Ways of measuring outcomes for use in Angelman clinical trials detailed

Mix of clinic visits and home monitoring used in yearlong study seen as feasible

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Combining outcomes at clinic visits with those of at-home monitoring may be an effective way of determining an experimental treatment’s effectiveness in Angelman syndrome (AS) clinical trials, researchers report.

Overall adherence in a yearlong observational study of AS patients “indicate that the key clinical aspects of AS identified by caregivers and clinicians — seizures, sleep, motor function, expressive communication, cognition, self-care, and maladaptive behaviors — can be measured” using a mix of clinician and digital health measures, they wrote.

The study, “Enabling endpoint development for interventional clinical trials in individuals with Angelman syndrome: a prospective, longitudinal, observational clinical study (FREESIAS),” was published in the Journal of Neurodevelopmental Disorders

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Clinical trials are rigorously designed human studies, considered the gold standard for determining if an experimental treatment works or not. One of the most important aspects of clinical trial design is figuring out exactly what to measure in order to evaluate efficacy.

Ideally, these measures need to accurately capture disease-relevant changes, and must be feasible for patients and caregivers.

With the goal of identifying measures of use in Angelman clinical trials, scientists conducted a study called FREESIAS, or FiRst Endpoint-Enabling Study in Angelman Syndrome. The work was funded by Roche, Biogen, and Ionis Pharmaceuticals, and carried out as a collaboration between these companies and the Angelman Syndrome Foundation (ASF) and Foundation for Angelman Syndrome Therapeutics (FAST).

FREESIAS enrolled 43 children with Angelman ages 1 to 12 — the age group most expected to be enrolled in future clinical trials, the researchers noted. For comparison, 20 typically developing children, mostly siblings of the Angelman children, also were enrolled.

It also enrolled 12 adults with Angelman, ages 18 or older, as there’s less data on Angelman in this age group. But the trial did not include adolescents ages 13 to 17, as this period of life is known to be a time of substantial change and variability for people with Angelman.

At the study’s start and again about one year later, participants underwent a detailed battery of clinician-led assessments lasting about eight hours in total. This on-site visits included assessments of overall health status, as well as standardized measures of mobility and communication abilities.

During the year in between, caregivers were asked to use smartphone-based tools to record any seizures that occurred, as well as daily recordings of sleep quality.

The original plan was also to perform several at-home assessments where patients’ brain activity was monitored during sleep. But the COVID-19 pandemic hit a few months after the FREESIAS study launched, and most of the planned at-home visits were canceled. The pandemic also necessitated a shift to perform remotely some assessments initially intended to be done at a clinic.

High attendance at clinic visits, suggested changes for at-home monitoring

Despite these setbacks, the researchers found that most of the clinician-rated measures were feasibly performed. All 75 patients completed the first clinic visit, and 71 finished the second, most of which were conducted at a clinic.

Analyses of data from these assessments showed that Angelman children ages 5 to 12 generally had better functional abilities than younger Angelman children, but similar abilities compared to adults with Angelman. Generally poorer functional abilities also were seen in children with Angelman caused by a genetic deletion, compared with other causes. These findings are in line with other research into Angelman severity, the researchers said.

Caregiver-based reporting of sleep and seizure frequency also was generally feasible, although the researchers noted some areas where improvements could be made.

For example, fewer seizures were reported toward the end of the yearlong trial than at its beginning. Since there’s no biological reason to expect fewer seizures at later times, some seizures probably went unreported, the researchers said, noting this assumption cannot be confirmed, as caregivers had no way to document an absence of seizures. The researchers suggested future studies should include ways for caregivers to regularly report such absences.

Although the pandemic led to fewer at-home measures of brain activity than originally planned, the researchers noted that most of the assessments carried out provided usable data, supporting the use of this strategy.

Overall, the measures used in the study generally met with satisfaction by caregivers. Based on data from a survey collected at the study’s end, “most participants were either satisfied or very satisfied with their overall experience of the study,” the researchers wrote.

“The current results and future works derived from them may inform the design and strengthen the analysis of future clinical trials in AS and other neurological and neurodevelopmental conditions and rare diseases,” the scientists concluded.