Clinical Assessment Tools Specific for Angelman Needed, Study Suggests

New instruments for researching Angelman syndrome should be developed to make sure patient outcomes are relevant and properly registered and catalogued in clinical trials, a new study suggests.

Current clinical outcomes assessments (COAs) that measure a patient’s symptoms, overall mental state, or the effects of a disease or condition on how the patient functions, should be adapted to include patients with Angelman syndrome.

These recommendations were supported in the study, “Conceptual Model of Angelman Syndrome and Review of Relevant Clinical Outcomes Assessments (COAs),” published in The Patient.

Angelman syndrome is a rare, neurological genetic condition characterized by developmental delays, learning disabilities, severe speech impairment, and lack of muscle coordination.

As research in Angelman syndrome progresses, it has become increasingly important to understand and record the clinical outcomes experienced by patients and their caregivers when evaluating the safety and effectiveness of new treatments.

This patient-centered approach is underscored by the U.S. Food and Drug Administration’s (FDA) Patient-Focused Drug Development (PFDD) initiative, in which the main purpose is to ensure that a patient’s perspective is taken into account when a new therapy is being developed and tested. That process includes identifying relevant endpoints and collecting  patient-reported or observer-reported information from “well-defined and reliable clinical outcomes assessments to inform decision-making.”

COAs are used to determine if a new treatment or alternative treatment is safe and effective during a clinical trial, based on patients’ symptoms, mental state and disease impact. Well-defined and reliable COAs are essential to perform an informed decision regarding the future of a new drug or treatment and to support novel medical findings.

Unfortunately, until now, there are no Angelman-specific COA instruments. Treatment benefits in clinical trials have been based, so far, on other COAs designed for pediatric populations or other conditions similar to Angelman syndrome. However, the use of these instruments in Angelman syndrome clinical trials has not been studied and validated. In addition, there also is a concerning and real possibility that these non-specific COAs can lead to unreliable results in clinical trials.

Research methods

A team of researchers from Ovid Therapeutics aimed to identify symptoms and affects relevant for  Angelman patients, in an attempt to develop a conceptual model for the disease and assess the validity of pre-selected COA instruments that might be included in future clinical trials to capture treatment benefits.

“Patient, caregiver, and clinician insights play an important role in the drug development process and can inform the appropriate and relevant selection of endpoints in clinical trials,” the authors wrote.

Four clinicians and 34 caregivers of children, adolescents, and adults with Angelman syndrome participated in concept elicitation (CE) interviews to discuss symptoms and relevant impacts for patients with the condition.

In addition, three clinicians and 36 caregivers participated in cognitive interviews (CI) to assess the validity of six potential COA instruments previously described in the literature for children and adults with Angelman syndrome: the Modified Performance-Oriented Mobility Assessment (MPOMA-G); the ProtoKinetics Zeno Walkway; the Pediatric Evaluation of Disability Inventory Computer Adaptive Test (PEDI-CAT); the Anxiety, Depression and Mood Scale (ADAMS); the Aberrant Behavior Checklist–Community (ABC-C); and the Morning Diary.

Researchers built a preliminary conceptual model, initially based on information from the literature, and then refined based on data gathered during the interviews.

The final model took into account a total of five signs, symptoms and characteristics of Angelman syndrome (cognitive and executive functioning, social-emotional, emotional-expressive behavior, sensory-compulsive behavior, and physical), together with three patient (activities of daily living, school, and social/community) and five caregiver (mental health, physical health, work, home, and social) domains of impact.

The team then assessed the validity of its model. All six COA instruments were simultaneously useful and problematic in the context of Angelman syndrome: useful, because all of them provided relevant information for patients affected by the disorder; and problematic, because they either took into account irrelevant aspects for patients with Angelman syndrome or they completely disregarded important concepts found during the interviews. None of these instruments fully captured all the relevant specific details of Angelman syndrome.

“While the instruments each covered relevant concepts for AS, particularly those related to mobility, fine and gross motor skills, sleep, and behavior-related issues, not one instrument covered all domains or was completely ready for use without adaptation in order to be fully applicable to an adult or child with AS,” the authors wrote.

The authors suggest that novel Angelman-specific COA instruments should be developed to ensure relevant patient outcomes are properly registered and catalogued in clinical trials. Also, current COAs should be further adapted to patients with the condition.

“… the findings of this study are instrumental in providing guidance in identifying the concepts that are most important to patients and caregivers. Researchers can then be sure these important concepts are being captured and appropriately measured in the context of a clinical trial. The insight provided in this study informed the development of the first conceptual model of AS,” they concluded.