TINSALT2D-II: Targeting Inflammation Using Salsalate for Type 2 Diabetes-Stage II

• Sponsor: Joslin Diabetes Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00799643
• Collaborator: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)
• Enrollment: 638
• Locations: 21
• Arms: 2
• Patients Per Site: 30.4

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Type 2 Diabetes Mellitus	Drug: Salsalate; Drug: Salsalate Placebo	Phase 2/Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 638 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Targeting Inflammation in Type 2 Diabetes: Clinical Trial Using Salsalate
• Study Start Date: Nov 1, 2008
• Actual Primary Completion Date: Sep 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 1 Salsalate, 3.5 g/d orally, divided dosing	Drug: Salsalate; Salsalate 3.5 g/d orally, divided dosing; Other Names: disalsid
Placebo Comparator: 2 Salsalate Placebo, orally, divided dosing	Drug: Salsalate Placebo

Outcome Measures

Primary Outcome Measures

1. 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

1. Change From Baseline in Fasting Glucose Over Time. [48 weeks from baseline]

2. 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]

3. 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]

4. Changes in WBC and Differential, High-sensitivity C Reactive Protein (hsCRP), Other Inflammatory Markers [24 and 48 weeks]

5. 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]

6. Response Rates in Patients Initially Treated With Lifestyle Modification, Insulin Secretagogue, Metformin or Combination Therapy [24 and 48 weeks]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama	Birmingham	Alabama	United States
2	University of California, San Diego	San Diego	California	United States
3	Chapel Medical Group	New Haven	Connecticut	United States
4	Emory University School of Medicine	Atlanta	Georgia	United States
5	Kaiser Permanente	Tucker	Georgia	United States
6	Indiana University	Indianapolis	Indiana	United States
7	Tulane University Health Sciences Center	New Orleans	Louisiana	United States
8	Medstar Research Institute	Hyattsville	Maryland	United States
9	Dr. Rudo, Westminster, MD	Westminster	Maryland	United States	21157
10	Joslin Diabetes Center	Boston	Massachusetts	United States	02215
11	University of Michigan	Ann Arbor	Michigan	United States	48106
12	Washington University School of Medicine	Saint Louis	Missouri	United States
13	University of Nebraska Medical Center	Omaha	Nebraska	United States
14	North Shore Diabetes and Endocrine Associates	New Hyde Park	New York	United States
15	Columbia University	New York	New York	United States
16	Lang Medical Center	Queens	New York	United States
17	Albert Einstein College of Medicine	The Bronx	New York	United States
18	Carolina's Health Care	Charlotte	North Carolina	United States
19	University of North Carolina	Durham	North Carolina	United States
20	University of Texas Southwestern	Dallas	Texas	United States
21	Scott and White	Temple	Texas	United States

Sponsors and Collaborators

• Joslin Diabetes Center
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

• Principal Investigator: Steven E. Shoelson, MD, PhD, Joslin Diabetes Center
• Study Director: Allison B. Goldfine, MD, Joslin Diabetes Center
• Study Director: Vivian Fonseca, MD, Tulane University
• Study Director: Kathleen Jablonski, PhD, George Washington University
• Study Director: Myrlene Staten, MD, National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK)

Study Documents (Full-Text)

None provided.

More Information

Publications

• 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, 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.
• 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.
• 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.

• Responsible Party: Joslin Diabetes Center
• ClinicalTrials.gov Identifier: NCT00799643
• Other Study ID Numbers: CHS 06-20-2; U01DK074556
• First Posted: Dec 1, 2008
• Last Update Posted: Dec 11, 2017
• Last Verified: Nov 1, 2017

• Keywords provided by Joslin Diabetes Center: Type 2 Diabetes Mellitus (T2D); Inflammation; Obesity; Metabolic Syndrome; Salicylates
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Inflammation; Salicylsalicylic acid; Sodium Salicylate

Study Results

Participant Flow

Pre-assignment Detail	The Enrollment number in the protocol section (638) is higher than the number of participants Started in the Participant Flow module (286) due to screen failures and drop out prior to randomization.

