The randomisation of patients and their progress through the study is summarised in figure . A total of 831 patients were recruited; 106 of these were excluded. Altogether 243 patients were randomly allocated to higher dose treatment, 243 to lower dose, and 239 to placebo. Demographic variables and disease characteristics at baseline were comparable across groups but there were more females (59% (428/725)) than males (41% (297/725)). Mean age was 72 years (range 45-95 years), and most patients (97% (703/725)) were white. The mean duration of dementia was 39 months; 41% (298/725) of patients had mild disease, 57% (411/725) moderate, and 2% (16/725) had severe disease.18
The mean scores at baseline on the Alzheimer’s disease assessment scale and the progressive deterioration scale for the three groups are shown in table . The mean score on the mini-mental state examination was 19.9 (range 10-29).
Outcome of allocation to treatment and reasons for withdrawal from the study
Mean (range) baseline scores analysed on an intention to treat basis
About 80% of patients (579/725) reported prior or current medical conditions, or both. These were most commonly cardiovascular. About 81% (590/725) were taking concomitant drug treatment at baseline. The mean number of medical conditions per patient was 2.5 and the mean number of concomitant drugs being taken per patient was 4.0. The most common drugs—that is, taken by >10% in each group—included anti-infectives and drugs for cardiovascular, gastrointestinal, respiratory, musculoskeletal, blood, and nervous system disorders.
By the end of the study the mean dose of rivastigmine was 10.4 (SD 2.13) mg/day in the higher dose group and 3.7 (SD 0.59) mg/day in the lower dose group. Of the patients who were taking rivastigmine until the end of the study, 64% (107/166) in the higher dose group and 90% (190/210) in the lower dose group reached the maximum prescribed dose.
Table summarises the effects of rivastigmine on all measures of efficacy.
Mean (95% confidence interval) change from baseline on measures of efficacy of rivastigmine at week 26
Cognitive subscale of the Alzheimer’s disease assessment scale
Cognitive function worsened progressively in patients taking placebo. The mean deterioration in the cognitive subscale was 1.41 points over 26 weeks among observed cases (fig ). The mean score on the subscale improved among patients in the higher dose group (mean improvement 1.17 points). Differences between the two groups in the mean change from baseline scores were statistically significant at weeks 12, 18, and 26 for all three analyses. Of the patients completing the study 55% (86/157) of those in the higher dose group improved from baseline measurements compared with 45% (93/205) of those treated with placebo (analysis of observed cases). The proportion of patients with a clinically meaningful improvement in their scores (defined as a change of four points or more from baseline) at the end of the study was significantly greater among patients receiving higher dose rivastigmine than among those taking placebo (24% (57/242) higher dose group v 16% (39/238) placebo in intention to treat analysis; 27% (53/199) higher dose group v 18% (40/225) last observation carried forward; and 29% (45/157) higher dose group v 19% (38/205) observed cases analysis (P<0.05)).
Figure 2 Mean change in baseline scores on cognitive subscale of Alzheimer’s disease assessment scale, observed cases analysis. P<0.05 compared with placebo (two tailed pairwise Student’s t tests using pooled error term from analysis of (more ...) Clinician interview based impression of change
At week 26 patients treated with placebo had deteriorated (mean rating 4.34) (table ). Patients in the higher dose rivastigmine group had improved (mean rating 3.93). The difference between the two groups at week 26 was statistically significant for all three efficacy analyses. At week 26 significantly more patients in both rivastigmine groups had ratings of marked, moderate, or minimal improvement on this scale when compared with those taking placebo (20% (46/230) placebo group v 30% (69/233) lower dose group (P<0.05) and 37% (80/219) higher dose group (P<0.001) in the intention to treat analysis; 22% (49/226) placebo group v 32% (71/224) lower dose group (P<0.01) and 40% (78/193) higher dose group (P<0.001) in the last observation carried forward; 22% (44/197) placebo group v 31% (62/198) lower dose group (P<0.05) and 41% (63/155) higher dose group (P<0.001) in the observed cases analysis).
