Efficacy and safety of a loading-dose regimen versus a no-loading-dose regimen of metrifonate in the symptomatic treatment of Alzheimer's disease: A randomized, double-masked, placebo-controlled trial

This prospective, randomized, double-masked, placebo-controlled, parallel-g roup Study assessed the safety and efficacy of 2 dosage regimens of once-da ily metrifonate in patients with probable Alzheimer's disease (AD) of mild- to-moderate severity. A total of 395 patients were randomized to receive pl acebo (n = 134) or metrifonate in I of 2 regimens. The loading-dose group ( n = 133) received a daily loading dose of metrifonate 100 mg or 150 mg (by weight) for 2 weeks, followed by a daily maintenance dose of metrifonate 50 mg for 4 weeks; the no-loading-dose group (n = 128) received the daily mai ntenance dose of metrifonate 50 mg for 6 weeks. The primary measure of effi cacy was the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS- Cog); secondary measures of efficacy included the Mini-Mental State Examina tion (MMSE), the Clinician's Interview Based Impression of Change with Care giver Input (CIBIC-Plus), the Clinician's Interview Based Impression of Sev erity with Caregiver Input (CIBIS-Plus), and the ADAS-Noncognitive Subscale (ADAS-Noncog). Safety was assessed by the prevalence of premature study te rmination and treatment-emergent adverse events, as well as by changes in v ital signs, findings on electrocardiographic and neurologic examinations, a nd abnormalities on laboratory tests. At 4 weeks of treatment, defined by t he protocol as the target efficacy determination, the mean ADAS-Cog scores of the intent-to treat population (last observation carried forward) favore d the loading-dose group versus the placebo group, but the difference was n ot statistically significant. However, at week 6, the difference in mean AD AS-Cog scores was statistically significant compared with placebo. At neith er week 4 nor week 6 was there a statistically significant difference in th e mean ADAS-Cog scores of the no-loading-dose and placebo groups. For the C IBIC-Plus, the treatment difference between the placebo and loading-dose gr oups significantly favored metrifonate at week 6 but not at week 4, whereas the treatment difference between the placebo and no-loading-dose groups wa s statistically significant at both time points. For the MMSE, CIBIS-Plus, and ADAS-Noncog, treatment differences for both groups versus placebo did n ot reach statistical significance at either week 4 or 6. Assessment of the frequency of adverse events in metrifonate-treated patients revealed that t he no-loading-dose regimen was better tolerated than the loading-dose regim en. Given the overall similar efficacy and more favorable safety profile as sociated with the no-loading-dose regimen versus the loading-dose regimen o bserved in this study, the no-loading-dose regimen appears to be the better strategy for initiating metrifonate treatment in patients with probable AD of mild-to-moderate severity.