Objective: To compare the long-term efficacy and safety of galantamine 24 mg/day and donepezil 10 mg/day in patients with Alzheimer's disease.
Both treatments were well tolerated; most adverse events were transient and of mild-to-moderate intensity, and were consistent with the findings of previous clinical trials.
Patients and Study Design: This was a rater-blinded, randomised, parallel-group multicentre study (18 outpatient clinics) in the UK. 182 patients (69 male, 113 female) with Alzheimer's disease were randomised to galantamine (n = 94) or donepezil (n = 88) for 52 weeks.
Both treatments were well tolerated; most adverse events were transient and of mild-to-moderate intensity, and were consistent with the findings of previous clinical trials.
Main outcome measures: The effects of galantamine and donepezil on function using the Bristol Activities of Daily Living Scale (BrADL); cognition using the Mini-Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog/11); behaviour using the Neuropsychiatric Inventory (NPI); caregiver burden using the Screen for Caregiver Burden; and safety were assessed.
Both treatments were well tolerated; most adverse events were transient and of mild-to-moderate intensity, and were consistent with the findings of previous clinical trials.
Results: BrADL total scores showed no significant difference between treatment groups in mean change from baseline to week 52. In the total population, in terms of cognition, galantamine patients' scores on the MMSE at week 52 did not differ significantly from baseline (-0.52 ± 0.39, p < 0.5 vs baseline), whereas donepezil patients' scores deteriorated significantly from baseline (-1.58 ± 0.42, p < 0.0005 vs baseline). The between-group difference in MMSE change, which showed a trend for superiority of galantamine, did not reach statistical significance (p ≤ 0.1). In the ADAS-cog/11 analysis, between-group differences for the total population were not significant, whereas galantamine-treated patients with MMSE scores of 12-18 demonstrated an increase (worsening) in the ADAS-cog/11 score of 1.61 ± 0.80 versus baseline, compared with an increase of 4.08 ± 0.84 for patients treated with donepezil, with a significant between-group difference in favour of galantamine (p ≤ 0.05). More caregivers of patients receiving galantamine reported reductions in burden compared with donepezil. Changes from baseline in NPI were similar for both treatments.
Both treatments were well tolerated; most adverse events were transient and of mild-to-moderate intensity, and were consistent with the findings of previous clinical trials.
Conclusions: Significant advantages were found in the treatment response to galantamine (versus donepezil) on cognition as measured by response rates on the MMSE and ADAS-cog/11.
Alzheimer's disease is a progressive disorder in which neurons in affected brain regions, including the temporal cortex, frontal cortex and hippocampus, degenerate and die. Of the two known families of cholinergic receptors in the human brain, nicotinic and muscarinic, the nicotinic receptor type appears to be disproportionately affected by both a reduction in number and a loss of function in subjects with Alzheimer's disease.[1]This observation correlates with deficits observed in subjects with Alzheimer's disease in domains strongly linked with nicotinic function, such as attention and vigilance.[2]
Numerous clinical trials have demonstrated that acetylcholinesterase inhibitors (AChEIs) symptomatically improve the cognitive and functional impairments associated with Alzheimer's disease.[3-11]Studies using galantamine[12]have consistently shown that an initial period of cognitive improvement (usually lasting 6-12 months) is followed by a resumption of decline.[3,5-7,9-11,13]Despite the temporary nature of the improvement, the delay in decline is cost-effective.[14]Treatments that slow the rate of decline in Alzheimer's disease subjects over the long term are the targets of current research.
In addition to inhibiting acetylcholinesterase (AChE), galantamine (unlike donepezil) allosterically modulates neuronal nicotinic receptors (allosteric potentiating ligand [APL] effect).[15,16]This additional mechanism of action amplifies the actions of acetylcholine (ACh) at pre- and postsynaptic nicotinic ACh receptors and, in particular, modulates the release of ACh and other neurotransmitters such as glutamate, serotonin, dopamine and GABA.[17,18]Through this modulatory action, galantamine may facilitate the release of the neurotransmitters that affect other aspects of cognition besides memory - for example, attention, executive function and others.[17]
Executive function involves higher-order cognitive capabilities that are used to formulate new plans of action and to select, schedule and monitor appropriate sequences of action. According to some theories, attention and executive function are closely related, as executive function may be governed by a 'supervisory attention system.'[19]Executive function and attentional abilities are increasingly impaired as Alzheimer's disease progresses.[20]It has been proposed that the APL effect of galantamine may enhance attention (and consequently executive function),[17]thus helping to explain the non-cognitive benefits seen with galantamine, as cognition affects functional performance and behaviour.[21]
As described above, galantamine interacts competitively and reversibly with AChE, is selective for AChE over butyrylcholinesterase, and has a nicotinic ACh receptor APL effect.[22]Four large-scale, placebo-controlled, double-blind trials in approximately 2900 subjects consistently demonstrated the efficacy and safety of galantamine for the treatment of mild-to-moderate Alzheimer's disease for up to 6 months.[3-6,23]Donepezil is approved for the treatment of mild-to-moderate Alzheimer's disease, based on studies in approximately 2000 subjects. Donepezil is a highly specific, reversible AChEI.[24]Clinical trials have reported benefits in cognition and global function with donepezil relative to placebo in studies lasting up to 6 months[7,8,25,26]as well as in double-blind, placebo-controlled studies of 1 year in duration.[9,13]No nicotinic receptor-modulating effects have been reported for donepezil.
Heterogeneous clinical trial designs involving different subject populations, outcome instruments and dosing paradigms make it difficult to compare the efficacy of different drugs. Head-to-head studies provide the best way to assure that study conditions are identical. To date, only two 12-week head-to-head trials of AChEIs have been reported.[27,28]The present study is the first long-term, head-to-head study of galantamine versus donepezil in subjects with Alzheimer's disease.