Patient Population and Trial Design

This international trial included male and female patients, 55 to 90 years of age, who met the diagnostic criteria for probable Alzheimer’s disease according to the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association.7 The exclusion criteria have been described previously.5,6 Unlike the EXPEDITION and EXPEDITION2 trials, the EXPEDITION3 trial included only patients with mild Alzheimer’s disease who had biomarker evidence of amyloid-related disease, determined by means of either florbetapir positron-emission tomography (PET) scan or Aβ1-42 measurements in cerebrospinal fluid (CSF).

Patients were randomly assigned in double-blind fashion to receive intravenous infusions of either solanezumab at a dose of 400 mg or placebo every 4 weeks for 76 weeks. Patients who completed the double-blind period could participate in an optional 24-month open-label period. Concomitant therapy, including treatments for symptoms of dementia (acetylcholinesterase inhibitors and memantine, alone or in combination) and nondrug treatments, was allowed in order to ensure that patients continued receiving the standard of care for Alzheimer’s disease. This article includes only the results from the double-blind, placebo-controlled period of the trial. The primary objective of the trial was to test the hypothesis that solanezumab would slow the cognitive decline of Alzheimer’s disease, as compared with placebo, in patients with mild dementia due to Alzheimer’s disease.

Safety Assessments

Key safety assessments included routine physical and neurologic examinations, routine clinical laboratory assessment, and the collection of adverse-event data. Magnetic resonance imaging (MRI) was used to detect any evidence of amyloid-related imaging abnormalities for either hemorrhage or hemosiderin deposition (cerebral microhemorrhage or hemosiderosis) or edema or effusions (vasogenic edema). Adverse events that are associated with immunogenicity or antidrug antibodies were evaluated. Additional safety assessments are described in the protocol, available with the full text of this article at NEJM.org.

Outcome Measures

The primary efficacy measure was the change from baseline to 80 weeks in the score on the 14-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog14; scores range from 0 to 90, with higher scores indicating greater cognitive impairment).8,9 Key secondary efficacy measures included scores on the following assessments: the MMSE10; the Alzheimer’s Disease Cooperative Study (ADCS) Activities of Daily Living Inventory (ADCS-ADL; scores range from 0 to 78, with lower scores indicating greater functional impairment); the ADCS instrumental subscale (ADCS-iADL), which assesses complex activities such as using public transportation, managing finances, or shopping (scores range from 0 to 56, with lower scores indicating greater functional loss)11,12; the Clinical Dementia Rating Scale–Sum of Boxes (CDR-SB; scores range from 0 to 18, with higher scores indicating greater impairment)13,14; the Functional Activities Questionnaire (FAQ; scores range from 0 to 30, with higher scores indicating greater functional loss)15; and the Integrated Alzheimer’s Disease Rating Scale (iADRS; scores range from 0 to 146, with lower scores indicating worse performance).16 Biomarker and neuroimaging methods are described in the Supplementary Appendix, available at NEJM.org.

Oversight

The trial protocol was approved by the ethics and institutional review boards at all the sites. All the participants provided written informed consent before participation in the trial. The sponsor (Eli Lilly) designed and funded the trial, provided solanezumab and placebo, participated in writing the manuscript, and oversaw contracted research organizations. The first draft of the manuscript was written by the first author and an author who was an employee of the sponsor. Several authors are former employees of the sponsor but were still employees at the time that the manuscript was written. All the statistical analyses that are reported here were performed by the sponsor or by a contract research organization. The statistical analysis plan is available with the trial protocol, and the informed-consent form is provided in the Supplementary Appendix. All the authors attest to the fidelity of the trial to the protocol and to the accuracy and completeness of the data and analysis. All the authors reviewed and approved versions of the manuscript for submission for publication.

Statistical Analysis

Analyses were conducted on the basis of a modified intention-to-treat principle and involved only patients who had outcome measurements both at and after baseline. All the tests of effects were conducted at a two-sided alpha level of 0.05, unless otherwise specified. Patients who did not have a postbaseline measure were not included in the analyses. Additional details, including information about the weighted imputation methods for missing data, are provided in the statistical analysis plan (see the protocol).

Randomization of the patients was stratified according to site and according to the method that was used to determine the presence of amyloid-related disease (florbetapir PET scan or CSF assessment). Fisher’s exact test or Pearson’s chi-square test was used for trial-group comparisons of categorical data; analysis of variance, with independent factors for treatment and site, was used for continuous data.

The primary outcome, the change from baseline to 80 weeks in the ADAS-cog14 score, was analyzed with the use of a mixed-model repeated-measures analysis, with the change from baseline in the ADAS-cog14 score at each scheduled visit at weeks 12, 28, 40, 52, 64, and 80 after baseline as the dependent variable. The model for the fixed effects included terms for seven effects: the baseline ADAS-cog14 score, site, trial group, visit, trial group–by–visit interaction, concomitant use of acetylcholinesterase inhibitors or memantine (or both) at baseline (yes or no), and age at baseline. Visits were considered to be a categorical variable, with values equal to the visit number at which the scales were assessed.

Each secondary efficacy outcome was assessed with the use of a mixed model with a repeated-measures analysis in the following hierarchical order: ADCS-iADL, MMSE, and FAQ. The CDR-SB score was assessed only at baseline and at the final study visit, so the change in the CDR-SB score was examined with the use of an analysis of covariance model that contained terms for baseline score, site, trial group, concomitant use of acetylcholinesterase inhibitors or memantine (or both) at baseline (yes or no), and age at baseline. The failure, at a two-sided P value of 0.05, of any analysis in the hierarchy would prevent the reporting of significance testing for all the items after the point of failure.

Safety was assessed by the summary and analysis of clinical laboratory results, adverse events, MRI scans, electrocardiograms, and immunogenicity results. Safety analyses for the double-blind period used comparisons between the solanezumab group and the placebo group. No adjustments for multiple comparisons were made. Analyses comparing the proportion of patients with abnormalities between trial groups during the double-blind period included only patients with both a baseline and a postbaseline observation for each variable. An independent data and safety monitoring committee met periodically to monitor accruing safety data. No interim efficacy analyses were conducted. Statistical methods that were used for biomarker and neuroimaging assessments are provided in the Supplementary Appendix.