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BACKGROUND: Improving the systemic and mucosal immune response following intranasal vaccination could enhance disease protection against respiratory pathogens. We assessed the safety and immunogenicity of a novel nanoemulsion mucosal adjuvant W(80)5EC combined with approved seasonal influenza antigens. METHODS: This was a first-in-human Phase I study in 199 healthy adult volunteers randomized to receive a single intranasal administration of 5%, 10%, 15% or 20% W(80)5EC, combined with 4 or 10 µg strain-specific Fluzone(®) HA, compared with intranasal PBS, intranasal Fluzone(®), or 15 ug strain-specific intramuscular Fluzone(®). Safety was evaluated by physical examination, laboratory parameters, symptom diaries, and adverse event reports. Serum HAI titers and nasal wash IgA were assessed at baseline as well as 28 and 60 days after vaccination. RESULTS: W(80)5EC adjuvant combined with seasonal influenza antigens was well tolerated without safety concerns or significant adverse events. The highest dose of 20% W(80)5EC combined with 10 µg strain-specific HA elicited clinically meaningful systemic immunity based on increases in serum HAI GMT and ≥ 70% seroprotection for all 3 influenza strains, as well as a rise in antigen-specific IgA in nasal wash specimens. CONCLUSIONS: W(80)5EC adjuvant was safe and well tolerated in healthy adult volunteers and elicited both systemic and mucosal immunity following a single intranasal vaccination.

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OBJECTIVE: To assess the feasibility of using MRI measurements as a surrogate endpoint for disease progression in a therapeutic trial for AD. METHODS: A total of 362 patients with probable AD from 38 different centers participated in the MRI portion of a 52-week randomized placebo-controlled trial of milameline, a muscarinic receptor agonist. The therapeutic trial itself was not completed due to projected lack of efficacy on interim analysis; however, the MRI arm of the study was continued. Of the 362 subjects who underwent a baseline MRI study, 192 subjects underwent a second MRI 1 year later. Hippocampal volume and temporal horn volume were measured from the MRI scans. RESULTS: The annualized percent changes in hippocampal volume (-4.9%) and temporal horn volume (16.1%) in the study patients were consistent with data from prior single-site studies. Correlations between the rate of MRI volumetric change and change in behavioral/cognitive measures were greater for the temporal horn than for the hippocampus. Decline over time was more consistently seen with imaging measures, 99% of the time for the hippocampus, than behavioral/cognitive measures (p < 0.001). Greater consistency in MRI than behavioral/clinical measures resulted in markedly lower estimated sample size requirements for clinical trials. The estimated number of subjects per arm required to detect a 50% reduction in the rate of decline over 1 year are: AD Assessment Scale-cognitive subscale 320; Mini-Mental Status Examination 241; hippocampal volume 21; temporal horn volume 54. CONCLUSION: The consistency of MRI measurements obtained across sites, and the consistency between the multisite milameline data and that obtained in prior single-site studies, demonstrate the technical feasibility of using structural MRI measures as a surrogate endpoint of disease progression in therapeutic trials. However, validation of imaging as a biomarker of therapeutic efficacy in AD awaits a positive trial.

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The safety of tacrine (Cognex), a centrally active, reversible acetylcholinesterase inhibitor approved in 1993 for the treatment of mild to moderate dementia of the Alzheimer type, was evaluated in 2,706 patients with Alzheimer disease (AD) in clinical trials and in 9861 patients with AD in a treatment investigational new drug (TIND) program. More than 190,000 patients in the United States received tacrine during the first 2 years following marketing approval. The most common tacrine-associated adverse events were elevated liver transaminase levels [alanine aminotransferase (ALT) and, to a lesser degree, aspartate aminotransferase] and peripheral cholinergic events involving primarily the digestive system (nausea, vomiting, diarrhea, dyspepsia, anorexia, and weight loss). Based on clinical trial experience, potentially clinically significant (>3 x upper limit of normal) ALT elevations occurred in 25% of patients, requiring routine monitoring early in treatment. The elevations were almost always asymptomatic, rarely accompanied by significant increases in bilirubin, and related to time on drug rather than to dose (90% occurred within the first 12 weeks of treatment). Gastrointestinal events were related to dose and generally of mild to moderate intensity. Tacrine-associated events, including ALT elevations, were reversible. Cholinergic events were manageable with dosage adjustment. Tacrine was not associated with permanent liver injury in clinical trials or a TIND setting.

