Omega-3 Fatty Acid Lipidomics in Diabetes Peripheral Neuropathy

NCT05169060 | Recruiting Phase 1 DMC FDA Drug

• 2 other identifiers: 2021103631R01DK126837-01A1
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 2

Brief Summary

Diabetic peripheral neuropathy (DPN) is the most common chronic complication of diabetes, affecting about 50% of patients with diabetes and leading to severe morbidity, poor quality of life, high mortality, and high health care costs. Due to the complex structure and anatomy of the peripheral nervous system, DPN presents with a very broad spectrum of clinical symptoms and deficits, including severe pain, sensory deficits, foot ulcers and amputations. Presently there is no treatment for DPN and even with good blood glucose control DPN develops especially in patients with type 2 diabetes. There is a need to identify effective interventions for DPN. Preclinical studies have provided evidence that the combination of fish oil and salsalate is an effective treatment of DPN. The human subject study to be performed will examine the effect of fish oil with and without salsalate on the blood lipid profile and circulating metabolites of omega-3 polyunsaturated fatty acids (PUFA). Fish oil is an excellent source for the nutrition dependent omega-3 PUFA, primarily eicosapentaenoic acid (EPA; 20:5) and docosahexaenoic acid (DHA; 22:6). These fatty acids are the source of anti-inflammatory metabolites known as resolvin, neuroprotectin and maresin. Preclinical studies have also demonstrated that the metabolites of EPA and DHA are neuroprotective. Furthermore, when fish oil is combined with salsalate the production of these metabolites is increased in vivo. Thus, the investigators hypothesize that fish oil and salsalate will be an effective therapy of DPN. However, prior to doing a formal study of the effect of fish oil + salsalate on DPN there is a need to learn more about what concentration combination will provide the most efficacious effect on the omega-3 index (defined as the sum of EPA and DHA, as a percentage of total fatty acids in red blood cells) and that will safely increase the production of the anti-inflammatory metabolites. These studies will be performed at two sites the University of Iowa (Dr. Yorek) and University of Michigan (Dr. Pop-Busui) by treating human subjects with type 2 diabetes and DPN with either 2g or 4g of fish oil per day (capsules) for 4 months and then adding salsalate 1.5 g or 3g per day (tablets) to the fish oil treatments for an additional 2 months. At baseline and after treatment with fish oil alone and after treatment with the combination of fish oil and salsalate the omega-3 index and levels of circulating omega-3 PUFA metabolites will be determined as primary endpoints. Secondary endpoints will include determination of circulatory inflammatory markers and non-invasive measurements for DPN. The risks to subjects are minimal and are very reasonable in relation to the importance of the knowledge to be gained.

Conditions

Diabetic Neuropathies

Keywords

diabetes; diabetic peripheral neuropathy; omega-3 polyunsaturated fatty acids; resolvin; neuroprotectin; inflammation; omega-3 index

Outcome Measures

Primary Outcomes (1)

• Change from baseline of omega-3 index at 16 and 24 weeks

  The omega-3 index is defined as defined as the sum of EPA and DHA, as a percentage of total fatty acids in red blood cells. Red blood cells will be isolated by centrifugation and subsequently analyzed for fatty acid composition following folch extraction of the lipids, derivatization and analysis of the fatty acid profile by gas liquid chromatography. These studies will be done in Dr. Yorek's laboratory.

  At baseline, 16 weeks and 24 weeks.

Secondary Outcomes (15)

• Change in baseline of serum levels of resolvin D1, resolvin E1 and neuroprotectin D1, omega-3 polyunsaturated fatty acid metabolites, at 16 and 32 weeks.

  At baseline, 16 weeks and 24 weeks.

• Changes from baseline of serum levels of C reactive protein at 16 and 24 weeks.

  At baseline, 16 weeks and 24 weeks.

• Changes from baseline of serum levels of tumor necrosis factor α at 16 and 24 weeks.

  At baseline, 16 weeks and 24 weeks.

• Changes from baseline of serum levels of interleukin 6 at 16 and 24 weeks.

  At baseline, 16 weeks and 24 weeks.

• Changes from baseline of serum levels of interleukin 10 at 16 and 24 weeks.

  At baseline, 16 weeks and 24 weeks.

Study Arms (2)

Fish oil capsules

EXPERIMENTAL

Subjects will be randomized for the treatment of fish oil capsules. Subjects will take daily supplements of two or four fish oil capsules per day, 2 and 4 g respectively. Treatment will continue for 16 weeks. Fish oil capsules are enriched in omega-3 polyunsaturated fatty acids.

Drug: Fish Oil Concentrate, 1000 Mg Oral Capsule

Fish oil and Salsalate

EXPERIMENTAL

Salsalate is a non-steroid anti-inflammatory drug. Subjects taking 2 or 4g of fish oil capsules will be randomized to take in addition 1.5 or 3.0 g of salsalate per day. The combined treatment of fish oil and salsalate will continue for 8 weeks.

Drug: Fish Oil Concentrate, 1000 Mg Oral Capsule; Drug: Salsalate Oral Tablet

Interventions

Fish Oil Concentrate, 1000 Mg Oral Capsule DRUG

Oral capsules, 2 grams or 4 grams per day.

Fish oil and Salsalate; Fish oil capsules

Salsalate Oral Tablet DRUG

Oral tablets, 1.5 gram or 3.0 gram per day.

Fish oil and Salsalate

Eligibility Criteria

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

You may qualify if:

• T2D according to American Diabetes Association (ADA) criteria (38).
• Age ≥ 18 yr.
• HbA1c \< 9.5%.
• Presence of DPN based on Michigan Neuropathy Screening Instrument (combined questionnaire and a clinical examination of the response to vibration perception examination using a 128 Hz tuning fork and ankle reflexes), a validated, sensitive, and specific instrument for the diagnosis of DPN as reported (39,40). Pin prick sensation will be performed (as measures of small-fiber neuropathy) for DPN confirmation (41-43).
• Be willing and capable of providing a written consent form and willing and able to cooperate with the medical procedures for the study duration.
• Women of childbearing potential must be willing to use appropriate contraception during the entire trial.

You may not qualify if:

• History of any other causes of neuropathy (e.g. other neurological disorders, medications-induced, occupational history, active hepatitis C infection, exposure to toxins).
• History of persistent macroalbuminuria \[random urine microalbumin creatinine ratio (ACR) up to 300 mg/gm\]is acceptable if calculated GFR is \>60 (16).
• Serum creatinine \>1.4 for women and \>1.5 for men or eGFR \<60 \[calculated using the CKD-EPI equation\].
• Use of warfarin (Coumadin), clopidogrel (Plavix), dipyridamole (Persantine), heparin or other anticoagulants, probenecid (Benemid, Probalan), sulfinpyrazone (Anturane) or other uricosuric agents; Participants 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.
• Uncontrolled hypertension
• Triglyceride \> 400 mg/100ml.
• History of previous organ transplantation (kidney, pancreas, liver, lung or cardiac transplantation).
• History of drug or alcohol abuse within 5 years, or current weekly alcohol consumption \>10 units/week.
• Pregnancy or breast feeding or desire to become pregnant in the next 12 months
• Requiring long-term glucocorticoid therapy or chronic immunosuppressive therapy including daily use of inhaled glucocorticoids. Periodic or intermittent use of inhaled glucocorticoids (less than daily) is allowable.
• 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;
• History of taking fish oil supplements in the 6 months prior to the screening visit.

Sponsors & Collaborators

• University of Iowa: lead
• University of Michigan: collaborator
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator
• Oregon Health and Science University: collaborator

Study Sites (2)

University of Iowa

Iowa City, Iowa, 52241, United States

RECRUITING

Oregon Health Science University

Portland, Oregon, 97239, United States

RECRUITING

MeSH Terms

Conditions

Diabetic Neuropathies; Diabetes Mellitus; Inflammation

Interventions

salicylsalicylic acid

Condition Hierarchy (Ancestors)

Peripheral Nervous System Diseases; Neuromuscular Diseases; Nervous System Diseases; Diabetes Complications; Endocrine System Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Mark A Yorek, PhD

  Professor of Medicine

  PRINCIPAL INVESTIGATOR

• Rodica Pop-Busui, MD

  Professor of Medicine

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Mark A Yorek, PhD

CONTACT

319-338-0581; mark-yorek@uiowa.edu

Rodica Pop-Busui, MD

CONTACT

503-494-3273; busui@ohsu.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine

Model Details: Following recruitment and eligibility confirmation the study subjects will be randomized to take either 2g or 4g (in the form of capsules) of fish oil and either 1.5g or 3g of salsalate in addition to the fish oil in the final 2 months of the study. Randomization will be performed using permuted blocks, with a block size that is known only to the statistician. Each enrolled subject will be assigned a study number and all data and specimens from the subject will be identifiable only by the number assigned.

Study Record Dates

• First Submitted: November 23, 2021
• First Posted: December 23, 2021
• Study Start: June 12, 2023
• Primary Completion (Estimated): February 1, 2027
• Study Completion (Estimated): July 1, 2027
• Last Updated: July 20, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)