<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT01719523</url>
  </required_header>
  <id_info>
    <org_study_id>120100953972412</org_study_id>
    <nct_id>NCT01719523</nct_id>
  </id_info>
  <brief_title>Open-Trial of EPI-743 for Adults With Tourette Syndrome</brief_title>
  <official_title>Open-Trial of EPI-743 for Adults With Tourette Syndrome</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Yale University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Rembrandt Foundation</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Edison Pharmaceuticals Inc</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Yale University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to examine the effects of EPI-743 on tic severity in adults with&#xD;
      Tourette syndrome.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Tourette syndrome (TS) is a childhood-onset neuropsychiatric disorder characterized by&#xD;
      multiple motor and vocal tics that last for at least a year in duration. Currently, there&#xD;
      exist several effective pharmacological treatments for childhood tics including alpha-2&#xD;
      agonist medications (guanfacine and clonidine) and neuroleptics (antipsychotic) medications.&#xD;
      These medications, however, have significant side-effects and are only partially effective in&#xD;
      treating tics.&#xD;
&#xD;
      EPI-743 is an orally absorbed small molecule that readily crosses into the central nervous&#xD;
      system. It works by targeting an enzyme NADPH quinone oxidoreductase 1 (NQO1). Its mode of&#xD;
      action is to synchronize energy generation in mitochondria with the need to counter cellular&#xD;
      redox stress. EPI-743 has recently received orphan drug status from the U.S. Food and Drug&#xD;
      Administration (FDA). The FDA has allowed an Expanded Access program to provide EPI-743 to&#xD;
      seriously ill patients diagnosed with inherited respiratory chain diseases of the&#xD;
      mitochondria.&#xD;
&#xD;
      The rationale for the use of this agent is indirect. Over the past 10 years, defects in&#xD;
      mitochondrial oxidative phosphorylation (OXPHOS) have been implicated in a wide variety of&#xD;
      neurodegenerative and neuromuscular diseases. One neurological symptom that has definitely&#xD;
      been associated with OXPHOS is the movement disorder dystonia. A specific missense mutation&#xD;
      in the mtDNA complex I (NADH dehydrogenase) gene, MTND6, has been linked to maternally&#xD;
      inherited dystonia along with the companion phenotype, Leber's hereditary optic neuropathy.&#xD;
      In addition, other mitochondrial diseases are also associated with movement disorders&#xD;
      including Friedreich's ataxia (ataxia) and Leigh's disease (loss of head control and other&#xD;
      motor skills). EPI-743 has been effective in treating children and adults with these&#xD;
      diseases. Over time, many TS patients develop complex motor tics, which are sudden, more&#xD;
      purposive appearing, stereotyped movements of variable duration. Examples are myriad and&#xD;
      include facial gestures and movements such as brushing hair back, possibly in combination&#xD;
      with head jerk, and body shrugs. Gyrating, bending, and twisting movements of the head or&#xD;
      torso are also seen. These slow twisting movements are usually referred to as dystonic tics.&#xD;
&#xD;
      A second line of evidence concerns the potential therapeutic value N-acetyl-cysteine (NAC) in&#xD;
      the treatment of neuropsychiatric conditions closely related to TS including Trichotillomania&#xD;
      (TTM) and Obsessive-compulsive disorder [OCD]. Recent double-blind, placebo-controlled&#xD;
      studies of NAC have provided evidence of efficacy in reducing the symptoms of&#xD;
      trichotillomania (TTM) in adults [49]. The effect size in this 12-week study was strikingly&#xD;
      large (d = 1.3). Trichotillomania, like TS, is considered to be an obsessive-compulsive&#xD;
      spectrum disorder. Individuals with TTM experience urges prior to hairpulling, similar to the&#xD;
      urges in TS. Case reports have also suggested the potential efficacy of NAC in treating OCD.&#xD;
      NAC is hypothesized to have two possible mechanisms of action. NAC is converted to cystine, a&#xD;
      substrate for the glutamate/cystine antiporter located on glial cells. The uptake of cystine&#xD;
      by glia causes the release of glutamate into the extrasynaptic space, where it stimulates&#xD;
      inhibitory metabotropic glutamate receptors on glutamatergic nerve terminals and thereby&#xD;
      reduces the synaptic release of glutamate. NAC is also a precursor of glutathione, the major&#xD;
      antioxidant in the brain. Through this mechanism NAC is hypothesized to improve OXPHOS. One&#xD;
      effect of EPI-743's activity on NQO1 is restoration of cellular glutathione stores.&#xD;
&#xD;
      A third line of indirect evidence is that in postmortem brain studies, the two classes of&#xD;
      interneurons that are reduced in number in the basal ganglia are &quot;high energy&quot; consuming&#xD;
      cells, i.e., GABAergic, fast spiking internerons and cholinergic tonically active&#xD;
      interneurons. Given the high energy demand associated with these cells perhaps their loss is&#xD;
      partially due to defects in OXPHOS.&#xD;
&#xD;
      A fourth line of indirect evidence is that when EPI-743 is effective in treating&#xD;
      mitochrondrial disease, brain regions with very low HMPAO uptake show a marked increase in&#xD;
      uptake. In the case of TS (50 cases and 20 controls) HMPAO uptake was found to be reduced in&#xD;
      the left caudate, anterior cingulate cortex and the left dorsolateral prefrontal cortex.&#xD;
      Severity of tics was related to hypoperfusion of the left caudate and cingulate and a left&#xD;
      medial temporal region.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>October 2012</start_date>
  <completion_date type="Actual">October 2013</completion_date>
  <primary_completion_date type="Actual">October 2013</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Yale Global Tic Severity Scale</measure>
    <time_frame>Baseline</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Yale Global Tic Severity Scale</measure>
    <time_frame>2 weeks</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Yale Global Tic Severity Scale</measure>
    <time_frame>4 weeks</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Premonitory Urge for Tics Scale</measure>
    <time_frame>Baseline</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Yale-Brown Obsessive Compulsive Scale</measure>
    <time_frame>Baseline</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Connors Adult Attention Deficit Hyperactivity Rating Scale</measure>
    <time_frame>Baseline</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hamilton Rating Scales for Depression and Anxiety</measure>
    <time_frame>Baseline</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical Global Improvement</measure>
    <time_frame>Week 4</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Columbia Suicide Severity Rating Scale</measure>
    <time_frame>Baseline</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adverse Events Rating Scale</measure>
    <time_frame>Week 2</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Premonitory Urge for Tics Scale</measure>
    <time_frame>Week 2</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Premonitory Urge for Tics Scale</measure>
    <time_frame>Week 4</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adverse Events Rating Scale</measure>
    <time_frame>Week 4</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Yale-Brown Obsessive Compulsive Scale</measure>
    <time_frame>Week 2</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Yale-Brown Obsessive Compulsive Scale</measure>
    <time_frame>Week 4</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Connors Adult Attention Deficit Hyperactivity Rating Scale</measure>
    <time_frame>Week 2</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Connors Adult Attention Deficit Hyperactivity Rating Scale</measure>
    <time_frame>Week 4</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hamilton Rating Scales for Depression and Anxiety</measure>
    <time_frame>Week 2</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hamilton Rating Scales for Depression and Anxiety</measure>
    <time_frame>Week 4</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical Global Improvement</measure>
    <time_frame>Week 2</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Columbia Suicide Severity Rating Scale</measure>
    <time_frame>Week 2</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Columbia Suicide Severity Rating Scale</measure>
    <time_frame>Week 4</time_frame>
  </secondary_outcome>
  <other_outcome>
    <measure>HMPAO Uptake in Frontal-Striatal Circuit on SPECT Scan</measure>
    <time_frame>Baseline</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>HMPAO Uptake in Frontal-Striatal Circuit on SPECT Scan</measure>
    <time_frame>Week 4</time_frame>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">10</enrollment>
  <condition>Tourette Syndrome</condition>
  <arm_group>
    <arm_group_label>EPI-743</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <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.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>EPI-743</intervention_name>
    <arm_group_label>EPI-743</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Adult between 18-65 years of age&#xD;
&#xD;
          -  Meet DSM IV criteria for the diagnosis of Tourette's syndrome&#xD;
&#xD;
          -  Significant current tic symptoms: YGTSS total tic score greater than or equal to 22 at&#xD;
             baseline&#xD;
