Discussion
heredodegenerative ataxias, Parkinson's disease, ataxia, SCA2 and SCA3, SCA3
STILL, MOVEMENT DISORDERS, NEURODEGENERATIVE DISORDERS, PARKINSON'S DISEASE, SPINOCEREBELLAR ATAXIA TYPE 2
This study shows that the vast majority of patients with SCA3 in a randomized, double‐blind, placebo‐controlled trial expected short‐term and long‐term health benefits when allocated to the active treatment arm in spite of an informed consent process with seemingly well‐balanced information. Most participants associated a lack of symptomatic improvement with probable or definite assignment to the sham group. High expectations of benefit were neither related to the type of intervention—device‐based or a (hypothetical) oral drug—nor to clinical or demographic characteristics.Trials in patients with heredodegenerative ataxias have thus far examined the potential of interventions to provide symptomatic improvement for a period of weeks to months. Only a small fraction of studies had a follow‐up duration of 1 year or longer. Strikingly, the recently published ATRIL trial investigating the efficacy of riluzole in spinocerebellar ataxia type 2 (SCA2), as well as our own tDCS trial, found absolute changes in SARA score at 1‐year follow‐up in the placebo arms (ATRIL: median 0.3 points; SCA3‐tDCS: mean −0.2 points) that were considerably different from the mean annual increases in natural history studies of patients with SCA2 and SCA3 (1.49 and 1.56 points, respectively).Although all patients probably hoped for the best personal outcome (ie, therapeutic optimism), which is usually not an ethical concern, we explicitly asked them about their expectations and not about hopes. Besides the common overestimation of direct benefits (ie, therapeutic misestimation), an important observation of this study was that one‐fifth of respondents stated that they had participated only to reduce the severity of their own symptoms. This response is at odds with the principal purpose of a clinical trial, namely, to produce generalizable knowledge by answering a scientific question that might eventually benefit future patients, and implies that these individuals failed to appreciate the difference between research and regular clinical care (ie, therapeutic misconception).In the field of movement disorders, therapeutic misestimation and therapeutic misconception are not confined to individuals with ataxia. A recent study showed that more than half of patients with Parkinson's disease expected long‐term improvement if randomized to the active treatment arm in a disease‐modification trial.Designing clinical trials in an area where hopes and expectations of participants and their families may have an unmeasurable influence on outcomes entails considerable difficulties. Preventing or reducing therapeutic misestimation and therapeutic misconception represents an important challenge for interventional studies in neurodegenerative disorders. Although evidence‐based guidelines to accomplish this task are lacking, we reflect on some potential strategies in the This study has several limitations. In addition to the restricted sample size, questionnaires were completed during trial conduct rather than at enrollment. Importantly, however, disclosure of treatment allocation had not yet occurred and there were no differences in anticipated improvement following real tDCS between patients in both study arms. Moreover, the decision whether or not to participate in a trial may have been prompted (mistakenly) by a priori expectations, which could have increased the prevalence of therapeutic misestimation in our study population. Finally, there was relatively little variability in delta SARA score after 2 weeks of tDCS, which, together with the restricted sample size, might have contributed to the lack of association between expected short‐term improvement and actual outcome.Still, we believe that our findings have important implications for the design of future therapeutic trials. First, high expectations of benefit feed the placebo response, may partly explain the considerable proportion of placebo responders in previous ataxia trials,