Prolonged Monitoring to Detect Ventricular Arrhythmias in Presymptomatic Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) Patients

Brief Title

Prolonged Monitoring to Detect Ventricular Arrhythmias in Presymptomatic Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) Patients

Official Title

Prolonged Monitoring to Detect Ventricular Arrhythmias in Presymptomatic ARVC Patients

Brief Summary

      Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is an inherited condition
      characterized by life threatening heart racing, presenting with palpitations, cardiac arrest
      (collapse requiring an ambulance) or sudden death. The disease affects the right ventricle,
      the part of the heart that pumps blood to the lungs. ARVC is diagnosed with a wide range of
      tests that focus on the pumping function and the electrical signals from the right ventricle.
      These factors are summarized in a score that forms the ARVC Task Force Criteria. Genetic
      testing has identified 5 different genes that lead to ARVC, which are detected in about 60%
      of patients with ARVC. This allows doctors to test family members of the patient with ARVC to
      determine if they are at risk of developing the condition. Currently, family members undergo
      testing that includes imaging and electrical tests such as a 24-hour monitor to determine if
      they have evidence of ARVC. With increasing frequency, family members are found to have the
      gene that may lead to ARVC, but little or no evidence that their hearts are affected. This
      may be because the family member is too young to develop the condition, or that other factors
      that we do not understand have protected them from developing it.

      The PREPARE study will study 100 patients that carry a gene that can lead to ARVC, but do not
      have anything more than minor evidence that the condition is present. These patients will not
      have heart racing on their initial 24-hour monitor. These patients will undergo long term
      monitoring with an implanted heart monitor that is inserted with a minor surgical procedure,
      which will detect abnormal heart rhythms that may provide a clue that heart racing from ARVC
      is present that is not detected with a 24-hour monitor that is performed on an annual basis
      (St. Jude Confirm implantable loop recorder). These patients will be enrolled in 10 adult and
      pediatric centers across Canada, and followed for 3 years after their heart monitor is
      implanted. If heart racing is detected, patients will discuss these results with their doctor
      to discuss what it means to them.
    

Detailed Description

      Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is a familial condition characterized
      by onset of life threatening ventricular arrhythmias in early adulthood, presenting with
      ventricular tachycardia, cardiac arrest or sudden death. The disease is diagnosed with tests
      that focus on imaging the right ventricle and assessing for ambient arrhythmia or abnormal
      electrical substrate. These factors are collated into a score that forms the ARVC Task Force
      Criteria, known to be specific but not sensitive. These criteria have been revised in 2010,
      introducing a broader and more quantitative approach to diagnosis including genetic testing
      results, intended to enhance sensitivity without reducing specificity. They account for
      findings from genetic testing, confounded in part by the unknown significance of a positive
      genetic test in the absence of a phenotype in a disease with variable penetrance and
      expressivity. Genetic testing identifies the underlying mutation in ≈60% of clearly affected
      patients. Recent access to genetic testing has demonstrated that family members of an
      affected individual often harbor the culprit mutation, with little evidence that they are
      affected from clinical testing. Given the risk of life threatening arrhythmia as a first
      presentation of disease expression, enhanced detection of ventricular arrhythmia would help
      to identify patients with manifest ARVC.

      The PREPARE study will test the hypothesis that prolonged monitoring with an implantable loop
      recorder (ILR) will provide evidence of progressive electrical disease in gene positive ARVC
      patients with a non-diagnostic phenotype (negative or mild) who do not receive an implantable
      cardioverter defibrillator (ICD). Detection of non-sustained ventricular tachycardia will
      have incremental value over routine periodic clinical follow-up and standard short term
      monitoring (24-48 hour Holter).

      100 gene positive patients without manifest ARVC after standard screening clinical testing
      will undergo ILR implantation. These patients will fail to meet 2010 revised Task Force
      Criteria for definite ARVC and will not be considered candidates for a primary prevention ICD
      by the local investigator. A Health Canada approved St. Jude Medical ConfirmTM loop recorder
      will be implanted using standard technique with local anesthetic, and patients will be
      followed for 3 years. Patients will undergo repeat clinical phenotype testing according to
      the local institutions standard practice, including testing at 3 years after enrollment to
      reassess Task Force Criteria (standard care), which will constitute the end of the study. A
      24-hour Holter monitor will be encouraged annually to provide standard surveillance for
      ventricular arrhythmia as a comparator to loop recorder findings. In the event that
      non-sustained or sustained ventricular tachycardia is detected by the loop recorder (≥8
      beats) and/or Holter monitor, clinical assessment by the local investigator will take place
      to review the tracing and discuss the findings with the patient. This will follow routine
      clinical care.

      The primary end point is detection of ≥8 beats of wide QRS complex tachycardia considered
      ventricular tachycardia by the ILR. Secondary endpoints will include comparison of
      ventricular arrhythmia burden between routine surveillance Holter monitoring and the ILR, and
      change in 2010 Task Force Criteria Score from enrollment to 3-year follow-up.

      Patients will provide written informed consent to participate in the study, with data
      collected in a password-protected web based database. Patients will undergo follow-up at 1
      and 4 weeks after implant, at 3 and 6 months and every 6 months thereafter. Follow-up will
      capture findings from loop recorder interrogation, along with change in clinical status and
      cardioactive drug use. A 24 Hour Holter monitor will be encouraged annually to provide
      standard surveillance for ventricular arrhythmia as a comparator to loop recorder findings.

      This is a pilot study to explore the prevalence and incidence of ambient asymptomatic
      ventricular arrhythmias in presymptomatic genotype carriers of ARVC. An empiric number of 100
      subjects was chosen based on disease prevalence and recruitment goals. End point adjudication
      will include a 3 member adjudication committee comprised of coinvestigators. A single interim
      analysis of end points will be performed by an independent Data and Safety Monitoring
      Committee after 50 patients have completed at least one year of follow-up.
    


Study Type

Observational


Primary Outcome

Detection of ≥8 beats of wide QRS complex tachycardia considered ventricular tachycardia (HR>120 bpm*) by the ILR

Secondary Outcome

 Comparison of ventricular arrhythmia burden between routine

Condition

Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)


Study Arms / Comparison Groups

 Presymptomatic ARVC gene carriers
Description:  ARVC gene positive patients without manifest ARVC after standard screening clinical testing.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information



Estimated Enrollment

100

Start Date

December 2010

Completion Date

October 2013

Primary Completion Date

October 2013

Eligibility Criteria

        Inclusion Criteria:

          1. Identification of a pathogenic mutation† categorized as associated or probably
             associated with ARVC

          2. Failure to meet definite revised Task Force Criteria for ARVC. Mutation carriers by
             definition have a major criterion, so included patients may have 1 minor criteria, but
             would meet Task Force Criteria for ARVC with 2 minor criteria or 1 major criterion.

          3. < 200 PVCs / hour on screening Holter monitor

          4. Age > 2 years

        Exclusion Criteria:

          1. Implantable device in place (pacemaker, ICD)

          2. Age < 2 years

          3. Mutation represents a variant of unknown significance with reasonable probability that
             it may not be disease causing

          4. Non-sustained ventricular tachycardia on screening Holter monitor (≥8 beats > 100 bpm)
             and/or ≥ 200 PVCs / hour

          5. Previous syncope or palpitations attributed to ARVC by the site investigator

          6. Meets definite revised Task Force Criteria for ARVC (≥2 minor criteria and/or ≥1
             additional major criterion). These ARVC patients who do not have an implanted device
             (ICD or pacemaker) will be included in a parallel voluntary registry separate from the
             study.
      

Gender

All

Ages

2 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Andrew Krahn, MD FRCPC, , 

Location Countries

Canada

Location Countries

Canada

Administrative Informations


NCT ID

NCT01271816

Organization ID

R-10-532

Secondary IDs

17390

Responsible Party

Principal Investigator

Study Sponsor

Lawson Health Research Institute

Collaborators

 Abbott Medical Devices

Study Sponsor

Andrew Krahn, MD FRCPC, Principal Investigator, University of Western Ontario, Canada


Verification Date

January 2014