Dgiclinical.com

Attainment of treatment goals by people
with Alzheimer’s disease receiving galantamine:
a randomized controlled trial
Kenneth Rockwood, Sherri Fay, Xiaowei Song, Chris MacKnight, Mary Gorman,
on behalf of the Video-Imaging Synthesis of Treating Alzheimer’s Disease (VISTA) Investigators
Published at www.cmaj.ca on Mar. 22, 2006.
0.27). Of the secondary outcome measures, the ADAS-cogscores differed significantly between groups (SRM = –0.36,p = 0.04), as did the CIBIC-plus scores (SRM = –0.40, p = Background: Although cholinesterase inhibitors have pro-
0.03); no significant differences were in either the DAD duced statistically significant treatment effects, their clinical scores (SRM = 0.28, p = 0.13) or the CBS scores (SRM = meaningfulness in Alzheimer’s disease is disputed. An im- portant aspect of clinical meaningfulness is the extent towhich an intervention meets the goals of treatment.
Interpretation: Clinicians, but not patients and caregivers,
observed a significantly greater improvement in goal attain-
Methods: In this randomized controlled trial, patients with
ment among patients with mild to moderate Alzheimer’s dis- mild to moderate Alzheimer’s disease were treated with ei- ease who were taking galantamine than among those who ther galantamine or placebo for 4 months, followed by a 4- month open-label extension during which all patients re-ceived galantamine. The primary outcome measures were Goal Attainment Scaling (GAS) scores from assessments byclinicians and by patients or caregivers of treatment goalsset before treatment and evaluated every 2 months. Sec-ondary outcome measures included the cognitive subscaleof the Alzheimer’s Disease Assessment Scale (ADAS-cog), theClinician’s Interview-based Impression of Change plus Care- The role of cholinesterase inhibitors in treating mild to moderate Alzheimer’s disease is controversial. Al-though these drugs have produced statistically sig- nificant treatment effects,1 their clinical meaningfulness is giver Input (CIBIC-plus), the Disability Assessment for De- disputed.2–7 How to test clinical meaningfulness is unclear.8 mentia (DAD) and the Caregiving Burden Scale (CBS). To In dementia drug trials, American regulators have required evaluate treatment effect, we calculated effect sizes (as stan- as primary outcome measures9 both a neuropsychologic dardized response means [SRMs]) and p values.
battery of tests (usually the cognitive subscale of the Results: Of 159 patients screened, 130 (mean age 77 [stan-
Alzheimer’s Disease Assessment Scale [ADAS-cog]10) and a dard deviation (SD) 7.7]; 63% women) were enrolled in the scale (usually the Clinician’s Interview-based Impression of study (64 in the galantamine group and 66 in the placebo Change plus Caregiver Input [CIBIC-plus])11 completed by group); 128 were included in the analysis because they had an experienced clinician. Still, critics have charged that the at least one post-baseline evaluation. In the intention-to- instruments do not translate to usual care, that the trials treat analysis, the clinician-rated GAS scores showed a sig- were too short and that the effects were too small.2–4,6,7 On nificantly greater improvement in goal attainment among the other hand, many physicians believe that the trials did patients in the galantamine group than among those in the not capture meaningful treatment effects that they recog- placebo group (change from baseline score 4.8 [SD 9.6]) v.
0.9 [SD 9.5] respectively; SRM = 0.41, p = 0.02). The patient– Clinical meaningfulness can be assessed in part by the ex- caregiver-rated GAS scores showed a similar improvement in tent to which an intervention meets the goals of treatment.13 the galantamine group (change from baseline score 4.2 [SD Here we report our findings from a clinical trial in which we 10.6]); however, because of the improvement also seen in the placebo group (2.3 [SD 9.0]), the difference between tested the efficacy of galantamine by using Goal Attainment groups was not statistically significant (SRM = 0.20, p = Scaling14 (GAS) to detect change, and we compared those findings with results from other validated instruments.
