title: 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 2 years. Detailed speech and language assessments included the Apraxia of Speech Rating Scale and Motor Speech Disorders 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.
authors.affiliation: Department of Radiology, Mayo Clinic, Rochester, MN, 55905, USA. whitwell.jennifer@mayo.edu.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Whitwell
authors.affiliation: Division of Speech Pathology, Department of Neurology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Duffy
authors.affiliation: Division of Speech Pathology, Department of Neurology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Edythe A
authors.initials: EA
authors.lastname: Strand
authors.affiliation: Division of Neuropsychology, Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Mary M
authors.initials: MM
authors.lastname: Machulda
authors.affiliation: Division of Biostatistics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: Nirubol
authors.initials: N
authors.lastname: Tosakulwong
authors.affiliation: Division of Biostatistics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Weigand
authors.affiliation: Department of Radiology, Mayo Clinic, Rochester, MN, 55905, USA.|Department of Information Technology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Senjem
authors.affiliation: Department of Radiology, Mayo Clinic, Rochester, MN, 55905, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Spychalla
authors.affiliation: Department of Radiology, Mayo Clinic, Rochester, MN, 55905, USA.|Department of Information Technology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Gunter
authors.affiliation: Division of Behavioral Neurology, Department of Neurology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Petersen
authors.affiliation: Department of Radiology, Mayo Clinic, Rochester, MN, 55905, USA.
authors.forename: Clifford R
authors.initials: CR
authors.lastname: Jack
authors.affiliation: Division of Behavioral Neurology, Department of Neurology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Josephs
mesh_terms: D000368:Aged; D001072:Apraxias / Q000188:drug therapy* / Q000473:pathology; D001284:Atrophy / Q000473:pathology; D001921:Brain / Q000473:pathology; D002986:Clinical Trials as Topic; D018450:Disease Progression; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D012107:Research Design; D018401:Sample Size; D024801:Tauopathies / Q000188:drug therapy* / Q000473:pathology
keywords: Apraxia of speech; Clinical treatment trials; MRI; PPAOS; Rates; Tau