Targeting Inflammation With Salsalate in Type 1 Diabetes Neuropathy

NCT02936843 | Completed Phase 2 Results DMC

• 1 other identifier: HUM00103828
• Study Type: interventional
• Target: 61
• Locations: 1 country
• Sites: 2

Brief Summary

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.

Conditions

Type 1 Diabetes; Peripheral Neuropathy

Keywords

Pain; Inflammation; Diabetes Mellitus; Adult; Neuropathy

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (16)

• Measures of Cardiac Autonomic Neuropathy (CAN) - Valsalva Ratio

  Baseline and 12 Months

• Measures of Cardiac Autonomic Neuropathy (CAN) - Expiration/Inspiration Ratio

  Baseline and 12 Months

• Measures of Cardiac Autonomic Neuropathy (CAN) - 30:15 Ratio

  Baseline and 12 Months

• Measures of Cardiac Autonomic Neuropathy (CAN) - SDNN

  Baseline and 12 Months

• Measures of Cardiac Autonomic Neuropathy (CAN) - RMSSD

  Baseline and 12 Months

Study Arms (2)

Salsalate

EXPERIMENTAL

Salsalate, 1 gram by mouth, 3 times daily (3 grams per day) for 12 months.

Drug: Salsalate

Comparator

PLACEBO COMPARATOR

Placebo for Salsalate, 2 tablets by mouth, 3 times daily for 12 months

Drug: PLACEBO

Interventions

Salsalate DRUG

1 gram, 3 times daily by mouth (total of 3 grams daily)

Also known as: disalcid

Salsalate

PLACEBO DRUG

Placebo for Salsalate; 2 Tablets, 3 times daily by mouth (total of 3 grams daily)

Comparator

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• T1DM;
• age 18-70;
• 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);
• sural nerve amplitude \> 0 μV. If sural nerve amplitude is 0 μV (unrecordable) peroneal motor nerve conduction velocity must be ≥ 35 m/second\*;
• on a stable insulin regimen for the 3 months prior to enrollment;
• 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;
• be willing to accept random treatment assignment to salsalate or placebo; and
• 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.

You may not qualify if:

• 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);
• 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.
• 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;
• serum creatinine \>1.4 for women and \>1.5 for men or eGFR \<60 \[possible chronic kidney disease stage 3 or greater calculated using the Modification of Diet in Renal Disease (MDRD) equation\];
• pregnancy or lactation, or intention to become pregnant in next 12 months;
• history of previous lung, kidney, pancreas, liver, cardiac or bone marrow transplant;
• history of drug or alcohol abuse within the previous 5 years, or current weekly alcohol consumption \>10 units/week;
• 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.
• use of lithium
• participation in an experimental medication trial within 3 months of starting the study;
• current therapy for malignant disease other than basal- cell or squamous-cell skin cancer;
• 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;
• You have developed keloid scarring in the past. Keloids are large, thick masses of scar tissue. These are more common among dark-skinned people.
• 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
• 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.

Sponsors & Collaborators

• University of Michigan: lead

Study Sites (2)

Veterans Administration Ann Arbor Health Center

Ann Arbor, Michigan, 48105, United States

Location

University of Michigan Health System

Ann Arbor, Michigan, 48109, United States

Location

Related Publications (1)

• Ang L, Gunaratnam S, Huang Y, Dillon BR, Martin CL, Burant A, Reiss J, Blakely P, Vasbinder A, Zhao L, Mizokami-Stout K, Tang Y, Feldman EL, Doria A, Spino C, Banerjee M, Hayek SS, Pop-Busui R. Inflammatory Markers and Measures of Cardiovascular Autonomic Neuropathy in Type 1 Diabetes. J Am Heart Assoc. 2025 Jan 7;14(1):e036787. doi: 10.1161/JAHA.124.036787. Epub 2024 Dec 27.

  PMID: 39727210 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 1; Peripheral Nervous System Diseases; Pain; Inflammation; Diabetes Mellitus

Interventions

salicylsalicylic acid

Condition Hierarchy (Ancestors)

Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases; Neuromuscular Diseases; Nervous System Diseases; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Pathologic Processes

Results Point of Contact

• Title: Rodica Pop-Busui, MD, PhD
• Organization: The University of Michigan

rpbusui@med.umich.edu

Phone 734-647-9809

Study Officials

• Rodica Pop-Busui, MD, PhD

  University of Michigan

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Internal Medicine

Study Record Dates

• First Submitted: June 30, 2016
• First Posted: October 18, 2016
• Study Start: October 1, 2016
• Primary Completion: May 1, 2023
• Study Completion: May 1, 2023
• Last Updated: May 16, 2025
• Results First Posted: May 16, 2025

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)