Targeting Inflammation Using Salsalate for Type 2 Diabetes-Stage II (TINSALT2D-II)

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. Enrollment in the first stage is complete. The primary objective of the first stage was to select a dose of salsalate that is both well-tolerated and demonstrates a trend toward improvement in glycemic control. 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.

Study Overview

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

• Study Type: Interventional
• Enrollment (Actual): 638
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States
      • University Of Alabama
  • California
    • San Diego, California, United States
      • University of California, San Diego
  • Connecticut
    • New Haven, Connecticut, United States
      • Chapel Medical Group
  • Georgia
    • Atlanta, Georgia, United States
      • Emory University School Of Medicine
    • Tucker, Georgia, United States
      • Kaiser Permanente
  • Indiana
    • Indianapolis, Indiana, United States
      • Indiana University
  • Louisiana
    • New Orleans, Louisiana, United States
      • Tulane University Health Sciences Center
  • Maryland
    • Hyattsville, Maryland, United States
      • Medstar Research Institute
    • Westminster, Maryland, United States, 21157
      • Dr. Rudo, Westminster, MD
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Joslin Diabetes Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48106
      • University of Michigan
  • Missouri
    • Saint Louis, Missouri, United States
      • Washington University School of Medicine
  • Nebraska
    • Omaha, Nebraska, United States
      • University of Nebraska Medical Center
  • New York
    • New Hyde Park, New York, United States
      • North Shore Diabetes and Endocrine Associates
    • New York, New York, United States
      • Columbia University
    • Queens, New York, United States
      • Lang Medical Center
    • The Bronx, New York, United States
      • Albert Einstein College of Medicine
  • North Carolina
    • Charlotte, North Carolina, United States
      • Carolina's Health Care
    • Durham, North Carolina, United States
      • University of North Carolina
  • Texas
    • Dallas, Texas, United States
      • University of Texas Southwestern
    • Temple, Texas, United States
      • Scott and White

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 73 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 (including SFU, non-SFU, and dipeptidyl peptidase IV (DPP-4) inhibitors), alpha-glucosidase inhibitors, or bile acid sequestrants (dosed once per day such that study drug can be administered ≥ 4 hours prior to sequestrant); or a combination of up to two of these at maximal dose. Dosing must be stable for 8 weeks prior to screening. Participant must have been diagnosed with T2D at least 8 weeks before screening.
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. No prior participation in Stage I of TINSAL-T2D ; exception: a participant who failed screening for HbA1c in Stage I will be allowed to re-screen for Stage II.
2. Type 1 diabetes and/or history of ketoacidosis determined by medical history
3. History of severe diabetic neuropathy including autonomic neuropathy, gastroparesis or lower limb ulceration or amputation
4. History of long-term therapy with insulin (>30 days) within the last year
5. Therapy with rosiglitazone (Avandia) or pioglitazone (Actos), alone or in combination in the previous 6 months; or exendin-4 (Byetta), alone or in combination in the previous 3 months
6. Pregnancy or lactation
7. Patients requiring oral corticosteroids within 3 months or recurrent continuous oral corticosteroid treatment (more than 2 weeks)
8. 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
9. Surgery within 30 days prior to screening
10. 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
11. History of chronic liver disease including hepatitis B or C
12. History of peptic ulcer or endoscopy demonstrated gastritis
13. History of acquired immune deficiency syndrome or human immunodeficiency virus (HIV)
14. 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
15. New York Heart Association Class III or IV cardiac status or hospitalization for congestive heart failure
16. History of unstable angina, myocardial infarction, cerebrovascular accident, transient ischemic attack or any revascularization within 6 months
17. 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). If on blood pressure medications, dosing should be stable for 2 weeks prior to randomization.
18. History of drug or alcohol abuse, or current weekly alcohol consumption >10 units/week (1 unit = 1 beer, 1 glass of wine, 1 mixed DCCktail containing 1 ounce of alcohol)
19. Hemoglobin <12 g/dL (males), <10 g/dL (females) at screening*
20. Platelets <100,000 cu mm at screening
21. AST (SGOT) >2.50 x ULN or ALT (SGPT) >2.50 x ULN at screening
22. Total Bilirubin >1.50 x ULN at screening
23. Triglycerides (TG) >500 mg/dL at screening
24. Poor mental function or any other reason to expect patient difficulty in complying with the requirements of the study
25. Previous allergy to aspirin
26. Chronic or continuous use (daily for more than 7 days) of nonsteroidal anti-inflammatory drugs within the preceding 2 months
27. Use of warfarin (Coumadin), clopidogrel (Plavix), dipyridamole (Persantine), heparin or other anticoagulants
28. Use of probenecid (Benemid, probalan), sulfinpyrazone (Anturane) or other uricosuric agents
29. Macroalbuminuria, defined as spot urine protein >300 mcg/mg Cr at screening
30. Pre-existing chronic tinnitus

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 1; Salsalate, 3.5 g/d orally, divided dosing	Drug: Salsalate; Salsalate 3.5 g/d orally, divided dosing; Other Names: disalsid
Placebo Comparator: 2; Salsalate Placebo, orally, divided dosing	Drug: Salsalate Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Primary Outcome for the TINSAL-T2D Study is Change in HbA1c Level From Baseline to Week 48 From Baseline, Compared Between Treatment Groups.	HbA1c (%, percentage of HbA1c) change from baseline.	48 weeks from baseline

Secondary Outcome Measures

Outcome Measure	Time Frame
Change From Baseline in Fasting Glucose Over Time.	48 weeks from baseline
Response Rates for Reduction in Fasting Glucose of ≥20 mg/dl, a Reduction in HbA1c of ≥0.5%, and a Reduction in HbA1c of ≥0.8%	24 and 48 weeks
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)	48 weeks
Changes in WBC and Differential, High-sensitivity C Reactive Protein (hsCRP), Other Inflammatory Markers	24 and 48 weeks
Response Rates for Exceeding Hyperglycemic Targets Between Active and Placebo Treated Groups; Need for Rescue Therapy; Need for Discontinuation of Study Medication	24 and 48 weeks
Response Rates in Patients Initially Treated With Lifestyle Modification, Insulin Secretagogue, Metformin or Combination Therapy	24 and 48 weeks

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; Study Director: Myrlene Staten, MD, National Institute of Diabetes & Digestive & 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, 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, 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, Buck JS, Desouza C, Fonseca V, Chen YD, Shoelson SE, Jablonski KA, Creager MA; TINSAL-FMD (Targeting Inflammation Using Salsalate in Type 2 Diabetes-Flow-Mediated Dilation) Ancillary Study Team. Targeting inflammation using salsalate in patients with type 2 diabetes: effects on flow-mediated dilation (TINSAL-FMD). Diabetes Care. 2013 Dec;36(12):4132-9. doi: 10.2337/dc13-0859. Epub 2013 Oct 15.

Study record dates

Study Major Dates

• Study Start: November 1, 2008
• Primary Completion (Actual): September 1, 2012

Study Registration Dates

• First Submitted: November 26, 2008
• First Submitted That Met QC Criteria: November 26, 2008
• First Posted (Estimate): December 1, 2008

Study Record Updates

• Last Update Posted (Actual): December 11, 2017
• Last Update Submitted That Met QC Criteria: November 8, 2017
• Last Verified: November 1, 2017

More Information

Terms related to this study

• Keywords: Inflammation; Obesity; Metabolic Syndrome; Type 2 Diabetes Mellitus (T2D); Salicylates
• 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 06-20-2; U01DK074556 (U.S. NIH Grant/Contract)