title: Clinical Trial Simulations Based on Genetic Stratification and the Natural History of a Functional Outcome Measure in Creutzfeldt-Jakob Disease.
abstract: OBJECTIVE
  A major challenge for drug development in neurodegenerative diseases is that adequately powered efficacy studies with meaningful end points typically require several hundred participants and long durations. Prion diseases represent the archetype of brain diseases caused by protein misfolding, the most common subtype being sporadic Creutzfeldt-Jakob disease (sCJD), a rapidly progressive dementia. There is no well-established trial method in prion disease.
  
  
  OBJECTIVE
  To establish a more powerful and meaningful clinical trial method in sCJD.
  
  
  METHODS
  A stratified medicine and simulation approach based on a prospective interval-cohort study conducted from October 2008 to June 2014. This study involved 598 participants with probable or definite sCJD followed up over 470 patient-years at a specialist national referral service in the United Kingdom with domiciliary, care home, and hospital patient visits. We fitted linear mixed models to the outcome measurements, and simulated clinical trials involving 10 to 120 patients (no dropouts) with early to moderately advanced prion disease using model parameters to compare the power of various designs.
  
  
  METHODS
  A total of 2681 assessments were done using a functionally orientated composite end point (Medical Research Council Scale) and associated with clinical investigations (brain magnetic resonance imaging, electroencephalography, and cerebrospinal fluid analysis) and molecular data (prion protein [PrP] gene sequencing, PrPSc type).
  
  
  RESULTS
  Of the 598 participants, 273 were men. The PrP gene sequence was significantly associated with decline relative to any other demographic or investigation factors. Patients with sCJD and polymorphic codon 129 genotypes MM, VV, and MV lost 10% of their function in 5.3 (95% CI, 4.2-6.9), 13.2 (95% CI, 10.9-16.6), and 27.8 (95% CI, 21.9-37.8) days, respectively (P < .001). Simulations indicate that an adequately powered (80%; 2-sided α = .05) open-label randomized trial using 50% reduction in Medical Research Council Scale decline as the primary outcome could be conducted with only 120 participants assessed every 10 days and only 90 participants assessed daily, providing considerably more power than using survival as the primary outcome. Restricting to VV or MV codon 129 genotypes increased power even further. Alternatively, single-arm intervention studies (half the total sample size) could provide similar power in comparison to the natural history cohort.
  