CMAJ • April 11, 2006 • 174(8) | 1099 2006 CMA Media Inc. or its licensors
signment. Given that the primary efficacy measure (the GoalAttainment Scaling [GAS] instrument14) was new to investi- We targeted English-speaking people with probable gators at the study sites and that some sites might have had to Alzheimer’s disease (as determined by NINCDS-ADRDA withdraw if investigators did not know how to complete GAS, criteria15) at 10 sites across Canada for treatment with the we randomized in blocks of 2, by site, to decrease the chance cholinesterase inhibitor galantamine.16 Patients with mild to moderate dementia (Mini-Mental State Examination Patients were instructed to take 1 tablet twice daily, prefer- [MMSE]17 score of 10–25 inclusive and an ADAS-cog18 score ably with food. During the placebo-controlled phase, patients of at least 18) were eligible. We excluded patients who were in in the galantamine group were given 8 mg/d (4 mg twice nursing homes, those who had disabling communication dif- daily) for 4 weeks, followed by 16 mg/d for another 4 weeks.
ficulties (problems in language, speech, vision or hearing), At the end of week 8, the dose could be increased to 24 mg/d other active medical issues or competing causes of dementia, depending on tolerability. At week 12, patients were re- patients who had taken anti-dementia medications within evaluated; the dose could then be reduced to 16 mg/d if neces- 30 days before screening for study enrolment, those who sary, after which it could not be changed. Patients assigned to were hypersensitive to cholinomimetic agents or bromide the placebo group followed a sham titration schedule. During and those who had been in other galantamine trials. Eligible the open-label phase, patients in the placebo group were patients needed to have daily contact with a responsible given galantamine in titrated doses for 12 weeks, and those in the galantamine group underwent a sham titration while con- For our study — the Video-Imaging Synthesis of Treated tinuing to receive the dose they were taking at the end of the Alzheimer’s disease (VISTA) trial — we used a 16-week ran- domized, double-blind, parallel-group, placebo-controlled The primary efficacy measure was the GAS instrument,14 design, with a 16-week open-label follow-up period during an individualized outcome measure in which goals are set which all study patients were given galantamine (see online and then followed over the course of a trial. The goals are per- Appendix 1, available at www.cmaj.ca/cgi/content/full/174 sonalized (i.e., people set goals according to their own /8/1099/DC1). To understand treatment effects better, inter- needs). What is standardized is the extent of their attainment, views were digitally video-recorded. After screening, eligible which can be either “no change,” or “much better” (or “much patients were randomly assigned to receive either galanta- worse”) than expected. (An example of how GAS is used can mine (16–24 mg/d) or placebo. Randomization was deter- be found in online Appendix 2, available at www.cmaj.ca mined immediately before medication was administered by /cgi/content/full/174/8/1099/DC1). Two independent GAS as- having a research nurse nurse phone into a contracted, inter- sessments were completed: one by physicians, after inter- active voice-response system for an assignment number; she viewing patients and caregivers and completing all study pro- was blind to the number’s meaning in terms of treatment as- cedures, and the other by patients and caregivers, in a Table 1: Characteristics at baseline of patients with mild to moderate Alzheimer’s
disease randomly assigned to receive galantamine or placebo
Note: MMSE = Mini-Mental State Examination, SD = standard deviation, ADAS-cog = cognitive subscale of the Alzheimer’s Disease Assessment Scale, CIBIC-plus = Clinician’s Interview-based Impression of Change plus Caregiver Input, DAD = Disability Assessment for Dementia, CBS = Caregiving Burden Scale. *Five patients (2 in galantamine group, 3 in placebo group) had MMSE scores that were outside the 10–25 range stipulated in the inclusion criteria; 1 had an MMSE score < 10, the other 4 had MMSE scores > 25. †Seven patients (4 in galantamine group, 3 in placebo group) had ADAS-cog scores that were outside the > 17 range stipulated in the inclusion criteria; in each case the score was below the lower limit, which indicated milder impairment. CMAJ • April 11, 2006 • 174(8) | 1100 separate interview facilitated by an experienced, independent indicating better performance. In the 13-item Caregiving Bur- health professional (usually a research nurse) who was den Scale (CBS)20 higher scores reflect higher burden. After blinded to all other outcomes and adverse events except for baseline, the DAD and CBS were administered at 4 and 8 the CIBIC-plus, which the health professional also scored.
