A Study of LY2409021 on Blood Pressure and Pulse Rate in Participants With Type 2 Diabetes Mellitus

Study Overview
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Brief Summary
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The main purpose of the trial is to determine the effect of a study drug known as LY2409021 on blood pressure and pulse rate in participants with type 2 diabetes mellitus (T2DM) when compared to placebo. The study has two periods. Each participant will receive LY2409021 or placebo in each period. At least 4 weeks will pass between periods. The study will last about 23 weeks for each participant. Participants may remain on stable dose metformin, as prescribed by their personal physician.

Official Title
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The Effect of LY2409021 on Blood Pressure and Pulse Rate, as Assessed by Ambulatory Blood Pressure Monitoring, in Subjects With Type 2 Diabetes Mellitus

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: LY2409021
* Drug: Placebo
* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have type 2 diabetes mellitus (according to the World Health Organization diagnostic criteria) and use diet and exercise alone or in combination with a stable dose of metformin ( >/=1000 mg/day [or <1000 mg, if documented intolerance to 1000 mg or higher dosages] immediate-release metformin or extended-release metformin for at least 2 months before screening). Have glycated hemoglobin (HbA1c) values >/=6.5% and </=8.5%, as determined by the central laboratory at screening. Have mean blood pressures >90/60 millimeters of mercury (mm Hg) and <140/90 mm Hg at screening. If being treated for hypertension, are taking 3 or fewer antihypertensive medications and have been taking stable doses of the same medications for at least 1 month before screening. Stable body weights (±5%) for >/=3 months before screening. Body mass indexes >/=20 kilograms/meters squared (kg/m²) and <40 kg/m². In the investigator's opinion, are well motivated, capable, and willing to: Reliably administer the oral study drug once daily; Maintain a study diary; Perform self-monitored blood glucose testing; and Wear an ambulatory blood pressure monitoring device for at least 24 hours (on multiple occasions). Are women not of child-bearing potential due to: Surgical sterilization, hysterectomy, or bilateral oophorectomy (at least 6 weeks postsurgery) or tubal ligation (confirmed by medical history); or Menopause. Women with an intact uterus are deemed menopausal if they have a cessation of menses for at least 1 year with follicle stimulating hormone >40 milli-international units per milliliter (mIU/mL), are not taking hormones or oral contraceptives within 1 year, and are otherwise healthy. Males who are sexually active and/or have partners of child-bearing age must use reliable methods of birth control during the study and until 3 months after the last doses of study medication. These requirements do not apply if a participant or his partner has been surgically sterilized or is not between menarche and 1 year postmenopausal. Exclusion Criteria: Have severe gastrointestinal disease that may significantly affect gastric emptying or motility. Previous histories or active diagnoses of pancreatitis. Acute or chronic hepatitis, signs or symptoms of any other liver disease, or alanine aminotransferase (ALT) level greater than 2.5 times the upper limit of normal (ULN). Elevated total bilirubin (greater than 2 times ULN), clinically suspicious signs or symptoms of cirrhosis or history of cirrhosis. Mean resting pulse rate (PR) less than 60 beats per minute (bpm) or greater than 100 bpm. Current diagnosis or personal history of neuroendocrine tumors, family history of any type of multiple endocrine neoplasia, or Von Hippel-Lindau disease.

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: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Single daily dose of placebo matching LY2409021 administered orally in 1 of 2 treatment periods. | Drug: Placebo<br>* Administered orally<br>Drug: Metformin<br>* Administered as background therapy.<br>|
| Experimental: LY2409021<br>Single daily dose of 20 milligrams (mg) LY2409021 administered orally in 1 of 2 treatment periods. | Drug: LY2409021<br>* Administered orally<br>Drug: Metformin<br>* Administered as background therapy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to 6 Weeks in Mean 24-Hour Systolic Blood Pressure | Systolic blood pressure obtained from Ambulatory Blood Pressure Monitoring (ABPM). | Baseline, 6 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to 6 Weeks in Mean 24-Hour Diastolic Blood Pressure | Diastolic blood pressure obtained from Ambulatory Blood Pressure Monitoring (ABPM). LS Mean of treatment differences, adjusted for country, diagnosis of hypertension, sequence, treatment, period, time within period, treatment by time within period interaction, and the baseline measurement as covariate. | Baseline, 6 Weeks | 
| Change From Baseline to 6 Weeks in Mean 24-Hour, Daytime, and Nighttime Peripheral Pulse Rate | Pulse rate obtained from Ambulatory Blood Pressure Monitoring (ABPM). LS Mean of treatment differences, adjusted for country, diagnosis of hypertension, sequence, treatment, period, time within period, treatment by time within period interaction, and the baseline measurement as covariate. | Baseline, 6 Weeks | 
| Change From Baseline to 6 Weeks in Mean 24-Hour, Daytime, and Nighttime Pulse Pressures | Pulse Pressures obtained from Ambulatory Blood Pressure Monitoring (ABPM). LS Mean of treatment differences, adjusted for country, diagnosis of hypertension, sequence, treatment, period, time within period, treatment by time within period interaction, and the baseline measurement as covariate. | Baseline, 6 Weeks | 
| Change From Baseline to 6 Weeks in Mean 24-Hour, Daytime, and Nighttime Mean Arterial Pressures (MAP) | Mean Arterial Pressures obtained from Ambulatory Blood Pressure Monitoring (ABPM). LS Mean of treatment differences, adjusted for country, diagnosis of hypertension, sequence, treatment, period, time within period, treatment by time within period interaction, and the baseline measurement as covariate. | Baseline, 6 Weeks | 
| Change From Baseline in Hemoglobin A1c (HbA1c) | LS Mean of treatment differences, adjusted for country, diagnosis of hypertension, sequence, treatment, period, time within period, treatment by time within period interaction, and the baseline measurement as covariate. | Baseline, 6 Weeks | 
| Population Pharmacokinetics: Apparent Clearance of LY2409021 | Population pharmacokinetic parameter apparent clearance (CL/F) is the apparent volume of the body fluid cleared of the drug per unit of time and was estimated by modeling of LY2409021 plasma concentration data from all LY2409021 groups. | Days 7, 21, 42, 70, 77, 91, 112, 140; 15 minute Predose and Days 7 and 77: 1 hour Postdose. | 
| Population Pharmacokinetics: Apparent Volume of Distribution of LY2409021 | Population pharmacokinetic parameter, apparent volume of distribution (V/F) is a theoretical volume that a drug would have to occupy (if it were uniformly distributed), to provide the same concentration as it currently is in blood plasma. Apparent volume of distribution (V/F) was estimated by modeling of LY2409021 plasma concentration data from all LY2409021 groups. | Days 7, 21, 42, 70, 77, 91, 112, 140; Predose and Days 7 and 77: 1 hour Postdose. |