Efficacy and Safety of Azilsartan Medoxomil Used in Combination With Metformin in Participants With Hypertension and Diabetes

• Change from Baseline in Glycosylated Hemoglobin (HbA1c) [ Time Frame: Baseline and Week 24. ] [ Designated as safety issue: No ]
  The change in the value of glycosylated hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at week 24 or final visit relative to baseline.
• Change from Baseline in Trough Sitting Clinic Diastolic Blood Pressure [ Time Frame: Baseline and Week 8. ] [ Designated as safety issue: No ]
  The change in trough diastolic blood pressure measured at final visit or week 8 relative to baseline. The trough is the average of the non-missing values of the 3 serial trough sitting diastolic blood pressure measurements.
• Change from Baseline in the 24-hour Mean Systolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring [ Time Frame: Baseline and Week 8. ] [ Designated as safety issue: No ]
  The change in 24-hour mean systolic blood pressure measured at final visit or week 8 relative to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. The 24-hour mean is the average of all measurements recorded for 24 hours after dosing.
• Change from Baseline in the 24-hour Mean Diastolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring [ Time Frame: Baseline and Week 8. ] [ Designated as safety issue: No ]
  The change in 24-hour mean diastolic blood pressure measured at final visit or week 8 relative to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. The 24-hour mean is the average of all measurements recorded for 24 hours after dosing.
• Change from Baseline in the Mean Daytime (6 AM to 10 PM) Systolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring [ Time Frame: Baseline and Week 8. ] [ Designated as safety issue: No ]
  The change in daytime (6am to 10pm) mean systolic blood pressure measured at final visit or week 8 relative to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. Daytime mean is the average of all measurements recorded between the hours of 6 am and 10 pm.
• Change from Baseline in the Mean Daytime (6 AM to 10 PM) Diastolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring [ Time Frame: Baseline and Week 8. ] [ Designated as safety issue: No ]
  The change in daytime (6am to 10pm) mean diastolic blood pressure measured at final visit or week 8 relative to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. Daytime mean is the average of all measurements recorded between the hours of 6 am and 10 pm.
• Change from Baseline in the Mean Nighttime (12 AM to 6 AM) Systolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring [ Time Frame: Baseline and Week 8. ] [ Designated as safety issue: No ]
  The change in nighttime (12am to 6am) mean systolic blood pressure measured at final visit or week 8 relative to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. Nighttime mean is the average of all measurements recorded between the hours of 12 am and 6 am.
• Change from Baseline in the Mean Nighttime (12 AM to 6 AM) Diastolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring [ Time Frame: Baseline and Week 8. ] [ Designated as safety issue: No ]
  The change in nighttime (12am to 6am) mean diastolic blood pressure measured at final visit or week 8 relative to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. Nighttime mean is the average of all measurements recorded between the hours of 12 am and 6 am.
• Change from Baseline in the 12-hr Mean Systolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring. [ Time Frame: Baseline and Week 8. ] [ Designated as safety issue: No ]
  The change between the 0 to 12 hours-after-dosing mean systolic blood pressure measured at week 8 or final visit relative to baseline. The mean consists of the average (arithmetic mean) of measurements collected at each time frame and includes all observations recorded in the first 12 hours after dosing. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night.
• Change from Baseline in the 12-hr Mean Diastolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring. [ Time Frame: Baseline and Week 8. ] [ Designated as safety issue: No ]
  The change between the 0 to 12 hours-after-dosing mean diastolic blood pressure measured at week 8 or final visit relative to baseline. The mean consists of the average (arithmetic mean) of measurements collected at each time frame and includes all observations recorded in the first 12 hours after dosing. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night.
• Change from Baseline in the Trough (22 to 24 hours after dosing) Systolic Blood Pressure as Measured by Ambulatory Blood Pressure Monitoring. [ Time Frame: Baseline and Week 8. ] [ Designated as safety issue: No ]
  The change in trough systolic blood pressure measured at final visit or week relative to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. The trough is the average of all measurements recorded from 22 to 24 hours after dosing.
