Abstract
Background: Galantamine is a reversible, competitive cholinesterase inhibitor that also allosterically modulates nicotinic acetylcholine receptors. These mechanisms of action provided the rationale for a therapeutic trial of galantamine in AD.
Methods: A 6-month, multicenter, double-blind trial was undertaken in 636 patients with mild to moderate AD. Patients were randomly assigned to placebo or galantamine and escalated to maintenance doses of 24 or 32 mg/d. Eligible patients then entered a 6-month, open-label study of the 24 mg/d dose. Primary efficacy measures were the 11-item AD Assessment Scale cognitive subscale (ADAS-cog/11) and the Clinician’s Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus). The Disability Assessment for Dementia (DAD) scale was a secondary efficacy variable.
Results: Galantamine significantly improved cognitive function relative to placebo; the treatment effects were 3.9 points (lower dose) and 3.8 points (higher dose) on the ADAS-cog/11 scale at month 6 (p < 0.001 in both cases). Both doses of galantamine produced a better outcome on CIBIC-plus than placebo (p < 0.05). Therapeutic response to galantamine was not affected by APOE genotype. At 12 months, mean ADAS-cog/11 and DAD scores had not significantly changed from baseline for patients who received galantamine 24 mg/d throughout the 12 months. The most common adverse events, which were predominantly gastrointestinal, decreased in frequency during long-term treatment. There was no evidence of hepatotoxicity.
Conclusions: Galantamine is effective and safe in AD. At 6 months, galantamine significantly improved cognition and global function. Moreover, cognitive and daily function were maintained for 12 months with the 24 mg/d dose.
Impairment of cholinergic function in AD contributes to the cognitive deficits that are characteristic of the illness.1 A deficit of central presynaptic cholinergic function has been demonstrated in AD, as indicated by decreased activity of choline acetyltransferase in the hippocampus and neocortex,2 and by degeneration of cholinergic neurons in the basal forebrain.3,4 These findings provide the rationale for cholinergic enhancement as an approach to improving cognitive function in AD.5 Acetylcholinesterase (AChE) inhibitors represent one way of implementing this strategy. They inhibit the enzyme that hydrolyzes acetylcholine (ACh), thereby increasing its availability for synaptic transmission. AChE inhibitors are the only class of drugs that have consistently produced improvements in cognitive function relative to placebo, in studies of up to 6 months’ duration.6 However, their long-term efficacy has been questioned.7
Combining cholinergic pharmacologic mechanisms has been proposed as a strategy for enhancing clinical benefit in patients with AD.5 Galantamine is a novel agent that reversibly and competitively inhibits AChE8,9 and allosterically modulates nicotinic ACh receptors.10,11 Galantamine’s modulatory effect on nicotinic receptors potentiates the response of these receptors to ACh.11 This enhancement of cholinergic nicotinic neurotransmission may be of clinical relevance because activation of presynaptic nicotinic receptors increases the release of ACh.12-14
We evaluated the efficacy and safety of two doses of galantamine compared with placebo over 6 months in patients with mild to moderate AD. Following this double-blind phase, the long-term effects of galantamine were monitored in patients eligible for an open-label extension phase of an additional 6 months.
Methods.
Patients.
Inclusion criteria were 1) a history of cognitive decline that had been gradual in onset and progressive over a period of at least 6 months; 2) a diagnosis of probable AD according to the criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer Disease and Related Disorders Association (NINCDS-ADRDA);15 and 3) presence of mild to moderate dementia: a Mini-Mental State Examination (MMSE)16 score of 11 to 24 and a score of ≥12 on the standard cognitive subscale of the AD Assessment Scale (ADAS-cog).17
Patients with stable and well-controlled concomitant medical disorders such as hypertension, heart failure (New York Heart Association class I or II), noninsulin-dependent diabetes mellitus, and hypothyroidism were included. Patients were excluded if they had evidence of any neurodegenerative disorders other than AD, cardiovascular disease thought likely to prevent completion of the study, clinically significant cerebrovascular disease, active major psychiatric disorders, hepatic, renal, pulmonary, metabolic or endocrine conditions or urinary outflow obstruction, an active peptic ulcer, or any history of epilepsy, drug abuse, or alcohol abuse.
