International CDKL5 Clinical Research Network

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Total Enrollment

1000 participants

Study Classification

OBSERVATIONAL

Study Start Date

2021-02-15

Study Completion Date

2027-02-15

Brief Summary

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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.

Detailed Description

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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.

Conditions

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CDKL5 CDKL5 Deficiency Disorder CDD

Study Design

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Observational Model Type

COHORT

Study Time Perspective

PROSPECTIVE

Interventions

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No intervention.

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

Intervention Type OTHER

Eligibility Criteria

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Inclusion Criteria

* 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.

Minimum Eligible Age

1 Month

Maximum Eligible Age

100 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Timothy A Benke, MD PhD

Role: PRINCIPAL_INVESTIGATOR

University of Colorado, Denver

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United States Australia

Central Contacts

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Sharon R Pincus, MA

Role: CONTACT

Phone: 303-949-7116

Email: [email protected]

Scott T Demarest, MD MSCS

International CDKL5 Clinical Research Network

Study Results

Basic Information

Brief Summary

Detailed Description

Conditions

Study Design

Interventions

No intervention.

Eligibility Criteria

Inclusion Criteria

Sponsors

National Institute of Neurological Disorders and Stroke (NINDS)

National Institutes of Health (NIH)

International Foundation for CDKL5 Research

University of Colorado, Denver

Responsible Party

Principal Investigators

Timothy A Benke, MD PhD

Locations

University of California Los Angeles/UCLA Mattel Children's Hospital

University of Colorado Denver/Children's Hospital Colorado

Harvard Medical School/Boston Children's Hospital

Washington University in St. Louis/St. Louis Children's Hospital

NYU Langone Health

Cleveland Clinic Foundation

Children's Hospital of Philadelphia

Baylor College of Medicine/ Texas Children's Hospital

Telethon Kids Institute/Perth Children's Hospital

Countries

Central Contacts

Sharon R Pincus, MA

Scott T Demarest, MD MSCS

Facility Contacts

Angela Martinez

Sharon R Pincus, MA

Maria F Abila

Isa Haviland

Jenna Lukash

Olga Novak

Ali Vonderheid

Jacob Sloane

Juliana Laze

Xiaoming Zhang

Honglian Huang

Holly Dubbs

Elif Dundar

Jacinta Saldaris, PhD

Jenny Downs, PhD

References

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.

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.

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.

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.

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.

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.

Benke TA, Kind PC. Proof-of-concept for a gene replacement approach to CDKL5 deficiency disorder. Brain. 2020 Mar 1;143(3):716-718. doi: 10.1093/brain/awaa055.

Other Identifiers

5U01NS114312

19-2756