Open-Trial of EPI-743 for Adults With Tourette Syndrome

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Brief Title

Open-Trial of EPI-743 for Adults With Tourette Syndrome

Official Title

Open-Trial of EPI-743 for Adults With Tourette Syndrome

Brief Summary

      The purpose of this study is to examine the effects of EPI-743 on tic severity in adults with
      Tourette syndrome.
    

Detailed Description

      Tourette syndrome (TS) is a childhood-onset neuropsychiatric disorder characterized by
      multiple motor and vocal tics that last for at least a year in duration. Currently, there
      exist several effective pharmacological treatments for childhood tics including alpha-2
      agonist medications (guanfacine and clonidine) and neuroleptics (antipsychotic) medications.
      These medications, however, have significant side-effects and are only partially effective in
      treating tics.

      EPI-743 is an orally absorbed small molecule that readily crosses into the central nervous
      system. It works by targeting an enzyme NADPH quinone oxidoreductase 1 (NQO1). Its mode of
      action is to synchronize energy generation in mitochondria with the need to counter cellular
      redox stress. EPI-743 has recently received orphan drug status from the U.S. Food and Drug
      Administration (FDA). The FDA has allowed an Expanded Access program to provide EPI-743 to
      seriously ill patients diagnosed with inherited respiratory chain diseases of the
      mitochondria.

      The rationale for the use of this agent is indirect. Over the past 10 years, defects in
      mitochondrial oxidative phosphorylation (OXPHOS) have been implicated in a wide variety of
      neurodegenerative and neuromuscular diseases. One neurological symptom that has definitely
      been associated with OXPHOS is the movement disorder dystonia. A specific missense mutation
      in the mtDNA complex I (NADH dehydrogenase) gene, MTND6, has been linked to maternally
      inherited dystonia along with the companion phenotype, Leber's hereditary optic neuropathy.
      In addition, other mitochondrial diseases are also associated with movement disorders
      including Friedreich's ataxia (ataxia) and Leigh's disease (loss of head control and other
      motor skills). EPI-743 has been effective in treating children and adults with these
      diseases. Over time, many TS patients develop complex motor tics, which are sudden, more
      purposive appearing, stereotyped movements of variable duration. Examples are myriad and
      include facial gestures and movements such as brushing hair back, possibly in combination
      with head jerk, and body shrugs. Gyrating, bending, and twisting movements of the head or
      torso are also seen. These slow twisting movements are usually referred to as dystonic tics.

      A second line of evidence concerns the potential therapeutic value N-acetyl-cysteine (NAC) in
      the treatment of neuropsychiatric conditions closely related to TS including Trichotillomania
      (TTM) and Obsessive-compulsive disorder [OCD]. Recent double-blind, placebo-controlled
      studies of NAC have provided evidence of efficacy in reducing the symptoms of
      trichotillomania (TTM) in adults [49]. The effect size in this 12-week study was strikingly
      large (d = 1.3). Trichotillomania, like TS, is considered to be an obsessive-compulsive
      spectrum disorder. Individuals with TTM experience urges prior to hairpulling, similar to the
      urges in TS. Case reports have also suggested the potential efficacy of NAC in treating OCD.
      NAC is hypothesized to have two possible mechanisms of action. NAC is converted to cystine, a
      substrate for the glutamate/cystine antiporter located on glial cells. The uptake of cystine
      by glia causes the release of glutamate into the extrasynaptic space, where it stimulates
      inhibitory metabotropic glutamate receptors on glutamatergic nerve terminals and thereby
      reduces the synaptic release of glutamate. NAC is also a precursor of glutathione, the major
      antioxidant in the brain. Through this mechanism NAC is hypothesized to improve OXPHOS. One
      effect of EPI-743's activity on NQO1 is restoration of cellular glutathione stores.

      A third line of indirect evidence is that in postmortem brain studies, the two classes of
      interneurons that are reduced in number in the basal ganglia are "high energy" consuming
      cells, i.e., GABAergic, fast spiking internerons and cholinergic tonically active
      interneurons. Given the high energy demand associated with these cells perhaps their loss is
      partially due to defects in OXPHOS.

      A fourth line of indirect evidence is that when EPI-743 is effective in treating
      mitochrondrial disease, brain regions with very low HMPAO uptake show a marked increase in
      uptake. In the case of TS (50 cases and 20 controls) HMPAO uptake was found to be reduced in
      the left caudate, anterior cingulate cortex and the left dorsolateral prefrontal cortex.
      Severity of tics was related to hypoperfusion of the left caudate and cingulate and a left
      medial temporal region.
    

Study Phase

Phase 1

Study Type

Interventional


Primary Outcome

Yale Global Tic Severity Scale

Secondary Outcome

 Premonitory Urge for Tics Scale

Condition

Tourette Syndrome

Intervention

EPI-743

Study Arms / Comparison Groups

 EPI-743
Description:  EPI-743- Participants will receive 200mg three times a day of EPI-743 for 2 weeks and then receive 300mg of EPI-743 for an additional 2 weeks.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

10

Start Date

October 2012

Completion Date

October 2013

Primary Completion Date

October 2013

Eligibility Criteria

        Inclusion Criteria:

          -  Adult between 18-65 years of age

          -  Meet DSM IV criteria for the diagnosis of Tourette's syndrome

          -  Significant current tic symptoms: YGTSS total tic score greater than or equal to 22 at
             baseline

          -  On stable psychiatric medication regimen for a minimum of 4 weeks prior to beginning
             the trial.

          -  Accepted method of birth control

          -  Willingness to participate in an HMPAO SPECT scan at baseline and after 4 weeks of
             treatment.

        Exclusion Criteria:

          -  Comorbid bipolar disorder, psychotic disorder, substance use disorder, developmental
             disorder or intellectual disability (IQ<70).

          -  Recent change (less than 4 weeks) in medications that have potential effects on tic
             severity. Medication change is defined to include dose changes or medication
             discontinuation.

          -  Recent change in behavioral treatment for Tourette syndrome or comorbid conditions
             (i.e. OCD) within the last 4 weeks or initiation of behavioral therapy for tics within
             the last 12 weeks.

          -  Known hypersensitivity or previous anaphylactoid reaction to EPI-743 or any components
             in its preparation

          -  Positive pregnancy test or drug screening test

          -  Clinical history of bleeding disorder or abnormal baseline PT/PTT

          -  Hepatic insufficiency with LFTs greater than two times upper limit of normal
      

Gender

All

Ages

18 Years - 65 Years

Accepts Healthy Volunteers

No

Contacts

Michael H Bloch, MD, MS, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT01719523

Organization ID

120100953972412


Responsible Party

Sponsor

Study Sponsor

Yale University

Collaborators

 Rembrandt Foundation

Study Sponsor

Michael H Bloch, MD, MS, Principal Investigator, Yale University


Verification Date

March 2014