Clinical Trials Outcome Measures

With a $281,824 grant from FRAXA Research Foundation from 2002-2011, Dr. Berry-Kravis at the Rush University Medical Center attempted to validate a new automated video tracking system for quantifying physical activity as an outcome measure for Fragile X clinical trials.

Elizabeth Berry-Kravis, MD, PhD, Fragile X researcher
$281,824 Grant
Elizabeth Berry-Kravis, MD, PhD
Principal Investigator
Rush University Medical Center
2009-2011 FRAXA Research Grant
$53,824
$228,000 over 6 Years (2002-2007)

Project: Markerless Motion Analysis System to Quantify Hyperkinesis as an Outcome Measure for Clinical Trials in Fragile X

The team conducting this project are Elizabeth Berry Kravis, MD, PhD; Markus Wimmer, PhD, Deborah A. Hall, MD, PhD and Joan A. O’Keefe, PT, PhD., at Rush University Medical Center

by Elizabeth Berry-Kravis, 4/11/2011

Excessive motor activity (hyperkinesis), including hyperactivity and repetitive movements, called stereotypies, is a core behavioral phenotype in both the Fragile X mouse model and humans with Fragile X syndrome (FXS), affecting 90% of boys with FXS and 35-50% of girls, and frequently requiring treatment intervention. These aberrant motor behaviors and hyperactivity interfere with functioning, including social interactions and learning. Given that motor hyperactivity is such a strong aspect of the FXS phenotype, a methodology to accurately quantify this would serve as an excellent outcome measure for clinical trials of new pharmacotherapy targeted to the underlying disorder. Indeed open field hyperactivity in the Fragile X mouse model has been one of the few behavioral phenotypes in the mouse that has been shown to be abnormal in multiple laboratories and reversed by mGluR5 blockers.

There currently are no adequate quantitative systems designed to accurately measure hyperkinesis or repetitive movements in individuals with FXS. Current outcome tools used when investigating pharmaceutical effects on hyperkinesis consist of rating scales or checklists. The limitations with using these scales for clinical trials research include lack of objectivity, variation between raters, inability to detect small increments of change, lack of specificity to FXS symptoms and floor and/or ceiling effects within the spectrum of hyperkinetic behaviors seen in persons with FXS.

This study is a unique collaboration between investigators with expertise in FXS, movement disorders, neuroscience of gait and movement, and computer engineering and will evaluate the use of a novel markerless motion analysis system to quantify hyperkinesis in a small group of children, teenagers and young adults (ages 5-30) with FXS. The study will utilize a commercially available multiple camera-based 3-dimensional motion analysis system developed by Organic Motion (www.organicmotion.com), which won “The Wall Street Journal 2009 Technology Innovation Award for Computing Systems” to quantify hyperkinesis in FXS. Our motion analysis system is analogous to the open field hyperactivity measure used in the Fragile X mouse and will allow us to design analyses to quantify the amount of hyperactive movement of all types (eg. both from walking around or from moving the hands and arms about) for an individual with FXS doing a standardized set of activities within the motion analysis space. The measure does not require the individual with FXS to wear anything, is not invasive, and does not put demands on the participant, and thus should be very easy for children and young adults with FXS to do. In this study we will pilot and develop the analyses for the motion analysis measure. These pilot data will be used to obtain further funding through NIH and/or industry, so that we can extend studies to more extensive validation and tests of pharmaceutical effects on the motion analysis measurements.

It is expected that this project will lead to development of the motion analysis system as a prototype to quantify hyperkinesis that would be included in a “toolkit” of validated outcome measures for use in proof-of-concept and early phase clinical trials of new medications targeting the underlying disorder in FXS. Given the findings using the analogous measure in the Fragile X mouse, development of this outcome measure will assist with direct translation of research findings in the FXS animal model to clinical trials in humans with FXS.

Elizabeth Berry-Kravis, MD, PhD, Fragile X researcher

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