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20 Clinical effectiveness Comparison: Outcome: Study 01 at 24 weeks Homma 2000 don Rogers 1998a don Subtotal (95% CI) 01 Donepezil: ADAS-cog change from baseline 03 Donepezil 5 mg Treatment n 126 152 278 Mean (SD) –2.43 (5.10) –0.67 (6.30) Test for heterogeneity 2 = 0.00, df = 1, p = 0.96 Test for overall effect z = 5.17, p < 0.00001 Control n 113 153 266 02 at 12 weeks Rogers 1998b don Subtotal (95% CI) Test for heterogeneity 2 156 –2.10 (5.40) 150 156 150 = 0.00, df = 0 Test for overall effect z = 4.09, p = 0.00004 Two of the four studies provided data (mean change and standard deviation) that allowed them to be combined in a meta-analysis (Figure 2). Pooling the data using a fixed-effect model showed an overall improvement in ADAS-cog with 10 mg/day donepezil compared with placebo [WMD –3.01 (95% CI: –3.91 to –2.10)]. Mean (SD) 0.11 (5.20) 1.82 (6.10) WMD (95% CI fixed) Weight % 32.5 28.7 61.3 0.40 (5.30) 38.7 38.7 WMD (95% CI fixed) –2.54 (–3.85 to –1.23) –2.49 (–3.88 to –1.10) –2.52 (–3.47 to –1.56) –2.50 (–3.70 to –1.30) –2.50 (–3.70 to –1.30) Total (95% CI) Test for heterogeneity 2 434 416 100.0 –2.51 (–3.26 to –1.76) = 0.00, df = 2, p = 1 Test for overall effect z = 6.59, p < 0.00001 FIGURE 1 ADAS-cog change from baseline with donepezil 5 mg Comparison: Outcome: Study 01 Donepezil: ADAS-cog change from baseline 01 Donepezil 10 mg Treatment n Mean (SD) Control n 01 at 24 weeks Rogers 1998a don Subtotal (95% CI) Test for heterogeneity 2 150 –1.06 (6.20) 153 150 153 = 0.0, df = 0 Test for overall effect z = 4.08, p = 0.00005 02 at 12 weeks Rogers 1998b don Subtotal (95% CI) Test for heterogeneity 2 155 –2.70 (5.40) 150 155 150 = 0.0, df = 0 Test for overall effect z = 5.06, p < 0.00001 –10 –5 0 5 10 Favours treatment Favours control 1.82 (6.10) 42.9 42.9 0.40 (5.30) 57.1 57.1 –2.88 (–4.27 to –1.49) –2.88 (–4.27 to –1.49) –3.10 (–4.30 to –1.90) –3.10 (–4.30 to –1.90) Total (95% CI) Test for heterogeneity 2 305 303 100.0 –3.01 (–3.91 to –2.10) = 0.06, df = 1, p = 0.81 Test for overall effect z = 6.49, p < 0.00001 FIGURE 2 ADAS-cog change from baseline with donepezil 10 mg Mean (SD) WMD (95% CI fixed) Weight % –10 –5 0 5 10 Favours treatment Favours control WMD (95% CI fixed) Heterogeneity was not significant at p = 0.81. No difference was noted using a random-effects model. One unpublished trial of mild AD participants reported mean change on a modified ADAS-cog scale. 55 Those in the 10 mg donepezil group (n = 91) demonstrated a mean change in
ADAS-cog of –1.7 (SEM 0.45) and those in the placebo group (n = 55) a mean change in ADAS-cog of 0.6 (SEM 0.57). The study demonstrated a statistically significant difference, p = 0.001. The mean mADAS-cog at baseline was 23.8 (SEM 0.85) in the donepezil group and 24.1 (SEM 0.93) in the placebo group. Cognitive responders on ADAS-cog One study reported data on ‘cognitive responders’. 51 Cognitive responders were defined as those with at least a 4-point improvement on the ADAS-cog; they also presented data on those with at least a 7-point improvement. In this study 37.8% of participants given 5 mg donepezil and 53.5% of participants given 10 mg donepezil had at least a 4-point improvement. These compare with 26.8% of those participants given the placebo intervention. Participants with at least a 7-point improvement on ADAS-cog were 15.4 and 25.2% in the two donepezil groups (5 and 10 mg/day, respectively) compared with 7.8% in the placebo group. The trial also reports that the percentage of participants with poorer ADAS-cog scores from baseline were 20.3% in the 5 mg donepezil group, 18.9% in the 10 mg donepezil group and 42.3% in the placebo group, hence cognitive worsening was higher in those treated with placebo. No statistical analyses were undertaken to compare differences in any of the groups’ responses on these outcomes. MMSE Nine included trials report the MMSE and results are given in Table 6. On the MMSE a positive mean change indicates a clinical improvement. Six trials were two-arm comparisons, two were three-arm trials and one was a four-arm trial. Change from baseline score for each trial is given in Table 6. The summary that follows will predominantly discuss comparisons between 5 mg donepezil and placebo and 10 mg donepezil and placebo, regardless of the number of arms in the individual trial. The two studies 41,47 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. The one trial where participants received either 5 or 10 mg donepezil is reported separately. The one trial that had 12 weeks of open-label treatment prior to randomisation is also reported separately. 