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Early diagnosis and treatment of AD is critical to maximize benefits for the patient and the caregiver. It is important to intervene early in the illness, before the quality of life of the patient and the caregiver has deteriorated to the point where treatment only prolongs an already difficult situation. If treatment begins early enough in the disease course, loss of functional independence may be delayed, just as nursing home placement was delayed in this study. In this way, quality of life is improved for both the patient and the caregiver.

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Survival analysis techniques using Cox proportional hazards regressions with time-dependent covariates, life table survival plots, and Kaplan-Meier estimates were used to evaluate the effect of long-term tacrine hydrochloride (Cognex) treatment on nursing home placement (NHP) and mortality in patients with Alzheimer's disease. Patients with probable Alzheimer's disease (NINCDS criteria) who were randomized in a 30-week double-blind, placebo-controlled, parallel-group, high-dose study of tacrine (1) were subsequently allowed to receive long-term, open-label treatment during which they could receive doses up to 160 mg/day. Using last tacrine dose, the analyses demonstrated a dose-response relationship where patients on higher tacrine doses were less likely to enter a nursing home or die than patients on lower doses. The Cox proportional hazards regression approach with time-dependent covariates is also compared to logistic regression, which looks only at the crude proportions of patients having the event. Since logistic regression does not allow for the use of time-dependent covariates, it provides somewhat less conservative estimates of the magnitude of the treatment effect.

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We studied the effects of 40 and 80 mg/day of tacrine on patients with probable Alzheimer's disease (AD) in an 8-week, randomized, double-blind, placebo-controlled crossover trial with an enriched-population design. In the initial dose titration phase, an intent-to-treat analysis showed significantly more improvement with 80 mg/day of tacrine than placebo. In the subsequent crossover trial that included only 'responders', no significant improvement was observed with tacrine, whether or not it was given with lecithin. We found that individualized dose titration and enrichment strategies were not helpful and had the effect of reducing the power of the study. In the dose titration phase of this study we found that more impaired subjects were as likely to improve as those who were less impaired, suggesting that tacrine should be further investigated in more severely demented AD patients.

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OBJECTIVE: To assess the possible association between tacrine (Cognex, manufactured by Parke-Davis, Morris Plains, NJ) dose and likelihood of nursing home placement (NHP) or death in patients with AD. DESIGN: A 30-week, randomized, double-blind, placebo-controlled, parallel-group multicenter clinical trial involving 663 patients, after which patients were treated openly and followed up a minimum of 2 years later. PATIENTS: At baseline, outpatients were at least 50 years of age, met criteria for probable AD, with baseline Mini-Mental State Examination scores between 10 and 26 (inclusive), were otherwise healthy, and had a caregiver who could provide assessments and ensure medication compliance. INTERVENTIONS: mandomized assignment to placebo or one of three ascending dosage regimens of tacrine over 30 weeks, followed by open label treatment for all patients who began the double-blind trial. OUTCOME MEASURES: NHP and death were examined using logistic regression. RESULTS: PATIENTS who remained on tacrine and were receiving doses > 80 mg/d or > 120 mg/d were less likely to have entered a nursing home than patients on lower doses (odds ratios > 2.7,2.8, respectively.) There was a trend for lower mortality for patients receiving > 120 mg/d (p = 0.063). CONCLUSIONS: Treatment with tacrine at doses > 80 mg/d was associated with a reduced likelihood of NHP. These data demonstrate that tacrine's 30-week effects on cognitive function and clinicians' global ratings may generalize to effects on a major milestone of AD. Future studies should attempt to replicate these findings prospectively.

