A Study of the Effect of LY2189265 on Blood Pressure and Heart Rate in Type 2 Diabetes

Study Overview
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Brief Summary
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The purpose of this study is to assess the effects of 2 doses of LY2189265 on blood pressure and heart rate using 24-hour ambulatory blood pressure monitoring (ABPM), in participants with type 2 diabetes mellitus treated with oral antihyperglycemic medications (OAMs).

Official Title
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The Effect of LY2189265 on Blood Pressure and Heart Rate, as Assessed by Ambulatory Blood Pressure Monitoring, in Patients With Type 2 Diabetes Mellitus

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: LY2189265
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 2 diabetes taking 1 or more oral diabetes medications and have taken these medications for at least 1 month prior to screening Glycosylated hemoglobin (HbA1c) value ≥7% and ≤9.5% at screening Mean blood pressure >90/60 millimeters of mercury (mmHg) and <140/90 mmHg at screening If treated for hypertension, are taking 3 or less antihypertensive medications and have been taking these medications for at least 1 month prior to screening Stable weight for 3 months prior to screening Body mass index (BMI) greater than or equal to 23 kilogram-meter squared (kg/m^2) Willing to wear an ambulatory blood pressure monitoring device for at least 24 hours on multiple occasions Women of childbearing potential must test negative for pregnancy and be willing to use a reliable method of birth control Male participants must use a reliable method of birth control Exclusion Criteria: Myocardial infarction, stroke, or hospitalization for heart failure within 3 months prior to screening, or heart failure Class III or IV at screening Ongoing or history of frequent intermittent tachyarrhythmia Resting heart rate <60 beats per minute (bpm) or >100 bpm at screening Work rotating shifts or work during the hours of 2200 to 0700 Chronic insulin therapy Use of a glucagon-like peptide 1 (GLP-1) receptor agonist within 3 months prior to screening, or a dipeptidylpeptidase-IV (DPP-IV) inhibitor within 2 weeks prior to screening Nondominant arm circumference >42 centimeter (cm) Use of drugs to promote weight loss Chronic use of systemic steroids Gastric emptying abnormality or bariatric surgery Hepatitis, other liver disease, or alanine transaminase (ALT) >3 times the upper limit of normal Acute or chronic pancreatitis Severe renal impairment Active autoimmune disease or uncontrolled endocrine abnormality Self or family history of thyroid cancer, medullary C-cell hyperplasia, or type 2A or 2B multiple endocrine neoplasia Calcitonin value greater than or equal to 20 picograms per milliliter (pg/ml) at screening Transplanted organ except corneal transplants Active or untreated cancer or in remission <5 years, except skin, in situ cervical, or prostate cancer Sickle-cell disease, hemolytic anemia, or another hematological condition that may interfere with HbA1c testing

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1.5 milligram (mg) LY2189265<br>LY2189265: 1.5 milligram (mg), subcutaneous (SC), once weekly (QW) | Drug: LY2189265<br>* Administered as a subcutaneous injection once weekly for 26 weeks<br>* Other names: Dulaglutide;|
| Experimental: 0.75 milligram (mg) LY2189265<br>LY2189265: 0.75 milligram (mg), subcutaneous (SC), once weekly (QW) | Drug: LY2189265<br>* Administered as a subcutaneous injection once weekly for 26 weeks<br>* Other names: Dulaglutide;|
| Placebo Comparator: Placebo<br>Placebo: subcutaneous (SC), once weekly (QW) | Drug: Placebo<br>* Administered as a subcutaneous injection once weekly for 26 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to 16 Weeks in Mean 24-hour Systolic Blood Pressure (SBP) | Mean 24-hour systolic blood pressure (SBP) was measured by using a 24-hour ambulatory blood pressure monitoring (ABPM) device attached to the participant's nondominant arm. Ambulatory blood pressure measurements were recorded every 20 minutes during the daytime (0700 to 2200 hours) and every 30 minutes during the nighttime hours (2200 to 0700), as preprogrammed into the device. For statistical analyses, diurnal hours were defined as 0800 to 2100 and nocturnal hours were defined as 0000 to 0600. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for baseline, pooled sites, treatment, visit, treatment-by-visit interaction, and the stratified variable of diagnosis of hypertension. | Baseline, 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to 26 Weeks in Mean 24-hour Systolic Blood Pressure (SBP) | Mean 24-hour systolic blood pressure (SBP) was measured by using a 24-hour ambulatory blood pressure monitoring (ABPM) device attached to the participant's nondominant arm. Ambulatory blood pressure measurements were recorded every 20 minutes during the daytime (0700 to 2200 hours) and every 30 minutes during the nighttime hours (2200 to 0700), as preprogrammed into the device. For statistical analyses, diurnal hours were defined as 0800 to 2100 and nocturnal hours were defined as 0000 to 0600. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for baseline, pooled sites, treatment, visit, treatment-by-visit interaction, and the stratified variable of diagnosis of hypertension. | Baseline, 26 weeks | 
| Change From Baseline to 16 and 26 Weeks in Mean 24-hour Diastolic Blood Pressure (DBP) | Mean 24-hour diastolic blood pressure (DBP) was measured by using a 24-hour ambulatory blood pressure monitoring (ABPM) device attached to the participant's nondominant arm. Ambulatory blood pressure measurements were recorded every 20 minutes during the daytime (0700 to 2200 hours) and every 30 minutes during the nighttime hours (2200 to 0700), as preprogrammed into the device. For statistical analyses, diurnal hours were defined as 0800 to 2100 and nocturnal hours were defined as 0000 to 0600. Least Squares (LS) means of change from baseline was analyzed using mixed model repeated measures (MMRM) adjusted by baseline, pooled sites, treatment, visit, treatment-by-visit interaction, and the stratified variable of diagnosis of hypertension. | Baseline, 16 and 26 weeks | 
| Change From Baseline to 16 and 26 Weeks in Mean 24-Hour Heart Rate (HR) | Mean 24-hour heart rate (HR) was measured by using a 24-hour ambulatory blood pressure monitoring (ABPM) device attached to the participant's nondominant arm. Heart rate measurements were recorded every 20 minutes during the daytime (0700 to 2200 hours) and every 30 minutes during the nighttime hours (2200 to 0700), as preprogrammed into the device. For statistical analyses, diurnal hours were defined as 0800 to 2100 and nocturnal hours were defined as 0000 to 0600. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for baseline, pooled sites, treatment, visit, treatment-by-visit interaction, and the stratified variable of diagnosis of hypertension. | Baseline, 16 and 26 weeks | 
| Change From Baseline to 16 and 26 Weeks in Mean 24-hour Pulse Pressure | Mean 24-hour pulse pressure (PP) was measured by using a 24-hour ambulatory blood pressure monitoring (ABPM) device attached to the participant's nondominant arm. Pulse pressure (PP) measurements were recorded every 20 minutes during the daytime (0700 to 2200 hours) and every 30 minutes during the nighttime hours (2200 to 0700), as preprogrammed into the device. For statistical analyses, diurnal hours were defined as 0800 to 2100 and nocturnal hours were defined as 0000 to 0600. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for baseline, pooled sites, treatment, visit, treatment-by-visit interaction, and the stratified variable of diagnosis of hypertension. | Baseline, 16 and 26 weeks | 
| Change From Baseline to 16 and 26 Weeks in Mean 24-hour Mean Arterial Pressure (MAP) | Mean 24-hour mean arterial pressure (MAP) was measured by a using 24-hour ambulatory blood pressure monitoring (ABPM) device attached to the participant's nondominant arm. Ambulatory blood pressure measurements were recorded every 20 minutes during the daytime (0700 to 2200 hours) and every 30 minutes during the nighttime hours (2200 to 0700), as preprogrammed into the device. For statistical analyses, diurnal hours were defined as 0800 to 2100 and nocturnal hours were defined as 0000 to 0600. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for baseline, pooled sites, treatment, visit, treatment-by-visit interaction, and the stratified variable of diagnosis of hypertension. | Baseline, 16 and 26 weeks | 
