Pleiotropic Effects of Azilsartan Medoxomil Over Insulin Resistance in Obese, Diabetic and Hypertensive Patients

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ClinicalTrials.gov Identifier: NCT02235519

Recruitment Status : Unknown

Verified September 2014 by Hospital General de México Dr. Eduardo Liceaga.
Recruitment status was: Recruiting

First Posted : September 10, 2014

Last Update Posted : March 30, 2015

View this study on Beta.ClinicalTrials.gov

Sponsor:

Information provided by (Responsible Party):

Hospital General de México Dr. Eduardo Liceaga

Study Description

Brief Summary:

The goal of this study is to build a mathematical model to explain the effect of two doses of azilsartan (40 and 80 mg) upon metabolic (insulin resistance, glucose) and inflammatory parameters (cytokines) in function of "metabolic strata" like obesity, type 2 diabetes mellitus, hypertension and their combinations.

Condition or disease	Intervention/treatment	Phase
Hypertension Obesity Type 2 Diabetes Mellitus	Drug: Azilsartan 40 mg. Drug: Azilsartan 80 mg	Phase 2 Phase 3

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Detailed Description:

There are data supporting angiotensin II receptor subtype 1 (AT1) antagonist have beneficial effects on metabolic control due to some pleiotropic effect mediated by peroxisome proliferator-activated receptor (PPAR) gamma induction. Azilsartan is a prodrug absorbed in the gastrointestinal tract that can improve metabolic milieu under diverse conditions like obesity, hypertension (can be considered a metabolic disease) or type 2 diabetes mellitus. Clinical studies that have been raised in this regard are few, and still show controversial issues.

The objective of any study with AT1 antagonist drug interested in pleiotropic effects should not only focus on antihypertensive improvement, but also the effect on other areas such as metabolism of lipids and carbohydrates in obese and/or type 2 diabetes.

This study is a randomized, open labeled, clinical study. The aim is to build a mathematical model for supporting the effect of azilsartan 40 or 80 mg on metabolic and inflammatory measurements in function of metabolic conditions (i.e. obesity, type 2 diabetes and hypertension, and their combinations).

Patients will be stratified according to their metabolic status and randomized by blocks of four for each strata. This strategy will help to maintain each treatment group in balance. All subjects will receive the treatment for 12 weeks.

Subjects who attend the outpatient consultation at the Hospital General de Mexico will be invited to participate in the study. Those who meet the inclusion criteria must sign an informed consent approved by the ethics committee. This document describes the follow-up visits as described below:

Screening visit (V-1):

This visit includes patient history, physical examination (weight, height, waist circumference and blood pressure) and a blood sample for measurement of: complete blood count, fasting glucose, HbA1c, creatinine, adiponectin, IL-1b, IL-6, IL-10, TNF-α, liver function tests, C-reactive protein, blood chemistry, proteinuria, 24-hours urinary glucose and creatinine.

Initial visit (V0):

Physical examination will be performed and blood samples for oral glucose tolerance test will be drawn at 0, 30, 60, 90 and 120 minutes, with these data points the Matsuda insulin sensitivity index will be calculated. Pharmacological treatment of 40mg or 80mg azilsartan 4 weeks will be assigned (open labeled but randomized).

Visit 1 and 2 (V1, V2):

These visits performed at 4 and 8 weeks respectively include: physical examination, recording of adverse events and medication count to check adherence to treatment accomplishment.

Visit 3 (V3):

Week 12 include physical examination, adverse events registration, complete blood count, fasting glucose, HbA1c, creatinine, adiponectin, IL-1b, IL-6, IL-10, TNF - α, liver function tests, C reactive protein, blood chemistry, proteinuria, 24-hours urinary glucose and creatinine. Furthermore an oral glucose tolerance test with samples at 0, 30, 60, 90 and 120 minutes will be taken, to calculate the index of insulin sensitivity by the Matsuda method.

