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

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