Targeting INflammation Using SALsalate in Type 2 Diabetes (TINSAL-T2D)

• Sponsor: Joslin Diabetes Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00392678
• Collaborator: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)
• Enrollment: 277
• Locations: 16
• Arms: 4
• Duration (Months): 50
• Patients Per Site: 17.3
• Patients Per Site Per Month: 0.3

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. 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.

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

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 277 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: Oct 1, 2006
• Actual Primary Completion Date: Jul 1, 2008
• Actual Study Completion Date: Dec 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Placebo, appearance matched to active drug	Drug: Placebo; Placebo to Salsalate; Other Names: Placebo to Salsalate
Active Comparator: 3 gram Salsalate 3.0 grams daily, divided	Drug: Salsalate; Placebo and Salsalate 3.0 g/d; 3.5 g/d; 4.0 g/d orally, divided; Other Names: Disalcid Salicylsalicylic acid
Active Comparator: 3.5 gram Salsalate 3.5 g daily, divided	Drug: Salsalate; Placebo and Salsalate 3.0 g/d; 3.5 g/d; 4.0 g/d orally, divided; Other Names: Disalcid Salicylsalicylic acid
Active Comparator: 4 gram Salsalate 4.0 g daily, divided	Drug: Salsalate; Placebo and Salsalate 3.0 g/d; 3.5 g/d; 4.0 g/d orally, divided; Other Names: Disalcid Salicylsalicylic acid

Outcome Measures

Primary Outcome Measures

1. Change in HbA1c Baseline to End of Trial in TINSAL-T2D Stage 1 [14 week]

   The primary outcome for the TINSAL-T2D study is change in HbA1c level from baseline to week 14 (stage 1) in the intent-to-treat (ITT) population with last observation carried forward.

Secondary Outcome Measures

1. Change in HbA1c [14 week]

   Change from baseline to either 14 or 26 weeks, or last HbA1c measurement prior to rescue therapy

2. Change From Baseline and Trends in Fasting Glucose Over Time [14 week]

3. Change in Lipids [14 week]

   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) LDL-C/HDL-C ratio not calculated

4. Change From Baseline in 14-week Insulin, C-peptide, Homeostasis Model [HOMA] Index [Baseline, week 14]

   HOMA-IR was not calcuated due to potential confounding effect of salicylates to inhibit insulin clearance. Change in insulin from Baseline to Week 14 in data table below.

5. Safety and Tolerability [14 weeks]

   See adverse event module for details. Safety and tolerability of salsalate compared to placebo as assessed by adverse events.

6. Change in Insulin, C-peptide, Homeostasis Model [HOMA] Index [Baseline, week 14]

   HOMA-IR was not calcuated due to potential confounding effect of salicylates to inhibit insulin clearance. Change in C-peptide from Baseline to Week 14 is in the data table below

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, 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Chapel Medical Group	New Haven	Connecticut	United States	06511
2	MedStar Research Institute	Washington	District of Columbia	United States	20003-4393
3	Endocrine Clinical Research	Winter Park	Florida	United States	32746
4	Kaiser Permanente	Atlanta	Georgia	United States	30084
5	Emory School of Medicine	Atlanta	Georgia	United States	30303
6	University of Illinois at Chicago	Chicago	Illinois	United States	60612
7	Tulane University	New Orleans	Louisiana	United States	70112
8	Joslin Diabetes Center	Boston	Massachusetts	United States	02215
9	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
10	University of Nebraska Medical Center	Omaha	Nebraska	United States	68105
11	Kaleida Health Center	Buffalo	New York	United States	14226
12	North Shore Diabetes and Endocrine Associates	New Hyde Park	New York	United States	11042
13	Columbia University	New York	New York	United States	10032
14	University of Rochester Medical Center	Rochester	New York	United States	14642
15	University of North Carolina	Chapel Hill	North Carolina	United States	27599
16	University of Texas Southwestern	Dallas	Texas	United States	75390

Sponsors and Collaborators

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

Investigators

• Principal Investigator: Steven E. Sheolson, 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 and Digestive and Kidney Diseases (NIDDK)

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• TINSAL-T2D website

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, 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.
• 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: NCT00392678
• Other Study ID Numbers: CHS 06-20, NIH U01 DK74556; U01DK074556
• First Posted: Oct 26, 2006
• Last Update Posted: Apr 8, 2019
• Last Verified: Mar 1, 2019

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

Study Results

Participant Flow

Recruitment Details	3 private practices and 14 universities. First patient recruited February 2007; last patient end of study visit, May 2008
Pre-assignment Detail	Screening, followed by 4-week single mask placebo lead-in. 277 participants signed screening consent. Some participants were ineligible, some withdrew consent, and some had treatment side effects during placebo lead-in.

