Famotidine for Levodopa-induced Dyskinesia in PD
Condition: Dyskinesia
MeSH terms: Dyskinesias
Study type: Interventional
Phase: Phase 2

Summary: 
      Levodopa-induced dyskinesia is a common problem in Parkinson's disease (PD). In particular,
      targeting non-dopaminergic systems may be an option for reducing dyskinesia without worsening
      motor symptoms. One such target may be histamine. The central histaminergic system is
      involved in diverse biological functions including thermoregulation, eating, and sleep; a
      role in motor activity is suggested by strong histaminergic innervation of the basal ganglia.
      Histamine H2 receptors are highly expressed in the striatum, particularly on the GABAergic
      striatal-pallidal and striatal-nigral pathways Histamine H2 stimulation modulates
      acetylcholine release. Previous studies have demonstrated that blocking acetylcholine with
      anticholinergic agents can induce chorea. The investigators propose that histamine H2
      receptor stimulation decreases acetylcholine in the striatum and increases activity of the
      direct striatal output pathway, a key component of the neural mechanisms underlying
      dyskinesia.

      The investigators hypothesise that H2 antagonists would reduce activity of the direct
      striatopallidal pathway and so potentially reduce levodopa-induced chorea

      Famotidine has also been assessed in schizophrenia in a small cases series to treat
      schizophrenia, with tolerability. Clinical experience thus suggests the suitability of using
      this agent as a histamine H2 antagonist in clinical studies for PD.
    

Detailed description: 
      The proposed study will be composed of multiple N -of 1 studies performed in a randomized,
      double-blind, placebo-controlled multiple (4) crossover fashion. Twelve PD patients (thus 12
      N-of-1 trials) with levodopa-induced dyskinesia will complete 4 treatment phases; one phase
      at each of the 3 doses of famotidine and one of placebo. The treatment doses will be:
      famotidine 40mg/day, 80mg/day, and 120mg/day. The phases will occur in a random order, but
      each subject will receive each of the treatment doses during the course of the study. After
      each phase of treatment (14 days), there will be a washout period (7 days, over 10 half-lives
      of famotidine) followed by a crossover. The primary outcome will be the change in Unified
      Dyskinesia Rating Scale (UDysRS) between placebo and famotidine at the end of each treatment
      phase and secondary outcomes will be Movement Disorder Society Unified Parkinson Disease
      Rating Scale (MDS-UPDRS) parts III and IV, Clinical Global Impression (CGI), Lang-Fahn
      activities of daily living dyskinesia scale (LFADLDS) and assessment of adverse effects.
    

Intervention name(s): Famotidine
Intervention type(s): Drug
Intervention description(s): Each patient will receive 4 randomized treatment phases - three famotidine (one at each of the dose levels) and one placebo. Each treatment phase will last for 14 days. Doses of drug will be titrated upwards, starting at 40mg once daily on day one, 40mg twice daily on day two, and 80mg twice daily (or placebo + drug equivalent) from day three and then continue on this dose for the next 12 days. Regardless of treatment phase, subjects will take 2 tablets twice daily, with varying ratios of active famotidine to placebo. Thus famotidine 80mg/d will consist of 1 tablet of 40 mg famotidine plus 1 tablet of placebo twice a day; 120 mg /d famotidine will be 2 tablets at 40 mg morning and 1 tablet famotidine 40 mg plus 1 tablet placebo evening; famotidine 160 mg/d will be famotidine 40 mg tablets, 2 tablets twice a day. The placebo phase will consist of 2 placebo tablets twice a day.
Intervention MeSH terms: Famotidine
Intervention model: Single Group Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment