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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.
Clin Ther 1999; 21(1):88-102CT

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.

Authors+Show Affiliations

Center for Clinical Research, Southern School of Pharmacy, Mercer University, Atlanta, Georgia 30341-4155, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

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 -