Abstract
Background: Laboratory and epidemiologic studies suggest that anti-inflammatory/immunosuppressive therapy may be useful in the treatment of AD. In preliminary studies, a regimen of low to moderate dose prednisone was found to suppress peripheral inflammatory markers without adverse effects in subjects with AD.
Methods: We conducted a randomized, placebo-controlled multicenter trial to determine whether prednisone treatment slowed the rate of cognitive decline in AD. The active treatment regimen consisted of an initial dose of 20 mg of prednisone daily for 4 weeks tapered to a maintenance dose of 10 mg daily for 1 year, followed by gradual withdrawal during an additional 16 weeks. The primary outcome measure was the 1-year change in the cognitive subscale of the AD Assessment Scale.
Results: A total of 138 subjects were randomized to the drug and placebo groups. There was no difference in cognitive decline between the prednisone and placebo treatment groups in the primary intent-to-treat analysis, or in a secondary analysis considering completers only. Subjects treated with prednisone showed behavioral decline compared with those in the placebo group.
Conclusion: A low-dose regimen of prednisone is not useful in the treatment of AD.
Inflammatory processes, including an acute phase response, complement activation, and the accumulation of activated microglia, accompany the amyloid deposition and neurofibrillary tangle formation that are the neuropathologic changes of AD.1,2 In a variety of experimental systems that model aspects of AD, inflammation contributes to neuronal damage, and anti-inflammatory medications have been shown to offer some neuroprotection.3 Many epidemiologic studies support the hypothesis that anti-inflammatory drugs decrease the incidence of AD.4 Recent evidence that human leukocyte antigen (HLA) genotype influences AD,5 perhaps via modulation of glial activity,6 is also consistent with an inflammatory mechanism contributing to the disease process.
Among the classes of anti-inflammatory drugs, glucocorticoids offer the broadest anti-inflammatory/immunosuppressive potential. This class of drugs is the most effective in suppressing the activity of autoimmune inflammatory diseases such as systemic lupus erythematosus that involve mechanisms implicated in AD. Because the clinical significance of the various inflammatory processes associated with AD is unknown, this broad activity favored the use of glucocorticoids in initial AD anti-inflammatory drug trials over nonsteroidal anti-inflammatory drugs (NSAIDs) with more restricted pharmacologic effects. However, systemic toxicity is a major concern with the long-term use of high-dose glucocorticoids. There is also substantial evidence in rodents, and some in humans, that excess glucocorticoid exposure may be associated with hippocampal toxicity,7,8 although recent evidence calls this theory into question.9 The relative benefits and risks of exogenous glucocorticoids in the treatment of human disease are determined by the specific disease, and the dose and duration of treatment.
Before initiating a multicenter treatment trial of prednisone, open-label pilot studies of treatment with the synthetic glucocorticoid prednisone in subjects with AD were conducted.10 In these studies, low-dose prednisone treatment over a period of weeks suppressed peripheral markers of the acute phase response and complement activation in AD, without significant systemic or neuropsychiatric toxicity. Using a treatment regimen based on the results of these studies, a multicenter placebo-controlled randomized study was initiated to determine whether moderate-dose prednisone treatment slowed the rate of cognitive decline in AD.
Methods.
Study design.
The study utilized a randomized, double-blind, two-group parallel design comparing prednisone treatment with placebo.
Subjects with probable AD11 were eligible if they did not have comorbid conditions that increased the risk of adverse events associated with prednisone treatment and were likely to remain testable for 1 year with our primary cognitive assessment tool. Inclusion criteria also included age greater than 50 years and Mini-Mental State Examination (MMSE)12 score within the range of 13 to 26. Subjects were excluded if they had comorbid conditions that might respond to prednisone (rheumatoid arthritis, asthma) or be aggravated by the drug (positive purified protein derivative [PPD] skin test, compression fractures on spine films, recent peptic ulcer disease, diabetes mellitus). Subjects were also excluded if within the prior 2 months they had regularly used anti-inflammatory medications (aspirin at a daily dose of 325 mg or less was allowed), neuroleptics, antidepressants, sedatives, anti-parkinsonian medications, tacrine, or any investigational treatment for AD.
