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

April 29, 2019 updated by: Joslin Diabetes Center

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

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.

Study Overview

Status

Completed

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

340

Phase

  • Phase 2
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • Maine
      • York, Maine, United States, 03939
        • Seacoast Cardiology
    • Massachusetts
      • Boston, Massachusetts, United States, 02215
        • Joslin Diabetes Center
      • Framingham, Massachusetts, United States, 01702
        • Heart Center of Metrowest
      • Milton, Massachusetts, United States, 02186
        • South Shore Internal Medicine
      • Newton, Massachusetts, United States, 02462
        • Newton-Wellesley Cardiology

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

21 years to 75 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: PREVENTION
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: QUADRUPLE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: 1- Active Pharmacologic
Salsalate
Salsalate, 500 mg, seven tablets daily by mouth, divided into two doses, for 30 months
Other Names:
  • Disalcid
PLACEBO_COMPARATOR: 2- Placebo
Placebo
Placebo matched to Salsalate, seven tablets daily by mouth, divided into two doses, for 30 months
Other Names:
  • Placebo to Salsalate

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Change in Non-calcified Plaque Volume in the Coronary Arteries Assessed by MDCTA From Baseline to 30 Months
Time Frame: Baseline to 30 months
Baseline to 30 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in Cholesterol
Time Frame: Baseline to 30 mo
secondary
Baseline to 30 mo
Change in Inflammation Marker: CRP
Time Frame: baseline to 30 mo
Secondary outcome of change in inflammation marker CRP
baseline to 30 mo
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
baseline to 30 mo

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Study Director: Francine Welty, MD, Beth Israel Deaconess Medical Center
  • Principal Investigator: Ernest Schaefer, MD, Tufts Medical Center
  • Principal Investigator: Melvin Clouse, MD, Beth Israel Deaconess Medical Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

September 1, 2008

Primary Completion (ACTUAL)

January 1, 2015

Study Completion (ACTUAL)

July 1, 2016

Study Registration Dates

First Submitted

February 19, 2008

First Submitted That Met QC Criteria

February 27, 2008

First Posted (ESTIMATE)

February 28, 2008

Study Record Updates

Last Update Posted (ACTUAL)

May 7, 2019

Last Update Submitted That Met QC Criteria

April 29, 2019

Last Verified

April 1, 2019

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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