Statistical analysis and sample size. The sample size was calculated for ANCOVA analysis considering 8 groups with 5 covariates. Considering an alpha error of 5%, effect size of 30%, and statistical power of 90% a total sample of 250 patient was calculated. If we consider a 20% attrition of the sample, giving a total of 300 patients, i.e. 150 patients per treatment group.

A descriptive analysis will be done. The contrast among groups will be analyzed by an ANCOVA model and the function fitness will be calculated using ordinary least squares. Dependent variables will be insulin sensitivity, proteinuria, stiffness of the carotid artery, cytokines. Fixed factors: sex, blood pressure category, metabolic status, drug treatment. Covariates: Age, waist circumference.

The greatest expected size of effect would be within the group of patients with obesity, hypertension, and type 2 diabetes mellitus (all three) treated with 80 mg and the lowest size of effect within the group of only obesity treated with 40 mg.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	300 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Randomized, Open Label Study to Evaluate the Pleiotropic Effects of Azilsartan Medoxomil 40 and 80 mg for 12 Weeks Over Metabolic Markers in Patients With Hypertension, Obesity or Type 2 Diabetes Mellitus
Study Start Date :	January 2014
Estimated Primary Completion Date :	June 2015
Estimated Study Completion Date :	June 2015

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Hypertension Type 2 diabetes

Drug Information available for: Azilsartan medoxomil

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Azilsartan low dosage Patients will take azilsartan 40 mg during 12 weeks	Drug: Azilsartan 40 mg. Patients will take 40 mg of azilsartan during 12 weeks Other Name: Edarbi 40 mg
Active Comparator: Azilsartan high dosage Patients will take azilsartan 80 mg during 12 weeks	Drug: Azilsartan 80 mg Patients will take 80 mg of azilsartan during 12 weeks Other Name: Edarbi 80 mg

Outcome Measures

Primary Outcome Measures :

Blood pressure [ Time Frame: 12 weeks ]
Effect size of azilsartan medoxomil 40 and 80 mg in lowering systolic and diastolic blood pressure stratified by metabolic condition (obesity or type 2 diabetes mellitus). The minimal size effect between groups will be at least 30% and absolute percentage of previous hypertensive subjects reaching targeted values of < 130/85 mmHg.

Secondary Outcome Measures :

Insulin sensitivity and HbA1c level [ Time Frame: 12 weeks ]
Effect over insulin sensitivity measured by Matsuda index of insulin sensitivity (ISI) and the level of HbA1c. The function will show a increase for ISI that in a within contrast will be larger for those with obesity with hypertension and diabetes. Meanwhile the HbA1 will show a deep decrease for the same group.
Effect of azilsartan on Inflammatory markers [ Time Frame: 12 weeks ]
Effect size between azilsartan 40 mg and 80 mg on inflammatory markers (IL-1b, IL-6, IL 10, TNF-α, and adiponectin). A decrease in this response will be more important for the 80 mg and those with obesity, hipertension and diabetes.
Endothelial function [ Time Frame: 12 weeks ]
Subjects with stiffness of the carotid and brachial artery will show improvement in relaxation, and the larger effect will be for 80 mg in the group of obesity, hypertension and diabetes mellitus.
Renal function improvement. [ Time Frame: 12 weeks ]
Proteinuria will show a significant decrease after 12 weeks of treatment with azilsartan. The larger effect will be for the 80 mg and the obese, hypertension and diabetic group.

Eligibility Criteria

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Ages Eligible for Study:	25 Years to 65 Years (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	Yes

Criteria

Inclusion Criteria:

Written informed consent in accordance with Good Clinical Practices and local legislations
Age between ≥25 and ≤ 65 years
Patients with hypertension stage 1 as defined by systolic blood pressure (SBP) ≥140 but <159 mmHg and diastolic blood pressure (DBP) ≥90 but < 99 mmHg at randomization
Ability to stop any current antihypertensive therapy without unacceptable risk to the patient (Investigator's discretion)
BMI ≥25 and ≤35.
Patients with type 2 diabetes mellitus can participate and will be stratified before randomization. Diagnosis can be established by clinical history, 75-g oral glucose tolerance test (ADA criteria), or fasting glucose > 126 mg/dL.

