Targeting INflammation Using SALsalate in Type 2 Diabetes (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.

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.

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