| Change From Baseline to 16 and 26 Weeks in Mean Daytime, Nighttime, and Clinic Systolic Blood Pressure (SBP) | Mean daytime and nighttime systolic blood pressure (SBP) was measured by using a 24-hour ambulatory blood pressure monitoring (ABPM) device attached to the participant's nondominant arm. Ambulatory blood pressure measurements were recorded every 20 minutes during the daytime (0700 to 2200 hours) and every 30 minutes during the nighttime hours (2200 to 0700), as preprogrammed into the device. For statistical analyses, diurnal hours were defined as 0800 to 2100 and nocturnal hours were defined as 0000 to 0600. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for baseline, pooled sites, treatment, visit, treatment-by-visit interaction, and the stratified variable of diagnosis of hypertension. Clinic SBP was measured in the clinic using the Omron HEM 907XL Blood Pressure monitor. | Baseline, 16 and 26 weeks | 
| Change From Baseline to 16 and 26 Weeks in Mean Daytime, Nighttime, and Clinic Diastolic Blood Pressure (DBP) | Mean daytime and nighttime diastolic blood pressure (DBP) was measured by using a 24-hour ambulatory blood pressure monitoring (ABPM) device attached to the participant's nondominant arm. Ambulatory blood pressure measurements were recorded every 20 minutes during the daytime (0700 to 2200 hours) and every 30 minutes during the nighttime hours (2200 to 0700), as preprogrammed into the device. For statistical analyses, diurnal hours were defined as 0800 to 2100 and nocturnal hours were defined as 0000 to 0600. Least Squares (LS) means of change from baseline was analyzed using mixed model repeated measures (MMRM) adjusted by baseline, pooled sites, treatment, visit, treatment-by-visit interaction, and the stratified variable of diagnosis of hypertension. Clinic DBP was measured in the clinic using the Omron HEM 907XL Blood Pressure monitor. | Baseline, 16 and 26 weeks | 
| Change From Baseline to 16 and 26 Weeks in Mean Daytime, Nighttime, and Clinic Heart Rate (HR) | Daytime and nighttime heart rate (HR) was measured by using a 24-hour ambulatory blood pressure monitoring (ABPM) device attached to the participant's nondominant arm. Heart rate measurements were recorded every 20 minutes during the daytime (0700 to 2200 hours) and every 30 minutes during the nighttime hours (2200 to 0700), as preprogrammed into the device. For statistical analyses, diurnal hours were defined as 0800 to 2100 and nocturnal hours were defined as 0000 to 0600. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for baseline, pooled sites, treatment, visit, treatment-by-visit interaction, and the stratified variable of diagnosis of hypertension. Clinic HR was measured in the clinic using the Omron HEM 907XL Blood Pressure monitor. | Baseline, 16 and 26 weeks | 
| Change From Baseline to 16 and 26 Weeks in Mean Daytime and Nighttime Pulse Pressure | Mean daytime and nighttime pulse pressure (PP) was measured by using a 24-hour ambulatory blood pressure monitoring (ABPM) device attached to the participant's nondominant arm. Pulse pressure (PP) measurements were recorded every 20 minutes during the daytime (0700 to 2200 hours) and every 30 minutes during the nighttime hours (2200 to 0700), as preprogrammed into the device. For statistical analyses, diurnal hours were defined as 0800 to 2100 and nocturnal hours were defined as 0000 to 0600. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for baseline, pooled sites, treatment, visit, treatment-by-visit interaction, and the stratified variable of diagnosis of hypertension. | Baseline, 16 and 26 weeks | 
| Change From Baseline to 16 and 26 Weeks in Mean Daytime and Nighttime Mean Arterial Pressure (MAP) | Mean daytime and nighttime mean arterial pressure (MAP) was measured by a using 24-hour ambulatory blood pressure monitoring (ABPM) device attached to the participant's nondominant arm. Ambulatory blood pressure measurements were recorded every 20 minutes during the daytime (0700 to 2200 hours) and every 30 minutes during the nighttime hours (2200 to 0700), as preprogrammed into the device. For statistical analyses, diurnal hours were defined as 0800 to 2100 and nocturnal hours were defined as 0000 to 0600. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for baseline, pooled sites, treatment, visit, treatment-by-visit interaction, and the stratified variable of diagnosis of hypertension. | Baseline, 16 and 26 weeks | 
| Change From Baseline to 16 and 26 Weeks in Glycosylated Hemoglobin (HbA1c) | Glycosylated hemoglobin (HbA1c) is a form of hemoglobin that is measured primarily to identify the average plasma glucose concentration over prolonged periods of time. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for baseline, pooled sites, treatment, visit, treatment-by-visit interaction, and the stratified variable of diagnosis of hypertension. | Baseline, 16 and 26 weeks | 
