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Abstract
Objective To determine whether preventive trials in genetic prion disease could be designed to follow presymptomatic mutation carriers to onset of disease.
Methods We 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.
Results Genetic 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.
Conclusion The 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.
Glossary
- AD=
- Alzheimer disease;
- FDA=
- Food and Drug Administration;
- HR=
- hazard ratio
Footnotes
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
This manuscript was previously posted to bioRxiv (doi.org/10.1101/401406) on August 29, 2018.
- Received November 2, 2018.
- Accepted in final form February 21, 2019.
- © 2019 American Academy of Neurology
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