  
  CONCLUSIONS
  Functional end points in neurodegeneration need not require long and very large clinical studies to be adequately powered for efficacy. Patients with sCJD may be an efficient and cost-effective group for testing disease-modifying therapeutics. Stratified medicine and natural history cohort approaches may transform the feasibility of clinical trials in orphan diseases.
authors.affiliation: Medical Research Council Prion Unit, Department of Neurodegnerative Disease, University College London Institute of Neurology, London, England2National Prion Clinic, National Hospital for Neurology and Neurosurgery, University College London Hospitals, NH.
authors.forename: Simon
authors.initials: S
authors.lastname: Mead
authors.affiliation: Department of Statistical Science, Faculty of Mathematical and Physical Sciences, University College London, London, England.
authors.forename: Matthew
authors.initials: M
authors.lastname: Burnell
authors.affiliation: National Prion Clinic, National Hospital for Neurology and Neurosurgery, University College London Hospitals, NHS Trust, London, England.
authors.forename: Jessica
authors.initials: J
authors.lastname: Lowe
authors.affiliation: National Prion Clinic, National Hospital for Neurology and Neurosurgery, University College London Hospitals, NHS Trust, London, England.
authors.forename: Andrew
authors.initials: A
authors.lastname: Thompson
authors.affiliation: National Prion Clinic, National Hospital for Neurology and Neurosurgery, University College London Hospitals, NHS Trust, London, England.
authors.forename: Ana
authors.initials: A
authors.lastname: Lukic
authors.affiliation: National Prion Clinic, National Hospital for Neurology and Neurosurgery, University College London Hospitals, NHS Trust, London, England.
authors.forename: Marie-Claire
authors.initials: MC
authors.lastname: Porter
authors.affiliation: National Prion Clinic, National Hospital for Neurology and Neurosurgery, University College London Hospitals, NHS Trust, London, England.
authors.forename: Christopher
authors.initials: C
authors.lastname: Carswell
authors.affiliation: National Prion Clinic, National Hospital for Neurology and Neurosurgery, University College London Hospitals, NHS Trust, London, England.
authors.forename: Diego
authors.initials: D
authors.lastname: Kaski
authors.affiliation: National Prion Clinic, National Hospital for Neurology and Neurosurgery, University College London Hospitals, NHS Trust, London, England.
authors.forename: Janna
authors.initials: J
authors.lastname: Kenny
authors.affiliation: National Prion Clinic, National Hospital for Neurology and Neurosurgery, University College London Hospitals, NHS Trust, London, England.
authors.forename: Tze How
authors.initials: TH
authors.lastname: Mok
authors.affiliation: National Prion Clinic, National Hospital for Neurology and Neurosurgery, University College London Hospitals, NHS Trust, London, England.
authors.forename: Nina
authors.initials: N
authors.lastname: Bjurstrom
authors.affiliation: National Prion Clinic, National Hospital for Neurology and Neurosurgery, University College London Hospitals, NHS Trust, London, England.
authors.forename: Edit
authors.initials: E
authors.lastname: Franko
authors.affiliation: National Prion Clinic, National Hospital for Neurology and Neurosurgery, University College London Hospitals, NHS Trust, London, England.
authors.forename: Michele
authors.initials: M
authors.lastname: Gorham
authors.affiliation: Medical Research Council Prion Unit, Department of Neurodegnerative Disease, University College London Institute of Neurology, London, England.
authors.forename: Ronald
authors.initials: R
authors.lastname: Druyeh
authors.affiliation: Medical Research Council Prion Unit, Department of Neurodegnerative Disease, University College London Institute of Neurology, London, England.
authors.forename: Jonathan D F
authors.initials: JD
authors.lastname: Wadsworth
authors.affiliation: Division of Neuropathology, National Hospital for Neurology and Neurosurgery, University College London Hospitals, NHS Trust, London, England.
authors.forename: Zane
authors.initials: Z
authors.lastname: Jaunmuktane
authors.affiliation: Division of Neuropathology, National Hospital for Neurology and Neurosurgery, University College London Hospitals, NHS Trust, London, England5Department of Neurodegenerative Disease, University College London Institute of Neurology, London, England.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Brandner
authors.affiliation: National Prion Clinic, National Hospital for Neurology and Neurosurgery, University College London Hospitals, NHS Trust, London, England.
authors.forename: Harpreet
authors.initials: H
authors.lastname: Hyare
authors.affiliation: Medical Research Council Prion Unit, Department of Neurodegnerative Disease, University College London Institute of Neurology, London, England2National Prion Clinic, National Hospital for Neurology and Neurosurgery, University College London Hospitals, NH.
authors.forename: Peter
authors.initials: P
authors.lastname: Rudge
authors.affiliation: MRC Clinical Trials Unit at University College London, London, England.
authors.forename: A Sarah
authors.initials: AS
authors.lastname: Walker
authors.affiliation: Medical Research Council Prion Unit, Department of Neurodegnerative Disease, University College London Institute of Neurology, London, England2National Prion Clinic, National Hospital for Neurology and Neurosurgery, University College London Hospitals, NH.
authors.forename: John
authors.initials: J
authors.lastname: Collinge
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002986:Clinical Trials as Topic / Q000379:methods*; D015331:Cohort Studies; D003198:Computer Simulation / Q000639:trends; D007562:Creutzfeldt-Jakob Syndrome / Q000175:diagnosis / Q000453:epidemiology* / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D016896:Treatment Outcome; D006113:United Kingdom / Q000453:epidemiology