Feature Article
|
Metrifonate Improves the Cognitive Deficits of Patients With Alzheimer's Disease Relative to Placebo Treatment and to Baseline Performance *Objective: To evaluate the relative efficacy of two doses of metrifonate, a long-acting acetylcholinesterase (AChE) inhibitor, in improving the cognitive performance of patients with mild to moderate Alzheimer's disease.
*Design:A retrospective analysis of data pooled from four prospective, randomized, placebo-controlled trials of metrifonate. Study A had a 12-week, double-blind treatment period; Studies B, C, and D involved a 26-week, double-blind treatment period.
*Setting: 120 ambulatory clinics, including contract research organizations, public health facilities, and universitiesin the United States, Canada, England, and France.
*Participants: Patients with Alzheimer's disease who had Mini-Mental State Examination scores of 10 to 26 and weighed between 43 kg and 98 kg.
*Intervention: Once-daily placebo or a metrifonate maintenance dose of either 30 mg-60 mg, or 60 mg or 80 mg based on weight.
*Measurements: The Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog).
*Results: As evaluated by the ADAS-Cog, 60 mg or 80 mg of metrifonate significantly improved cognitive performance, both when compared with placebo (= 3.81, P = .0001) and when compared with the patients' baseline (ie, pretreatment) performance (= 2.21, P = .0001). The difference shown by those taking 60 mg or 80 mg of metrifonate versus those taking placebo was statistically superior to that shown by those taking 30 mg to 60 mg of metrifonate (P = .0068), confirming a dose–response effect. The 60-mg or 80-mg dose of metrifonate demonstrated efficacy by week 12 of treatment and maintained effectiveness through week 26. Metrifonate was safe and well-tolerated: 85% of patients receiving 60 mg or 80 mg of metrifonate completed double-blind treatment; only 6% discontinued as a result of adverse events.
*Conclusion: Metrifonate safely improves the cognitive performance of patients with mild to moderate Alzheimer's disease, not only relative to placebo, but also relative to baseline levels--the first such finding reported for an AChE inhibitor. Furthermore, metrifonate at a dose of 60 mg or 80 mg daily provides superior efficacy when compared with a dose of 30 mg to 60 mg daily for the treatment of the cognitive deficits of patients with Alzheimer's disease.
(Annals of Long-Term Care 1999;7[9]:328-333)
Introduction
Alzheimer's disease is neuropathologically characterized by a selective loss of cholinergic neurons and cholinergic hypofunction in the central nervous system,1,2 and clinically by a progressive cognitive deterioration, psychiatric and behavioral disturbances, and an impaired ability to perform instrumental and basic activities of daily living.3,4 The objective of this analysis was to evaluate the relative efficacy of two different doses of metrifonate, a new acetylcholinesterase (AChE) inhibitor,5-9 in improving the cognitive performance of patients with mild to moderate Alzheimer's disease.
Methods, Patients, and Measurements
To provide a more comprehensive view of the magnitude of the metrifonate treatment effect, the data pooled from four studies were evaluated in a retrospective analysis.6-9 The four studies (A, B, C, and D) were prospective, multicenter, randomized, double-blind, parallel group, placebo-controlled trials of metrifonate in patients with probable Alzheimer's disease of mild to moderate severity. Study A6 consisted of a 12-week, double-blind treatment period; Studies B, C, and D7-9 involved a 26-week, double-blind treatment period.
The authors used 120 ambulatory clinics in the United States, Canada, England, and France, involving a variety of settings, including contract research organizations, public health facilities, and universities.
Patients met diagnostic criteria for Alzheimer's disease as defined by the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV)10 or the Work Group of the National Institute for Neurological and Communicative Diseases and Stroke and the Alzheimer's Disease and Related Disorders Association.11 They had Mini-Mental State Examination12 scores of 10 to 26 and Ischemia Scores (Rosen Modification)13 of less than 4, and they weighed between 43 kg and 98 kg. Patients were excluded if they had a medical condition or received medication known to significantly impact their cognition.
