I5T-MC-AACO: Global Study to Investigate Safety and Efficacy of Donanemab in Early Symptomatic Alzheimer’s Disease

The primary objective of this study is to assess the effect of donanemab versus placebo on clinical progression in participants with early symptomatic Alzheimer's disease. This evaluation is clinically relevant as it aims to determine whether donanemab, an antibody directed at amyloid beta, can modify disease progression in the early stages of Alzheimer's disease, a period when therapeutic intervention may have the greatest potential to alter the disease trajectory and preserve cognitive function.

The clinical trial enrolled a total of **1062 participants** diagnosed with **early symptomatic Alzheimer's Disease**. The study population included both **male and female** **adults** aged 60 to 85 years. Participants were required to demonstrate gradual and progressive memory function changes reported by themselves or informants for at least 6 months prior to enrollment. Eligibility was determined based on cognitive assessment, with participants having a **Mini-Mental State Examination (MMSE)** score ranging from 20 to 28 at screening, indicating mild cognitive impairment to mild dementia. A critical selection criterion involved meeting specific **amyloid scan** criteria through central read evaluation, confirming the presence of **amyloid pathology** consistent with Alzheimer's Disease. Additionally, each participant was required to have a study partner who provided written informed consent to participate, ensuring adequate support and reliable reporting throughout the trial duration. The trial population excluded vulnerable populations and focused on individuals with confirmed biomarker evidence of the disease.

This is a phase III randomized, double-blind, placebo-controlled clinical trial designed to evaluate the safety and efficacy of **donanemab** compared to **placebo** in participants with early symptomatic **Alzheimer's disease**. The investigational medicinal product donanemab is an **antibody** directed at **amyloid beta**, administered as a **solution for injection** via **intravenous infusion**. The trial also utilizes auxiliary medicinal products including **florbetapir (18F)** and **flortaucipir (18F)**, both administered as solutions for injection via intravenous infusion, for diagnostic imaging purposes. Sodium chloride is used as placebo. The primary objective is to assess the effect of donanemab versus placebo on clinical progression in this patient population. The primary endpoint measures change from baseline on the **Integrated Alzheimer's Disease Rating Scale (iADRS)** at week 76 in at least one of the low-medium tau pathology population or no-very low and low-medium tau pathology populations.

Participants eligible for enrollment must demonstrate gradual and progressive change in memory function reported by the participant or informant for at least 6 months. At screening, participants must have a **Mini-Mental State Examination (MMSE)** score between 20 and 28 inclusive. Participants must meet amyloid scan criteria based on central read evaluation. A study partner who provides written informed consent to participate is required for each participant. The screening visit includes assessment of inclusion criteria, cognitive testing, and amyloid imaging to confirm eligibility.

The estimated recruitment start date is November 2025, with an estimated trial completion date of June 2028. The maximum treatment period is defined, with specific dosing schedules for the investigational and auxiliary products. Follow-up visits are conducted at regular intervals throughout the study period to assess efficacy endpoints, monitor safety parameters, and evaluate disease progression. The end-of-study visit occurs at week 76, at which time the primary efficacy assessment is completed. Participant involvement extends for the duration of the treatment period and follow-up assessments as specified in the protocol. Conditions that may lead to early termination from the study include safety concerns, withdrawal of consent, protocol violations, or investigator decision based on the participant's best interest.

**Donanemab** (sponsor product code LY3002813) is the experimental medicinal product in this clinical trial. It is an **antibody directed at amyloid beta** and is formulated as a **solution for injection**. The active substance is donanemab, which is a protein of non-chemical origin. The medicinal product is administered via **intravenous infusion**. Specific dosage information, including the maximum daily dose amount and maximum total dose amount, has not been specified in the available data. The maximum treatment period is defined as 1 day for the purposes of regulatory documentation.

**Sodium chloride Ph. Eur.** is utilized as the **placebo** comparator in this study. It is formulated as an injection and contains sodium chloride of chemical origin as the active substance. The placebo is administered via **intravenous infusion**. The maximum daily dose amount and maximum total dose amount are not specified. The maximum treatment period is 1 day. This placebo serves as the control treatment against which the efficacy and safety of donanemab are evaluated.

**Florbetapir (18F)** (sponsor product code LY3078786), also known as **Florbetapir F18**, is employed as an **auxiliary medicinal product** in this trial. It is a radiopharmaceutical formulated as a **solution for injection** containing the chemical active substance florbetapir (18F). The product is administered via **intravenous infusion**. The **maximum daily dose amount** is 7.43 units, and the **maximum total dose amount** is 29.72 units. The maximum treatment period is 1 day. This auxiliary agent is used for diagnostic imaging purposes to support the assessment of participants in the study.

**Flortaucipir (18F)** (sponsor product code LY3191748), also referred to as **Flortaucipir F18**, is another **auxiliary medicinal product** utilized in the trial. It is a radiopharmaceutical presented as a **solution for injection** with flortaucipir (18F) as the chemical active substance. Administration is performed via **intravenous infusion**. The **maximum daily dose amount** is 9.10 units, which also represents the **maximum total dose amount**. The maximum treatment period is 1 day. This auxiliary product serves as a diagnostic imaging agent to facilitate clinical assessments within the study protocol.

The primary efficacy endpoint will be assessed by measuring the change from baseline on the **Integrated Alzheimer's Disease Rating Scale** (iADRS) at Week 76. The evaluation will be conducted in at least one of the following populations: the low-medium **tau pathology** population or the no-very low and low-medium tau pathology populations. The iADRS will be used to evaluate the effect of **donanemab** versus **placebo** on clinical progression in participants with **early symptomatic Alzheimer's disease**.