Original Article
Tetrahydroaminoacridine–Lecithin Combination Treatment in Patients with Intermediate-Stage Alzheimer's Disease — Results of a Canadian Double-Blind, Crossover, Multicenter Study
N Engl J Med 1990; 322:1272-1276May 3, 1990
- Abstract
- Abstract
We studied the efficacy and safety of oral tetrahydroaminoacridine (THA) combined with lecithin in 52 patients with Alzheimer's disease. The maximal tolerated dose of THA (up to 100 mg per day) was determined during an eight-week titration period, after which the tolerated dose of THA or placebo was given during two sequential randomized periods of treatment lasting eight weeks each. Highly purified lecithin (4.7 g per day) was administered during all phases of the study. Efficacy was expressed in terms of scores on the Mini—Mental State (MMS) test, the modified MMS test, the Hierarchic Dementia Scale, the Rapid Disability Rating Scale—ll, and the behavioral scale of Reisberg et al. Safety was assessed by careful clinical monitoring as well as serial measurements of liver aminotransferases.
Forty-six patients completed the titration period, and 39 completed the double-blind period, during which only the MMS score showed a small but significant increase (P<0.05) after four weeks of treatment with THA.
Autonomic side effects of THA were common but mild. Reversible elevations of serum aspartate and alanine aminotransferase levels to three or more times the upper limit of normal occurred in 17 percent of patients; most of the patients affected were women. A liver biopsy performed in one patient showed resolving focal liver-cell necrosis.
These studies fail to demonstrate a significant clinical benefit of THA given orally in a maximal dose of 100 mg per day over a period of eight weeks in combination with lecithin. (N Engl J Med 1990; 322:1272–6.)
Media in This Article
Table 1
Side Effects of THA among 52 Patients during the Titration Period.*Table 2
Side Effects of THA among 39 Patients during the Double-Blind Phase.*Article Activity
- Article
ALZHEIMER'S disease is a devastating and common neurologic disorder, and the search for symptomatic therapy has proceeded at an accelerated pace since the finding a decade ago of reduced cholinergic markers in the neocortex and hippocampus of patients.1 Oral loading with acetylcholine precursors such as choline2 or lecithin3 has failed to help appreciably. Intracerebroventricular infusion of bethanechol, a direct muscarinic agonist, led to only modest increases in scores on the Mini—Mental State (MMS) test; in view of the surgical risks involved in implanting a pump and catheter, this treatment was abandoned.4 Short-term acetylcholinesterase inhibitors such as physostigmine administered orally or parenterally have clinical efficacy but limited applicability because of their short duration of action and narrow therapeutic window.5 In a recent study5 tetrahydroaminoacridine (THA), a long-acting acetylcholinesterase inhibitor, was reported to be effective in doses of up to 200 mg per day in combination with lecithin.6
In our initial attempt to study the efficacy and safety of THA combined with lecithin, we conducted a double-blind, crossover trial in patients in the intermediate stages of Alzheimer's disease; the study had to be stopped because dose-related hepatotoxicity occurred during titration of doses of up to 200 mg per day given orally. Nevertheless, a statistically significant increase (9 percent) in the MMS score was observed in 19 patients when they received a mean dose of 88 mg per day.7 Our second attempt at titration, using a maximal daily dose of 100 mg, was more successful, at least in terms of drug tolerance and safety, with an 8 percent increase in the MMS score for 46 patients when they received a mean dose of 94 mg per day.8 These preliminary studies were not controlled or double-blind. We now report the results of a double-blind period of treatment, including a full analysis of toxicity. These observations were made after completion of the titration period previously described.8
Methods
Subjects
Fifty-two patients participated in the study (25 men and 27 women, with a mean age of 67.0 years; range, 51 to 88); each had a clinical diagnosis of probable (n = 50) or definite (n = 2) Alzheimer's disease according to the criteria of the Work Group on the Diagnosis of Alzheimer's Disease, established by the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association.9 After the study protocol was approved by local research-ethics boards and the Canadian Health Protection Branch, informed consent was given by the patients if competent or by their guardians if not. The patients were ambulatory and could function either by themselves or under the supervision of a spouse or "significant other." They were thus in stage 4 or 5 of the Global Deterioration Scale of Reisberg et al.10 Patients with parkinsonian features, active heart disease, seizure disorders, or active hepatic or hematologic dysfunction were not included, nor were those with modified Hachinski's ischemic scores of 4 or more.11 Investigators at eight urban hospitals in the provinces of Quebec and New Brunswick were responsible for the enrollment and care of their patients and used the same data base and procedures.
