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

Study Overview
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Brief Summary
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The purpose of this study was 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 was inadequate on metformin alone.

Detailed Description
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The study included a Screening Period of up to 4 weeks, which coincided 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 was approximately 30 weeks. The planned number of participants (n=450) was not reached; actual enrollment consisted of 105 particpants. Due to low enrollment this study was terminated early by Takeda.

Official Title
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A Randomized, Double-Blind, Phase 3b Proof-of-Concept Study to Evaluate the Efficacy and Safety of TAK-491 Compared to Placebo When Used in Combination With Metformin in Subjects With Hypertension and Type 2 Diabetes

Conditions
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Hypertension, Diabetes

Intervention / Treatment
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* Drug: Placebo
* Drug: Azilsartan medoxomil
* Drug: Azilsartan medoxomil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Was male or female and ≥18 years. Had type 2 diabetes mellitus with HbA1c of ≥7.5 to ≤9.5% at Screening. Was treated with metformin alone (no treatment with any antidiabetic agents other than metformin within the 3 months prior to Screening) and was 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 was documented to be less than 1500 mg of metformin could also be enrolled if this dose had been stable for 8 weeks prior to Screening. Was treated with antihypertensive therapy and had 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 had not received antihypertensive treatment within 28 days before Screening and had a mean sitting clinic SBP ≥135 and < 160 mm Hg at the Screening Visit and on Day -1. Had clinical laboratory evaluations (including clinical chemistry, hematology, and complete urinalysis) within the reference range for the testing laboratory or results that were deemed not clinically significant in this participant population for inclusion in this study, by the investigator. Exclusion Criteria: Had a mean, trough, sitting clinic diastolic blood pressure (DBP) ≥ 100 mm Hg at Day -1. Had type 1 or poorly controlled type 2 diabetes mellitus (HbA1c >9.5%) at Screening. Was taking or expected to take an excluded medication. Had a history of myocardial infarction, heart failure, unstable angina, coronary artery bypass graft, percutaneous coronary intervention, hypertensive encephalopathy, cerebrovascular accident, or transient ischemic attack. Had clinically significant cardiac conduction defects (for example, 3rd degree atrioventricular block, left bundle branch block, sick sinus syndrome, atrial fibrillation). Had hemodynamically significant left ventricular outflow obstruction due to aortic valvular disease. Had secondary hypertension of any etiology (e.g., renovascular disease, pheochromocytoma, Cushing's syndrome). Had renal dysfunction defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 at Screening. Had albuminuria defined as >200 mg/g at Screening. Had known or suspected unilateral or bilateral renal artery stenosis. Had unexplained microhematuria ≥3 RBCs/HPF or macrohematuria at Screening and confirmed on repeat testing. 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. Had hyperkalemia as defined by central laboratory normal reference range at Screening.

