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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. Metrifonate Study Group.

Abstract

This prospective, randomized, double-masked, placebo-controlled, parallel-group study assessed the safety and efficacy of 2 dosage regimens of once-daily metrifonate in patients with probable Alzheimer's disease (AD) of mild-to-moderate severity. A total of 395 patients were randomized to receive placebo (n = 134) or metrifonate in 1 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 maintenance dose of metrifonate 50 mg for 6 weeks. The primary measure of efficacy was the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog); secondary measures of efficacy included the Mini-Mental State Examination (MMSE), the Clinician's Interview Based Impression of Change with Caregiver Input (CIBIC-Plus), the Clinician's Interview Based Impression of Severity with Caregiver Input (CIBIS-Plus), and the ADAS-Noncognitive Subscale (ADAS-Noncog). Safety was assessed by the prevalence of premature study termination and treatment-emergent adverse events, as well as by changes in vital signs, findings on electrocardiographic and neurologic examinations, and abnormalities on laboratory tests. At 4 weeks of treatment, defined by the protocol as the target efficacy determination, the mean ADAS-Cog scores of the intent-to-treat population (last observation carried forward) favored the loading-dose group versus the placebo group, but the difference was not statistically significant. However, at week 6, the difference in mean ADAS-Cog scores was statistically significant compared with placebo. At neither week 4 nor week 6 was there a statistically significant difference in the mean ADAS-Cog scores of the no-loading-dose and placebo groups. For the CIBIC-Plus, the treatment difference between the placebo and loading-dose groups significantly favored metrifonate at week 6 but not at week 4, whereas the treatment difference between the placebo and no-loading-dose groups was statistically significant at both time points. For the MMSE, CIBIS-Plus, and ADAS-Noncog, treatment differences for both groups versus placebo did not reach statistical significance at either week 4 or 6. Assessment of the frequency of adverse events in metrifonate-treated patients revealed that the no-loading-dose regimen was better tolerated than the loading-dose regimen. Given the overall similar efficacy and more favorable safety profile associated with the no-loading-dose regimen versus the loading-dose regimen observed 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.

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  • Authors+Show Affiliations

    ,

    Center for Clinical Research, Southern School of Pharmacy, Mercer University, Atlanta, Georgia 30341-4155, USA.

    , , , ,

    Source

    Clinical therapeutics 21:1 1999 Jan pg 88-102

    MeSH

    Acetylcholinesterase
    Aged
    Aged, 80 and over
    Alzheimer Disease
    Cholinesterase Inhibitors
    Double-Blind Method
    Drug Administration Schedule
    Erythrocytes
    Female
    Humans
    Male
    Mental Status Schedule
    Middle Aged
    Prospective Studies
    Trichlorfon

    Pub Type(s)

    Clinical Trial
    Journal Article
    Multicenter Study
    Randomized Controlled Trial
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    10090427

    Citation

    Jann, M W., et al. "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. Metrifonate Study Group." Clinical Therapeutics, vol. 21, no. 1, 1999, pp. 88-102.
    Jann MW, Cyrus PA, Eisner LS, et al. 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. Metrifonate Study Group. Clin Ther. 1999;21(1):88-102.
    Jann, M. W., Cyrus, P. A., Eisner, L. S., Margolin, D. I., Griffin, T., & Gulanski, B. (1999). 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. Metrifonate Study Group. Clinical Therapeutics, 21(1), pp. 88-102.
    Jann MW, et al. 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. Metrifonate Study Group. Clin Ther. 1999;21(1):88-102. PubMed PMID: 10090427.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - 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. Metrifonate Study Group. AU - Jann,M W, AU - Cyrus,P A, AU - Eisner,L S, AU - Margolin,D I, AU - Griffin,T, AU - Gulanski,B, PY - 1999/3/25/pubmed PY - 1999/3/25/medline PY - 1999/3/25/entrez SP - 88 EP - 102 JF - Clinical therapeutics JO - Clin Ther VL - 21 IS - 1 N2 - This prospective, randomized, double-masked, placebo-controlled, parallel-group study assessed the safety and efficacy of 2 dosage regimens of once-daily metrifonate in patients with probable Alzheimer's disease (AD) of mild-to-moderate severity. A total of 395 patients were randomized to receive placebo (n = 134) or metrifonate in 1 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 maintenance dose of metrifonate 50 mg for 6 weeks. The primary measure of efficacy was the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog); secondary measures of efficacy included the Mini-Mental State Examination (MMSE), the Clinician's Interview Based Impression of Change with Caregiver Input (CIBIC-Plus), the Clinician's Interview Based Impression of Severity with Caregiver Input (CIBIS-Plus), and the ADAS-Noncognitive Subscale (ADAS-Noncog). Safety was assessed by the prevalence of premature study termination and treatment-emergent adverse events, as well as by changes in vital signs, findings on electrocardiographic and neurologic examinations, and abnormalities on laboratory tests. At 4 weeks of treatment, defined by the protocol as the target efficacy determination, the mean ADAS-Cog scores of the intent-to-treat population (last observation carried forward) favored the loading-dose group versus the placebo group, but the difference was not statistically significant. However, at week 6, the difference in mean ADAS-Cog scores was statistically significant compared with placebo. At neither week 4 nor week 6 was there a statistically significant difference in the mean ADAS-Cog scores of the no-loading-dose and placebo groups. For the CIBIC-Plus, the treatment difference between the placebo and loading-dose groups significantly favored metrifonate at week 6 but not at week 4, whereas the treatment difference between the placebo and no-loading-dose groups was statistically significant at both time points. For the MMSE, CIBIS-Plus, and ADAS-Noncog, treatment differences for both groups versus placebo did not reach statistical significance at either week 4 or 6. Assessment of the frequency of adverse events in metrifonate-treated patients revealed that the no-loading-dose regimen was better tolerated than the loading-dose regimen. Given the overall similar efficacy and more favorable safety profile associated with the no-loading-dose regimen versus the loading-dose regimen observed 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. SN - 0149-2918 UR - https://www.unboundmedicine.com/medline/citation/10090427/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__Metrifonate_Study_Group_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0149291800882703 DB - PRIME DP - Unbound Medicine ER -