TINSAL-CVD: Targeting Inflammation Using Salsalate in CardioVascular Disease

• Sponsor: Joslin Diabetes Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00624923
• Collaborator: Beth Israel Deaconess Medical Center (Other), Tufts Medical Center (Other), National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 340
• Locations: 5
• Arms: 2
• Actual Duration (Months): 94
• Patients Per Site: 68
• Patients Per Site Per Month: 0.7

Study Details

Study Description

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.

Study Design

• Study Type: Interventional
• 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: Sep 1, 2008
• Actual Primary Completion Date: Jan 1, 2015
• Actual Study Completion Date: Jul 1, 2016

Arms and Interventions

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 Names: 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 Names: Placebo to Salsalate

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

1. Change in Cholesterol [Baseline to 30 mo]

   secondary

2. Change in Inflammation Marker: CRP [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 [baseline to 30 mo]

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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Locations

	Site	City	State	Country	Postal Code
1	Seacoast Cardiology	York	Maine	United States	03939
2	Joslin Diabetes Center	Boston	Massachusetts	United States	02215
3	Heart Center of Metrowest	Framingham	Massachusetts	United States	01702
4	South Shore Internal Medicine	Milton	Massachusetts	United States	02186
5	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

• 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

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Home page for Joslin Diabetes Center, Boston, MA.

Publications

• 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.
• 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. Epub 2007 Oct 24.
• 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.
• 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.
• 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.
• 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. Review.
• 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.
• 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.
• Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest. 2006 Jul;116(7):1793-801. Review. Erratum in: J Clin Invest. 2006 Aug;116(8):2308.

• Responsible Party: Joslin Diabetes Center
• ClinicalTrials.gov Identifier: NCT00624923
• Other Study ID Numbers: CHS 06-13; P50HL083813; CCI: 2006-P-00175; CHS: 06-13
• First Posted: Feb 28, 2008
• Last Update Posted: May 7, 2019
• Last Verified: Apr 1, 2019

• 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; Salicylsalicylic acid; Sodium Salicylate

Study Results

Participant Flow

Pre-assignment Detail	340 subjects signed consent and were screened for eligibility.

Arm/Group Title	1- Active Pharmacologic	2- Placebo
Arm/Group Description	Salsalate Salsalate: Salsalate, 500 mg, seven tablets daily by mouth, divided into two doses, for 30 months	Placebo Placebo: Salsalate Placebo, seven tablets daily by mouth, divided into two doses, for 30 months
Period Title: Overall Study
STARTED	127	124
COMPLETED	89	101
NOT COMPLETED	38	23

Baseline Characteristics

Arm/Group Title	1- Active Pharmacologic	2- Placebo	Total
Arm/Group Description	Salsalate Salsalate: Salsalate, 500 mg, seven tablets daily by mouth, divided into two doses, for 30 months	Placebo Placebo: Salsalate Placebo, seven tablets daily by mouth, divided into two doses, for 30 months	Total of all reporting groups
Overall Participants	127	124	251
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61.5 (6.8)	60.1 (7.2)	60.8 (7.0)
Sex: Female, Male (Count of Participants)
Female	9 7.1%	6 4.8%	15 6%
Male	118 92.9%	118 95.2%	236 94%
Region of Enrollment (participants) [Number]
United States	127 100%	124 100%	251 100%
Statin use (participants) [Number]
Number [participants]	126 99.2%	122 98.4%	248 98.8%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Intention to Treat

Arm/Group Title	1- Active Pharmacologic	2-Placebo
Arm/Group Description	Salsalate Salsalate: Salsalate, 500 mg, seven tablets daily by mouth, divided into two doses, for 30 months	Placebo Placebo: Salsalate Placebo, seven tablets daily by mouth, divided into two doses, for 30 months
Measure Participants	84	89
Mean (95% Confidence Interval) [mm^3]	0	0

2. Secondary Outcome

Title	Change in Cholesterol
Description	secondary
Time Frame	Baseline to 30 mo

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	1- Active Pharmacologic	2- Placebo
Arm/Group Description	Salsalate Salsalate: Salsalate, 500 mg, seven tablets daily by mouth, divided into two doses, for 30 months	Placebo Placebo: Placebo matched to Salsalate, seven tablets daily by mouth, divided into two doses, for 30 months
Measure Participants	127	124
Mean (95% Confidence Interval) [mg/dL]	5.1	2.0

3. Secondary Outcome

Title	Change in Inflammation Marker: CRP
Description	Secondary outcome of change in inflammation marker CRP
Time Frame	baseline to 30 mo

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	1- Active Pharmacologic	2- Placebo
Arm/Group Description	Salsalate Salsalate: Salsalate, 500 mg, seven tablets daily by mouth, divided into two doses, for 30 months	Placebo Placebo: Salsalate Placebo, seven tablets daily by mouth, divided into two doses, for 30 months
Measure Participants	127	124
Mean (95% Confidence Interval) [mg/L]	-0.1	-0.1

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	1- Active Pharmacologic	2- Placebo
Arm/Group Description	Salsalate Salsalate: Salsalate, 500 mg, seven tablets daily by mouth, divided into two doses, for 30 months	Placebo Placebo: Salsalate Placebo, seven tablets daily by mouth, divided into two doses, for 30 months
Measure Participants	127	124
Mean (95% Confidence Interval) [U/L]	-1.1	-0.6

Adverse Events

Adverse Event Reporting Description	Standard FDA definitions of AE/SAE used.
Arm/Group Title	1- Active Pharmacologic		2- Placebo
Arm/Group Description	Salsalate Salsalate: Salsalate, 500 mg, seven tablets daily by mouth, divided into two doses, for 30 months		Placebo Placebo: Salsalate Placebo, seven tablets daily by mouth, divided into two doses, for 30 months
All Cause Mortality
	1- Active Pharmacologic		2- Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	1- Active Pharmacologic		2- Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	33/127 (26%)		32/124 (25.8%)
Blood and lymphatic system disorders
Vascular	3/127 (2.4%)		2/124 (1.6%)
Cardiac disorders
Cardiac	13/127 (10.2%)		19/124 (15.3%)
Gastrointestinal disorders
Gastrointestinal	4/127 (3.1%)		6/124 (4.8%)
General disorders
General	3/127 (2.4%)		2/124 (1.6%)
Hepatobiliary disorders
Hepatobiliary	1/127 (0.8%)		1/124 (0.8%)
Infections and infestations
Infectious	3/127 (2.4%)		1/124 (0.8%)
Musculoskeletal and connective tissue disorders
Musculoskeletal	5/127 (3.9%)		4/124 (3.2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasm	1/127 (0.8%)		2/124 (1.6%)
Renal and urinary disorders
Renal	5/127 (3.9%)		0/124 (0%)
Respiratory, thoracic and mediastinal disorders
Pulmonary	2/127 (1.6%)		3/124 (2.4%)
Skin and subcutaneous tissue disorders
Dermatologic	1/127 (0.8%)		0/124 (0%)
Other (Not Including Serious) Adverse Events
	1- Active Pharmacologic		2- Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	127/127 (100%)		112/124 (90.3%)
Ear and labyrinth disorders
Ear and Labyrinth	35/127 (27.6%)		13/124 (10.5%)
Gastrointestinal disorders
Gastrointestinal	15/127 (11.8%)		9/124 (7.3%)
Mouth sores	13/127 (10.2%)		8/124 (6.5%)
General disorders
General	17/127 (13.4%)		13/124 (10.5%)
Respiratory, thoracic and mediastinal disorders
Respiratory	64/127 (50.4%)		54/124 (43.5%)
Dyspnea	21/127 (16.5%)		15/124 (12.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.