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Factor analysis methodology applied to Alzheimer's Disease Assessment Scale (ADAS) subtest profiles for patients in two large-scale clinical trials of the antidementia drug tacrine yielded three oblique factors interpreted as dysfunctions in memory, language, and praxis. The factor structures confirmed reliable assessment of primary dimensions of cognitive impairment in Alzheimer's disease that the original authors of the ADAS proposed to measure and that correspond well to that of the only previously reported factor analysis of the ADAS-COG. The presence of a strong general factor, supported by stable correlations among the oblique primary factors, justifies the recommendation to continue reliance on the ADAS-COG total score as a primary outcome measure in clinical trials, whereas the factor scores are recommended for evaluation of differential treatment effects on more specific aspects of the general cognitive decline. The stability of correlations across time appears to satisfy a primary requirement for application of repeated measures ANOVA to ADAS-COG total score and factor scores in longitudinal clinical trials.

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The efficacy of tacrine hydrochloride (Cognex) for the treatment of Alzheimer's disease (AD) has been confirmed in two randomized, double-blind, placebo-controlled, parallel-group studies. More than 1100 patients with mild to moderate, probable AD were randomized to receive placebo or tacrine for 12 or 30 weeks. Outcome measures included objective assessments of cognitive function, qualitative assessments of treatment response from the caregiver and clinician perspective, and assessments of activities of daily living. Statistically significant treatment effects favoring tacrine were demonstrated in each domain. These results suggest several considerations for clinicians. Because response to treatment is dose related, patients should be titrated to their maximum tolerated dose. Response may be subtle and may range from improvement to stabilization or slowed decline. A minimum treatment period of 6 months is recommended to evaluate a response and treatment should be continued depending on patient tolerability.

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The efficacy of tacrine in the treatment of patients with probable Alzheimer's disease (AD) was evaluated in a double-blind, placebo-controlled, enriched population multicenter study in France. A total of 280 patients entered the dose titration phase of the study. The assessment of potential benefit of tacrine ("best dose") was based on demonstrating improvement on the Alzheimer's Disease Assessment Scale (ADAS) total score versus a blinded placebo. One hundred and thirty of 242 (54%) patients achieved a "best dose" and were eligible for the double-blind, parallel group (pivotal) phase. Primary efficacy measures were ADAS-Cognitive and Clinical Global Impression of Change; secondary efficacy measures of cognition and activities of daily living were also included. Results indicated that tacrine-treated patients showed improved functioning based on the ADAS-Cognitive in comparison to placebo-treated patients. Transaminase elevations above the upper limit of normal occurred in 32% of patients, were more frequent in women than in men, demonstrated a delayed onset, and returned to normal limits for all patients following discontinuation of treatment The results from this study are supportive of the efficacy of tacrine in the treatment of AD as demonstrated in a study of similar design conducted in the US and studies using different designs.

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Global assessments are Food and Drug Administration-required primary outcome measures in trials of putative antidementia drugs. Global ratings are intended to provide an index of clinical importance of change that cannot be obtained from quantitative assessment measures such as mental status examinations. We examined the performance of a global assessment of change instrument, the Clinician Interview-Based Impression (CIBI), in the placebo group of a 30-week, randomized, double-blind clinical trial of tacrine in patients with Alzheimer's disease. Initially there were 184 placebo patients, of whom 125 completed the 30-week study. Descriptive statistics, correlations with changes on other assessment instruments, and test-retest reliability were determined for the CIBI. At week 30, clinicians rated more than 40% of patients on the CIBI as unchanged. The CIBI ratings were weakly but significantly correlated, in the expected direction, with change scores on the quantitative cognitive assessments. The CIBI was modestly reliable on test-retest at weeks 22 and 24 but less reliable compared with other quantitative outcome measures. Modifications of the CIBI that might improve its reliability and acceptance include (1) no restrictions on the form of the bedside mental status assessment, (2) inclusion of caregiver input, and (3) better definition of ratings on the global scale. Global instruments, if properly constructed, can provide an index of clinically important change for the assessment of dementia patients.