months, and the others every 2 months. We also introduced GAS raters completed a 4-hour training session. Blinded the Allocation of Caregiver Time Survey,21 the Red Pen Task22 qualitative raters from the coordinating study site coded every and the locally developed Examination of Memory and video-recorded interview and made domain assignments; this Temporality, but we have not reported on these findings in step provided quality assurance for how goals were set but did Although the GAS instrument can be more responsive Secondary outcome measures included the CIBIC-plus,11 than standard measures because it is personalized, this attrib- with scores anchored at 4 (no change) and ranging from ute had not been tested in a controlled trial in dementia. For 1 (very much improved) to 7 (very much worse). The 11-item this exploratory analysis, we estimated the sample size from ADAS-cog10,18 was used to assess memory, language and our limited experience with GAS in anti-dementia drug praxis, with scores ranging from 0 (no impairment) to 70 (se- trials.13,23 Assuming a moderate effect size of about 0.524 and vere impairment). The Disability Assessment for Dementia a 15% dropout at 4 months, we determined that 152 subjects (DAD)19 was used to evaluate 23 aspects of instrumental and would be required to detect differences at the 5% significance 17 aspects of basic activities of daily living, with scores deter- level (2-tailed) with 80% power.25 We recognized that this mined as a percentage of applicable items, and higher scores might not result in statistically significant results for the sec- • Did not meet inclusion criteria n = 23• Withdrew consent n = 4• Died n = 1• Other (no reason recorded) n = 1 Fig. 1: Flow of patients through the study. R = randomization.
CMAJ • April 11, 2006 • 174(8) | 1101 ondary outcomes, which we used to compare with the pri- tients in the galantamine group than in the placebo group mary outcomes and with results from other studies.1 withdrew because of adverse events (8% v. 5%), including 1 All of the patients who were randomly assigned were in- cluded in analyses of safety, demographic and baseline char- Four patients in the galantamine group and one in the acteristics. The intention-to-treat analysis included all ran- placebo group withdrew before completing a post-baseline domly assigned patients who took at least 1 dose (treatment GAS assessment. Two patients (both in the galantamine drug or placebo) during the placebo-controlled phase and group) had no follow-up GAS or any other assessments and who provided any follow-up GAS. Missing data were imputed were excluded from analysis. One patient (assigned to the based on the last observation carried forward (excluding base- galantamine group) had follow-up data only for the clinician- line data) during the placebo-controlled phase. The observedcase analysis included only data from scheduled time points.
We report the mean change from baseline for efficacy Clinician-rated GAS scores
measures by treatment group (galantamine v. placebo).
Analysis of variance of the mean change in GAS scores from baseline to week 16 was the primary efficacy comparison.
Our protocol specified that the statistical significance of the primary outcomes be tested only at 16 weeks; otherwise, effect sizes were estimated at relevant points. Nevertheless, pre-publication assessments favoured calculating p values for secondary outcome measures; these calculations are limited to the 16-week test results. To evaluate clinical detectability and measurement responsiveness, we calculated effect sizes,24 estimated as standardized response means (SRMs), derived as the mean difference between groups divided by the pooled standard deviation of their change.26 For scales whose higher scores indicate worse outcomes (ADAS-cog, CIBIC-plus, CBS), negative effect sizes (less than zero) indicated a Patient-caregiver–rated GAS scores
positive treatment effect; the opposite was true for scaleswhose higher scores indicate better outcomes (GAS, DAD).
As detailed below, group assignment was imbalanced, with more patients who had moderate dementia being randomly assigned to the placebo group than to the galantamine group.
In a secondary analysis we used a mixed-effects model, with dementia severity as the fixed effect and patient as a random effect. This analysis allowed us to assess the effects of dropout and to adjust for dementia severity at baseline.
For the initial analysis, the statistician at the coordinating centre was blind to group assignments. An independent, un- blinded statistician verified all analyses.
