New research provides lessons for clinical-trial design in Friedreich’s ataxia

Reuters Health - 08/04/2021 - New data provide insights into clinical and functional changes over four years in a large cohort of patients with genetically confirmed Friedreich's ataxia, a rare inherited disease that causes progressive nervous system damage and movement problems.

"Our data have substantial implications for future research, and in particular for the design of upcoming clinical trials in Friedreich's ataxia as they provide a better understanding of suitable clinical and functional measures," researchers write in The Lancet Neurology.

Of the 602 patients in the European Friedreich's Ataxia Consortium for Translational Studies (EFACTS), 552 (92%) contributed data with at least one follow-up visit and 253 (42%) attended all five visits spread out over four years.

The four-year data extend earlier results in showing the usefulness of the Scale for the Assessment and Rating of Ataxia (SARA), a clinical rating scale for ataxia and the patient-reported activities of daily living (ADL) scale, report Dr. Kathrin Reetz of RWTH Aachen University, in Germany, and colleagues.

SARA scores range from zero (no ataxia) to 40 (most severe ataxia) and are based on patient performance on eight items: gait, stance, sitting, speech disturbance, finger chase, nose-finger test, fast alternating hand movements and heel-shin slide.

In the EFACTS cohort, annual progression rates for SARA was 0.82 points overall and higher in patients who were ambulatory (1.12 points) than non-ambulatory (0.50 points).

ADL worsened by 0.93 points annually in the entire cohort, with similar progression rates in patients who were ambulatory (0.94) and non-ambulatory (0.91).

"A novelty of this study is the clear evidence that the easily applicable activities of daily living (ADL) scale, as a patient-reported measure of functional decline reflecting the severity of a health condition, shows in most cases higher responsiveness than the SARA, especially in early-onset Friedreich's ataxia," the researchers note.

Both SARA and ADL showed slightly greater worsening in patients with typical symptom onset at age 24 years or younger than those with late symptom onset (25+ years), but the differences in progression slopes were not significant.

For a two-year parallel-group trial, the researchers calculate that 230 patients with Friedreich's ataxia (115 per group) would be needed to detect a 50% reduction in SARA progression at 80% power; 118 patients (59 per group) would be needed if only ambulatory patients were included.

With ADL as the primary outcome, 190 patients (95 per group) would be needed and fewer patients would be required if only individuals with early-onset are included.

Summing up, the researchers say the four-year EFACTS data provide a "robust estimation of disease progression based on a large number of patients and five timepoints extending our two-year analyses, particularly in terms of stage-dependent progression characterization and tailored clinical trial preparation. Specifically, during a pandemic with a growing need for online study assessments, ADL with its simple applicability and sensitivity to change is well suited to serve as a functional primary outcome for clinical trials in Friedreich's ataxia."

Dr. Masha Savelieff and Dr. Eva Feldman of the NeuroNetwork for Emerging Therapies, University of Michigan, in Ann Arbor, write in a linked comment, "No effective therapies for Friedreich's ataxia exist; however, the drug development pipeline holds several exciting, potentially disease-modifying candidates (eg, oligonucleotides and gene therapy). With novel therapies on the horizon, it is anticipated that more clinical trials will be launched. Unfortunately, heterogeneity is a recurrent theme in Friedreich's ataxia; heterogeneity in clinical presentation, disease severity, tissue involvement, and FXN mutation render it essential to select the best and most robust outcome measures to track progression. This necessity is reinforced by the relative rarity of this disease and by its slowly progressive nature," they write.

"EFACTS provides a valuable guide for highly anticipated upcoming Friedreich's ataxia clinical trials and a set of valuable lessons for future clinical trial design in neurological diseases," they conclude.

Funding for EFACTS is provided by the European Commission, Voyager Therapeutics, and EuroAtaxia.

SOURCE: https://bit.ly/3cX4x33 and https://bit.ly/39QquyM Lancet Neurology, online March 23, 2021.

By Reuters Staff



Posted on 8 April, 202120 April, 2021