Evidence map›Paper›PMID 26902324›Full record

ArticleJAMA neurology2016

Clinical Trial Simulations Based on Genetic Stratification and the Natural History of a Functional Outcome Measure in Creutzfeldt-Jakob Disease.

Simon Mead, Matthew Burnell, Jessica Lowe, Andrew Thompson, Ana Lukic, Marie-Claire Porter, Christopher Carswell, Diego Kaski, Janna Kenny, Tze How Mok and 11 more

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in JAMA neurology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.

0numbers the graph read from it
0cells of the map it votes in
25citing papers in PubMed
2.4field-weighted citation impact, top 11% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

25 citing papers in PubMed, 47 citations in OpenAlex.

  1. Doxycycline in early CJD: a double-blinded randomised phase II and observational study.Journal of neurology, neurosurgery, and psychiatry · 2017
    Trial
  2. Article
  3. Article
  4. Review
  5. Article
  6. Review
  7. Article
  8. Article
  9. Genetic aspects of human prion diseases.Frontiers in neurology · 2022
    Review
  10. Article
  11. Article
  12. Review
  13. Article
  14. Article
  15. Article
  16. Article
  17. Baseline neuropsychological profiles in prion disease predict survival time.Annals of clinical and translational neurology · 2020
    Article
  18. Article
  19. Article
  20. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

21 authors at 5 institutions in 1 country.

Simon MeadMedical 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.
Matthew BurnellDepartment of Statistical Science, Faculty of Mathematical and Physical Sciences, University College London, London, England.
Jessica LoweNational Prion Clinic, National Hospital for Neurology and Neurosurgery, University College London Hospitals, NHS Trust, London, England.
Andrew ThompsonNational Prion Clinic, National Hospital for Neurology and Neurosurgery, University College London Hospitals, NHS Trust, London, England.
Ana LukicNational Prion Clinic, National Hospital for Neurology and Neurosurgery, University College London Hospitals, NHS Trust, London, England.
Marie-Claire PorterNational Prion Clinic, National Hospital for Neurology and Neurosurgery, University College London Hospitals, NHS Trust, London, England.
Christopher CarswellNational Prion Clinic, National Hospital for Neurology and Neurosurgery, University College London Hospitals, NHS Trust, London, England.
Diego KaskiNational Prion Clinic, National Hospital for Neurology and Neurosurgery, University College London Hospitals, NHS Trust, London, England.
Janna KennyNational Prion Clinic, National Hospital for Neurology and Neurosurgery, University College London Hospitals, NHS Trust, London, England.
Tze How MokNational Prion Clinic, National Hospital for Neurology and Neurosurgery, University College London Hospitals, NHS Trust, London, England.
Nina BjurstromNational Prion Clinic, National Hospital for Neurology and Neurosurgery, University College London Hospitals, NHS Trust, London, England.
Edit FrankoNational Prion Clinic, National Hospital for Neurology and Neurosurgery, University College London Hospitals, NHS Trust, London, England.
Michele GorhamNational Prion Clinic, National Hospital for Neurology and Neurosurgery, University College London Hospitals, NHS Trust, London, England.
Ronald DruyehMedical Research Council Prion Unit, Department of Neurodegnerative Disease, University College London Institute of Neurology, London, England.
Jonathan D F WadsworthMedical Research Council Prion Unit, Department of Neurodegnerative Disease, University College London Institute of Neurology, London, England.
Zane JaunmuktaneDivision of Neuropathology, National Hospital for Neurology and Neurosurgery, University College London Hospitals, NHS Trust, London, England.
Sebastian BrandnerDivision 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.
Harpreet HyareNational Prion Clinic, National Hospital for Neurology and Neurosurgery, University College London Hospitals, NHS Trust, London, England.
Peter RudgeMedical 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.
A Sarah WalkerMRC Clinical Trials Unit at University College London, London, England.
John CollingeMedical 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.
National Hospital for Neurology and Neurosurgery · GBUniversity College London · GBUniversity College London Hospitals NHS Foundation Trust · GBMedical Research Council · GBMRC Prion Unit · GB

Funding

Department of HealthMedical Research Council MC_U123160651Medical Research Council MC_U123160655Medical Research Council MC_U123160657Medical Research Council MC_UU_12023/22
6 · The paper itself

Abstract

importanceA 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.

objectiveTo establish a more powerful and meaningful clinical trial method in sCJD. DESIGN, SETTING, AND

participantsA 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. MAIN OUTCOMES AND MEASURES: 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).

resultsOf 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 AND RELEVANCE: 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.

Indexed as

Computer SimulationAdultAgedAged, 80 and overClinical Trials as TopicCohort StudiesCreutzfeldt-Jakob SyndromeFemaleHumansMaleMiddle AgedProspective StudiesTreatment OutcomeUnited Kingdom

Identifiers

PMID26902324
PMCPMC5701731
OpenAlexW2277673148

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.