<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/NCT04469283</url>
  </required_header>
  <id_info>
    <org_study_id>APHP200193</org_study_id>
    <nct_id>NCT04469283</nct_id>
  </id_info>
  <brief_title>Caffeine Efficacy in ADCY5-related Dyskinesia</brief_title>
  <acronym>ADCY5-CAF</acronym>
  <official_title>Study of Caffeine Efficacy in ADCY5-related Dyskinesia - a Retrospective Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Assistance Publique - Hôpitaux de Paris</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Assistance Publique - Hôpitaux de Paris</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Heterozygous mutations in ADCY5 induce hyperactivity of striatal adenylate cyclase type 5&#xD;
      (AC5), manifesting as early-onset hyperkinetic movement disorders. Numerous treatments have&#xD;
      been tried without much efficacy thus far. Two patients from the same family reported&#xD;
      efficacy of caffeine on paroxysmal episodes, both to prevent episodes and to reduce their&#xD;
      duration (efficacy estimated to be around 80%), which was specific to caffeine as it was&#xD;
      reproduced with caffeine citrate capsules. Interestingly, there is a rationale underlying&#xD;
      this observation. Indeed, caffeine is an antagonist of adenosine A2A receptors (A2AR), which&#xD;
      activate AC5 and are localized preferentially in striatal neurons that express dopamine&#xD;
      receptors D2 .Caffeine therefore likely induces AC5 inhibition, and thus clinical improvement&#xD;
      in patients with hyperactivity of this protein. This observation has been recently published&#xD;
      in2019.&#xD;
&#xD;
      The investigators will collect preliminary data by interviewing our neurologist and&#xD;
      neuropediatric colleagues, in France and abroad since it is a rare disease, on the effect of&#xD;
      caffeine on motor symptoms and global clinical status in their ADCY5 patients.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Heterozygous mutations in ADCY5 induce hyperactivity of striatal adenylate cyclase type 5&#xD;
      (AC5) manifesting as early-onset hyperkinetic movement disorders. The phenotype combines&#xD;
      chorea, dystonia and/or myoclonus with frequent facial involvement, axial hypotonia,&#xD;
      fluctuations and/or episodes of paroxysmal dyskinesia which can be nocturnal and/or painful,&#xD;
      generally without intellectual deficiency, epilepsy or cerebellar syndrome . It is a very&#xD;
      rare disease, affecting around twenty patients in France.&#xD;
&#xD;
      Scientific context of the research:&#xD;
&#xD;
      Numerous treatments have been tried without much efficacy thus far.&#xD;
&#xD;
      Scientific justification for the study:&#xD;
&#xD;
      Two patients from the same family reported efficacy of caffeine on paroxysmal episodes, both&#xD;
      to prevent episodes and to reduce their duration (efficacy estimated to be around 80%), which&#xD;
      was specific to caffeine as it was reproduced with caffeine citrate capsules. Interestingly&#xD;
      there is a rationale underlying this situation. Indeed, caffeine is an antagonist of&#xD;
      adenosine A2A receptors (A2AR), which activate AC5 and are localized preferentially in&#xD;
      striatal neurons that express dopamine receptors D2. Caffeine therefore likely induces&#xD;
      inhibition of AC5, and thus clinical improvement in patients with hyperactivity of this&#xD;
      protein. This observation has been recently published in 2019 HYPOTHESIS Our hypothesis is&#xD;
      that most patients with ADCY5-related dyskinesia respond well to caffeine.&#xD;
&#xD;
      This study is a multicentric retrospective study, which will be conducted in neurology and&#xD;
      neuropediatric departments across the world.&#xD;
&#xD;
      Participants will be recruited by their own physician. This research will take place over 18&#xD;
      months in total: 12 month to collect all patients' data and 6 months to analyse data.&#xD;
&#xD;
      The number of participants will be between 5 and 20, depending on colleagues replies.&#xD;
&#xD;
      This research will take place over 18 months in total: 12 month to collect all patients' data&#xD;
      and 6 months to analyse data.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date type="Anticipated">July 15, 2020</start_date>
  <completion_date type="Anticipated">July 15, 2021</completion_date>
  <primary_completion_date type="Anticipated">July 15, 2021</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Retrospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Percentage of responders to caffeine</measure>
