Targeting Inflammation to Treat Cardiovascular Aging (TIVA)

This study is currently recruiting participants. (see Contacts and Locations)
Verified January 2013 by University of Iowa
Sponsor:
Information provided by (Responsible Party):
University of Iowa
ClinicalTrials.gov Identifier:
NCT01775865
First received: January 4, 2013
Last updated: January 22, 2013
Last verified: January 2013
  Purpose

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 (the large blood vessel that leaves the heart and supplies blood to the body). 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 (fluctuations in blood pressure through the day), 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 cellular production of 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 typically 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 Intervention Phase
Vascular Stiffness
Endothelial Dysfunction
Diastolic Dysfunction
Drug: Salsalate
Drug: Placebo (for salsalate)
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Targeting Inflammation to Treat Cardiovascular Aging in Humans (TIVA Study)

Resource links provided by NLM:


Further study details as provided by University of Iowa:

Primary Outcome Measures:
  • Carotid-femoral pulse wave velocity (CFPWV) [ Time Frame: Change from baseline CFPWV at 4 weeks ] [ Designated as safety issue: No ]
    Aortic stiffness


Secondary Outcome Measures:
  • Brachial artery flow-mediated dilation (FMD) [ Time Frame: Change from baseline brachial artery FMD at 4 weeks ] [ Designated as safety issue: No ]
    Vascular endothelium-dependent dilation


Other Outcome Measures:
  • Tissue doppler left ventricular relaxation velocity (E') [ Time Frame: Change from baseline E' at 4 weeks ] [ Designated as safety issue: No ]
    Left ventricular diastolic dysfunction


Estimated Enrollment: 48
Study Start Date: September 2012
Estimated Primary Completion Date: September 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Salsalate
Salsalate capsule 1.5 g/day twice per day by mouth for 4 weeks
Drug: 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)
Other Name: Placebo capsule sugar pill to mimic salsalate

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.

  Eligibility

Ages Eligible for Study:   50 Years to 79 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01775865

Contacts
Contact: Veronica Howsare 319-337-5677 veronica-howsare@uiowa.edu

Locations
United States, Iowa
University of Iowa Recruiting
Iowa City, Iowa, United States, 52242
Contact: Veronica Howsare    319-467-5677    veronica-howsare@uiowa.edu   
Principal Investigator: Gary L Pierce, PhD         
Sub-Investigator: William G Haynes, MD, PhD         
Sponsors and Collaborators
University of Iowa
Investigators
Principal Investigator: Gary L Pierce, PhD University of Iowa
  More Information

Publications:

Responsible Party: University of Iowa
ClinicalTrials.gov Identifier: NCT01775865     History of Changes
Other Study ID Numbers: 201201739
Study First Received: January 4, 2013
Last Updated: January 22, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by University of Iowa:
aortic stiffness
endothelium-dependent dilation
vascular aging
oxidative stress
inflammation
nitric oxide
nuclear factor kappa B

Additional relevant MeSH terms:
Inflammation
Pathologic Processes
Sodium Salicylate
Salicylsalicylic acid
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Pharmacologic Actions
Anti-Inflammatory Agents
Therapeutic Uses
Antirheumatic Agents
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Central Nervous System Agents

ClinicalTrials.gov processed this record on August 28, 2014