Arm/Group Title	3 Gram	3.5 Gram	4 Gram	Placebo
Arm/Group Description	Salsalate 3.0 g daily, divided	Salsalate 3.5 g daily, divided	Salsalate 4.0 g daily, divided	Matched by appearance to active drug
Period Title: Overall Study
STARTED	27	27	27	27
COMPLETED	27	26	25	26
NOT COMPLETED	0	1	2	1

Baseline Characteristics

Arm/Group Title	3 Gram	3.5 Gram	4 Gram	Placebo	Total
Arm/Group Description	Salsalate 3.0 g daily, divided	Salsalate 3.5 g daily, divided	Salsalate 4.0 g daily, divided	matched to active drug	Total of all reporting groups
Overall Participants	27	27	27	27	108
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	23 85.2%	22 81.5%	24 88.9%	22 81.5%	91 84.3%
>=65 years	4 14.8%	5 18.5%	3 11.1%	5 18.5%	17 15.7%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55.4 (9.4)	56.7 (9.8)	55.0 (10.2)	55.9 (8.2)	56 (9)
Sex: Female, Male (Count of Participants)
Female	13 48.1%	9 33.3%	11 40.7%	12 44.4%	45 41.7%
Male	14 51.9%	18 66.7%	16 59.3%	15 55.6%	63 58.3%
Region of Enrollment (participants) [Number]
United States	27 100%	27 100%	27 100%	27 100%	108 100%

Outcome Measures

1. Primary Outcome

Title	Change in HbA1c Baseline to End of Trial in TINSAL-T2D Stage 1
Description	The primary outcome for the TINSAL-T2D study is change in HbA1c level from baseline to week 14 (stage 1) in the intent-to-treat (ITT) population with last observation carried forward.
Time Frame	14 week

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	3.0 g/d	3.5 g/d	4.0 g/d	Placebo
Arm/Group Description	Salsalate 3.0 g/d, divided	Salsalate 3.5 g/d, divided	Salsalate 4.0 g/d, divided	Placebo matched to active drug
Measure Participants	27	26	25	26
Mean (95% Confidence Interval) [% (units of HbA1c)]	-0.36	-0.34	-0.49	-0.01

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	3.0 g/d, 3.5 g/d, 4.0 g/d, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	Mixed Models Analysis
	Comments

2. Secondary Outcome

Title	Change in HbA1c
Description	Change from baseline to either 14 or 26 weeks, or last HbA1c measurement prior to rescue therapy
Time Frame	14 week

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Salsalate 3.0 g/d	Salsalate 3.5 g/d	Salsalate 4.0 g/d
Arm/Group Description	Placebo matched to active drug	Salsalate 3.0 g/d, divided	Salsalate 3.5 g/d, divided	Salsalate 4.0 g/d, divided
Measure Participants	26	27	26	25
Mean (95% Confidence Interval) [% HbA1c]	0	-0.4	-0.3	-0.5

3. Secondary Outcome

Title	Change From Baseline and Trends in Fasting Glucose Over Time
Time Frame	14 week

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Salsalate 3.0 g/d	Salsalate 3.5 g/d	Salsalate 4.0 g/d
Arm/Group Description	Placebo matched to active drug	Salsalate 3.0 g/d, divided	Salsalate 3.5 g/d, divided	Salsalate 4.0 g/d, divided
Measure Participants	26	27	26	25
Mean (95% Confidence Interval) [mg/dl]	13	-19	-14	-15

4. Secondary Outcome

Title	Change in Lipids
Description	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) LDL-C/HDL-C ratio not calculated
Time Frame	14 week

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Salsalate 3.0 g/d	Salsalate 3.5 g/d	Salsalate 4.0 g/d
Arm/Group Description	Placebo matched to active	Salsalate 3.0 g/d, divided	Salsalate 3.5 g/d, divided	Salsalate 4.0 g/d, divided
Measure Participants	26	27	26	27
Cholesterol	0	8	-1	6
HDL	0	3	1	2
LDL	0	15	3	8
TG	15	-34	-22	-16
Total to HDL ratio	0	0.1	-0.1	0.2

5. Secondary Outcome

Title	Change From Baseline in 14-week Insulin, C-peptide, Homeostasis Model [HOMA] Index
Description	HOMA-IR was not calcuated due to potential confounding effect of salicylates to inhibit insulin clearance. Change in insulin from Baseline to Week 14 in data table below.
Time Frame	Baseline, week 14

