Effects of galantamine in a 2-year, randomized, placebo-controlled study in Alzheimer's disease

Abstract

Background: Currently available treatments for Alzheimer's disease (AD) can produce mild improvements in cognitive function, behavior, and activities of daily living in patients, but their influence on long-term survival is not well established. This study was designed to assess patient survival and drug efficacy following a 2-year galantamine treatment in patients with mild to moderately severe AD.

Methods: In this multicenter, double-blind study, patients were randomized 1:1 to receive galantamine or placebo. One primary end point was safety; mortality was assessed. An independent Data Safety Monitoring Board monitored mortality for the total deaths reaching prespecified numbers, using a time-to-event method and a Cox-regression model. The primary efficacy end point was cognitive change from baseline to month 24, as measured by the Mini-Mental State Examination (MMSE) score, analyzed using intent-to-treat analysis with the 'last observation carried forward' approach, in an analysis of covariance model.

Results: In all, 1,024 galantamine- and 1,021 placebo-treated patients received study drug, with mean age ~73 years, and mean (standard deviation [SD]) baseline MMSE score of 19 (4.08). A total of 32% of patients (661/2,045) completed the study, 27% (554/2,045) withdrew, and 41% (830/2,045) did not complete the study and were discontinued due to a Data Safety Monitoring Board-recommended early study termination. The mortality rate was significantly lower in the galantamine group versus placebo (hazard ratio [HR] =0.58; 95% confidence interval [CI]: 0.37; 0.89) (P=0.011). Cognitive impairment, based on the mean (SD) change in MMSE scores from baseline to month 24, significantly worsened in the placebo (-2.14 [4.34]) compared with the galantamine group (-1.41 [4.05]) (P<0.001). Functional impairment, based on mean (SD) change in the Disability Assessment in Dementia score (secondary end point), at month 24 significantly worsened in the placebo (-10.81 [18.27]) versus the galantamine group (-8.16 [17.25]) (P=0.002). Incidences of treatment-emergent adverse events were 54.0% for the galantamine and 48.6% for the placebo group.

Conclusion: Long-term treatment with galantamine significantly reduced mortality and the decline in cognition and daily living activities, in mild to moderate AD patients.

Identification: This study is registered at ClinicalTrials.gov (NCT00679627).

Keywords: cholinesterase inhibitors; cognition; long-term treatment; mortality; nicotinic.

Figure 1

Patient disposition. Notes: ^aUptitration (from 16 mg/day to 24 mg/day) or downtitration (from 24 mg/day to 16 mg/day) of dose was allowed, based on tolerability and the investigator’s judgment. Patients unable to tolerate a minimum of 16 mg/day dose were to discontinue treatment and were followed until the end of the maintenance and posttreatment period. The total number of patients included in the safety analysis set was n=2,045; ^bearly study termination, per Data Safety Monitoring Board recommendation, when the prespecified number of deaths was ascertained and a significant imbalance favoring galantamine was observed; ^ca one-time dose titration to 16 or 24 mg/day was allowed, based on the investigator’s judgment and patient tolerability. Abbreviation: Gal, galantamine.

Figure 2

Time from randomization to death (safety analysis set).

Figure 3

Mean change in MMSE scores over time (LOCF) (ITT analysis set). Notes: *Significant difference between galantamine and placebo in MMSE score change from baseline. Two sites (049134 and 049137) were excluded from the analysis due to GCP noncompliance. Estimates of treatment differences (95% CIs) of MMSE using the repeated measures model (OC) were: −0.48 (−0.73 to −0.22) at month 6, and −1.10 (−1.67 to −0.52) at month 24. Abbreviations: CI, confidence interval; GCP, Good Clinical Practice; ITT, intent-to-treat; LOCF, last observation carried forward; MMSE, Mini-Mental State Examination; OC, observed case; SE, standard error.

Figure 4

Mean change in DAD scores over time (LOCF) (ITT analysis set). Notes: *Significant difference between galantamine and placebo in DAD score change from baseline. Two sites (049134 and 049137) were excluded from the analysis due to GCP noncompliance. Abbreviations: DAD, Disability Assessment in Dementia; GCP, Good Clinical Practice; ITT, intent-to-treat; LOCF, last observation carried forward; SE, standard error.