In terms of ethics, we reckoned that treatment in a care- fully monitored placebo-controlled phase was ethically per- missible for up to 16 weeks, given that patients had an oppor- tunity to withdraw. All patients and caregivers provided written, informed consent, including specific consent forvideo-recording. Each institution’s research ethics committee Fig. 2: Mean change in GAS (Goal Attainment Scaling) scores
as well as the Therapeutics Product Directorate of Health among patients with mild to moderate Alzheimer’s disease, by treatment group. Top panel: clinician-rated GAS scores. Bottompanel: patient-caregiver–rated GAS scores. Error bars represent 95% confidence intervals. GAL-GAL (black triangles) = patientswho received galantamine during both the placebo-controlled Between November 2001 and July 2004, 130 patients were en- phase (months 0–4) and the open-label phase (months 4–8); rolled from 14 Canadian sites. We added 4 sites to the original PLA-GAL (white squares) = patients who received placebo dur- 10, to aid recruitment. No interaction between site and treat- ing the placebo-controlled phase and galantamine during the ment was present. Despite randomization, more patients with open-label phase. (Missing data were imputed based on thelast observation carried forward, excluding baseline data; for moderate dementia were assigned to the placebo group (Table the comparison between groups in the open-label phase, only 1). During the placebo-controlled phase, similar proportions observations in the galantamine group during the placebo-con- of patients in the galantamine and placebo groups withdrew from the study (17% and 15% respectively), although more pa- CMAJ • April 11, 2006 • 174(8) | 1102 based GAS assessment, and one from each group had data patients (47%) in the placebo group and 19 (29%) in the galant- only for patient-caregiver–based GAS assessments; in all 3 amine group met none of the goals set by the clinicians at the cases, other secondary outcome measures were completed.
end of the placebo-controlled phase; the corresponding num-bers of patients who met none of the goals set by patients and Intention-to-treat analyses
caregivers were 20 (30%) and 15 (23%). The largest differencesin goal attainment, as determined by both the patient-care- Clinicians set fewer goals than did the patients and caregivers giver–based and clinician-based assessments, occurred at (377 v. 439), although each set a median of 3 and no more 6 months (2 months after the start of the open-label phase).
than 6 goals per patient. Both the patients and caregivers and Patients who had been taking placebo during the first 4 the clinicians set most goals in areas of cognition and func- months attained fewer goals at 6 months than did patients who tion (67% and 60% respectively) and fewest in leisure and so- were taking galantamine for the entire 6 months (absolute dif- ference in patient-caregiver–rated GAS score = 4.3 [SRM = Both the patient-caregiver–based and clinician-based GAS 0.39] and in clinician-rated GAS score = 4.5 [SRM = 0.42]).
assessments indicated that patients in both groups showed The secondary outcome measures mostly showed effects net mean goal attainment at 2 months (Fig. 2). After 4 that favoured initial treatment with galantamine. The ADAS- months, although the patient–caregiver-based assessments cog scores (Fig. 3) showed readily detectable differences be- showed no significant difference in mean goal attainment be- tween groups at 2 and 4 months (e.g., 4-month SRM = –0.36, tween the galantamine and placebo groups (absolute differ- p = 0.04), as did the CIBIC-plus (SRM = –0.40, p = 0.03) (Fig.
ence between groups 1.9, p = 0.27; SRM = 0.20), the clini- 4). No significant differences in either the DAD scores (SRM cians detected significantly higher levels of goal attainment = 0.28, p = 0.13) or the CBS scores (SRM = –0.17, p = 0.38) among patients in the galantamine group (absolute differ- ence between groups 4.0, p = 0.02; SRM = 0.41). Higher goalattainment was seen among patients with moderate demen- Observed case analysis and analyses stratified
tia, and because more patients with moderate dementia were by severity
in the placebo group, the bias of the imbalance at baselinewas conservative (i.e., against demonstrating a galantamine In the observed case analysis, effect sizes favouring treatment effect). This finding was confirmed by the post hoc mixed- with galantamine were similar to those seen in the intention-to- effects model analysis (see the following section).
