Clinical trial NCT00392678: Targeting INflammation Using SALsalate in Type 2 Diabetes (TINSAL-T2D)
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
Keywords: Type 2 Diabetes
Inflammation
Obesity
Metabolic Syndrome
Lead sponsor: Joslin Diabetes Center
Sponsor class: OTHER
Collaborators: name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2006-10-26
Enrollment: 277
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. 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.

Eligibility 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

Primary outcomes:
measure: Change in HbA1c Baseline to End of Trial in TINSAL-T2D Stage 1
timeFrame: 14 week
Secondary outcomes:
measure: Change in HbA1c
timeFrame: 14 week
measure: Change From Baseline and Trends in Fasting Glucose Over Time
timeFrame: 14 week
measure: Change in Lipids
timeFrame: 14 week
measure: Change From Baseline in 14-week Insulin, C-peptide, Homeostasis Model [HOMA] Index
timeFrame: Baseline, week 14
measure: Safety and Tolerability
timeFrame: 14 weeks
measure: Change in Insulin, C-peptide, Homeostasis Model [HOMA] Index
timeFrame: Baseline, week 14
Other outcomes:
Locations:
city: New Haven
country: United States
facility: Chapel Medical Group
state: Connecticut
city: Washington
country: United States
facility: MedStar Research Institute
state: District of Columbia
city: Winter Park
country: United States
facility: Endocrine Clinical Research
state: Florida
city: Atlanta
country: United States
facility: Kaiser Permanente
state: Georgia
city: Atlanta
country: United States
facility: Emory School of Medicine
state: Georgia
city: Chicago
country: United States
facility: University of Illinois at Chicago
state: Illinois
city: New Orleans
country: United States
facility: Tulane University
state: Louisiana
city: Boston
country: United States
facility: Joslin Diabetes Center
state: Massachusetts
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: Buffalo
country: United States
facility: Kaleida Health Center
state: New York
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: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina
state: North Carolina
city: Dallas
country: United States
facility: University of Texas Southwestern
state: Texas
Study officials:
affiliation: Joslin Diabetes Center
name: Steven E. Sheolson, 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 and Digestive and 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, 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, 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.