Efficacy and Safety of Trontinemab in Participants with Early Symptomatic Alzheimer’s Disease (MCI to Mild Dementia)

The primary objective is to evaluate the effect of trontinemab on clinical progression in participants with Alzheimer’s disease at week 72 compared to a placebo. Secondary objectives include:

• Evaluation of efficacy regarding clinical progression and time to clinical progression.
• Assessment of safety.
• Evaluation of pharmacodynamic effects.

This clinical trial involves 535 participants diagnosed with early symptomatic Alzheimer’s disease, encompassing individuals with mild cognitive impairment or mild dementia. The study population includes both males and females within specific age ranges categorized as 3 and 4. Participants must demonstrate evidence of an amyloid pathological process confirmed via amyloid positron emission tomography or cerebrospinal fluid analysis. Inclusion requires a Mini-Mental State Examination score of 22 or higher, a Clinical Dementia Rating global score of 0.5 or 1.0, and a Repeatable Battery for the Assessment of Neuropsychological Status delayed memory index score of 85 or lower. Additionally, subjects must possess adequate visual acuity and auditory acuity for neuropsychological testing, fluency in the testing language, and the availability of a study partner.

This Phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study evaluates the efficacy and safety of trontinemab in participants with early symptomatic Alzheimer’s disease, ranging from mild cognitive impairment to mild dementia. The primary objective is to assess the effect of the investigational product on clinical progression at Week 72 compared to a placebo. The methodology involves measuring changes in the Clinical Dementia Rating Sum of Boxes as the primary endpoint, alongside various secondary outcomes including cognitive assessments, activities of daily living, and biomarker changes. Study procedures begin with a screening visit to confirm the presence of amyloid pathology via positron emission tomography or cerebrospinal fluid analysis, and to evaluate neuropsychological status through the Mini-Mental State Examination and other standardized scales. Following screening, participants receive intravenous infusion of either trontinemab or placebo. The trial monitors clinical laboratory assessments, vital signs, electrocardiogram, and potential adverse events, including amyloid-related imaging abnormalities. Participant involvement is expected to continue through the evaluation period at Week 72, with study completion occurring at the end-of-study visit. Early termination may occur based on clinical safety or investigator judgment.

The experimental treatment consists of trontinemab, administered as a solution for injection/infusion via intravenous infusion.

The control group receives placebo Trontinemab.

Auxiliary treatments utilized in the study include several diagnostic agents: florbetapir (18F) administered as a solution for injection via intravenous bolus injection/IV infusion at a dose of 370 MBq; flutemetamol (18f) administered as a solution for injection via intravenous bolus injection/IV infusion at a dose of 185 MBq; florbetaben (18f) administered as a solution for injection via intravenous bolus injection/IV infusion at a dose of 300 MBq; and florquinitau (18f) administered as a solution for injection.

The primary efficacy endpoint is the change from baseline to Week 72 in the Clinical Dementia Rating, Sum of Boxes (CDR-SB). Secondary efficacy parameters include changes from baseline through Week 72 in the following measures: Alzheimer’s Disease Assessment Scale-Cognition 13 (ADAS-Cog-13), Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory (ADCS-ADL) total and instrumental scores, Integrated Alzheimer’s Disease Rating Scale (iADRS), and MMSE. The study also evaluates the time to increase in CDR-GS.

Assessment of biological markers involves measuring changes from baseline through Week 72 in brain amyloid load using amyloid positron emission tomography (PET) scans. In a subset of participants, brain tau load will be measured via tau PET scans. Additionally, changes from baseline through Week 72 in cerebrospinal fluid (CSF) biomarkers, including phosphorylated tau 181 (p-tau181), Neurogranin, and amyloid-beta 42 (Aβ42), will be evaluated in a subset of participants. Blood biomarker assessments will include changes from baseline through Week 72 in p-tau217 and glial fibrillar acidic protein (GFAP).