Abstract
BackgroundClinical endpoints for upcoming therapeutic trials in frontotemporal dementia (FTD) are increasingly urgent. Cognitive composite scores are often used as endpoints but are lacking in genetic FTD. We aimed to create cognitive composite scores for genetic frontotemporal dementia (FTD) as well as recommendations for recruitment and duration in clinical trial design.MethodsA standardized neuropsychological test battery covering six cognitive domains was completed by 69 C9orf72, 41 GRN, and 28 MAPT mutation carriers with CDR® plus NACC-FTLD ≥ 0.5 and 275 controls. Logistic regression was used to identify the combination of tests that distinguished best between each mutation carrier group and controls. The composite scores were calculated from the weighted averages of test scores in the models based on the regression coefficients. Sample size estimates were calculated for individual cognitive tests and composites in a theoretical trial aimed at preventing progression from a prodromal stage (CDR® plus NACC-FTLD 0.5) to a fully symptomatic stage (CDR® plus NACC-FTLD ≥ 1). Time-to-event analysis was performed to determine how quickly mutation carriers progressed from CDR® plus NACC-FTLD = 0.5 to ≥ 1 (and therefore how long a trial would need to be).ResultsThe results from the logistic regression analyses resulted in different composite scores for each mutation carrier group (i.e. C9orf72, GRN, and MAPT). The estimated sample size to detect a treatment effect was lower for composite scores than for most individual tests. A Kaplan-Meier curve showed that after 3 years, ~ 50% of individuals had converted from CDR® plus NACC-FTLD 0.5 to ≥ 1, which means that the estimated effect size needs to be halved in sample size calculations as only half of the mutation carriers would be expected to progress from CDR® plus NACC FTLD 0.5 to ≥ 1 without treatment over that time period.DiscussionWe created gene-specific cognitive composite scores for C9orf72, GRN, and MAPT mutation carriers, which resulted in substantially lower estimated sample sizes to detect a treatment effect than the individual cognitive tests. The GENFI-Cog composites have potential as cognitive endpoints for upcoming clinical trials. The results from this study provide recommendations for estimating sample size and trial duration.
Highlights
Clinical endpoints for upcoming therapeutic trials in frontotemporal dementia (FTD) are increasingly urgent
Of the mutation carrier group, 41 chromosome 9 open reading frame 72 (C9orf72), 17 GRN, and 16 microtubule-associated protein tau (MAPT) mutation carriers fulfilled the diagnostic criteria for behavioural variant FTD (bvFTD) [2] (C9orf72 = 36, GRN = 11, MAPT = 16), progressive aphasia (PPA) [3] (GRN = 6), or FTD with amyotrophic lateral sclerosis (FTD-ALS) [32] (C9orf72 = 5)
The focus of future studies is likely to be on treating people with very early symptomatic disease, and so, we focused on calculating the sample sizes for a trial of prodromal mutation carriers (i.e. CDR® plus NACC FTLD = 0.5) where the therapeutic drug had an effect on the progression to being fully symptomatic (i.e. CDR® plus NACC FTLD = 1)
Summary
Clinical endpoints for upcoming therapeutic trials in frontotemporal dementia (FTD) are increasingly urgent. Cognitive composite scores are often used as endpoints but are lacking in genetic FTD. We aimed to create cognitive composite scores for genetic frontotemporal dementia (FTD) as well as recommendations for recruitment and duration in clinical trial design. Frontotemporal dementia (FTD) encompasses a heterogeneous group of early-onset neurodegenerative disorders caused by prominent frontal and/or temporal lobe degeneration with a wide range of overlapping clinical features [1]. The most common causes of genetic FTD are mutations in the microtubule-associated protein tau (MAPT), progranulin (GRN), and chromosome 9 open reading frame 72 (C9orf72) genes [4]. Clinical trials testing disease-modifying treatments for FTD are underway, and clinical endpoints to monitor treatment response are urgently needed. It is believed that interventions may have the most profound effect if initiated in the earliest stages of the disease; a major challenge facing these clinical trials is the lack of outcome measures that are sensitive enough to track the effects of treatment in the early stages of the disease [5,6,7]
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