International CDKL5 Clinical Research Network

Официальное название

Multi-Site Validation of Biomarkers and Core Clinical Outcome Measures for Clinical Trials Readiness in CDKL5 Deficiency Disorder

Обзор

Pathogenic variants in the Cyclin-dependent kinase like 5 (CDKL5) gene cause CDKL5 deficiency disorder (CDD, MIM 300672, 105830), a severe developmental and epileptic encephalopathy associated with cognitive and motor impairments and cortical visual impairment. While capability for disease modifying therapies is accelerating, there is a critical barrier for clinical trial readiness that may result in failure of these therapies, not due to lack of efficacy but due to lack of validated outcome measures and biomarkers. The measures and biomarkers validated here will be adaptable to other developmental and epileptic encephalopathies.

Подробное описание

Pathogenic variants in the Cyclin-dependent kinase like 5 (CDKL5) gene cause CDKL5 deficiency disorder (CDD, MIM 300672, 105830) a severe developmental and epileptic encephalopathy (DEE) associated with cognitive and motor dysfunction and cortical visual impairment. Recent data suggest CDD is one of the most common genetic causes of DEE. Work in CDD animal models has demonstrated the ability for disease modification and symptom reversal: worldwide efforts are now underway to develop therapeutic strategies (including gene therapy) to treat and potentially cure CDD. While there are four active clinical trials, none assesses the full spectrum of this DEE to address true disease modification. While capability for disease modifying therapies is accelerating, there is a critical barrier for clinical trial readiness that may result in failure of these therapies, not due to lack of efficacy but due to lack of validated outcome measures.

CDD has been associated historically with Rett syndrome but there are many clear distinctions and CDD has emerged as an independent disorder. Some Clinical Outcome Measures (COMs) can be adapted from Rett syndrome COMs, whereas others need to be developed specifically for CDD. Our research network is uniquely positioned to develop clinical trial readiness for CDD by pairing exceptional experience in the development and validation of outcome measures with an extensive network of CDD experts and clinical trialists. Our goals are to 1) refine and validate appropriate quantitative COMs and biomarkers and 2) conduct a multi-site clinical trial readiness study to ensure that they can be successfully implemented. We will test the hypothesis that CDD specific COMs can be refined to accurately and reproducibly track meaningful changes in clinical trials:

Aim 1: Generate and validate a suite of COMs and biomarkers necessary to comprehensively assess disease modification in CDD.

Aim 2: Conduct a multi-site clinical trial readiness study to assess implementation, longitudinal stability, and collect baseline COMs and EEG/evoked potential data.

Overall Impact: These outcome measures will establish clinical trial readiness for CDD and generate historic baseline outcome data, ensuring optimal testing of potential new therapeutics including gene therapy. Furthermore, these measures will be adaptable to other DEEs by enabling choices of outcome measures beyond existing NINDS supported measurement tools (NeuroQoL, PROMIS, Toolbox) that are not designed for the severity of the DEE populations.

Вмешательства

• Другое No intervention.
  No intervention administered as part of this study; observational only.

Первичные конечные точки

• CDKL5 Deficiency Disorder (CDD) Clinical Severity Assessment - Clinician (CCSA-Clinician) [Срок оценки: 5 years]
• CDKL5 Deficiency Disorder (CDD) Clinical Severity Assessment - Caregiver (CCSA-Caregiver) [Срок оценки: 5 years]
• CDKL5 Deficiency Disorder (CDD) Development Questionnaire - Caregiver (CDQ-Caregiver) [Срок оценки: 5 years]
• Communication and Symbolic Behavior Scales - Developmental Profile Infant Toddler Checklist (CSBS-DP ITC) [Срок оценки: 5 years]
• Sleep Disorder Scale for Children (SDSC) [Срок оценки: 5 years]
• Quality of Life Inventory - Disability (QI-Disability) [Срок оценки: 5 years]
• CDKL5 Deficiency Disorder (CDD) Gross Motor (CDD-Motor) [Срок оценки: 5 years]
• CDKL5 Deficiency Disorder (CDD) Fine Motor (CDD-Hand) [Срок оценки: 5 years]
• Electroencephalogram/Evoked Potentials (EEG/EP) characteristics in CDKL5 Deficiency Disorder. [Срок оценки: 5 years]

Вторичные конечные точки (3)

• Frequency of different mutations in the CDKL5 Deficiency Disorder population [Срок оценки: 5 years]
• Frequency of medications and their indications in the CDKL5 Deficiency Disorder population [Срок оценки: 5 years]
• Social Determinants of Health (SDOH) in CDKL5 Deficiency Disorder population [Срок оценки: 5 years]

Критерии участия

Критерии включения

• All children diagnosed with CDD age 1-month to 100 years of age that are receiving care at one of the study institutions or are registered with the International CDKL5 Disorder Database will be considered for the study population.

