<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/NCT03235037</url>
  </required_header>
  <id_info>
    <org_study_id>IRB PRO00004116</org_study_id>
    <nct_id>NCT03235037</nct_id>
  </id_info>
  <brief_title>Clinical Trial of Levodopa/Carbidopa ( Sinemet) Therapy in Angel Man Syndrome</brief_title>
  <official_title>Clinical Trial of Levodopa/Carbidopa ( Sinemet) Therapy in Angel Man Syndrome</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Bennett Lavenstein</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Children's National Research Institute</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to evaluate the safety and effectiveness (how well a drug works)&#xD;
      of Carbidopa/levodopa (Sinemet) in individuals with Angelman syndrome. Sinemet is a&#xD;
      medication that helps to raise dopamine levels (a chemical that signals nerve cells) in the&#xD;
      brain and central nervous system. There is evidence that dopamine concentrations may be&#xD;
      abnormal in patients with Angelman syndrome. This study is investigating whether Sinemet&#xD;
      helps motor control, intellectual function and the achievement of developmental milestones in&#xD;
      people with Angelman syndrome&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Angelman syndrome (AS) is a well-recognized cause of disability in children who present with&#xD;
      movement or balance disorder, usually ataxia and/or tremulous movement of the limbs, severe&#xD;
      speech and cognitive delay behavior disorders and was initially described by Harry Angelman&#xD;
      as the &quot; happy puppet syndrome&quot; due to their disposition. Seizures, abnormal sleep-wake&#xD;
      cycles and distinctive facial features have been also commonly seen. This disorder is almost&#xD;
      exclusively diagnosed in childhood but adults have been reported. Angelman syndrome affects&#xD;
      an estimated 1 in 12,000 to 20,000 people. Many of the characteristic features are caused by&#xD;
      the loss of function of maternally inherited UBE3A allele on chromosome 15q11-q13 locus.&#xD;
      Several different genetic mechanisms can cause loss of function of maternally inherited UBE3A&#xD;
      gene. Majority of AS is caused by deletion of chromosome 15q11.2-q13 (approximately 70%), 11%&#xD;
      is caused by a mutation in maternal copy of UBE3A. Paternal uniparental disomy (pat UPD)&#xD;
      occurs in 7%. Rarely, a defect in imprinting region and chromosome rearrangement can also&#xD;
      lead to AS.&#xD;
&#xD;
      Ubiquitin-protein ligase E3A (UBE3A) is involved in protein degradation through the ubiquitin&#xD;
      proteasome pathway and displays predominantly in human fetal brain and adult frontal cortex.&#xD;
      UBE3a is essential in the regulation of GTP cyclohydrolase I, an essential enzyme in dopamine&#xD;
      biosynthesis. Knockout mouse studies have evaluated dopamine dependent behaviors as well as&#xD;
      dopamine synthesis, content and release in the mesolimbic and nigrostriatal pathway of AS&#xD;
      model mice. Impairment of UBE3A results in the accumulation of protein substrate and is also&#xD;
      associated with a loss of dopaminergic neuronal function which plays a role in the clinical&#xD;
      symptomatology. AS ( knockout) mice were reported to have maternal deficiency of Ube3a with&#xD;
      reduced dopamine cell number in the substantia nigra pars compacta ((basal ganglia) . They&#xD;
      demonstrated motoric and cognitive deficits. There are several mouse models that have&#xD;
      demonstrated both the disorder and the beneficial effect of L dopa in the knockout mouse&#xD;
      providing a basis for clinical human trials.&#xD;
&#xD;
      To date the primary treatment of children with Angelman syndrome has been only supportive and&#xD;
      symptomatic such as physical, occupation and speech therapies, melatonin and Benadryl for&#xD;
      insomnia and the treatment of seizure disorders. Little attention or success has been&#xD;
      directed to the primary gait disturbance, namely ataxia and the cognitive impairment&#xD;
      including processing, attention and speech delays which are cardinal features of the&#xD;
      disorder.&#xD;
&#xD;
      In 2001, Harbord has reported two adults with Angelman syndrome and Parkinson's disease who&#xD;
      had a positive response to L Dopa constituting the first report of the use of levodopa in&#xD;
      Angelman syndrome.&#xD;
&#xD;
      Pediatric neurotransmitter disorders have previously been recognized involving the dopamine&#xD;
      pathway. In the past investigators have reported on the distinct developmental and behavioral&#xD;
      profile, cognitive deficits, motor and language skills utilizing standardized testing in the&#xD;
      NIH Rare Disease Clinical Research Network, Angelman Rett collaborative.&#xD;
&#xD;
      This study will look at the effects of L Dopa on motor control including ataxia, cognitive&#xD;
      function and developmental milestones in subjects with Angelman syndrome.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 26, 2013</start_date>
  <completion_date type="Actual">February 1, 2019</completion_date>
  <primary_completion_date type="Actual">February 1, 2019</primary_completion_date>
  <phase>N/A</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>
    <intervention_model_description>This is an open label study to assess the motor and cognitive and developmental effects of carbidopa/levodopa when administered orally in doses of 1 -10mg per kg per day. This study will recruit and monitor patients over a 2 year period.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Improvement in motor control determined through composite measure- Tremor</measure>
    <time_frame>2 years</time_frame>
    <description>Documented improvement in motor control including tremor using SARA Scale ( Short Ataxia Rating Assesment)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Improvement in motor control determined through composite measure-Ataxia</measure>
    <time_frame>2 years</time_frame>
    <description>Documented improvement in motor control including ataxia, using SARA Scale ( Short Ataxia Rating Assesment)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Improvement in motor control determined through composite measure- SARA score</measure>
    <time_frame>2 years</time_frame>
    <description>Documented improvement in SARA score</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Improvement in development determined through composite measure-Psychoeducational Testing</measure>
    <time_frame>2 years</time_frame>
    <description>Documented improvement in development based upon Bailey, Denver, Vanderbilt, Educational testing.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">10</enrollment>
  <condition>Angelman Syndrome</condition>
  <arm_group>
    <arm_group_label>Sinemet</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>The target dose of Sinemet is 2-10 mg per kilogram per day of levodopa. The initial dose will be determined by your weight and age and will start at a low dosage level, 1 mg per kilogram per day. The dose will be re-evaluated after the first 2 weeks and may be adjusted at each visit depending on your response to the drug.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Levodopa</intervention_name>
    <description>The target dose of Sinemet is 2-10 mg per kilogram per day of levodopa. The initial dose will be determined by your weight and age and will start at a low dosage level, 1 mg per kilogram per day. The dose will be re-evaluated after the first 2 weeks and may be adjusted at each visit depending on your response to the drug.</description>
    <arm_group_label>Sinemet</arm_group_label>
    <other_name>Sinemet</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Diagnosis of Angelman syndrome confirmed by molecular genetic testing.&#xD;
&#xD;
          -  Age between 18 months and 16 years of age&#xD;
&#xD;
          -  Absence of any contraindication to the use of Sinemet as determined by the PI&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Intractable epilepsy not responsive to anticonvulsive therapy in the patient with this&#xD;
             syndrome.&#xD;
&#xD;
          -  History of prior drug intolerances/drug hypersensitivity to any agent that may be&#xD;
             similar to L Dopa .&#xD;
&#xD;
          -  Progressively deteriorating EEG pattern.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Months</minimum_age>
    <maximum_age>16 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Bennett Lavenstein, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Children's National Health System, Department of Neurology</affiliation>
  </overall_official>
  <verification_date>April 2019</verification_date>
  <study_first_submitted>July 28, 2017</study_first_submitted>
  <study_first_submitted_qc>July 28, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 1, 2017</study_first_posted>
  <last_update_submitted>April 18, 2019</last_update_submitted>
  <last_update_submitted_qc>April 18, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">April 22, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Children's National Research Institute</investigator_affiliation>
    <investigator_full_name>Bennett Lavenstein</investigator_full_name>
    <investigator_title>MD</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Angelman Syndrome</mesh_term>
    <mesh_term>Syndrome</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Levodopa</mesh_term>
  </intervention_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/NCT03235037
org study id: IRB PRO00004116
nct id: NCT03235037
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
The purpose of this study is to evaluate the safety and effectiveness (how well a drug works)
      of Carbidopa/levodopa (Sinemet) in individuals with Angelman syndrome. Sinemet is a
      medication that helps to raise dopamine levels (a chemical that signals nerve cells) in the
      brain and central nervous system. There is evidence that dopamine concentrations may be
      abnormal in patients with Angelman syndrome. This study is investigating whether Sinemet
      helps motor control, intellectual function and the achievement of developmental milestones in
      people with Angelman syndrome
Angelman syndrome (AS) is a well-recognized cause of disability in children who present with
      movement or balance disorder, usually ataxia and/or tremulous movement of the limbs, severe
      speech and cognitive delay behavior disorders and was initially described by Harry Angelman
      as the " happy puppet syndrome" due to their disposition. Seizures, abnormal sleep-wake
      cycles and distinctive facial features have been also commonly seen. This disorder is almost
      exclusively diagnosed in childhood but adults have been reported. Angelman syndrome affects
      an estimated 1 in 12,000 to 20,000 people. Many of the characteristic features are caused by
      the loss of function of maternally inherited UBE3A allele on chromosome 15q11-q13 locus.
      Several different genetic mechanisms can cause loss of function of maternally inherited UBE3A
      gene. Majority of AS is caused by deletion of chromosome 15q11.2-q13 (approximately 70%), 11%
      is caused by a mutation in maternal copy of UBE3A. Paternal uniparental disomy (pat UPD)
      occurs in 7%. Rarely, a defect in imprinting region and chromosome rearrangement can also
      lead to AS.

