Targeting Inflammation Using Salsalate for Type 2 Diabetes-Stage II

NCT ID: NCT00799643

Last Updated: 2017-12-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 638 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-11-30

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. Enrollment in the first stage is complete. The primary objective of the first stage was to select a dose of salsalate that is both well-tolerated and demonstrates a trend toward improvement in glycemic control. 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.

Conditions

Type 2 Diabetes Mellitus

Keywords

Type 2 Diabetes Mellitus (T2D); Inflammation; Obesity; Metabolic Syndrome; Salicylates

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

1

Salsalate, 3.5 g/d orally, divided dosing

Group Type: ACTIVE_COMPARATOR

Salsalate

Intervention Type: DRUG

Salsalate 3.5 g/d orally, divided dosing

2

Salsalate Placebo, orally, divided dosing

Group Type: PLACEBO_COMPARATOR

Salsalate Placebo

Intervention Type: DRUG

Interventions

Salsalate

Salsalate 3.5 g/d orally, divided dosing

Intervention Type: DRUG

Salsalate Placebo

Intervention Type: DRUG

Other Intervention Names

disalsid

Eligibility Criteria

Inclusion Criteria

1. Type 2 diabetes on diet and exercise therapy or monotherapy with metformin, insulin secretagogue (including SFU, non-SFU, and dipeptidyl peptidase IV (DPP-4) inhibitors), alpha-glucosidase inhibitors, or bile acid sequestrants (dosed once per day such that study drug can be administered ≥ 4 hours prior to sequestrant); or a combination of up to two of these at maximal dose. Dosing must be stable for 8 weeks prior to screening. Participant must have been diagnosed with T2D at least 8 weeks before screening.

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. No prior participation in Stage I of TINSAL-T2D ; exception: a participant who failed screening for HbA1c in Stage I will be allowed to re-screen for Stage II.

2. Type 1 diabetes and/or history of ketoacidosis determined by medical history

3. History of severe diabetic neuropathy including autonomic neuropathy, gastroparesis or lower limb ulceration or amputation

4. History of long-term therapy with insulin (>30 days) within the last year

5. Therapy with rosiglitazone (Avandia) or pioglitazone (Actos), alone or in combination in the previous 6 months; or exendin-4 (Byetta), alone or in combination in the previous 3 months

6. Pregnancy or lactation

7. Patients requiring oral corticosteroids within 3 months or recurrent continuous oral corticosteroid treatment (more than 2 weeks)

8. 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

9. Surgery within 30 days prior to screening

10. 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

11. History of chronic liver disease including hepatitis B or C

12. History of peptic ulcer or endoscopy demonstrated gastritis

13. History of acquired immune deficiency syndrome or human immunodeficiency virus (HIV)

14. 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

15. New York Heart Association Class III or IV cardiac status or hospitalization for congestive heart failure

16. History of unstable angina, myocardial infarction, cerebrovascular accident, transient ischemic attack or any revascularization within 6 months

17. 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). If on blood pressure medications, dosing should be stable for 2 weeks prior to randomization.

18. History of drug or alcohol abuse, or current weekly alcohol consumption >10 units/week (1 unit = 1 beer, 1 glass of wine, 1 mixed DCCktail containing 1 ounce of alcohol)

19. Hemoglobin <12 g/dL (males), <10 g/dL (females) at screening*

20. Platelets <100,000 cu mm at screening

21. AST (SGOT) >2.50 x ULN or ALT (SGPT) >2.50 x ULN at screening

22. Total Bilirubin >1.50 x ULN at screening

23. Triglycerides (TG) >500 mg/dL at screening

24. Poor mental function or any other reason to expect patient difficulty in complying with the requirements of the study

25. Previous allergy to aspirin

26. Chronic or continuous use (daily for more than 7 days) of nonsteroidal anti-inflammatory drugs within the preceding 2 months

27. Use of warfarin (Coumadin), clopidogrel (Plavix), dipyridamole (Persantine), heparin or other anticoagulants

28. Use of probenecid (Benemid, probalan), sulfinpyrazone (Anturane) or other uricosuric agents

29. Macroalbuminuria, defined as spot urine protein >300 mcg/mg Cr at screening

30. Pre-existing chronic tinnitus

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

NIH

Sponsor Role: collaborator

Joslin Diabetes Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Steven E. Shoelson, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Joslin Diabetes Center

Allison B. Goldfine, MD

Role: STUDY_DIRECTOR

Joslin Diabetes Center

Vivian Fonseca, MD

Role: STUDY_DIRECTOR

Tulane University

Kathleen Jablonski, PhD

Role: STUDY_DIRECTOR

George Washington University

Myrlene Staten, MD

Role: STUDY_DIRECTOR

National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK)

Locations

University of Alabama

Birmingham, Alabama, United States

University of California, San Diego

San Diego, California, United States

Chapel Medical Group

New Haven, Connecticut, United States

Emory University School of Medicine

Atlanta, Georgia, United States

Kaiser Permanente

Tucker, Georgia, United States

Indiana University

Indianapolis, Indiana, United States

Tulane University Health Sciences Center

New Orleans, Louisiana, United States

Medstar Research Institute

Hyattsville, Maryland, United States

Dr. Rudo, Westminster, MD

Westminster, Maryland, United States

Joslin Diabetes Center

Boston, Massachusetts, United States

University of Michigan

Ann Arbor, Michigan, United States

Washington University School of Medicine

St Louis, Missouri, United States

University of Nebraska Medical Center

Omaha, Nebraska, United States

North Shore Diabetes and Endocrine Associates

New Hyde Park, New York, United States

Columbia University

New York, New York, United States

Lang Medical Center

Queens, New York, United States

Albert Einstein College of Medicine

The Bronx, New York, United States

Carolina's Health Care

Charlotte, North Carolina, United States

University of North Carolina

Durham, North Carolina, United States

University of Texas Southwestern

Dallas, Texas, United States

Scott and White

Temple, Texas, United States

Countries

United States

References

Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest. 2006 Jul;116(7):1793-801. doi: 10.1172/JCI29069.

Reference Type: BACKGROUND

PMID: 16823477 (View on PubMed)

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. doi: 10.2337/dc07-1338. Epub 2007 Oct 24.

Reference Type: BACKGROUND

PMID: 17959861 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 19337387 (View on PubMed)

Goldfine AB, Fonseca V, Jablonski KA, Pyle L, Staten MA, Shoelson SE; TINSAL-T2D (Targeting Inflammation Using Salsalate in Type 2 Diabetes) Study Team. The effects of salsalate on glycemic control in patients with type 2 diabetes: a randomized trial. Ann Intern Med. 2010 Mar 16;152(6):346-57. doi: 10.7326/0003-4819-152-6-201003160-00004.

Reference Type: BACKGROUND

PMID: 20231565 (View on PubMed)

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.

Reference Type: RESULT

PMID: 23817699 (View on PubMed)

Goldfine AB, Buck JS, Desouza C, Fonseca V, Chen YD, Shoelson SE, Jablonski KA, Creager MA; TINSAL-FMD (Targeting Inflammation Using Salsalate in Type 2 Diabetes-Flow-Mediated Dilation) Ancillary Study Team. Targeting inflammation using salsalate in patients with type 2 diabetes: effects on flow-mediated dilation (TINSAL-FMD). Diabetes Care. 2013 Dec;36(12):4132-9. doi: 10.2337/dc13-0859. Epub 2013 Oct 15.

Reference Type: DERIVED

PMID: 24130358 (View on PubMed)

Other Identifiers

U01DK074556

Identifier Type: NIH

Identifier Source: secondary_id

View Link

CHS 06-20-2

Identifier Type: -

Identifier Source: org_study_id