Ketamine for Treatment of MS Fatigue
Condition: Multiple Sclerosis; Fatigue
MeSH terms: Multiple Sclerosis; Sclerosis; Fatigue
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Multiple sclerosis (MS) is an inflammatory, demyelinating and degenerative disease of the
      central nervous system and, after trauma, is the most common cause of disability in young
      adults, affecting more than 400,000 individuals in the US. Of all the symptoms that can occur
      with MS, chronic fatigue is the most common and disabling, reported by at least 75% of
      patients at some point. Fatigue limits patients' daily activities, and challenges employment,
      resulting in substantial socioeconomic consequences. Despite this negative impact, fatigue
      treatments have been inconsistently studied, in part due to poorly understood underlying
      pathophysiological mechanisms. Yet to be defined biological processes and lack of clear
      treatment targets have also hampered the development of drugs for fatigue. As a result, there
      are no medications approved by the Food and Drug Administration (FDA) for the treatment of MS
      fatigue.

      The investigators recently reported that riluzole, a medication with anti-glutamatergic
      effects, increased the fatigue severity in patients with relapsing MS who had participated in
      a clinical trial evaluating potential neuroprotective effects of riluzole versus placebo.
      Three other clinic trials which examined memantine effects on cognition in patient with MS
      also reported worsening fatigue as a major side effect. Memantine main mechanism of action is
      blocking the N-methyl D-aspartate (NMDA) glutamate receptor. These observations prompted the
      investigators that glutamatergic transmission probably plays an important role in fatigue
      pathogenesis and modulating these pathways could have potential therapeutic effect on
      MS-related fatigue. A recent paper reported that ketamine, an NMDA receptor blocker with
      different kinetics compared to memantine, had a strong and prolonged effect in reducing
      fatigue in bipolar patients who participated in a clinical trial, evaluating anti-depressive
      effects of ketamine versus placebo. Interestingly, the effect of ketamine on fatigue was
      independent of its antidepressant effects.

      The primary objective of this study is to determine if modulating glutamatergic transmission
      with ketamine is safe and efficacious in improving MS-related fatigue. These objectives will
      be answered in a proof of concept, randomized controlled trial of ketamine versus an active
      placebo (midazolam) in patients with relapsing or progressive MS who have clinically
      significant fatigue.

      18 patients with MS and reported fatigue, will be randomized 2:1 to one infusion of ketamine
      0.5 mg/kg over 40 minutes versus one infusion of midazolam 0.05 mg/kg over 40 minutes.
      Midazolam is chosen as an active placebo to keep the participants blinded to participants'
      medication assignment. Primary outcome of the study will be Daily Fatigue Severity measured
      daily from day one through day seven post-infusion.

      Secondary outcomes of the study include other fatigue questionnaires, depression and
      sleepiness. The length of study will be around 28 days.
    


Intervention name(s): Ketamine; Midazolam
Intervention type(s): Drug; Drug
Intervention description(s): One intravenous infusion of ketamine 0.5 mg/kg over 40 minutes; One intravenous infusion of midazolam 0.05 mg/kg over 40 minutes
Intervention MeSH terms: Midazolam; Ketamine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment