Targeting Inflammation Using Salsalate for Type 2 Diabetes-Stage II

Type 2 Diabetes Mellitus Clinical Trial

— TINSALT2D-II  

Official title:

Targeting Inflammation in Type 2 Diabetes: Clinical Trial Using Salsalate

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00799643
• Other study ID #: CHS 06-20-2
• Secondary ID: U01DK074556
• Status: Completed
• Phase: Phase 2/Phase 3
• First received: November 26, 2008
• Last updated: November 8, 2017
• Start date: November 2008

Study information

• Verified date: November 2017
• Source: Joslin Diabetes Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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. 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 638
• Est. primary completion date: September 2012
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• Inflammation
• Type 2 Diabetes Mellitus

Intervention

Drug:
• Salsalate
Salsalate 3.5 g/d orally, divided dosing
• Salsalate Placebo

Locations

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

Sponsors (2)

Lead Sponsor	Collaborator
Joslin Diabetes Center	National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Country where clinical trial is conducted

United States, 

References & Publications (5)

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. — View Citation

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; — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Change From Baseline in Fasting Glucose Over Time.		48 weeks from baseline
Secondary	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
Secondary	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
Secondary	Changes in WBC and Differential, High-sensitivity C Reactive Protein (hsCRP), Other Inflammatory Markers		24 and 48 weeks
Secondary	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
Secondary	Response Rates in Patients Initially Treated With Lifestyle Modification, Insulin Secretagogue, Metformin or Combination Therapy		24 and 48 weeks

External Links

•   description of trial for patients and medical professionals