Targeting Inflammation With Salsalate in Type 1 Diabetes Neuropathy (TINSAL-T1DN)

Targeting Inflammation With Salsalate in Type 1 Diabetes Neuropathy-TINSAL -T1DN

Diabetic neuropathy (DN) is the most common chronic complication of diabetes, affecting up to50% of individuals with type 1 diabetes (T1DM).

Multiple pre-clinical and clinical studies demonstrate a pathogenic role for inflammation, especially cytokine production, in the disease course of DN and CAN. This suggests that agents with known anti-inflammatory properties, such as salicylates, may prevent the development of DN and the pain associated with DN. This study builds upon and expands on prior work done by the investigators with salsalate, a pro-drug form of salicylate, as an agent to address inflammatory pathways in people with T1DM.

Study Overview

• Status: Completed
• Conditions: Type 1 Diabetes; Peripheral Neuropathy
• Intervention / Treatment: Drug: Salsalate; Drug: PLACEBO

Detailed Description

Diabetic neuropathy (DN) is the most common chronic complication of diabetes, affecting up to50% of individuals with type 1 diabetes (T1DM). DN is a progressive disease, leading to severe morbidity and staggering health care costs. Patients experience poor quality of life due to pain, loss of sensation leading to poor balance, falls and eventual foot deformities with high rates of ulcerations and amputations. While not as commonly diagnosed as DN, cardiovascular autonomic neuropathy (CAN) carries equal morbidity with patients experiencing orthostasis, arrhythmias and premature death).

Despite the high morbidity associated with DN, most randomized clinical trials evaluating therapies for established DN have been disappointing. To date there is no pathogenetic treatment for this condition. The Diabetes Control and Complications Trial (DCCT) demonstrated that intensive control designed to achieve near-normal glycemia is essential in reducing the risk of DN development in type 1 diabetes (8, 9). However, attainable intensive glycemic control, although necessary, is insufficient to prevent adverse nervous system effects, justifying a therapeutic need to identify new drug targets to treat DN early in its course. One such new therapeutic target is inflammation. Multiple pre-clinical and clinical studies demonstrate a pathogenic role for inflammation, especially cytokine production, in the disease course of DN and CAN. This suggests that agents with known anti-inflammatory properties, such as salicylates, may prevent the development of DN and the pain associated with DN. Salsalate, a pro-drug form of salicylate, is a FDA approved drug commonly indicated for relief of the signs and symptoms of rheumatoid arthritis, osteoarthritis and related rheumatic disorders. In vitro and in vivo studies and human trials have shown that salicylate therapy is effective in controlling low grade inflammation in diabetes by inhibition of the inhibitor of the κB kinase (IKKβ)/NF-κB pathway. It has a large margin of safety (unlike other salicylates), and a low cost. There is also extensive experience with long-term human use of salsalate.

Several studies show that salsalate causes no greater intestinal occult blood loss than placebo and has no suppressive effects on renal prostaglandin production in contrast to aspirin or NSAIDs. The recently published NIDDK-funded "Targeting Inflammation Using Salsalate in Type 2 Diabetes (TINSAL-T2D)" trial confirmed salutary effects of 3.5 gram/day salsalate on markers of inflammation, glucose control and overall safety after 48 weeks patients with type 2 diabetes. The Investigators' initial NIDDK funded R03 (DK 094499) grant confirmed the safety and feasibility of targeting inflammation with salsalate treatment in T1DM subjects with DN. The Investigators' current study builds upon and expands their initial promising results and will either confirm or refute the therapeutic efficacy of salsalate in a larger T1DM cohort.

• Study Type: Interventional
• Enrollment (Actual): 61
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United States
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Health System
    • Ann Arbor, Michigan, United States, 48105
      • Veterans Administration Ann Arbor Health Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria

1. T1DM;
2. age 18-70;
3. mild DN as defined by symptoms and/or signs, confirmed by at least one abnormality in electrophysiology studies (abnormality of at least one attribute among conduction velocity, latency, amplitude or F-Wave in at least one nerve among sural sensory, ulnar sensory, or peroneal motor);
4. sural nerve amplitude > 0 μV. If sural nerve amplitude is 0 μV (unrecordable) peroneal motor nerve conduction velocity must be ≥ 35 m/second*;
5. on a stable insulin regimen for the 3 months prior to enrollment;
6. be willing and capable of signing the IRB approved consent form and willing and able to cooperate with the medical procedures for the study duration;
7. be willing to accept random treatment assignment to salsalate or placebo; and
8. women of childbearing age agree to use an appropriate contraceptive method (hormonal, IUD, or diaphragm) for the duration of the study and must have a negative urine pregnancy test at screening.

