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TIVA: Targeting Inflammation to Treat Cardiovascular Aging

Sponsor
Gary L. Pierce (Other)
Overall Status
Completed
CT.gov ID
NCT01775865
Collaborator
(none)
59
Enrollment
1
Location
3
Arms
41
Duration (Months)
1.4
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the United States with older age being a primary risk factor. The number of adults greater than age 65 years will almost double to 70 million by 2030, therefore identifying therapeutic strategies for treating or preventing age-related disorders in humans is of major biomedical importance. Cardiovascular aging, defined as a reduction in vascular and cardiac functions with normal aging, occurs even in the absence of CVD risk factors and overt CVD. A key feature of cardiovascular aging is stiffening of the large elastic central arteries such as the aorta. This is important because aortic stiffness directly contributes to clinical problems such as increased blood pressure, reduced blood flow to the heart muscle, and thickening of the heart muscle. Therefore, these clinical consequences are hypothesized to mediate a substantial proportion of the increase in CVD risk in older adults. However, effective drug treatments for aortic stiffness are not currently available and the biological reasons (mechanisms) involved in causing aortic stiffening remain undefined. In addition, the inability of smaller blood vessels to relax, impairment of the heart to relax during the filling phase of the heart cycle (i.e., diastole), and increased blood pressure variability, have all been linked to aortic stiffness. Furthermore, chronic low-grade inflammation with advancing age has been proposed to be a common mechanistic link (i.e., biological reason) between these reductions in cardiovascular function in older adults. Therefore, the investigators propose that inflammation could be a novel therapeutic target to treat cardiovascular aging in older adults. Our central hypothesis is that inflammation mediates the age-related deterioration in cardiovascular functions observed with advancing age through the development of oxidative stress (i.e., imbalance between damaging oxygen free radicals vs. protective antioxidants). Our hypothesis predicts that chronic inhibition of inflammation with Salsalate, an FDA-approved anti-inflammatory drug similar to aspirin that is used to treat rheumatoid arthritis pain and known to inhibit the 'master' regulator of inflammation in the cell (i.e., nuclear factor kappa B), will improve cardiovascular function in older adults. In addition, the investigators hypothesize that the mechanism for the improvement in cardiovascular function during inhibition of inflammation will be by suppressing oxidative stress. To test our hypothesis, the investigators will randomize older healthy adults (age 50-79 years) to 3 g/day of salsalate or placebo (i.e., pill with inactive substance) pills for 4 weeks and have cardiovascular function measured at baseline and again after 4 weeks.

Condition or Disease Intervention/Treatment Phase
Phase 2

Detailed Description

Aim 1: To measure aortic wall stiffness and circulating biomarkers of oxidative stress during both acute (IV) intravenous infusions of saline and then the antioxidant vitamin C at baseline and after 4 weeks of salsalate or placebo in healthy older adults. Hypothesis 1: Inhibition of inflammation in older adults will decrease aortic wall stiffness in part by reductions in oxidative stress.

Aim 2: To measure brachial artery endothelium-dependent vasodilation (EDV) and circulating markers of oxidative stress during acute intravenous infusions of saline and then the vitamin C at baseline and after 4 weeks of salsalate or placebo in healthy older adults. Hypothesis 2: Inhibition of inflammation in older adults will improve vascular endothelial vasodilatory function in older adults in part by reductions in oxidative stress.

Aim 3: To measure left ventricular (LV) diastolic relaxation and filling dynamics and circulating markers of oxidative stress during both acute intravenous infusions of saline and then vitamin C at baseline and after 4 weeks of Salsalate or placebo in healthy older adults. Hypothesis 3: Inhibition of inflammation in older adults will improve LV diastolic function in part by reductions in oxidative stress.

Exploratory Aim: To measure 24-hour pressure variability and short-term baroreflex sensitivity before and after 4 weeks of oral Salsalate or placebo treatment in older adults. Exploratory hypothesis: Inhibition of inflammation in older adults will improve cardiovascular autonomic dysregulation in older healthy adults.

