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

Phase 2

Completed

Conditions: Type 2 Diabetes

Interventions: Drug: Salsalate
Drug: Placebo

Registration Number: NCT00392678

Lead Sponsor: Joslin Diabetes Center

Brief 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. 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 277

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
3.5 gram	Salsalate	Salsalate 3.5 g daily, divided
4 gram	Salsalate	Salsalate 4.0 g daily, divided
3 gram	Salsalate	Salsalate 3.0 grams daily, divided
Placebo	Placebo	Placebo, appearance matched to active drug

Primary Outcome Measures

Name	Time	Method
Change in HbA1c Baseline to End of Trial in TINSAL-T2D Stage 1	14 week	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.

Secondary Outcome Measures

Name	Time	Method
Change in HbA1c	14 week	Change from baseline to either 14 or 26 weeks, or last HbA1c measurement prior to rescue therapy
Change From Baseline and Trends in Fasting Glucose Over Time	14 week
Change in Lipids	14 week	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
Change From Baseline in 14-week Insulin, C-peptide, Homeostasis Model [HOMA] Index	Baseline, week 14	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.
Change in Insulin, C-peptide, Homeostasis Model [HOMA] Index	Baseline, week 14	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
Safety and Tolerability	14 weeks	See adverse event module for details. Safety and tolerability of salsalate compared to placebo as assessed by adverse events.

Trial Locations

Locations (16): Endocrine Clinical Research
🇺🇸
Winter Park, Florida, United States
Kaiser Permanente
🇺🇸
Atlanta, Georgia, United States
Emory School of Medicine
🇺🇸
Atlanta, Georgia, United States
University of Illinois at Chicago
🇺🇸
Chicago, Illinois, United States
Washington University School of Medicine
🇺🇸
Saint Louis, Missouri, United States
Kaleida Health Center
🇺🇸
Buffalo, New York, United States
Columbia University
🇺🇸
New York, New York, United States
University of North Carolina
🇺🇸
Chapel Hill, North Carolina, United States
North Shore Diabetes and Endocrine Associates
🇺🇸
New Hyde Park, New York, United States
University of Texas Southwestern
🇺🇸
Dallas, Texas, United States
Joslin Diabetes Center
🇺🇸
Boston, Massachusetts, United States
MedStar Research Institute
🇺🇸
Washington, District of Columbia, United States
Chapel Medical Group
🇺🇸
New Haven, Connecticut, United States
University of Rochester Medical Center
🇺🇸
Rochester, New York, United States
Tulane University
🇺🇸
New Orleans, Louisiana, United States
University of Nebraska Medical Center
🇺🇸
Omaha, Nebraska, United States