International CDKL5 Clinical Research Network (ICCRN)

December 5, 2023 updated by: University of Colorado, Denver

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

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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.

Study Type

Observational

Enrollment (Estimated)

1000

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Australia
    • Nedlands Western Australia
      • Perth, Nedlands Western Australia, Australia, 6009
  • United States
    • California
      • Los Angeles, California, United States, 90095
        • Recruiting
        • University of California Los Angeles/UCLA Mattel Children's Hospital
        • Contact:
        • Principal Investigator:
          • Rajsekar Rajaraman, MD
    • Colorado
      • Aurora, Colorado, United States, 80045
        • Recruiting
        • University of Colorado Denver/Children's Hospital Colorado
        • Contact:
        • Principal Investigator:
          • Timothy A Benke, MD PhD
        • Sub-Investigator:
          • Scott T Demarest, MD MSCS
        • Contact:
    • Massachusetts
    • Missouri
      • Saint Louis, Missouri, United States, 63110
        • Recruiting
        • Washington University in St. Louis/St. Louis Children's Hospital
        • Contact:
        • Contact:
        • Principal Investigator:
          • Judith Weisenberg, MD
    • New York
    • Ohio
      • Cleveland, Ohio, United States, 44195
        • Recruiting
        • Cleveland Clinic Foundation
        • Contact:
        • Contact:
        • Principal Investigator:
          • Elia Pestana Knight, MD
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19104
        • Recruiting
        • Children's Hospital of Philadelphia
        • Contact:
        • Principal Investigator:
          • Eric Marsh, MD PhD
        • Sub-Investigator:
          • Erin Prange, MSN CRNP
    • Texas
      • Houston, Texas, United States, 77030
        • Recruiting
        • Baylor College of Medicine/ Texas Children's Hospital
        • Contact:
        • Principal Investigator:
          • Bernhard Suter

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

1 month to 100 years (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Sampling Method

Probability Sample

Study Population

Patients with CDKL5 Deficiency Disorder (CDD).

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
CDKL5 Deficiency Disorder (CDD) Clinical Severity Assessment - Clinician (CCSA-Clinician)
Time Frame: 5 years
Measured by clinician rating of patient. Item scores are transformed to a scale of 0-100 and the total score is calculated as a mean item score. Higher scores indicate higher severity.
5 years
CDKL5 Deficiency Disorder (CDD) Clinical Severity Assessment - Caregiver (CCSA-Caregiver)
Time Frame: 5 years
Measured by caregiver/parent rating of patient on a scale of 0-100 with a higher score indicating higher severity.
5 years
CDKL5 Deficiency Disorder (CDD) Development Questionnaire - Caregiver (CDQ-Caregiver)
Time Frame: 5 years
Measured by caregiver/parent rating of patient on a scale of 0-100 with a higher score indicating higher severity.
5 years
Communication and Symbolic Behavior Scales - Developmental Profile Infant Toddler Checklist (CSBS-DP ITC)
Time Frame: 5 years
Measured by caregiver/parent rating of patient on a 24-item questionnaire. Three composite scores and a total score can be derived. Items contribute to the 0-57 point scale for the total score with lower scores indicating concerns for communication skills.
5 years
Sleep Disorder Scale for Children (SDSC)
Time Frame: 5 years
Measured by caregiver/parent rating of patient on a 26- Likert type item questionnaire. Scale goes from 0-39 with a higher score indicating higher severity of sleep disorder. Each subscale is scored through the summation of all the subscale items. Comparing scores were the normative data reported in the initial validation paper, z-scores and t-scores can be derived. The t-score enables scores to be dichotomized as within normal range or outside of normal range, compared to the general population.
5 years
Quality of Life Inventory - Disability (QI-Disability)
Time Frame: 5 years
This is a quality of life measure for children with intellectual disability. The measure comprises 32 items that are rated on a five-point Likert scale and group into six subscales: physical health, positive emotions, negative emotions, social interactions, independence, and leisure and outdoors. Following transformation to a 100-point scale, item scores in each subscale are summed and divided by the number of items to give a subscale score. The mean of the six subscale scores is calculated to give the total QOL score.
5 years
CDKL5 Deficiency Disorder (CDD) Gross Motor (CDD-Motor)
Time Frame: 5 years
This is a video measure of gross motor function, based on the Rett Syndrome Gross Motor Scale with additional items that enable measurement of head control and sitting. Parents are provided with a filming protocol, video clips are uploaded to the investigators, and data are coded according to a predetermined coding system.
5 years
CDKL5 Deficiency Disorder (CDD) Fine Motor (CDD-Hand)
Time Frame: 5 years
This is a video measure of fine motor function based on the Rett Syndrome Hand Function Scale with additional instructions on filming for if the patient has Cortical Visual Impairment. Parents are provided with a filming protocol, video clips are uploaded to the investigators, and data are coded according to a predetermined coding system.
5 years
Electroencephalogram/Evoked Potentials (EEG/EP) characteristics in CDKL5 Deficiency Disorder.
Time Frame: 5 years
Measured by correlations of EEG/EP with other study scales.
5 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Frequency of different mutations in the CDKL5 Deficiency Disorder population
Time Frame: 5 years
Measured by information obtained from genetic reports of enrolled participants.
5 years
Frequency of medications and their indications in the CDKL5 Deficiency Disorder population
Time Frame: 5 years
Measured by medication/indication data obtained from medical record review and/or caregiver report.
5 years
Social Determinants of Health (SDOH) in CDKL5 Deficiency Disorder population
Time Frame: 5 years
Measured by data elements that are collected to describe the socioeconomic status of the study population. Examples include caregiver education level, marital status and employment status, patient living situation, household income, and primary caregiver information.
5 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Colorado, Denver

Collaborators

National Institute of Neurological Disorders and Stroke (NINDS)
National Institutes of Health (NIH)
International Foundation for CDKL5 Research

Investigators

  • Principal Investigator: Timothy A Benke, MD PhD, University of Colorado, Denver

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 15, 2021

Primary Completion (Estimated)

February 15, 2026

Study Completion (Estimated)

February 15, 2027

Study Registration Dates

First Submitted

July 28, 2022

First Submitted That Met QC Criteria

September 23, 2022

First Posted (Actual)

September 28, 2022

Study Record Updates

Last Update Posted (Estimated)

December 6, 2023

Last Update Submitted That Met QC Criteria

December 5, 2023

Last Verified

December 1, 2023

More Information

Terms related to this study

Other Study ID Numbers

  • 19-2756
  • 5U01NS114312 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

The ICCRN will be utilizing the National Institute of Mental Health (NIMH) Data Archive (NDA), previously known as the National Database for Autism Research (NDAR), as our final deidentified repository of our data. We will utilize Global Unique Identifiers to ensure we have deconflicted patient data across all institutions. Each institution will be directly uploading patient data to our central REDCap database to allow for cleaning of data prior to upload to NDA. Our data elements will be harmonized with other NDA elements where appropriate at the start of the study. The one exception is patient videos which will be reviewed at Telethon kids secure network for analysis, but the scored results of validated motor scales will be uploaded to NDAR in a deidentified fashion. All scales, outcome measures, and protocols (both for scoring and implementation of COMs) will also be shared through publications.

IPD Sharing Time Frame

Available data will be released to the repository and will become available to the scientific community one year after publication of planned analyses, or after a period of 5 years from the date when the data were collected, whichever comes first.

IPD Sharing Access Criteria

NIMH NDA policy will govern access criteria.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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