Targeting Inflammation With Salsalate in Type 1 Diabetes Neuropathy
- Conditions
- Peripheral NeuropathyType 1 Diabetes
- Interventions
- Drug: PLACEBO
- Registration Number
- NCT02936843
- Lead Sponsor
- University of Michigan
- 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.
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 61
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Salsalate Salsalate Salsalate, 1 gram by mouth, 3 times daily (3 grams per day) for 12 months. Comparator PLACEBO Placebo for Salsalate, 2 tablets by mouth, 3 times daily for 12 months
- Primary Outcome Measures
Name Time Method Skin Biopsy - Intraepidermal Nerve Fiber Density (IENFD) - Distal Thigh 12 months 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.
- Secondary Outcome Measures
Name Time Method Measures of Cardiac Autonomic Neuropathy (CAN) - Valsalva Ratio Baseline and 12 Months Valsalva Ratio is the ratio of max tachycardia to max bradycardia caused by Valsalva maneuver
Measures of Cardiac Autonomic Neuropathy (CAN) - SDNN Baseline and 12 Months 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
Measures of Cardiac Autonomic Neuropathy (CAN) - Expiration/Inspiration Ratio Baseline and 12 Months 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
Measures of Cardiac Autonomic Neuropathy (CAN) - 30:15 Ratio Baseline and 12 Months Ratio of max RR interval \~30 heartbeats to min RR interval \~15 heartbeats
Measures of Cardiac Autonomic Neuropathy (CAN) - RMSSD Baseline and 12 Months 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.
Nerve Conduction Baseline and 12 months 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.
Quantitative Sensory Testing - Just Noticeable Difference in COLD Detection Baseline and 12 months 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.
Quantitative Sensory Testing - Just Noticeable Difference- Vibration Baseline and 12 months 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.
Diabetic Neuropathy Symptoms Baseline to 12 months 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.
Survey of Autonomic Symptoms (SAS) Baseline to 12 months 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.
The DCCT/EDIC Structured Neurological Examination Baseline and 12 months 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.
NeuroQOL Baseline, 6 months and 12 months 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.
Neuropathic Pain Scale baseline, 6 months, 12 months 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.
The Berg Balance Scale Baseline and 12 months 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.
8 Foot Up and Go Test Baseline and 12 months 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.
The Modified Falls Efficacy Scale Baseline and 12 months 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.
Trial Locations
- Locations (2)
University of Michigan Health System
🇺🇸Ann Arbor, Michigan, United States
Veterans Administration Ann Arbor Health Center
🇺🇸Ann Arbor, Michigan, United States