Targeting INflammation Using SALsalate in Type 2 Diabetes (TINSAL-T2D) (TINSAL-T2D)

• ClinicalTrials.gov Identifier: NCT00392678
• Recruitment Status: Completed
• First Posted: October 26, 2006
• Results First Posted: July 26, 2013
• Last Update Posted: April 8, 2019
• Sponsor: Joslin Diabetes Center
• Collaborator: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Information provided by (Responsible Party): Joslin Diabetes Center

Study Description

Brief Summary:

Growing evidence over recent years supports a potential role for low grade chronic inflammation in the pathogenesis of insulin resistance and type 2 diabetes. In this study we will determine whether salsalate, a member of the commonly used Non-Steroidal Anti-Inflammatory Drug (NSAID) class, is effective in lowering sugars in patients with type 2 diabetes. The study will determine whether salicylates represent a new pharmacological option for diabetes management. The study is conducted in two stages. The first stage is a dose ranging study, administering salsalate compared to placebo over three months. The primary objective of Stage 2 of the study is to evaluate the effects of salsalate on blood sugar control in diabetes; the tolerability of salsalate use in patients with type 2 diabetes (T2D); and the effects of salsalate on measures of inflammation, the metabolic syndrome, and cardiac risk.

The second stage is a second trial and posted under alternate registration.

Condition or disease	Intervention/treatment	Phase
Type 2 Diabetes	Drug: Salsalate; Drug: Placebo	Phase 2; Phase 3

Detailed Description:

The primary objective of the first stage of the TINSAL-T2D trial is to select a dose of salsalate that is both well-tolerated and demonstrates a trend toward improvement in glycemic control. The trial is a multicenter, single mask lead-in, double masked placebo controlled dose ranging study, comparing salsalte to placebo over 3 months.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 277 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Targeting Inflammation in Type 2 Diabetes: Clinical Trial Using Salsalate
• Study Start Date: October 2006
• Actual Primary Completion Date: July 2008
• Actual Study Completion Date: December 2010

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: Placebo; Placebo, appearance matched to active drug	Drug: Placebo; Placebo to Salsalate; Other Name: Placebo to Salsalate
Active Comparator: 3 gram; Salsalate 3.0 grams daily, divided	Drug: Salsalate; Placebo and Salsalate 3.0 g/d; 3.5 g/d; 4.0 g/d orally, divided; Other Names: Disalcid; Salicylsalicylic acid
Active Comparator: 3.5 gram; Salsalate 3.5 g daily, divided	Drug: Salsalate; Placebo and Salsalate 3.0 g/d; 3.5 g/d; 4.0 g/d orally, divided; Other Names: Disalcid; Salicylsalicylic acid
Active Comparator: 4 gram; Salsalate 4.0 g daily, divided	Drug: Salsalate; Placebo and Salsalate 3.0 g/d; 3.5 g/d; 4.0 g/d orally, divided; Other Names: Disalcid; Salicylsalicylic acid

Outcome Measures

Primary Outcome Measures :

1. Change in HbA1c Baseline to End of Trial in TINSAL-T2D Stage 1 [ Time Frame: 14 week ]
   The primary outcome for the TINSAL-T2D study is change in HbA1c level from baseline to week 14 (stage 1) in the intent-to-treat (ITT) population with last observation carried forward.

Secondary Outcome Measures :

1. Change in HbA1c [ Time Frame: 14 week ]
   Change from baseline to either 14 or 26 weeks, or last HbA1c measurement prior to rescue therapy
2. Change From Baseline and Trends in Fasting Glucose Over Time [ Time Frame: 14 week ]
3. Change in Lipids [ Time Frame: 14 week ]

   Change in lipids (low-density lipoprotein cholesterol [LDL-C], non-high-density lipoprotein cholesterol [non-HDL-C], triglycerides [TG], total cholesterol [TC], high-density lipoprotein cholesterol [HDL C], TC/HDL-C ratio, and LDL-C/HDL-C ratio)

   LDL-C/HDL-C ratio not calculated

4. Change From Baseline in 14-week Insulin, C-peptide, Homeostasis Model [HOMA] Index [ Time Frame: Baseline, week 14 ]
   HOMA-IR was not calcuated due to potential confounding effect of salicylates to inhibit insulin clearance. Change in insulin from Baseline to Week 14 in data table below.
5. Safety and Tolerability [ Time Frame: 14 weeks ]
   See adverse event module for details. Safety and tolerability of salsalate compared to placebo as assessed by adverse events.
6. Change in Insulin, C-peptide, Homeostasis Model [HOMA] Index [ Time Frame: Baseline, week 14 ]
   HOMA-IR was not calcuated due to potential confounding effect of salicylates to inhibit insulin clearance. Change in C-peptide from Baseline to Week 14 is in the data table below

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Type 2 diabetes on diet and exercise therapy or monotherapy with metformin, insulin secretagogue, or alpha-glucosidase inhibitors, or a low-dose combination of these at ≤ 50% maximal dose (see Appendix). Dosing is stable for 8 weeks prior to randomization.
2. FPG ≤ 225 mg/dL and HbA1c>7% and ≤9.5% at screening
3. Age ≥18 and <75
4. Women of childbearing potential agree to use an appropriate contraceptive method (hormonal, IUD, or diaphragm)

Exclusion Criteria:

