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Coronary Artery DiseasePhase 2/3TINSAL-CVDNCT00624923

Targeting Inflammation Using Salsalate in CardioVascular Disease

A Phase 2/3 study testing Salsalate in people with Coronary Artery Disease and Overweight, run by Joslin Diabetes Center at 5 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 21 to 75 years
Conditions the study is for
Coronary Artery Disease, Overweight
What is being tested?
Salsalate
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
340 participants
Where
5 sitesUnited States
Study dates
Sep 2008to Jul 2016
Phase
Phase 2/3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 21 to 75 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
Show all 26Show fewer
  • 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:
  • Transient cavity dilation
  • More than one vascular territory involved with reversible defect (multiple defects)
  • Reversible defects involving the anterior wall, septum or apex (LAD territory)
  • Exclusions based on echocardiography imaging:
  • More than one vascular territory involved with inducible wall motion abnormalities (multiple defects)
  • 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:
  • aged 21- 75 years inclusive,
  • 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)
  • on a stable dose of an HMG CoA reductase inhibitor (statin) for 1 month at screening or unable to tolerate a statin,
  • 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],
  • have liver function (ALT, AST) < 3 times upper limits of normal),
  • normal thyroid function (on stable dose replacement therapy is acceptable),
  • 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
  • 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.

Who cannot join

  • Unstable angina (increase in frequency or severity of anginal episodes or development of chest pain at rest)
  • significant obstructive disease (≥ 70%) in left main coronary artery, ostial LAD or three-vessel disease by MDCTA
  • Significant heart failure (NYHA class III and IV)
  • Current atrial fibrillation or Wolf-Parkinson-White (WPW) syndrome
  • Allergy to beta-blocker in subjects with resting heart rate > 65 bpm
  • Systolic blood pressure > 160 mm Hg
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  • Diastolic BP > 100 mm Hg
  • Persons with allergies to contrast material
  • History of asthma if unable to tolerate beta blocker
  • Allergy to iodinated contrast material or shellfish
  • Allergy to nitroglycerin
  • BMI > 35 kg/m2 if female and > 40 kg/m2 if male
  • Body weight > 350 lbs
  • 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
  • Surgery within 30 days of screening
  • History of acquired immune deficiency syndrome or human immunodeficiency virus (HIV)
  • 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
  • Medicine for erectile dysfunction within 72 hours prior to MDCTA
  • History of significant chronic rheumatologic or other chronic inflammatory disease (including foot ulcers)
  • Prior hemorrhagic stroke
  • persons with known aspirin allergy
  • Use of continuous oral corticosteroid treatment (more than 2 weeks), or patients requiring corticosteroids within 3 months
  • Anti-diabetic medication including thiazolidinedione (pioglitazone or rosiglitazone), or insulin or Extendin-4 (Byetta)
  • History of peptic ulcer or gastritis within 5 years
  • Positive stool guaiac
  • Hemoglobin 2 standard deviations below normal
  • Low platelet count (2 standard deviations below normal)
  • Known bleeding disorder
  • Coumadin (warfarin compounds)
  • History of type 1 diabetes and/or history of ketoacidosis
  • Daily use of NSAIDS (including salsalate) for arthritis
  • 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
  • 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)
  • Use of probenecid (Benemid, Probalan), sulfinpyrazone (Anturane) or other uricosuric agents
  • Chronic tinnitus.

Trial locations and contacts

5 sites in 1 country.

5 sites in 1 country

United States5 sites

  • Joslin Diabetes Center

    Boston, Massachusetts, 02215

  • Heart Center of Metrowest

    Framingham, Massachusetts, 01702

  • South Shore Internal Medicine

    Milton, Massachusetts, 02186

  • Newton-Wellesley Cardiology

    Newton, Massachusetts, 02462

  • Seacoast Cardiology

    York Village, Maine, 03939

Other trials in United States

About this study

Official title: 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.

Read the 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.

Being tested
Salsalate, Placebo
Keywords
Coronary Artery Disease, Inflammation, Overweight, Metabolic Syndrome, Salsalate
Medical subject headings
Coronary Artery Disease, Overweight, Inflammation, Metabolic Syndrome

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • SalsalateDrug

    Also called Disalcid

    Salsalate, 500 mg, seven tablets daily by mouth, divided into two doses, for 30 months

  • PlaceboDrug

    Also called Placebo to Salsalate

    Placebo matched to Salsalate, seven tablets daily by mouth, divided into two doses, for 30 months

Study groups in NCT00624923
Study groupRoleWhat they receive
1- Active PharmacologicExperimentalSalsalate
Receives: Drug: Salsalate
2- PlaceboPlacebo comparatorPlacebo
Receives: Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Change in Non-calcified Plaque Volume in the Coronary Arteries Assessed by MDCTA From Baseline to 30 Months