Patients who had been treated for AD with a cholinesterase inhibitor in the preceding 3 months were also excluded. Any other antidementia medication had to be discontinued before entry to the study. The use of drugs for concomitant conditions was permitted during the study, except sedative—hypnotics and sedating cough and cold remedies, which were discontinued, if possible, 48 hours before cognitive evaluation. Any other drugs with anticholinergic or cholinomimetic effects were avoided where possible. Patients were eligible to enter the extension phase of the study if they had completed the first phase and still did not meet the initial exclusion criteria.
All eligible patients had a responsible caregiver, who, together with the patient (or appropriate representative), provided written informed consent to participate in the study. The study was conducted according to the Declaration of Helsinki and subsequent revisions, and approved by institutional review boards at each center or centrally.
Design.
The initial phase of the study was a 6-month, parallel-group, placebo-controlled, double-blind trial undertaken at 33 sites in the United States. Following a 4-week, single-blind placebo run-in period, patients were randomly assigned (using a computer-generated code) to one of two oral galantamine treatment groups or placebo. Both the active treatment groups received galantamine 8 mg/d for the first week, followed by 16 mg/d in the second and 24 mg/d in the third week. In the fourth week, one group continued to receive the 24 mg/d dose; in the other, the dose was increased to 32 mg/d. Patients then continued with their target dose of galantamine or placebo for an additional 5 months. Galantamine and placebo were administered as identical single tablets taken twice daily.
All patients who entered the extension phase received open-label galantamine 8 mg/d in week 1, 16 mg/d in week 2, and then 24 mg/d for 5.5 months. At all doses, galantamine was administered as single tablets taken twice daily. Restrictions on the use of concomitant medications during the extension study were the same as during the double-blind phase. Throughout the 12 months, investigators remained blinded to the treatment to which patients had been randomly assigned at the start of the double-blind phase.
Outcome measures.
Efficacy.
The primary efficacy measures were the standard 11-item ADAS-cog subscale (ADAS-cog/11), with a score range of 0 to 70,17 and the Clinician’s Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus).18 The CIBIC-plus was scored by a trained clinician based on separate interviews with the patient and the caregiver. Scores ranged from 1 (markedly improved compared with baseline) to 7 (markedly worse).
Secondary efficacy variables included the expanded (13-item) version of the standard ADAS-cog subscale (ADAS-cog/13) with a score range of 0 to 8519 and the proportions of “responders,” defined as improvement in ADAS-cog/11 of ≥4 points compared with baseline.20 Activities of daily living (ADL) were assessed with the Disability Assessment for Dementia (DAD) scale, which is based on interviews with the caregiver and assesses basic ADL, instrumental ADL, leisure activities, initiation, planning and organization, and effective performance; there are 46 questions, with a score range of 0 to 100.21
Assessments were performed at baseline, at 3 weeks (ADAS-cog only), and then at 3 and 6 months in the double-blind phase of the study. The ADAS-cog/11, CIBIC-plus, and DAD assessments were performed after 3 and 6 months in the extension phase. All efficacy variables were analyzed as a change from baseline (baseline referred to the first visit in the 6-month double-blind phase), except for CIBIC-plus at 12 months, which was analyzed as a change from the initial visit of the open-label phase.
Safety.
Safety evaluations conducted throughout the study comprised physical examinations, EKG, vital sign measurements, and standard laboratory tests (blood chemistry, hematology, urinalysis). Monitoring for adverse events (classified according to World Health Organization Preferred Terms) were recorded weekly for the first month of both the double-blind and open-label phases of the study, and at monthly intervals thereafter.
APOE genotyping.
A blood sample was taken at baseline to assess whether APOE genotypes affected response to galantamine. DNA was purified from whole blood samples according to standard protocols, and APOE genotyping was performed as previously described by Wenham et al.22
Statistical analysis.
Data from an early phase II trial on galantamine (data on file, Janssen Research Foundation) indicated that about 125 patients were needed in each treatment group of the double-blind phase to achieve 80% power (α = 0.025 with a Bonferroni adjustment) to detect a difference of 2.75 points in the change in ADAS-cog/11 score between placebo and galantamine.
All randomly assigned patients who took at least one dose of trial medication were included in the analyses of baseline characteristics and safety data. The primary analysis of 6-month efficacy data were based on patients who also provided postbaseline data for any of the ADAS-cog/11, CIBIC-plus, or DAD variables at designated assessment times—a traditional “observed cases” (OC) analysis. Furthermore, to confirm the robustness of the efficacy results, a more conservative 6-month intention-to-treat (ITT) analysis was performed using the last-observation-carried-forward (LOCF) method (i.e., the last postbaseline observation available for each randomly assigned patient who received treatment). For the extension study, OC and ITT analyses were performed. All results discussed are based on OC analysis unless otherwise stated.
Baseline characteristics of the different treatment groups were compared using two-way analysis of variance (ANOVA) for continuous variables, and the generalized Cochran-Mantel-Haenszel test for categorical variables. Changes in outcome variables, vital signs and body weight from baseline were assessed using two-tailed, paired t-tests. Comparisons of variables between each galantamine group and the placebo group were made with the ANOVA model, including treatment and investigator as factors, and pairwise Dunnett’s tests for changes from baseline in ADAS-cog subscales and DAD during the double-blind phase. An analysis of covariance (ANCOVA) model was also used in the analysis of change from baseline score, with baseline ADAS-cog value as a covariate. The ANCOVA and ANOVA models produced similar conclusions; therefore, results based on the ANOVA model are reported in this paper. Treatment by investigator interaction was tested and removed from the model as it was not significant at the 5% level. Generalized Cochran—Mantel—Haenszel tests were used to compare ADAS-cog/11 response rates and Van Elteren tests23 for CIBIC-plus. ANOVA with pairwise Fisher’s least-significant-difference tests were used to compare changes from baseline in vital signs, body weight in the double-blind phase, and ADAS-cog subscales and DAD during the extension phase. The time—response relationship for change in ADAS-cog/11 was analyzed using generalized linear interactive modelling, and exploratory ANOVA was used to investigate any relationship between baseline characteristics, including APOE genotype and changes in ADAS-cog/11. The statistical software used in these analyses was SAS Version 6.12 (SAS Institute, Cary, NC).
Results.
Figure 1 illustrates the trial profile. Of the 764 patients screened for the initial phase, 636 were randomly assigned to trial medication, of whom 438 (69%) completed the double-blind phase. Of these 438 subjects, 353 entered the open-label extension, of whom 268 (76%) completed the study. The baseline demographic and medical characteristics of the three treatment groups were comparable (table 1). The only significant difference between the groups at baseline was the time since diagnosis of probable AD (p = 0.02), although the magnitude of this difference is unlikely to be clinically meaningful.
Figure 1. Trial profile.
Baseline characteristics
During the double-blind phase, the proportions of patients taking concomitant psychotropic medications, or taking them within 48 hours of the 6-month cognitive assessment, were similar in each group. On entry to the extension phase of the study, the baseline characteristics of the patients in each treatment group remained comparable.
As protocol deviations occurred in only 62 (10%) of randomly assigned patients (41 of whom used prohibited medication) and were comparable across the treatment groups, no per-protocol analyses were performed for the double-blind phase. Similarly, no per-protocol analyses were performed in the extension phase due to a low rate (12%) of protocol deviations.
Primary efficacy variables.
At 6 months, OC analysis demonstrated a significant difference in the change in ADAS-cog/11 scores between galantamine- and placebo-treated patients (table 2). The differences in favor of galantamine were 3.9 points for the 24 mg/d and 3.8 points for the 32 mg/d groups (p < 0.001 in both cases). These differences were confirmed using the more conservative ITT analyses (p < 0.001 for both doses versus placebo) (see table 2). The differences in change in ADAS-cog/11 scores between galantamine and placebo groups increased over time for both doses (p < 0.001).
Primary efficacy outcomes after 6 months
Improvements in cognitive function over baseline (ADAS-cog/11) appeared within 1 week of reaching a galantamine dose of 24 mg/d and increased after 3 months of treatment (p < 0.001 for both galantamine groups versus baseline at both time points). By 6 months, cognitive function improved from baseline by a mean of 1.7 points in the 24 mg/d group (p < 0.001) and by 1.6 points in the 32 mg/d group (p = 0.02). This improvement from baseline with both galantamine doses was confirmed by the ITT analyses (p < 0.01). In contrast, cognitive function declined in the placebo group by a mean of 2.2 points (p < 0.001) (see table 2). Patients’ APOE-ε4 genotype did not appear to influence the effect of galantamine on ADAS-cog/11 score (table 3).