• Change from Baseline in the Trough (22 to 24 hours after dosing) Diastolic Blood Pressure as Measured by Ambulatory Blood Pressure Monitoring. [ Time Frame: Baseline and Week 8. ] [ Designated as safety issue: No ]
  The change in trough diastolic blood pressure measured at final visit or week relative to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. The trough is the average of all measurements recorded from 22 to 24 hours after dosing.
• Percentage of Participants Requiring Rescue Glycemic Therapy [ Time Frame: 24 Weeks. ] [ Designated as safety issue: No ]
  Percentage of participants requiring rescue glycemic therapy during study.
• Time to First Glycemic Rescue [ Time Frame: 24 Weeks. ] [ Designated as safety issue: No ]
  The time to the first instance of participants requiring glycemic rescue during study.
• Change from Baseline in HbA1c [ Time Frame: Baseline, Week 2, Week 4, Week 6, Week 8, Week 12, Week 16 and Week 20. ] [ Designated as safety issue: No ]
  The change in the value of glycosylated hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at each week indicated including final visit relative to baseline.
• Change from Baseline in Fasting Plasma Glucose [ Time Frame: Baseline, Week 2, Week 4, Week 6, Week 8, Week 12, Week 16, Week 20 and Week 24. ] [ Designated as safety issue: No ]
  The change between the fasting plasma glucose value collected at each week indicated including final visit relative to baseline.
• Change from Baseline to Week 6 and Week 24 in 2h Glucose during Oral Glucose Tolerance Testing (OGTT) [ Time Frame: Baseline, Week 6 and Week 24. ] [ Designated as safety issue: No ]
  The change between the glucose value collected at each week indicated including final visit relative to baseline. Oral glucose tolerance test measures glucose, insulin, C-peptide, insulin/glucose ratio, and glucagon through blood samples drawn at 0, 30, 60, and 120 minutes following consumption of a 75 g glucose beverage.
• Change from Baseline to Week 6 and Week 24 in the Area Under the Plasma Concentration-time Curve (AUC) for Glucose During OGTT [ Time Frame: Baseline, Week 6 and Week 24. ] [ Designated as safety issue: No ]
  The change between the AUC for glucose at each week indicated including final visit relative to baseline. AUC will be calculated based on measurements at 0, 30, 60 and 120 minutes. Oral glucose tolerance test measures glucose, insulin, C-peptide, insulin/glucose ratio, and glucagon through blood samples drawn at 0, 30, 60, and 120 minutes following consumption of a 75 g glucose beverage.
• Change from Baseline to Week 6 and Week 24 in AUC for Insulin During OGTT [ Time Frame: Baseline, Week 6 and Week 24. ] [ Designated as safety issue: No ]
  The change between the AUC for insulin at each week indicated including final visit relative to baseline. AUC will be calculated based on measurements at 0, 30, 60 and 120 minutes. Oral glucose tolerance test measures glucose, insulin, C-peptide, insulin/glucose ratio, and glucagon through blood samples drawn at 0, 30, 60, and 120 minutes following consumption of a 75 g glucose beverage.
• Change from Baseline to Week 6 and Week 24 in AUC for C-peptide During OGTT [ Time Frame: Baseline, Week 6 and Week 24. ] [ Designated as safety issue: No ]
  The change between the AUC for C-peptide at each week indicated including final visit relative to baseline. AUC will be calculated based on measurements at 0, 30, 60 and 120 minutes. Oral glucose tolerance test measures glucose, insulin, C-peptide, insulin/glucose ratio, and glucagon through blood samples drawn at 0, 30, 60, and 120 minutes following consumption of a 75 g glucose beverage.
• Change from Baseline to Week 6 and Week 24 in AUC for Insulin/Glucose ratio During OGTT [ Time Frame: Baseline, Week 6 and Week 24. ] [ Designated as safety issue: No ]
  The change between the AUC for insulin/glucose ratio at each week indicated including final visit relative to baseline. AUC will be calculated based on measurements at 0, 30, 60 and 120 minutes. Oral glucose tolerance test measures glucose, insulin, C-peptide, insulin/glucose ratio, and glucagon through blood samples drawn at 0, 30, 60, and 120 minutes following consumption of a 75 g glucose beverage.
• Change from Baseline to Week 6 and Week 24 in AUC for Glucagon During OGTT [ Time Frame: Baseline, Week 6 and Week 24. ] [ Designated as safety issue: No ]
  The change between the AUC for glucagon at each week indicated including final visit relative to baseline. AUC will be calculated based on measurements at 0, 30, 60 and 120 minutes. Oral glucose tolerance test measures glucose, insulin, C-peptide, insulin/glucose ratio, and glucagon through blood samples drawn at 0, 30, 60, and 120 minutes following consumption of a 75 g glucose beverage.

