Trial Outcomes & Findings for Targeting Inflammation With Salsalate in Type 1 Diabetes Neuropathy (NCT NCT02936843)

Ninety-six (96) people underwent eligibility screening to participate in the study. Of these, 64 satisfied the eligibility criteria for participation, and 61 were randomly assigned and entered the treatment phase of the study (and shown as started in the table below). Three of the 64 eligible participants did not complete visit 2, and therefore, were not assigned to treatment. Informed consent was obtained from all participants at the time of their screening visit.

Targeting Inflammation With Salsalate in Type 1 Diabetes Neuropathy

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.

Valsalva Ratio is the ratio of max tachycardia to max bradycardia caused by Valsalva maneuver

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

Ratio of max RR interval \~30 heartbeats to min RR interval \~15 heartbeats

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

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 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.

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.

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.

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) 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 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 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.

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 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.

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 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.