treat analysis (e.g., at week 16, clinician GAS SRM = 0.38, pa- The clinician- and patient-caregiver–based GAS assess- tient–caregiver GAS SRM = 0.22; ADAS-cog = –0.41; CIBIC-plus ments differed somewhat in terms of non-response. Thirty-one = –0.27; DAD = 0.19; CBS = –0.18). Because randomization re- baseline
CIBIC-plus
Fig. 3: Mean change in the ADAS-cog (cognitive subscale of the
Fig. 4: Mean CIBIC-plus (CIinician’s Interview-based Impres-
Alzheimer’s Disease Assessment Scale) scores, by treatment sion of Change plus Caregiver Input) scores, by treatment group. Error bars represent 95% confidence intervals. See Fig. 2 group. Error bars represent 95% confidence intervals. See Fig. 2 for description of GAL-GAL (black triangles) and PLA-GAL for description of GAL-GAL (black triangles) and PLA-GAL (white squares) data sets. (Missing data were imputed based (white squares) data sets. (Missing data were imputed based on the last observation carried forward, excluding baseline on the last observation carried forward, excluding baseline data; for the comparison between groups in the open-label data; for the comparison between groups in the open-label phase, only observations in the galantamine group during the phase, only observations in the galantamine group during the placebo-controlled phase were carried forward.) placebo-controlled phase were carried forward.) CMAJ • April 11, 2006 • 174(8) | 1103 and caregivers were less able to discern a difference during Table 2: Adverse events during the placebo-controlled phase of
the placebo-controlled phase, chiefly because they recognized the trial that occurred at least 5% more often in the improvement in both patient groups. The ADAS-cog and the galantamine group than in the placebo group CIBIC-plus scores showed appreciable effect sizes, which were also statistically significant.
Our data must be interpreted with caution. The study was small, with only 128 patients available for analysis, and the time spent in the placebo-controlled phase was short, al- though that phase was as long as we considered ethically permissible. Interpretation of missing data is problematic instudies of degenerative disorders. In dementia trials, carry- ing forward baseline scores of patients who drop out earlymeans that there is no opportunity to demonstrate decline that might occur after dropout. One remedy would be to carry forward the mean scores of the placebo group.27 In ourstudy, given the mean positive goal attainment in the placebo sulted in more patients with moderate Alzheimer’s disease be- group, it would have been more conservative to carry forward ing assigned to the placebo group than to the galantamine cases in which no goals were met. However, doing so group, we first stratified by severity of dementia. For both sets of showed no appreciable differences between patient groups GAS assessments, patients with moderate dementia had higher in either the SRMs or in the p values. Similarly, the differ- degrees of goal attainment than did patients with mild demen- ences between the clinician-based and patient- tia; for example, clinician-rated mean GAS scores were 53.9 and caregiver–based GAS assessments did not reflect that pa- 47.7 in the galantamine and placebo groups respectively among tients and caregivers had set more goals than clinicians or patients with moderate dementia, compared with 56.0 and 53.8 that only the goals set by the patients and caregivers were respectively among patients with mild dementia. Still, there was weighted. The bias of there being more patients with moder- no significant difference in the patient–caregiver-rated GAS ate dementia in the placebo group than in the galantamine scores by severity of dementia between groups.
group proved to be conservative, since patients with moder- The mixed-effects analyses confirmed that the treatment ef- ate dementia were more likely than those with mild dementia fects determined from the clinician-rated GAS scores and the to respond to treatment, and the primary analysis was con- CIBIC-plus scores remained significant at 16 weeks. After ad- firmed by the mixed-effects model. Because most sites used justment for dementia severity and dropout, the significance of the same physician to complete the clinician-based GAS as- findings that were significant in the unadjusted analyses was sessment and to evaluate side effects, physicians may have increased. The 4-month DAD score was at the threshold of sta- been unblinded by adverse events. However, the data suggest tistical significance (p = 0.051) in the mixed-effects analysis.
not: in the galantamine group, the mean clinician-rated GASscore was higher among patients who did not have gastroin- Adverse events
testinal side effects than among those who did (54.8 v. 50.6).
