<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/NCT03803215</url>
  </required_header>
  <id_info>
    <org_study_id>CPM 30102018</org_study_id>
    <nct_id>NCT03803215</nct_id>
  </id_info>
  <brief_title>Theophylline for Low Adenosine Syncope</brief_title>
  <acronym>THEO-USA</acronym>
  <official_title>Theophylline in Patients With Unexplained Syncope and Low Adenosine. Study Verified by ICM, Controlled by Propensity-score Matching</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Centro Prevenzione Malattie Cardiovascolari N. e V. Corbella</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Gruppo Italiano Multidisciplinare per lo Studio della Sincope</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Centro Prevenzione Malattie Cardiovascolari N. e V. Corbella</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      The study aims at assessing that theophylline is effective in patients with no prodromes,&#xD;
      normal heart and with low values of plasmatic adenosine compared with a propensity-score&#xD;
      matched untreated control population who have received an implantable cardiac monitor (ICM)&#xD;
      for diagnosis of unexplained or atypical reflex syncope.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Theophylline has been used for 3 decades in ordinary medical practice to tentatively prevent&#xD;
      syncopal recurrences in patients affected by neurally-mediated syncope. Observational studies&#xD;
      report a recurrence rate with this drug ranging between 12% and 22%. Theophylline was much&#xD;
      more effective in selected patients with syncope without prodromes and normal heart who had&#xD;
      ECG documentation of long pauses at the time of syncopal attack and low values of baseline&#xD;
      plasmatic adenosine. Since theophylline is a non-selective antagonist of purinergic&#xD;
      receptors, it has been hypothesized that purinergic receptors are involved in the mechanism&#xD;
      of syncope in such patients. Conversely, theophylline was suspected to be ineffective (or&#xD;
      less effective) in patients affected by other forms of neurally-mediated syncope.&#xD;
&#xD;
      The present study aims at assessing that theophylline is effective in patients with no&#xD;
      prodromes, normal heart and with low values of plasmatic adenosine compared with a&#xD;
      propensity-score matched untreated control population.&#xD;
&#xD;
      This will be a multicenter, non interventional study, verified by ICM, with 2 predefined&#xD;
      subgroups:&#xD;
&#xD;
      Subgroup #1&#xD;
&#xD;
        -  Low adenosine group: Patients with Low Adenosine values (&lt;0.40 μmol/L)&#xD;
&#xD;
        -  Normal/high adenosine (≥0.40 μmol/L) group: any other patient Subgroup #2&#xD;
&#xD;
        -  Patients with no prodromes or very short prodromes (≤5 sec), normal heart and normal ECG&#xD;
           (No prodrome group)&#xD;
&#xD;
        -  Any other form of atypical neurally-mediated syncope with prodromes &gt;5 sec. Remote or&#xD;
           in-hospital periodic follow-up will be done according to centre's clinical practice for&#xD;
           ICM monitoring.&#xD;
&#xD;
      Patients will be followed up until the first primary endpoint event with a maximum follow-up&#xD;
      of 24 months since start of theophylline treatment.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 11, 2016</start_date>
  <completion_date type="Actual">December 30, 2020</completion_date>
  <primary_completion_date type="Actual">November 30, 2020</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Control</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Asystolic syncope</measure>
    <time_frame>24 months</time_frame>
    <description>Number of patients. The primary objective aims to test the hypothesis that theophylline is able to reduce asystolic events in the Low-Adenosine subgroup compared with the propensity-score matched control group</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Time to first syncope recurrence</measure>
    <time_frame>24 months</time_frame>
    <description>Months from enrolment to the first recurrence of syncope</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Asystolic syncope in the subgroup with low adenosine plasmatic values</measure>
    <time_frame>24 months</time_frame>
    <description>Number of patients with asystolic syncope during follow-up</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Asystolic syncope in patients without prodrome, normal heart and normal ECG</measure>
    <time_frame>24 months</time_frame>
    <description>Number of patients with asystolic syncope during follow-up</description>
  </secondary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Actual">77</enrollment>
  <condition>Syncope</condition>
  <arm_group>
    <arm_group_label>Theophylline group</arm_group_label>
    <description>Patients who have electrocardiographic documentation of asystolic syncope will be treated with oral theophylline at tailored dosage</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control untreated group</arm_group_label>
    <description>A propensity-score matched control group is generated from the large database of patients who had received an implantable loop recorder</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Theophylline</intervention_name>
    <description>Oral theophylline initially 600 mg bid and then titrated at the maximum tolerated dose</description>
    <arm_group_label>Theophylline group</arm_group_label>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        Patients who have received an implantable cardiac monitor (ICM) for diagnosis of&#xD;
        unexplained or atypical reflex syncope&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Male or female gender with age &gt;18 years&#xD;
&#xD;
          2. Unexplained syncope without prodrome or neurally-mediated syncope with atypical&#xD;
             prodrome, with normal heart and normal ECG&#xD;
&#xD;
          3. Two syncopes /last year or 3 syncopes /last 2 years before start of theophylline&#xD;
             treatment&#xD;
&#xD;
          4. Having received an ICM according to conventional guideline-based indications&#xD;
&#xD;
          5. Being treated with oral theophylline therapy, while been waiting for ICM diagnosis&#xD;
&#xD;
          6. Having signed a written informed consent to the study participation and to the&#xD;
             treatment of personal data&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Typical vaso-vagal syncope with long prodromes and situational syncope&#xD;
&#xD;
          2. Any other form of syncope/T-LOC different from reflex syncope&#xD;
&#xD;
          3. Pregnant or breast-feeding patients -&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Michele Brignole, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Department of Cardiology, Ospedali del Tigullio</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Department of Cardiology, Ospedali del Tigullio</name>
      <address>
        <city>Lavagna</city>
        <zip>16033</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <verification_date>January 2020</verification_date>
  <study_first_submitted>January 10, 2019</study_first_submitted>
  <study_first_submitted_qc>January 11, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 14, 2019</study_first_posted>
  <last_update_submitted>January 18, 2021</last_update_submitted>
  <last_update_submitted_qc>January 18, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">January 20, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>theophylline</keyword>
  <keyword>asystole</keyword>
  <keyword>implantable loop recorder</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Syncope</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Theophylline</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/NCT03803215
org study id: CPM 30102018
nct id: NCT03803215
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
The study aims at assessing that theophylline is effective in patients with no prodromes,
      normal heart and with low values of plasmatic adenosine compared with a propensity-score
      matched untreated control population who have received an implantable cardiac monitor (ICM)
      for diagnosis of unexplained or atypical reflex syncope.
Theophylline has been used for 3 decades in ordinary medical practice to tentatively prevent
      syncopal recurrences in patients affected by neurally-mediated syncope. Observational studies
      report a recurrence rate with this drug ranging between 12% and 22%. Theophylline was much
      more effective in selected patients with syncope without prodromes and normal heart who had
      ECG documentation of long pauses at the time of syncopal attack and low values of baseline
      plasmatic adenosine. Since theophylline is a non-selective antagonist of purinergic
      receptors, it has been hypothesized that purinergic receptors are involved in the mechanism
      of syncope in such patients. Conversely, theophylline was suspected to be ineffective (or
      less effective) in patients affected by other forms of neurally-mediated syncope.

