Efficacy of tacrine and lecithin in mild to moderate Alzheimer's disease: double blind trial

Subjects and methods

Fifty three subjects (26 women and 27 men) participated in the study. They were recruited from referring neurologists, psychiatrists, and other physicians. All subjects fulfilled the criteria for dementia in the Diagnostic and Statistical Manual of Mental Disorders, third edition, revised (DSM-III- R)24 and the criteria for probable Alzheimer's disease of the National Institute of Neurological and Communicative Disorders and Stroke.25 All the subjects lived at home and had a carer willing to complete questionnaires. Exclusion criteria were concurrent terminal illness or end organ failure, inability to speak English or to comprehend the instructions for the verbal selective reminding task,26 which was used to assess efficacy. Carers and, whenever possible, the patients gave informed written consent.

All patients initially underwent a dose finding phase with tacrine. Memory performance, liver enzyme concentrations, and carers' assessment of functioning were recorded at baseline and after two weeks of treatment with lecithin alone (9 x 1200 mg capsules daily). Subjects were then given tacrine, starting at 25 mg daily; doses were increased by 25 mg every two weeks to a maximum daily dose of 100 mg if there were no side effects and liver enzyme concentrations were not raised. Doses are expressed in terms of the hydrochloride salt of tacrine; an equivalent maximum dose of the base of tacrine is 80 mg daily. We defined a best dose of tacrine as either the highest tolerated dose or the tolerated dose at which performance on memory tests was at least 50% better than at baseline.

After a four week wash out period on lecithin alone, 41 subjects who could tolerate at least 25 mg tacrine daily were randomly assigned to one of two treatment groups for the nine month double blind phase: placebo plus lecithin or tacrine plus lecithin. Subjects took their own best dose and were assessed monthly for drug efficacy and safety.

Assessment

We assessed memory using verbal and visual selective reminding tasks consisting of lists of 10 words or seven objects respectively.^26,27 Subjects were given 10 attempts to learn the lists. Multiple forms of the verbal and visuospatial tests were available so that different lists were presented to the patient at each test, thus minimising practice effects.

A battery of psychometric tests aimed at the specific cholinergic effects of tacrine was completed at baseline and after three and six months of treatment. The tests were selected on the basis of reported effects in healthy volunteers given the cholinergic blocking drug hyoscine. The battery included cholinergic sensitive tests (that is, hyoscine impairs test performance) and cholinergic insensitive tests. Further details have been reported.28

A clinical examination, including a standardised neurological examination and the mini-mental state examination,29 was repeated every three months. We calculated the extrapyramidal score taking into account resting tremor, glabella tap, rigidity of upper or lower limbs, nuchal rigidity, cogwheeling, fine finger movement, postural flexion, arm swing, and bradykinesia. Each measure was scored on a scale of 0 (normal) to 3 (severe defect), and the scores were summed.

Carers rated the patient's functioning and mood using the London psychogeriatric rating scale30 and a profile of mood states scale31 modified for use by carers. They assessed the patients' instrumental activities of daily living32 and their own symptoms of stress (using a 30 item general health questionnaire33, every three months.

We used standardised neurological tests to assess patients before inclusion in the trial and after the nine month double blind phase. Based on the neuropsychological approach of Walsh,34 the tests assessed language, attention, memory and learning, visuospatial and constructional skills, frontal or executive function, visual agnosia, and apraxia. In addition the national adult reading test35 and geriatric depression scale were administered.36

Side effects

Carers reported side effects by completing a monthly checklist of 20 symptoms of cholinergic and liver dysfunction. Side effects were regarded as present if they were noted at least once by a carer during three months and had not been noted at baseline.

We tested liver function monthly. If enzyme concentrations were raised, they were measured weekly; if the rise continued or worsened the dose of tacrine (or placebo) was reduced. Treatment was stopped if concentrations reached three times the upper limit of normal.