In the placebo group, the mean GAS score was likewise in- During the placebo-controlled phase, adverse events occurred distinguishable between those with and those without gas- in 54 (84%) of the 64 patients in the galantamine group and 41 trointestinal side effects (50.8 and 50.4 respectively). A re- (62%) of the 66 patients in the placebo group (Table 2). Serious view of cholinesterase inhibitors discounted clinical adverse events occurred in 5 and 10 patients respectively after 4 meaningfulness and suggested in particular that failure to months. During the open-label phase, 47 of 54 patients newly correct for multiple comparisons gave a falsely positive inter- receiving galantamine experienced adverse events; none re- pretation of drug effects.4 Here, even a correction as conser- ported serious adverse events. Of the patients who had already vative as Bonferroni would not undermine the statistical sig- been taking galantamine, 4 reported serious adverse events nificance of the main result — that is, the primary outcomes during the open-label phase. A possible, probable or very likely at the end of the placebo-controlled phase.
association with the drug treatment was inferred in 28% of the Because the clinician-based GAS assessment showed a adverse events that occurred in patients taking galantamine statistically significant difference between patient groups and in 15% of those in patients taking placebo. These rates are whereas the patient-caregiver–based GAS assessment did comparable to those in other galantamine trials.16 not, it may take a Rorschach test to determine whether thistrial argues for clinical meaningfulness of galantamine treat- Interpretation
ment. If so, here is what we see. The clinicians who com-pleted the GAS assessments were blinded to the CIBIC-plus In this trial involving patients with mild to moderate scores, which were based on patient–caregiver interviews.
Alzheimer’s disease, 4 months of treatment with galanta- This means that, in our study, 2 observers independently mine, compared with placebo, resulted in clinicians identify- judged that more patients taking galantamine than those tak- ing statistically significant levels of goal attainment through ing placebo demonstrated clinically meaningful responses.
GAS assessment. Using the same outcome measure, patients These data suggest that clinicians can reliably detect mean- CMAJ • April 11, 2006 • 174(8) | 1104 ingful treatment responses. We need to routinely use meth- 9. Leber PD. Developing safe and effective anti-dementia drugs. In Necker R, Gia- cobini E, editors. Alzheimer’s disease: from molecular biology to therapy. Boston: ods that help clinicians understand — and adjudicate — whether treatment meets the goals of patients and caregivers.
Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer’s disease. Am JPsychiatry 1984;141:1356-64.
Schneider LS, Olin JT, Doody RS, et al. Validity and reliability of the Alzheimer'sDisease Cooperative Study–Clinical Global Impression of Change. The Alz- This article has been peer reviewed.
heimer's Disease Cooperative Study. Alzheimer Dis Assoc Disord 1997;11(Suppl From the Division of Geriatric Medicine (Rockwood, Fay, Song, MacKnight, Rockwood K, Blass SE, Robillard A, et al. Potential treatment effects of donepezil Gorman), Dalhousie University, Halifax, NS, and St. Martha’s Regional Hos- not detected in Alzheimer’s disease in clinical trials: physicians survey. Int J Geriatr Rockwood K, Fay S, Graham JE, et al. Goal setting and attainment in Alzheimer’s Competing interests: None declared for Sherri Fay and Xiaowei Song. Ken-
disease patients treated with donepezil. J Neurol Neurosurg Psychiatry 2002;73: neth Rockwood has undertaken consultancies and received honoraria from Janssen Ortho, the study’s co-sponsor, and from Pfizer, Novartis and Merck, Kiresuk TJ, Sherman RE. Goal attainment scaling: a general method for evaluating and he was lead author of an earlier galantamine study. He owns no stock in community mental health programs. Community Ment Health J 1968;4:443-53.
pharmaceutical companies. He is part owner of DementiaGuide, which is de- McKhann G, Drachman D, Folstein M, et al. Clinical diagnosis of Alzheimer's dis- veloping a Web site to aid in goal setting for people with dementia. As princi- ease: report of the NINCDS-ADRDA Work Group under the auspices of Depart- pal investigator, he had full access to the data and had final responsibility for ment of Health and Human Services Task Force on Alzheimer's Disease. Neurol-ogy 1984;34:939-44.
the decision to submit the paper for publication. Chris MacKnight has re- Loy C, Schneider L. Galantamine for Alzheimer’s disease [Cochrane review].
ceived research grants from Janssen Ortho, Pfizer, Lundbeck and Novartis.
