<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/NCT02241382</url>
  </required_header>
  <id_info>
    <org_study_id>UKK-CCS-2014</org_study_id>
    <nct_id>NCT02241382</nct_id>
  </id_info>
  <brief_title>Cologne Cardioversion Study</brief_title>
  <official_title>Randomized Controlled Trial Comparing Internal vs External Cardioversion in ICD Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Universitätsklinikum Köln</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Medtronic</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Universitätsklinikum Köln</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Implantation of internal defibrillators, capable of monitoring the heart and shocking life&#xD;
      threatening arrhythmias back to normal rhythm, for patients with severe heart failure&#xD;
      increases the probability of survival. Arrhythmias of the atria of the heart are common in&#xD;
      these patients. Administering a direct current electrical shock under anesthesia&#xD;
      (cardioversion) is the method of choice to reestablish normal sinus rhythm in this instance.&#xD;
      Safety and efficacy of external electrical cardioversion (CV) in patients with ICDs was&#xD;
      demonstrated in several studies. Safety of internal cardioversion (shocking the heart back&#xD;
      into normal rhythm via the implanted defibrillator) was described in several smaller trials.&#xD;
&#xD;
      Performing external instead of internal cardioversion in patients with implanted ICDs is more&#xD;
      feasible for most hospitals, as CV can be performed without a programming computer and an&#xD;
      additional specialist present, e.g. on the intensive care ward, and device interrogation can&#xD;
      be done after CV at the remote ICD/pacemaker clinic.&#xD;
&#xD;
      No scientific data on safety and efficacy endpoints comparing internal vs external CV is&#xD;
      currently available. The aim of the study is to compare external vs internal electrical&#xD;
      cardioversion for atrial arrhythmias and establish a safety and efficacy profile for external&#xD;
      and internal cardioversion in large cohort of ICD patients.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Introduction A mortality benefit of implanted cardiac defibrillators in patients (pts) with&#xD;
      severely impaired LV function has been established in multiple large trials. Atrial&#xD;
      fibrillation, -flutter and -tachycardia are a common comorbidity in this patient population.&#xD;
      Cardioversion is the method of choice to reestablish normal sinus rhythm in this instance.&#xD;
      Safety and efficacy of external electrical cardioversion (CV) in patients with pacemakers and&#xD;
      ICDs could be shown in several smaller single center trials. Safety of internal cardioversion&#xD;
      was described in several smaller trials. Reports on efficacy of internal CV vary between 33%&#xD;
      and 83% .&#xD;
&#xD;
      Performing external instead of internal cardioversion in pts with implanted ICDs is more&#xD;
      feasible for most hospitals, as CV can be performed without a programmer present, e.g. on the&#xD;
      ICU ward, and device interrogation can be done after CV at the remote ICD/pacemaker clinic. A&#xD;
      working group of the German cardiac society recommends internal CV for patients carrying an&#xD;
      ICD, suggesting a superior safety profile for internal CV, despite conflicting data and a&#xD;
      lack of evidence and on this issue. Thus, posing a problem in logistics for many hospitals.&#xD;
&#xD;
      No scientific data on safety and efficacy endpoints comparing internal vs external CV is&#xD;
      currently available.&#xD;
&#xD;
      Aim of the study To compare external vs internal electrical cardioversion for atrial&#xD;
      arrhythmias and establish a safety and efficacy profile for external and internal&#xD;
      cardioversion in large cohort of ICD patients. This study will provide vital evidence for&#xD;
      future recommendations regarding cardioversion in the growing population of patients carrying&#xD;
      implanted ICD and pacemakers. The main purpose will be to establish non-inferiority of&#xD;
      external electrical cardioversion to internal electrical cardioversion. This would impact day&#xD;
      to day practice in many arrhythmia centers and smaller hospitals around the world.&#xD;
&#xD;
      Trial populations and choice of primary analysis set The full-analysis set (FAS) is derived&#xD;
      from the intention-to-treat (ITT) principle. This dataset includes all trial subjects&#xD;
      randomized, with any valid data on the primary target variables &quot;occurrence of severe lead&#xD;
      and device impairment&quot; and &quot;restoration of normal sinus rhythm&quot;.&#xD;
&#xD;
      The per-protocol set includes all trial subjects who were essentially treated according to&#xD;
      protocol (i.e. who have been cardioverted as assigned) and for whom the primary target&#xD;
      variables &quot;occurrence of severe lead and device impairment&quot; and &quot;restoration of normal sinus&#xD;
      rhythm&quot; could be determined based on complete and meaningful documentation.&#xD;
&#xD;
      In a non-inferiority trial there are special issues in the choice of primary analysis set.&#xD;
      Conservatism or anticonversatism of the ITT or PP analysis depends on various factors as type&#xD;
      of protocol deviation and missingness, and the method of handling missing data in ITT&#xD;
      population (see Sanchez MM, Chen X. Choosing the analysis population in non-inferiority&#xD;
      studies: per protocol or intent-to-treat. Stat Med. 25, 1169-81;2006). Due to our setting&#xD;
      (randomization immediately before intervention, allowance for cross-over from internal to&#xD;
