Targeting Inflammation Using Salsalate for Type 2 Diabetes-Stage II

Phase 2

Completed

• Conditions: Type 2 Diabetes Mellitus
• Interventions: Drug: Salsalate Placebo; Drug: Salsalate

• Registration Number: NCT00799643
• 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. 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.

Detailed Description

Not available

Study Timeline

• Study Start: 2008-11
• Study First Submitted: 2008-11-26
• Study First Submitted QC: 2008-11-26
• Study First Posted: 2008-12-01
• Primary Completion: 2012-09
• Results First Submitted: 2013-09-13
• Results First Submitted QC: 2013-09-13
• Results First Posted: 2013-11-25
• Status Verified: 2017-11
• Last Update Submitted: 2017-11-08
• Last Update Posted: 2017-12-11

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 638

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
2	Salsalate Placebo	Salsalate Placebo, orally, divided dosing
1	Salsalate	Salsalate, 3.5 g/d orally, divided dosing

Primary Outcome Measures

Name	Time	Method
The Primary Outcome for the TINSAL-T2D Study is Change in HbA1c Level From Baseline to Week 48 From Baseline, Compared Between Treatment Groups.	48 weeks from baseline	HbA1c (%, percentage of HbA1c) change from baseline.

Secondary Outcome Measures

Name	Time	Method
Changes in WBC and Differential, High-sensitivity C Reactive Protein (hsCRP), Other Inflammatory Markers	24 and 48 weeks
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%	24 and 48 weeks
Response Rates for Exceeding Hyperglycemic Targets Between Active and Placebo Treated Groups; Need for Rescue Therapy; Need for Discontinuation of Study Medication	24 and 48 weeks
Change From Baseline in Fasting Glucose Over Time.	48 weeks from baseline
Response Rates in Patients Initially Treated With Lifestyle Modification, Insulin Secretagogue, Metformin or Combination Therapy	24 and 48 weeks
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)	48 weeks

Trial Locations

Locations (21)

Emory University School of Medicine; 🇺🇸 Atlanta, Georgia, United States

Kaiser Permanente; 🇺🇸 Tucker, Georgia, United States

University of Texas Southwestern; 🇺🇸 Dallas, Texas, United States

Joslin Diabetes Center; 🇺🇸 Boston, Massachusetts, United States

University of Nebraska Medical Center; 🇺🇸 Omaha, Nebraska, United States

Chapel Medical Group; 🇺🇸 New Haven, Connecticut, United States

Indiana University; 🇺🇸 Indianapolis, Indiana, United States

University of Michigan; 🇺🇸 Ann Arbor, Michigan, United States

University of North Carolina; 🇺🇸 Durham, North Carolina, United States

University of Alabama; 🇺🇸 Birmingham, Alabama, United States

University of California, San Diego; 🇺🇸 San Diego, California, 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

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

Scott and White; 🇺🇸 Temple, Texas, United States

Washington University School of Medicine; 🇺🇸 Saint Louis, Missouri, United States