Setting the goalposts for ALS clinical trials

In the fight against a relentless neurodegenerative disease such as ALS (amyotrophic lateral sclerosis), a critical question for research is: what is the definition of success?

Emory neurologists, with advice from other experts, have created a new disability rating scale for ALS. This is a set of questions patients or their caregivers answer to gauge how much ALS is eroding someone’s ability to manage daily life. The researchers think it can become a resource for testing new treatments for ALS in clinical trials.

The research used to develop the new rating scale was published on December 30 in JAMA Neurology. The rating scale itself will be available on the Emory ALS Center web site.

ALS’s attack on motor neurons makes it progressively more difficult to accomplish tasks such as household chores, daily hygiene, and eventually speaking and eating. Some patients live a year or two after diagnosis, some live ten.

Christina Fournier, MD

“If our goal in clinical trials is to have that decline happen more slowly, how we measure it matters,” says lead author Christina Fournier, MD, assistant professor of neurology at Emory University School of Medicine and co-director of Emory’s ALS Center.

Update: see Fournier’s comments to Medscape/Reuters Health here.

The current standard outcome measure is the ALSFRS-R (Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised). While widely accepted in the field, the ALSFRS-R has some uneven aspects, or nonlinear weighting, which become problems when it is used to determine drug approval.

One example: a patient’s score will decline 3 points if they change from climbing stairs normally to holding a handrail, and will decline the same amount if they change from normal dressing and hygiene to being unable to dress or perform hygiene tasks without assistance. So 3 points can represent small or large changes in their lives. Also, the ALSFRS-R can change depending on symptom management, rather than underlying biology.

To put this in perspective, the most recent drug to be approved by the FDA (edaravone) displayed an effect size of 2.5 points – and the same drug faced resistance from European regulators. According to the Wall Street Journal, about 20 drugs are in clinical testing for ALS and 5 are in the late stages of development.

In creating the new rating scale, Emory neurologists and other experts winnowed down a list of more than 100 questions about daily life to a set of 28. A draft questionnaire with 119 questions was initially evaluated by 243 people with ALS from the Emory and Atlanta VAMC ALS clinics.

Some questions probe initial problems with more difficult tasks, such as getting a heavy object off a shelf. Others test whether motor neuron impairment impacts the ability to use a knife and fork, roll over in bed, blow out a candle or drink a milkshake.

The increased discriminatory power of the new scale comes from the relevance of the questions, rather than granularity of responses, since patients can only answer either 0 (unable to perform), 1 (perform with difficulty) or 2 (normal). The new rating scale is called the Rasch-built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS). The researchers used methodology developed by mathematician and statistician Georg Rasch.

The senior author of the JAMA Neurology paper is Jonathan Glass, MD, professor of neurology and co-director of Emory’s ALS Center. Outside neurologists consulted were Richard Bedlack, MD, PhD from Duke, Colin Quinn, MD from Penn, and James Russell, DO from Lahey Hospital in Massachusetts. Additional experts include physical therapist Diane Beckwith and speech-language pathologist Kathleen Kaminski. The research was supported by the Department of Veterans Affairs (grant IK2CX001595).

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Posted on by Quinn Eastman in Neuro Leave a comment

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Quinn Eastman

Science Writer, Research Communications qeastma@emory.edu 404-727-7829 Office

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