Double-blind, controlled phase II study of a 5-HT6 receptor antagonist, SB-742457, in Alzheimer's disease.
BACKGROUND
This randomized, double-blind, placebo-controlled study investigated the efficacy and tolerability of the 5-HT6 receptor antagonist, SB-742457, in subjects with mild-to-moderate probable Alzheimer's disease (AD).


METHODS
Participating subjects had a Mini-Mental State Examination (MMSE) score of 12 to 26 after a 4-week, single-blind, placebo run-in phase, and were randomized (2:1:1:2) to receive placebo, SB-742457 5 mg, 15 mg, or 35 mg once daily for 24 weeks. Coprimary efficacy endpoints were the Clinician's Interview-Based Impression of Change with caregiver input (CIBIC+) score and change from baseline in Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) score at Week 24, in the intent-to-treat (ITT) population. A model-based design provided 90% power to detect a linear trend in treatment response across increasing doses and > or =90% power to compare SB-742457 35 mg with placebo.


RESULTS
371 subjects were randomized. In the ITT population (n=357), linear trend analysis at Week 24 suggested a dose response for CIBIC+ with a mean slope of -0.05 points/5-mg dose increase (95% confidence interval [CI]: -0.09, -0.01; p=0.016). The dose response slope for change from baseline in ADAS-Cog was -0.22 points/5-mg dose increase (95% CI: -0.45, 0.01; p=0.059). The adjusted mean treatment difference from placebo at Week 24 for SB-742457 35 mg (-0.31) was significant on CIBIC+ (95% CI: -0.62, -0.00; p=0.047) but non-significant on ADAS-Cog (-1.28 [95% CI: -2.96, 0.40]; p=0.135). Adverse events occurred in 24-37% in the SB-742457 groups vs 29% for placebo; 11-16% discontinued SB-742457 vs 15% for placebo.


CONCLUSIONS
SB-742457 was generally safe and well tolerated and may be efficacious in AD.
Maher-Edwards
G
G
GlaxoSmithKline, Uxbridge, Middlesex, UK. Gareth.C.Maher-Edwards@gsk.com
Zvartau-Hind
M
M
Hunter
A J
AJ
Gold
M
M
Hopton
G
G
Jacobs
G
G
Davy
M
M
Williams
P
P
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000523:psychology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011804:Quinolines / Q000627:therapeutic use*; D011985:Receptors, Serotonin / Q000502:physiology*; D012702:Serotonin Antagonists / Q000627:therapeutic use*; D016037:Single-Blind Method; D013450:Sulfones / Q000627:therapeutic use*
C548140:3-benzenesulfonyl-8-piperazin-1-ylquinoline; D011804:Quinolines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013450:Sulfones; C097216:serotonin 6 receptor