Safety and Tolerability of Perampanel in Cervical Dystonia
Condition: Cervical Dystonia
MeSH terms: Dystonia; Dystonic Disorders; Torticollis
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Cervical dystonia (CD) is the most common focal dystonia. Currently there are no effective
      oral medications for the treatment of CD. While botulinum toxin injections improve symptoms,
      they require repeated injections by a trained physician and some patients stop responding to
      injections or never respond at all. Therefore, alternative treatment options for CD are
      needed. One new agent is a drug that targets glutamate receptors that are thought to be
      involved dystonia. This drug, perampanel, was originally developed for epilepsy and is
      licensed for use in the USA and Canada for treating epilepsy. The purpose of this study is to
      test the effectiveness of perampanel in treating the symptoms of CD.
    

Detailed description: 
      Idiopathic cervical dystonia (CD) is the most common form of focal dystonia with a prevalence
      of approximately 60 cases per million population.(Nutt et al.,1988). Current oral medical
      treatments for CD have variable efficacy and often with marked side effects. Botulinum toxin
      injections may be more effective than pharmacological therapies, and are currently the best
      available therapeutic option. However, repeat injections, administered by a physician trained
      in this area are required every 3-4 months.(Brans et al.,1996) This can often be difficult
      and costly for patients. Furthermore, there are subgroups of patients who simply do not
      respond to this treatment and between 5-20% of patients may become secondary non responders
      due to the development of blocking antibodies to the botulinum toxin.(Mejia et al., 2005)
      Thus, new therapeutic options are required.

      The neural mechanisms underlying idiopathic dystonia are not well known. Classical basal
      ganglia circuitry models predict underactivity of the output regions of the basal ganglia,
      the medial globus pallidus and substantia nigra pars reticulata (;Mitchell et al 1990). In
      subjects with dystonia undergoing DBS, intraoperative recordings have demonstrated
      underactivity of the medial globus pallidus (Vitek et al, 1999, Lozano et al 1997). One
      mechanism responsible for these basal ganglia output changes may be overactivity of
      corticostriatal glutamatergic pathways, as similar neural mechanism are thought to underlie
      other hyperkinetic movements (Brotchie 2005). The best studied hyperkinetic movement disorder
      is levodopa-induced dyskinesia in Parkinson's disease in which dystonia, often of the head
      and neck, may occur. In animal models of levodopa-induced dyskinesia, increased striatal
      glutamatergic signaling via alpha-amino-2,3-dihydro-5-methyl-3-oxo-4-isoxazolepropanoic acid
      (AMPA) receptors has been demonstrated (Perier et al 2002, Silverdale et al 2010). To date
      there are few validated animal models of idiopathic dystonia. However, one model that has
      been use for pharmacological studies, and the results extrapolated to idiopathic dystonia, is
      the paroxysmal dt(sz) dystonic hamster (Loscher and Richter 1998). In this model,
      intrastriatal and systemic injection of NBQX a selective AMPA receptor antagonist reduced
      dystonic severity (Richter et al 1993, Sander and Richter 2002, Kohling et al 2004). Other
      studies have suggested that cerebellar outflow pathways, using AMPA receptors may also
      mediate dystonic symptoms. Thus the excitatory amino-acid kainite injected into rodent
      cerebellar vermis resulted in dystonic symptoms, an effect revered by NBQX, suggesting an
      action on AMPA receptors (Pizoli et al 2002). Thus AMPA receptor antagonists may alleviate
      dystonia.

      To date, clinical studies using glutamate antagonists in CD have been limited due to lack of
      available drugs. A single 6-week open-label pilot study of the non-selective glutamate
      antagonist riluzole (50 mg twice a day) in six patients with cervical dystonia (CD) reported
      a 26% improvement in CD with no side-effects (Muller et al 2002).

      The aim of this study is to conduct a multicentre phase I/IIa open label study to determine
      the safety and tolerability of the AMPA antagonist, perampanel in subjects with primary
      cervical dystonia. Exploratory analysis will determine effects on dystonia disability and
      subjective measures including quality of life and global impression of change. The importance
      of such an initial safety study is due to the lack of knowledge related to the use of this
      class of drug (AMPA antagonist) in this population of patients. The longer term aim is thus
      to generate preliminary data for further randomised controlled efficacy studies.
    

Intervention name(s): Perampanel
Intervention type(s): Drug
Intervention description(s): oral drug
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment