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

• ClinicalTrials.gov Identifier: NCT02936843
• Recruitment Status: Recruiting
• First Posted: October 18, 2016
• Last Update Posted: December 4, 2019
• Sponsor: University of Michigan
• Information provided by (Responsible Party): Rodica Pop-Busui, University of Michigan

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Type 1 Diabetes; Peripheral Neuropathy	Drug: Salsalate; Drug: PLACEBO	Phase 2; Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 70 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Targeting Inflammation With Salsalate in Type 1 Diabetes Neuropathy-TINSAL -T1DN
• Study Start Date: October 2016
• Estimated Primary Completion Date: December 2021
• Estimated Study Completion Date: June 2023

Arms and Interventions

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 Name: disalcid
Placebo Comparator: Comparator; Placebo for Salsalate, 2 tablets by mouth, 3 times daily for 12 months	Drug: PLACEBO; Placebo for Salsalate; 2 Tabets, 3 times daily by mouth (total of 3 grams daily)

Outcome Measures

Primary Outcome Measures :

1. Skin Biopsy - Intraepidermal Nerve Fiber Density (IENFD) - Distal Thigh [ Time Frame: 12 months ]
   Change from baseline to month 12 in the intraepidermal nerve fiber density. 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 subjects with and without neuropathy. The morphometric quantification of IENFD, most commonly expressed as the number of IENFs per length of section (IENF/mm e.g. density) is possible with skin biopsy (IENFD) at the distal thigh.

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Contacts

Contact: Rodica Pop-Busui, MD, PhD; 734-763-3056; rpbusui@umich.edu

Contact: Jacob Reiss, BS; 734-763-0177; jereiss@med.umich.edu

Locations

United States, Michigan

University of Michigan Health System; Recruiting

Ann Arbor, Michigan, United States, 48109

Contact: Abby Burant, BS 734-615-0552 aburant@med.umich.edu

Contact: Jacob Reiss, BS 734-763-0177 jereiss@med.umich.edu

Principal Investigator: Rodica Pop-Busui, MD, PhD

Sub-Investigator: Lynn Ang, MD

Principal Investigator: Eva Feldman, MD, PhD

Sub-Investigator: Kara Mizukami-Stout, MD

Henry Ford Health System; Recruiting

Detroit, Michigan, United States, 48202

Contact: Liz Warner 313-916-3608 ewarner1@hfhs.org

Contact: Heather Remtema, MPH 313-916-3906 hremtem1@hfhs.org

Principal Investigator: Davida F Kruger, MSN, APN-BC, BC-ADM

Sponsors and Collaborators

University of Michigan

Investigators

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

More Information

• Responsible Party: Rodica Pop-Busui, Professor of Internal Medicine, University of Michigan
• ClinicalTrials.gov Identifier: NCT02936843 History of Changes
• Other Study ID Numbers: HUM00103828
• First Posted: October 18, 2016
• Last Update Posted: December 4, 2019
• Last Verified: December 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Keywords provided by Rodica Pop-Busui, University of Michigan:

Pain; Inflammation; Diabetes Mellitus; Adult; Neuropathy

Additional relevant MeSH terms:

Peripheral Nervous System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Inflammation; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Pathologic Processes; Autoimmune Diseases; Immune System Diseases; Neuromuscular Diseases; Nervous System Diseases; Salicylsalicylic acid; Sodium Salicylate; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action