    <time_frame>12 months</time_frame>
    <description>the response being defined as an improvement of overall involuntary movements of 40% or more.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Global improvement of involuntary movements,</measure>
    <time_frame>12 MONTHS</time_frame>
    <description>Global change of involuntary movements ranging from 0 (no change) to 10 (disappearance of involuntary movements)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Global clinical change</measure>
    <time_frame>12 months</time_frame>
    <description>Global clinical change ranging from 0 (no change) to 10 (normalization of the global clinical state)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of paroxysmal episodes of movement disorders</measure>
    <time_frame>12 months</time_frame>
    <description>Change of the duration of paroxysmal episodes of movement disorders with caffeine</description>
  </secondary_outcome>
  <number_of_groups>1</number_of_groups>
  <enrollment type="Anticipated">20</enrollment>
  <condition>ADCY5-related Dyskinesia</condition>
  <arm_group>
    <arm_group_label>caffeine efficacy</arm_group_label>
    <description>Collection of preliminary data on caffeine efficacy on movement disorders in patients with ADCY5-related dyskinesia.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>caffeine and movement disorders</intervention_name>
    <description>Caffeine efficacy on movement disorders in patients with ADCY5-related dyskinesia.</description>
    <arm_group_label>caffeine efficacy</arm_group_label>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        patients with genetically proven ADCY5-related dyskinesia&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion criteria&#xD;
&#xD;
          -  Proven genetic diagnosis of ADCY5-related dyskinesia&#xD;
&#xD;
          -  Adults or children without age limits&#xD;
&#xD;
          -  Past or present caffeine intake&#xD;
&#xD;
          -  Non-opposition by the patient (adults) or the legal representatives (minors) in&#xD;
             France, and patient information according to each country's legislation in other&#xD;
             countries.&#xD;
&#xD;
        4.2. Exclusion criteria None.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Aurélie MENERET, MD</last_name>
    <phone>1 42 16 24 61</phone>
    <phone_ext>+33</phone_ext>
    <email>aurelie.meneret@aphp.fr</email>
  </overall_contact>
  <reference>
    <citation>Meneret A, Gras D, McGovern E, Roze E. Caffeine and the Dyskinesia Related to Mutations in the ADCY5 Gene. Ann Intern Med. 2019 Sep 17;171(6):439. doi: 10.7326/L19-0038. Epub 2019 Jun 11. No abstract available.</citation>
    <PMID>31181574</PMID>
  </reference>
  <verification_date>June 2020</verification_date>
  <study_first_submitted>June 23, 2020</study_first_submitted>
  <study_first_submitted_qc>July 8, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 14, 2020</study_first_posted>
  <last_update_submitted>July 8, 2020</last_update_submitted>
  <last_update_submitted_qc>July 8, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">July 14, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>ADCY5</keyword>
  <keyword>dyskinesia</keyword>
  <keyword>caffeine</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Dyskinesias</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Caffeine</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/NCT04469283
org study id: APHP200193
nct id: NCT04469283
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Heterozygous mutations in ADCY5 induce hyperactivity of striatal adenylate cyclase type 5
      (AC5), manifesting as early-onset hyperkinetic movement disorders. Numerous treatments have
      been tried without much efficacy thus far. Two patients from the same family reported
      efficacy of caffeine on paroxysmal episodes, both to prevent episodes and to reduce their
      duration (efficacy estimated to be around 80%), which was specific to caffeine as it was
      reproduced with caffeine citrate capsules. Interestingly, there is a rationale underlying
      this observation. Indeed, caffeine is an antagonist of adenosine A2A receptors (A2AR), which
      activate AC5 and are localized preferentially in striatal neurons that express dopamine
      receptors D2 .Caffeine therefore likely induces AC5 inhibition, and thus clinical improvement
      in patients with hyperactivity of this protein. This observation has been recently published
      in2019.

