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

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ClinicalTrials.gov Identifier: NCT00624923
Recruitment Status : Completed
First Posted : February 28, 2008
Results First Posted : December 12, 2017
Last Update Posted : May 7, 2019
Sponsor:
Collaborators:
Beth Israel Deaconess Medical Center
Tufts Medical Center
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Joslin Diabetes Center

Brief Summary:

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 or disease Intervention/treatment Phase
Coronary Artery Disease Overweight Drug: Salsalate Drug: Placebo Phase 2 Phase 3

Detailed Description:

OBJECTIVE:

To determine whether targeting inflammation using salsalate compared with placebo reduces progression of noncalcified coronary artery plaque.

DESIGN, SETTING, AND PARTICIPANTS:

In the Targeting Inflammation Using Salsalate in Cardiovascular Disease (TINSAL-CVD) trial participants were randomly assigned to 30 months of salsalate or placebo in addition to standard, guideline-based therapies. Randomization was computerized and centrally allocated, with patients, health care professionals, and researchers masked to treatment assignment. Participants were overweight and obese statin-using patients with established, stable coronary heart disease.

INTERVENTIONS:

Salsalate (3.5 g/d) or placebo orally over 30 months.

MAIN OUTCOMES AND MEASURES:

The primary outcome was progression of noncalcified coronary artery plaque assessed by multidetector computed tomographic angiography. Secondary outcomes were other measures of safety and efficacy.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 340 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Targeting Inflammation Using Salsalate in CardioVascular Disease (TINSAL-CVD)
Actual Study Start Date : September 2008
Actual Primary Completion Date : January 2015
Actual Study Completion Date : July 2016

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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
Placebo
Drug: Placebo
Placebo matched to Salsalate, seven tablets daily by mouth, divided into two doses, for 30 months
Other Name: Placebo to Salsalate




Primary Outcome Measures :
  1. Change in Non-calcified Plaque Volume in the Coronary Arteries Assessed by MDCTA From Baseline to 30 Months [ Time Frame: Baseline to 30 months ]

Secondary Outcome Measures :
  1. Change in Cholesterol [ Time Frame: Baseline to 30 mo ]
    secondary

  2. Change in Inflammation Marker: CRP [ Time Frame: baseline to 30 mo ]
    Secondary outcome of change in inflammation marker CRP

  3. Change in Inflammation in the Liver Associated With Nonalcoholic Steatohepatitis (NASH), ALT [ Time Frame: baseline to 30 mo ]
    Secondary outcome, change in liver inflammation associated with NASH: ALT



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Ages Eligible for Study:   21 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00624923


Locations
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United States, Maine
Seacoast Cardiology
York, Maine, United States, 03939
United States, Massachusetts
Joslin Diabetes Center
Boston, Massachusetts, United States, 02215
Heart Center of Metrowest
Framingham, Massachusetts, United States, 01702
South Shore Internal Medicine
Milton, Massachusetts, United States, 02186
Newton-Wellesley Cardiology
Newton, Massachusetts, United States, 02462
Sponsors and Collaborators
Joslin Diabetes Center
Beth Israel Deaconess Medical Center
Tufts Medical Center
National Heart, Lung, and Blood Institute (NHLBI)
Investigators
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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

Additional Information:
Publications of Results:
Other Publications:

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Responsible Party: Joslin Diabetes Center
ClinicalTrials.gov Identifier: NCT00624923     History of Changes
Other Study ID Numbers: CHS 06-13
P50HL083813 ( U.S. NIH Grant/Contract )
CCI: 2006-P-00175 ( Other Identifier: Beth Israel Deaconess Medical Center, Boston, MA, USA )
CHS: 06-13 ( Other Identifier: Joslin Diabetes Center, Boston, MA, USA )
First Posted: February 28, 2008    Key Record Dates
Results First Posted: December 12, 2017
Last Update Posted: May 7, 2019
Last Verified: April 2019

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

Additional relevant MeSH terms:
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Inflammation
Cardiovascular Diseases
Coronary Artery Disease
Myocardial Ischemia
Coronary Disease
Overweight
Pathologic Processes
Heart Diseases
Arteriosclerosis
Arterial Occlusive Diseases
Vascular Diseases
Body Weight
Signs and Symptoms
Salicylsalicylic acid
Sodium Salicylate
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action