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OBJECTIVE: To evaluate the efficacy and safety of high-dose tacrine hydrochloride over 30 weeks in patients with probable Alzheimer's disease. DESIGN: A 30-week randomized, double-blind, placebo-controlled, parallel-group trial. SETTING: Outpatients at 33 US centers. PATIENTS: Men and women at least 50 years of age with mild to moderate Alzheimer's disease and otherwise in good health. INTERVENTIONS: Group 1 received placebo; group 2 received 40 mg/d of tacrine for 6 weeks, then 80 mg/d for 24 weeks; groups 3 and 4 received 40 mg/d of tacrine for 6 weeks, 80 mg/d for 6 weeks, and 120 mg/d for 6 weeks. Group 3 remained on a dosage of 120 mg/d for a total of 18 weeks; after 6 weeks at 120 mg/d, group 4 titrated to 160 mg/d for the last 12 weeks. PRIMARY OUTCOME MEASURES: Clinician Interview-Based Impression (CIBI), Alzheimer's Disease Assessment Scale--Cognitive subscale (ADAS-Cog), and Final Comprehensive Consensus Assessment (FCCA). RESULTS: A total of 663 patients entered the study; 653 patients were included in an intent-to-treat (ITT) analysis; 263 had evaluable data at 30 weeks. The results of the ITT analysis revealed significant (P < or = .05) dose-response trends and between-group comparisons on CIBI and ADAS-Cog. In evaluable patients, significant dose-response trends were observed for all three primary measures (P < or = .001). Significant differences in favor of 160 mg/d of tacrine vs placebo were observed on the CIBI (P < or = .002) and ADAS-Cog and FCCA (P < or = .001), as well as caregiver-global and quality-of-life assessments (P < or = .05). On the CIBI, 23% and 42% of tacrine-treated patients in the ITT and evaluable-patient populations, respectively, were rated improved compared with 17% and 18% of placebo patients, respectively. The primary reasons for withdrawal of tacrine-treated patients were asymptomatic liver transaminase elevations (28%) and gastrointestinal complaints (16%). These adverse events were reversible on discontinuation of treatment, and many patients were able to restart tacrine. CONCLUSIONS: Tacrine produced statistically significant, dose-related improvements on objective performance-based tests, clinician- and caregiver-rated global evaluations, and measures of quality of life. There was no evidence that the large number of patient withdrawals biased the overall conclusions of the study.

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OBJECTIVE: To characterize the hepatic effects of tacrine treatment in patients with Alzheimer's disease. DESIGN: Controlled trials of tacrine therapy consisting of two blinded, parallel-group trials; three blinded, enrichment-design trials; and their respective open-label extensions. SETTING: Multicenter clinical trials in the United States, France, and Canada. PATIENTS: A total of 2446 men and women at least 50 years of age with a diagnosis of probable Alzheimer's disease of mild to moderate severity and in good health without significant hepatic, cardiovascular, or renal disease. INTERVENTION: Administration of tacrine vs placebo, with weekly measurement of serum hepatic enzymes. MAIN OUTCOME MEASURES: Incidence, maximum severity, and timing of event for serum alanine aminotransferase (ALT) elevation. RESULTS: Among the 2446 patients who received tacrine in clinical trials, ALT levels greater than the upper limit of normal (ULN) occurred on at least one occasion in 1203 patients (49%), ALT levels greater than three times the ULN occurred in 621 patients (25%), and ALT levels greater than 20 times the ULN occurred in 40 patients (2%). The elevated ALT levels were generally asymptomatic and occurred more frequently in women than men. The mean time from initiation of tacrine treatment to first ALT level greater than three times the ULN was 50 days, and 90% of all initial ALT levels greater than three times the ULN occurred during the first 12 weeks of treatment. Of 145 patients who discontinued tacrine treatment because of an ALT level greater than three times the ULN and were rechallenged, 127 (88%) were able to resume long-term therapy with the drug. In all instances, discontinuing tacrine completely reversed elevations in ALT levels, and no deaths related to hepatotoxicity occurred. CONCLUSIONS: These data suggest that the potential for serious hepatic toxicity can be reduced through careful monitoring of ALT levels in patients who may benefit from tacrine therapy.

