Requiring an amyloid-beta1-42 biomarker for prodromal Alzheimer's disease or mild cognitive impairment does not lead to more efficient clinical trials

Abstract

Background: Low cerebrospinal fluid (CSF) amyloid-beta(1-42) concentration and high total-tau/Abeta(1-42) ratio have been recommended to support the diagnosis of prodromal Alzheimer's disease (AD) in patients with amnestic mild cognitive impairment (aMCI) and also to select patients for clinical trials (Shaw et al, Ann Neurol 2009;65:403-13; Dubois et al, Lancet Neurol 2007;6:734-46).

Methods: We tested this recommendation with clinical trials simulations using patients from the Alzheimer Disease Neuroimaging Initiative who fulfilled the following entry criteria: (1) aMCI, (2) aMCI with CSF Abeta(1-42) <or=192 mg/mL, (3) and aMCI with total-tau/Abeta(1-42) >0.39. For each criterion, we randomly resampled the database obtaining samples for 1000 trials for each trial scenario, planning for 1 or 2 year trials with samples from 50 to 400 patients per treatment or placebo group, with up to 40% dropouts, outcomes after using the AD assessment scale-cognitive subscale and clinical dementia rating scale with effect sizes ranging from 0.15 to 0.75, and calculated statistical power.

Findings: Approximately 70% to 74% of aMCI patients with CSF measures met biomarker criteria. The addition of the low Abeta(1-42) or high tau/Abeta(1-42) requirement resulted in minimal or no increase in the power of the trials compared with enrolling aMCI without requiring the biomarker criteria. Slightly larger mean differences between the placebo and treatment groups fulfilling biomarker criteria were offset by increased outcome variability within the groups.

Interpretations: Although patients with aMCI or patients with prodromal AD meeting CSF biomarkers criteria were slightly more cognitively impaired and showed greater decline than patients with aMCI diagnosed without considering the biomarkers, the requirement of biomarker-positive patients would most likely not result in more efficient clinical trials, and trials would take longer because fewer patients would be available. A CSF Abeta(1-42) marker, however, could be useful as an explanatory variable or covariate when warranted by the action of a drug.

Trial registration: ClinicalTrials.gov NCT00106899.

Fig. 1

Power for Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) outcomes in 24-month-long trials with 20% dropouts. Power calculations for the ADAS-cog in patients with amnestic mild cognitive impairment (aMCI), with aMCI plus low cerebrospinal fluid (CSF) Aβ_1-42, and aMCI plus high CSF t-tau/Aβ_1-42 by effect size and sample size. Addition of a biomarker selection criterion did not appreciably increase power under any of the scenarios. Simulation parameters included α = 0.05, χ² random errors, and 20% dropouts with mixed model analysis for participants with missing data.

Fig. 2

Power for ADAS-cog outcomes in 24-month-long trials with 40% dropouts. Power calculations for the ADAS-cog in patients with aMCI, with aMCI plus low CSF Aβ_1-42, and aMCI plus high CSF t-tau/ Aβ_1-42 by effect size and sample size. Addition of a CSF biomarker selection criterion did not appreciably increase power under any of the scenarios. Simulation parameters included a α = 0.05, χ² random errors, and 40% dropouts with mixed model analysis for participants with missing data.

Fig 3

Power for clinical dementia rating sum of the boxes score (CDR-sb) outcomes in 24-month-long trials with 20% dropouts. Power calculations for the CDR-sb in patients with aMCI, aMCI plus low CSF Aβ_1-42, and aMCI plus high CSF t-tau/ Aβ_1-42 by effect size and sample size. Addition of the biomarkers resulted in very small increases in statistical power, mainly for smaller samples at large effect sizes. Simulation parameters included α = 0.05, χ² random errors, and 20% dropouts with mixed model analysis for participants with missing data.

Fig. 4

Power for CDR-sb outcomes in 24-month-long trials with 40% dropouts. Power calculations for the CDR-sb in patients with aMCI, aMCI plus low CSF Aβ_1-42, and aMCI plus high CSF t-tau/ Aβ_1-42 by effect size and sample size. Addition of biomarkers resulted in only small increases in statistical power, mainly with smaller sample sizes and large effect sizes. Simulation parameters included α = 0.05 with 24-month-long trials, χ² random errors, and 40% dropouts with mixed model analysis for participants with missing data.