Clinical trial NCT01496430: Efficacy and Safety of Azilsartan Medoxomil Used in Combination With Metformin in Participants With Hypertension and Diabetes
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Hypertension
Diabetes
Keywords: Drug Therapy
Hypertension and Diabetes
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2011-12-21
Enrollment: 105
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. Was male or female and ≥18 years.
2. Had type 2 diabetes mellitus with HbA1c of ≥7.5 to ≤9.5% at Screening.
3. 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.
4. 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.
5. 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:

1. Had a mean, trough, sitting clinic diastolic blood pressure (DBP) ≥ 100 mm Hg at Day -1.
2. Had type 1 or poorly controlled type 2 diabetes mellitus (HbA1c \>9.5%) at Screening.
3. Was taking or expected to take an excluded medication.
4. 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.
5. Had clinically significant cardiac conduction defects (for example, 3rd degree atrioventricular block, left bundle branch block, sick sinus syndrome, atrial fibrillation).
6. Had hemodynamically significant left ventricular outflow obstruction due to aortic valvular disease.
7. Had secondary hypertension of any etiology (e.g., renovascular disease, pheochromocytoma, Cushing's syndrome).
8. Had renal dysfunction defined as estimated glomerular filtration rate (eGFR) \<60 mL/min/1.73 m2 at Screening.
9. Had albuminuria defined as \>200 mg/g at Screening.
10. Had known or suspected unilateral or bilateral renal artery stenosis.
11. Had unexplained microhematuria ≥3 RBCs/HPF 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. Had hyperkalemia as defined by central laboratory normal reference range at Screening.

Primary outcomes:
measure: Change From Baseline in Trough Sitting Clinic Systolic Blood Pressure
timeFrame: Baseline and Week 8
Secondary outcomes:
measure: Change From Baseline in Glycosylated Hemoglobin (HbA1c)
timeFrame: Baseline and Week 24
measure: Change From Baseline in Trough Sitting Clinic Diastolic Blood Pressure
timeFrame: Baseline and Week 8
measure: Change From Baseline in the 24-hour Mean Systolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring
timeFrame: Baseline and Week 8
measure: Change From Baseline in the 24-hour Mean Diastolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring
timeFrame: Baseline and Week 8
measure: Change From Baseline in the Mean Daytime (6 AM to 10 PM) Systolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring
timeFrame: Baseline and Week 8
measure: Change From Baseline in the Mean Daytime (6 AM to 10 PM) Diastolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring
timeFrame: Baseline and Week 8
measure: Change From Baseline in the Mean Nighttime (12 AM to 6 AM) Systolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring
timeFrame: Baseline and Week 8
measure: Change From Baseline in the Mean Nighttime (12 AM to 6 AM) Diastolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring
timeFrame: Baseline and Week 8
measure: Change From Baseline in the 12-hr Mean Systolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring
timeFrame: Baseline and Week 8
measure: Change From Baseline in the 12-hr Mean Diastolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring
timeFrame: Baseline and Week 8
measure: Change From Baseline in the Trough (22 to 24 Hours After Dosing) Systolic Blood Pressure as Measured by Ambulatory Blood Pressure Monitoring
timeFrame: Baseline and Week 8
measure: Change From Baseline in the Trough (22 to 24 Hours After Dosing) Diastolic Blood Pressure as Measured by Ambulatory Blood Pressure Monitoring
timeFrame: Baseline and Week 8
measure: Percentage of Participants Requiring Rescue Glycemic Therapy
timeFrame: 24 Weeks
measure: Time to First Glycemic Rescue
timeFrame: 24 Weeks
measure: Change From Baseline in HbA1c
timeFrame: Baseline and Weeks 2, 4, 6, 8, 12, 16 and 20
measure: Change From Baseline in Fasting Plasma Glucose
timeFrame: Baseline and Weeks 2, 4, 6, 8, 12, 16, 20, and 24
measure: Change From Baseline to Week 6 and Week 24 in 2h Glucose During Oral Glucose Tolerance Testing (OGTT)
timeFrame: Baseline and Weeks 6 and 24
measure: Change From Baseline to Week 6 and Week 24 in the Area Under the Plasma Concentration-time Curve (AUC) for Glucose During OGTT
timeFrame: Baseline and Weeks 6 and 24