Change in ADAS-cog/11 score at 6 months by APOE genotype
After 12 months of therapy, mean ADAS-cog/11 scores indicated that cognitive function had been maintained relative to baseline in those patients who received galantamine 24 mg/d throughout that period (confirmed by the ITT analysis) (figure 2). Furthermore, this group of patients had a better outcome on ADAS-cog/11 (as measured by change from baseline in ADAS-cog/11 score) than patients who had received placebo for the first 6 months (p = 0.03; confirmed by ITT analysis). In those patients who switched from the higher to the lower galantamine dose for the extension phase of the study, there was a small deterioration in the ADAS-cog/11 score relative to baseline (mean [SEM], 1.8 [0.86] points; p = 0.04) (see figure 2).
Figure 2. Mean change from baseline in 11-item AD Assessment Scale cognitive subscale (ADAS-cog/11) scores over 12 months (observed cases analysis). ▪ = Galantamine 24 mg/galantamine 24 mg; ▴ = galantamine 32 mg/galantamine 24 mg; ⧫ = placebo/galantamine 24 mg.
Using the CIBIC-plus as a measure of overall clinical response to therapy, 70% of patients on galantamine 24 mg/d and 68% of those on 32 mg/d remained stable or improved over 6 months, compared with only 55% of those in the placebo group (see table 2). Both doses of galantamine produced a better outcome on CIBIC-plus ratings than placebo at 3 and 6 months, which was confirmed by the ITT analyses (p < 0.05 for all comparisons). During the 6 months of the extension phase, the proportions of patients who had remained stable or improved, according to CIBIC-plus, were comparable across the three treatment groups (54% to 61%).
Secondary efficacy variables.
In the double-blind phase, there were approximately twice as many ADAS-cog/11 responders in the galantamine-treated groups (33.3% and 33.6%) as in placebo-treated group (16.6%, p < 0.01 for both comparisons). Galantamine also produced a better outcome on ADAS-cog/13 compared with placebo at 6 months; the treatment effect was 4.5 points for the lower dose and 4.1 points for the higher dose (p < 0.001 for both comparisons). Galantamine’s advantages over placebo on these secondary outcome measures was confirmed on ITT analyses (p < 0.01 for all comparisons on both efficacy measures).
After 6 months of treatment, there were no significant differences between treatment groups in the mean change in total DAD score from baseline. At the end of the extension phase, the change in total DAD score from baseline in patients who had received galantamine 24 mg/d for 12 months was not significant (mean [SEM] decrease of 1.7 [1.78]). DAD cluster scores revealed that both instrumental and basic ADL had been maintained at baseline levels in this group of patients. In contrast, the total DAD score at 12 months in the group of patients who received placebo during the double-blind phase decreased relative to baseline (8.1 [1.94]; p < 0.001 versus baseline). The mean [SEM] decrease in total DAD score at 12 months in those patients who had received galantamine 32 mg/d during the double-blind phase was 6.2 (1.71) (p < 0.001 versus baseline). All of these findings were confirmed with the ITT analyses.
Safety.
Adverse events occurring at least 5% more often in either galantamine group than in the placebo group during the double-blind phase are listed in table 4. The majority of adverse events were mild to moderate in severity and predominantly gastrointestinal. Nausea was the most commonly reported event with galantamine. Reports of muscle weakness on galantamine were rare and no more common than that reported with placebo. The proportions of serious adverse events were comparable across treatment groups during the double-blind phase (13% to 16%); these included one death in each group, neither of which was considered related to the study drug by the investigator. During the extension phase, the incidence of treatment-emergent adverse events was low in patients who had received galantamine during the double-blind phase (see table 4). Furthermore, no unexpected, time-dependent, adverse events were reported during the extension phase.
Treatment-emergent adverse events during the double-blind and extension phases
Discontinuations due to adverse events during the double-blind phase were more common in galantamine-treated patients than in those receiving placebo (23% in the 24 mg/d group and 32% in the 32 mg/d group versus 8% with placebo) (see figure 1); 42% (49/116) of galantamine discontinuations due to adverse events occurred during dose escalation, compared with 13% (2/16) in the placebo group. Only 16% of patients withdrew from the extension phase due to adverse events.
There were no clinically significant differences between treatment groups in blood chemistry, hematology, urinalysis, pulse rate, blood pressure, or EKG variables during the double-blind phase. At 6 months, mean body weight had decreased by 2.1 to 2.5 kg in galantamine-treated patients, compared with a slight increase (0.1 kg) in the placebo group (p < 0.001). However, weight loss of 10% or more occurred mostly in patients with moderate to high baseline weights (>50 kg for women and >70 kg for men). Furthermore, the weight loss recovered somewhat during the extension phase with a mean weight loss compared with baseline of only 1.5 kg after 12 months in galantamine-treated patients.
