Safety and Tolerability of Perampanel in Cervical Dystonia
Safety and Tolerability of Perampanel in Cervical Dystonia
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.
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.
Inclusion Criteria:

 -  • 18-65 year old male and female patients with primary cervical dystonia.

 -  Subject may be untreated with botulinum toxin; treated with botulinum toxin but
 who are at least 8 weeks (+ 1 week) from a previous injection; or who have
 experienced an insufficient response to botulinum toxin in the opinion of the
 enrolling investigator. Note: We will aim to include subjects who have a stable
 response that lasts 12 weeks or longer.

 -  Subjects may be on stable anti-dystonia treatment (for at least one month)
 including anticholinergics, baclofen, and anxiolytics including benzodiazepines.

 Exclusion Criteria:

 -  Secondary cervical dystonia,

 -  Significant dystonia in body areas other than cervical region,

 -  Cognitive impairment (e.g., Montreal Cognitive assessment (MOCA) < 26);

 -  Active psychosis;

 -  History of aggression;

 -  Active depression (Hamilton Depression Rating Scale (HDRS) score ≥ 12).

 -  Current abuse of alcohol or subjects who do not agree to avoid alcohol during
 treatment,

 -  Substance abuse (current or prior);

 -  Active infection,

 -  Hypersensitivity to perampanel,

 -  Significant renal dysfunction (Creatinine clearance < 50ml/min),

 -  Significant laboratory abnormalities (ALT or AST greater than twice normal value;
 elevated bilirubin, active liver disease: hepatitis, cholestasis, cirrhosis,
 etc.),

 -  Significant medical illness,

 -  Women who are pregnant or plan to become pregnant, women who are breastfeeding,

 -  Subjects who do not agree to avoid consumption of grapefruit or
 grapefruit-containing products throughout the study,

 -  Galactose intolerance, the Lapp lactase deficiency or glucose-galactose
 malabsorption

 -  Use of prohibited medications known to be inducers of CYP3A including, but not
 limited to: rifampicin, troglitazone, St John's Wort, efavirenz, nevirapine,
 barbiturates, glucocorticoids (other than topical usage), modafinil,
 pioglitazone, and rifabutin; and any other interactions as per Product Monograph