Targeting Inflammation Using Salsalate in CardioVascular Disease (TINSAL-CVD)

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
Beth Israel Deaconess Medical Center
Tufts Medical Center
Information provided by (Responsible Party):
Allison Goldfine, Joslin Diabetes Center
ClinicalTrials.gov Identifier:
NCT00624923
First received: February 19, 2008
Last updated: July 31, 2013
Last verified: July 2013
  Purpose

The hypothesis is that western lifestyle, with sedentary behaviors and caloric excess promote a chronic, subacute inflammatory state that participates in the development and progression of atherosclerosis. We will evaluate the effects of targeting inflammation using the anti-inflammatory drug salsalate, compared to placebo, on coronary artery plaque volume assessed by multi-detector computed tomographic angiography (MDCTA). The TINSAL-CVD study is a randomized, double-masked, placebo-controlled, 2 arm, clinical trial.

The purpose of the study is to compare the effect of salsalate or placebo on sub-acute inflammation and coronary plaque, in people with cardiovascular disease. Participants are randomized to active intervention (salsalate) or placebo interventions for a period of 30 months. The primary endpoint is change in plaque volume in the coronary arteries assessed by MDCTA from baseline to 30 months.


Condition Intervention Phase
Coronary Artery Disease
Overweight
Drug: Salsalate
Drug: Placebo
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Targeting Inflammation Using Salsalate in CardioVascular Disease (TINSAL-CVD)

Resource links provided by NLM:


Further study details as provided by Joslin Diabetes Center:

Primary Outcome Measures:
  • Change in soft plaque volume in the coronary arteries assessed by MDCTA from baseline to 30 months [ Time Frame: 30 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Improvement in the metabolic syndrome assessed by measures by waist/hip ratio, systolic and diastolic blood pressure, lipid profiles (total cholesterol, triglycerides, HDL and LDL), and abdominal adiposity quantitated by computerized tomography [ Time Frame: 30 mo ] [ Designated as safety issue: No ]
  • Reduction of mediators of inflammation in the circulation (such as CRP), and markers of oxidative stress. [ Time Frame: 30 mo ] [ Designated as safety issue: No ]
  • Reduction of insulin resistance assessed by fasting insulin and homeostasis model assessment of insulin resistance (HOMA-IR). [ Time Frame: 30 mo ] [ Designated as safety issue: No ]
  • Reduction of inflammation in the liver associated with nonalcoholic steatohepatitis (NASH), and reduction of fatty liver quantitated by computerized tomography and levels of AST and ALT as markers of liver inflammation related to NASH. [ Time Frame: 30 mo ] [ Designated as safety issue: No ]
  • Comparison of rates of addition of anti-hypertensive, diabetic, or lipid lowering medication. [ Time Frame: 30 mo ] [ Designated as safety issue: No ]
  • Comparison of numbers of persons with metabolic syndrome who progress to diabetes between groups. [ Time Frame: 30 mo ] [ Designated as safety issue: No ]
  • Comparison of numbers of persons who regress from ATPIII metabolic syndrome criteria (for those with metabolic syndrome at baseline) [ Time Frame: 30 mo ] [ Designated as safety issue: No ]
  • Relationship between vitamin D status and coronary calcification, as well as with insulin resistance (HOMA-IR), beta-cell function (HOMA-%beta), and serum levels of inflammatory cytokines and adhesion molecules, known to be related to CVD risk. [ Time Frame: Baseline evaluation ] [ Designated as safety issue: No ]
  • Determination of whether baseline vitamin D levels predict clinical response to salsalate, and whether hypovitaminosis D is associated with plaque progression. [ Time Frame: 30 mo ] [ Designated as safety issue: No ]

Estimated Enrollment: 278
Study Start Date: September 2008
Estimated Primary Completion Date: January 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1- Active Pharmacologic
Salsalate
Drug: Salsalate
Salsalate, 500 mg, seven tablets daily by mouth, divided into two doses, for 30 months
Other Name: Disalcid
Placebo Comparator: 2
Placebo
Drug: Salsalate
Salsalate, 500 mg, seven tablets daily by mouth, divided into two doses, for 30 months
Other Name: Disalcid
Drug: Placebo
Salsalate Placebo, seven tablets daily by mouth, divided into two doses, for 30 months

  Eligibility

Ages Eligible for Study:   21 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Eligibility will be based upon the presence of established coronary artery disease including

  • previous myocardial infarction (≥6 months ago), or
  • previous coronary bypass surgery (> 12 months ago), or
  • stable angina, or
  • significant non-calcified plaque in at least one coronary artery, or
  • abnormal exercise tolerance test or
  • an area of reversible ischemia on nuclear imaging study or pharmacologic stress, with subsequent revascularization, or angioplasty, or
  • abnormal exercise treadmill stress test with or without nuclear imaging or echocardiography with the following exclusions:

Exclusions based on nuclear imaging:

  1. Transient cavity dilation
  2. More than one vascular territory involved with reversible defect (multiple defects)
  3. Reversible defects involving the anterior wall, septum or apex (LAD territory)

Exclusions based on echocardiography imaging:

  1. More than one vascular territory involved with inducible wall motion abnormalities (multiple defects)
  2. Inducible wall motion abnormalities involving the anterior wall, septum or apex (LAD territory)

Subjects should be at list 6 months after a myocardial infarction and/or revascularization procedure to be eligible.

In addition, subjects must be:

  1. aged 21- 75 years inclusive,
  2. BMI ≥ 27 kg/m2 and ≤ 35 kg/m2 if female and ≤ 40 kg/m2 if male (a BMI ≥24.5 for subjects from Asian origin)
  3. on a stable dose of an HMG CoA reductase inhibitor (statin) for 1 month at screening or unable to tolerate a statin,
  4. have normal renal function, (note estimated creatinine clearance calculated using Cockcroft-Gault (CG) equation ≥60 at screening [eCrCLCG (ml/min) = [(140 - age) x weight (kg)]/[SCr(mg/dl) x 72] x [0.85 if female],
  5. have liver function (ALT, AST) < 3 times upper limits of normal),
  6. normal thyroid function (on stable dose replacement therapy is acceptable),
  7. if women are of child bearing potential they must have a pregnancy test prior to the CT angio and use contraception for the remainder of the study
  8. patients with T2D must have a fasting glucose of ≤ 200 mg/dl at screening and cannot be treated with thiazolidinedione class agents or insulin or Extendin-4 (Byetta) therapy.

Subjects must be willing to have at least three visits at the Beth Israel-Deaconess Medical Center/Joslin Diabetes Center with a baseline and a 30-month follow-up series of imaging studies including CT angiography of the coronary arteries and imaging of the aorta, abdominal adiposity and liver, and interim visit at 1 year.

Exclusion Criteria:

