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Age of onset in genetic prion disease and the design of preventive clinical trials

View ORCID ProfileEric Vallabh Minikel, Sonia M Vallabh, Margaret C Orseth, Jean-Philippe Brandel, Stéphane Haïk, Jean-Louis Laplanche, Inga Zerr, Piero Parchi, Sabina Capellari, Jiri Safar, Janna Kenny, Jamie C Fong, Leonel T Takada, Claudia Ponto, Peter Hermann, Tobias Knipper, Christiane Stehmann, Tetsuyuki Kitamoto, Ryusuke Ae, Tsuyoshi Hamaguchi, Nobuo Sanjo, Tadashi Tsukamoto, Hidehiro Mizusawa, Steven J Collins, Roberto Chiesa, Ignazio Roiter, Jesús de Pedro-Cuesta, Miguel Calero, Michael D Geschwind, Masahito Yamada, Yosikazu Nakamura, Simon Mead
doi: https://doi.org/10.1101/401406
Eric Vallabh Minikel
1Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
2Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, 02114, USA
3Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, 02115, USA
4Prion Alliance, Cambridge, MA, 02139, USA
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  • ORCID record for Eric Vallabh Minikel
  • For correspondence: eminikel@broadinstitute.org
Sonia M Vallabh
1Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
3Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, 02115, USA
4Prion Alliance, Cambridge, MA, 02139, USA
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Margaret C Orseth
5Harvard Business School, Boston, MA, 02163, USA
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Jean-Philippe Brandel
6Institut du Cerveau et de la Moelle épinière, ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Université, Paris, 75013, France
7Cellule Nationale de Référence des Maladies de Creutzfeldt-Jakob, Assistance Publique-Hôpitaux de Paris, Paris, 75013, France
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Stéphane Haïk
6Institut du Cerveau et de la Moelle épinière, ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Université, Paris, 75013, France
7Cellule Nationale de Référence des Maladies de Creutzfeldt-Jakob, Assistance Publique-Hôpitaux de Paris, Paris, 75013, France
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Jean-Louis Laplanche
7Cellule Nationale de Référence des Maladies de Creutzfeldt-Jakob, Assistance Publique-Hôpitaux de Paris, Paris, 75013, France
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Inga Zerr
8National Reference Center for TSE, Georg-August University, Göttingen, 37073, Germany
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Piero Parchi
9IRCCS - Institute of Neurological Sciences, Bologna, 40139, Italy
10Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, 40123, Italy
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Sabina Capellari
9IRCCS - Institute of Neurological Sciences, Bologna, 40139, Italy
11Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, 40138, Italy
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Jiri Safar
12National Prion Disease Pathology Surveillance Center, Case Western Reserve University, Cleveland, OH, 44106, USA
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Janna Kenny
13MRC Prion Unit at UCL, Institute of Prion Diseases, University College London, London, W1W 7FF, UK
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Jamie C Fong
14Memory and Aging Center, University of California San Francisco, San Francisco, CA, 94158, USA
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Leonel T Takada
14Memory and Aging Center, University of California San Francisco, San Francisco, CA, 94158, USA
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Claudia Ponto
8National Reference Center for TSE, Georg-August University, Göttingen, 37073, Germany
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Peter Hermann
8National Reference Center for TSE, Georg-August University, Göttingen, 37073, Germany
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Tobias Knipper
8National Reference Center for TSE, Georg-August University, Göttingen, 37073, Germany
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Christiane Stehmann
15Australian National CJD Registry, University of Melbourne, Parkville, 3010, Australia
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Tetsuyuki Kitamoto
16Department of Neurological Science, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan
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Ryusuke Ae
17Department of Public Health, Jichi Medical University, Shimotsuke, 329-0498, Japan
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Tsuyoshi Hamaguchi
18Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Sciences, Kanazawa, 920-8640, Japan
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Nobuo Sanjo
19Department of Neurology and Neurological Science, Tokyo Medical and Dental University, Tokyo, 113-8519, Japan
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Tadashi Tsukamoto
20National Center of Neurology and Psychiatry, Kodaira, 187-8551, Japan
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Hidehiro Mizusawa
20National Center of Neurology and Psychiatry, Kodaira, 187-8551, Japan
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Steven J Collins
15Australian National CJD Registry, University of Melbourne, Parkville, 3010, Australia
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Roberto Chiesa
21Laboratory of Prion Neurobiology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, 20156, Italy
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Ignazio Roiter
22AULSS2 Ca’ Foncello Hospital, Treviso, 31100, Italy
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Jesús de Pedro-Cuesta
23Spanish National Reference Center for CJD, Instituto de Salud Carlos III and CIBERNED, Madrid, 28031, Spain
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Miguel Calero
23Spanish National Reference Center for CJD, Instituto de Salud Carlos III and CIBERNED, Madrid, 28031, Spain
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Michael D Geschwind
14Memory and Aging Center, University of California San Francisco, San Francisco, CA, 94158, USA
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Masahito Yamada
18Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Sciences, Kanazawa, 920-8640, Japan
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Yosikazu Nakamura
17Department of Public Health, Jichi Medical University, Shimotsuke, 329-0498, Japan
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Simon Mead
13MRC Prion Unit at UCL, Institute of Prion Diseases, University College London, London, W1W 7FF, UK
24NHS National Prion Clinic, National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, London, WC1N 3BG, UK
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Abstract

Regulatory agencies worldwide have adopted programs to facilitate drug development for diseases where the traditional approach of a randomized trial with a clinical endpoint is expected to be prohibitively lengthy or difficult. Here we provide quantitative evidence that this criterion is met for the prevention of genetic prion disease. We assemble age of onset or death data from N=1,094 individuals with high penetrance mutations in the prion protein gene (PRNP), generate survival and hazard curves, and estimate statistical power for clinical trials. We show that, due to dramatic and unexplained variability in age of onset, 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. Instead, the characterization of biomarkers suitable to serve as surrogate endpoints will be essential for the prevention of genetic prion disease. Biomarker-based trials may require post-marketing studies to confirm clinical benefit. Parameters such as longer trial duration, increased enrollment, and the use of historical controls in a post-marketing study could provide opportunities for subsequent determination of clinical benefit.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted August 29, 2018.
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Age of onset in genetic prion disease and the design of preventive clinical trials
Eric Vallabh Minikel, Sonia M Vallabh, Margaret C Orseth, Jean-Philippe Brandel, Stéphane Haïk, Jean-Louis Laplanche, Inga Zerr, Piero Parchi, Sabina Capellari, Jiri Safar, Janna Kenny, Jamie C Fong, Leonel T Takada, Claudia Ponto, Peter Hermann, Tobias Knipper, Christiane Stehmann, Tetsuyuki Kitamoto, Ryusuke Ae, Tsuyoshi Hamaguchi, Nobuo Sanjo, Tadashi Tsukamoto, Hidehiro Mizusawa, Steven J Collins, Roberto Chiesa, Ignazio Roiter, Jesús de Pedro-Cuesta, Miguel Calero, Michael D Geschwind, Masahito Yamada, Yosikazu Nakamura, Simon Mead
bioRxiv 401406; doi: https://doi.org/10.1101/401406
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Age of onset in genetic prion disease and the design of preventive clinical trials
Eric Vallabh Minikel, Sonia M Vallabh, Margaret C Orseth, Jean-Philippe Brandel, Stéphane Haïk, Jean-Louis Laplanche, Inga Zerr, Piero Parchi, Sabina Capellari, Jiri Safar, Janna Kenny, Jamie C Fong, Leonel T Takada, Claudia Ponto, Peter Hermann, Tobias Knipper, Christiane Stehmann, Tetsuyuki Kitamoto, Ryusuke Ae, Tsuyoshi Hamaguchi, Nobuo Sanjo, Tadashi Tsukamoto, Hidehiro Mizusawa, Steven J Collins, Roberto Chiesa, Ignazio Roiter, Jesús de Pedro-Cuesta, Miguel Calero, Michael D Geschwind, Masahito Yamada, Yosikazu Nakamura, Simon Mead
bioRxiv 401406; doi: https://doi.org/10.1101/401406

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