      external CV, intervention in hospital setting) we do not expect a relevant amount of protocol&#xD;
      violations. As the follow-up period of 2 weeks is short, we expect &lt;1% losses to follow-up.&#xD;
      So we assume only minor discrepancies between ITT and PP population.&#xD;
&#xD;
      We do not expect any missing data for the primary efficacy endpoint, as it is measured&#xD;
      immediately after CV. The primary safety endpoint is measured within two weeks after CV, and&#xD;
      we do not expect non-trivial missingness such as dropout due to lack of efficacy. As the&#xD;
      expected number of events for the primary safety endpoint is low, especially for internal CV&#xD;
      patients, any method of handling of missing data in ITT analysis may cause relevant bias.&#xD;
      Thus, the per-protocol set is considered the primary analysis population; the ITT analysis is&#xD;
      treated secondary/supportive and should lead to similar conclusions. Patients without any&#xD;
      valid data on the primary target variables will be excluded from the FAS (modified ITT), in&#xD;
      case of missing data on safety endpoint the valid value will be used. In a sensitivity&#xD;
      analysis a conservative scenario will be performed treating missing values as event in&#xD;
      external CV group and as no event in internal CV group. Any relevant discrepancies in&#xD;
      drop-out rates between CV groups will be discussed.&#xD;
&#xD;
      Outcome data and data analysis In case of cross-over from internal to external CV the primary&#xD;
      endpoints will be assessed after internal shock. Patient's death during intervention or&#xD;
      within the follow-up period is unlikely and not to be expected. In the case of patient death&#xD;
      during intervention, after the shock, the primary efficacy endpoint will be treated as&#xD;
      failure. In the case of a patient death during intervention, after the shock or during follow&#xD;
      up, the primary safety value will be counted as failure/severe device or lead impairment.&#xD;
      This may be revised after the cause of death was proven not to be lead or device associated&#xD;
      by interrogation and analysis by the manufacturer.&#xD;
&#xD;
      Stratification by study center is not feasible due to the low number of expected events, and&#xD;
      subgroup analyses by study center will be done for descriptive reasons only.&#xD;
&#xD;
      Duration and study size This study is a multicenter trial. Additional local ethics&#xD;
      application is required at each center.&#xD;
&#xD;
      For the primary safety endpoint &quot;severe lead and device impairment&quot; we expect an incidence of&#xD;
      10% in the external CV group and of 5% in the internal CV group. Thus, for one-sided alpha&#xD;
      5%, non-inferiority margin of 15%, and power 80%, a sample size of 103 patients per arm, i.e.&#xD;
      206 in total, is required. To account for loss to follow-up (&lt;1% within 2 weeks after CV) and&#xD;
      heterogeneity between centers, 230 patients (≈206/(1-0.05)^2) (see Donner, A. Approaches to&#xD;
      sample size estimation in the design of clinical trials--a review. Stat Med 3, 199-214;1984)&#xD;
      will be randomized. A non-inferiority margin of 15% is large, however, we chose several&#xD;
      endpoints acting as sensitive surrogates of possible or temporary lead affectation, rather&#xD;
      than relying solely on hard endpoints such as permanent lead or device failure with necessity&#xD;
      of surgical revision.&#xD;
&#xD;
      As no data on placebo-controlled trials exists in the setting of ICD trials to determine the&#xD;
      non-inferiority margin on statistical grounds, the margin was chosen on clinically as well as&#xD;
      practicality grounds. A relevantly smaller alpha or tighter margin would lead to an&#xD;
      unachievable sample size and render the trial unfeasible (see D'Agostino, R. B., Massaro, J.&#xD;
      M. &amp; Sullivan, L. M. Non-inferiority trials: design concepts and issues - the encounters of&#xD;
      academic consultants in statistics. Stat Med 22, 169-186;2003).&#xD;
&#xD;
      Of note, to detect an absolute risk reduction of 20% in the primary efficacy endpoint&#xD;
      &quot;restoration of normal sinus rhythm&quot;, assuming an incidence of 90% in the external CV group&#xD;
      and 70% in the internal CV group, a sample size of 72 patients per arm, i.e. 144 in total, is&#xD;
      required (two-sided alpha 5%, power 80%, continuity corrected chi-squared test). Sample size&#xD;
      determination was performed with ADDPLAN™ 6.0.&#xD;
&#xD;
      Description of trial subject groups At baseline (i.e. before CV) treatment groups will be&#xD;
      described and compared using mean, standard deviation and percentiles (0, 25, 50, 75, 100)&#xD;
      for continuous variables, count and percentage for categorical variables. Variables to be&#xD;
      summarized include among other sex, age, BMI, comorbidities, type of device, site of&#xD;
      implantation, LV ejection fraction, type of anticoagulation, duration of arrhythmia, left&#xD;
      atrial diameter, pacing threshold, lead impedance, shock impedance, ventricular and&#xD;
      biventricular pacing percentage, battery voltage.&#xD;
&#xD;
      Primary safety endpoint The primary hypothesis &quot;non-inferiority of external CV to internal&#xD;
      CV&quot; regarding the primary safety endpoint &quot;severe lead and device impairment&quot; will be&#xD;
      evaluated using the confidence interval (CI) approach. A one-sided 95% CI for the difference&#xD;
      &quot;observed proportion in external group - observed proportion in internal group&quot; will be&#xD;
      calculated by Newcombe's method 10 and non-inferiority is declared to be shown at one-sided&#xD;
      level 5% if its upper bound lies below the non-inferiority bound of 15%.&#xD;