  1. Unstable angina (increase in frequency or severity of anginal episodes or development of chest pain at rest)
  2. significant obstructive disease (≥ 70%) in left main coronary artery, ostial LAD or three-vessel disease by MDCTA
  3. Significant heart failure (NYHA class III and IV)
  4. Current atrial fibrillation or Wolf-Parkinson-White (WPW) syndrome
  5. Allergy to beta-blocker in subjects with resting heart rate > 65 bpm
  6. Systolic blood pressure > 160 mm Hg
  7. Diastolic BP > 100 mm Hg
  8. Persons with allergies to contrast material
  9. History of asthma if unable to tolerate beta blocker
  10. Allergy to iodinated contrast material or shellfish
  11. Allergy to nitroglycerin
  12. BMI > 35 kg/m2 if female and > 40 kg/m2 if male
  13. Body weight > 350 lbs
  14. Use of drugs for weight loss [e.g. Xenical (orlistat), Meridia (sibutramine), Acutrim (phenylpropanolamine) or similar over-the counter medications] within three months of screening
  15. Surgery within 30 days of screening
  16. History of acquired immune deficiency syndrome or human immunodeficiency virus (HIV)
  17. Poor mental function or history of dementia/ Alzheimer's Disease or on medications used for treatment of dementia [e.g. Tacrine (Cognex), Rivastigmine (Exelon), Galantamine (Razadyne, Reminyl), Donepezil (Aricept), Memantine (Namenda)] or any other reason to expect patient difficulty in complying with the requirements of the study
  18. Medicine for erectile dysfunction within 72 hours prior to MDCTA
  19. History of significant chronic rheumatologic or other chronic inflammatory disease (including foot ulcers)
  20. Prior hemorrhagic stroke
  21. persons with known aspirin allergy
  22. Use of continuous oral corticosteroid treatment (more than 2 weeks), or patients requiring corticosteroids within 3 months
  23. Anti-diabetic medication including thiazolidinedione (pioglitazone or rosiglitazone), or insulin or Extendin-4 (Byetta)
  24. History of peptic ulcer or gastritis within 5 years
  25. Positive stool guaiac
  26. Hemoglobin 2 standard deviations below normal
  27. Low platelet count (2 standard deviations below normal)
  28. Known bleeding disorder
  29. Coumadin (warfarin compounds)
  30. History of type 1 diabetes and/or history of ketoacidosis
  31. Daily use of NSAIDS (including salsalate) for arthritis
  32. History of malignancy, except subjects who have been disease-free for greater than 5 years, or whose only malignancy has been basal or squamous cell skin carcinoma
  33. History of drug or alcohol abuse, or current weekly alcohol consumption >14 units/week (1 unit = 1 beer, 1 glass of wine, 1 mixed cocktail containing 1 ounce of alcohol)
  34. Use of probenecid (Benemid, Probalan), sulfinpyrazone (Anturane) or other uricosuric agents
  35. Chronic tinnitus.
  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: NCT00624923

Locations
United States, Maine
Seacoast Cardiology
York, Maine, United States
United States, Massachusetts
Joslin Diabetes Center
Boston, Massachusetts, United States
Heart Center of Metrowest
Framingham, Massachusetts, United States, 01702
South Shore Internal Medicine
Milton, Massachusetts, United States
Newton-Wellesley Cardiology
Newton, Massachusetts, United States
Sponsors and Collaborators
Allison Goldfine
Beth Israel Deaconess Medical Center
Tufts Medical Center
Investigators
Study Director: Francine Welty, MD Beth Israel Deaconess Medical Center
Principal Investigator: Allison B. Goldfine, MD Joslin Diabetes Center
Principal Investigator: Ernest Schaefer, MD Tufts Medical Center
Principal Investigator: Melvin Clouse, MD Beth Israel Deaconess Medical Center
Principal Investigator: Steven E. Shoelson, MD, PhD Joslin Diabetes Center
  More Information

Additional Information:
Publications:
Goldfine AB, Silver S, 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, Clinical and Translational Science, 2008 May;1(1):36-43

Responsible Party: Allison Goldfine, Principal Investigator, TINSAL-CVD, Joslin Diabetes Center
ClinicalTrials.gov Identifier: NCT00624923     History of Changes
Other Study ID Numbers: CHS 06-13, NHLBI: P50 HL083813;, CCI: 2006-P-00175, CHS: 06-13
Study First Received: February 19, 2008
Last Updated: July 31, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Joslin Diabetes Center:
Coronary Artery Disease
Inflammation
Overweight
Metabolic Syndrome
Salsalate

Additional relevant MeSH terms:
Cardiovascular Diseases
Coronary Artery Disease
Myocardial Ischemia
Coronary Disease
Inflammation
Overweight
Heart Diseases
Arteriosclerosis
Arterial Occlusive Diseases
Vascular Diseases
Pathologic Processes
Body Weight
Signs and Symptoms
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 July 22, 2014