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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Targeting Inflammation in Type 2 Diabetes: Clinical Trial Using Salsalate

Conditions
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Type 2 Diabetes

Intervention / Treatment
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* Drug: Salsalate
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. FPG ≤ 225 mg/dL and HbA1c>7% and ≤9.5% at screening Age ≥18 and <75 Women of childbearing potential agree to use an appropriate contraceptive method (hormonal, IUD, or diaphragm) Exclusion Criteria: Type 1 diabetes and/or history of ketoacidosis determined by medical history History of severe diabetic neuropathy including autonomic neuropathy, gastroparesis or lower limb ulceration or amputation History of long-term therapy with insulin (>30 days) within the last year Therapy with rosiglitazone (Avandia) or pioglitazone (Actos), or extendin-4 (Byetta), alone or in combination in the previous 6 months Pregnancy or lactation Patients requiring corticosteroids within 3 months or recurrent continuous oral corticosteroid treatment (more than 2 weeks) 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 Surgery within 30 days prior to screening 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. History of chronic liver disease including hepatitis B or C History of peptic ulcer or endoscopy demonstrated gastritis History of acquired immune deficiency syndrome or human immunodeficiency virus (HIV) 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 New York Heart Association Class III or IV cardiac status or hospitalization for congestive heart failure History of unstable angina, myocardial infarction, cerebrovascular accident, transient ischemic attack or any revascularization within 6 months 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) 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) Hemoglobin <12 g/dL (males), <10 g/dL (females) at screening Platelets <100,000 cu mm at screening. AST (SGOT) >2.50 x ULN or ALT (SGPT) >2.50 x ULN at screening Total Bilirubin >1.50 x ULN at screening Triglycerides (TG) >500 mg/dL at screening Poor mental function or any other reason to expect patient difficulty in complying with the requirements of the study Previous allergy to aspirin Chronic or continuous use (daily for more than 7 days) of nonsteroidal anti-inflammatory drugs within the preceding 2 months Use of warfarin (Coumadin), clopidogrel (Plavix) or other anticoagulants Use of probenecid (Benemid, Probalan), sulfinpyrazone (Anturane) or other uricosuric agents

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo, appearance matched to active drug | Drug: Placebo<br>* Placebo to Salsalate<br>* Other names: Placebo to Salsalate;|
| Active Comparator: 3 gram<br>Salsalate 3.0 grams daily, divided | Drug: Salsalate<br>* Placebo and Salsalate 3.0 g/d; 3.5 g/d; 4.0 g/d orally, divided<br>* Other names: Salicylsalicylic acid;|
| Active Comparator: 3.5 gram<br>Salsalate 3.5 g daily, divided | Drug: Salsalate<br>* Placebo and Salsalate 3.0 g/d; 3.5 g/d; 4.0 g/d orally, divided<br>* Other names: Salicylsalicylic acid;|
| Active Comparator: 4 gram<br>Salsalate 4.0 g daily, divided | Drug: Salsalate<br>* Placebo and Salsalate 3.0 g/d; 3.5 g/d; 4.0 g/d orally, divided<br>* Other names: Salicylsalicylic acid;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 2 Diabetes, Inflammation, Obesity, Metabolic Syndrome