&#xD;
      Primary efficacy endpoint If non-inferiority regarding the primary safety endpoint &quot;severe&#xD;
      lead and device impairment&quot; could be demonstrated, the hypothesis &quot;superiority of external CV&#xD;
      to internal CV&quot; regarding the primary efficacy endpoint &quot;restoration of normal sinus rhythm&quot;&#xD;
      will be tested in a confirmatory way at two-sided level 5%. Due to the fixed sequence of&#xD;
      these two hypotheses, the type I error is not inflated. The proportion of the primary&#xD;
      efficacy endpoint will be compared between treatment groups by Fisher's exact test with&#xD;
      two-sided 95% CI calculated by Newcombe's method 10.&#xD;
&#xD;
      Secondary endpoints The components of the primary safety endpoint (i.e. a rise in threshold&#xD;
      (at constant duration) of &gt;0.5V, exit block, loss of programming, rise in shock impedance by&#xD;
      50%, rise in charge time by 50%, drop in battery voltage of ≥0.2V within 2 weeks) will be&#xD;
      analyzed along the same line as the composite.&#xD;
&#xD;
      Moreover, recurrence of atrial arrhythmia at FU, lead impedance and sensing changes,&#xD;
      inadvertent induction of VF during CV, high-sensitive Troponin T level 3h after CV will be&#xD;
      summarized by treatment group and compared by statistical hypothesis tests as applicable;&#xD;
      confidence intervals for treatment differences/effect sizes will be calculated to aid&#xD;
      interpretation.&#xD;
&#xD;
      Subgroup analysis&#xD;
&#xD;
      A subanalysis of predefined subgroups will be performed for:&#xD;
&#xD;
        -  CRT-D patients to assess safety of external CV in pts with LV leads.&#xD;
&#xD;
        -  CRT-D patients with quadripolar leads (including thresholds for all 16 pacing vectors)&#xD;
&#xD;
        -  CRT-D patients with AV-VV optimization algorithms&#xD;
&#xD;
      Safety and suspension/termination criteria Based on published data and own previous work 10&#xD;
      an interim safety analysis will be performed after 50% of target sample size, i.e. 115 pts,&#xD;
      have been included. A statistically significant difference in the primary safety endpoint&#xD;
      between the groups at interim analysis will lead to a subsequent early termination of the&#xD;
      trial (using Fisher's exact test, two-sided level 5%).&#xD;
&#xD;
      Specific termination criteria:&#xD;
&#xD;
        -  Significant difference in primary safety endpoint at interim analysis&#xD;
&#xD;
        -  Induction of VF in internal CV group n &gt; 3&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 2014</start_date>
  <completion_date type="Actual">January 24, 2018</completion_date>
  <primary_completion_date type="Actual">January 24, 2018</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Combined Safety Endpoint</measure>
    <time_frame>2 weeks after CV</time_frame>
    <description>Any one of the following as assessed by device interrogation:&#xD;
a rise in threshold (at constant duration) of &gt;0.5V&#xD;
exit block of one of the pacing leads&#xD;
loss of programming of the device&#xD;
a rise in shock impedance by 50% as compared to prior to CV&#xD;
a drop in battery voltage of ≥0.2V within 2 weeks</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Efficacy Endpoint: restoration of sinus rhythm</measure>
    <time_frame>Within 1 minute after CV</time_frame>
    <description>Assessed by ECG, within the first seconds after DC shock application (via external CV or internal shock)&#xD;
- Restoration of sinus rhythm&#xD;
In all patients a single p wave after cardioversion counts as a successful shock. Early recurrence of AF does not count as shock failure. In case of early recurrence of AF/AT, the successful shock may be performed once more, according to randomization. Adjunctive antiarrhythmic drug administration is left to the physician's discretion</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Induction of ventricular fibrillation</measure>
    <time_frame>during CV procedure</time_frame>
    <description>Inadvertent induction of VF during CV, assessed by 3 or 5 lead ECG monitoring during the procedure.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Lead parameter indicators of impairment</measure>
    <time_frame>within 15 minutes after CV and 2 weeks after CV</time_frame>
    <description>Assessed by device interrogation within 15 minutes after CV and at follow-up after 2 weeks:&#xD;
Lead impedance &gt; 1000 Ohm&#xD;
Lead impedance doubled&#xD;
Ventricular lead sensing &lt; 2mV&#xD;
Ventricular lead sensing halved, compared to prior to CV&#xD;
Atrial lead sensing &lt; 1mV&#xD;
Atrial lead sensing halved, compared to prior to CV</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Troponin</measure>
    <time_frame>3h after CV</time_frame>
    <description>Comparison of Troponin T levels prior to and 3h after cardioversion</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Recurrence at follow-up</measure>
    <time_frame>at follow-up 2 weeks after CV</time_frame>
    <description>Rhythm at follow-up assessed by ECG and device interrogation. Atrial fibrillation and atrial flutter or atrial tachycardia will be counted as recurrence.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Subgroup Analysis</measure>
    <time_frame>immediately after CV and at follow-up</time_frame>
    <description>The following subgroups will be analyzed:&#xD;
patients with CRT devices&#xD;
patients with quadripolar leads&#xD;
patients with ineffective external shock and crossover to external shock&#xD;
patients with AV-VV delay optimization algorithms</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">230</enrollment>
  <condition>Atrial Arrhythmia</condition>
  <condition>Heart Failure</condition>
  <arm_group>
