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Angiotensin II Blockade and Inflammation in Obesity (ARB)

Primary Purpose

Overweight, Obese, Prehypertension

Status
Completed
Phase
Phase 4
Locations
Study Type
Interventional
Intervention
Olmesartan medoxomil
Sponsored by
Virginia Polytechnic Institute and State University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Overweight focused on measuring angiotensin II, obesity, diabetes

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • 18-75 years of age
  • Weight stable for previous 6 months (+2.0kg)
  • Sedentary to recreationally active
  • Willing to be randomized to treatment or placebo
  • Verbal and written informed consent
  • Approved for participation by Medical Director (Jose Rivero, M.D.)

Exclusion Criteria:

  • Blood pressure outside stated range
  • Diabetes or taking diabetes medications
  • Total cholesterol >6.2 mmol/L; triglycerides >4.5 mmol/L
  • Past or current ischemic heart disease, stroke, respiratory disease, endocrine or metabolic disease, neurological disease, or hematological-oncological disease
  • Evidence of renal insufficiency; GFR< 60 ml/min*
  • Medications (including but not limited to antihypertensives, statins or other with anti-inflammatory actions) or antioxidant vitamins or supplements
  • Known allergy or hypersensitivity to olmesartan or any of its components
  • Pregnant or planning to become pregnant

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Experimental

    Experimental

    Arm Label

    Olmesartan Medoxomil first, then No Drug

    No Drug first, then Olmesartan Medoxomil

    Arm Description

    During the First Intervention (8 weeks), subjects will be provided with daily 20 mg of olmesartan for the first 2 weeks. Subjects receive additional daily doses of 40 mg olmesartan for the remainder of the study period (6 weeks). The dose remains at 20 mg per day, however, if BP falls below 110/70 during the first 2 weeks. In addition, subjects will continue taking the drug during the 2-week follow-up testing period. Subjects will then proceed to the Washout period (2 weeks). During the Second Intervention (8 weeks), no drug will be administered to the subjects.

    During the First Intervention (8 weeks), no drug will be administered to the subjects. Subjects will then proceed to the Washout period (2 weeks). During the Second Intervention (8 weeks), subjects will be provided with daily 20 mg of olmesartan for the first 2 weeks. Subjects then receive daily doses of 40 mg olmesartan for the remainder of the study period (6 weeks). The dose remains at 20 mg per day, however, if BP falls below 110/70 during the first 2 weeks. In addition, subjects will continue taking the drug during the 2-week follow-up testing period.

    Outcomes

    Primary Outcome Measures

    Insulin Sensitivity by Intravenous Glucose Tolerance Testing (Change Over Time)
    Data collected from the intravenous glucose tolerance tests included blood concentrations of glucose and insulin. Glucose was measured immediately on a YSI glucose analyzer and insulin was measured via ELISA colormetric kits once all study samples were collected. To analyze changes in insulin sensitivity, the MINMOD software was used. The MINMOD software uses Bergman's minimal model to determine insulin sensitivity during an intravenous glucose tolerance test. Both glucose and insulin values were inserted at each timepoint collected (33 in total over the 3-hour protocol) and the software was run to generate the insulin sensitivity value at baseline and post-test. This information was then used to calculate the change of insulin sensitivity from baseline to post-testing after each 8-week intervention.

    Secondary Outcome Measures

    Full Information

    First Posted
    September 6, 2012
    Last Updated
    December 6, 2017
    Sponsor
    Virginia Polytechnic Institute and State University
    Collaborators
    National Heart, Lung, and Blood Institute (NHLBI)
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    1. Study Identification

    Unique Protocol Identification Number
    NCT01684748
    Brief Title
    Angiotensin II Blockade and Inflammation in Obesity
    Acronym
    ARB
    Official Title
    Angiotensin II Blockade and Adipose Tissue Inflammation in Obesity
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    December 2017
    Overall Recruitment Status
    Completed
    Study Start Date
    February 2009 (undefined)
    Primary Completion Date
    August 2011 (Actual)
    Study Completion Date
    August 2011 (Actual)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Principal Investigator
    Name of the Sponsor
    Virginia Polytechnic Institute and State University
    Collaborators
    National Heart, Lung, and Blood Institute (NHLBI)

    4. Oversight

    Data Monitoring Committee
    Yes

    5. Study Description

    Brief Summary
    Overweight and obesity, which afflicts ~65% of the U.S. population and more than 1 billion people worldwide, increases the risk of developing hypertension. Activation of the renin angiotensin system (RAS) is an important mechanism by which obesity leads to hypertension. In addition to its vasoconstricting and sodium retaining actions, angiotensin II also has potent pro-inflammatory actions including macrophage infiltration and expression of proinflammatory cytokines in target tissues. Adipose tissue and skeletal muscle appear to be a key sites for the generation of proinflammatory cytokines. Although angiotensin II receptor blockade reduces inflammation in many tissues, the effects on adipose tissue and skeletal muscle in humans are not clear. Importantly, the chronic low grade inflammatory state that accompanies obesity complicates hypertension by contributing to insulin resistance and accelerating cardiovascular disease. Therefore, the general aim of the present proposal will be to determine the influence of angiotensin II receptor blockade on adipose tissue and skeletal muscle inflammation and its relation to improvements in insulin sensitivity, if observed, in obese hypertensive humans. To address these aims, 44 obese (BMI>30 kg/m2) hypertensive (BP>140 systolic and/or 90 diastolic) individuals (age=50-65 years) will be randomized to receive 8 weeks of either the angiotensin II receptor antagonist, olmesartan medoxomil, or no treatment in a crossover manner. Subcutaneous adipose tissue and skeletal muscle biopsies will be obtained and insulin sensitivity (intravenous glucose tolerance tests) will be assessed at baseline and following 8 weeks of each intervention. A two week washout period will separate the interventions.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Overweight, Obese, Prehypertension, Hypertension
    Keywords
    angiotensin II, obesity, diabetes

