Clinical trial NCT00799643: Targeting Inflammation Using Salsalate for Type 2 Diabetes-Stage II
Official title: Targeting Inflammation in Type 2 Diabetes: Clinical Trial Using Salsalate
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Type 2 Diabetes Mellitus
Keywords: Type 2 Diabetes Mellitus (T2D)
Inflammation
Obesity
Metabolic Syndrome
Salicylates
Lead sponsor: Joslin Diabetes Center
Sponsor class: OTHER
Collaborators: name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2008-12-01
Enrollment: 638
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: The Primary Outcome for the TINSAL-T2D Study is Change in HbA1c Level From Baseline to Week 48 From Baseline, Compared Between Treatment Groups.
timeFrame: 48 weeks from baseline
Secondary outcomes:
measure: Change From Baseline in Fasting Glucose Over Time.
timeFrame: 48 weeks from baseline
measure: 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%
timeFrame: 24 and 48 weeks
measure: 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)
timeFrame: 48 weeks
measure: Changes in WBC and Differential, High-sensitivity C Reactive Protein (hsCRP), Other Inflammatory Markers
timeFrame: 24 and 48 weeks
measure: Response Rates for Exceeding Hyperglycemic Targets Between Active and Placebo Treated Groups; Need for Rescue Therapy; Need for Discontinuation of Study Medication
timeFrame: 24 and 48 weeks
measure: Response Rates in Patients Initially Treated With Lifestyle Modification, Insulin Secretagogue, Metformin or Combination Therapy
timeFrame: 24 and 48 weeks
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama
state: Alabama
city: San Diego
country: United States
facility: University of California, San Diego
state: California
city: New Haven
country: United States
facility: Chapel Medical Group
state: Connecticut
city: Atlanta
country: United States
facility: Emory University School of Medicine
state: Georgia
city: Tucker
country: United States
facility: Kaiser Permanente
state: Georgia
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: New Orleans
country: United States
facility: Tulane University Health Sciences Center
state: Louisiana
city: Hyattsville
country: United States
facility: Medstar Research Institute
state: Maryland
city: Westminster
country: United States
facility: Dr. Rudo, Westminster, MD
state: Maryland
city: Boston
country: United States
facility: Joslin Diabetes Center
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: New Hyde Park
country: United States
facility: North Shore Diabetes and Endocrine Associates
state: New York
city: New York
country: United States
facility: Columbia University
state: New York
city: Queens
country: United States
facility: Lang Medical Center
state: New York
city: The Bronx
country: United States
facility: Albert Einstein College of Medicine
state: New York
city: Charlotte
country: United States
facility: Carolina's Health Care
state: North Carolina
city: Durham
country: United States
facility: University of North Carolina
state: North Carolina
city: Dallas
country: United States
facility: University of Texas Southwestern
state: Texas
city: Temple
country: United States
facility: Scott and White
state: Texas
Study officials:
affiliation: Joslin Diabetes Center
name: Steven E. Shoelson, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Joslin Diabetes Center
name: Allison B. Goldfine, MD
role: STUDY_DIRECTOR
affiliation: Tulane University
name: Vivian Fonseca, MD
role: STUDY_DIRECTOR
affiliation: George Washington University
name: Kathleen Jablonski, PhD
role: STUDY_DIRECTOR
affiliation: National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK)
name: Myrlene Staten, MD
role: STUDY_DIRECTOR
References:
citation: Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest. 2006 Jul;116(7):1793-801. doi: 10.1172/JCI29069.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.