| Change From Baseline to 16 and 26 Weeks in Fasting Blood Glucose (FBG) | Fasting blood glucose (FBG) is a test to determine how much glucose (sugar) is in a blood sample after an overnight fast. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for baseline, pooled sites, treatment, visit, treatment-by-visit interaction, and the stratified variable of diagnosis of hypertension. | Baseline, 16 and 26 weeks | 
| Percentage of Participants Achieving an Glycosylated Hemoglobin (HbA1c) of <7% or ≤6.5% | Percentages of participants who achieved glycosylated hemoglobin (HbA1c) levels of <7% or ≤6.5% were analyzed with Chi-squared test/Fisher's exact test. | Baseline and 16 and 26 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 one or more TEAE is summarized cumulatively at 26 weeks. 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 | 
| Change From Baseline to 16 and 26 Weeks on Pancreatic Enzymes | Amylase (total and pancreas-derived) and lipase concentrations were measured. | Baseline, 16 and 26 weeks | 
| Change From Baseline to 16 and 26 Weeks on Serum Calcitonin |  | Baseline, 16 and 26 weeks | 
| Change From Baseline to 16 Weeks in High-Sensitivity C-Reactive Protein (Hs-CRP) |  | Baseline, 16 weeks | 
| Change From Baseline to 16 and 26 Weeks on Electrocardiogram Parameters, Fridericia Corrected QT (QTcF) Interval 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 were calculated using mixed model repeated measures (MMRM) adjusting for baseline, pooled sites, treatment, visit, treatment-by-visit interaction, and the stratified variable of diagnosis of hypertension. | Baseline, 16 and 26 weeks | 
| Number of Events of Adjudicated Pancreatitis up to 26 Weeks | The number of adjudicated (by an independent Clinical Endpoint Committee [CEC]) pancreatic events is summarized at 26 weeks. 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 Adjudicated Cardiovascular Events up to 26 Weeks | 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. 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 | 
| Anti-LY2189265 Antibodies | LY2189265 anti-drug antibodies (ADA) were assessed at baseline, 16 and 26 weeks, and at the safety follow-up visit 4 weeks after study drug discontinuation (30 weeks). The number of participants with initial postbaseline detection of treatment-emergent (defined as a 4-fold increase in the ADA titer from baseline) anti-drug (LY2189265) ADA at each time point were summarized. | Baseline, 16, 26, and 30 weeks | 
| Rate of Hypoglycemic Episodes | Hypoglycemic events (HE) were classified as severe (defined as an HE requiring assistance of another person to actively administer resuscitative actions), documented symptomatic (defined as an HE with typical symptoms of hypoglycemia and a blood glucose level of ≤3.9 millimoles per liter [mmol/L]), asymptomatic (defined as an HE without typical symptoms of hypoglycemia but with a measured blood glucose of ≤3.9 mmol/L), nocturnal (defined as any HE occurring between bedtime and waking with a measured blood glucose of ≤3.9 mmol/L), or non-nocturnal. 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 Logit link. Negative binomial mean was adjusted by treatment, visit, and visit by treatment interaction. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module. | Baseline, 16 and 26 weeks | 
| Change From Baseline to 16 and 26 Weeks in Body Weight | Least Squares (LS) means was calculated using mixed model repeated measures (MMRM) adjusting for baseline, pooled sites, treatment, visit, treatment-by-visit interaction, and the stratified variable of diagnosis of hypertension. | Baseline, 16 and 26 weeks | 
| Measurement of LY2189265 Drug Concentration for Pharmacokinetics - Area Under the Concentration Time Curve (AUC) | The population mean estimates and standard deviations were calculated for pharmacokinetic parameters (area under the concentration time curve [AUC] at steady state from time zero to 168 hours after study drug administration). Evaluable pharmacokinetic concentrations from the 4, 8, 12, 16, and 26 weeks timepoints were combined and utilized in a population approach to determine the population mean estimate and standard deviation at steady-state. | 4, 8, 12, 16, and 26 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 2 Diabetes, Diabetes, Ambulatory Blood Pressure Monitoring, ABPM, Blood Pressure, Heart Rate