      Ubiquitin-protein ligase E3A (UBE3A) is involved in protein degradation through the ubiquitin
      proteasome pathway and displays predominantly in human fetal brain and adult frontal cortex.
      UBE3a is essential in the regulation of GTP cyclohydrolase I, an essential enzyme in dopamine
      biosynthesis. Knockout mouse studies have evaluated dopamine dependent behaviors as well as
      dopamine synthesis, content and release in the mesolimbic and nigrostriatal pathway of AS
      model mice. Impairment of UBE3A results in the accumulation of protein substrate and is also
      associated with a loss of dopaminergic neuronal function which plays a role in the clinical
      symptomatology. AS ( knockout) mice were reported to have maternal deficiency of Ube3a with
      reduced dopamine cell number in the substantia nigra pars compacta ((basal ganglia) . They
      demonstrated motoric and cognitive deficits. There are several mouse models that have
      demonstrated both the disorder and the beneficial effect of L dopa in the knockout mouse
      providing a basis for clinical human trials.

      To date the primary treatment of children with Angelman syndrome has been only supportive and
      symptomatic such as physical, occupation and speech therapies, melatonin and Benadryl for
      insomnia and the treatment of seizure disorders. Little attention or success has been
      directed to the primary gait disturbance, namely ataxia and the cognitive impairment
      including processing, attention and speech delays which are cardinal features of the
      disorder.

      In 2001, Harbord has reported two adults with Angelman syndrome and Parkinson's disease who
      had a positive response to L Dopa constituting the first report of the use of levodopa in
      Angelman syndrome.

      Pediatric neurotransmitter disorders have previously been recognized involving the dopamine
      pathway. In the past investigators have reported on the distinct developmental and behavioral
      profile, cognitive deficits, motor and language skills utilizing standardized testing in the
      NIH Rare Disease Clinical Research Network, Angelman Rett collaborative.

      This study will look at the effects of L Dopa on motor control including ataxia, cognitive
      function and developmental milestones in subjects with Angelman syndrome.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: This is an open label study to assess the motor and cognitive and developmental effects of carbidopa/levodopa when administered orally in doses of 1 -10mg per kg per day. This study will recruit and monitor patients over a 2 year period.
primary purpose: Treatment
masking: None (Open Label)
measure: Improvement in motor control determined through composite measure- Tremor
time frame: 2 years
description: Documented improvement in motor control including tremor using SARA Scale ( Short Ataxia Rating Assesment)
measure: Improvement in motor control determined through composite measure-Ataxia
time frame: 2 years
description: Documented improvement in motor control including ataxia, using SARA Scale ( Short Ataxia Rating Assesment)
measure: Improvement in motor control determined through composite measure- SARA score
time frame: 2 years
description: Documented improvement in SARA score
measure: Improvement in development determined through composite measure-Psychoeducational Testing
time frame: 2 years
description: Documented improvement in development based upon Bailey, Denver, Vanderbilt, Educational testing.
arm group label: Sinemet
arm group type: Other
description: The target dose of Sinemet is 2-10 mg per kilogram per day of levodopa. The initial dose will be determined by your weight and age and will start at a low dosage level, 1 mg per kilogram per day. The dose will be re-evaluated after the first 2 weeks and may be adjusted at each visit depending on your response to the drug.
intervention type: Drug
intervention name: Levodopa
description: The target dose of Sinemet is 2-10 mg per kilogram per day of levodopa. The initial dose will be determined by your weight and age and will start at a low dosage level, 1 mg per kilogram per day. The dose will be re-evaluated after the first 2 weeks and may be adjusted at each visit depending on your response to the drug.
arm group label: Sinemet
other name: Sinemet
criteria: 
gender: All
minimum age: 18 Months
maximum age: 16 Years
healthy volunteers: No
last name: Bennett Lavenstein, MD
role: Principal Investigator
affiliation: Children's National Health System, Department of Neurology
responsible party type: Sponsor-Investigator
investigator affiliation: Children's National Research Institute
investigator full name: Bennett Lavenstein
investigator title: MD
mesh term: Angelman Syndrome
mesh term: Syndrome
mesh term: Levodopa