In the pilot studies, prednisone 20 mg daily suppressed serum levels of α-1 antichymotrypsin (ACT); levels remained suppressed as the dose was reduced to 10 mg.10 Considering these results, along with the clinical experience that long-term treatment with prednisone doses of about 10 mg daily for rheumatologic diseases is well-tolerated in elderly subjects, we selected the following treatment protocol: an initial dose of prednisone 20 mg daily for 4 weeks, tapered to a maintenance dose of 10 mg daily for 1 year, followed by gradual taper over an additional 16 weeks of observation. Subjects randomized to the placebo group received inactive tablets identical in appearance to the prednisone tablets.
Safety assessments were performed every 2 weeks during the first 8 weeks, and at 12 weeks following the baseline visit. After the 12-week visit, safety assessments were conducted at 8-week intervals until the end of 1 year, and at 4-week intervals during the taper period.
Screening, week 12, and week 52 evaluations included x-rays of the spine and ophthalmologic examinations; bone densitometry was performed at screening and at week 52. Cognitive and behavioral assessments were performed at baseline and at weeks 4, 8, 28, 52, and 68.
Outcome measures.
The primary outcome measure for this trial was the 1-year change score on the cognitive subscale of the AD Assessment Scale (ADAS-cog).13 We considered a significant glucocorticoid benefit to be a 50% reduction in ADAS-cog change score compared with placebo. Using longitudinal ADAS-cog data from an earlier multicenter trial,14 we estimated that 60 subjects were required in each treatment group (prednisone and matching placebo) for a power of 0.8. A drop-out rate of 20% was anticipated.
Secondary outcome measures included the Clinical Dementia Rating sum of boxes (CDR-SOB),15 the Blessed Dementia Rating Scale (BDRS),16 the Hamilton Depression Rating Scale (Ham-D),17 and the Brief Psychiatric Rating Scale (BPRS).18 Blood chemistries and urinalysis were obtained at each study visit.
Statistical analysis.
The primary analysis was a comparison of the ADAS-cog between the prednisone and placebo groups using analysis of covariance (ANCOVA), with the baseline ADAS-cog score as a covariate. We planned to assess the treatment groups for considerable imbalance in age that might influence outcome; if such imbalance was present (p < 0.15), and this factor influenced ADAS-cog change scores (p < 0.1), age would be included in the ANCOVA model.
The primary analysis was conducted on an intent-to-treat (ITT) basis. Because AD is a disease of progressive cognitive deterioration, our protocol specified an alternative imputation scheme rather than conventional last observation carried forward (LOCF) analysis (which would overestimate a treatment effect if excess dropouts due to adverse effects occurred in the active drug group). To impute a subject’s missing week 52 score, an estimate of change over the unobserved period based on all individuals with complete data from the subject’s treatment group was applied to the subject’s last observed score. A linear rate of progression was not assumed. We also conducted secondary analyses of ADAS-cog changes using LOCF imputation, and in a completers analysis, analyzed subjects who completed the week 52 visit.
ITT analysis of secondary measures utilized the imputation scheme described above for missing week 52 values of the CDR and the BDRS. However, LOCF was used for missing week 52 values for the Ham-D and the BPRS, as change in these behavioral measures with disease progression is less predictable.
No interim analysis was performed.
Assignment and masking.
Twenty-two sites participated in this trial after obtaining approval from their local Institutional Review Boards. Prednisone (10 mg and 2.5 mg tablets; Deltasone, Pharmacia & Upjohn, Inc., Kalamazoo, MI) and matching placebo tablets were assembled into identical containers with coded labels. Codes were randomized at the packaging center; the randomization scheme was approved by the Alzheimer’s Disease Cooperative Study (ADCS) statistical core. Randomization was stratified by site and utilized a block size of eight. “Scratch-off” codebreakers were used so that instances of unblinding would be documented; all codebreakers were collected at the end of the trial.
Randomization codes were broken in two instances. In each case, the code was broken by investigators at local sites to determine whether stress-dose glucocorticoid treatment was necessary for subjects who required surgical procedures. Study personnel involved in administering assessment tools were shielded from group assignment data in these two instances.
Adequacy of masking was assessed by questionnaires completed by subjects, caregivers, psychometrists, and site investigators.
