Safety Profile of a Cognitively Unimpaired Older Population with Elevated Cerebral Amyloid in a 4.5-Year Clinical Trial.

BACKGROUND

Preclinical Alzheimer's disease is increasingly studied in clinical trials. Although safety signals are routinely monitored in clinical trial populations with Alzheimer's disease, it can be challenging to identify new safety signals against background rates of age-related medical comorbidities.

OBJECTIVES

To report detailed safety data from a cognitively unimpaired older population with evidence of elevated cerebral amyloid levels on amyloid positron emission tomography in the placebo arm of a Phase 3 clinical trial.

DESIGN

Phase 3, 4.5-year, multicenter, placebo-controlled trial.

SETTING

Placebo data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study.

PARTICIPANTS

Enrolled participants were aged 65-85 years with a global Clinical Dementia Rating score of 0, a Mini-Mental State Examination score of 25-30, a Wechsler Memory Scale Logical Memory IIa (delayed recall) score of 6-18, and elevated brain amyloid levels on 18F-florbetapir positron emission tomography.

MEASUREMENTS

Study participants who received placebo were followed up with post-baseline safety measures. Assessments included review of concomitant medication and adverse events, the Columbia Suicide Severity Rating Scale, electrocardiograms, and neuroimaging (brain magnetic resonance imaging).

RESULTS

In total, 591 study participants (mean age [standard deviation] 71.9 [5.0] years) were assigned to and received placebo in the A4 study, and were followed up to 240 weeks. Participants were primarily White (93.9%) and from the United States (86.8%); 60.4% were women. The most common serious adverse events (incidence rate per 100 person-years) were pneumonia (incidence rate=0.4; 95% confidence interval=0.2-0.7) and atrial fibrillation (incidence rate=0.4; 95% confidence interval=0.2-0.7). The most common treatment-emergent adverse events were upper respiratory tract infection (incidence rate=10.9; 95% confidence interval=9.4-12.5), fall (incidence rate=7.7; 95% confidence interval=6.6-9.0), and nasopharyngitis (incidence rate=5.8; 95% confidence interval=4.8-6.9). The most common ischemia-related findings on magnetic resonance imaging were subcortical infarction (incidence rate=1.4; 95% confidence interval=1.0-2.0) and acute ischemia (incidence rate=0.6; 95% confidence interval=0.3-1.0). Emergent amyloid-related imaging abnormalities with hemosiderin deposition occurred in 32.8% of participants who received placebo; the primary factor associated with these events during the post-baseline period was the number of microhemorrhages at baseline (odds ratio=349.9; 95% confidence interval=247.6-494.4; adjusted p<0.001).

CONCLUSION

Safety findings in the placebo-treated group from the A4 study provide a robust characterization of expected safety in a clinical trial population with preclinical Alzheimer's disease. These results may provide context in planning future studies and safety evaluations during ongoing blinded studies in preclinical Alzheimer's disease.

Déclaration de conflit d'intérêts

Roy Yaari, Karen C. Holdridge, Michele Mancini, Michael Case, Chakib Battioui, and John R. Sims are full-time employees of Eli Lilly and Company and are minority holders of company stock. Roy Yaari and Karen C. Holdridge have received support for attending meetings and/or travel from Eli Lilly and Company. Michael S. Rafii has received grants from Esai and Eli Lilly and Company; has received consulting fees from AC Immune and Ionis; and has participated in data safety monitoring boards or advisory boards for Alzheon, Aptah Bio, Biohaven, Keystone Bio, Prescient Imaging, Positrigo, and Embic. Paul S. Aisen has received grants from Eisai, Eli Lilly and Company, the National Institutes of Health, and Alzheimer’s Association; and has received consulting fees from Merck, Biogen, Abbvie, Genentech, Roche, ImmunoBrain Checkpoint, and Arrowhead. Reisa A. Sperling has received grants from NIA, GHR Foundation, Alzheimer’s Association, and Eisai; and has received consulting fees from AC Immune, Acumen, Alnylam, AbbVie, Genentech, Janssen, Bristol-Myers-Squibb, Merck, Prothena, Shionogi, Alector, Ionis, Vaxxinity, and Roche.