Study Design

Study Type:
Interventional
Actual Enrollment :
59 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
Targeting Inflammation to Treat Cardiovascular Aging in Humans (TIVA Study)
Study Start Date :
Sep 1, 2012
Actual Primary Completion Date :
Feb 1, 2016
Actual Study Completion Date :
Feb 1, 2016

Arms and Interventions

Arm Intervention/Treatment
Experimental: Salsalate

Salsalate capsule 1.5 g/day twice per day by mouth for 4 weeks

Drug: Salsalate
4 weeks of daily salsalate
Other Names:
  • Disalcid
  • Mono-Gesic
  • Salflex
  • Salsitab

    		•
    Placebo Comparator: Placebo

    Placebo capsule twice per day by mouth for 4 weeks

    Drug: Placebo (for salsalate)
    4 week of daily placebo
    Other Names:
  • Placebo capsule sugar pill to mimic salsalate

    		•
    No Intervention: Young Control

    No intervention; Baseline measurements only

    Outcome Measures

    Primary Outcome Measures

    1. Carotid-femoral Pulse Wave Velocity (CFPWV) [Change in CFPWV from baseline at 4 weeks]

      Aortic stiffness

    Secondary Outcome Measures

    1. Brachial Artery Flow-mediated Dilation (FMD) [Change from baseline brachial artery FMD at 4 weeks]

      Endothelial function

    Other Outcome Measures

    1. Tissue Doppler Left Ventricular Relaxation Velocity (E') [Change from baseline E' at 4 weeks]

      Left ventricular diastolic dysfunction

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 79 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    Yes
    Inclusion Criteria:

    • Willing and able to provide written, signed informed consent after the nature of the study has been explained, and prior to any research-related procedures.

    • Age is > or = 50 and < or = 79 years (older) or > or = 18 and < or = 39 years of age

    • healthy, as determined by health history questionnaire, medical history and physical examination by physician or nurse practitioner, blood and urine chemistries, resting blood pressure and exercise 12-lead ECG

    • blood chemistries indicative of normal renal (creatinine <2.2 mg/dl), normal liver, i.e., <3 times upper limit for alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and thyroid function (TSH between 0.4 - 5.0 mU/L)

    • If currently receiving treatment with or taking any of the following supplements, be willing and able to discontinue taking them for 2 weeks prior and throughout the treatment period: Vitamin C, E or other multivitamins containing vitamin C or E; nutraceuticals containing vitamin C or E

    • No history of cardiovascular disease (e.g., heart attack, stroke, heart failure, valvular heart disease, cardiomyopathy), Type 2 diabetes, chronic obstructive pulmonary or peripheral arterial disease

    • Middle-aged/older females will be postmenopausal at least 1 year, had tubal ligation at least 1 year prior to screening, or who have had a total hysterectomy.

    • Sedentary or recreationally active defined as performs regular aerobic exercise (30 min or more of vigorous walking, jogging, swimming, cycling, etc) less than 3 days/week or less than 12 days/month over the last year

    • Non-smokers, defined as no history of smoking, no smoking for at least the past 1 year

    • Normal resting 12-lead ECG.

    Exclusion Criteria:

    • History of cardiovascular disease such as heart angioplasty/stent or bypass surgery, myocardial infarction, stroke, heart failure with or without LV ejection fraction <40%, cardiomyopathy, valvular heart disease, cardiomyopathy, heart transplantation, Type 2 diabetes and Type 1 diabetes

    • Smoking or history of smoking within past one year

    • History of gastric ulcers, bleeding disorders, dyspepsia, severe gastroesophageal reflux disease (GERD), or metabolic acidosis

    • History of asthma or lung disease (chronic obstructive pulmonary disease, COPD)

    • Abnormal resting 12-lead ECG (e.g., evidence of myocardial infarction, left ventricular hypertrophy, left-bundle branch block, 2nd or 3rd degree atrioventricular (AV) block, atrial fibrillation/flutter)

    • Serious neurologic disorders including seizures

    • History of renal failure, dialysis or kidney transplant

    • Serum creatinine > 2.2 mg/dL, or hepatic enzyme concentrations > 3 times the upper limit of normal

    • History of HIV infection, hepatic cirrhosis, other preexisting liver disease, or positive HIV, Hepatitis B or C test at screening.

    • Use of any investigational product or investigational medical device within 30 days prior to screening, or requirement for any investigational agent prior to completion of all scheduled study assessments.

    • History of recent chicken pox, shingles or influenza (ie., risk of Reye's syndrome) Recent flu-like symptoms within the past 2 weeks

    • Pregnant or breastfeeding at screening, or planning to become pregnant (self or partner) at any time during the study. A urinary pregnancy test will be done on all females. If test is positive, the subject will be excluded.

    • Women with history of hormone replacement therapy within the past 6 months

    • History of rheumatoid arthritis, Grave's disease, systemic lupus erythematosis, and Wegener's granulomatosis;

    • Taking medications for diabetes mellitus, kidney disease, liver disease, asthma, sepsis or seizure disorders;

    • Taking lipid lowering (e.g., statins, niacin), glycemic control (e.g. metformin, insulin), anticoagulation, anti-seizure, anti-depression or antipsychotic agents

    • History of co-morbid condition that would limit life expectancy to < 6 months.