&#xD;
          -  On stable psychiatric medication regimen for a minimum of 4 weeks prior to beginning&#xD;
             the trial.&#xD;
&#xD;
          -  Accepted method of birth control&#xD;
&#xD;
          -  Willingness to participate in an HMPAO SPECT scan at baseline and after 4 weeks of&#xD;
             treatment.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Comorbid bipolar disorder, psychotic disorder, substance use disorder, developmental&#xD;
             disorder or intellectual disability (IQ&lt;70).&#xD;
&#xD;
          -  Recent change (less than 4 weeks) in medications that have potential effects on tic&#xD;
             severity. Medication change is defined to include dose changes or medication&#xD;
             discontinuation.&#xD;
&#xD;
          -  Recent change in behavioral treatment for Tourette syndrome or comorbid conditions&#xD;
             (i.e. OCD) within the last 4 weeks or initiation of behavioral therapy for tics within&#xD;
             the last 12 weeks.&#xD;
&#xD;
          -  Known hypersensitivity or previous anaphylactoid reaction to EPI-743 or any components&#xD;
             in its preparation&#xD;
&#xD;
          -  Positive pregnancy test or drug screening test&#xD;
&#xD;
          -  Clinical history of bleeding disorder or abnormal baseline PT/PTT&#xD;
&#xD;
          -  Hepatic insufficiency with LFTs greater than two times upper limit of normal&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Michael H Bloch, MD, MS</last_name>
    <role>Principal Investigator</role>
    <affiliation>Yale University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Yale Child Study Center</name>
      <address>
        <city>New Haven</city>
        <state>Connecticut</state>
        <zip>06520</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>March 2014</verification_date>
  <study_first_submitted>October 29, 2012</study_first_submitted>
  <study_first_submitted_qc>October 29, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 1, 2012</study_first_posted>
  <last_update_submitted>March 4, 2014</last_update_submitted>
  <last_update_submitted_qc>March 4, 2014</last_update_submitted_qc>
  <last_update_posted type="Estimate">March 5, 2014</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Tourette syndrome</keyword>
  <keyword>Tics</keyword>
  <keyword>Tic Disorders</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tourette Syndrome</mesh_term>
    <mesh_term>Syndrome</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01719523
org study id: 120100953972412
nct id: NCT01719523
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
The purpose of this study is to examine the effects of EPI-743 on tic severity in adults with
      Tourette syndrome.
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.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Yale Global Tic Severity Scale
time frame: Baseline
measure: Yale Global Tic Severity Scale
time frame: 2 weeks
measure: Yale Global Tic Severity Scale
time frame: 4 weeks
measure: Premonitory Urge for Tics Scale
time frame: Baseline
measure: Yale-Brown Obsessive Compulsive Scale
time frame: Baseline
measure: Connors Adult Attention Deficit Hyperactivity Rating Scale
time frame: Baseline
measure: Hamilton Rating Scales for Depression and Anxiety
time frame: Baseline
measure: Clinical Global Improvement
time frame: Week 4
measure: Columbia Suicide Severity Rating Scale
time frame: Baseline
measure: Adverse Events Rating Scale
time frame: Week 2
measure: Premonitory Urge for Tics Scale
time frame: Week 2
measure: Premonitory Urge for Tics Scale
time frame: Week 4
measure: Adverse Events Rating Scale
time frame: Week 4
measure: Yale-Brown Obsessive Compulsive Scale
time frame: Week 2
measure: Yale-Brown Obsessive Compulsive Scale
time frame: Week 4
measure: Connors Adult Attention Deficit Hyperactivity Rating Scale
time frame: Week 2
measure: Connors Adult Attention Deficit Hyperactivity Rating Scale
time frame: Week 4
measure: Hamilton Rating Scales for Depression and Anxiety
time frame: Week 2
measure: Hamilton Rating Scales for Depression and Anxiety
time frame: Week 4
measure: Clinical Global Improvement
time frame: Week 2
measure: Columbia Suicide Severity Rating Scale
time frame: Week 2
measure: Columbia Suicide Severity Rating Scale
time frame: Week 4
measure: HMPAO Uptake in Frontal-Striatal Circuit on SPECT Scan
time frame: Baseline
measure: HMPAO Uptake in Frontal-Striatal Circuit on SPECT Scan
time frame: Week 4
arm group label: EPI-743
arm group type: Experimental
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.
intervention type: Drug
intervention name: EPI-743
arm group label: EPI-743
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Michael H Bloch, MD, MS
role: Principal Investigator
affiliation: Yale University
facility: 
country: United States
responsible party type: Sponsor
mesh term: Tourette Syndrome
mesh term: Syndrome