    Measured: Baseline to 30 months

Secondary outcomes (3)

  1. Change in Cholesterol

    secondary

    Measured: Baseline to 30 mo

  2. Change in Inflammation Marker: CRP

    Secondary outcome of change in inflammation marker CRP

    Measured: baseline to 30 mo

  3. Change in Inflammation in the Liver Associated With Nonalcoholic Steatohepatitis (NASH), ALT

    Secondary outcome, change in liver inflammation associated with NASH: ALT

    Measured: baseline to 30 mo

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted28 Feb 2008 (estimated)
  2. Study startSep 2008
  3. Primary completionJan 2015
  4. Study completionJul 2016

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2/3
Primary purpose
Prevention
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
340 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00624923
Sponsor's protocol ID
CHS 06-13
Other IDs
P50HL083813, CCI: 2006-P-00175, CHS: 06-13
Acronym
TINSAL-CVD
Status last verified
Apr 2019
First submitted
19 Feb 2008
Last updated
7 May 2019
Data monitoring committee
Yes

Publications

  • Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest. 2006 Jul;116(7):1793-801. doi: 10.1172/JCI29069.

    PubMed 16823477

  • 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.

    PubMed 17959861

  • 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.

    PubMed 19337387

  • 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.

    PubMed 20231565

  • Goldfine AB, Fonseca V, Jablonski KA, Chen YD, Tipton L, Staten MA, Shoelson SE; Targeting Inflammation Using Salsalate in Type 2 Diabetes Study Team. Salicylate (salsalate) in patients with type 2 diabetes: a randomized trial. Ann Intern Med. 2013 Jul 2;159(1):1-12. doi: 10.7326/0003-4819-159-1-201307020-00003.

    PubMed 23817699

  • Goldfine AB, Conlin PR, Halperin F, Koska J, Permana P, Schwenke D, Shoelson SE, Reaven PD. A randomised trial of salsalate for insulin resistance and cardiovascular risk factors in persons with abnormal glucose tolerance. Diabetologia. 2013 Apr;56(4):714-23. doi: 10.1007/s00125-012-2819-3. Epub 2013 Jan 31.

    PubMed 23370525

  • Avadhani R, Fowler K, Barbato C, Thomas S, Wong W, Paul C, Aksakal M, Hauser TH, Weinger K, Goldfine AB. Glycemia and cognitive function in metabolic syndrome and coronary heart disease. Am J Med. 2015 Jan;128(1):46-55. doi: 10.1016/j.amjmed.2014.08.025. Epub 2014 Sep 16.

    PubMed 25220612

  • Goldfine AB, Shoelson SE. Therapeutic approaches targeting inflammation for diabetes and associated cardiovascular risk. J Clin Invest. 2017 Jan 3;127(1):83-93. doi: 10.1172/JCI88884. Epub 2017 Jan 3.

    PubMed 28045401

  • Ridker PM. Informative Neutral Studies Matter-Why the Targeting Inflammation With Salsalate in Cardiovascular Disease (TINSAL-CVD) Trial Deserves Our Attention. JAMA Cardiol. 2016 Jul 1;1(4):423-4. doi: 10.1001/jamacardio.2016.0604. No abstract available.

    PubMed 27438318

  • Hauser TH, Salastekar N, Schaefer EJ, Desai T, Goldfine HL, Fowler KM, Weber GM, Welty F, Clouse M, Shoelson SE, Goldfine AB; Targeting Inflammation Using Salsalate in Cardiovascular Disease (TINSAL-CVD) Study Team. Effect of Targeting Inflammation With Salsalate: The TINSAL-CVD Randomized Clinical Trial on Progression of Coronary Plaque in Overweight and Obese Patients Using Statins. JAMA Cardiol. 2016 Jul 1;1(4):413-23. doi: 10.1001/jamacardio.2016.0605.

    PubMed 27438317

  • Day EA, Ford RJ, Smith BK, Houde VP, Stypa S, Rehal S, Lhotak S, Kemp BE, Trigatti BL, Werstuck GH, Austin RC, Fullerton MD, Steinberg GR. Salsalate reduces atherosclerosis through AMPKbeta1 in mice. Mol Metab. 2021 Nov;53:101321. doi: 10.1016/j.molmet.2021.101321. Epub 2021 Aug 21.

    PubMed 34425254

Questions about this trial

What is this clinical trial studying?

A Phase 2/3 study testing Salsalate in people with Coronary Artery Disease and Overweight, run by Joslin Diabetes Center at 5 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 26 inclusion and 35 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 7 May 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 5 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 12 Dec 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change in Non-calcified Plaque Volume in the Coronary Arteries Assessed by MDCTA From Baseline to 30 Months (time frame: Baseline to 30 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00624923, which also lists 11 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 May 2019.

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