49 Donepezil 5 mg/day versus placebo. Three trials included an intervention group with a daily dose of 5 mg donepezil. The mean change from © Queen’s Printer and Controller of HMSO 2006. All rights reserved. Health Technology Assessment 2006; Vol. 10: No. 1 baseline MMSE was between 0.24 and 2.0 for the donepezil group and between –0.97 and 1.2 for the placebo groups. The mean treatment difference in change from baseline scores between donepezil and placebo was ~1 point. Overall, all studies demonstrated improvement in MMSE in the donepezil groups compared with the placebo groups, although these differences reached statistical significance in only two. 51,52 Some of the variation between trials may be due to sample size as the one trial that did not reach statistical significance had small sample sizes. There may also be differences attributed to the properties of the scale (see discussion in Chapter 10). Two of the three studies provided data (mean change and standard deviation) that allowed them to be combined in a meta-analysis (Figure 3). Pooling the data using a fixed-effects model showed an overall improvement in MMSE with 5 mg/day donepezil compared with placebo [WMD 1.08 (95% CI: 0.57 to 1.58)]. Heterogeneity was not statistically significant, p = 0.63. No difference was noted using a random-effects model. Donepezil 10 mg/day versus placebo. Six trials included an intervention group with a daily dose of 10 mg donepezil. The mean change from baseline MMSE was between –0.46 and 1.7 for the donepezil group and between –2.18 and 0.5 for the placebo groups. This variation may in part be explained by differences in the study duration, with longer duration reducing the mean change MMSE score from baseline. Baseline MMSE scores were generally similar between these trials. The mean treatment difference in change from baseline scores between donepezil and placebo was ~1.5 points. Overall, all studies demonstrated statistically significant improvement in MMSE in the donepezil groups compared with the placebo groups. Two of the six studies provided data (mean change and standard deviation) that allowed them to be combined in a meta-analysis (Figure 4). Pooling the data using a fixed-effect model showed an overall improvement in MMSE with 10 mg/day donepezil compared with placebo [WMD 1.30 (95% CI: 0.78 to 1.82)]. Heterogeneity was not statistically significant, p = 0.85. No difference was noted using a random-effects model. In one study, the dose of donepezil was 5 or 10 mg/day, with approximately half receiving each dose. 43 The reported MMSE change from baseline in the donepezil-treated group at 60 weeks was –1.5. The reported MMSE change from baseline in the placebo group at 60 weeks was –1.75. 21
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
Page 13: Galantamine Five published economic
Page 17 and 18: Description of underlying health pr
Page 19 and 20: TABLE 1 Estimated prevalence of AD
Page 21 and 22: as one component of their care. A n
Page 23 and 24: The a priori methods used for syste
Page 25: Data synthesis Data were synthesise
Page 28 and 29: 14 Clinical effectiveness TABLE 3 C
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Page 38 and 39: 24 Clinical effectiveness donepezil
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70 Clinical effectiveness ● One R
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72 Clinical effectiveness by the pa
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74 Clinical effectiveness TABLE 42
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76 Clinical effectiveness TABLE 46
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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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90 Economic analysis term). Where w
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94 Economic analysis Fenn and Gray
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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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110 Economic analysis survey studie
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112 Economic analysis vascular deme
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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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