Patients randomized in Studies A6 and B7 received once-daily administrations of placebo (N = 255) or a metrifonate maintenance dose of 30 mg to 60 mg based on weight (0.65 mg per kg; N = 392). Patients in Study C8 received placebo (N = 208), a metrifonate maintenance dose of 40 mg or 50 mg based on weight (N = 200), or a metrifonate maintenance dose of 60 mg or 80 mg based on weight (N = 197). Patients in Study D9 received either placebo (N = 87) or 50 mg of metrifonate (N = 177) once daily for 26 weeks. No dose titration was employed in any study.
The Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog)14 was a primary measure of efficacy in all four studies. The ADAS-Cog is a well-validated and reliable instrument for measuring changes in memory and cognition. It evaluates 11 items on a 70-point scale. Higher scores reflect poorer performance, and positive numerical changes from baseline score represent a worsening in cognitive ability.
Statistical analyses were performed for patients who completed double-blind treatment. ADAS-Cog scores were analyzed in two ways:
* As a change from baseline (pretreatment) score
* As the drug-versus-placebo difference in the change
from baseline ADAS-Cog score
The primary analysis was of the change from baseline in ADAS-Cog score at treatment endpoint (week 12 for Study A and week 26 for Studies B, C, and D).
In the pooled analyses, patients who completed double-blind treatment and who received a metrifonate maintenance dose of 30 mg to 60 mg based on weight (Studies A and B), 40 mg or 50 mg based on weight (Study C), or a 50-mg fixed dose (Study D) were considered to be the same treatment group (ie, 30 mg to 60 mg of metrifonate [N = 640]). Patients from Study C who completed double-blind treatment and who received 60 mg or 80 mg of metrifonate based on weight comprised the metrifonate 60-mg or 80-mg group (N = 167). Patients from all four studies completing double-blind treatment and receiving placebo constituted the placebo group (N = 483). Efficacy variables were analyzed using the least squares means and two-tailed statistical tests (t tests, two-way analysis of variance [ANOVA], or three-way ANOVA, as appropriate) conducted at the 5% significance level.
Main Results
The demographic characteristics of the enrolled patients are summarized in the Table. The demographic data show that the three patient groups were similar with respect to the mean age, height, and weight of the patients and the distributions according to gender. The three groups of patients also had comparable baseline ADAS-Cog scores, suggesting that their levels of cognitive impairment were similar.
Metrifonate was safe and well-tolerated. Of the patients randomized in the four studies, 88% of those receiving placebo, 83% of those receiving 30 mg to 60 mg of metrifonate, and 85% of those receiving 60 mg or 80 mg of metrifonate completed the double-blind treatment. Few patients discontinued the study prematurely due to adverse events: only 6% of the placebo patients, 9% of the patients receiving 30 mg to 60 mg of metrifonate, and 8% of the patients receiving 60 mg or 80 mg of metrifonate.
Generally, adverse events were mild to moderate in intensity. During the clinical development of metrifonate, the most frequent adverse events associated with metrifonate treatment--defined as those for which the rate in either metrifonate treatment group was twice the placebo rate and greater than the placebo rate by at least 5%--were limited to leg cramps (placebo, 1%; 30 mg to 60 mg of metrifonate, 8%; 60 mg or 80 mg of metrifonate, 4%).6-9,15 Other adverse events that occurred with metrifonate treatment at a rate greater than the placebo rate were predominantly gastrointestinal in nature, and they included diarrhea (placebo, 8%; 30 mg to 60 mg of metrifonate, 15%; 60 mg or 80 mg of metrifonate, 14%) and nausea (placebo, 6%; 30 mg to 60 mg of metrifonate, 10%; 60 mg or 80 mg of metrifonate, 12%).6-9,15 These events were consistent with those expected for this pharmacologic class of drug.
In patients with mild to moderate Alzheimer's disease, metrifonate significantly improved cognitive performance as compared with placebo, and this effect was dose-related (Figure 1). At the study endpoint, the metrifonate-versus-placebo difference for the change from baseline ADAS-Cog score was 3.81 for those receiving 60 mg or 80 mg of metrifonate (P = .0001) and 2.23 for those receiving 30 mg to 60 mg of metrifonate (P = .0001). The 60-mg or 80-mg dose produced a significantly greater response than the 30-mg to 60-mg dose (P = .0068).