Mean scores (95% confidence intervals) on the clinician interview based impression of change scale (incorporating caregiver information) at weeks 12, 18, and 26 among the observed cases population
Progressive deterioration scale
At week 26 the difference in mean change from baseline in scores on the progressive deterioration scale between patients receiving placebo and those receiving higher dose rivastigmine was statistically significant in the analysis of the last observation carried forward (P<0.05) (fig ). Of the 581 patients completing the study, a significant difference in those showing any improvement in these scores was observed for those taking higher dose rivastigmine compared with those taking placebo (49% (98/198) v 39% (88/223) respectively; P=0.04 in analysis of the last observation carried forward). Significantly more patients in the higher dose group improved by at least 10% than did in the placebo group both in the intention to treat analysis (29% (70/241) v 19% (45/237), P<0.01) and the analysis of the last observation carried forward (33% (66/198) v 20% (45/223), P<0.01).
Figure 3 Mean change in baseline scores on the progressive deterioration scale, analysis of last observation carried forward. P<0.05 compared with placebo (two tailed pairwise Student’s t tests using pooled error term from analysis of covariance (more ...) Global deterioration scale and mini-mental state examination
At week 26 patients who had received rivastigmine 6-12
mg/day had a significantly better response than those in the placebo group in the mean change from baseline scores on the mini-mental state examination and the global deterioration scale. Patients receiving placebo deteriorated by 0.47 points from baseline on the mini-mental state and those receiving rivastigmine 6-12
mg/day improved by 0.21 points over baseline using the intention to treat analysis. Significantly less deterioration occurred on the global deterioration scale among patients taking 6-12
mg/day rivastigmine compared with those taking placebo.
Of the 725 patients initially randomly allocated 581 (80%) completed treatment. The proportion who discontinued treatment for any reason was significantly higher in the higher dose group than in the lower dose or placebo groups (33% (79/243) v 14% (34/243) and 13% (31/239), respectively) as was the proportion who discontinued because of adverse events (23% (55/242) v 7% (18/242) and 7% (16/239), respectively). Most of the discontinuations related to adverse events occurred during dose escalation (69% (38/55) in the higher dose group).
The safety of the drug could be evaluated in 242 patients in each of the rivastigmine treatment groups and in 239 patients in the placebo group. A summary of the adverse events that occurred at least 5% more often with rivastigmine than with placebo or that occurred with an incidence significantly different from placebo is given in table . Overall, significantly more patients reported at least one treatment related adverse event in the higher dose group (91% (220/242)) than in the lower dose (71% (172/242)) or placebo (72% (172/239)) groups.
Number (percentage) of adverse effects occurring at least 5% more often in patients taking rivastigmine than in patients taking placebo or occurring with an incidence significantly different from placebo
Adverse events related to treatment were generally not severe and occurred most frequently during the dose escalation phase. The adverse events most commonly reported with rivastigmine were cholinergic: nausea, vomiting, diarrhoea, abdominal pain, and anorexia. Dizziness, headache, fatigue, and malaise also occurred more frequently with higher doses of rivastigmine than with placebo. Apart from the incidence of nausea, there was no significant difference in the incidence of adverse events between the lower dose group and the group treated with placebo. The frequency of serious adverse events was similar in all groups (about 18%).
There were no obvious overall trends or clinically relevant differences between treatment groups in vital signs (mean systolic and diastolic blood pressure, abnormalities of blood pressure, heart rate, and body temperature), physical examination, haematological or biochemical analyses (including hepatic enzyme levels), electrocardiographic measurement, or urine analysis. Mean body weight increased in the placebo group (mean change +0.72 kg at week 26) but decreased in the rivastigmine groups (mean change −1.39
kg in the higher dose group and −0.13
kg in the lower dose). The difference in the mean change in body weight between the placebo group and the higher dose rivastigmine group was statistically significant (Fisher’s exact test P<0.05). In the higher dose group 24% of patients (55/234) lost >7% of body weight compared with 9% of patients (21/236) in the lower dose group and 7% (16/236) in the placebo group.