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We examined the performance of patients with probable Alzheimer's disease (AD) who participated in the placebo arm of a 12-week clinical trial. Assessments occurred at baseline and at 4, 6, 10, and 12 weeks after starting study medication. Patients received the Alzheimer's Disease Assessment Scale--Cognitive on all five occasions and the Mini-Mental State Examination on three occasions (baseline, week 6, and week 12). Their primary caregivers completed the Progressive Deterioration Scale on all five visits. This self-administered questionnaire consists of 29 items regarding the patient's behavioral and functional status. The extrapolated yearly rate of change of the mental status examinations was considerably smaller than expected compared with uncontrolled natural history studies. In addition, there was a large within-subject variability on all three measures. Scores from the baseline assessments contributed more to the variability than did the later assessments. The small magnitude of change, as well as the large between-subjects and within-subject variability, points out the methodologic drawbacks of short-duration therapeutic trials in patients with AD and the challenges in demonstrating reliable treatment effects for potential therapeutic agents.

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OBJECTIVE: To compare efficacy and safety of tacrine hydrochloride with placebo in patients with probable Alzheimer's disease. DESIGN: A 12-week, double-blind, placebo-controlled, parallel-group study. SETTING: Outpatients at 23 centers. PATIENTS: Men and women with probable Alzheimer's disease, at least 50 years old, mildly to moderately impaired, without other significant medical conditions. INTERVENTIONS: In the initial 6 weeks, patients received placebo, 20 mg/d of tacrine, or 40 mg/d of tacrine. In the second 6 weeks, half received the same treatment and half increased tacrine dose: those receiving placebo increased to 20 mg/d, those receiving 20 mg/d increased to 40 mg/d, and those receiving 40 mg/d increased to 80 mg/d. PRIMARY OUTCOME MEASURES: Alzheimer's Disease Assessment Scale (ADAS) cognitive component and clinician-rated Clinical Global Impression of Change (CGIC). RESULTS: Four hundred sixty-eight patients entered. After 12 weeks, dose-related improvement was significant on the ADAS cognitive (P = .014), clinician-rated CGIC (P = .014), and caregiver-rated CGIC (P = .006). Comparison of 80 mg/d with placebo showed significant improvement on the ADAS cognitive (P = .015), clinician-rated CGIC (P = .016), and caregiver-rated CGIC (P = .028). Significant effects appeared as early as 6 weeks on the ADAS cognitive and caregiver-rated CGIC. Among patients receiving 80 mg/d of tacrine, 51% achieved a four-point or greater improvement of the ADAS cognitive component after 12 weeks of treatment. Reversible asymptomatic transaminase elevations greater than three times normal occurred in 25% of patients. Other treatment-related events included nausea and/or vomiting (8%), diarrhea (5%), abdominal pain (4%), dyspepsia (3%), and rash (3%). CONCLUSIONS: These results confirm the efficacy and safety of tacrine in some patients with Alzheimer's disease. After 12 weeks, the magnitude of the treatment effect is clinically important and recognized by the physician and caregiver. Liver toxicity is reversible and easily detected by weekly alanine aminotransferase determinations.

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