measure: Change From Baseline to Week 6 and Week 24 in AUC for Insulin During OGTT
timeFrame: Baseline and Weeks 6 and 24
measure: Change From Baseline to Week 6 and Week 24 in AUC for C-peptide During OGTT
timeFrame: Baseline and Weeks 6 and 24
measure: Change From Baseline to Week 6 and Week 24 in AUC for Insulin/Glucose Ratio During OGTT
timeFrame: Baseline and Weeks 6 and 24
measure: Change From Baseline to Week 6 and Week 24 in AUC for Glucagon During OGTT
timeFrame: Baseline and Weeks 6 and 24
Other outcomes:
Locations:
city: Birmingham
country: United States
state: Alabama
city: Green Valley
country: United States
state: Arizona
city: Tempe
country: United States
state: Arizona
city: Tucson
country: United States
state: Arizona
city: Buena Park
country: United States
state: California
city: Hawaiian Gardens
country: United States
state: California
city: Norwalk
country: United States
state: California
city: Paramount
country: United States
state: California
city: Rancho Cucamonga
country: United States
state: California
city: Sacramento
country: United States
state: California
city: San Diego
country: United States
state: California
city: Tustin
country: United States
state: California
city: Denver
country: United States
state: Colorado
city: Bradenton
country: United States
state: Florida
city: Brooksville
country: United States
state: Florida
city: Hallandale Beach
country: United States
state: Florida
city: Jupiter
country: United States
state: Florida
city: Miami
country: United States
state: Florida
city: Orlando
country: United States
state: Florida
city: Pembroke Pines
country: United States
state: Florida
city: St Petersburg
country: United States
state: Florida
city: Tampa
country: United States
state: Florida
city: Winter Park
country: United States
state: Florida
city: Roswell
country: United States
state: Georgia
city: Chicago
country: United States
state: Illinois
city: Evergreen Park
country: United States
state: Illinois
city: Gurnee
country: United States
state: Illinois
city: Avon
country: United States
state: Indiana
city: Greenfield
country: United States
state: Indiana
city: Lexington
country: United States
state: Kentucky
city: Paducah
country: United States
state: Kentucky
city: Baltimore
country: United States
state: Maryland
city: Columbia
country: United States
state: Missouri
city: Omaha
country: United States
state: Nebraska
city: Las Vegas
country: United States
state: Nevada
city: Margate
country: United States
state: New Jersey
city: Albuquerque
country: United States
state: New Mexico
city: Brooklyn
country: United States
state: New York
city: Calabash
country: United States
state: North Carolina
city: Greensboro
country: United States
state: North Carolina
city: Lenoir
country: United States
state: North Carolina
city: Morehead City
country: United States
state: North Carolina
city: Salisbury
country: United States
state: North Carolina
city: Wilmington
country: United States
state: North Carolina
city: Winston-Salem
country: United States
state: North Carolina
city: Centerville
country: United States
state: Ohio
city: Cincinnati
country: United States
state: Ohio
city: Oklahoma City
country: United States
state: Oklahoma
city: Downingtown
country: United States
state: Pennsylvania
city: Fleetwood
country: United States
state: Pennsylvania
city: Reading
country: United States
state: Pennsylvania
city: Providence
country: United States
state: Rhode Island
city: Anderson
country: United States
state: South Carolina
city: Chattanooga
country: United States
state: Tennessee
city: Kingsport
country: United States
state: Tennessee
city: Nashville
country: United States
state: Tennessee
city: Dallas
country: United States
state: Texas
city: Houston
country: United States
state: Texas
city: Irving
country: United States
state: Texas
city: North Richland Hills
country: United States
state: Texas
city: Pearland
country: United States
state: Texas
city: San Antonio
country: United States
state: Texas
city: Salt Lake City
country: United States
state: Utah
city: Burke
country: United States
state: Virginia
city: Manassas
country: United States
state: Virginia
city: Richmond
country: United States
state: Virginia
city: Virginia Beach
country: United States
state: Virginia
city: Wauwatosa
country: United States
state: Wisconsin
Study officials:
affiliation: Takeda
name: Director, Clinical Science
role: STUDY_DIRECTOR
References: