Sample size calculations for clinical trials targeting tauopathies: a new potential disease target

Abstract

Disease-modifying therapies are being developed to target tau pathology, and should, therefore, be tested in primary tauopathies. We propose that progressive apraxia of speech should be considered one such target group. In this study, we investigate potential neuroimaging and clinical outcome measures for progressive apraxia of speech and determine sample size estimates for clinical trials. We prospectively recruited 24 patients with progressive apraxia of speech who underwent two serial MRI with an interval of approximately two years. Detailed speech and language assessments included the Apraxia of Speech Rating Scale (ASRS) and Motor Speech Disorders (MSD) severity scale. Rates of ventricular expansion and rates of whole brain, striatal and midbrain atrophy were calculated. Atrophy rates across 38 cortical regions were also calculated and the regions that best differentiated patients from controls were selected. Sample size estimates required to power placebo-controlled treatment trials were calculated. The smallest sample size estimates were obtained with rates of atrophy of the precentral gyrus and supplementary motor area, with both measures requiring less than 50 subjects per arm to detect a 25% treatment effect with 80% power. These measures outperformed the other regional and global MRI measures and the clinical scales. Regional rates of cortical atrophy therefore provide the best outcome measures in progressive apraxia of speech. The small sample size estimates demonstrate feasibility for including progressive apraxia of speech in future clinical treatment trials targeting tau.

Advances in neuroimaging in frontotemporal dementia

“…), demonstrated that annual rates of atrophy in the precentral and supplementary motor areas outperformed other regional and more global MRI measures (Whitwell et al . ).…”

“…Investigations in svPPA suggest improved sensitivity when measuring disease progression with temporal lobar volume change instead of hemispheric or whole-brain measurements (Rohrer et al 2008a;Krueger et al 2010). In addition, a recent study of progressive apraxia of speech patients (who almost exclusively present with tau pathology at post-mortem; Deramecourt et al 2010;Dickson et al 2010), demonstrated that annual rates of atrophy in the precentral and supplementary motor areas outperformed other regional and more global MRI measures (Whitwell et al 2015). Table 1 Summary of annualised global and regional atrophy rates (expansion rates for ventricles) from previously published studies Publication and cohort The utility of these rates of change markers, based on estimated sample sizes to demonstrate a relevant therapeutic effect, varies accordingly across method and patient subtype ( Table 2).…”

Primary Progressive Aphasias and Apraxia of Speech

“…No studies have formally evaluated the prevalence of primary progressive apraxia of speech, but based on the proportion of patients with primary progressive apraxia of speech included in observational studies relative to disorders for which prevalence has been established, it has been estimated to be approximately 4.4 per 100,000. 16 Age of onset varies considerably, ranging from the late forties to early eighties, although it is older than age 65 in about two-thirds of cases. It appears to affect men and women approximately equally, and no demographic, socioeconomic, or environmental risk factors are known.…”

A molecular pathology, neurobiology, biochemical, genetic and neuroimaging study of progressive apraxia of speech

“…The syndrome of PPAOS was later more fully characterized and shown to relate to degeneration of a network of regions that include the lateral premotor cortex and supplementary motor area (SMA) 9 . The prevalence of PAOS, which encompasses PPAOS, has been estimated to be about 4.4 per 100,000 individuals 10 .…”