Exclusion Criteria

1. history of severe DN, active lower limb ulceration or lower limb amputation directly caused by diabetic neuropathy, or risk factors for any other causes of neuropathy (e.g. active hepatitis C, end stage renal disease, systemic lupus erythematosus or a known hereditary neuropathy) as determined through medical history, family history, history of medications, occupational history, history of exposure to toxins, physical and neurological examinations);
2. history of recent severe hypoglycemia (within prior 6 months) as defined by hypoglycemia resulting in coma or seizure or a history of recurrent diabetic ketoacidosis (DKA) or any diabetic ketoacidosis within the last three months.
3. history of persistent macroalbuminuria [random urine microalbumin creatinine ratio (ACR) >300 mg/gm]. ACR up to 300 mg/gm is acceptable if serum creatinine is <1.4 for women, <1.5 for men AND estimated GFR (eGFR) is > 60;
4. 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];
5. pregnancy or lactation, or intention to become pregnant in next 12 months;
6. history of previous lung, kidney, pancreas, liver, cardiac or bone marrow transplant;
7. history of drug or alcohol abuse within the previous 5 years, or current weekly alcohol consumption >10 units/week;
8. use of warfarin (Coumadin), clopidogrel (Plavix), dipyridamole (Persantine), heparin or other anticoagulants, probenecid (Benemid, Probalan), sulfinpyrazone (Anturane) or other uricosuric agents; Subjects must agree to not use high-dose aspirin during the course of the study. Daily low-dose aspirin treatment (not more than 81 mg per day) may be continued if currently prescribed.
9. requiring long-term glucocorticoid therapy or chronic immunosuppressive therapy; Inhaled steroid use for management of asthma is not an absolute exclusion.
10. use of lithium
11. participation in an experimental medication trial within 3 months of starting the study;
12. current therapy for malignant disease other than basal- cell or squamous-cell skin cancer;
13. history of gastrointestinal bleeding or active gastric ulcer; screening laboratory abnormalities including AST (SGOT) and or ALT (SGPT) > 2.5 x the upper limit of normal (ULN), total bilirubin > 1.5 x ULN, platelets < 100,000;
14. You have developed keloid scarring in the past. Keloids are large, thick masses of scar tissue. These are more common among dark-skinned people.
15. presence of any condition that, in the opinion of the investigator would make it unlikely for the subject to complete 12 months of study participation, e.g., history of non- adherence to therapeutic regimens, presence of conditions likely to limit life expectancy, living situation that would interfere with study visit schedules such as a job requiring frequent or extended travel
16. known hypersensitivity to salsalate. Patients who have experienced asthma, hives, or other allergic-type reactions to aspirin or other NSAIDs are excluded from participation. Patients with known or suspected aspirin or NSAID-sensitive asthma are excluded.

In addition, subjects with concurrent chicken pox, influenza, flu-like symptoms or other symptomatic viral illnesses should not be enrolled in the study until the illness or condition has resolved.

