PRION-1 scales analysis supports use of functional outcome measures in prion disease

Abstract

Objectives: 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.

Figure 1. Distribution of scores at enrollment and completion of MMSE over time

(A) Distribution of observed scores at enrollment by maximum possible score (ceiling = best), minimum possible score (floor = worst), and intermediate terciles (in 101 symptomatic patients). “Unable” means this was given as a reason for noncompletion on the enrollment form. (B) Completion of MMSE, by months after enrollment (in 101 symptomatic patients). This is shown to illustrate the impact of survival and advanced clinical state on a cognitive rating scale in PRION-1. ADAS-cog = cognitive component of the Alzheimer's Disease Assessment Scale; BPRS = Brief Psychiatric Rating Scale; CDR-SB = Clinical Dementia Rating Scale Sum of Boxes; GCS = Glasgow Coma Scale; GIC = Global Impression of Change; MMSE = Mini-Mental State Examination.

Figure 2. Longitudinal profiles of patients according to cognitive (MMSE, ADAS-cog, BPRS), functional (Barthel), and clinician-rated scales (Rankin, CDR-SB), GIC, and combined Barthel/CDR-SB (combination)

(A–I) Gray lines indicate individual patient trajectories. Red points and orange lines connect the last patient scale measurement with the time of death (allocated the worst possible score, except for BPRS, where the worst score observed during PRION-1 [64] was used rather than the worst possible score for the scale [168]; see appendix e-1). These are shown to illustrate the heterogeneity of individual patient trajectories. ADAS-cog = cognitive component of the Alzheimer's Disease Assessment Scale; BART = Barthel; BPRS = Brief Psychiatric Rating Scale; CDR-SB = Clinical Dementia Rating Scale Sum of Boxes; GCS = Glasgow Coma Scale; GIC = Global Impression of Change; MMSE = Mini-Mental State Examination.

Figure 3. Linear mixed model fitted to cognitive (MMSE, ADAS-cog, BPRS), functional (Barthel), and clinician-rated scales (Rankin, CDR-SB), GIC, and combined Barthel/CDR-SB (combination)

(A–I) These graphs illustrate the mean declines and observed values for each of the outcome measures that could be used in a clinical trial setting. Data are from the imputation model, i.e., censoring an individual's trajectory after observing the worst score and, if the worst score was not previously observed, imputing the worst possible score at the point of death (see appendix e-1). ADAS-cog = cognitive component of the Alzheimer's Disease Assessment Scale; BART = Barthel; BPRS = Brief Psychiatric Rating Scale; CDR-SB = Clinical Dementia Rating Scale Sum of Boxes; GCS = Glasgow Coma Scale; GIC = Global Impression of Change; MMSE = Mini-Mental State Examination.