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

Targeting Inflammation in Type 2 Diabetes: Clinical Trial Using Salsalate

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.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes
• Intervention / Treatment: Drug: Placebo; Drug: Salsalate

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 Type: Interventional
• Enrollment (Actual): 277
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06511
      • Chapel Medical Group
  • District of Columbia
    • Washington, District of Columbia, United States, 20003-4393
      • Medstar Research Institute
  • Florida
    • Winter Park, Florida, United States, 32746
      • Endocrine Clinical Research
  • Georgia
    • Atlanta, Georgia, United States, 30084
      • Kaiser Permanente
    • Atlanta, Georgia, United States, 30303
      • Emory School of Medicine
  • Illinois
    • Chicago, Illinois, United States, 60612
      • University of Illinois at Chicago
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Tulane University
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Joslin Diabetes Center
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • Nebraska
    • Omaha, Nebraska, United States, 68105
      • University of Nebraska Medical Center
  • New York
    • Buffalo, New York, United States, 14226
      • Kaleida Health Center
    • New Hyde Park, New York, United States, 11042
      • North Shore Diabetes and Endocrine Associates
    • New York, New York, United States, 10032
      • Columbia University
    • Rochester, New York, United States, 14642
      • University of Rochester Medical Center
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Placebo, appearance matched to active drug	Drug: Placebo; Placebo to Salsalate; Other Names: 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in HbA1c Baseline to End of Trial in TINSAL-T2D Stage 1	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.	14 week

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in HbA1c	Change from baseline to either 14 or 26 weeks, or last HbA1c measurement prior to rescue therapy	14 week
Change From Baseline and Trends in Fasting Glucose Over Time		14 week
Change in Lipids	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	14 week
Change From Baseline in 14-week Insulin, C-peptide, Homeostasis Model [HOMA] Index	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.	Baseline, week 14
Safety and Tolerability	See adverse event module for details. Safety and tolerability of salsalate compared to placebo as assessed by adverse events.	14 weeks
Change in Insulin, C-peptide, Homeostasis Model [HOMA] Index	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	Baseline, week 14

Collaborators and Investigators

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

Publications and helpful links

General Publications

• Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest. 2006 Jul;116(7):1793-801. doi: 10.1172/JCI29069. 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. doi: 10.2337/dc07-1338. 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.
• 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.

Study record dates

Study Major Dates

• Study Start: October 1, 2006
• Primary Completion (Actual): July 1, 2008
• Study Completion (Actual): December 1, 2010

Study Registration Dates

• First Submitted: October 25, 2006
• First Submitted That Met QC Criteria: October 25, 2006
• First Posted (Estimate): October 26, 2006

Study Record Updates

• Last Update Posted (Actual): April 8, 2019
• Last Update Submitted That Met QC Criteria: March 25, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Keywords: Inflammation; Obesity; Metabolic Syndrome; Type 2 Diabetes
• Additional Relevant MeSH Terms: Pathologic Processes; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Inflammation; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Salicylsalicylic acid; Sodium Salicylate
• Other Study ID Numbers: CHS 06-20, NIH U01 DK74556; U01DK074556 (U.S. NIH Grant/Contract)