210 patients living in the community who had a mini-mental state examination (MMSE) score of 15-26 were randomly assigned to receive
tarenflurbil twice per day (400 mg [n=69] or 800 mg [n=70]) or placebo (n=71) for 12 months in a phase II, multicentre, double-blind study. Primary efficacy outcomes were the AD assessment scale cognitive subscale (ADAS-cog), the
Alzheimer's Disease Cooperative Study
activities of daily living scale (ADCS-
ADL), and the clinical dementia rating sum of boxes (CDR-sb). In a 12-month extended treatment phase, patients who had received
tarenflurbil continued to receive the same dose, and patients who had received placebo were randomly assigned to
tarenflurbil at 800 mg or 400 mg twice per day. Primary efficacy analyses were done by intention to treat. This trial is registered with Health Canada (084527) and the Medicines and Healthcare products Regulatory Agency in the UK (20365/0001/A 69316).
FINDINGS: A prespecified interaction analysis revealed that patients with mild AD (baseline MMSE 20-26) and moderate AD (baseline MMSE 15-19) responded differently to
tarenflurbil in the ADAS-cog and the ADCS-
ADL (p>or=0.10); therefore, these groups were analysed separately. Patients with mild AD in the 800 mg
tarenflurbil group had lower rates of decline than did those in the placebo group in
activities of daily living (ADCS-
ADL difference in slope 3.98 [95% CI 0.33 to 7.62] points per year, effect size [reduction from placebo decline rate] 46.4%, Cohen's d 0.45; p=0.033) and global function (CDR-sb difference -0.80 [-1.57 to -0.03] points per year, effect size 35.7%, Cohen's d 0.42; p=0.042); slowing of
cognitive decline did not differ significantly (ADAS-cog difference -1.36 [-4.07 to 1.36] points per year, effect size 33.7%, Cohen's d 0.20; p=0.327). In patients with moderate AD, 800 mg
tarenflurbil twice per day had no significant effects on ADCS-
ADL and ADAS-cog and had a negative effect on CDR-sb (-52%, Cohen's d -1.08; p=0.003). The most common adverse events were diarrhoea (in seven, nine, and five patients in the 800 mg, 400 mg, and placebo groups, respectively),
nausea (in seven, seven, and four patients), and
dizziness (in five, nine, and four patients). Patients with mild AD who were in the 800 mg
tarenflurbil group for 24 months had lower rates of decline for all three primary outcomes than did patients who were in the placebo group for months 0-12 and a
tarenflurbil group for months 12-24 (all p<0.001), and had better outcomes than did patients who were in the placebo group for months 0-12 and the 800 mg
tarenflurbil group for months 12-24 (all p<0.05).
INTERPRETATION: