Clinical trial NCT05548855: Natural History of Danon Disease
Official title: A Retrospective, Multicenter, International Study to Characterize the Natural History of Danon Disease
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Danon Disease
Keywords: Danon Disease
Observational
Lead sponsor: Rocket Pharmaceuticals Inc.
Sponsor class: INDUSTRY
First posted: 2022-09-22
Enrollment: 59
Sex: ALL
Minimum age (years): 6
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: RETROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Female and male patients with confirmed diagnosis of Danon disease based on a genetic test positive for a mutation in LAMP2

Brief summary: This is a multicenter, international, non-interventional, natural history study designed to collect longitudinal retrospective clinical information on patients with Danon disease (DD). This study is composed of 2 parts:

* Feasibility study: to identify participating sites, assess site and team capabilities, confirm the site and investigator qualification for taking part in the study,
* Retrospective chart review: Data will be collected retrospectively by means of a chart review of living and/or deceased DD patients with a confirmed lysosome associated membrane protein-2 gene (LAMP2) mutation, and,
* For living patients (who have not undergone heart transplantation or placement of a cardiac assist device), availability of at least 6-month cardiology follow-up data,
* For living patients who underwent heart transplantation or placement of a cardiac assist device, and for deceased patients, at least 1 MRI or echo assessment prior to heart transplantation/cardiac assist device placement or death.

Detailed description: Danon disease (DD) is a rare X-linked dominant genetic disorder characterized by cardiomyopathy, skeletal myopathy, and neurocognitive deficits. The disease is caused by a mutation in the lysosome associated membrane protein-2 gene (LAMP2). LAMP2 functions as a lysosomal membrane receptor in autophagy. Most men and many women with LAMP2 gene mutations will develop cardiac disease that includes hypertrophic cardiomyopathy and/or dilated cardiomyopathy, cardiac pre-excitation syndrome, and a propensity for arrhythmias. The prognosis is directly related to the severity of the cardiac disease, and many patients will die from sudden cardiac death. Males are typically more severely affected than females.

There is currently no therapy available to cure, or even prevent disease progression. DD treatment is thus primarily supportive therapy, and survival beyond 25 years without a cardiac transplantation is improbable for afflicted male patients.

Rocket Pharmaceuticals, a clinical-stage company advancing an integrated and sustainable pipeline of genetic therapies for rare pediatric disorders, is developing Rocket Pharmaceuticals Adeno-associated- vector-501 (RP-A501) (AAV9.LAMP2B), an investigational gene therapy product for DD and the first potential gene therapy for monogenic heart failure.

This retrospective, multicenter, international, longitudinal, non- interventional study of DD patients with confirmed LAMP2 mutation aims at characterizing the Natural History of disease in males and females. The Real-world data collected from patients in this natural history study will help support the overall development and protocol design of the RP-A501 gene therapy pivotal trial to be submitted to the health authorities.

Additionally, this study will allow identification of the core centers managing DD patients in several countries as well as the description of the disease characteristics, diagnosis pathway and disease progression. This will inform the development of patient profiles for future studies, including a potential prospective observational study to investigate the burden of disease among DD patients and an international patient registry for Danon disease.

The overarching goal of this retrospective, multicenter, international study is to gain a better understanding of the Natural History of Danon disease, by collecting de-identified information from patients with this condition treated.

Primary objective: Determine how specific cardiac manifestations in patients diagnosed with Danon disease change over time. Essential echocardiography and/or MRI-based parameters include: thickness of the Left Ventricular Posterior Wall at end-diastole (LVPWd); thickness of the Interventricular Septum at end-diastole (IVSd); Left Ventricular mass (LVmass); Left Ventricular Ejection Fraction (LVEF).

Secondary objectives: Describe the progression of other cardiac and extracardiac manifestations in patients diagnosed with Danon disease, including, but not limited to: serologic markers of heart failure, serologic markers of muscle injury, risk and frequency of arrhythmias, comprehensive echocardiogram and MRI-based assessments of cardiomyopathy, overall survival, and event-free survival (as defined subsequently).

Exploratory objectives:

1. Describe the diagnostic pathway of Danon disease, therapeutic management and local centers' approaches to genetic testing for LAMP2 mutations.
2. Identify key Natural History trends to inform a prospective European Union (EU) natural history study and plan for a potential gene therapy trial for DD patients in the EU.

Eligibility criteria: Inclusion Criteria:

1. Patients older than 6 years old and any sex.
2. Patients with a confirmed genetic mutation in LAMP2. 3a. Living patients (who have not undergone heart transplantation or placement of a cardiac assist device):

   * A minimum of 6 months of longitudinal data, including at least 2 echocardiograms or MRIs at least 6 months apart, prior to most recent follow-up visit or enrollment in Sponsor's gene therapy clinical trial.

     3b. Deceased patients or living patients who underwent heart transplantation or cardiac assist device placement:
   * At least 1 echocardiogram or MRI assessment prior to heart transplantation/ cardiac assist device placement or death

4. Informed consent/assent by the patient and/or their legally authorized representative (if the patient is living at the time of enrollment).

Exclusion Criteria:

1. Diagnosis of Danon disease without genetic testing confirmation.

Primary outcomes:
measure: Cardiac Manifestations- LVPWd
timeFrame: Retrospective minimum of 6 months
measure: Cardiac Manifestations- lVSd
timeFrame: Retrospective minimum of 6 months
measure: Cardiac Manifestations- LVmass
timeFrame: Retrospective minimum of 6 months
measure: Cardiac Manifestations - LVEF
timeFrame: Retrospective minimum of 6 months
Secondary outcomes:
measure: Serologic Markers & Imaging - BNP
timeFrame: Retrospective minimum of 6 months
measure: Serologic Markers & Imaging Pro-BNP
timeFrame: Retrospective minimum of 6 months
measure: Serologic Markers & Imaging- CK-MB
timeFrame: Retrospective minimum of 6 months
measure: Serologic Markers & Imaging- Troponin
timeFrame: Retrospective minimum of 6 months
measure: Serologic Markers & Imaging- CPK
timeFrame: Retrospective minimum of 6 months
measure: Serologic Markers & Imaging- transaminases
timeFrame: Retrospective minimum of 6 months
measure: Serologic Markers & Imaging- Echo/MRI
timeFrame: Retrospective minimum of 6 months
measure: Serologic Markers & Imaging- BP
timeFrame: Retrospective minimum of 6 months
measure: Serologic Markers & Imaging- GLS
timeFrame: Retrospective minimum of 6 months
measure: Serologic Markers & Imaging- E/A
timeFrame: Retrospective minimum of 6 months
measure: Arrhythmias
timeFrame: Retrospective minimum of 6 months
measure: Wolf-Parkinson-White syndrome
timeFrame: Retrospective minimum of 6 months
measure: ICD Placement
timeFrame: Retrospective minimum of 6 months
measure: Reason for ICD Placement
timeFrame: Retrospective minimum of 6 months
measure: Overall Survival
timeFrame: Retrospective minimum of 6 months
measure: Event-free survival
timeFrame: Retrospective minimum of 6 months
Other outcomes:
Locations:
city: Prague
country: Czechia
facility: Institut klinické a experimentální medicíny (IKEM)- Institute for Clinical and Experimental Medicine
city: Nantes
country: France
facility: CHU de Nantes, Hôpital Laennec
city: Paris
country: France
facility: APHP, Hôpital de la Pitié Salppêtrière - Charles Foix
city: Rennes
country: France
facility: CHU de Rennes, Hôpital Pontchaïllou
city: Dublin
country: Ireland
facility: Mater Misericordiae University Hospital
city: Bergamo
country: Italy
facility: Ospedale Papa Giovanni XXIII di Bergamo ASST Pap Giovanni XXIII Hospital
city: Florence
country: Italy
facility: University of Florence Dept. of Experimental and Clinical Medicine
city: Trieste
country: Italy
facility: IRCCS Burlo Garogolo- Hospital Burlo Garofolo
city: Barcelona
country: Spain
facility: Hospital Clínic de Barcelona - Barnaclínic+
city: Barcelona
country: Spain
facility: Hospital Universitario de Bellvitge- Bellvitge University Hospital
city: Madrid
country: Spain
facility: Hospital Universitario La Paz - La Paz University Hospital
city: Madrid
country: Spain
facility: Hospital Universitario Puerta de Hierro Majadahonda Puerta de Hierro Majadahonda - University Hospital
city: Málaga
country: Spain
facility: Hospital Universitario Virgen de la Victoria- Virgen de la Victoria University Hosptial
city: Pontevedra
country: Spain
facility: Hospital Álvaro Cunqueiro
city: Valencia
country: Spain
facility: Hospital Universitario y Politécnico La Fe, Instituto De Investigación Sanitaria La Fe, La Fe University and Polytechnic Hospital
Study officials:
References: