The following changes were made as per Amendment 1: The Health Care RU instrument was replaced by the Alzheimer’s Disease Cooperative Study – Resource Use Inventory (ADCS-RUI) within the protocol. Additional assessments for the project partners were added including the European Quality of Life Scale (Euro-Qol EQ-5D) and the Work Productivity and Activity Impairment Questionnaire: Mood and Mental State, Caregiver Version (WPAI:MM-CG). The ADCS Alzheimer’s Disease Cooperative Study Activities of Daily Living – Preventive instrument/Mild Cognitive Impairment (ADL-PI/MCI) was updated to the ADCS Alzheimer’s Disease Cooperative Study Activities of Daily Living – Mild Cognitive Impairment (ADL-MCI) version. The adjudication decision option of MCI due to Alzheimer’s Disease (AD) was removed. The 2 options of meets AD dementia or does not meet criteria for AD dementia more appropriately support the endpoint for this study MRI were added as a requirement for adjudication. The 36-Item Short Form Health Survey (SF-36) was removed from the study as all necessary information related to health-related quality of life (HRQoL) was captured from the revised assessment schedule of the European Quality of Life 5-Dimension (EQ-5D).

The following changes were made as per Amendment 2: Due to the change in the study design for the AD-833/TOMM40_301 study, that impacted the effect size, the potential number of subjects anticipated to rollover into the 303 study has been reduced from approximately 316 to 149. Changed the scope of site participation in the extension study, AD-4833/TOMM40_303. Since not all sites participated in the extension study, not all participants with an adjudicated diagnosis of mild cognitive impairment (MCI) due to AD in the 301 study were able to participate in 303. Russia and Italy were removed from AD-4833/TOMM40_301 and therefore, were also removed from this extension study. Exclusion criterion #8 was updated to be consistent with the AD-4833/TOMM40_301 study to clarify allowable repeat testing for hematuria. Criterion #12 was re-worded to be consistent with the AD-4833/TOMM40_301 study, where the correction of removing “any maculopathy” was made and approved in Amendment 1, then inadvertently reinserted in the body of the Amendment 2. Updated excluded medications table. Updated the assessor expectations for the Alzheimer’s Disease Cooperative Study – Resource Use Inventory (ADCS-RUI) assessment.

The following changes were made as per Amendment 3: HbA1c >8% as a criteria for exclusion was removed because this assessment was collected at Baseline, it was no longer considered an important eligibility criterion for this study. Exclusion criterion #8 was modified to allow the eligibility decision to be based on the laboratory results available prior to the AD-4833/TOMM40_301 EOS/303 Baseline visit to confirm/ensure eligibility for this extension study. Removed the adjudication process for confirmation of the diagnosis of dementia and added CDR Global score of ≥1.0 as a minimum standard for consistency in diagnosis of AD dementia. Removed magnetic resonance imaging (MRI) and computerized axial tomography (CT) scan (for participants with contraindication to MRI) at the Unscheduled Visit to support the possible dementia diagnosis.