Cochrane Database Syst Rev 2004;(4):CD001747.
He has received no personal payments. Mary Gorman has received honoraria Folstein M, Folstein S, McHugh P. Mini-Mental State: a practice method for grad- and travel grants from Janssen Ortho, Pfizer and Merck.
ing the cognitive status of patients for the clinician. J Psychiatr Res 1975;12:189-98.
Standish TI, Molloy DW, Bedard M, et al. Improved reliability of the Standardised Contributors: Kenneth Rockwood (principal investigator) designed the study
Alzheimer’s disease Assessment Scale (SADAS) compared with the Alzheimer’s and wrote the grant application and clinical trial protocol. He supervised the disease Assessment Scale (ADAS). J Am Geriatr Soc 1996;44:712-6.
analyses and wrote the paper. Sherri Fay was project coordinator, assisted in Gélinas I, Gauthier L, McIntyre M, et al. Development of a fundamental measure the analyses and contributed to interim drafts. Xiaowei Song supervised the for persons with Alzheimer’s disease: the Disability Assessment for Dementia. Am statistical analyses. Chris MacKnight and Mary Gorman were site investiga- 20. Gerritsen JC, van der Ende PC. The development of a care-giving burden scale. Age tors and contributed to the grant application and interim drafts. All of the au- thors approved the final draft of the manuscript.
Blesa R. Galantamine: therapeutic effects beyond cognition. Dement Geriatr CognDisord 2001;11(Suppl 1):28-34.
Acknowledgements: Kenneth Rockwood and Chris MacKnight each receive
22. Dobbs AR, Rule EG. Prospective memory and self-reports of memory abilities in career support from the Canadian Institutes of Health Research through In- older adults. Can J Psychol 1987;41:209-22.
vestigator Awards. Kenneth Rockwood is also supported by the Dalhousie 23. Rockwood K, Stolee P, Howard K, et al. Use of Goal Attainment Scaling to meas- Medical Research Foundation as the Kathryn Allen Weldon Professor of ure treatment effects in an anti-dementia drug trial. Neuroepidemiology 1996;15: This peer-reviewed, investigator-initiated trial was jointly funded by 24. Cohen J. Statistical power analysis for the behavioral sciences. 2nd ed. Hillsdale (NJ): Lawrence Erlbaum Associates; 1988.
Janssen-Ortho Canada (80%) and the Canadian Institutes of Health Research 25. Kraemer HC, Thiemann S. How many subjects? Statistical power analysis in re- (20%) (grant no. DCT-49981). The sponsor provided all medications and search. Newbury Park (NJ): Sage; 1987.
matching placebos, conducted on-site monitoring and gathered and elec- 26. Liang MH, Fossel AH, Larson MG. Comparison of five health status instruments tronically coded the case report forms. All data are held by the principal in- for orthopedic evaluation. Med Care 1990;28:632-42.
vestigator (Kenneth Rockwood), who initiated and supervised all analyses.
27. Unnebrink K, Windeler J. Intention-to-treat: methods for dealing with missing val- Janssen-Ortho received the paper 45 days before submission to verify proto- ues in clinical trials of progressively deteriorating disease. Stat Med 2001;20:3931-46.
col details. At our request, their statisticians answered questions about theuse of the mixed effects model but had no other input in the analyses.
Correspondence to: Dr.Kenneth Rockwood, Division of Geriatric
Medicine, Dalhousie University, 1421–5955 Veterans’ Memorial
Lane, Halifax NS B3H 2E1; fax 902 473-1050;
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James Sommers, Capital District Health Authority, Halifax, NS CMAJ • April 11, 2006 • 174(8) | 1105

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