Results.
Participant flow and follow-up.
The flow of subjects through the study protocol is shown in the figure. From a total of 190 subjects screened, 138 met the study criteria and were randomized to receive prednisone or placebo. The most common reasons for ineligibility were vertebral compression fractures and hyperglycemia.
Figure. Progress of patients through the trial.
The primary outcome measure (ADAS-cog at week 52) was obtained for 50/69 subjects in the prednisone group, and 58/69 in the placebo group. The predominant reasons for early discontinuation of study medication were caregiver issues and perceived lack of efficacy. No subjects discontinued medication because of serious adverse events attributed to the treatment.
Six subjects in the prednisone group and five in the placebo group started treatment with cholinesterase inhibitors before the week 52 visit. These subjects were included in the ITT analyses. There were 36 subject using low dose aspirin regularly for at least 3 months, 22 in the prednisone group and 14 in the placebo group; aspirin use did not influence change in ADAS-cog in the ITT analysis (p = 0.75).
The results of questionnaires indicated that the percentage of subjects and site investigators who correctly guessed treatment assignment did not differ from chance; there was a trend toward correct guessing of treatment assignment by caregivers (57% correct, p = 0.07).
Analysis.
The demographic and clinical characteristics of the two treatment groups at baseline are shown in table 1. There were no significant differences between the groups on any of the demographic or baseline characteristics.
Demographics and assessment scores at baseline
ITT analyses.
The effect of treatment on the primary and secondary measures in the ITT analysis is shown in table 2. There was no significant difference between the treatment groups on the primary measure, the change in ADAS-cog. When LOCF imputation of the ADAS-cog was substituted for the primary imputation scheme, the result was similar (prednisone group: mean ADAS-cog change = 6.8 ± 7.8; placebo group: mean ADAS-cog change = 5.9 ± 6.9, p = 0.54).
One-year change in assessment scores, intent-to-treat analysis
Among the secondary measures, a significant difference between treatment groups was noted in the BPRS, at weeks 28 and 52, with greater behavioral decline in the prednisone group. Analysis of BPRS factor subscores19 indicated that the prednisone group showed greater increase in agitation and hostility/suspicious factors.
There was a trend toward greater decline (i.e., increase in score) on the CDR-SOB in the prednisone group (prednisone group: mean CDR-SOB change = 2.9 ± 1.8; placebo group: mean CDR-SOB change = 2.2 ± 2.5, p = 0.07). Post-hoc analysis of mean 1 year change in CDR items indicated that subjects in the prednisone group showed greater decline in memory (0.5 ± 0.7 versus 0.3 ± 0.4, p = 0.03), and a trend toward greater decline in orientation (0.5 ± 0.6 versus 0.3 ± 0.5, p = 0.06).
Completers analysis.
Analysis of subjects who completed the 52-week visit on study medication yielded similar results. A small difference between groups in mean ADAS-cog change was not significant (prednisone group: 8.3 ± 8.5; placebo group: 6.9 ± 6.9, p = 0.39). The completers analysis showed no difference between groups on the CDR-SOB change score (prednisone group: 2.7 ± 0.4; placebo group: 2.4 ± 0.3, p = 0.69). There was no significant difference between groups in mean change on the Ham-D (1.6 ± 4.6 versus 1.0 ± 3.5, p = 0.52) or the BDRS (1.4 ± 1.8 versus 1.7 ± 2.0, p = 0.28). The prednisone group again showed greater deterioration on the BPRS (5.7 ± 8.9 versus 2.6 ± 7.3, p = 0.03).
Adverse events.
There were no clinically apparent spinal compression fractures during the study, but radiographs revealed evidence of new compression fractures in four subjects in the prednisone group, compared with two subjects in the placebo group, a difference that was not significant (p = 0.4). Bone densitometry revealed decline in density at the lumbar spine in the prednisone group as compared with the placebo group (0.021 ± 0.006 g/cm2 versus 0.003 ± 0.008, p = 0.02 for difference between treatment groups). There was no significant change in density at the femoral neck or greater trochanter in either group.
Random glucose values greater than 200 mg/dL occurred in 10 subjects in the prednisone group, compared with two in the placebo group (p = 0.02).
