Human prion diseases: progress in clinical trials

The progress made in understanding disease pathology and phenomenology in prion disorders and recent advances in diagnostic techniques might encourage researchers now to consider therapeutic trials in patients with Creutzfeldt–Jakob disease. Although attempts have been made in the past (Trevitt and Collinge, 2006; Stewart et al., 2008), the drugs tested involved a variety of compounds that belong to antimicrobial, anti-inflammatory or analgesic substance classes and most of the studies are limited to extremely small series or single case reports. Controlled trials are rare but progress in diagnostic techniques, such as imaging, CSF biomarkers and recently developed methods to detect abnormal prion protein in easily accessible body fluids, will hopefully lead to early diagnosis of the disease. Although clinical trials are difficult to perform, they are feasible and clinicians must contemplate several specific problems when evaluating the efficacy of a drug in Creutzfeldt-Jakob disease.

Sporadic Creutzfeldt–Jakob disease is the most common human prion disease form, but still rare, with an annual incidence range between one and two cases per million per year worldwide (Ladogana et al., 2005). Any potential benefit of a drug must be proven on a large number of patients. Low disease incidence and prevalence are therefore problematic in terms of sample size. The median disease duration reported for all forms of sporadic Creutzfeldt–Jakob disease is ∼6 months (Pocchiari et al., 2004; Heinemann et al., 2007). The disease duration varies, and major determinants of survival such as age at onset, gender and PRNP codon 129 genotype have been identified (Ladogana et al., 2005). Unlike more chronic neurological disorders, prolonging survival from time of diagnosis offers one obvious and tractable outcome for a clinical trial. However, because of rapid disease progression, the clinical diagnosis of Creutzfeldt–Jakob disease is frequently not made until middle and late disease stages.

There is a wide scope of clinical phenomenology in human prion disease with respect to presenting features, rate of progression and appearance of other clinical manifestation (Parchi et al., 1999; Zerr et al., 2000; Heinemann et al., 2007). Phenotypic variability in the clinical syndrome and neuropathological changes in sporadic Creutzfeldt-Jakob disease were recognized long ago and some attempts have been made to define disease subtypes based on a molecular disease classification (Parchi et al., 1999). But as with many neurological disorders, heterogeneity of the clinical and pathological phenotype may reduce power even if an adequate sample can be recruited for a particular study.

Taking these considerations into account, clinicians face important decisions when designing a trial to assess efficacy and safety in the context of Creutzfeldt–Jakob disease. Scales have been designed to monitor disease progression in Alzheimer’s disease; and for vascular dementia and frontotemporal dementia (Braaten et al., 2006). Unfortunately, these systems are not suitable for monitoring cognitive decline in patients with Creutzfeldt-Jakob disease because of the different neuropsychological profiles. Also, neurological abnormalities such as ataxia, rigidity or myoclonus need to be monitored in a standard way. Because of the variability in clinical syndromes across molecular Creutzfeldt–Jakob disease subtypes, specific scales, weighted for particular subtypes, would be needed. Anticipating this issue, trial protocols need to include a variety of rating scales designed to probe neurological, cognitive, psychiatric and general functional status.

The paper by Andrew Thompson and colleagues in the current issue of Brain directly addresses these issues. The goal was to develop a rating scale for the progression of symptoms in prion diseases (the MRC Prion Disease Rating Scale) that could be used as an outcome measure in future clinical trials, as no single scale has been able to capture progression across the full range of functional domains affected in patients with prion diseases. The analysis was performed on data obtained from 437 clinical trial participants over a period of several years. Scale development included semi-quantitative and qualitative carer interviews, item response modelling, inter-rater reliability testing, construct analysis and correlation with several existing scales. The proposed 20-point MRC Prion Disease Rating Scale assesses domains of cognitive function, speech, mobility, personal care/feeding and continence. An important point is that the items are weighted according to their relative importance documented by interview with carers. Another advantage is easy application; the scale can be used over the telephone and will allow frequent assessments, which are necessary because of the rapid progression of the disease.

This is an important and timely study and analysis was carried out in a large cohort. The study addresses a fundamental issue in clinical trials of prion diseases: which scales can be used to monitor the rapid change in several domains including cognitive, motor and global decline? The scales need to be validated in future prospective studies on prion diseases but potentially other rapid progressive neurological conditions too (including Alzheimer’s disease or dementia with Lewy bodies with rapid progression). Clinical research in rare diseases is extremely challenging for logistic, statistical and financial reasons and systematic data collection in a multi-centre/multi-national setting is required to obtain sufficient information in a reasonable time frame. The work presented here is one important step towards achieving the challenging goal to find and then evaluate an effective treatment, or even a cure, for this devastating disorder.