1. Type 1 diabetes and/or history of ketoacidosis determined by medical history
2. History of severe diabetic neuropathy including autonomic neuropathy, gastroparesis or lower limb ulceration or amputation
3. History of long-term therapy with insulin (>30 days) within the last year
4. Therapy with rosiglitazone (Avandia) or pioglitazone (Actos), or extendin-4 (Byetta), alone or in combination in the previous 6 months
5. Pregnancy or lactation
6. Patients requiring corticosteroids within 3 months or recurrent continuous oral corticosteroid treatment (more than 2 weeks)
7. Use of weight loss drugs [e.g., Xenical (orlistat), Meridia (sibutramine), Acutrim (phenylpropanol-amine), or similar over-the-counter medications] within 3 months of screening or intentional weight loss of ≥ 10 lbs in the previous 6 months
8. Surgery within 30 days prior to screening
9. Serum creatinine >1.4 for women and >1.5 for men or eGFR <60 [possible chronic kidney disease stage 3 or greater calculated using the Modification of Diet in Renal Disease (MDRD) equation.
10. History of chronic liver disease including hepatitis B or C
11. History of peptic ulcer or endoscopy demonstrated gastritis
12. History of acquired immune deficiency syndrome or human immunodeficiency virus (HIV)
13. History of malignancy, except participants who have been disease-free for greater than 10 years, or whose only malignancy has been basal or squamous cell skin carcinoma
14. New York Heart Association Class III or IV cardiac status or hospitalization for congestive heart failure
15. History of unstable angina, myocardial infarction, cerebrovascular accident, transient ischemic attack or any revascularization within 6 months
16. Uncontrolled hypertension (defined as systolic blood pressure >150 mmHg or diastolic blood pressure >95 mmHg on three or more assessments on more than one day)
17. History of drug or alcohol abuse, or current weekly alcohol consumption >10 units/week (1 unit = 1 beer, 1 glass of wine, 1 mixed cocktail containing 1 ounce of alcohol)
18. Hemoglobin <12 g/dL (males), <10 g/dL (females) at screening
19. Platelets <100,000 cu mm at screening.
20. AST (SGOT) >2.50 x ULN or ALT (SGPT) >2.50 x ULN at screening
21. Total Bilirubin >1.50 x ULN at screening
22. Triglycerides (TG) >500 mg/dL at screening
23. Poor mental function or any other reason to expect patient difficulty in complying with the requirements of the study
24. Previous allergy to aspirin
25. Chronic or continuous use (daily for more than 7 days) of nonsteroidal anti-inflammatory drugs within the preceding 2 months
26. Use of warfarin (Coumadin), clopidogrel (Plavix) or other anticoagulants
27. Use of probenecid (Benemid, Probalan), sulfinpyrazone (Anturane) or other uricosuric agents

Contacts and Locations

Locations

United States, Connecticut

Chapel Medical Group

New Haven, Connecticut, United States, 06511

United States, District of Columbia

MedStar Research Institute

Washington, District of Columbia, United States, 20003-4393

United States, Florida

Endocrine Clinical Research

Winter Park, Florida, United States, 32746

United States, Georgia

Kaiser Permanente

Atlanta, Georgia, United States, 30084

Emory School of Medicine

Atlanta, Georgia, United States, 30303

United States, Illinois

University of Illinois at Chicago

Chicago, Illinois, United States, 60612

United States, Louisiana

Tulane University

New Orleans, Louisiana, United States, 70112

United States, Massachusetts

Joslin Diabetes Center

Boston, Massachusetts, United States, 02215

United States, Missouri

Washington University School of Medicine

Saint Louis, Missouri, United States, 63110

United States, Nebraska

University of Nebraska Medical Center

Omaha, Nebraska, United States, 68105

United States, New York

Kaleida Health Center

Buffalo, New York, United States, 14226

North Shore Diabetes and Endocrine Associates

New Hyde Park, New York, United States, 11042

Columbia University

New York, New York, United States, 10032

University of Rochester Medical Center

Rochester, New York, United States, 14642

United States, North Carolina

University of North Carolina

Chapel Hill, North Carolina, United States, 27599

United States, Texas

University of Texas Southwestern

Dallas, Texas, United States, 75390

Sponsors and Collaborators

Joslin Diabetes Center

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

• Principal Investigator: Steven E. Sheolson, MD, PhD; Joslin Diabetes Center
• Study Director: Allison B. Goldfine, MD; Joslin Diabetes Center
• Study Director: Vivian Fonseca, MD; Tulane University
• Study Director: Kathleen Jablonski, PhD; George Washington University
• Study Director: Myrlene Staten, MD; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

More Information

Additional Information:

TINSAL-T2D website 

Publications of Results:

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.

Other Publications:

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.

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, 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.

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.

• Responsible Party: Joslin Diabetes Center
• ClinicalTrials.gov Identifier: NCT00392678
• Other Study ID Numbers: CHS 06-20, NIH U01 DK74556; U01DK074556 ( U.S. NIH Grant/Contract )
• First Posted: October 26, 2006
• Results First Posted: July 26, 2013
• Last Update Posted: April 8, 2019
• Last Verified: March 2019

Keywords provided by Joslin Diabetes Center:

Type 2 Diabetes; Inflammation; Obesity; Metabolic Syndrome

Additional relevant MeSH terms:

Diabetes Mellitus; Diabetes Mellitus, Type 2; Inflammation; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Pathologic Processes; 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