Clinical trial NCT05558371: International CDKL5 Clinical Research Network
Official title: Multi-Site Validation of Biomarkers and Core Clinical Outcome Measures for Clinical Trials Readiness in CDKL5 Deficiency Disorder
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: CDKL5
CDKL5 Deficiency Disorder
CDD
Lead sponsor: University of Colorado, Denver
Sponsor class: OTHER
Collaborators: name: National Institute of Neurological Disorders and Stroke (NINDS)
name: National Institutes of Health (NIH)
name: International Foundation for CDKL5 Research
First posted: 2022-09-28
Enrollment: 1000
Sex: ALL
Minimum age (years): 1
Maximum age (years): 100
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Patients with CDKL5 Deficiency Disorder (CDD).

Brief summary: 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: 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.

Eligibility criteria: 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.

Exclusion Criteria:

* Individuals who do not meet study inclusion criteria.

Primary outcomes:
measure: CDKL5 Deficiency Disorder (CDD) Clinical Severity Assessment - Clinician (CCSA-Clinician)
timeFrame: 5 years
measure: CDKL5 Deficiency Disorder (CDD) Clinical Severity Assessment - Caregiver (CCSA-Caregiver)
timeFrame: 5 years
measure: CDKL5 Deficiency Disorder (CDD) Development Questionnaire - Caregiver (CDQ-Caregiver)
timeFrame: 5 years
measure: Communication and Symbolic Behavior Scales - Developmental Profile Infant Toddler Checklist (CSBS-DP ITC)
timeFrame: 5 years
measure: Sleep Disorder Scale for Children (SDSC)
timeFrame: 5 years
measure: Quality of Life Inventory - Disability (QI-Disability)
timeFrame: 5 years
measure: CDKL5 Deficiency Disorder (CDD) Gross Motor (CDD-Motor)
timeFrame: 5 years
measure: CDKL5 Deficiency Disorder (CDD) Fine Motor (CDD-Hand)
timeFrame: 5 years
measure: Electroencephalogram/Evoked Potentials (EEG/EP) characteristics in CDKL5 Deficiency Disorder.
timeFrame: 5 years
Secondary outcomes:
measure: Frequency of different mutations in the CDKL5 Deficiency Disorder population
timeFrame: 5 years
measure: Frequency of medications and their indications in the CDKL5 Deficiency Disorder population
timeFrame: 5 years
measure: Social Determinants of Health (SDOH) in CDKL5 Deficiency Disorder population
timeFrame: 5 years
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of California Los Angeles/UCLA Mattel Children's Hospital
state: California
city: Aurora
country: United States
facility: University of Colorado Denver/Children's Hospital Colorado
state: Colorado
city: Boston
country: United States
facility: Harvard Medical School/Boston Children's Hospital
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University in St. Louis/St. Louis Children's Hospital
state: Missouri
city: New York
country: United States
facility: NYU Langone Health
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Houston
country: United States
facility: Baylor College of Medicine/ Texas Children's Hospital
state: Texas
city: Perth
country: Australia
facility: Telethon Kids Institute/Perth Children's Hospital
state: Nedlands Western Australia
Study officials:
affiliation: University of Colorado, Denver
name: Timothy A Benke, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.