    • It is unknown if Salsalate is transferred in seminal fluid of men. However, it is recommended that proper protection such as a condom be used during intercourse during the study.

    • Concomitant treatment with: aspirin, baby aspirin, indomethacin, naproxen (Aleve), acetaminophen (Tylenol), ibuprofen (Advil, Motrin), any other non-steroidal anti-inflammatory drugs; cox-2 inhibitors (Celebrex, Vioxx, etc); allopurinol (Zyloprim, Lopurin, Allopurin; coumadin (Warfarin), enoxaparin (Lovenox); clopidogrel (Plavix); dipyridamole (Persantine); heparin; diabetic medications (Metformin, glyburide, insulin, etc), thiazolidinediones (Avandia, Rezulin, Actos); corticosteroids (prednisone); methotrexate, infliximab (Remicade), etanercept (Enbrel); levothyroxine (Levoxyl, Synthroid, Levoxyl, Unithroid); Levodopa; Phosphodiesterase (PDE) 5 inhibitors (e.g., Viagra®, Cialis®, Levitra®, or Revatio®); PDE 3 inhibitors (e.g., cilostazol, milrinone, or vesnarinone); lithium

    • May participate if use of the following medications are discontinued 2 weeks prior to participation: salicylate medications, aspirin, antioxidants, herbal supplements, vitamins, omega-3 fatty acids; cox-2 inhibitors (Celebrex, Vioxx, etc)

    • May participate if no use of the following medications in the 48 hours prior to experimental visits: naproxen (Aleve), acetaminophen (Tylenol), ibuprofen (Advil, Motrin), other any non-steroidal anti-inflammatory drugs

    • Vulnerable populations (prisoners, etc.) are not included in this study because we are studying healthy middle-aged/older adults.

    • Any condition that, in the view of the PI, places the subject at high risk of poor treatment compliance or of not completing the study.

    • Hemoglobin <12 mg/dl for men; < 10 mg/dl for women

    • History of alcohol abuse or >10 alcoholic units per week (1 unit= 1 beer, 1 glass of wine, 1 mixed cocktail containing 1 oz alcohol)

    • Low platelets (<100,000 cu mm)

    • On weight loss drugs (e.g., Xenical (orlistat), Meridia (sibutramine), Acutrim (phenylpropanol-amine), or similar over-the-counter medications) within 3 months of screening

    • Any surgery within 30 days of screening

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 University of Iowa Iowa City Iowa United States 52242

    Sponsors and Collaborators

    • Gary L. Pierce

    Investigators

    • Principal Investigator: Gary L Pierce, PhD, University of Iowa

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    Responsible Party:
    Gary L. Pierce, Assistant Professor, University of Iowa
    ClinicalTrials.gov Identifier:
    NCT01775865
    Other Study ID Numbers:
    • 201201739
    First Posted:
    Jan 25, 2013
    Last Update Posted:
    May 31, 2018
    Last Verified:
    Apr 1, 2018
    Individual Participant Data (IPD) Sharing Statement:
    Undecided
    Plan to Share IPD:
    Undecided
    Keywords provided by Gary L. Pierce, Assistant Professor, University of Iowa
    aortic stiffness
    endothelium-dependent dilation
    vascular aging
    oxidative stress
    inflammation
    nitric oxide
    nuclear factor kappa B
    Additional relevant MeSH terms:
    Inflammation
    Salicylsalicylic acid
    Sodium Salicylate

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail A total of 59 participants were consented/enrolled. A total of 13 were excluded or lost to follow up after consent (n=8 did not meet inclusion criteria after screening; n=1 lost to follow up; n=1 time committment; n=1 moved out of state; n=2 other).
    Arm/Group Title Salsalate Placebo Young Control
    Arm/Group Description Salsalate capsule 1.5 g twice per day by mouth for 4 weeks Salsalate Placebo capsule twice per day by mouth for 4 weeks Placebo (for salsalate) No intervention; Baseline measurements only, participants not randomized
    Period Title: Overall Study
    STARTED 14 14 17
    COMPLETED 11 13 17
    NOT COMPLETED 3 1 0

