The severity of the frataxin mutation, which causes Friedreich’s ataxia (FA), is the main factor determining the speed of the disease’s progression, next to age — a finding that may improve the design of future clinical trials for Friedreich’s ataxia therapies, researchers found.
The study, “Progression of Friedreich ataxia: quantitative characterization over 5 years,” published in the journal Annals of Clinical and Translational Neurology, suggests that trials would do well to focus on younger participants. Following people for a longer time might also be a way to reduce the number of patients in any particular trial.
Researchers at the Children’s Hospital of Philadelphia noted that several trials focusing on Friedreich’s ataxia treatment failed because of poor study design. The failures, they argue, are caused by a lack of knowledge of how the disease progresses in the long run, which has made it difficult to calculate how many patients are needed for a study.
To better understand which factors are driving progression, the team followed 812 patients. Since the study is ongoing, and patients are enrolled on a rolling basis, only 234 patients were followed for a full five years. Patients were examined with the Friedreich’s ataxia-specific neurological exams: the Friedreich Ataxia Rating Scale (FARS), the modified FARS, and ataxia staging.
In addition, patients performed the 9-Hole Peg Test, Timed 25-foot Walk, vision tests, and reported activities of daily living. Analyses showed that age, along with the number of GAA (guanine-adenine-adenine) repeats in the frataxin gene, predicted patients’ performance on all tests.
The team examined factors influencing progression rate and found that age was the main factor impacting disease progression, with younger people progressing more rapidly. The number of GAA repeats on the longer gene copy had more of an impact on disease progression, while the number of repeats on the shorter gene copy did not.
However, when stratifying the group according to age, researchers noted that the speed of progression also depended on disease stage. Running a new analysis taking, among other things, age and genetic severity into account, the team noted that the severity of disease at the study’s start was the most important factor predicting speed of progression in later years.
In a final analysis, adjusted for disease severity at the start of the study, the number of GAA repeats was the most significant predictive factor. However, researchers noted that it is difficult to separate the effect of age and genetic severity, so clinical trials would benefit from enrolling younger subjects.