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 |
| --- | --- |
| Placebo Comparator: Placebo QD<br>Azilsartan medoxomil placebo-matching tablets, orally, once daily for up to 24 weeks. | Drug: Placebo<br> <br> |
| Experimental: Azilsartan Medoxomil 40 mg QD<br>Azilsartan medoxomil 40 mg, tablets, orally, once daily for up to 24 weeks. | Drug: Azilsartan medoxomil<br> <br> * Other names: TAK-491;|
| Experimental: Azilsartan Medoxomil 80 mg QD<br>Azilsartan medoxomil 80 mg, tablets, orally, once daily for up to 24 weeks. | Drug: Azilsartan medoxomil<br> <br> * Other names: TAK-491;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Trough Sitting Clinic Systolic Blood Pressure | The change in trough systolic blood pressure measured at week 8 relative to baseline. The trough is the average of the non-missing values of the 3 serial trough sitting systolic blood pressure measurements. | Baseline and Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Mean Daytime (6 AM to 10 PM) Diastolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring | The change in daytime (6am to 10pm) mean diastolic blood pressure measured at 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. | Baseline and Week 8 | 
| Change From Baseline in the Mean Nighttime (12 AM to 6 AM) Systolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring | The change in nighttime (12am to 6am) mean systolic blood pressure measured at 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. | Baseline and Week 8 | 
| Change From Baseline in the Mean Nighttime (12 AM to 6 AM) Diastolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring | The change in nighttime (12am to 6am) mean diastolic blood pressure measured at 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. | Baseline and Week 8 | 
| Change From Baseline in the 12-hr Mean Systolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring | The change in 12-hour mean systolic blood pressure measured at week 8 relative to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. The 12-hour mean is the average of all measurements recorded during the first 12 hours after dosing. | Baseline and Week 8 | 
| Change From Baseline in the 12-hr Mean Diastolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring | The change in 12-hour mean systolic blood pressure measured at week 8 relative to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. The 12-hour mean is the average of all measurements recorded during the first 12 hours after dosing. | Baseline and Week 8 | 
| Change From Baseline in the Trough (22 to 24 Hours After Dosing) Systolic Blood Pressure as Measured by Ambulatory Blood Pressure Monitoring | The change in trough systolic blood pressure measured at week 8 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. | Baseline and Week 8 | 
| Change From Baseline in the Trough (22 to 24 Hours After Dosing) Diastolic Blood Pressure as Measured by Ambulatory Blood Pressure Monitoring | The change in trough diastolic blood pressure measured at week 8 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. | Baseline and Week 8 | 
| Percentage of Participants Requiring Rescue Glycemic Therapy | Percentage of participants requiring rescue glycemic therapy during study. | 24 Weeks | 
| Time to First Glycemic Rescue | The time to the first instance of participants requiring glycemic rescue during study. | 24 Weeks | 
| Change From Baseline in HbA1c | 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 relative to baseline. | Baseline and Weeks 2, 4, 6, 8, 12, 16 and 20 | 
| Change From Baseline in Fasting Plasma Glucose | The change between the fasting plasma glucose value collected at each week indicated relative to baseline. | Baseline and Weeks 2, 4, 6, 8, 12, 16, 20, and 24 | 
| Change From Baseline to Week 6 and Week 24 in 2h Glucose During Oral Glucose Tolerance Testing (OGTT) | The change between the glucose value collected at weeks 6 and 24 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. | Baseline and Weeks 6 and 24 | 
| Change From Baseline to Week 6 and Week 24 in the Area Under the Plasma Concentration-time Curve (AUC) for Glucose During OGTT | The change between the AUC for glucose at weeks 6 and 24 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. | Baseline and Weeks 6 and 24 | 
| Change From Baseline to Week 6 and Week 24 in AUC for Insulin During OGTT | The change between the AUC for insulin at weeks 6 and 24 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. | Baseline and Weeks 6 and 24 | 
| Change From Baseline to Week 6 and Week 24 in AUC for C-peptide During OGTT | The change between the AUC for C-peptide at weeks 6 and 24 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. | Baseline and Weeks 6 and 24 | 
| Change From Baseline to Week 6 and Week 24 in AUC for Insulin/Glucose Ratio During OGTT | The change between the AUC for insulin/glucose ratio at weeks 6 and 24 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. | Baseline and Weeks 6 and 24 | 
| Change From Baseline to Week 6 and Week 24 in AUC for Glucagon During OGTT | The change between the AUC for glucagon at weeks 6 and 24 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. | Baseline and Weeks 6 and 24 | 
| Change From Baseline in Glycosylated Hemoglobin (HbA1c) | 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 relative to baseline. | Baseline and Week 24 | 
| Change From Baseline in Trough Sitting Clinic Diastolic Blood Pressure | The change in trough diastolic blood pressure measured at 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. | Baseline and Week 8 | 
| Change From Baseline in the 24-hour Mean Systolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring | The change in 24-hour mean systolic blood pressure measured at 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. | Baseline and Week 8 | 
| Change From Baseline in the 24-hour Mean Diastolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring | The change in 24-hour mean diastolic blood pressure measured at 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. | Baseline and Week 8 | 
| Change From Baseline in the Mean Daytime (6 AM to 10 PM) Systolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring | The change in daytime (6am to 10pm) mean systolic blood pressure measured 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. | Baseline and Week 8 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug Therapy, Hypertension and Diabetes