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18 Clinical effectiveness particularly important when using subjective outcome measures. Seven studies adequately reported the point estimates and measures of variability for all outcomes; however, none of these included an appropriate ITT analysis. All studies state that an ITT analysis was undertaken; however, this was defined as being on all participants randomised to treatment who received at least one dose of medication and who had baseline and at least one post-baseline assessment of efficacy (LOCF). In each case some participants were missing from the analysis as they did not have at least one postbaseline assessment, and therefore these studies were judged to have inadequate ITT analysis. All but one study 48 gives details of the numbers of withdrawals from the study; however, four do not give reasons for withdrawal. [Commercial/academic confidential information relating to Seltzer and colleagues 55 removed] Assessment of effectiveness Cognitive outcomes ADAS-cog Seven parallel RCTs and one crossover RCT report the ADAS-cog (Homma and colleagues 44 use a Japanese version) and results are given in Table 5. Results in this table are ordered by the number of comparison groups and then alphabetically: the results from the trials with two comparisons are shown first followed by the trials with three and four comparisons. Results for the crossover study were presented in several different ways, for groups A and B, for all who received placebo (whether in A or B) and similarly for all who received donepezil, for those who completed both parts of the crossover and for whom no data points were missing. In the current review only data reported in terms of donepezil treatment versus placebo treatment (therefore treated as a parallel comparison) are discussed. The ‘ITT’ (LOCF) results are presented unless not reported in an individual trial. These conventions will apply throughout the report. One trial only reported the treatment difference and the statistical significance value without any data and has therefore been omitted from this table. 48 In this and later tables, values estimated from figures are given in italics. On the ADAS-cog a negative mean change indicates a clinical improvement. Three trials were two-arm comparisons, three were three-arm trials and one was a four-arm trial. Changes from baseline scores for each individual trial are given in Table 5. The summary that follows will predominantly discuss comparisons between 5 mg donepezil and placebo and between 10 mg donepezil and placebo, regardless of the number of arms in the individual trial. The one study 45 where the intervention dose of donepezil was 5 mg/day for 28 days followed by 10 mg/day until study completion will be treated as having a 10 mg/day dose. Donepezil 5 mg/day versus placebo. Six trials included an intervention group with a daily dose of 5 mg donepezil. The mean change from baseline ADAS-cog score was between –2.43 and 0.2 for the donepezil group and between 0.11 and 3.2 for the placebo groups. Some of this variation may be explained by differences in the sample sizes, length of follow-up and study quality. Sample sizes ranged from 103 in the study by Greenberg and colleagues 54 to 545 in the two relevant groups in Burns and colleagues’ comparison. 50 Length of follow-up was 24 weeks in five studies and 12 weeks in two studies. 52,53 No studies reported an adequate ITT analysis, and only Greenberg and colleagues 54 were rated as having adequate randomisation and concealment of allocation procedures. Blinding of outcome assessors was only adequate in two studies 52,54 and blinding of care provider and participants was rated as being adequate in only one study. 54 Baseline ADAS-cog scores were similar between trials. The mean treatment difference in change from baseline scores between donepezil and placebo was ~0.90. Overall, all studies found that ADAS-cog scores were statistically significantly lower (better) with 5 mg donepezil per day than placebo. Three of the six studies provided data (mean change and standard deviation) that allowed them to be combined in a meta-analysis (Figure 1). Pooling the data using a fixed-effect model showed an overall improvement in ADAS-cog with 5 mg/day donepezil compared with placebo [WMD –2.51 (95% CI: –3.26 to –1.76)]. Heterogeneity was not significant at p = 1. No difference was noted using a random-effects model. Donepezil 10 mg/day versus placebo. Four trials included an intervention group with a daily dose of 10 mg donepezil. The mean change from baseline ADAS-cog score was between –2.7 and 0.2 for the donepezil group and between 0.4 and 3.2 for the placebo groups. Some of this variation may be explained by differences in the sample sizes which range from 66 in the study by Krishnan and
TABLE 5 ADAS-cog for donepezil colleagues 45 to 547 in the two relevant groups in Burns and colleagues’ comparison. 50 Study quality also differed between studies; no studies were rated as having both adequate randomisation and concealment of allocation procedures, blinding of outcome assessors was only adequate in one trial 52 and blinding of care provider and participants was rated as only being adequate in one study. 