TY - JOUR
T1 - Age at onset in genetic prion disease and the design of preventive clinical trials
AU - Minikel, Eric Vallabh
AU - Vallabh, Sonia M.
AU - Orseth, Margaret C.
AU - Brandel, Jean Philippe
AU - Haïk, Stéphane
AU - Laplanche, Jean Louis
AU - Zerr, Inga
AU - Parchi, Piero
AU - Capellari, Sabina
AU - Safar, Jiri
AU - Kenny, Janna
AU - Fong, Jamie C.
AU - Takada, Leonel T.
AU - Ponto, Claudia
AU - Hermann, Peter
AU - Knipper, Tobias
AU - Stehmann, Christiane
AU - Kitamoto, Tetsuyuki
AU - Ae, Ryusuke
AU - Hamaguchi, Tsuyoshi
AU - Sanjo, Nobuo
AU - Tsukamoto, Tadashi
AU - Mizusawa, Hidehiro
AU - Collins, Steven J.
AU - Chiesa, Roberto
AU - Roiter, Ignazio
AU - De Pedro-Cuesta, Jesús
AU - Calero, Miguel
AU - Geschwind, Michael D.
AU - Yamada, Masahito
AU - Nakamura, Yosikazu
AU - Mead, Simon
N1 - Ricercatori distaccati presso IRCCS a seguito Convenzione esclusiva con Università di Bologna (Parchi Piero, Capellari Sabina).
PY - 2019/7/9
Y1 - 2019/7/9
N2 - ObjectiveTo determine whether preventive trials in genetic prion disease could be designed to follow presymptomatic mutation carriers to onset of disease.MethodsWe assembled age at onset or death data from 1,094 individuals with high penetrance mutations in the prion protein gene (PRNP) in order to generate survival and hazard curves and test for genetic modifiers of age at onset. We used formulae and simulations to estimate statistical power for clinical trials.ResultsGenetic prion disease age at onset varies over several decades for the most common mutations and neither sex, parent's age at onset, nor PRNP codon 129 genotype provided additional explanatory power to stratify trials. Randomized preventive trials would require hundreds or thousands of at-risk individuals in order to be statistically powered for an endpoint of clinical onset, posing prohibitive cost and delay and likely exceeding the number of individuals available for such trials.ConclusionThe characterization of biomarkers suitable to serve as surrogate endpoints will be essential for the prevention of genetic prion disease. Parameters such as longer trial duration, increased enrollment, and the use of historical controls in a postmarketing study could provide opportunities for subsequent determination of clinical benefit.
AB - ObjectiveTo determine whether preventive trials in genetic prion disease could be designed to follow presymptomatic mutation carriers to onset of disease.MethodsWe assembled age at onset or death data from 1,094 individuals with high penetrance mutations in the prion protein gene (PRNP) in order to generate survival and hazard curves and test for genetic modifiers of age at onset. We used formulae and simulations to estimate statistical power for clinical trials.ResultsGenetic prion disease age at onset varies over several decades for the most common mutations and neither sex, parent's age at onset, nor PRNP codon 129 genotype provided additional explanatory power to stratify trials. Randomized preventive trials would require hundreds or thousands of at-risk individuals in order to be statistically powered for an endpoint of clinical onset, posing prohibitive cost and delay and likely exceeding the number of individuals available for such trials.ConclusionThe characterization of biomarkers suitable to serve as surrogate endpoints will be essential for the prevention of genetic prion disease. Parameters such as longer trial duration, increased enrollment, and the use of historical controls in a postmarketing study could provide opportunities for subsequent determination of clinical benefit.
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U2 - 10.1212/WNL.0000000000007745
DO - 10.1212/WNL.0000000000007745
M3 - Article
C2 - 31171647
AN - SCOPUS:85066755709
VL - 93
SP - E125-E134
JO - Neurology
JF - Neurology
SN - 0028-3878
IS - 2
ER -