Optimizing clinical trial design for multiple system atrophy: lessons from the rifampicin study

Abstract

Multiple system atrophy (MSA) is a fatal neurodegenerative disorder characterized by autonomic failure and parkinsonism/ataxia; no treatment exists to slow disease progression. A number of factors have prevented or compromised trials targeting disease modification. A major hurdle has been uncertainty about the number of patients needed to achieve adequate power. Information based on natural history studies suggested such numbers to be so large that only international multi-center models seemed feasible. When designing the rifampicin trial in MSA we sought to identify and apply strategies that would improve power and reduce the number needed to treat to allow for an oligocenter approach. Strategies included: (1) inclusion/exclusion criteria designed to enroll patients with relatively early, actively progressing disease; (2) minimizing dropouts; (3) pre-defined interim analysis; and (4) approaches to reduce scoring variability. The model allowed for the number needed to treat to be only 50 patients per treatment arm. Ten selected sites managed to reach the recruitment goal within 12 months. The dropout rate was less than 10%, and the goal of enrolling patients with actively progressing disease was accomplished as reflected by the progression rate in the placebo group. Data from this unfortunately negative trial can now be effectively used to more realistically power future trials. A number of ways to further improve trial design and feasibility have been identified and include rigorous site selection and training, designated primary site investigators, improved error trapping, early site visits, remedial training, and future biomarkers for earlier diagnosis and tracking of disease progression.

Fig. 1

Translational view of MSA pathogenesis

Fig. 2

Sigmoid progression of clinical impairment and deficits over time. A preclinical stage is followed by a stage of evolving early disease, which is clinically non-specific and escapes current consensus criteria. This is followed by a phase with still steep progression, captured by consensus criteria (“possible” MSA and “early probable” MSA), and finally a late plateau phase that almost invariably meets consensus criteria for “probable” MSA

Fig. 3

Planned versus actual recruitment of patients for the rifampicin treatment trial. Recruitment was completed within one year and one year ahead of plan

Fig. 4

Sample size estimations for future studies in MSA by effect size. The required sample size is estimated based on disease progression as observed in the rifampicin treatment trial (early disease stage, solid lines) versus the prospective North American Natural History study of MSA (late disease stage, dotted lines). Sample sizes are estimated for 80% (black) and 90 % (gray) power and an alpha level of 0.05 based on a two-sample t test