Statistical analysis

For the verbal selective reminding task, total words recalled over 10 trials (maximum 100) were scored as outlined by Buschke et al.26 A similar scoring system was used for the visuospatial selective reminding task (maximum 70). The total London psychogeriatric rating score and subscores of mental disorganisation (confusion), physical disability, socially irritating behaviour, and disengagement were calculated according to standard scoring procedures.30 Scores of fatigue (worn out, fatigued, weary), vigour (alert, lively, vigorous), depression (sad, miserable, gloomy), and confusion (confused, forgetful, unable to concentrate) were calculated from the modified profile of mood states.31

For measures performed monthly, we averaged the scores over three months to minimise missing data and increase the reliability of the measurement. The baseline score was the average of scores at the pretrial assessment, the lecithin only assessment in the dose finding phase, and the assessment after the wash out phase. Paired t tests of the verbal memory test score before dose finding with the score after the wash out phase indicated no significant carry over effect of the drug after the wash out phase (P=0.85). We analysed data for patients completing 36 weeks of treatment using repeated measures analysis of variance. Treatment (tacrine v placebo) was the independent groups factor and testing occasion (baseline, 1-3 months, 4-6 months, and 7-9 months) the repeated measures factor. We also used repeated measures analysis of variance to compare the results of the neurological tests before and after in the two treatment groups. The t test and X² test were used to compare other measures as appropriate.

Doses administered

No studies since that of Summers et al11 have reported clinically relevant results of treatment with tacrine. Chatellier et al, Molloy et al, and Wilcock et al were unable to detect any significant effect of tacrine.^17,23,45 Two studies reported that tacrine produced significant changes in mini-mental state score but not in other measures after 13 and four weeks of treatment, ^16,46 and Davis et al noted marginal improvements over six weeks of treatment.20

The most important factor limiting the tolerated dose of tacrine was liver toxicity. Raised liver enzyme concentrations have often been reported, ranging in incidence from 13% to 42%.^20,22 In this trial 14 of the 53 patients (26%) given tacrine in the dose finding phase had liver enzyme concentrations three times the upper limit of normal. Although there are no reported incidents of permanent damage and all our subjects had normal concentrations within a month of withdrawing the drug, biopsies of patients with raised liver function test results have reported damage ranging from focal inflammatory infiltration to extensive hepatocellular necrosis.*RF 46-49* We therefore decided to restrict doses to 100 mg daily. The trials which found a noticeable effect of tacrine used doses up to 150 mg and 200 mg daily.^11,16

We used a dose finding phase before randomisation to determine personal best doses for each subject, largely on the basis of the subject's highest tolerated dose. The mean best dose of tacrine was 72.6 (SD 28.94) mg daily. Therapeutic serum concentrations of tacrine four hours after the last dose are suggested to be 7 to 20 μg/l.46 We did not always collect blood exactly four hours after the last dose and the methods did not take into account the metabolites of tacrine or differential protein binding. The plasma concentrations can therefore be considered only a rough estimate. However, in the dose finding phase the mean concentration of tacrine when patients were taking their best dose was 13.3 μg/l (SE 1.91; range 0 to 49.64). This is potentially a therapeutic dose.

We found a marginally significant correlation between memory (selective reminding task scores) and blood tacrine concentrations (R=0.33; P=0.04). This seems to support the argument that higher doses of tacrine are needed for a cognitive effect. Analysis of the subgroup of patients whose ‘best dose' for the trial was 100 mg daily, however, showed no evidence of a long term treatment effect on the mini-mental state score. Because of liver toxicity, higher doses could be used only in selected patients and would require conservative titration and frequent monitoring.

Compliance may be a problem in subjects with dementia, but all our subjects had a carer who took responsibility for ensuring drugs were taken. General inquiry by the neurologists at three monthly assessments suggested that compliance was excellent, but this was not assessed independently.

Responsive subgroups

Eagger et al suggested that some patients respond better than others to tacrine.16 If tacrine is an effective centrally acting cholinergic agonist it might be expected to be most effective in mild Alzheimer's disease, when the deficits are predominantly cholinergic. We carried out a sub analysis on a group of patients with mild Alzheimer's disease who had a pattern of cognitive performance consistent with a purely cholinergic deficit.28 However, we found no difference between the tacrine and placebo treatments.

Although patients were randomly assigned to treatment groups, patients treated with tacrine had a longer duration of disease than those treated with placebo. Our results could be falsely negative if subjects with a short duration of disease respond better to treatment. However, within the tacrine treated group there was no correlation between response to tacrine (as measured by the mini-mental state examination) and duration of disease (P=0.50), and analysis of the whole group showed no correlation between duration of disease and baseline mini-mental state score (R=0.25) or verbal memory (P=0.21).