Inosine 5'-Monophosphate to Raise of Serum Uric Acid Level in Patients With Multiple System Atrophy: a Multi-center, Randomized Controlled, Double Blind, Parallel Assigned Clinical Trial
Condition: Multiple System Atrophy
MeSH terms: Multiple System Atrophy; Shy-Drager Syndrome; Atrophy
Study type: Interventional
Phase: Phase 2

Summary: 
      A purpose of the present study is to investigate the capability of serum uric acid elevation,
      safety, and tolerability of inosine 5'-monophosphate in patients with multiple system atrophy
      with multicenter, randomized, placebo controlled, parallel assigned design. This may provide
      the cornerstone for future extended trial in multiple system atrophy, a debilitating disease
      to date.
    

Detailed description: 
      Background and objective:

      Uric acid (UA) is the end product of purine metabolism in human body, which is converted from
      the precursor metabolite inosine and finally excreted via route of urine and gastrointestinal
      tract. A high level of UA, usually ≥ 7.0 mg/dL, may lead to development of gout,
      nephrolithiasis, or to give detrimental effect to a variety of medical diseases, such as
      chronic kidney disease, cardiovascular disorders, and diabetes. Meanwhile, UA is the very
      well-known antioxidant, in which the biological antioxidant act as scavenging free radicals
      (e.g. peroxynitrite), chelating iron, and preventing peroxidation of lipid. Although there
      have been two faced aspects on UA, antioxidant versus pro-inflammatory potentials, toward
      neurodegenerative disorders, converging evidences have been highlighting the effects of
      potential disease modification so far. Given the certain contribution of oxidative stress to
      the pathogenesis of various neurodegenerative disorders, a therapeutic attempts to
      anti-oxidation may be promising and feasible. In observational study, ample evidence has been
      suggested to be beneficial associations between higher uric acid level and lower the risk of
      disease, clinical severity and progression in Parkinson's disease, Alzheimer's disease,
      Huntington's disease, amyotrophic lateral sclerosis, ischemic stroke, and even up to
      myasthenia gravis across clinical, epidemiological, and radiological studies. In addition, on
      aspect of interventional study, there have been 4 randomized clinical trials of increasing
      serum uric acid via administration of inosine so far in multiple sclerosis, stroke,
      amyotrophic lateral sclerosis, and Parkinson's disease. All of the studies have demonstrated
      reliable capability of increasing serum uric acid level, and favorable safety and
      tolerability profile. Currently, a phase II trial in Parkinson's disease demonstrated hopeful
      view in disease modifying strategy by modulating disease progression rate on the inosine
      administered group with a dose dependent manner.

      In case of multiple system atrophy (MSA), there have been a couple of previous reports
      including increased serum level of UA in MSA compared to healthy control, and strong
      correlation in serum uric acid level with either motor or cognitive functions. However, no
      interventional studies have been undertaken to date at all regarding UA. We aimed to
      investigate the UA elevating capability, safety, and tolerability of inosine
      5'-monophosphate, a precursor of uric acid, in MSA patients with randomized, placebo
      controlled, and parallel assigned design.

      Methods:

      All participants are randomized to study drugs, either tablet of placebo or inosine
      5'-monophosphate, in 1 to 1 ratio and then undergo scheduled titration. Study drugs are
      initiated with 1 tablet 2 times per day, and then titrate up by 1 tablet per every visit up
      to visit 2. That is, 1 tablet two times per day for initial 2 weeks, 1 tablet three times per
      day from next week 3 to 4, and 2 tablets two times per day from next week 4 to 6, and then
      maintain throughout to week 24. Laboratory tests including serum uric acid level, urine
      analysis, and stone analysis are scheduled to be checked at time of week 2, 4, 6, 12, 18, and
      24, respectively. A maximum limit of elevated serum uric acid level is 9 mg/dL, and thus
      reducing dose of administration may be considered in case of exceeding the limited level.
      Comparison of the extent of altered serum uric acid level, safety, and tolerability from
      baseline to week 24 will be analyzed after study termination.
    

Intervention name(s): 1) Inosine 5'-monophosphate; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 1) Subjects are initiated with 1 tablet (500mg of inosine 5'-monophosphate per one tablet) two times per day, and then titrated up by 1 tablet per every visit up to visit 2, i.e. increased up to 2 tablets two times a day by week 6. A maximum limit of elevated serum uric acid level is 9 mg/dL, so that reducing dose of administration may be considered in case of being way over the top of limited level.; 2) Subjects are initiated with 1 tablet (500mg of placebo tablet with inactive therapeutic effect) two times a day, and then titrated up by 1 tablet per every visit up to visit 2, i.e. increased up to 2 tablets two times a day by week 6. A maximum limit of elevated serum uric acid level is 9 mg/dL.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Multiple system atrophy; Uric acid; Inosine 5'-monophosphate; Inosine monophosphate; Inosinic acid