Metrifonate significantly improved the cognitive performance of the patients with Alzheimer's disease when compared with their baseline (pretreatment) performance as well (Figure 2). At the study endpoint, patients receiving placebo showed a significant mean 1.60-point deterioration in the ADAS-Cog score relative to the baseline score (P = .0001). In contrast, patients administered 60 mg or 80 mg of metrifonate had a significant 2.21-point improvement in their cognitive performance when compared with their baseline performance (P = .0001). The group receiving 30 mg to 60 mg of metrifonate produced a mean 0.63-point improvement in the ADAS-Cog score relative to the baseline score (P = .0073), but a statistically significant finding was not consistently observed in the individual four studies, and the response magnitude was smaller than that observed in those taking 60 mg or 80 mg of metrifonate.
The effect of 60 mg or 80 mg of metrifonate on the ADAS-Cog scores of patients with Alzheimer's disease over time is illustrated in Figure 3. The cognitive performance of the placebo patients, as assessed using the ADAS-Cog, progressively deteriorated over time. The ADAS-Cog score of the placebo patients had declined by 0.71 points from the baseline score after 12 weeks (P = .0022), by 1.22 points after 18 weeks (P = .0001), and by 1.91 points after 26 weeks (P = .0001). In marked contrast, the cognitive performance of the patients receiving 60 mg or 80 mg of metrifonate was improved after 12 weeks, a response that was maintained for the duration of the 26-week study period. The ADAS-Cog score of these patients had improved by 2.20 points relative to the baseline score after 12 weeks (P = .0001), by 2.02 points after 18 weeks (P = .0001), and by 1.85 points after 26 weeks (P = .0005).
Discussion
Metrifonate significantly improves cognitive performance in patients with Alzheimer's disease as assessed using the ADAS-Cog. Of particular note, 60 mg or 80 mg of metrifonate improves the cognitive performance of patients with Alzheimer's disease, not just with respect to placebo (= 3.81, P = .0001). It actually improves performance with respect to baseline (pretreatment) levels (= 2.21, P= .0001)--the first such finding reported for an AChE inhibitor. The effect of 60 mg or 80 mg of metrifonate is significantly superior to that of 30 mg to 60 mg of metrifonate (P = .0068), confirming a dose–response effect. Additionally, 60 mg or 80 mg of metrifonate significantly improves cognitive ability relative to the baseline level at 12 weeks, an effect that appears to be durable and that was maintained through week 26 (ie, completion) of therapy.
The magnitude of the drug-versus-placebo difference in the ADAS-Cog score for 60 mg or 80 mg of metrifonate compares favorably with that reported for other AChE inhibitors.16,17 A 30-week tacrine hydrochloride study reported a somewhat greater mean treatment effect size of 5.3 for the patients completing treatment with high-dose tacrine hydrochloride (160 mg daily)16; however, only 27% of the patients receiving 160 mg per day of tacrine hydrochloride tolerated this dose and completed the trial. The treatment effect size for the intention-to-treat population receiving 160 mg per day of tacrine hydrochloride was only 2.2. Similarly, donepezil hydrochloride (high-dose, 10 mg daily) demonstrated modest treatment effect sizes on the ADAS-Cog after 24 weeks of treatment that ranged from 2.88 for the intention-to-treat population to 3.2 for the population completing treatment.17
The numerically superior efficacy observed with metrifonate treatment may be related to its distinct pharmacologic action. Metrifonate safely produces a stable inhibition of AChE that is longer-lasting than that observed with either tacrine hydrochloride or donepezil hydrochloride; indeed, the metrifonate-mediated AChE inhibition persists well after the elimination (elimination t1/2 ~ 2 hours) of the drug from the body.18 Alternatively, the differences in response magnitude may reflect the levels of AChE inhibition achieved by the three cholinesterase inhibitors.
The magnitude of the effects of 60 mg or 80 mg of metrifonate, as evaluated with the ADAS-Cog, suggests that it produces demonstrable, clinically significant benefits on cognitive performance. It has been reported that untreated patients with Alzheimer's disease will deteriorate annually by 6 to 12 points on the ADAS-Cog scale.19 Thus, the difference of 3.81 points on the ADAS-Cog scale between those taking 60 mg or 80 mg of metrifonate and those taking placebo, determined in the current analysis, may be interpreted as at least an eight-month reversal of symptomatic cognitive decline. However, the placebo patients in these trials deteriorated by only 1.6 points during the six-month study period. In most other reported trials of cholinesterase inhibitors, the placebo decline on the ADAS-Cog scale has been considerably larger.16,17 This interpretation of the data may considerably underestimate the positive treatment effect of metrifonate in patients with Alzheimer's disease.
