Clinical trials.

Arguably the most important goal of prion research is the discovery of a safe and effective treatment for the human diseases. The final stages of the pathway to develop a treatment require clinical trials. Choices about how a trial is designed and conducted have a large impact on the chances of success. The gold-standard large randomized double-blind placebo-controlled study, which minimizes sources of bias and has been incredibly successful in other diseases, has been hard to achieve in Creutzfeldt-Jakob disease principally because of the rarity and rapidity of the clinical syndrome. To date, clinical trials have been restricted to repurposed compounds, doxycycline, quinacrine, pentosan polysulfate (PPS), and flupertine. In most cases, these trials have used survival as an endpoint, which, whilst clearcut, has limitations. Biomarkers have played a strong role in diagnosis and entry criteria, but only a limited role as secondary outcome measures. Recent developments suggest some possible improvements in trial design by use of new outcome measures that have more favorable properties, and biomarkers of neuronal damage and/or prion seeding activity. Alternative patient populations, including those at risk of genetic forms of prion disease, warrant more consideration. In the future, improved trial designs will be employed to test compounds designed specifically to treat prion diseases.