Protocol
This study consisted of a dose-titration period followed by a simple crossover period (the double-blind phase) in which the largest tolerated dose of THA (up to a maximum of 100 mg per day) was used. The dose-titration period with lecithin and THA lasted 10 weeks; it was followed by a 4-week washout period with an abrupt (not tapered) withdrawal of THA, an 8-week period of treatment with THA or placebo after randomization, a second 4-week washout period with an abrupt withdrawal of the study medication, and finally a second 8-week period with the alternate treatment (THA or placebo). All patients who tolerated THA throughout the titration period were eligible for the double-blind phase of the study. Randomization was performed after titration. Neither the patients nor their families knew the study design, beyond the fact that a placebo was used at some point instead of THA.
After two base-line assessments, the dose of highly purified lecithin (Maxicholine, a brand of phosphatidylcholine; 775-mg capsules with a 75 percent phosphatidylcholine content) was gradually increased over a period of two weeks to up to six capsules a day and then given throughout the study. The dose of THA (Alzyme, 25-mg capsules) was gradually increased over a period of eight weeks, to a maximum of 100 mg per day, given in three divided doses with meals. This dose was arbitrarily determined on the basis of the previous aborted study,7 in which a dose of 200 mg per day caused side effects in 80 percent of the patients. To maintain the blinding of the study participants, THA or placebo capsules were ingested throughout the study. Both the lecithin and THA were supplied by Pharmascience (Montreal).
The patients and families were seen at least every other week to ensure drug tolerance and compliance, as well as to acquire serial data. At each visit, they were questioned by the responsible investigator about the patient's clinical status and possible side effects; a diary filled out weekly by the principal care giver on selected aspects of self-care was reviewed. Also during each visit, an independent investigator or a research assistant blinded to the protocol administered the MMS test of Folstein et al.,12 the modified MMS (3MS) test,13 and testing according to the Rapid Disability Rating Scale—II (RDRS—II) of Linn and Linn, which yields a score for the activities of daily living and a total score14; higher scores on the RDRS—II indicate deterioration of functional autonomy. At the beginning and end of each eight-week treatment period, testing was administered according to the behavioral scale for Alzheimer's disease (BS-AD) established by Reisberg et al., which yields a symptoms score and a global-impression score,15 and the Hierarchic Dementia Scale (HDS) of Cole et al.16; higher scores on the BS-AD indicate worsening of behavioral disturbances. Finally, at the end of each visit, a blood sample was obtained for the measurement of serum levels of aspartate aminotransferase, alanine aminotransferase, or both. If the levels of these enzymes were three times or more the upper limit of normal, THA was stopped and the enzyme levels were measured weekly until they became normal; if they were between two and three times the upper limit of normal, the dose of THA was not increased further during the titration period or was halved during the treatment period, with weekly measurement of the enzyme levels.
Finally, data were collected one month after the end of the study to determine the progression of Alzheimer's disease in our group of patients as reflected by the clinical scales.
Statistical Analysis
All data were recorded and mailed to a clinical monitor at the McGill Centre for Studies in Aging, who checked the completeness of the information and stored it by means of a DBASE III program (Ashton—Tate). The first analysis assessed the potential carry-over effect of the crossover design, according to the approach described by Armitage and Berry.17 When no evidence of a carry-over effect could be found, a repeated-measures analysis of variance of intrapatient differences between periods was used to assess each variable for differences between treatment with THA and placebo two, four, six, and eight weeks into the respective periods of the study. This latter assessment used univariate and multivariate analysis to determine the effect of treatment, as well as interactions between treatment and sex and between treatment and disease severity. If evidence of a carry-over effect was found, a parallel analysis was used that excluded the data from the second eight-week period. Finally, matched-pair comparisons were made for data obtained before and after study, with the two-tailed t-test for the MMS, 3MS, RDRS—II, and HDS and the Wilcoxon signed-rank test for the BS-AD.
Results
Drug Tolerance
Lecithin was well tolerated by all patients. THA was associated with side effects on the autonomic nervous system in 48 percent of patients during dose titration (Table 1Table 1
Side Effects of THA among 52 Patients during the Titration Period.*) and in 36 percent during the double-blind phase (Table 2Table 2Side Effects of THA among 39 Patients during the Double-Blind Phase.*). On the basis of drug tolerance as assessed during the double-blind period, 24 patients received a daily maximal dose of 100 mg, 7 received 75 mg, and 8 received only 50 mg, for a mean of 85 mg per day.Compliance
Six patients (12 percent) could not complete the 14-week titration—washout period, and seven (13 percent) could not complete the 20-week double-blind period because of behavioral deterioration during the titration period (six patients), an increase in aminotransferase levels to more than the predetermined threshold of three times the upper limit of normal (three), an exacerbation of asthma secondary to pneumonia (one), a skin rash while receiving THA (one), diarrhea while receiving placebo (one), or inability to travel during winter (one).
