Pilot Randomized Controlled Study of a Histamine Receptor Inverse Agonist in the Symptomatic Treatment of AD

We performed a clinical trial to evaluate the effects of the histamine subtype-3 receptor inverse agonist MK- 0249 on cognition in AD patients. Mild-to-moderate AD patients were randomized 1:1 to 4 weeks of double-blind daily treatment with oral MK-0249 5-mg or placebo. Pharmacokinetic and PET data suggested that MK-0249 5-mg daily would achieve approximately 85% brain receptor occupancy at Cmax in elderly patients. Primary efficacy measures were the short Computerized-Neuropsychological-Test-Battery (CNTB) summary score and ADAS-Cog score. A secondary efficacy measure was a Cognition Summary Score summarizing results from 7 cognitive tests. Of 144 patients randomized, 132 completed 4 weeks (MK-0249 = 65, placebo = 67). Most patients (88.2%) were on concomitant symptomatic AD treatment. There were no significant differences between treatments on primary and secondary endpoints at week 4: short CNTB summary score = 0.89 (95% CI: -0.74,2.52); ADAS-Cog score = -0.25 (95% CI: -1.61,1.11); Cognition Summary Score = 1.38 (95% CI: -0.64,3.40). MK-0249 was generally well tolerated but was associated with an increased percentage of patients with adverse events (41/73; 56.2%) versus placebo (18/70; 25.7%). Adverse events in >5% of patients on MK-0249 were diarrhea (8.2% vs. 2.9%), headache (8.2% vs. 1.4%), muscle spasms (5.5% vs. 0%), insomnia (5.5% vs. 0%) and stomach discomfort (5.5% vs. 0%). MK-0249 5-mg once daily over 4 weeks was not effective in improving cognitive function in mild to moderate AD patients who were on concomitant symptomatic AD treatment. (ClinicalTrials.gov trial registration, NCT00420420).