Multi-Site Validation of Biomarkers and Core Clinical Outcome Measures for Clinical Trials Readiness in CDKL5 Deficiency Disorder
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 1,000
- 试验地点
- 9
- 主要终点
- CDKL5 Deficiency Disorder (CDD) Clinical Severity Assessment - Caregiver (CCSA-Caregiver)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 1 Month 至 100 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •Individuals who do not meet study inclusion criteria.
结局指标
主要结局
CDKL5 Deficiency Disorder (CDD) Clinical Severity Assessment - Caregiver (CCSA-Caregiver)
时间窗: 5 years
Measured by caregiver/parent rating of patient on a scale of 0-100 with a higher score indicating higher severity.
Communication and Symbolic Behavior Scales - Developmental Profile Infant Toddler Checklist (CSBS-DP ITC)
时间窗: 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.
CDKL5 Deficiency Disorder (CDD) Gross Motor (CDD-Motor)
时间窗: 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.
CDKL5 Deficiency Disorder (CDD) Fine Motor (CDD-Hand)
时间窗: 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.
Sleep Disorder Scale for Children (SDSC)
时间窗: 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.
Electroencephalogram/Evoked Potentials (EEG/EP) characteristics in CDKL5 Deficiency Disorder.
时间窗: 5 years
Measured by correlations of EEG/EP with other study scales.
CDKL5 Deficiency Disorder (CDD) Clinical Severity Assessment - Clinician (CCSA-Clinician)
时间窗: 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.
CDKL5 Deficiency Disorder (CDD) Development Questionnaire - Caregiver (CDQ-Caregiver)
时间窗: 5 years
Measured by caregiver/parent rating of patient on a scale of 0-100 with a higher score indicating higher severity.
Quality of Life Inventory - Disability (QI-Disability)
时间窗: 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.
次要结局
- Frequency of different mutations in the CDKL5 Deficiency Disorder population(5 years)
- Social Determinants of Health (SDOH) in CDKL5 Deficiency Disorder population(5 years)
- Frequency of medications and their indications in the CDKL5 Deficiency Disorder population(5 years)