PRION-1 scales analysis supports use of functional outcome measures in prion disease.
OBJECTIVE
Human prion diseases are heterogeneous but invariably fatal neurodegenerative disorders with no known effective therapy. PRION-1, the largest clinical trial in prion disease to date, showed no effect of the potential therapeutic quinacrine on survival. Although there are several limitations to the usefulness of survival as an outcome measure, there have been no comprehensive studies of alternatives.


METHODS
To address this we did comparative analyses of neurocognitive, psychiatric, global, clinician-rated, and functional scales, focusing on validity, variability, and impact on statistical power over 77 person-years follow-up in 101 symptomatic patients in PRION-1.


RESULTS
Quinacrine had no demonstrable benefit on any of the 8 scales (p > 0.4). All scales had substantial numbers of patients with the worst possible score at enrollment (Glasgow Coma Scale score being least affected) and were impacted by missing data due to disease progression. These effects were more significant for cognitive/psychiatric scales than global, clinician-rated, or functional scales. The Barthel and Clinical Dementia Rating scales were the most valid and powerful in simulated clinical trials of an effective therapeutic. A combination of selected subcomponents from these 2 scales gave somewhat increased power, compared to use of survival, to detect clinically relevant effects in future clinical trials of feasible size.


CONCLUSIONS
Our findings have implications for the choice of primary outcome measure in prion disease clinical trials. Prion disease presents the unusual opportunity to follow patients with a neurodegenerative disease through their entire clinical course, and this provides insights relevant to designing outcome measures in related conditions.
MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, and National Prion Clinic, National Hospital for Neurology and Neurosurgery, UCLH NHS Trust, Queen Square, London, UK.
S
S
Mead
M
M
Ranopa
G S
GS
Gopalakrishnan
A G B
AG
Thompson
P
P
Rudge
S
S
Wroe
A
A
Kennedy
F
F
Hudson
A
A
MacKay
J H
JH
Darbyshire
J
J
Collinge
A S
AS
Walker
D000328:Adult; D000368:Aged; D000962:Antimalarials / Q000627:therapeutic use; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D017063:Outcome Assessment, Health Care; D017096:Prion Diseases / Q000188:drug therapy* / Q000401:mortality; D011796:Quinacrine / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D015203:Reproducibility of Results; D015996:Survival Rate; D016896:Treatment Outcome
D000962:Antimalarials; D011796:Quinacrine