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

Abstract

Importance 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. Design, Setting, and Participants 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. 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). 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 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.

Feasibility of Remote Assessment of Human Prion Diseases for Research and Surveillance

“…Heterozygotes were also more likely to perform better on cognitive assessments. This finding is similar to findings in a study by Mead et al [14], in which codon 129 genotype was associated with rate of decline, with heterozygotes demonstrating the slowest decline. Technology was a limitation of the study with most initial study visits being interrupted due to technological reasons.…”

Doxycycline in early CJD: a double-blinded randomised phase II and observational study

“…Future studies need to consider specific trial designs. 19 The ultimate goal in a pharmacological intervention is the enrolment of patients at an early disease stage. Exactly this point was addressed in quinacrine trials and in our cohort.…”

The language disorder of prion disease is characteristic of a dynamic aphasia and is rarely an isolated clinical feature

“…Descriptive statistics (mean, median, interquartile range) for all patient MRC scores at each level of verbal component (0–4) were calculated (total patients n = 568, total individual assessments n = 2458, SPSS Statistics v22, IBM). A linear mixed modelling approach was used in 261 patients with sporadic CJD (1753 MRC Scale assessments) with 2 or more scores, to estimate linear rates of decline in verbal and non-verbal components of the MRC Scale (methodology as per [ 30 ]).…”