Cognitive improvements are not the only clinical benefits experienced by patients with Alzheimer's disease following treatment with metrifonate. The cognitive improvements observed with metrifonate treatment are consistent with previously published findings of a significant, metrifonate-mediated relief of psychiatric and behavioral disturbances as assessed with the Neuropsychiatric Inventory (NPI),7-9, 20 an improvement in the ability to perform instrumental and basic activities of daily living as evaluated with the Disability Assessment for Dementia (DAD),8,21 and an improvement in global function as measured with the Clinician's Interview Based Impression of Change with Caregiver Input (CIBIC-Plus).6-9 Thus, metrifonate helps control many of the most troubling symptoms in patients with mild to moderate Alzheimer's disease.
The efficacy of metrifonate observed in this analysis was accompanied by good tolerability and a favorable safety profile. Side effects with metrifonate therapy were very modest compared with those previously reported for other AChE inhibitor trials: 85% of patients completed treatment with 60 mg or 80 mg of metrifonate, and only 8% discontinued as a result of adverse events. In contrast, 55% of patients receiving 160 mg per day of tacrine hydrochloride stopped treatment prematurely because of side effects, including clinically significant elevations in hepatic alanine aminotransferase.16 A report of a 24-week donepezil hydrochloride trial described a 68% completion rate for patients receiving 10 mg per day of donepezil hydrochloride; 16% of the donepezil hydrochloride–treated patients discontinued therapy due to adverse events.17 Thus, the safety and tolerability profile of metrifonate compares favorably with the profiles of currently available cholinesterase inhibitors.
AChE inhibition is the only symptomatic treatment approach for Alzheimer's disease that has been clinically proven to benefit patients with the disease. Currently, tacrinehydrochloride16 and donepezilhyrdrochloride17 are the only available AChE inhibitors. Metrifonate is a new AChE inhibitor that differs from tacrine hydrochloride and donepezil hydrochloride in its pharmacodynamic and pharmacokinetic profiles. Metrifonate produces a longer-lasting AChE inhibition than either tacrine hydrochloride or donepezil hydrochloride, and, unlike either of these agents, it is not metabolized by the hepatic cytochrome P-450 enzyme system, a property that may result in fewer drug–drug interactions.
Metrifonate is also the only AChE inhibitor to have demonstrated under prospective and placebo-controlled conditions the capacity to improve not only cognition, but also psychiatric and behavioral disturbances, the ability to conduct activities of daily living, and global functioning of patients with mild to moderate Alzheimer's disease. Furthermore, an analysis of the interaction of demographic variables and patient response to metrifonate suggests that gender, race, age, and education level do not predict treatment response.15, 22
Thus, metrifonate may potentially provide clinical benefit to a wide range of patients with mild to moderate Alzheimer's disease. Given the published efficacy and safety data for the currently available AChE inhibitors, metrifonate appears to be a valuable therapeutic option for the symptomatic treatment of Alzheimer's disease.
Conclusion
In summary, the current analysis demonstrates that metrifonate safely improves the cognitive performance of patients with mild to moderate Alzheimer's disease, both with respect to placebo and baseline performance. Furthermore, 60 mg or 80 mg of metrifonate daily provides superior efficacy when compared with the 30-mg to 60-mg per day dose for the treatment of the cognitive deficits of patients with Alzheimer's disease.
Acknowledgment
The authors would like to acknowledge the contribution of Bianca B. Ruzicka, PhD, to the writing of this manuscript.
The data presented herein were derived from protocols D93-029, D95-018, D96-010, and 0115 developed by Bayer Corporation (West Haven, CT, USA; Etobicoke, ON, Canada; and Newbury, UK). Dr. Farlow does not own stock or options in Bayer Corporation but has received research support from Bayer Corporation. Dr. Cyrus is an employee of Bayer Corporation.
About the Authors
Dr. Farlow is with the Indiana University School of Medicine, Indianapolis. Dr. Cyrus is with the Bayer Corporation, West Haven, CT. Address for correspondence: Martin R. Farlow, MD, Indiana University School of Medicine, Department of Neurology, 541 Clinical Dr, CL 583, Indianapolis, IN 46202-5111. E-mail: MFARLOW@IUPUI.EDU.
