Clinical trial design for Friedreich ataxia - Where are we now and what do we need?

ABSTRACT

Introduction: Since the discovery of the mutation in Friedreich ataxia, a series of clinical trials have been conducted to provide symptomatic or disease-modifying therapy. At this point none have reached regulatory approval. This review examines several aspects of the design of FRDA clinical trials to understand better their shortcomings.

Areas covered: The mechanisms for performing clinical trials have been well developed in FRDA, including the presence of two ongoing longterm natural history studies and a patient registry that captures more than 3000 potential subjects. Still, trials to this point have not utilized this information in many situations. Studies have been smaller and shorter than predicted based on natural history studies. In addition, studies have not always matched outcome measures to specific sub cohorts or chosen subjects in the most responsive phases of the disease.

Expert opinion: The optimization of clinical trials in FRDA should lead to a greater likelihood of success. Such improvements should include longer studies with more subjects, and directing of studies to optimal populations. Along with more extensive preclinical development, improved design will facilitate future success in clinical trials in FRDA.

KEYWORDS:

• Ataxia
• mitochondrial disease
• decline phase
• registry
• natural history study

Article highlights

• Previous clinical trials in FRDA have been largely underpowered based on natural history studies.

• More sensitive trials could target stratified cohorts, and direct interventions to the decline phase of the disorder.

• Clinical measures in FRDA are complicated and frequently not applied in the correct context.

• Natural history studies in FRDA provide a general framework for sample size calculations, but detailed extrapolations of such data are difficult.

• The diversity of FRDA confounds clinical trial performance, but can also be used as a mechanisms to stratify participants.

This box summarizes key points contained in the article.

Declaration of Interest

D Lynch receives grants from the Friedreich Ataxia Research association, the muscular dystrophy association, and the national institutes of health, Reata pharmaceuticals, Takeda Pharmaceuticals, Viropharma, Horizon and Edison Pharmaceuticals. C Rummey receives funding from the Friedreich ataxia research alliance and has performed consulting for Santhera and Voyager. Dr. Kichula has served as an advisor to Avexa and PTC. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This paper was not funded