Safety and Tolerability of Perampanel in Cervical Dystonia (SAFE-PER-CD)
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|ClinicalTrials.gov Identifier: NCT02131467|
Recruitment Status : Recruiting
First Posted : May 6, 2014
Last Update Posted : February 4, 2019
|Condition or disease||Intervention/treatment||Phase|
|Cervical Dystonia||Drug: Perampanel||Phase 1 Phase 2|
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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||30 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||An Open-label Phase 2a Study to Evaluate the Safety and Tolerability of Perampanel (E2007) in Subjects With Cervical Dystonia (SAFE-Per CD)|
|Actual Study Start Date :||September 1, 2017|
|Estimated Primary Completion Date :||January 2020|
|Estimated Study Completion Date :||January 2020|
Perampanel 2 mg tablets will be initiated once daily at bedtime. The dose will be titrated over 6 weeks starting at 2 mg OD at baseline visit for 1 week, followed by 2mg increases every 1 week to a maximum of 12 mg/day. If side effects occur then patients will be decreased to previous dose level. If unable to tolerate increases, patients will enter the maintenance phase at previously tolerated dose, for minimum 4 weeks. Patients reaching 12 mg (maximal dose) will be maintained at that dose for 4 weeks. Taper will be over 2 weeks 1 tablet every 2 days from a maximum of 6 tablets per day to stop.
- Number of subjects able to remain on study drug for minimum of 4 weeks. [ Time Frame: Measured at week 12. ]Tolerability will be assessed by counting number of subjects able to remain on drug
- Safety will be evaluated as the cumulative number of new adverse events collected at each visit from Baseline to visit 4 [ Time Frame: Adverse events at study visits weeks 0, 2, 6, 8, 9, 10 and 12 ]Adverse events will be assessed at each visit by direct questioning patients, measuring weight, vital signs, Hamilton depression scale and laboratory tests and ECG
- Change from baseline to end of maintenance in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) [ Time Frame: week 12 ]The TWSTRS is a validated rating scale that measures disability due to cervical dystonia.
- CDIP58 [ Time Frame: week 12 ]Change in impact of Cervical Dystonia on quality of life using the CDIP 58 from baseline to end of maintenance
- CGI [ Time Frame: week 12 ]Change in Clinical global Impression (CGI) of Cervical Dystonia severity (patient and investigator) from baseline to end of maintenance
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02131467
|Contact: Susan H Fox, MRCP(UK), PhD||416 603 email@example.com|
|Contact: Brandon Rothberg||416 603 5800 ext firstname.lastname@example.org|
|United States, Georgia|
|Emory University School of Medicine||Recruiting|
|Atlanta, Georgia, United States, 30322|
|Contact: Buz Jinnah, MD PhD email@example.com|
|Principal Investigator: Buz Jinnah, MD PhD|
|United States, Illinois|
|Rush University Medical Center||Recruiting|
|Chicago, Illinois, United States, 60612|
|Contact: Cindy Comella, MD Cynthia_Comella@rush.edu|
|Contact: Teresa Chmura Teresa_Chmura@rush.edu|
|Principal Investigator: Cindy Comella, MD|
|United States, New York|
|Beth Israel Medical Center||Recruiting|
|New York, New York, United States, 10003|
|Contact: Matthew Swan, MD Matthew.Swan@mountsinai.org|
|Contact: Laura Ramirez firstname.lastname@example.org|
|Principal Investigator: Matthew Swan, MD|
|United States, Ohio|
|Cleveland, Ohio, United States, 44195|
|Contact: Hubert Fernandez, MD FERNANH@ccf.org|
|Principal Investigator: Hubert Fernandez, MD|
|Toronto Western Hospital||Recruiting|
|Toronto, Ontario, Canada, M5T 2S8|
|Contact: Susan Fox email@example.com|
|Contact: Brandon Rothberg firstname.lastname@example.org|
|Principal Investigator: Susan Fox|
|Principal Investigator:||Susan H Fox, MRCP(UK), PhD||University Health Network, Toronto|