Targeting Inflammation With Salsalate in Type 1 Diabetes Neuropathy
Condition: Type 1 Diabetes; Peripheral Neuropathy
MeSH terms: Peripheral Nervous System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Inflammation
Study type: Interventional
Phase: Phase 2/Phase 3

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.
    

Intervention name(s): Salsalate; PLACEBO
Intervention type(s): Drug; Drug
Intervention description(s): 1 gram, 3 times daily by mouth (total of 3 grams daily); Placebo for Salsalate; 2 Tabets, 3 times daily by mouth (total of 3 grams daily)
Other intervention name(s): disalcid
Intervention MeSH terms: Salicylsalicylic acid
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Pain; Inflammation; Diabetes Mellitus; Adult; Neuropathy