    Baseline Characteristics

    Arm/Group Title Salsalate Placebo Young Control Total
    Arm/Group Description Salsalate capusule 1.5 g twice per day by mouth for 4 weeks Placebo capsule twice per day by mouth for 4 weeks No intervention, not randomized; Baseline measurements only Total of all reporting groups
    Overall Participants 14 14 17 45
    Age (Years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Years]
    60.6
    (7.4)
    55.8
    (5.3)
    26.2
    (5.2)
    48.1
    (16.8)
    Sex: Female, Male (Count of Participants)
    Female
    8
    57.1%
    9
    64.3%
    7
    41.2%
    24
    53.3%
    Male
    6
    42.9%
    5
    35.7%
    10
    58.8%
    21
    46.7%

    Outcome Measures

    1. Primary Outcome
    Title Carotid-femoral Pulse Wave Velocity (CFPWV)
    Description Aortic stiffness
    Time Frame Change in CFPWV from baseline at 4 weeks

    Outcome Measure Data

    Analysis Population Description
    After baseline measurements, there were 3 dropouts in salsalate group for a total of 11 completed in salsalate, and 1 dropout in the placebo group for a total of 13 completed in placebo.
    Arm/Group Title Salsalate Placebo Young Control Group
    Arm/Group Description Received 4 weeks of daily oral salsalate Received 4 weeks of placebo No Intervention; Baseline measurements only, participants not randomized
    Measure Participants 14 14 17
    Baseline
    831.3
    (45.3)
    785.1
    (41.1)
    538.0
    (17.9)
    4 weeks
    839.6
    (66.4)
    740.01
    (45.6)
    NA
    (NA)
    2. Secondary Outcome
    Title Brachial Artery Flow-mediated Dilation (FMD)
    Description Endothelial function
    Time Frame Change from baseline brachial artery FMD at 4 weeks

    Outcome Measure Data

    Analysis Population Description
    After baseline measurements, there were 3 dropouts in salsalate group and 1 FMD that was not able to be anayzed (poor image quality) for a total of 10 in salsalate for FMD. There was 1 dropout in the placebo group and 2 FMDs not analyzed (poor image quality) for a total of 11 analyzed in placebo for FMD.
    Arm/Group Title Salsalate Placebo Young Control Group
    Arm/Group Description Salsalate capsule 1.5 g twice per day by mouth for 4 weeks Placebo capsule twice per day by mouth for 4 weeks No intervention; Baseline measurements only; participants not randomized
    Measure Participants 14 14 17
    Baseline
    3.49
    (1.05)
    3.57
    (1.14)
    5.88
    (0.97)
    4 Weeks
    4.60
    (1.24)
    2.50
    (1.32)
    NA
    (NA)
    3. Other Pre-specified Outcome
    Title Tissue Doppler Left Ventricular Relaxation Velocity (E')
    Description Left ventricular diastolic dysfunction
    Time Frame Change from baseline E' at 4 weeks

    Outcome Measure Data

    Analysis Population Description
    Data were not obtained because cardiac echos could not be performed in participants because of lack of equipment
    Arm/Group Title Salsalate Placebo Young Control Group
    Arm/Group Description Salsalate capsule 1.5 g twice per day by mouth for 4 weeks Placebo capsules twice per day by mouth for 4 weeks No intervention; Baseline measurements only, participants not randomized
    Measure Participants 0 0 0

    Adverse Events

    Time Frame
    Adverse Event Reporting Description
    Arm/Group Title Salsalate Placebo Young Control Group
    Arm/Group Description Salsalate 1.5 g twice per day by mouth for 4 weeks Placebo capusule twice per day by mouth for 4 weeks No intervention; Baseline measurements only; Participants not randomized
    All Cause Mortality
    Salsalate Placebo Young Control Group
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/14 (0%) 0/14 (0%) 0/17 (0%)
    Serious Adverse Events
    Salsalate Placebo Young Control Group
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/14 (0%) 0/14 (0%) 0/17 (0%)
    Other (Not Including Serious) Adverse Events
    Salsalate Placebo Young Control Group
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 1/14 (7.1%) 1/14 (7.1%) 0/17 (0%)
    Eye disorders
    Allergic reaction 0/14 (0%) 0 1/14 (7.1%) 1 0/17 (0%) 0
    Hepatobiliary disorders
    Elevated AST/ALT 1/14 (7.1%) 1 0/14 (0%) 0 0/17 (0%) 0

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    All Principal Investigators ARE employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Gary Pierce
    Organization University of Iowa
    Phone 319-335-9487
    Email gary-pierce@uiowa.edu
    Responsible Party:
    Gary L. Pierce, Assistant Professor, University of Iowa
    ClinicalTrials.gov Identifier:
    NCT01775865
    Other Study ID Numbers:
    • 201201739
    First Posted:
    Jan 25, 2013
    Last Update Posted:
    May 31, 2018
    Last Verified:
    Apr 1, 2018