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Salsalate 3.0 g/d	Salsalate 3.5 g/d	Salsalate 4.0 g/d
Arm/Group Description	Placebo matched to active	Salsalate 3.0 g/d, divided	Salsalate 3.5 g/d, divided	Salsalate 4.0 g/d, divided
Measure Participants	26	27	26	25
Median (Inter-Quartile Range) [pmol/l]	-3.0	15	7.6	27

6. Secondary Outcome

Title	Safety and Tolerability
Description	See adverse event module for details. Safety and tolerability of salsalate compared to placebo as assessed by adverse events.
Time Frame	14 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Salsalate 3.0 g/d	Salsalate 3.5 g/d	Salsalate 4.0 g/d	Placebo
Arm/Group Description	Salsalate 3.0 g/d, divided	Salsalate 3.5 g/d, divided	Salsalate 4.0 g/d, divided	Placebo matched to active
Measure Participants	27	27	27	27
Number [participants]	17 63%	16 59.3%	16 59.3%	14 51.9%

7. Secondary Outcome

Title	Change in Insulin, C-peptide, Homeostasis Model [HOMA] Index
Description	HOMA-IR was not calcuated due to potential confounding effect of salicylates to inhibit insulin clearance. Change in C-peptide from Baseline to Week 14 is in the data table below
Time Frame	Baseline, week 14

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Salsalate 3.0 g/d	Salsalate 3.5 g/d	Salsalate 4.0 g/d
Arm/Group Description	Placebo matched to active	Salsalate 3.0 g/d, divided	Salsalate 3.5 g/d, divided	Salsalate 4.0 g/d, divided
Measure Participants	26	27	26	25
Mean (95% Confidence Interval) [C-peptide in nmol/l]	0.10	-0.07	-0.03	0.03

Adverse Events

Time Frame	Screening, 4 week placebo run in, 14 week treatment.
Adverse Event Reporting Description	AE/SAE use standard FDA definition.
Arm/Group Title	Salsalate 3.0 g/d		Salsalate 3.5 g/d		Salsalate 4.0 g/d		Placebo
Arm/Group Description	Active: Salsalate 3.0 g/d		Active: Salsalate 3.5 g/d		Active: Salsalate 4.0 g/d		Identical Placebo
All Cause Mortality
	Salsalate 3.0 g/d		Salsalate 3.5 g/d		Salsalate 4.0 g/d		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/27 (0%)		0/27 (0%)		0/27 (0%)		0/27 (0%)
Serious Adverse Events
	Salsalate 3.0 g/d		Salsalate 3.5 g/d		Salsalate 4.0 g/d		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/27 (3.7%)		2/27 (7.4%)		0/27 (0%)		1/27 (3.7%)
Cardiac disorders
Congestive Heart Failure with Diastolic Dysfunction	0/27 (0%)	0	1/27 (3.7%)	1	0/27 (0%)	0	0/27 (0%)	0
Gastrointestinal disorders
Acute Cholecystitis	1/27 (3.7%)	1	0/27 (0%)	0	0/27 (0%)	0	0/27 (0%)	0
Musculoskeletal and connective tissue disorders
Cervical Disc Herniation	0/27 (0%)	0	1/27 (3.7%)	1	0/27 (0%)	0	0/27 (0%)	0
Lumbar laminectomy	0/27 (0%)	0	0/27 (0%)	0	0/27 (0%)	0	1/27 (3.7%)	1
Other (Not Including Serious) Adverse Events
	Salsalate 3.0 g/d		Salsalate 3.5 g/d		Salsalate 4.0 g/d		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	27/27 (100%)		27/27 (100%)		27/27 (100%)		25/27 (92.6%)
Cardiac disorders
Cardiorespiratory	4/27 (14.8%)	5	1/27 (3.7%)	1	3/27 (11.1%)	5	3/27 (11.1%)	7
Endocrine disorders
Hypoglycemia	5/27 (18.5%)	63	6/27 (22.2%)	46	6/27 (22.2%)	7	2/27 (7.4%)	2
Hyperglycemia	0/27 (0%)	0	0/27 (0%)	0	0/27 (0%)	0	2/27 (7.4%)	7
Gastrointestinal disorders
Gastrointestinal	11/27 (40.7%)	13	8/27 (29.6%)	8	8/27 (29.6%)	8	2/27 (7.4%)	3
General disorders
General	7/27 (25.9%)	8	4/27 (14.8%)	4	2/27 (7.4%)	2	4/27 (14.8%)	4
Musculoskeletal and connective tissue disorders
Musculoskeletal	8/27 (29.6%)	10	5/27 (18.5%)	5	3/27 (11.1%)	3	7/27 (25.9%)	9
Nervous system disorders
Neurologic	7/27 (25.9%)	9	10/27 (37%)	13	8/27 (29.6%)	8	7/27 (25.9%)	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.