    7. Study Design

    Primary Purpose
    Prevention
    Study Phase
    Phase 4
    Interventional Study Model
    Crossover Assignment
    Masking
    None (Open Label)
    Allocation
    Randomized
    Enrollment
    20 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    Olmesartan Medoxomil first, then No Drug
    Arm Type
    Experimental
    Arm Description
    During the First Intervention (8 weeks), subjects will be provided with daily 20 mg of olmesartan for the first 2 weeks. Subjects receive additional daily doses of 40 mg olmesartan for the remainder of the study period (6 weeks). The dose remains at 20 mg per day, however, if BP falls below 110/70 during the first 2 weeks. In addition, subjects will continue taking the drug during the 2-week follow-up testing period. Subjects will then proceed to the Washout period (2 weeks). During the Second Intervention (8 weeks), no drug will be administered to the subjects.
    Arm Title
    No Drug first, then Olmesartan Medoxomil
    Arm Type
    Experimental
    Arm Description
    During the First Intervention (8 weeks), no drug will be administered to the subjects. Subjects will then proceed to the Washout period (2 weeks). During the Second Intervention (8 weeks), subjects will be provided with daily 20 mg of olmesartan for the first 2 weeks. Subjects then receive daily doses of 40 mg olmesartan for the remainder of the study period (6 weeks). The dose remains at 20 mg per day, however, if BP falls below 110/70 during the first 2 weeks. In addition, subjects will continue taking the drug during the 2-week follow-up testing period.
    Intervention Type
    Drug
    Intervention Name(s)
    Olmesartan medoxomil
    Other Intervention Name(s)
    Benicar
    Intervention Description
    Crossover intervention comparing antihypertensive medication to no drug intervention.
    Primary Outcome Measure Information:
    Title
    Insulin Sensitivity by Intravenous Glucose Tolerance Testing (Change Over Time)
    Description
    Data collected from the intravenous glucose tolerance tests included blood concentrations of glucose and insulin. Glucose was measured immediately on a YSI glucose analyzer and insulin was measured via ELISA colormetric kits once all study samples were collected. To analyze changes in insulin sensitivity, the MINMOD software was used. The MINMOD software uses Bergman's minimal model to determine insulin sensitivity during an intravenous glucose tolerance test. Both glucose and insulin values were inserted at each timepoint collected (33 in total over the 3-hour protocol) and the software was run to generate the insulin sensitivity value at baseline and post-test. This information was then used to calculate the change of insulin sensitivity from baseline to post-testing after each 8-week intervention.
    Time Frame
    Baseline testing to post-testing after 8-week intervention
    Other Pre-specified Outcome Measures:
    Title
    Collagen Gene Expression in Skeletal Muscle (Change Over Time)
    Description
    RNA extraction and quantification were determined using an RNeasy Mini Fibrous Kit and DNase I treatment (Qiagen, Valencia, CA, USA) in accordance to the manufacturer's directions for mRNA extraction. Quantitative real-time polymerase chain reaction (qRT-PCR) measured the expression of collagen III using an ABI PRISM 7900 Sequence Detection System instrument and TaqMan Universal PCR Master Mix according to the manufacturer's instructions (Applied Biosystems, Foster City, CA, USA). Relative gene expression levels were determined using the number of cycles necessary to reach threshold and results were normalized to cyclophilin B RNA levels.
    Time Frame
    Baseline testing to post-testing after 8-week intervention

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Maximum Age & Unit of Time
    75 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: 18-75 years of age Weight stable for previous 6 months (+2.0kg) Sedentary to recreationally active Willing to be randomized to treatment or placebo Verbal and written informed consent Approved for participation by Medical Director (Jose Rivero, M.D.) Exclusion Criteria: Blood pressure outside stated range Diabetes or taking diabetes medications Total cholesterol >6.2 mmol/L; triglycerides >4.5 mmol/L Past or current ischemic heart disease, stroke, respiratory disease, endocrine or metabolic disease, neurological disease, or hematological-oncological disease Evidence of renal insufficiency; GFR< 60 ml/min* Medications (including but not limited to antihypertensives, statins or other with anti-inflammatory actions) or antioxidant vitamins or supplements Known allergy or hypersensitivity to olmesartan or any of its components Pregnant or planning to become pregnant
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Kevin P. Davy, Ph.D.
    Organizational Affiliation
    Virginia Polytechnic Institute and State University
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

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    Angiotensin II Blockade and Inflammation in Obesity

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