References
1. Whitehouse PJ, Price DL, Clark AW, et al. Alzheimer's disease: Evidence for selective loss of cholinergic neurons in the nucleus basalis. Ann Neurol 1981;10:122-126.
2. Perry EK, Perry RH, Blessed G, Tomlinson BE. Necropsy evidence of central cholinergic deficits in senile dementia. Lancet 1977;1:189-191.
3. Gélinas I, Auer S. Functional autonomy. In: Gauthier S, ed. Clinical Diagnosis and Management of Alzheimer's Disease. London, England: Martin Dunitz Ltd; 1996:191-202.
4. Cummings JL, Kaufer D. Neuropsychiatric aspects of Alzheimer's disease: The cholinergic hypothesis revisited. Neurology 1996;47:876-883.
5. Pettigrew LC, Bieber F, Lettieri J, et al. A study of the pharmacokinetics, pharmacodynamics and safety of metrifonate in Alzheimer's disease patients. J Clin Pharmacol 1998;38:236-245.
6. Cummings JL, Cyrus, PA, Bieber, F, et al. Metrifonate treatment of the cognitive deficits of Alzheimer's disease. Neurology 1998;50:1214-1221.
7. Morris JC, Cyrus PA, Orazem J, et al. Metrifonate benefits cognitive, behavioral and global function in Alzheimer's disease patients. Neurology 1998;50:1222-1230.
8. McKeith I. The clinical trial protocol of the Metrifonate in Alzheimer's Trial (MALT). Dementia 1998;9(suppl 2):2-7.
9. Raskind M, Cyrus PA, Ruzicka BB, Gulanski B. The effects of metrifonate on the cognitive, behavioral and functional performance of Alzheimer's disease patients. J Clin Psychiatry 1999;60:318-325.
10. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: APA; 1994.
11. McKhann G, Drachman D, Folstein M, et al. Clinical diagnosis of Alzheimer's disease: Report of the NINCDS-ADRDA Work Group under the auspices of the Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 1984;34:39-44.
12. Folstein MF, Folstein SE, McHugh PR. "Mini-Mental State." A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189-198.
13. Rosen WG, Terry RD, Fuld P, et al. Pathological verification of Ischemia Score in differentiation of dementias. Ann Neurol 1980;7:486-488.
14. Rosen WG, Mohs RC, Davis KL. A new rating scale for the cognitive deficits of Alzheimer's disease. Am J Psychiatry 1984;141:1356-1364.
15. Bayer Corporation, Pharmaceutical Division, West Haven, CT. Data on file.
16. Knapp MJ, Knopman DS, Solomon PR, et al. A 30-week randomized controlled trial of high-dose tacrine in patients with Alzheimer's disease. JAMA 1994;271:985-991.
17. Rogers SL, Farlow MR, Doody RS, et al. A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer's disease. Neurology 1998;50:136-145.
18. Schmidt BH, Hinz VC, Blokland A, et al. Preclinical pharmacology of metrifonate: A promise for Alzheimer therapy. In: Becker R, Giacobini E, Robert P, eds. Alzheimer Disease: From Molecular Biology to Therapy. Boston, MA: Birkhäuser; 1996:217-221.
19. Stern RG, Mohs RC, Davidson M, et al. A longitudinal study of Alzheimer's disease measurement, rate and predictors of cognitive deterioration. Am J Psychiatry 1994;151:390-396.
20. Cummings JL, Cyrus PA, Gulanski B. Metrifonate efficacy in the treatment of psychiatric and behavioral disturbances of Alzheimer's disease patients. J Am Geriatr Soc 1998;46(9):S65 (P196).
21. Gauthier S, Gélinas I, Cyrus PA, Gulanski B. Metrifonate enhances the ability of Alzheimer's disease patients to perform instrumental and basic activities of daily living. J Am Geriatr Soc 1998;46(9):S35(P73).
22. Cyrus PA, Camicioli R. Patients with Alzheimer's Disease benefit from metrifonate treatment regardless of their demographic characteristics and previous cholinesterase therapy. Neurology 1999;52(6):S2(A482). Annals of Long-Term Care - ISSN: 1524-7929 - Volume 7 - Issue 09 - September 1999 |