Registry and Natural History Study for Progressive Myoclonus Epilepsy Type 1 (EPM1)

Обзор

The Registry and Natural History Study for Progressive Myoclonus Epilepsy Type 1 (EPM1) is focused on gathering longitudinal clinical data as well as biological samples (blood and/or urine) from male and female patients, of all ages, who have a molecular diagnosis of EPM1or CSTB-null-related disease. Currently, there are no therapies that halt disease progression in any CSTB-related diseases, highlighting the urgency for translational research into this condition. The primary objective of the registry is to determine the natural history and genotype-phenotype correlations of disease-causing variants in EPM1 and CSTB-null-related disease.

Подробное описание

Progressive myoclonus-epilepsies (PME) are severe epilepsies that insinuate into the lives of previously healthy children or young adults, irrevocably intensify, and become intractable. Progressive Myoclonic Epilepsy type 1 (EPM1), also known as Unverricht-Lundborg disease (ULD), is the prototypical and most common PME. It is caused by bi-allelic variants in the CSTB gene. The phenotypic spectrum of EPM1 is broad and reflects the amount of residual CSTB protein function in an individual. Individuals with classic EPM1 typically develop seizures between 6-16 years of age, followed by progressive non-epileptic action- and stimulus-induced myoclonus, ataxia, and cerebellar dysfunction with speech and swallowing impairment. These individuals generally have one or both CSTB variants partially functional. On the severe end of the spectrum are patients with a complete loss of the CSTB protein due to bi-allelic null variants.

The characterization of disease progression and biomarker discovery are necessary to define clinically meaningful endpoints for future interventional trials and to meet regulatory requirements for phase 1/2 and later-stage trials.

As an ultra-rare disease, patients with EPM1 are dispersed across the United States, making on-site visits for natural history studies burdensome to families. In this study, we will overcome this obstacle by adapting a remote- assessment-driven natural history study with clinical, electrophysiological, and biochemical biomarkers. The proposed study will delineate the natural history and evolution of myoclonus as a key disease feature in EPM1 and CSTB-related disease, will create a biobank for biospecimen, and will assess health-related quality of life. This approach will further clinical trial readiness for EPM1-related disease.

Specifically, the objectives of this protocol are to:

1. Determine the natural history and genotype-phenotype correlations of disease-causing variants in EPM1-related disease. 2. Facilitate an early diagnosis, enable counseling with anticipatory guidance of affected families and help define clinically meaningful endpoints for future interventional traits.

Specific aims include:

1. Perform longitudinal Unified Myoclonus Rating Scale (UMRS) assessments and clinical interviews via video-teleconference with study participants to track functional impairment and disease progression. 2. Establish a biobank for samples from participants with CSTB mutations, including EPM1 and CSTB-null disease, enabling quantitative profiling of biochemical biomarkers. 3. Conduct a health-related quality of life survey about participants with EPM1 and CSTB-null disease to understand the impact on patients and caregivers.

Первичные конечные точки

• Unified Myoclonus Rating Scale (UMRS) [Срок оценки: 5 years]
• Creation of Biorepository [Срок оценки: 5 years]
• Assess Health-Related Quality of Life [Срок оценки: 5 years]

Вторичные конечные точки (1)

• Establish clinical trial readiness [Срок оценки: 5 years]

Критерии участия

Критерии включения

• Molecular diagnosis of EPM1-related disease
• Access to web-based communication, including video-teleconference
• Permanent address in the United States

Критерии исключения

• Not having such a diagnosis of EPM1-related disease.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Модель наблюдения

Когортное

Центры проведения

США · 1 центр

• Boston Childrens Hospital — Boston

Публикации

• Rissanen SM, Hypponen J, Silvennoinen K, Saisanen L, Karjalainen PA, Mervaala E, Kalviainen R. Wearable monitoring of positive and negative myoclonus in progressive myoclonic epilepsy type 1. Clin Neurophysiol. 2021 Oct;132(10):2464-2472. doi: 10.1016/j.clinph.2021.06.026. Epub 2021 Jul 30. PMID 34454274
• Joensuu T, Lehesjoki AE, Kopra O. Molecular background of EPM1-Unverricht-Lundborg disease. Epilepsia. 2008 Apr;49(4):557-63. doi: 10.1111/j.1528-1167.2007.01422.x. Epub 2007 Nov 19. PMID 18028412
• Hadady L, Klivenyi P, Fabo D, Beniczky S. Real-world user experience with seizure detection wearable devices in the home environment. Epilepsia. 2023 Dec;64 Suppl 4:S72-S77. doi: 10.1111/epi.17189. Epub 2022 Feb 23. PMID 35195898
• Hainque E, Vidailhet M, Cozic N, Charbonnier-Beaupel F, Thobois S, Tranchant C, Brochard V, Glibert G, Drapier S, Mutez E, Doe De Maindreville A, Lebouvier T, Hubsch C, Degos B, Bonnet C, Grabli D, Legrand AP, Meneret A, Azulay JP, Bissery A, Zahr N, Clot F, Mallet A, Dupont S, Apartis E, Corvol JC, Roze E. A randomized, controlled, double-blind, crossover trial of zonisamide in myoclonus-dystonia PMID 27053715
• Mullard A. NfL makes regulatory debut as neurodegenerative disease biomarker. Nat Rev Drug Discov. 2023 Jun;22(6):431-434. doi: 10.1038/d41573-023-00083-z. No abstract available. PMID 37198334
• Nasseri M, Pal Attia T, Joseph B, Gregg NM, Nurse ES, Viana PF, Worrell G, Dumpelmann M, Richardson MP, Freestone DR, Brinkmann BH. Ambulatory seizure forecasting with a wrist-worn device using long-short term memory deep learning. Sci Rep. 2021 Nov 9;11(1):21935. doi: 10.1038/s41598-021-01449-2. PMID 34754043
• Okuneva O, Korber I, Li Z, Tian L, Joensuu T, Kopra O, Lehesjoki AE. Abnormal microglial activation in the Cstb(-/-) mouse, a model for progressive myoclonus epilepsy, EPM1. Glia. 2015 Mar;63(3):400-11. doi: 10.1002/glia.22760. Epub 2014 Oct 18. PMID 25327891
• O'Brien A, Marshall CR, Blaser S, Ray PN, Yoon G. Severe neurodegeneration, progressive cerebral volume loss and diffuse hypomyelination associated with a homozygous frameshift mutation in CSTB. Eur J Hum Genet. 2017 Jun;25(6):775-778. doi: 10.1038/ejhg.2017.39. Epub 2017 Apr 5. PMID 28378817

Идентификаторы

NCT: NCT06593951 · IRB-P00048807

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