseline to 26, 52 and 78 Weeks in the Low Blood Sugar Survey [ Time Frame: Baseline, 26, 52, and 78 weeks ]
    The Low Blood Sugar Survey (LBSS) contains 33 items comprised of 2 subscales (behavior and worry), each of which is rated on a 5-point numeric rating scale from 0 (never) to 4 (almost always). It captures behavioral changes associated with the concerns and experiences of hypoglycemia and the degree to which participants are worried about certain aspects associated with hypoglycemia during the previous 4 weeks. The behavior (or avoidance) subscale has 15 items, and the worry (or affect) subscale has 18 items. Subscale scores are calculated by summing participant responses to items (behavior range 0-60; worry range 0-72). A total score is calculated as the sum of both subscales (range 0-132). Higher scores indicate greater negative impact on subscales and total score. Least Squares (LS) means of change from baseline were calculated using analysis of covariance (ANCOVA) with country and treatment as fixed effects and baseline as a covariate.

  13. Number of Participants With Treatment Emergent Adverse Events at 26, 52 and 78 Weeks [ Time Frame: 26, 52, and 78 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 one or more TEAE is summarized cumulatively at 26, 52, and 78 weeks. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module.

  14. Number of Self-reported Hypoglycemic Events at 26, 52 and 78 Weeks [ Time Frame: Baseline through 26, 52, and 78 weeks ]
    Hypoglycemic events (HE) were classified as severe (defined as episodes requiring the assistance of 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 mmol/L), asymptomatic (defined as events not accompanied by typical symptoms of hypoglycemia but with a measured plasma glucose of =<3.9 mmol/L), nocturnal (defined as any hypoglycemic event that occurred between bedtime and waking), or probable symptomatic (defined as events during which symptoms of hypoglycemia were not accompanied by a plasma glucose determination). The number of self-reported hypoglycemic events is summarized cumulatively at 26, 52, and 78 weeks. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module.

  15. Rate of Self-reported Hypoglycemic Events at 26, 52 and 78 Weeks [ Time Frame: Baseline through 26, 52, and 78 weeks ]
    Hypoglycemic events (HE) were classified as severe (defined as episodes requiring the assistance of 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 mmol/L), asymptomatic (defined as events not accompanied by typical symptoms of hypoglycemia but with a measured plasma glucose of =<3.9 mmol/L), nocturnal (defined as any hypoglycemic event that occurred between bedtime and waking), or probable symptomatic (defined as events during which symptoms of hypoglycemia were not accompanied by a plasma glucose determination). The 1-year adjusted rate of hypoglycemic events is summarized cumulatively at 26, 52, and 78 weeks. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module.

  16. Number of Participants Requiring Additional Intervention Due to Hyperglycemia at 26, 52 and 78 Weeks [ Time Frame: 26, 52, and 78 weeks ]
    Additional intervention was defined as any additional therapeutic intervention in participants who developed persistent, severe hyperglycemia despite full compliance with the assigned therapeutic regimen, or initiation of an alternative antihyperglycemic medication following study drug discontinuation. The number of participants requiring additional intervention due to hyperglycemia is summarized cumulatively at 26, 52, and 78 weeks.

  17. Change From Baseline to 26, 52 and 78 Weeks on Pancreatic Enzymes [ Time Frame: Baseline, 26, 52, and 78 weeks ]
    Amylase (total and pancreas-derived) and lipase concentrations were measured.

  18. Number of Participants With Adjudicated Pancreatitis at 26, 52 and 78 Weeks [ Time Frame: Baseline through 26, 52, and 78 weeks ]
    The number of participants with pancreatitis confirmed by adjudication is summarized cumulatively at 26, 52, and 78 weeks. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module.

  19. Change From Baseline to 26, 52 and 78 Weeks on Serum Calcitonin [ Time Frame: Baseline, 26, 52, and 78 weeks ]
  20. Number of Participants With Adjudicated Cardiovascular Events at 26, 52 and 78 Weeks [ Time Frame: Baseline through 26, 52, and 78 weeks ]
    Information on cardiovascular (CV) risk factors was collected at baseline. Data on any new 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 at 26, 52, and 78 weeks. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module.

  21. Change in Baseline to 26, 52 and 78 Weeks on Pulse Rate [ Time Frame: Baseline, 26, 52, and 78 weeks ]
    Sitting pulse rate was 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.

  22. Change From Baseline to 26, 52, and 78 Weeks on Blood Pressure [ Time Frame: Baseline, 26, 52, and 78 weeks ]
    Sitting systolic blood pressure (SBP) and sitting 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.

