Requiring an amyloid-β_1-42 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-β_1-42 concentration and high total-tau/Aβ_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 Aβ_1-42 ≤192 mg/mL, (3) and aMCI with total-tau/Aβ_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 Aβ_1-42 or high tau/Aβ_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 Aβ_1-42 marker, however, could be useful as an explanatory variable or covariate when warranted by the action of a drug.

Keywords: Alzheimer disease, Mild cognitive impairment, Biomarkers, Clinical trials, Simulations, Amyloid-beta protein, Alzheimer’s disease neuroimaging initiative (ADNI), Alzheimer’s disease assessment scale, Clinical dementia rating