Age at onset in genetic prion disease and the design of preventive clinical trials
Eric Vallabh Minikel
(1, 2, 3)
,
Sonia Vallabh
(1, 3)
,
Margaret Orseth
(4)
,
Jean-Philippe Brandel
(5)
,
Stéphane Haïk
(5)
,
Jean-Louis Laplanche
(6)
,
Inga Zerr
(7)
,
Piero Parchi
(8)
,
Sabina Capellari
(8)
,
Jiri Safar
(9)
,
Janna Kenny
(10)
,
Jamie Fong
(11)
,
Leonel Takada
(11)
,
Claudia Ponto
(7)
,
Peter Hermann
(7)
,
Tobias Knipper
(7)
,
Christiane Stehmann
(12)
,
Tetsuyuki Kitamoto
(13)
,
Ryusuke Ae
(14)
,
Tsuyoshi Hamaguchi
(15)
,
Nobuo Sanjo
(16)
,
Tadashi Tsukamoto
(17)
,
Hidehiro Mizusawa
(16, 17)
,
Steven Collins
(12)
,
Roberto Chiesa
(18)
,
Ignazio Roiter
,
Jesús de Pedro-Cuesta
(19, 20)
,
Miguel Calero
(20, 19)
,
Michael Geschwind
(11)
,
Masahito Yamada
(15)
,
Yosikazu Nakamura
(14)
,
Simon Mead
(10, 21)
1
BROAD INSTITUTE -
Broad Institute of MIT and Harvard
2 Massachusetts General Hospital [Boston]
3 HMS - Harvard Medical School [Boston]
4 Harvard Business School
5 ICM - Institut du Cerveau = Paris Brain Institute
6 OPTeN (UMR_S_1144 / U1144) - Optimisation thérapeutique en Neuropsychopharmacologie
7 Georg-August-University = Georg-August-Universität Göttingen
8 UNIBO - Alma Mater Studiorum Università di Bologna = University of Bologna
9 Case Western Reserve University [Cleveland]
10 UCL - University College of London [London]
11 UC San Francisco - University of California [San Francisco]
12 University of Melbourne
13 Tohoku University [Sendai]
14 Jichi Medical University [Tochigi-Ken, Japan]
15 School of Medicine [Kanazawa Medical University]
16 TMDU - Tokyo Medical and Dental University [Japan]
17 NCNP - National Center of Neurology and Psychiatry
18 IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri"
19 ISC - Instituto de Salud Carlos III [Madrid]
20 CIBERNED - Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas
21 UCLH - University College London Hospitals NHS Foundation Trust [London, UK]
2 Massachusetts General Hospital [Boston]
3 HMS - Harvard Medical School [Boston]
4 Harvard Business School
5 ICM - Institut du Cerveau = Paris Brain Institute
6 OPTeN (UMR_S_1144 / U1144) - Optimisation thérapeutique en Neuropsychopharmacologie
7 Georg-August-University = Georg-August-Universität Göttingen
8 UNIBO - Alma Mater Studiorum Università di Bologna = University of Bologna
9 Case Western Reserve University [Cleveland]
10 UCL - University College of London [London]
11 UC San Francisco - University of California [San Francisco]
12 University of Melbourne
13 Tohoku University [Sendai]
14 Jichi Medical University [Tochigi-Ken, Japan]
15 School of Medicine [Kanazawa Medical University]
16 TMDU - Tokyo Medical and Dental University [Japan]
17 NCNP - National Center of Neurology and Psychiatry
18 IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri"
19 ISC - Instituto de Salud Carlos III [Madrid]
20 CIBERNED - Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas
21 UCLH - University College London Hospitals NHS Foundation Trust [London, UK]
Eric Vallabh Minikel
- Function : Author
- PersonId : 1378575
- ORCID : 0000-0003-2206-1608
Sonia Vallabh
- Function : Author
- PersonId : 1378576
- ORCID : 0000-0003-3824-2702
Inga Zerr
- Function : Author
- PersonId : 1378577
- ORCID : 0000-0002-6722-2463
Roberto Chiesa
- Function : Author
- PersonId : 1378578
- ORCID : 0000-0002-3842-3733
Ignazio Roiter
- Function : Author
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.