Therapeutic Misestimation in Patients with Degenerative Ataxia: Lessons from a Randomized Controlled Trial.

Background: The absence of effective treatments may render patients with degenerative cerebellar ataxias susceptible to a placebo response, which could affect the outcome of clinical trials.

Objective: To retrospectively examine expectations of benefit in participants of an ataxia trial and identify determinants of possible therapeutic misestimation.

Methods: Individuals with spinocerebellar ataxia type 3 who participated in a randomized, double-blind, sham-controlled trial received a custom-designed questionnaire about short-term and long-term treatment expectations, allocation preferences, and interpretation of treatment arm assignment based on the presence or absence of clinical improvement. To evaluate whether expectations were specifically related to the application of cerebellar transcranial direct current stimulation (tDCS) or more generally reflect an overly positive attitude of patients with ataxia toward trial participation and results, the last questions involved a hypothetical scenario in which an oral drug was tested against placebo with an aim identical to that of our tDCS study.

Results: All 20 trial participants completed the questionnaire. If allocated to the active treatment arm, 75% of patients expected short-term health benefits and 55% thought they would still have less severe ataxia at 1-year follow-up compared with baseline. After 2 weeks, an average reduction in ataxia severity of 31.5% (standard deviation, 22.2%) was anticipated. Conversely, 65% associated a lack of improvement with probable or definite allocation to the placebo group. High expectations of benefit were neither related to the type of intervention nor to clinical or demographic characteristics.

Conclusion: Therapeutic misestimation is common in patients with degenerative ataxia and requires special attention in future trials. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.