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

Information source: Joslin Diabetes Center
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Type 2 Diabetes

Intervention: Salsalate (Drug); Placebo (Drug)

Phase: Phase 2/Phase 3

Status: Completed

Sponsored by: Allison Goldfine

Official(s) and/or principal investigator(s):
Steven E. Sheolson, MD, PhD, Principal Investigator, Affiliation: Joslin Diabetes Center
Allison B. Goldfine, MD, Study Director, Affiliation: Joslin Diabetes Center
Vivian Fonseca, MD, Study Director, Affiliation: Tulane University
Kathleen Jablonski, PhD, Study Director, Affiliation: George Washington University
Myrlene Staten, MD, Study Director, Affiliation: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

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.

Clinical Details

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

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Primary outcome: 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:

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

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%

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)

Change in Insulin, C-peptide, Homeostasis Model [HOMA] Index

Response Rates for Exceeding Hyperglycemic Targets Between Active and Placebo Treated Groups

Need for Rescue Therapy

Need for Discontinuation of Study Medication

Response Rates in Patients Initially Treated With Lifestyle Modification, Insulin Secretagogue, Metformin or Combination Therapy

Response Rates for a Reduction in HbA1c for Obese vs Non-obese Participants

Safety and Tolerability of Salsalate Compared to Placebo as Assessed by Adverse Events.

Change in Insulin, C-peptide, Homeostasis Model [HOMA] Index

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.

Eligibility

Minimum age: 18 Years. Maximum age: 75 Years. Gender(s): Both.

Criteria:

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

Locations and Contacts

Chapel Medical Group, New Haven, Connecticut 06511, United States

MedStar Research Institute, Washington DC, District of Columbia 20003-4393, United States

Endocrine Clinical Research, Winter Park, Florida 32746, United States

Emory School of Medicine, Atlanta, Georgia 30303, United States

Kaiser Permanente, Atlanta, Georgia 30084, United States

University of Illinois at Chicago, Chicago, Illinois 60612, United States

Tulane University, New Orleans, Louisiana 70112, United States

Joslin Diabetes Center, Boston, Massachusetts 02215, United States

Washington University School of Medicine, St. Louis, Missouri 63110, United States

University of Nebraska Medical Center, Omaha, Nebraska 68105, United States

Kaleida Health Center, Buffalo, New York 14226, United States

North Shore Diabetes and Endocrine Associates, New Hyde Park, New York 11042, United States

Columbia University, New York City, New York 10032, United States

University of Rochester Medical Center, Rochester, New York 14642, United States

University of North Carolina, Chapel Hill, North Carolina 27599, United States

University of Texas Southwestern, Dallas, Texas 75390, United States

Additional Information

TINSAL-T2D website

Related publications:

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.

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.

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.

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;159(1):1-12. doi: 10.7326/0003-4819-159-1-201307020-00003.

Starting date: October 2006
Last updated: July 25, 2013

Page last updated: August 23, 2015

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