Targeting Inflammation to Treat Cardiovascular Aging

NCT01775865 | Completed Phase 2 Results DMC

• 1 other identifier: 201201739
• Study Type: interventional
• Target: 59
• Locations: 1 country
• Sites: 1

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.

Conditions

Vascular Stiffness; Endothelial Dysfunction; Diastolic Dysfunction

Keywords

aortic stiffness; endothelium-dependent dilation; vascular aging; oxidative stress; inflammation; nitric oxide; nuclear factor kappa B

Outcome Measures

Primary Outcomes (1)

• Carotid-femoral Pulse Wave Velocity (CFPWV)

  Aortic stiffness

  Change in CFPWV from baseline at 4 weeks

Secondary Outcomes (1)

• Brachial Artery Flow-mediated Dilation (FMD)

  Change from baseline brachial artery FMD at 4 weeks

Other Outcomes (1)

• Tissue Doppler Left Ventricular Relaxation Velocity (E')

  Change from baseline E' at 4 weeks

Study Arms (3)

Salsalate

EXPERIMENTAL

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

Drug: Salsalate

Placebo

PLACEBO COMPARATOR

Placebo capsule twice per day by mouth for 4 weeks

Drug: Placebo (for salsalate)

Young Control

NO INTERVENTION

No intervention; Baseline measurements only

Interventions

Salsalate DRUG

4 weeks of daily salsalate

Also known as: Disalcid, Mono-Gesic, Salflex, Salsitab

Salsalate

Placebo (for salsalate) DRUG

4 week of daily placebo

Also known as: Placebo capsule sugar pill to mimic salsalate

Placebo

Eligibility Criteria

• Age: 18 Years - 79 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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;

Sponsors & Collaborators

• Gary L. Pierce: lead

Study Sites (1)

University of Iowa

Iowa City, Iowa, 52242, United States

Location

Related Publications (8)

• Goldfine AB, Silver R, Aldhahi W, Cai D, Tatro E, Lee J, Shoelson SE. Use of salsalate to target inflammation in the treatment of insulin resistance and type 2 diabetes. Clin Transl Sci. 2008 May;1(1):36-43. doi: 10.1111/j.1752-8062.2008.00026.x.

  PMID: 19337387 BACKGROUND

• Fleischman A, Shoelson SE, Bernier R, Goldfine AB. Salsalate improves glycemia and inflammatory parameters in obese young adults. Diabetes Care. 2008 Feb;31(2):289-94. doi: 10.2337/dc07-1338. Epub 2007 Oct 24.

  PMID: 17959861 BACKGROUND

• Goldfine AB, Fonseca V, Jablonski KA, Pyle L, Staten MA, Shoelson SE; TINSAL-T2D (Targeting Inflammation Using Salsalate in Type 2 Diabetes) Study Team. The effects of salsalate on glycemic control in patients with type 2 diabetes: a randomized trial. Ann Intern Med. 2010 Mar 16;152(6):346-57. doi: 10.7326/0003-4819-152-6-201003160-00004.

  PMID: 20231565 BACKGROUND

• Chai W, Liu J, Jahn LA, Fowler DE, Barrett EJ, Liu Z. Salsalate attenuates free fatty acid-induced microvascular and metabolic insulin resistance in humans. Diabetes Care. 2011 Jul;34(7):1634-8. doi: 10.2337/dc10-2345. Epub 2011 May 26.

  PMID: 21617098 BACKGROUND

• Jablonski KL, Chonchol M, Pierce GL, Walker AE, Seals DR. 25-Hydroxyvitamin D deficiency is associated with inflammation-linked vascular endothelial dysfunction in middle-aged and older adults. Hypertension. 2011 Jan;57(1):63-9. doi: 10.1161/HYPERTENSIONAHA.110.160929. Epub 2010 Nov 29.

  PMID: 21115878 BACKGROUND

• McCarty MF. Salsalate may have broad utility in the prevention and treatment of vascular disorders and the metabolic syndrome. Med Hypotheses. 2010 Sep;75(3):276-81. doi: 10.1016/j.mehy.2009.12.027. Epub 2010 Jan 18.

  PMID: 20080359 BACKGROUND

• Pierce GL, Lesniewski LA, Lawson BR, Beske SD, Seals DR. Nuclear factor-kappaB activation contributes to vascular endothelial dysfunction via oxidative stress in overweight/obese middle-aged and older humans. Circulation. 2009 Mar 10;119(9):1284-92. doi: 10.1161/CIRCULATIONAHA.108.804294. Epub 2009 Feb 23.

  PMID: 19237660 BACKGROUND

• Lesniewski LA, Durrant JR, Connell ML, Folian BJ, Donato AJ, Seals DR. Salicylate treatment improves age-associated vascular endothelial dysfunction: potential role of nuclear factor kappaB and forkhead Box O phosphorylation. J Gerontol A Biol Sci Med Sci. 2011 Apr;66(4):409-18. doi: 10.1093/gerona/glq233. Epub 2011 Feb 8.

  PMID: 21303813 BACKGROUND

MeSH Terms

Conditions

Inflammation

Interventions

salicylsalicylic acid; Sugars

Condition Hierarchy (Ancestors)

Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Carbohydrates

Results Point of Contact

• Title: Gary Pierce
• Organization: University of Iowa

gary-pierce@uiowa.edu

319-335-9487

Study Officials

• Gary L Pierce, PhD

  University of Iowa

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Assistant Professor

Study Record Dates

• First Submitted: January 4, 2013
• First Posted: January 25, 2013
• Study Start: September 1, 2012
• Primary Completion: February 1, 2016
• Study Completion: February 1, 2016
• Last Updated: May 31, 2018
• Results First Posted: May 31, 2018

Record last verified: 2018-04

Locations

US (1)