Ophthalmologic examinations did not reveal significant progression of cataracts in either treatment group. There was a small rise in mean intraocular pressure in the prednisone group between screening (15.7 ± 3.5 mm) and week 12 (16.7 ± 4.1 mm, p = 0.0001); this change disappeared by week 52 (15.7 ± 3.5 mm).
Adverse events reported during the course of the trial were grouped into categories for analysis; those categories with more frequent reports in the prednisone group (p ≤ 0.1) are shown in table 3. Not unexpectedly, edema, which was predominantly facial, was more common in the prednisone group. The significant differences in endocrine, genitourinary, and laboratory categories reflected mainly hyperglycemia and glycosuria. The increase in dental events in the prednisone group may be significant, as most of these events were dental infections that may be attributable to glucocorticoids. There were no significant differences between treatment groups in prevalence of psychiatric or neurologic symptoms. When the analysis considered only events reported as moderate or severe, the only category that differed between groups was laboratory abnormalities.
Adverse events reported more frequently by subjects in the prednisone group
In addition to adverse events reported on case report forms, study subjects were asked specifically about each of 31 symptoms that might arise with glucocorticoid toxicity. When the proportion of each treatment group reporting new symptoms (not present at baseline) was compared, the difference was only substantial for facial swelling (prednisone group 17%, placebo group 3%, p = 0.009). There was a trend toward increased reporting of easy bruising, dry mouth, constipation, and headache in the prednisone group.
Relationship between behavioral disturbance and cognitive impairment.
There was a correlation between the change in BPRS score and the change in ADAS-cog (r = 0.43, p = 0.0001), indicating a relationship between behavioral disturbance and cognitive dysfunction. As noted above, the prednisone treatment group showed significant behavioral decline as indicated by change in BPRS score compared with the placebo group, and there was a trend toward more severe behavioral adverse events (agitation, depression, psychosis, sleep disturbance) in the prednisone group (46% of subjects in the prednisone group reported moderate or severe behavioral adverse events compared with 35% in the placebo group, p = 0.13). Among subjects with behavioral adverse events, there was a trend toward greater cognitive decline in the prednisone group (prednisone group: n = 51, mean ADAS-cog change = 9.7 ± 7.6; placebo group: n = 44, mean ADAS-cog change = 6.8 ± 6.7, p = 0.06). In contrast, among subjects without behavioral adverse events, there was slightly less cognitive decline, not reaching statistical significance, in the prednisone group (prednisone group: n = 18, mean ADAS-cog change = 3.9 ± 6.8; placebo group: n = 25, mean ADAS-cog change = 5.5 ± 6.0, p = 0.48). When the ITT analysis of ADAS-cog change was adjusted to control for BPRS change, the difference between treatment groups was smaller than in the primary analysis (prednisone group: adjusted mean ADAS-cog change = 7.7 ± 6.7; placebo group: adjusted mean ADAS-cog change = 7.0 ± 6.7, p = 0.56).
Discussion.
The low dose of prednisone used in this study was ineffective in slowing the rate of cognitive decline in subjects with probable AD as measured by the ADAS-cog. There was no significant difference between treatment groups on change in ADAS-cog, and a trend toward more rapid decline with treatment on the clinical composite measure CDR-SOB. Treatment with prednisone was associated with behavioral decline as measured by the BPRS.
This regimen of prednisone may be insufficient to suppress destructive brain inflammatory activity. Much higher doses are used to treat inflammatory diseases of brain such as lupus cerebritis and CNS vasculitis. However, higher doses may not be tolerable for prolonged treatment, particularly in the elderly, as indicated by the serious toxicity associated with high-dose glucocorticoids in the treatment of temporal arteritis.20 In the current study, the incidence of hyperglycemia and edema, as well as a significant decline in bone mineral density at the lumbar spine in the prednisone group, suggests that higher doses might cause substantial health risk. Further, the significant effect of prednisone treatment on BPRS scores suggests that the AD population may be particularly sensitive to adverse behavioral effects of glucocorticoids. The analysis of ADAS-cog changes in subgroups with and without behavioral adverse events suggests that behavioral toxicity may have limited the efficacy of prednisone treatment.