  23. Change From Baseline to 26, 52 and 78 Weeks on Electrocardiogram Parameters, Heart Rate [ Time Frame: Baseline, 26, 52, and 78 weeks ]
    Electrocardiogram (ECG) heart rate was 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.

  24. Change From Baseline to 26, 52 and 78 Weeks on Electrocardiogram Parameters, Fridericia Corrected QT (QTcF) Interval and PR Interval [ Time Frame: Baseline, 26, 52, and 78 weeks ]
    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.

  25. Number of Participants With LY2189265 Antibodies at 26, 52, 78 Weeks and 4 Weeks After Last Dose of Study Drug (83 Weeks Maximum) [ Time Frame: Baseline, 26, 52, 78, and 83 weeks ]
    LY2189265 (Dulaglutide) anti-drug antibodies (ADA) were assessed at baseline, 26, 52, and 78 weeks, and at the safety follow-up visit 30 days after study drug discontinuation (83 weeks). The number of participants with initial postbaseline detection of treatment emergent (defined as a 4-fold increase in the ADA titer from baseline) LY2189265 ADA at each time point were summarized.


Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Type 2 Diabetes not well controlled on 1, 2, or 3 oral antidiabetic medications (at least one of them must be metformin and/or a sulfonylurea)

    1. Glycosylated hemoglobin (HbA1c) greater than or equal to 7 and less than or equal to 11 if taking 1 oral antidiabetic medication
    2. HbA1c greater than or equal to 7 and less than or equal to 10 if on 2 or 3 oral antidiabetic medications
  • Accept treatment with metformin and glimepiride throughout the study, as per protocol
  • Willing to inject subcutaneous medication once weekly for LY2189265 or once daily for Insulin Glargine.
  • Stable weight for 3 months prior to screening
  • Body mass index (BMI) between 23 and 45 kilograms per square meter (kg/m^2)
  • Females of child bearing potential must test negative for pregnancy at screening by serum pregnancy test and be willing to use a reliable method of birth control during the study and for 1 month following the last dose of study drug

Exclusion Criteria:

  • Type 1 Diabetes
  • HbA1c equal to or less than 6.5 at randomization
  • Chronic insulin use
  • Taking drugs to promote weight loss by prescription or over the counter
  • Taking systemic steroids for greater than 14 days except for topical, eye, nasal, or inhaled
  • History of Heart Failure New York Heart Classification III or IV, or acute myocardial infarction, or stroke within 2 months of screening
  • Gastrointestinal (GI) problems such as diabetic gastroparesis or bariatric surgery (stomach stapling) or chronically taking drugs that directly affect GI motility
  • Hepatitis or liver disease or ALT (alanine transaminase) greater than 3.0 of upper normal limit
  • Acute or chronic pancreatitis of any form
  • Renal disease (kidney) with a serum creatinine of greater than or equal to 1.5 milligrams per deciliter (mg/dL) for males and greater than or equal to 1.4 mg/dL for females, or a creatinine clearance of less than 60 milliliters per minute (ml/min)
  • History (includes family) of type 2A or 2B Multiple Endocrine Neoplasia (MEN 2A or 2B) or medullary c-cell hyperplasia or thyroid cancer
  • A serum calcitonin greater than or equal to 20 picograms per milliliter (pcg/ml) at screening
  • Significant active autoimmune disease such as Lupus or Rheumatoid Arthritis
  • History of or active malignancy except skin or in situ cervical or prostate cancer for within last 5 years
  • Sickle cell, hemolytic anemia, or other hematological condition that may interfere with HbA1c testing
  • Organ transplant except cornea
  • Have enrolled in another clinical trial within the last 30 days
  • Have previously signed an informed consent or participated in a LY2189265 study
  • Have taken a glucagon-like peptide 1 (GLP-1) receptor agonist within the 3 months prior to screening
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01075282


Locations
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Sponsors and Collaborators
Eli Lilly and Company
Investigators
Layout table for investigator information
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
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Eli Lilly and Company
ClinicalTrials.gov Identifier: NCT01075282    
Other Study ID Numbers: 11374
H9X-MC-GBDB ( Other Identifier: Eli Lilly and Company )
First Posted: February 25, 2010    Key Record Dates
Results First Posted: January 16, 2015
Last Update Posted: January 16, 2015
Last Verified: January 2015
Additional relevant MeSH terms:
Layout table for MeSH terms
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Metformin
Insulin Glargine
 Glimepiride
Dulaglutide
Hypoglycemic Agents
Physiological Effects of Drugs
Anti-Arrhythmia Agents
Immunosuppressive Agents
Immunologic Factors