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Working towards strong clinical trials for CDKL5 Deficiency Disorder

Contributors: Jacinta Saldaris and Jenny Downs on behalf of the ICCRN, the CDKL5 Outcome Measures team

Working towards strong clinical trials for CDKL5 Deficiency Disorder (CDD): Content validation of the Clinician reported CDD Clinical Severity Assessment

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.

Background:

Cyclin-dependent kinase-like 5 (CDKL5) Deficiency Disorder (CDD) is a rare condition. Most children with CDD develop epilepsy in infancy which is hard to control with medicines [1] and most children have difficulties with learning and movement  [2 3]. There can be other health issues such as breathing problems, disrupted sleep, gastrointestinal issues and cortical visual impairment.

Research is currently underway to develop new medicines for CDD, including gene therapies. To test these medicines, we also need outcome measures that can identify whether the new medicines have worked. A critical obstacle towards clinical trial readiness is that no CDD specific outcome measures have been developed. Promising medicines and strong outcome measures are required for strong clinical trials. This is also a requirement of the Food and Drug Administration (FDA) who approve new trials to begin [4].

Our team (see figure above) is working on a program of research funded by the NIH which will develop and test measures for CDD to capture the different areas important to families, including clinical severity, gross motor, fine motor, communication, and quality of life.

We are following a pipeline of activities for each of these outcome measures to prepare the community for clinical trial readiness.

What we did:

Our work for this study was based on a previous study, led by Professor Tim Benke, which captured the opinions of clinicians, researchers, and parent advocacy group representatives as to what should be included in a severity assessment for CDD [5]. The assessment evaluated medical issues experienced in CDD with a section for clinicians to complete and a separate section for parents.

In the current study, we refined the clinician reported portion of the initial severity assessment to construct the CDD Clinical Severity Assessment-Clinician (CCSA-Clinician). All USA Centre of Excellence (COE) clinicians, who have extensive experience in evaluating CDD patients, were involved in this work.

We worked intensively as a team to refine the CCSA-Clinician through:

  1. Eight individual interviews, held with the COE clinicians to “think aloud’ through the items and to ask them:
    1. “Why did you give that rating?”
    2. “How would you restate this question in your own words?”
    3. “Was there anything that you found confusing or did not understand?”.

From these interviews, we determined items to be added, removed or revised.

What we found:

The original CCSA-Clinician included 26 items. After reviewing all interview data, 11 items were added, 8 removed and 18 revised. Therefore, the revised CCSA-Clinician comprised 29 items. We grouped the items into domains of:

  1. Functional abilities (13 items for gross and hand function, communication, vision and attention)
  2. Neurological impairment (16 items for abnormal eye alignment and movement, altered muscle tone, dystonia, dyskinesias, stereotypies, autonomic function and behaviour).

An important modification was made to the gross motor item set, so that the CCSA-Clinician could measure children of different ages, including children who have not learnt some skills because they are too young. To solve this problem, we added extra items (head control, lying to sit and sit to stand) to the gross motor item set. Clinicians will assess the appropriate items for each child depending on their age [6].

The CCSA-Clinician also evaluates how the child is on the day. This is because the child’s current state of health and wellness, including ‘time since the last seizure’ or ‘current medications’, could impact the child’s abilities on any given day. This information is an important addition to the CCSA-Clinician.

A scoring protocol was then designed to make sure that all groups of items in a domain (e.g., Gross motor function, Communication) had the same total score, as it is not known if any one group of items is more important than another, in terms of severity.

We achieved a consensus that the revised CCSA-Clinician items:

  1. Were appropriate to CDD and could be observed during a clinical visit.
  2. Were clearly described and the scoring categories did not overlap, to assist clinicians to score the CCSA-Clinician consistently.

What this will achieve and why this is important?

We are working along the pipeline of validation for the CCSA-Clinician (Figure 2). This initial validation of the CCSA-Clinician is an essential first step in developing the measure towards clinical trial readiness and is important information for the FDA [4].

Figure 2: CDD Clinician reported Clinical Severity Assessment (CCSA-Clinician) development to clinical trial readiness

We took a novel approach to developing the CCSA-Clinician through interview and consensus methods which allowed greater thought processes to fine tune the measure to children with CDD. The next step is to test its reliability – that is, do the clinicians use the CCSA-Clinician consistently? Reliability testing will be completed with clinic videos to show whether the clinicians score the items on the CCSA-Clinician consistently. In a separate study, the initial parent reported severity items are being developed and validated through interviews with parents of a child with CDD to create CCSA-Parent. The CCSA-Parent will add to the CCSA-Clinician on important areas such as epilepsy and sleep. Ultimately, the scores of the CCSA-Clinician and CCSA-Parent will combine to give a total clinical severity score.

References

1. Fehr S, Wilson M, Downs J, et al. The CDKL5 disorder is an independent clinical entity associated with early-onset encephalopathy. Eur J Hum Genet 2013;21(3):266-73 doi: 10.1038/ejhg.2012.156.

2. Hagebeuk E, Van den Bosshe R, de Weerd A. Respiratory and sleep disorders in female children with atypical Rett syndrome caused by mutations in the CDKL5 gene. Developmental Medicine and Child Neurology 2013;55(5):480-84 doi: 10.1111/j.1469-8749.2012.04432.x.

3. Mangatt M, Wong K, Anderson B, et al. Prevalence and onset of comorbidities in the CDKL5 disorder differ from Rett syndrome. Orphanet J Rare Dis 2016;11(39):39 doi: 10.1186/s13023-016-0418-y.

4. U.S. Department of Health and Human Services FaDA, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), Center for Devices and Radiological Health (CDRH). Guidance for Industry: Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims. Silver Spring, MD: Food and Drug Administration, U.S. Department of Health and Human Services, 2009.

5. Demarest S, Pestana-Knight EM, Olson HE, et al. Severity Assessment in CDKL5 Deficiency Disorder. Pediatric Neurology 2019;97:38-42 doi: 10.1016/j.pediatrneurol.2019.03.017.

6. Group. WMGRS. WHO Motor Development Study: Windows of achievement for six gross motor development milestones. . Acta Paediatrica Supplement 2006;450:86-95.

Original abstract:

CDKL5 deficiency disorder (CDD) results in early onset seizures and severe developmental impairments. A CDD clinical severity assessment (CCSA) was previously developed with clinician and parent-report items to capture information on a range of domains. Consistent with FDA guidelines, content validation is the first step in evaluating its psychometric properties of an outcome measure. The aim of this study was to validate the content of the clinician-reported items in the CCSA (CCSA-Clinician). Eight neurologists leading the USA CDD Center of Excellence clinics were interviewed using the ‘think aloud’ technique to critique 26 clinician-reported items. Common themes were aggregated and a literature search of related assessments informed item modifications. The clinicians then participated in two consensus meetings to review themes and finalise the items. A consensus was achieved for the content of the CCSA-Clinician. Eight of the original items were omitted, eleven items were added, and the remaining 18 items were revised. The final 29 items were classified into two domains: functioning and neurological impairments.This study enabled refinement of the CCSA-Clinician and provided evidence for its content validity. This preliminary validation is essential before field testing and further validation, in order to advance the instrument towards clinical trial readiness.

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