      The investigators will collect preliminary data by interviewing our neurologist and
      neuropediatric colleagues, in France and abroad since it is a rare disease, on the effect of
      caffeine on motor symptoms and global clinical status in their ADCY5 patients.
Heterozygous mutations in ADCY5 induce hyperactivity of striatal adenylate cyclase type 5
      (AC5) manifesting as early-onset hyperkinetic movement disorders. The phenotype combines
      chorea, dystonia and/or myoclonus with frequent facial involvement, axial hypotonia,
      fluctuations and/or episodes of paroxysmal dyskinesia which can be nocturnal and/or painful,
      generally without intellectual deficiency, epilepsy or cerebellar syndrome . It is a very
      rare disease, affecting around twenty patients in France.

      Scientific context of the research:

      Numerous treatments have been tried without much efficacy thus far.

      Scientific justification for the study:

      Two patients from the same family reported efficacy of caffeine on paroxysmal episodes, both
      to prevent episodes and to reduce their duration (efficacy estimated to be around 80%), which
      was specific to caffeine as it was reproduced with caffeine citrate capsules. Interestingly
      there is a rationale underlying this situation. Indeed, caffeine is an antagonist of
      adenosine A2A receptors (A2AR), which activate AC5 and are localized preferentially in
      striatal neurons that express dopamine receptors D2. Caffeine therefore likely induces
      inhibition of AC5, and thus clinical improvement in patients with hyperactivity of this
      protein. This observation has been recently published in 2019 HYPOTHESIS Our hypothesis is
      that most patients with ADCY5-related dyskinesia respond well to caffeine.

      This study is a multicentric retrospective study, which will be conducted in neurology and
      neuropediatric departments across the world.

      Participants will be recruited by their own physician. This research will take place over 18
      months in total: 12 month to collect all patients' data and 6 months to analyse data.

      The number of participants will be between 5 and 20, depending on colleagues replies.

      This research will take place over 18 months in total: 12 month to collect all patients' data
      and 6 months to analyse data.
observational model: Cohort
time perspective: Retrospective
measure: Percentage of responders to caffeine
time frame: 12 months
description: the response being defined as an improvement of overall involuntary movements of 40% or more.
measure: Global improvement of involuntary movements,
time frame: 12 MONTHS
description: Global change of involuntary movements ranging from 0 (no change) to 10 (disappearance of involuntary movements)
measure: Global clinical change
time frame: 12 months
description: Global clinical change ranging from 0 (no change) to 10 (normalization of the global clinical state)
measure: Duration of paroxysmal episodes of movement disorders
time frame: 12 months
description: Change of the duration of paroxysmal episodes of movement disorders with caffeine
arm group label: caffeine efficacy
description: Collection of preliminary data on caffeine efficacy on movement disorders in patients with ADCY5-related dyskinesia.
intervention type: Other
intervention name: caffeine and movement disorders
description: Caffeine efficacy on movement disorders in patients with ADCY5-related dyskinesia.
arm group label: caffeine efficacy
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: N/A
maximum age: N/A
healthy volunteers: No
last name: Aurélie MENERET, MD
phone: 1 42 16 24 61
phone ext: +33
email: aurelie.meneret@aphp.fr
citation: Meneret A, Gras D, McGovern E, Roze E. Caffeine and the Dyskinesia Related to Mutations in the ADCY5 Gene. Ann Intern Med. 2019 Sep 17;171(6):439. doi: 10.7326/L19-0038. Epub 2019 Jun 11. No abstract available.
PMID: 31181574
responsible party type: Sponsor
mesh term: Dyskinesias
mesh term: Caffeine