Drug Toxicity
Before the study, all patients had normal serum levels of aspartate and alanine aminotransferases. While receiving THA, nine patients (17 percent) were found to have levels three or more times the upper limit of normal as determined in the laboratories of the respective study centers (Table 3Table 3
Elevations of Serum Aminotransferase Levels in Nine Patients during THA Treatment.). Within one to six weeks after THA was stopped, the levels returned to normal. Only three patients had gastrointestinal symptoms while their enzyme levels were elevated. One (Patient 7) underwent a liver biopsy five days after THA (75 mg per day) was stopped during titration because of elevated levels of aspartate aminotransferase (137 U per liter) and alanine aminotransferase (374 U per liter); resolving focal cell necrosis was found. The enzyme levels of this patient became normal within three weeks after THA was stopped, and the patient tolerated a lower dose of 50 mg per day during the double-blind phase, as did two others (Patients 2 and 6) who had changes in liver enzyme levels during titration (Table 3). Three patients elected not to continue in the study when told of liver enzyme changes.Cognitive, Functional, and Behavioral Changes
During the Study
The score on the MMS and the global-impression score on the BS-AD did not change significantly during the 38 weeks of study, whereas the scores on the 3MS and HDS, both the score for activities of daily living and the total score on the RDRS—II, and the symptom score on the BS-AD reflected a decline in cognition, functional autonomy, and behavior (Table 4Table 4
Scores for Cognitive, Functional, and Behavioral Assessment before and after Study.).During the Double-Blind Phase
There was no carry-over effect on the scores for the MMS and 3MS and on the activities-of-daily-living score of the RDRS—II, but there was evidence of carry-over on the total score for the RDRS—II (P<0.05). The statistical analysis was adjusted appropriately (see Methods).
The only statistically significant improvement (P = 0.03) occurred in the MMS score after four weeks of treatment with oral THA in a mean dose of 85 mg per day (Table 5Table 5
Scores for Assessment at the Midpoint of Each Eight-Week Treatment Period.). No significant change occurred during the other weeks of treatment. An analysis of scores on the BS-AD and HDS that were recorded at the beginning and end of each treatment period failed to reveal significant changes (data not shown). The power of the study was determined under the conditions of a study population of 39, a two-sided level of significance of 5 percent, and a clinically important change of 10 percent in the mean score for each variable. The power was 74 to 89 percent with the MMS, 80 to 98 percent with the 3MS, and with the RDRS—II, 63 to 96 percent for the activities-of-daily-living score and 81 to 90 percent for the total score.The weekly diaries and comments from the families revealed an increase in spontaneity of speech and functional activities (such as setting a table or answering the telephone) during the titration period and a diminution in these features during the washout period. Spontaneity was not regained during the subsequent rechallenge with THA during the doubleblind phase.
Discussion
In view of the marked cholinergic deficit in neocortical and hippocampal structures, there are good reasons why acetylcholinesterase inhibitors should be effective in the symptomatic treatment of Alzheimer's disease, at least in its early and intermediate stages. On the other hand, multiple neurotransmitter deficits (noradrenergic, serotoninergic, and somatostatinergic) probably also have a role in the clinical syndrome of dementia as well as the loss of neurons in critical areas of the brain. Thus, cholinergic enhancement alone may not bring about clinically demonstrable benefits. There are difficulties in reaching an indisputable clinical diagnosis of Alzheimer's disease. Even among the patients with this disorder there is heterogeneity in the progression of cognitive loss, which reflects variation in the degree of cortical involvement, and possibly in the progression of neurotransmitter involvement, at any given stage. Our study addressed some of these issues by including patients with intermediate stages of the disease (stages 4 and 5 of the Global Deterioration Scale10), diagnosed as probable or definite (by cortical biopsy in one patient and by autopsy in another) according to the Work Group criteria,9 and by using a crossover design in which patients served as their own controls.
We had elected not to use an "enriched" sample of patients during the double-blind phase — i.e., patients who had a predetermined increase in the score on a given scale during dose titration — in order to avoid obtaining results that might not be generalizable to the overall population of patients with Alzheimer's disease. Furthermore, examination of our data to identify patients who had a response, defined as an increase of 3 points or more in the score on the MMS, during titration revealed that 13 of 46 (28 percent) had this level of improvement, of whom only 4 had a similar increase in the MMS score during the double-blind phase. Conversely, of the 14 of 39 (36 percent) who had this level of improvement in the MMS halfway through the double-blind phase, only 4 would have been identified as responders during titration. Thus, the occurrence of a response during titration did not predict improvement during the double-blind phase of our study, at least in terms of change in MMS score.
The side effects of THA were well tolerated by the patients and disappeared when the dose of the drug was reduced. No patients withdrew because of intolerance of side effects on the autonomic nervous system. Although individual doses were adjusted upward during titration to a maximal tolerated dose (ceiling of 100 mg per day), 36 percent of the patients were symptomatic while receiving THA and 26 percent while receiving placebo during the double-blind phase. This high rate of symptoms during the administration of placebo may be a reflection of our vigilance in identifying side effects and may in part be due to the ingestion of lecithin. The randomization code was broken only for a patient who had intractable diarrhea (while receiving placebo) and a patient who presented with a macular rash (while receiving THA); both were excluded from the analysis.
The cognitive scales used for this study included the MMS, 3MS, and HDS; between the beginning and end of the study (38 weeks), the scores on these scales decreased by 3 percent, 6 percent, and 6 percent, respectively (Table 4). The mean improvement of 1.2 points (4 percent) in the MMS score halfway through the THA treatment period was statistically significant but of doubtful clinical importance in view of the lack of change in scores on other cognitive, functional, and behavioral scales. Some observations by the patients' families deserve mention: spontaneity of speech and initiative in the activities of daily living were clearly increased during titration but not during the doubleblind phase, suggesting that the patients became adapted to potential clinical effects of THA, that benefit is not observed after an abrupt or a prolonged washout, or that the apparent clinical benefit was not related to THA but to the expectations of the families early in the study. Furthermore, a loss of behavioral spontaneity was apparent to some observers and families during subsequent washout periods, although no improvement itself had been noticed. Such features of Alzheimer's disease may have to be monitored in future studies, with targeted functional and behavioral scales and possibly the videotaping of selected activities of daily living. Tapered (progressive) washouts may also be better tolerated.
In conclusion, we could not demonstrate any significant clinical benefit in patients with Alzheimer's disease in stages 4 and 5 who received THA orally in a maximal dose of 100 mg per day over a period of eight weeks. It is possible that higher doses of THA might achieve clinically observable results that would be statistically significant according to cognitive, functional, and behavioral scales, as suggested by Summers et al.6 In that study the daily dose of lecithin was 10.9 g, as compared with 4.7 g in the present study. Also, Summers et al. gave their patients 150 to 200 mg of THA per day, whereas we gave ours 50 to 100 mg. It is unlikely that other crossover studies of THA will yield clinically important results, considering the carry-over effect that we observed, at least for one variable (the total score on the RDRS—II), the significant decline in mental function over time (Table 4), and the dose limitation due to toxicity to the autonomic nervous system and liver. Whether additional trials of THA using a parallel design would show positive effects remains to be seen.
Supported by the J. Hutchison Fund of the Montreal General Hospital Foundation, Mr. J. Hartman, la Fondation de l'Hôpital de l'Enfant-Jésus, la Société Alzheimer de Québec, and the Saint John Regional Hospital Foundation. Dr. Masson was a Sandoz Scholar, and Dr. Suissa is a Research Scholar of the Fonds de la Recherche en Santé du Québec.
We are indebted to the pharmacists of our institutions for their dedicated help throughout this study; to our research assistants (S. Bailey, D. Hallée, H. Laberge, A. Lagacé, M. Levine, L. Liu, and M. Shugar) for carefully collecting the data on the patients and their care givers; to Mr. Paul Starr for performing all computer programming related to the data base; to Accurex Clinical Data Research (Scarborough, Ont.), Dr. R. Elie (Hôpital L.H. Lafontaine, Montreal), and Mr. Todd MacKenzie (Division of Clinical Epidemiology, Montreal General Hospital, Montreal) for statistical analysis; to the personnel of the Canadian Health Protection Branch for their advice and support; and to Mrs. Lyne Jean for helping to prepare the manuscript.
Source Information
From the McGill Centre for Studies in Aging, McGill University, and Montreal General Hospital, Montreal (S.G., L.C., H.M.); Hôpital de l'Enfant-Jésus, Quebec City, Que. (R.B., J.M.); Centre Hospitalier Hotel-Dieu de Sherbrooke, Sherbrooke, Que. (A.L., M.G.); Saint John Regional Hospital, Saint John, N.B. (P.B.); Sir Mortimer B. Davis—Jewish General Hospital (H.B., A.M.C.), Maimonides Hospital Geriatric Centre (J.R., S.K.), Douglas Hospital (Y.T., D.D., V.N.), and Hôpital Saint-Luc (M.S.-M., Y.B., R.C., C.K., M.K.), Montreal; the Department of Pharmacology and Therapeutics (B.C.) and the School of Physical and Occupational Therapy (L.G.), McGill University, Montreal; Pharmascience, Montreal (L.N.); and the Department of Epidemiology and Statistics, McGill University, and the Division of Clinical Epidemiology, Montreal General Hospital, Montreal (S.S.). Address reprint requests to Dr. Gauthier at the McGill Centre for Studies in Aging, 1650 Cedar Ave., Montreal, PQ H3G 1A4, Canada.
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