    <arm_group_label>External Electrocardioversion</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Cardioversion with an external cardioverter-defibrillator with a step-up energy protocol (100, 150, 200, 360 J biphasic) in antero-posterior orientation, maintaining a &gt; 8 cm distance between shock electrodes and device and complying with a &quot;cool-down&quot; phase of 2 minute between shocks, if more than one shock is required.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Internal Electrocardioversion</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Cardioversion via the implanted ICD with a maximum energy synchronized shock (41 J, with a RV -&gt; SVC+can shock orientation in pts with SVC leads). After 1 ineffective internal shock, the patient will be counted as internal CV failure and cardioverted externally, following the same protocol as the external CV group.</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Internal Electrocardioversion</intervention_name>
    <description>Cardioversion by internal shock application via the implanted ICD</description>
    <arm_group_label>Internal Electrocardioversion</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>External Electrocardioversion</intervention_name>
    <description>Cardioversion by external shock application via a cardioverter/defibrillator.</description>
    <arm_group_label>External Electrocardioversion</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age ≥ 18 years&#xD;
&#xD;
          -  Informed, written consent&#xD;
&#xD;
          -  Atrial arrhythmia with indication for CV&#xD;
&#xD;
          -  Status post ICD implantation, including CRT-D&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Age &lt; 18 years&#xD;
&#xD;
          -  Patients under guardianship or with mental disorders / disabilities&#xD;
&#xD;
          -  ICD implantation &lt; 4 weeks prior to CV&#xD;
&#xD;
          -  ICD lead implantation &lt; 4 weeks prior to CV&#xD;
&#xD;
          -  Battery in EOL, ERM or ERI, ERT&#xD;
&#xD;
          -  Indications of compromised leads (Impedance &lt;200 or &gt;2000 Ohm, Pacing threshold&#xD;
             &gt;5V/0.4ms), RV Sensing &lt;4mV or RA sensing &lt;0,1mV)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>99 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Daniel Steven, Prof. Dr.</last_name>
    <role>Study Director</role>
    <affiliation>University Hospital Cologne</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Jakob Lüker, Dr.</last_name>
    <role>Principal Investigator</role>
    <affiliation>University Hospital Cologne</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Royal Adelaide Hospital</name>
      <address>
        <city>Adelaide</city>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital Lübeck</name>
      <address>
        <city>Lübeck</city>
        <state>Schleswig-Holstein</state>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital Aachen</name>
      <address>
        <city>Aachen</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Heart &amp; Diabetes Center NRW</name>
      <address>
        <city>Bad Oeynhausen</city>
        <zip>32545</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital Bonn</name>
      <address>
        <city>Bonn</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Klinikum Coburg GmbH</name>
      <address>
        <city>Coburg</city>
        <zip>96450</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital Cologne</name>
      <address>
        <city>Cologne</city>
        <zip>50937</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Vinzenz Hospital</name>
      <address>
        <city>Cologne</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Krankenhaus Neu-Bethlehem</name>
      <address>
        <city>Göttingen</city>
        <zip>37073</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Heart Center Hamburg</name>
      <address>
        <city>Hamburg</city>
        <zip>20249</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>St.Georg Hospital</name>
      <address>
        <city>Hamburg</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Klinikum Leverkusen GmbH</name>
      <address>
        <city>Leverkusen</city>
        <zip>51375</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Klinikum Oldenburg</name>
      <address>
        <city>Oldenburg</city>
        <zip>26133</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Australia</country>
    <country>Germany</country>
  </location_countries>
  <verification_date>January 2018</verification_date>
  <study_first_submitted>September 5, 2014</study_first_submitted>
  <study_first_submitted_qc>September 12, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 16, 2014</study_first_posted>
  <last_update_submitted>January 24, 2018</last_update_submitted>
  <last_update_submitted_qc>January 24, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">January 26, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Heart Failure</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/NCT02241382
org study id: UKK-CCS-2014
nct id: NCT02241382
lead sponsor: 
collaborator: 
has dmc: Yes
Implantation of internal defibrillators, capable of monitoring the heart and shocking life
      threatening arrhythmias back to normal rhythm, for patients with severe heart failure
      increases the probability of survival. Arrhythmias of the atria of the heart are common in
      these patients. Administering a direct current electrical shock under anesthesia
      (cardioversion) is the method of choice to reestablish normal sinus rhythm in this instance.
      Safety and efficacy of external electrical cardioversion (CV) in patients with ICDs was
      demonstrated in several studies. Safety of internal cardioversion (shocking the heart back
      into normal rhythm via the implanted defibrillator) was described in several smaller trials.

      Performing external instead of internal cardioversion in patients with implanted ICDs is more
      feasible for most hospitals, as CV can be performed without a programming computer and an
      additional specialist present, e.g. on the intensive care ward, and device interrogation can
      be done after CV at the remote ICD/pacemaker clinic.

      No scientific data on safety and efficacy endpoints comparing internal vs external CV is
      currently available. The aim of the study is to compare external vs internal electrical
      cardioversion for atrial arrhythmias and establish a safety and efficacy profile for external
      and internal cardioversion in large cohort of ICD patients.
Introduction A mortality benefit of implanted cardiac defibrillators in patients (pts) with
      severely impaired LV function has been established in multiple large trials. Atrial
      fibrillation, -flutter and -tachycardia are a common comorbidity in this patient population.
      Cardioversion is the method of choice to reestablish normal sinus rhythm in this instance.
      Safety and efficacy of external electrical cardioversion (CV) in patients with pacemakers and
      ICDs could be shown in several smaller single center trials. Safety of internal cardioversion
      was described in several smaller trials. Reports on efficacy of internal CV vary between 33%
      and 83% .

      Performing external instead of internal cardioversion in pts with implanted ICDs is more
      feasible for most hospitals, as CV can be performed without a programmer present, e.g. on the
      ICU ward, and device interrogation can be done after CV at the remote ICD/pacemaker clinic. A
      working group of the German cardiac society recommends internal CV for patients carrying an
      ICD, suggesting a superior safety profile for internal CV, despite conflicting data and a
      lack of evidence and on this issue. Thus, posing a problem in logistics for many hospitals.

      No scientific data on safety and efficacy endpoints comparing internal vs external CV is
      currently available.

      Aim of the study To compare external vs internal electrical cardioversion for atrial
      arrhythmias and establish a safety and efficacy profile for external and internal
      cardioversion in large cohort of ICD patients. This study will provide vital evidence for
      future recommendations regarding cardioversion in the growing population of patients carrying
      implanted ICD and pacemakers. The main purpose will be to establish non-inferiority of
      external electrical cardioversion to internal electrical cardioversion. This would impact day
      to day practice in many arrhythmia centers and smaller hospitals around the world.

      Trial populations and choice of primary analysis set The full-analysis set (FAS) is derived
      from the intention-to-treat (ITT) principle. This dataset includes all trial subjects
      randomized, with any valid data on the primary target variables "occurrence of severe lead
      and device impairment" and "restoration of normal sinus rhythm".

      The per-protocol set includes all trial subjects who were essentially treated according to
      protocol (i.e. who have been cardioverted as assigned) and for whom the primary target
      variables "occurrence of severe lead and device impairment" and "restoration of normal sinus
      rhythm" could be determined based on complete and meaningful documentation.

      In a non-inferiority trial there are special issues in the choice of primary analysis set.
      Conservatism or anticonversatism of the ITT or PP analysis depends on various factors as type
      of protocol deviation and missingness, and the method of handling missing data in ITT
      population (see Sanchez MM, Chen X. Choosing the analysis population in non-inferiority
      studies: per protocol or intent-to-treat. Stat Med. 25, 1169-81;2006). Due to our setting
      (randomization immediately before intervention, allowance for cross-over from internal to
      external CV, intervention in hospital setting) we do not expect a relevant amount of protocol
      violations. As the follow-up period of 2 weeks is short, we expect <1% losses to follow-up.
      So we assume only minor discrepancies between ITT and PP population.

      We do not expect any missing data for the primary efficacy endpoint, as it is measured
      immediately after CV. The primary safety endpoint is measured within two weeks after CV, and
      we do not expect non-trivial missingness such as dropout due to lack of efficacy. As the
      expected number of events for the primary safety endpoint is low, especially for internal CV
      patients, any method of handling of missing data in ITT analysis may cause relevant bias.
      Thus, the per-protocol set is considered the primary analysis population; the ITT analysis is
      treated secondary/supportive and should lead to similar conclusions. Patients without any
      valid data on the primary target variables will be excluded from the FAS (modified ITT), in
      case of missing data on safety endpoint the valid value will be used. In a sensitivity
      analysis a conservative scenario will be performed treating missing values as event in
      external CV group and as no event in internal CV group. Any relevant discrepancies in
      drop-out rates between CV groups will be discussed.

      Outcome data and data analysis In case of cross-over from internal to external CV the primary
      endpoints will be assessed after internal shock. Patient's death during intervention or
      within the follow-up period is unlikely and not to be expected. In the case of patient death
      during intervention, after the shock, the primary efficacy endpoint will be treated as
      failure. In the case of a patient death during intervention, after the shock or during follow
      up, the primary safety value will be counted as failure/severe device or lead impairment.
      This may be revised after the cause of death was proven not to be lead or device associated
      by interrogation and analysis by the manufacturer.

      Stratification by study center is not feasible due to the low number of expected events, and
      subgroup analyses by study center will be done for descriptive reasons only.

      Duration and study size This study is a multicenter trial. Additional local ethics
      application is required at each center.

      For the primary safety endpoint "severe lead and device impairment" we expect an incidence of
      10% in the external CV group and of 5% in the internal CV group. Thus, for one-sided alpha
      5%, non-inferiority margin of 15%, and power 80%, a sample size of 103 patients per arm, i.e.
      206 in total, is required. To account for loss to follow-up (<1% within 2 weeks after CV) and
      heterogeneity between centers, 230 patients (≈206/(1-0.05)^2) (see Donner, A. Approaches to
      sample size estimation in the design of clinical trials--a review. Stat Med 3, 199-214;1984)
      will be randomized. A non-inferiority margin of 15% is large, however, we chose several
      endpoints acting as sensitive surrogates of possible or temporary lead affectation, rather
      than relying solely on hard endpoints such as permanent lead or device failure with necessity
      of surgical revision.

      As no data on placebo-controlled trials exists in the setting of ICD trials to determine the
      non-inferiority margin on statistical grounds, the margin was chosen on clinically as well as
      practicality grounds. A relevantly smaller alpha or tighter margin would lead to an
      unachievable sample size and render the trial unfeasible (see D'Agostino, R. B., Massaro, J.
      M. & Sullivan, L. M. Non-inferiority trials: design concepts and issues - the encounters of
      academic consultants in statistics. Stat Med 22, 169-186;2003).

      Of note, to detect an absolute risk reduction of 20% in the primary efficacy endpoint
      "restoration of normal sinus rhythm", assuming an incidence of 90% in the external CV group
      and 70% in the internal CV group, a sample size of 72 patients per arm, i.e. 144 in total, is
      required (two-sided alpha 5%, power 80%, continuity corrected chi-squared test). Sample size
      determination was performed with ADDPLAN™ 6.0.

      Description of trial subject groups At baseline (i.e. before CV) treatment groups will be
      described and compared using mean, standard deviation and percentiles (0, 25, 50, 75, 100)
      for continuous variables, count and percentage for categorical variables. Variables to be
      summarized include among other sex, age, BMI, comorbidities, type of device, site of
      implantation, LV ejection fraction, type of anticoagulation, duration of arrhythmia, left
      atrial diameter, pacing threshold, lead impedance, shock impedance, ventricular and
      biventricular pacing percentage, battery voltage.

      Primary safety endpoint The primary hypothesis "non-inferiority of external CV to internal
      CV" regarding the primary safety endpoint "severe lead and device impairment" will be
      evaluated using the confidence interval (CI) approach. A one-sided 95% CI for the difference
      "observed proportion in external group - observed proportion in internal group" will be
      calculated by Newcombe's method 10 and non-inferiority is declared to be shown at one-sided
      level 5% if its upper bound lies below the non-inferiority bound of 15%.

      Primary efficacy endpoint If non-inferiority regarding the primary safety endpoint "severe
      lead and device impairment" could be demonstrated, the hypothesis "superiority of external CV
      to internal CV" regarding the primary efficacy endpoint "restoration of normal sinus rhythm"
      will be tested in a confirmatory way at two-sided level 5%. Due to the fixed sequence of
      these two hypotheses, the type I error is not inflated. The proportion of the primary
      efficacy endpoint will be compared between treatment groups by Fisher's exact test with
      two-sided 95% CI calculated by Newcombe's method 10.

      Secondary endpoints The components of the primary safety endpoint (i.e. a rise in threshold
      (at constant duration) of >0.5V, exit block, loss of programming, rise in shock impedance by
      50%, rise in charge time by 50%, drop in battery voltage of ≥0.2V within 2 weeks) will be
      analyzed along the same line as the composite.

      Moreover, recurrence of atrial arrhythmia at FU, lead impedance and sensing changes,
      inadvertent induction of VF during CV, high-sensitive Troponin T level 3h after CV will be
      summarized by treatment group and compared by statistical hypothesis tests as applicable;
      confidence intervals for treatment differences/effect sizes will be calculated to aid
      interpretation.

      Subgroup analysis

      A subanalysis of predefined subgroups will be performed for:

        -  CRT-D patients to assess safety of external CV in pts with LV leads.

        -  CRT-D patients with quadripolar leads (including thresholds for all 16 pacing vectors)

        -  CRT-D patients with AV-VV optimization algorithms

      Safety and suspension/termination criteria Based on published data and own previous work 10
      an interim safety analysis will be performed after 50% of target sample size, i.e. 115 pts,
      have been included. A statistically significant difference in the primary safety endpoint
      between the groups at interim analysis will lead to a subsequent early termination of the
      trial (using Fisher's exact test, two-sided level 5%).

      Specific termination criteria:

        -  Significant difference in primary safety endpoint at interim analysis

        -  Induction of VF in internal CV group n > 3
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Combined Safety Endpoint
time frame: 2 weeks after CV
description: Any one of the following as assessed by device interrogation:
a rise in threshold (at constant duration) of >0.5V
exit block of one of the pacing leads
loss of programming of the device
a rise in shock impedance by 50% as compared to prior to CV
a drop in battery voltage of ≥0.2V within 2 weeks
measure: Efficacy Endpoint: restoration of sinus rhythm
time frame: Within 1 minute after CV
description: Assessed by ECG, within the first seconds after DC shock application (via external CV or internal shock)
- Restoration of sinus rhythm
In all patients a single p wave after cardioversion counts as a successful shock. Early recurrence of AF does not count as shock failure. In case of early recurrence of AF/AT, the successful shock may be performed once more, according to randomization. Adjunctive antiarrhythmic drug administration is left to the physician's discretion
measure: Induction of ventricular fibrillation
time frame: during CV procedure
description: Inadvertent induction of VF during CV, assessed by 3 or 5 lead ECG monitoring during the procedure.
measure: Lead parameter indicators of impairment
time frame: within 15 minutes after CV and 2 weeks after CV
description: Assessed by device interrogation within 15 minutes after CV and at follow-up after 2 weeks:
Lead impedance > 1000 Ohm
Lead impedance doubled
Ventricular lead sensing < 2mV
Ventricular lead sensing halved, compared to prior to CV
Atrial lead sensing < 1mV
Atrial lead sensing halved, compared to prior to CV
measure: Troponin
time frame: 3h after CV
description: Comparison of Troponin T levels prior to and 3h after cardioversion
measure: Recurrence at follow-up
time frame: at follow-up 2 weeks after CV
description: Rhythm at follow-up assessed by ECG and device interrogation. Atrial fibrillation and atrial flutter or atrial tachycardia will be counted as recurrence.
measure: Subgroup Analysis
time frame: immediately after CV and at follow-up
description: The following subgroups will be analyzed:
patients with CRT devices
patients with quadripolar leads
patients with ineffective external shock and crossover to external shock
patients with AV-VV delay optimization algorithms
arm group label: External Electrocardioversion
arm group type: Active Comparator
description: Cardioversion with an external cardioverter-defibrillator with a step-up energy protocol (100, 150, 200, 360 J biphasic) in antero-posterior orientation, maintaining a > 8 cm distance between shock electrodes and device and complying with a "cool-down" phase of 2 minute between shocks, if more than one shock is required.
arm group label: Internal Electrocardioversion
arm group type: Experimental
description: Cardioversion via the implanted ICD with a maximum energy synchronized shock (41 J, with a RV -> SVC+can shock orientation in pts with SVC leads). After 1 ineffective internal shock, the patient will be counted as internal CV failure and cardioverted externally, following the same protocol as the external CV group.
intervention type: Device
intervention name: Internal Electrocardioversion
description: Cardioversion by internal shock application via the implanted ICD
arm group label: Internal Electrocardioversion
intervention type: Device
intervention name: External Electrocardioversion
description: Cardioversion by external shock application via a cardioverter/defibrillator.
arm group label: External Electrocardioversion
criteria: 
gender: All
minimum age: 18 Years
maximum age: 99 Years
healthy volunteers: No
last name: Daniel Steven, Prof. Dr.
role: Study Director
affiliation: University Hospital Cologne
last name: Jakob Lüker, Dr.
role: Principal Investigator
affiliation: University Hospital Cologne
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country: Australia
country: Germany
responsible party type: Sponsor
mesh term: Heart Failure