Discussion.
The present trial shows that at 6 months, galantamine significantly improved cognitive and global function relative to placebo, and at 12 months cognitive performance and daily functioning were maintained. Over the 12-month study period, galantamine was safe with only a minority of patients discontinuing treatment due to adverse events.
The double-blind phase of the study indicated that galantamine therapy significantly improved cognition compared with placebo, by about 4 points on the standard ADAS-cog/11 subscale. Furthermore, the treatment effect of galantamine relative to placebo increased over the 6-month double-blind period. The data from the ADAS-cog/13 scale and the analysis of responder rates confirmed the benefits of galantamine on cognitive function. At 6 months, the improvement from baseline on ADAS-cog/11 was significant for both doses of galantamine, indicating a sustained improvement in cognitive function during this period. The cognitive decline at 6 months in the placebo group (2.2 points on the ADAS-cog/11 subscale) was comparable with that generally found in placebo groups in other studies.24-30 There were no clinically significant differences between the 24 mg/d and 32 mg/d doses of galantamine on ADAS-cog/11 or CIBIC-plus, suggesting no additional benefit from the higher dose.
The efficacy of galantamine in this study, as assessed by change in ADAS-cog/11, did not appear to be affected by patients’ APOE genotype. This result is in contrast to reports of reduced efficacy of tacrine in AD subjects expressing the APOE-ε4 allele compared with those not expressing it.31,32 However, a recent analysis of pooled data from metrifonate studies also suggests that APOE genotype does not predict response to treatment.33 Further investigation of the effects of APOE genotype on therapeutic response to other cholinergic treatments would help clarify these divergent findings.
Long-term, placebo-controlled studies are the ideal way to assess the duration of benefit of treatments in AD. However, such studies are difficult to conduct because of ethical reasons and high drop-out rates. An alternative, but less robust, method is to conduct an open-label extension study.34,35 Data from patients on extended treatment can be compared with either data from untreated patient cohorts or with data extrapolated from the placebo group that participated in the double-blind phase of the study. At 12 months, the group of patients treated with galantamine 24 mg/d had a mean ADAS-cog/11 score that was not significantly different from baseline. The average annual decline in ADAS-cog/11 for untreated AD patients is about 8 points, but the rate of change is less for patients with mild AD.36 In the present study, linear extrapolation of the change in ADAS-cog/11 in the placebo group at 6 months (2.2 points) suggests a 1 year decline in the placebo group of some 4 to 5 points. These data indicate that galantamine produces clinically significant benefits for at least 12 months.
The group of patients who were switched from galantamine 32 mg/d to 24 mg/d at 6 months demonstrated less benefit in cognitive function than those receiving 24 mg/d for 12 months. Although the reason for this difference in benefit is not clear, it may be that the reduction in dose (from 32 to 24 mg/d) was associated with a rebound effect that led to some loss of efficacy. Patients who received galantamine 24 mg/d for 12 months did significantly better on ADAS-cog/11 than patients who received this dose following 6 months of placebo. This may indicate a beneficial effect of early therapy with galantamine.
Although the double-blind phase did not demonstrate a statistically significant benefit of galantamine on ADL, at the end of the open-label phase there was a strong indication of galantamine’s favorable effects on patients’ ADL. In the group who received galantamine 24 mg/d for 12 months, daily functioning was preserved, as indicated by a total DAD score that was not significantly different from baseline. This benefit was observed for both basic and instrumental ADL. Functional decline in AD is progressive and, once lost, the ability to perform daily activities is rarely recovered.37 Moreover, functional disability is an important determinant of caregiver distress and use of healthcare resources.38 A treatment that preserves patients’ functional abilities would be expected to reduce the burden on caregivers and therefore may delay institutionalization.
The proportion of all discontinuations due to adverse events occurring during the dose-escalation phase was greater with galantamine than with placebo. In clinical practice, slow dose escalation may improve compliance with cholinergic agents by minimizing side effects.39 In a recent 5-month placebo-controlled study, in which the galantamine dose was slowly escalated over an 8-week period to 24 mg/d, only 10% of patients discontinued treatment due to adverse events, which was comparable with the discontinuation rate in the placebo group (7%).40
The adverse events reported more commonly in patients receiving galantamine were those expected from cholinergic stimulation. They are generally consistent with those reported in 6 month AD trials of other cholinergic drugs.24-30 The most common adverse effects of galantamine were gastrointestinal, particularly nausea. However, slowly escalating the galantamine dose, or using a lower dose, has been shown to substantially reduce the frequency of gastrointestinal side effects such as nausea.40 Reports of muscle weakness on galantamine were rare and no more common than with placebo. Furthermore, the incidence of clinically significant abnormalities on liver function tests for patients treated with galantamine did not differ from patients treated with placebo.
The tolerability of galantamine improved with duration of treatment, and no unexpected adverse events were seen in patients who received 12 months of treatment. These 12-month data, together with its effects on cognitive and daily function, suggest that galantamine produces long-term benefits in the treatment of AD.
Disclosures. This report includes data generated by protocols GAL-USA-1 and GAL-USA-3, sponsored by Janssen Research Foundation. M.A.R. and E.R.P. received compensation from the Janssen Research Foundation for consulting activities. T.W. and W.Y. are employees of the Janssen Research Foundation.
Appendix
The Principal Investigators for the Galantamine USA-1 Study Group were F.H. Allen Jr, MD (Carolina Neurologic Clinic, Charlotte, NC); S.M. Aronson, MD (Oakwood Hospital and Medical Center, Dearborn, MI); B. Baumel, MD, and L. Eisner, MD (Baumel-Eisner Neuromedical Institute, Miami Beach and Fort Lauderdale, FL); R. Brenner, MD, and S. Madhusoodanah, MD (St. John’s Episcopal Hospital, Far Rockaway, NY); S. Cheren, MD, and S. Verma, MD (The ICPS Group, Boston, MA); D.G. Daniel, MD (Washington Clinical Research Center, Falls Church, VA); M. DePriest, MD, and J.M. Ferguson, MD (Pharmacology Research Corporation, Salt Lake City, UT); D. England, MD (Oregon Research Group, Eugene, OR); M.V. Farmer, MD (Clinical Studies, St. Petersburg, FL); J. Frey, MD and S.S. Flitman, MD (Neurology Group, Ltd., Phoenix, AZ); L.E. Harrell, MD, PhD (University of Alabama at Birmingham); R. Holub, MD (Neurologic Associates of Albany, NY); A. Jacobson, PhD, G.F Olivera, MD, and R.L. Ownby, MD, PhD (The MRI Center, Port Charlotte, FL); L.R. Jenkyn, MD (Dartmouth-Hitchcock Medical Center, Lebanon, NH); R. Landbloom, MD (St. Paul-Ramsey Medical Center, Saint Paul, MN); M.T. Leibowitz, MD, and P.P. Zolnouni, MD (California Clinical Trials Medical Group, Beverly Hills); C. Lyketosos, MD (Johns Hopkins Hospital, Baltimore, MD); J.E. Mintzer, MD (Medical University of South Carolina, Charleston); R. Nakra, MD (Washington University School of Medicine, St. Louis, MO); J.J. Pahl, MD (Pahl Brain Associates, Oklahoma City, OK); S.G. Potkin, MD (Irving Medical Center, Orange, CA); M.A. Raskind, MD, and E.R. Peskind, MD (Veteran Affairs Puget Sound Health Care System and the Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle); B.C. Richardson, MD (East Bay Neurology, Berkeley, CA); R.W. Richter, MD (Clinical Pharmaceutical Trials, Inc., Tulsa, OK); M.M. Rymer, MD (Center Clinical Neurologic Studies, Kansas City, MO); D.P. Saur, MD (Overlook Hospital, Summit, NJ); K.R. Daffner, MD, and L. Scinto, PhD (Brigham and Women’s Hospital, Boston, MA); J. Stoukides, MD (Clinical Studies, Providence, East Providence, RI); S.D. Targum, MD (Memory Institute, Philadelphia, PA); S.G. Thein Jr, PhD, and S.G. Thein, MD (Pacific Research Network, San Diego, CA); and J.R. Tomlinson, MD (Grayline Clinical Drug Trials, Wichita Falls, TX).
Acknowledgments
Supported by funding from the Janssen Research Foundation.
Acknowledgment
The authors acknowledge the study investigators and staff at each center as well as the participating patients and caregivers. They also acknowledge Kathleen Iveson, for her help with trial coordination.
Footnotes
- Received December 3, 1999.
- Accepted in final form February 29, 2000.
References
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