      The present study aims at assessing that theophylline is effective in patients with no
      prodromes, normal heart and with low values of plasmatic adenosine compared with a
      propensity-score matched untreated control population.

      This will be a multicenter, non interventional study, verified by ICM, with 2 predefined
      subgroups:

      Subgroup #1

        -  Low adenosine group: Patients with Low Adenosine values (<0.40 μmol/L)

        -  Normal/high adenosine (≥0.40 μmol/L) group: any other patient Subgroup #2

        -  Patients with no prodromes or very short prodromes (≤5 sec), normal heart and normal ECG
           (No prodrome group)

        -  Any other form of atypical neurally-mediated syncope with prodromes >5 sec. Remote or
           in-hospital periodic follow-up will be done according to centre's clinical practice for
           ICM monitoring.

      Patients will be followed up until the first primary endpoint event with a maximum follow-up
      of 24 months since start of theophylline treatment.
observational model: Case-Control
time perspective: Prospective
measure: Asystolic syncope
time frame: 24 months
description: Number of patients. The primary objective aims to test the hypothesis that theophylline is able to reduce asystolic events in the Low-Adenosine subgroup compared with the propensity-score matched control group
measure: Time to first syncope recurrence
time frame: 24 months
description: Months from enrolment to the first recurrence of syncope
measure: Asystolic syncope in the subgroup with low adenosine plasmatic values
time frame: 24 months
description: Number of patients with asystolic syncope during follow-up
measure: Asystolic syncope in patients without prodrome, normal heart and normal ECG
time frame: 24 months
description: Number of patients with asystolic syncope during follow-up
arm group label: Theophylline group
description: Patients who have electrocardiographic documentation of asystolic syncope will be treated with oral theophylline at tailored dosage
arm group label: Control untreated group
description: A propensity-score matched control group is generated from the large database of patients who had received an implantable loop recorder
intervention type: Drug
intervention name: Theophylline
description: Oral theophylline initially 600 mg bid and then titrated at the maximum tolerated dose
arm group label: Theophylline group
study pop: 
sampling method: Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Michele Brignole, MD
role: Principal Investigator
affiliation: Department of Cardiology, Ospedali del Tigullio
facility: 
country: Italy
responsible party type: Sponsor
mesh term: Syncope
mesh term: Theophylline