Критерии исключения

• Individuals who do not meet study inclusion criteria.

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 · 8 центров

• University of California Los Angeles/UCLA Mattel Children's Hospital — Los Angeles
• University of Colorado Denver/Children's Hospital Colorado — Aurora
• Harvard Medical School/Boston Children's Hospital — Boston
• Washington University in St. Louis/St. Louis Children's Hospital — St Louis
• NYU Langone Health — New York
• Cleveland Clinic Foundation — Cleveland
• Children's Hospital of Philadelphia — Philadelphia
• Baylor College of Medicine/ Texas Children's Hospital — Houston

Австралия · 1 центр

• Telethon Kids Institute/Perth Children's Hospital — Perth

Публикации

• Olson HE, Daniels CI, Haviland I, Swanson LC, Greene CA, Denny AMM, Demarest ST, Pestana-Knight E, Zhang X, Moosa AN, Fidell A, Weisenberg JL, Suter B, Fu C, Neul JL, Percy AK, Marsh ED, Benke TA, Poduri A. Current neurologic treatment and emerging therapies in CDKL5 deficiency disorder. J Neurodev Disord. 2021 Sep 16;13(1):40. doi: 10.1186/s11689-021-09384-z. PMID 34530725
• Brock D, Fidell A, Thomas J, Juarez-Colunga E, Benke TA, Demarest S. Cerebral Visual Impairment in CDKL5 Deficiency Disorder Correlates With Developmental Achievement. J Child Neurol. 2021 Oct;36(11):974-980. doi: 10.1177/08830738211019284. PMID 34547934
• Saldaris J, Weisenberg J, Pestana-Knight E, Marsh ED, Suter B, Rajaraman R, Heidary G, Olson HE, Devinsky O, Price D, Jacoby P, Leonard H, Benke TA, Demarest S, Downs J. Content Validation of Clinician-Reported Items for a Severity Measure for CDKL5 Deficiency Disorder. J Child Neurol. 2021 Oct;36(11):998-1006. doi: 10.1177/08830738211019576. Epub 2021 Aug 11. PMID 34378447
• Olson HE, Costantini JG, Swanson LC, Kaufmann WE, Benke TA, Fulton AB, Hansen R, Poduri A, Heidary G. Cerebral visual impairment in CDKL5 deficiency disorder: vision as an outcome measure. Dev Med Child Neurol. 2021 Nov;63(11):1308-1315. doi: 10.1111/dmcn.14908. Epub 2021 May 24. PMID 34028805
• MacKay CI, Bick D, Prokop JW, Munoz I, Rouse J, Downs J, Leonard H. Expanding the phenotype of the CDKL5 deficiency disorder: Are seizures mandatory? Am J Med Genet A. 2020 May;182(5):1217-1222. doi: 10.1002/ajmg.a.61504. Epub 2020 Feb 8. PMID 32034940
• Dale T, Downs J, Wong K, Leonard H. The perceived effects of cannabis products in the management of seizures in CDKL5 Deficiency Disorder. Epilepsy Behav. 2021 Sep;122:108152. doi: 10.1016/j.yebeh.2021.108152. Epub 2021 Jun 18. PMID 34148781
• Leonard H, Junaid M, Wong K, Demarest S, Downs J. Exploring quality of life in individuals with a severe developmental and epileptic encephalopathy, CDKL5 Deficiency Disorder. Epilepsy Res. 2021 Jan;169:106521. doi: 10.1016/j.eplepsyres.2020.106521. Epub 2020 Dec 1. PMID 33341033
• MacKay CI, Wong K, Demarest ST, Benke TA, Downs J, Leonard H. Exploring genotype-phenotype relationships in the CDKL5 deficiency disorder using an international dataset. Clin Genet. 2021 Jan;99(1):157-165. doi: 10.1111/cge.13862. Epub 2020 Oct 20. PMID 33047306

Идентификаторы

NCT: NCT05558371 · 19-2756 · 5U01NS114312

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