Subjects with known or suspected hypersensitivity to lidocaine or epinephrine may not be able to participate as these agents are used for local anesthesia during skin biopsies. The study investigators should consider the nature and severity of past reported reactions to these agents, and may consider alternative anesthesia options for local anesthesia on a case by case basis.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Salsalate; Salsalate, 1 gram by mouth, 3 times daily (3 grams per day) for 12 months.	Drug: Salsalate; 1 gram, 3 times daily by mouth (total of 3 grams daily); Other Names: disalcid
Placebo Comparator: Comparator; Placebo for Salsalate, 2 tablets by mouth, 3 times daily for 12 months	Drug: PLACEBO; Placebo for Salsalate; 2 Tablets, 3 times daily by mouth (total of 3 grams daily)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Skin Biopsy - Intraepidermal Nerve Fiber Density (IENFD) - Distal Thigh	The intraepidermal nerve fiber density (IENFD) is the number of small nerve fibers which can be counted (under a microscope) in a 3 mm piece of skin taken from the distal (lower) thigh. IENFD is a continuous measure of small fiber neuropathy, with high positive and negative predictive values along with a high diagnostic efficiency in differentiating between people with and without neuropathy. People with neuropathy will generally have fewer nerve fibers (lower IENFD) than people without neuropathy. This study examined the change in IENFD after taking salsalate or a placebo daily for 12 months in people with diabetic neuropathy. Skin samples taken at the start of the study were compared to skin samples taken 12 months later to see if salsalate caused an increase in IENFD (suggesting improvement), or smaller decrease in IENFD (suggesting slower progression of neuropathy) relative to placebo.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Measures of Cardiac Autonomic Neuropathy (CAN) - Valsalva Ratio	Valsalva Ratio is the ratio of max tachycardia to max bradycardia caused by Valsalva maneuver	Baseline and 12 Months
Measures of Cardiac Autonomic Neuropathy (CAN) - Expiration/Inspiration Ratio	The expiration/inspiration ratio (E/I) ratio is measured during a period of slow, deep breathing (6 breaths per minute). It is the average heart rate increase divided by the average heart rate decrease over 6 breath cycles per minute	Baseline and 12 Months
Measures of Cardiac Autonomic Neuropathy (CAN) - 30:15 Ratio	Ratio of max RR interval ~30 heartbeats to min RR interval ~15 heartbeats	Baseline and 12 Months
Measures of Cardiac Autonomic Neuropathy (CAN) - SDNN	Standard deviation of NN intervals. The value indicates the amount of variability in the interval between each heart beat (the R-R interval). Value is expressed in milliseconds	Baseline and 12 Months
Measures of Cardiac Autonomic Neuropathy (CAN) - RMSSD	Root mean square of successive differences between normal heartbeats. It represents the average variation between the beat to beat intervals. The result is expressed in milliseconds.	Baseline and 12 Months
Nerve Conduction	Nerve Conduction Studies of the sural, peroneal, and ulnar nerves will be obtained at screening and 12 months. Nerve conduction studies are used to detect abnormalities in how the nerves are working. Nerve Conduction is represented as number of nerves with abnormal nerve conduction per participant.	Baseline and 12 months
Quantitative Sensory Testing - Just Noticeable Difference in COLD Detection	The Just Noticeable Difference (JND) in response to a cold stimulus applied to the top of the foot was measured using the CASE IV System. The range of JND values is from 1 to 25. A JND value of 1 means a person can detect temperature decrease of 0.063 degrees Celsius while a JND value of 25 means that the temperature has to drop by 20 degrees Celsius colder than before the person can notice the change in temperature. People with neuropathy will have higher JND values than people without neuropathy, indicating that they are less able to detect changes in temperature. For this study, the cold JND at the first visit was compared to the JND at the second visit to see if JND for cold detection after 12 months of treatment with salsalate or placebo.	Baseline and 12 months
Quantitative Sensory Testing - Just Noticeable Difference- Vibration	The Just Noticeable Difference (JND) in response to a vibrating stimulus (probe) applied to the toe was measured using the CASE IV System. The range of JND values is from 1 to 25. A JND value of 1 means a person can detect very light vibration (vibration magnitude of 0.106 micrometers) while a 25 means a much stronger vibration stimulus had to be applied to be detected (vibration magnitude of 576.603 micrometers). People with neuropathy will have higher JND values than people without neuropathy, indicating that they are less able to detect vibration. For this study, the vibration JND at the first visit was compared to the vibration JND at the second visit to see if the values had changed after 12 months.	Baseline and 12 months
Diabetic Neuropathy Symptoms	DN symptoms as evaluated by the Neuropathy Total Symptom Score-6 (NTSS-6). The NTSS-6 has 6 questions with individual scores between 0 and 3.66. Cumulative scores range from 0 to 21.96 with 21.96 being the worst neuropathy and 0 being no neuropathy.	Baseline to 12 months
Survey of Autonomic Symptoms (SAS)	Survey of Autonomic Symptoms (SAS) is a 12-item questionnaire. The range of scores is 0-60 for men and 0-55 for women, with higher scores indicating a higher degree of autonomic symptoms. Men and Women were not analyzed separately due to the comparable gender distribution between arms.	Baseline to 12 months
The DCCT/EDIC Structured Neurological Examination	The DCCT/EDIC Structured Neurological Examination is an examination that determines whether or not someone has evidence of neuropathy from diabetes. The examination categorizes patients into 3 categories: Definite Clinically Evident Peripheral Neuropathy, Possible Clinically Evident Peripheral Neuropathy, and No Clinically Evident Peripheral Neuropathy.	Baseline and 12 months
NeuroQOL	NeuroQOL is a self-administered questionnaire that measures the impact of neuropathy symptoms, especially those affecting the feet and legs, on quality of life. Shown are results from baseline, 6 and 12 months for the item "Overall, I would say problem with my feet reduced my quality of life". Responses are on a five-point scale (1 = "not at all" up to 5 = "very much") with higher values indicating a greater reduction in quality of life.	Baseline, 6 months and 12 months
Neuropathic Pain Scale	The Neuropathic Pain Scale is a questionnaire where participants rate the intensity of their pain and the quality of the pain (e.g., burning, aching, stabbing). Higher scores indicate greater pain. Scores range from 0 to 100.	baseline, 6 months, 12 months
The Berg Balance Scale	The Berg Balance Scale measures balance in 14 separate activities of daily living such as going from sitting-to-stand and standing on one leg; the unipedal stance portion that had been shown to be particularly reflective of neuropathy-related mobility loss. Scores range from 0 to 56, where lower scores indicate worst mobility and balance and 56 indicates best mobility and balance.	Baseline and 12 months
8 Foot Up and Go Test	The 8 Foot Up and Go Test, a test of functional mobility that assesses the time needed for a subject to arise from sitting position, walk 8 ft and turn 180 degrees around a cone and return sitting; Test results are expressed in seconds. The test is performed twice and the fastest speed is reported.	Baseline and 12 months
The Modified Falls Efficacy Scale	The Modified Falls Efficacy Scale assessing patient's self-reported ability to perform activities of daily living (e.g. get dressed/ undressed, walking, shopping). Scores range from 0 to 10 on 14 items. Resulting score is average score across those 14 questions, resulting in a score from 0 to 10. 0 represents the participant being not at all confident that they can complete activities without falling and 10 represents participant being entirely confident that they can complete activities without falling.	Baseline and 12 months

Collaborators and Investigators

• Sponsor: University of Michigan
• Investigators: Principal Investigator: Rodica Pop-Busui, MD, PhD, University of Michigan

Study record dates

Study Major Dates

• Study Start: October 1, 2016
• Primary Completion (Actual): May 1, 2023
• Study Completion (Actual): May 1, 2023

Study Registration Dates

• First Submitted: June 30, 2016
• First Submitted That Met QC Criteria: October 17, 2016
• First Posted (Estimated): October 18, 2016

Study Record Updates

• Last Update Posted (Actual): May 16, 2025
• Last Update Submitted That Met QC Criteria: May 14, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: Inflammation; Pain; Diabetes Mellitus; Adult; Neuropathy
• Additional Relevant MeSH Terms: Endocrine System Diseases; Nervous System Diseases; Pathologic Processes; Neuromuscular Diseases; Metabolic Diseases; Autoimmune Diseases; Immune System Diseases; Glucose Metabolism Disorders; Inflammation; Diabetes Mellitus; Peripheral Nervous System Diseases; Diabetes Mellitus, Type 1; Physiological Effects of Drugs; Anti-Inflammatory Agents; Peripheral Nervous System Agents; Antirheumatic Agents; Sensory System Agents; Analgesics, Non-Narcotic; Analgesics; Anti-Inflammatory Agents, Non-Steroidal; Salicylsalicylic acid
• Other Study ID Numbers: HUM00103828

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO