Genetic Autopsy and Sudden Death (AGEMOS)

• ClinicalTrials.gov Identifier: NCT02920203
• Recruitment Status: Unknown
• First Posted: September 30, 2016
• Last Update Posted: November 6, 2017
• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: Pathology department and forensic Institute, Raymond Poincaré hospital, Garches; Referal Center for Inherited cardiac diseases, Pitié Salpêtrière Hospital, Paris; Pitié-Salpêtrière Hospital; Clinical research Unit, Ambroise Paré Hospital, Boulogne Billancourt; Cardiogenetic and molecular and cellular myogenetic functionnal unit Pitié Salpêtrière hospital, Paris; Molecular and medical Virology Laboratory, Medical School, Reims
• Information provided by (Responsible Party): Assistance Publique - Hôpitaux de Paris

Tracking Information

• First Submitted Date: September 7, 2016
• First Posted Date: September 30, 2016
• Last Update Posted Date: November 6, 2017
• Actual Study Start Date: October 11, 2017
• Estimated Primary Completion Date: September 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 7, 2016)

Comparison of sudden death elucidation rate obtained by high throughput sequencing (NGS) versus conventional autopsy (macroscopic and / or microscopic) [ Time Frame: 27 months ]

Aim is to determine if elucidation rate of unexpected sudden death causes obtained by high throughput sequencing (NGS) is significantly better than conventional autopsy (macroscopic and / or microscopic) alone. Inclusion of a series of 100 consecutive and exhaustive cases (index cases) recruited by forensic institutes or pathology departements. Determine the rate of sudden death elucidation after NGS (after targeted capturing of 100 genes responsible for inherited cardiac diseases, including cardiomyopathy and electrical diseases) and comparison of sudden death elucidation rate obtained with conventional autopsy (macroscopic and microscopic) by chi 2 analysis.

Original Primary Outcome Measures (submitted: September 28, 2016)

Comparison of sudden death elucidation rate obtained by high throughput sequencing (NGS) versus conventional autopsy (macroscopic and / or microscopic) [ Time Frame: 27 months ]

Aim is to determine if elucidation rate of unexpected sudden death causes obtained by high throughput sequencing (NGS) is significantly better than conventional autopsy (macroscopic and / or microscopic) alone. Inclusion of a series of 100 consecutive and exhaustive cases (index cases) recruited by forensic institutes or pathology departements. Determine the rate of sudden death elucidation after NGS (after targeted capturing of 100 genes responsible for inherited cardiac diseases, including cardiomyopathy and electrical diseases). Determine the rate of sudden death elucidation after conventional autopsy (macroscopic and microscopic) Comparison of sudden death elucidation rate between the two approaches by chi 2 analysis.

Current Secondary Outcome Measures (submitted: September 28, 2016)

• Describe the epidemiology of causes of sudden death [ Time Frame: 27 months ]
  Inclusion of a serie of consecutive and exhaustive subjects recruited by forensic institutes or pathology departements. Determination all the causes of death after conventional autopsy (unnatural, toxicological, non-cardiovascular, vascular, cardiological and coronary, cardiological and non-coronary causes such as cardiomyopathies & myocarditis, no cause identified Descriptive analysis. All quantitative data will be analyzed with the average, standard deviation and median. Frequencies and Clopper-Pearson confidence interval of 95% will be provided
• Comparison of elucidation rates of cause of sudden death including systematic cardiac screening in relatives [ Time Frame: 39 months ]
  Aim is to determine the impact of systematic family cardiac screening in the understanding of sudden deaths Comparison of elucidation rates of cause of sudden death according to three methods: i) identification of a hereditary heart disease via the systematic cardiac screening performed in relative; ii) by the conventional autopsy; iii) by sequencing NGS analysis; Statistics: test of McNemar (mated series). The threshold for level of statistical significance is chosen at 5 %.
• Medico-economic modeling of the various diagnostic approaches [ Time Frame: 39 months ]
  Cost-effectiveness modeling evaluation of medical and economic impact of the genetic molecular autopsy, efficacy being estimated by years of life saved in the family

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Genetic Autopsy and Sudden Death
• Official Title: Genetic Autopsy and Sudden Death of Young Subject
• Brief Summary: The purpose of the study is to better identify hereditary cardiac causes of sudden unexpected death in young subjects through Next-Generation Sequencing of autopsy tissue

Detailed Description

Monitoring :

For index cases group, all the data will be monitored. For the relatives group, only the informed consent will be monitored

Statistical analysis :

• Evaluate the additional elucidation rate of unexpected sudden death
• Evaluate causes obtained by Next Generation Sequencing (NGS) ( in comparison with conventional autopsy (macroscopic and / or microscopic)
• Descriptive study of the causes of sudden unexpected death, identified hereditary cardiac causes percentages compared via various diagnostic approaches
• Cost-effectiveness analysis

Data Management :

A database is created for the AGEMOS study with control of the discrepancies. All the index cases' data entered in the data base will be double checked

• Study Type: Observational
• Study Design: Observational Model: Family-Based; Time Perspective: Prospective
• Target Follow-Up Duration: Not Provided

Biospecimen

Retention:   Samples With DNA

Description:

Heart and spleen tissue (from autopsy)

• Sampling Method: Non-Probability Sample
• Study Population: Index cases enrolled: series of consecutive and exhaustive cases recruited by forensic institutes or pathology departements Relatives enrolled: as many as possible during the recruitment period
• Condition: Sudden Death

Intervention

Genetic: Heart and spleen tissue

genetic sequencing

Study Groups/Cohorts

• index cases group
  unexpected sudden death cases recruited by forensic institutes or pathology departements
  Intervention: Genetic: Heart and spleen tissue
• first degree relatives group
  Relatives enrolled of unexpected sudden death index cases

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Unknown status
• Estimated Enrollment (submitted: September 28, 2016): 300
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 2020
• Estimated Primary Completion Date: September 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Index cases :

Inclusion Criteria:

• Subjects of more than 2 years old and less than 41 years old
• Sudden unexpected death from natural and nontraumatic causes
• Macroscopic autopsy performed within 72 hours after death and without signs of body decomposition
• No extracardiac obvious causes, including toxicological analysis when available
• No significant coronary cause after autopsy (such as tight coronary stenosis, congenital abnormality of the arteries, coronary vasculitis)
• Informed consent of the close relation (family/reliable person) and / or legal representative

Relatives :

Inclusion Criteria:

• To be a first degree relative (parents, sister, brother, child) of a deceased subject included in the AGEMOS study and accept to perform medical examination and transmit results of examination

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 2 Years to 40 Years (Child, Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: France

Administrative Information

• NCT Number: NCT02920203
• Other Study ID Numbers: NI 13007
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Assistance Publique - Hôpitaux de Paris
• Original Responsible Party: Same as current
• Current Study Sponsor: Assistance Publique - Hôpitaux de Paris
• Original Study Sponsor: Same as current

Collaborators

• Pathology department and forensic Institute, Raymond Poincaré hospital, Garches
• Referal Center for Inherited cardiac diseases, Pitié Salpêtrière Hospital, Paris
• Pitié-Salpêtrière Hospital
• Clinical research Unit, Ambroise Paré Hospital, Boulogne Billancourt
• Cardiogenetic and molecular and cellular myogenetic functionnal unit Pitié Salpêtrière hospital, Paris
• Molecular and medical Virology Laboratory, Medical School, Reims

Investigators

• Principal Investigator: Geoffroy Lorin de la Grandmaison, Pr; Assistance Publique Hoptiaux de Paris
• Study Director: Philippe Charron, MD, PhD; +33 (0)1 42 16 13 47

• PRS Account: Assistance Publique - Hôpitaux de Paris
• Verification Date: November 2017