Exclusion Criteria:

Pre-menopausal women (last menstruation ≤1 year prior to signing informed consent) who are not surgically sterile, nursing, are pregnant or without any anticonceptive methods.
Known hypersensitivity to the study drug
Gastrointestinal surgery which might alter absorption, distribution, or drug metabolism.
History of angioedema related to ACE inhibitors or angiotensin II receptor blockers.
Night shift workers who routinely sleep during the daytime and whose work hours include midnight to 4:00 a.m.
Known or suspected secondary hypertension (e.g., renal artery stenosis or phaeochromocytoma)
SBP≥160 mmHg and/or DBP ≥100 mmHg
Renal dysfunction as defined by: serum creatinine >3.0 mg/dL (or >265 umol/L) and/or creatinine clearance <30 ml/min and/or other clinical markers of severe renal impairment.
Bilateral renal arterial stenosis, renal artery stenosis in a solitary functional kidney, post-renal transplant patients or patients with one kidney
Clinically relevant hypokalemia or hyperkalemia (i.e., <3.5 mmol/L or >5.5 mmol/L, may be rechecked for suspected error in result)
Uncorrected sodium or volume depletion
Primary aldosteronism.
Hereditary fructose intolerance
Biliary obstructive disorders (e.g., cholestasis) or hepatic insufficiency
Congestive heart failure class III-IV according to criteria fron the New York Heart Association.
Clinically significant ventricular tachycardia, atrial fibrillation, atrial flutter or other clinically relevant cardiac arrhythmias as determined by the Investigator.
Hypertrophic obstructive cardiomyopathy, severe obstructive coronary artery disease, aortic stenosis, hemodynamically relevant stenosis of the aortic or mitral valve
Patients whose diabetes has not been stable and controlled for at least the past 3 months as defined by an Glycosylated Hemoglobin A1c >=10% or fasting glucose greater than 400 mg/dL.
Patients who have previously experienced symptoms characteristic of angioedema during treatment with ACE inhibitors or angiotensin-II receptor antagonists
History of drug or alcohol dependency within 6 months prior to signing the informed consent form
Concomitant administration of any medications known to affect blood pressure, except medications allowed by the protocol
Any investigational drug therapy within 1 month of signing the informed consent
Known hypersensitivity to any component of the trial drugs (telmisartan, hydrochlorothiazide, or placebo)
History of non-compliance or inability to comply with prescribed medications or protocol procedures (less than 80% or more than 120%, especially during run-in).
Any other clinical condition which, in the opinion of the investigator, would not allow safe completion of the protocol and safe administration of the trial medication

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02235519

Contacts

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Contact: Antonio Peralta, MD	521(55)43466306	juan_peca@hotmail.com

Locations

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Mexico
Hospital General de Mexico "Dr. Eduardo Liceaga"	Recruiting
Mexico, Mexico, D.F., Mexico, 06720
Contact: Juan A Peralta, bachelor

Sponsors and Collaborators

Hospital General de México Dr. Eduardo Liceaga

Investigators

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Principal Investigator:	Antonio Peralta, MD	HGM
Study Chair:	Rogelio Zapata, MD	HGM
Study Director:	Estrella Martinez, RN	HGM

More Information

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Responsible Party:	Hospital General de México Dr. Eduardo Liceaga
ClinicalTrials.gov Identifier:	NCT02235519
Other Study ID Numbers:	DI/12/404B/4/85
First Posted:	September 10, 2014 Key Record Dates
Last Update Posted:	March 30, 2015
Last Verified:	September 2014

Additional relevant MeSH terms:

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Hypertension Obesity Diabetes Mellitus Diabetes Mellitus, Type 2 Overweight Overnutrition Nutrition Disorders Body Weight Glucose Metabolism Disorders	Metabolic Diseases Endocrine System Diseases Vascular Diseases Cardiovascular Diseases Azilsartan medoxomil Angiotensin II Type 1 Receptor Blockers Angiotensin Receptor Antagonists Molecular Mechanisms of Pharmacological Action

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