45 The primary outcome in one trial 45 was brain N-acetylaspartate concentrations and therefore © Queen’s Printer and Controller of HMSO 2006. All rights reserved. Health Technology Assessment 2006; Vol. 10: No. 1 Greenberg et al., 2000 54 Change in ADAS-cog mean ± SEM Donepezil 5 mg/day (n = 51) Placebo (n = 52) p-Value versus placebo –1.50 ± 0.58 0.62 ± 0.61 Not reported Homma et al., 200044 JADAS-cog mean change from baseline ± SE Donepezil 5 mg/day (n = 134) Placebo (n = 129) p-Value versus placebo –2.43 ± 0.45, n = 126 0.11 ± 0.49, n = 113 p = 0.001 Krishnan et al., 200345 Change from baseline Numbers estimated from figure Donepezil 10 mg/day (n = 34) Placebo (n = 32) p-Value versus placebo 0.2 3.2 p < 0.04 Burns et al., 199950 Least-squares mean change from baseline Numbers estimated from figure 1. Donepezil 5 mg/day 2. Donepezil 10 mg/day 3. Placebo (n = 274) p-Value versus placebo (n = 271) (n = 273) 0.2 –1.2 1.7 1. p = 0.0021 2. p < 0.0001 Rogers et al., 199851 Mean change from baseline ± SEM 1. Donepezil 5 mg/day 2. Donepezil 10 mg/day 3. Placebo (n = 153) p-Value versus placebo (n = 152) (n = 150) –0.67 ± 0.51 –1.06 ± 0.51 1.82 ± 0.49 1. p < 0.0001 2. p < 0.0001 Rogers et al., 199852 Least-squares mean change from baseline ± SEM 1. Donepezil 5 mg/day 2. Donepezil 10 mg/day 3. Placebo (n = 150) p-Value versus placebo (n = 156) (n = 155) –2.1 ± 0.43 –2.7 ± 0.43 0.4 ± 0.43 1. p < 0.001 2. p < 0.001 Rogers et al., 199653 Mean change from baseline ± SE Numbers estimated from figure 1. Donepezil 2. Donepezil 3. Donepezil 4. Placebo p-Value versus placebo 1 mg/day (n = 42) 3 mg/day 5 mg/day (n = 40) (n = 40) (n = 39) –0.9 –1.4 –2.5 0.7 3. p < 0.003 Rogers et al., 199653 Adjusted mean (min., max.) change from baseline 1. Donepezil 2. Donepezil 3. Donepezil 4. Placebo p-Value versus placebo 1 mg/day 3 mg/day 5 mg/day (n = 40) (n = 42) (n = 40) (n = 39) –0.9 (–11.3, 12.0) –1.4 (–12.0, 11.0) –2.5 (–8.0, 7.0) 0.7 (–7.0, 14.5) 1. p = 0.105 2. p = 0.036 3. p = 0.002 this study may not have been powered for changes in the ADAS-cog. The length of follow-up was 24 weeks in all but one study (12 weeks). 52 Baseline ADAS-cog scores were similar between trials. The mean treatment difference in change from baseline scores between donepezil and placebo was approximately 2.97 points. Overall, all four studies found that ADAS-cog scores were statistically significantly lower (better) with 10 mg/day donepezil than placebo. 19
Page 1 and 2: Health Technology Assessment 2006;
Page 3 and 4: The clinical and cost-effectiveness
Page 5 and 6: Objectives: To provide an update re
Page 7 and 8: List of abbreviations .............
Page 9 and 10: AChEI acetylcholinesterase inhibito
Page 11 and 12: Epidemiology and background Alzheim
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Page 17 and 18: Description of underlying health pr
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68 Clinical effectiveness TABLE 35
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70 Clinical effectiveness ● One R
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72 Clinical effectiveness by the pa
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78 Clinical effectiveness donepezil
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80 Evidence from systematic reviews
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82 Economic analysis TABLE 48 Chara
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84 TABLE 49 Economic analysis Outli
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86 Economic analysis The UK study r
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88 Economic analysis The AD2000 stu
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96 Economic analysis one another. W
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98 Economic analysis outcomes: (1)
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100 Economic analysis respond to ga
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102 Economic analysis donepezil, ri
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104 Economic analysis of this study
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106 Economic analysis independent,
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108 Economic analysis classificatio
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114 Economic analysis Livingston an
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116 Economic analysis sensitive to
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118 Economic analysis Neumann and c
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120 Economic analysis The model str
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122 Economic analysis CEA, given th
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124 Economic analysis TABLE 70 Key
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126 Economic analysis TABLE 73 Prof
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128 Economic analysis Probability o
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130 Economic analysis Results are s
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132 Economic analysis 4. The model
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134 Economic analysis perspective e
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136 Economic analysis indicating th
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Ongoing research, with relevance to
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The increasing numbers of the very
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146 Discussion and conclusions dose
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148 Discussion and conclusions effo
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150 Discussion and conclusions Stre
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1. Clegg A, Bryant J, Nicholson T,
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placebo-controlled study of donepez
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94. Brooks E, Deal L. The effect of
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of memantine in patients with moder
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This version of HTA monograph volum
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