It is also possible that the diverse actions of glucocorticoids produced other deleterious effects that nullified a beneficial anti-inflammatory effect. Thus hippocampal toxicity may have canceled out a palliative effect on the disease. Further, recent evidence suggests that some inflammatory mediators, such as the anaphylatoxin C5a21 and the cytokine TNFα,22 may have both neurodegenerative and neuroprotective effects. A more specific, targeted anti-inflammatory strategy may prove successful despite the negative result of this trial.
NSAIDs are under investigation for the prevention or treatment of AD. One small randomized trial suggested that indomethacin slows cognitive decline in AD,23 and a recent report of a study of diclofenac had similar results, although not reaching significance.24 A number of epidemiologic studies provide evidence that use of NSAIDs, including aspirin, confer protection against AD,25-29 and may slow the rate of cognitive decline in AD30; low-dose aspirin was used by about one third of the subjects in this trial, but aspirin use did not influence cognitive decline. With more limited anti-inflammatory activity than glucocorticoids, and without the issue of possible hippocampal toxicity, NSAIDs are appropriate candidates for future trials. However, the high drop-out rate in the NSAID-treated groups in both small trials23,24 represents a major concern in the design of a definitive long-term study.
Recent studies suggest that cyclooxygenase (COX)-2 may be involved in neurodegenerative mechanisms in the AD brain,31,32 and may represent a specific therapeutic target for anti-inflammatory drugs. Glucocorticoids inhibit the induction of brain COX-233; however, the necessary dose is unknown. COX-2 inhibitors, including traditional NSAIDs and new selective COX-2 inhibitors, may be more useful in reducing the potentially deleterious effects of COX-2 in AD. The epidemiologic evidence that anti-inflammatory drugs protect against AD may be explained by the effect of such agents on brain COX-2. Selective COX-2 inhibitors are well-tolerated at full anti-inflammatory doses, and are thus attractive candidates for clinical trials in AD. Other anti-inflammatory drugs, including hydroxychloroquine and colchicine, have mechanisms of action distinct from glucocorticoids or NSAIDs, and are also currently under evaluation as possible therapeutic agents in AD.
Appendix
The following members of the AD Cooperative Study participated in this trial: J.P. Blass and R. Cirio, Burke Medical Research Institute; M. Sano and A. Lawton, Columbia University; M.R. Farlow and S. Weitlauf, Indiana University; C. Lyketsos and B. Galik, Johns Hopkins University; C.S. De Carli and M. White, Kansas University; N. Graff-Radford and F. Parfitt, Mayo Clinic, Jacksonville; D. Marin and J. Santoro, Mt. Sinai School of Medicine; S.H. Ferris and M. Shapiro, New York University Medical Center; L.E. Harrell and P. Forsyth, University of Alabama, Birmingham; B. Miller and M. Wohl, University of California, Los Angeles; M. Grundman and S. Johnson, University of California, San Diego; V. Kumar and S. Saunders, University of Miami; D. Knopman and M. Prod’Homme, University of Minnesota; C.M. Clark and G. Wilson, University of Pennsylvania; S.T. DeKosky and G. Hlivko, University of Pittsburgh; P.N. Tariot and B. Goldstein, University of Rochester Medical Center; E. Pfeiffer and B. Candelora, University of South Florida; L.S. Schneider and N. Taggart, University of Southern California; M.F. Weiner and D. Svetlik, University of Texas; R. Margolin and D. Kent, Vanderbilt University; E. Zamrini and D. Baker, Veterans Administration Medical Center, Augusta; E.H. Rubin, J.C. Morris, and M. Coats, Washington University; data monitoring and coordinating staff: J. Bochenek, K. Schafer, C. Ernesto, P. Woodbury, J. Mackel, M. Schittini, A. Berry, R. Price; statistical consultant: M. Klauber; safety monitoring committee: E. Jackson, T. Sunderland, D. Bennett, K. Kieburtz.
Acknowledgments
Supported by a grant (U01-AG10483) from the National Institutes of Health. Prednisone and matching placebo were provided by Pharmacia & Upjohn, Inc.
Footnotes
- Received October 8, 1999.
- Accepted November 1, 1999.
References
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