The purpose of this study is to evaluate the antihypertensive and antiglycemic effects, as well as the safety and tolerability of TAK-491 (azilsartan medoxomil), once daily (QD), in stage 1 hypertensive, type 2 diabetes mellitus (T2DM) participants whose glycemic control is inadequate on metformin alone.

The study includes a Screening Period of up to 4 weeks, which coincides with a 2-week single-blind, placebo Run-in Period, a 24 week Treatment Period, and a 2-week Follow-up Period. The duration of the study will be approximately 30 weeks.

• Hypertension
• Diabetes

• Drug: Placebo
• Drug: Azilsartan medoxomil
  Other Name: TAK-491

• Placebo Comparator: Placebo QD
  Azilsartan medoxomil placebo-matching tablets, orally, once daily for up to 24 weeks.
  Intervention: Drug: Placebo
• Experimental: Azilsartan Medoxomil 40 mg QD
  Azilsartan medoxomil 40 mg, tablets, orally, once daily for up to 24 weeks.
  Intervention: Drug: Azilsartan medoxomil
• Experimental: Azilsartan Medoxomil 80 mg QD
  Azilsartan medoxomil 80 mg, tablets, orally, once daily for up to 24 weeks.
  Intervention: Drug: Azilsartan medoxomil

Inclusion Criteria:

1. The participant is male or female and ≥18 years.
2. The participant has type 2 diabetes mellitus with HbA1c of ≥7.5 to ≤9.5% at Screening.
3. Participant is currently treated with metformin alone (no treatment with any antidiabetic agents other than metformin within the 3 months prior to Screening) and is experiencing inadequate glycemic control. The participant should have received metformin monotherapy for ≥8 weeks prior to Screening at a stable dose ≥1500 mg). Participants with a maximum tolerated dose (MTD) that is documented to be less than 1500 mg of metformin may also be enrolled if this dose has been stable for 8 weeks prior to Screening.
4. The participant is treated with antihypertensive therapy and has a mean, trough, sitting clinic systolic blood pressure (SBP) ≥135 and < 160 mm Hg on Day -1 (after washout of prior antihypertensive therapy) or the participant has not received antihypertensive treatment within 28 days before Screening and has a mean sitting clinic SBP ≥135 and < 160 mm Hg at the Screening Visit and on Day -1.
5. The participant has clinical laboratory evaluations (including clinical chemistry, hematology, and complete urinalysis) within the reference range for the testing laboratory or results that are deemed not clinically significant in this participant population for inclusion into this study by the investigator.

Exclusion Criteria:

1. The participant has a mean, trough, sitting clinic diastolic blood pressure (DBP) ≥100 mm Hg at Day -1.
2. The participant has type 1 or poorly controlled type 2 diabetes mellitus (HbA1c >9.5%) at Screening.
3. The participant is taking or expected to take an excluded medication.
4. The participant has a history of myocardial infarction, heart failure, unstable angina, coronary artery bypass graft, percutaneous coronary intervention, hypertensive encephalopathy, cerebrovascular accident, or transient ischemic attack.
5. The participant has clinically significant cardiac conduction defects (for example, 3rd degree atrioventricular block, left bundle branch block, sick sinus syndrome, atrial fibrillation).
6. The participant has hemodynamically significant left ventricular outflow obstruction due to aortic valvular disease.
7. The participant has secondary hypertension of any etiology (e.g., renovascular disease, pheochromocytoma, Cushing's syndrome).
8. The participant has renal dysfunction defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 at Screening.
9. The participant has albuminuria defined as >200 mg/g at Screening.
10. The participant has known or suspected unilateral or bilateral renal artery stenosis.
11. The participant has unexplained microhematuria ≥3 RBCs/HPG or macrohematuria at Screening and confirmed on repeat testing.
12. Treatment with antidiabetic agents (sulfonylureas, glucagon-like peptide-1 (GLP-1) analogues, dipeptidyl peptidase-4 (DPP-4) inhibitors, glinides, thiazolidinediones (TZDs), and/or insulin) other than metformin during the 3 months prior to Screening.
13. The participant has hyperkalemia as defined by central laboratory normal reference range at Screening.