Arm/Group Title	Placebo	Salsalate
Arm/Group Description	Placebo for salsalate, orally, divided dosing	Salsalate, 3.5 g/d orally,divided dosing
Period Title: Overall Study
STARTED	140	146
COMPLETED	115	119
NOT COMPLETED	25	27

Baseline Characteristics

Arm/Group Title	Placebo	Salsalate	Total
Arm/Group Description	Placebo for salsalate, orally, divided dosing	Salsalate, 3.5 g/d orally, divided dosing	Total of all reporting groups
Overall Participants	140	146	286
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	112 80%	118 80.8%	230 80.4%
>=65 years	28 20%	28 19.2%	56 19.6%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55.8 (10)	55.8 (9.2)	55.8 (9.6)
Sex: Female, Male (Count of Participants)
Female	65 46.4%	64 43.8%	129 45.1%
Male	75 53.6%	82 56.2%	157 54.9%
Region of Enrollment (participants) [Number]
United States	140 100%	146 100%	286 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Participants with complete data at both Baseline and 48 weeks

Arm/Group Title	Placebo	Salsalate
Arm/Group Description	Placebo for salsalate, orally, divided dosing	Salsalate, 3.5 g/d orally, divided dosing
Measure Participants	137	146
Mean (95% Confidence Interval) [HbA1c units are %]	-0.04	-0.33

2. Secondary Outcome

Title	Change From Baseline in Fasting Glucose Over Time.
Time Frame	48 weeks from baseline

Outcome Measure Data

Analysis Population Description

Participants with complete data at both Baseline and 48 weeks

Arm/Group Title	Placebo	Salsalate
Arm/Group Description	Placebo for salsalate, orally, divided dosing	Salsalate, 3.5 g/d orally,divided dosing
Measure Participants	137	146
Mean (95% Confidence Interval) [mg/dl]	2.0	-13.1

3. Secondary Outcome

Title	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%
Time Frame	24 and 48 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	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)
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	Changes in WBC and Differential, High-sensitivity C Reactive Protein (hsCRP), Other Inflammatory Markers
Time Frame	24 and 48 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Secondary Outcome

Title	Response Rates for Exceeding Hyperglycemic Targets Between Active and Placebo Treated Groups; Need for Rescue Therapy; Need for Discontinuation of Study Medication
Time Frame	24 and 48 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Secondary Outcome

Title	Response Rates in Patients Initially Treated With Lifestyle Modification, Insulin Secretagogue, Metformin or Combination Therapy
Time Frame	24 and 48 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	48 weeks
Arm/Group Title	Placebo		Salsalate
Arm/Group Description	Placebo for salsalate, orally, divided dosing		Salsalate, 3.5 g/d orally,divided dosing
All Cause Mortality
	Placebo		Salsalate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Salsalate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/140 (4.3%)		10/146 (6.8%)
Blood and lymphatic system disorders
Chronic Lymphoid Leukemia	1/140 (0.7%)	1	0/146 (0%)	0
Hepatobiliary disorders
Gallstones/Cholycystectomy	0/140 (0%)	0	1/146 (0.7%)	1
Musculoskeletal and connective tissue disorders
Degenerative Joint Disease	0/140 (0%)	0	1/146 (0.7%)	1
Traumatic Fracture or Joint Diastasis	0/140 (0%)	0	2/146 (1.4%)	2
Cervical Disectomy	1/140 (0.7%)	1	0/146 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Prostate Cancer	2/140 (1.4%)	2	0/146 (0%)	0
Renal and urinary disorders
Hematuria/Bladder Cancer	0/140 (0%)	0	1/146 (0.7%)	1
Benign Prostate Hypertrophy/TURP	1/140 (0.7%)	1	1/146 (0.7%)	1
Kidney Stone	0/140 (0%)	0	2/146 (1.4%)	2
Respiratory, thoracic and mediastinal disorders
Reactive Airway Disease	1/140 (0.7%)	1	0/146 (0%)	0
Skin and subcutaneous tissue disorders
Cellulitis	0/140 (0%)	0	1/146 (0.7%)	1
Vascular disorders
Peripheral Vascular Disease	0/140 (0%)	0	1/146 (0.7%)	1
Other (Not Including Serious) Adverse Events
	Placebo		Salsalate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	64/140 (45.7%)		85/146 (58.2%)
Ear and labyrinth disorders
Tinnitus	7/140 (5%)		16/146 (11%)
Gastrointestinal disorders
Vomiting	10/140 (7.1%)		11/146 (7.5%)
General disorders
Dizzy	10/140 (7.1%)		11/146 (7.5%)
Weakness or Fatigue	9/140 (6.4%)		13/146 (8.9%)
Musculoskeletal and connective tissue disorders
Muscle Stiffness	9/140 (6.4%)		14/146 (9.6%)
Respiratory, thoracic and mediastinal disorders
Cough	19/140 (13.6%)		20/146 (13.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.