A Phase IB/IIA, Randomized, Double-Blind, Placebo-Controlled, Multiple-Ascending Dose, Parallel-Group Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of RO7126209 following Intravenous Infusion in Patients with Prodromal or Mild To Moderate Alzheimer’s Disease

The primary objective of this study is to evaluate the safety and tolerability of multiple-ascending doses of RO7126209 administered intravenously in patients with prodromal or mild to moderate Alzheimer's disease. This includes assessment of multiple-ascending doses in Parts 1 and 2, single intravenous doses in Part 3, and long-term administration of intravenous doses in Part 4. Additionally, the primary objective encompasses evaluation of the pharmacodynamic effects of multiple doses of RO7126209 in Part 3. These objectives are clinically relevant for determining the therapeutic potential and acceptable dosing regimen of this novel trontinemab-based intervention in Alzheimer's disease populations.

The secondary objectives include:

• Evaluation of pharmacodynamic effects of multiple doses in Parts 1-2 and long-term administration in Part 4 of RO7126209
• Investigation of pharmacokinetics in plasma following multiple intravenous doses in Parts 1-4 and single intravenous dose in Part 3
• Investigation of pharmacokinetics and cerebrospinal fluid penetration of a selected dose in plasma in Part 4
• Investigation of cerebrospinal fluid penetration after multiple doses in Parts 1-3
• Evaluation of immunogenicity of single dose in Part 3 and multiple doses in Parts 1-3
• Evaluation of immunogenicity of long-term administration in Part 4

This clinical trial enrolled a total of **157 participants** diagnosed with **Alzheimer's disease**. The study population consisted of both **male and female subjects** aged **50 to 85 years** at the time of screening. Participants presented with either probable **mild to moderate AD dementia** consistent with NIA-AA core clinical criteria or **prodromal AD** consistent with NIA-AA diagnostic criteria for **mild cognitive impairment** due to AD. Eligible individuals demonstrated a **Mini-Mental State Examination (MMSE)** score ranging from 18 to 28 points and a **Clinical Dementia Rating-Global Score (CDR-GS)** of 0.5, 1, or 2. A key requirement for inclusion was confirmation of amyloid pathology through a positive **amyloid PET scan** exceeding 50 Centiloid units obtained within 12 months prior to baseline. Participants receiving symptomatic AD medications were required to maintain a stable dosing regimen for at least 8 weeks before baseline and continue through randomization. The trial included a **vulnerable population**.

This is a **Phase Ib/IIa**, **randomized**, **double-blind**, **placebo-controlled**, **multiple-ascending dose**, **parallel-group study** investigating **Trontinemab** (RO7126209) administered via **intravenous infusion** in patients with **prodromal** or **mild to moderate Alzheimer's disease**. The study is designed to evaluate the **safety**, **tolerability**, **pharmacokinetics**, and **pharmacodynamics** of Trontinemab across multiple parts. The investigational medicinal product is a solution for injection/infusion containing trontinemab as the active substance, administered alongside a matching placebo. **Flortaucipir F18**, a solution for injection used as an auxiliary diagnostic agent, is employed for **tau imaging** via **PET scan**. The trial includes participants aged 50 to 85 years with confirmed **amyloid** positivity on **PET scan** (cut-off greater than 50 Centiloid units), **Mini-Mental State Examination** (MMSE) scores between 18 and 28 points, and **Clinical Dementia Rating-Global Score** (CDR-GS) of 0.5, 1, or 2. Participants receiving symptomatic Alzheimer's disease medications must maintain a stable dosing regimen for at least 8 weeks prior to baseline.

The study comprises multiple parts (Part 1, 2, 3, and 4), each designed to assess different aspects of the treatment. Part 1 and Part 2 evaluate multiple-ascending doses of Trontinemab, while Part 3 focuses on intravenous dosing regimens and Part 4 assesses long-term administration. The trial duration extends from the estimated recruitment start date in March 2021 to the estimated end date in September 2027, representing an extended period of investigation. Participant involvement varies depending on the study part, with long-term follow-up included in Part 4 to assess sustained effects and safety over time.

The **primary endpoints** include the assessment of the nature, frequency, severity, and timing of **adverse events** (AEs), including **dose-limiting adverse events** (DLAEs) in Part 1. Safety assessments encompass clinical laboratory evaluations, **vital signs**, physical and neurological examinations, **12-lead electrocardiogram** (ECG), and **brain magnetic resonance imaging** (MRI) findings, specifically monitoring for **vasogenic edema** and **hemorrhage**. In Part 3, the primary endpoint also includes the change from baseline in brain amyloid load as measured by amyloid PET scan. **Secondary endpoints** encompass the change from baseline in brain amyloid load in Parts 1, 2, and 4, plasma and **cerebrospinal fluid** (CSF) concentrations of Trontinemab at specified timepoints, and the incidence and titer of **anti-drug antibodies** (ADAs) against Trontinemab over time.

Study visits are structured to include a screening period during which eligibility criteria are confirmed, including amyloid PET scan results, MMSE scores, and CDR-GS assessments within specified timeframes before baseline. Following enrollment, participants undergo baseline assessments and randomization to receive either Trontinemab or placebo via intravenous infusion. Subsequent follow-up visits are scheduled to monitor safety parameters, collect pharmacokinetic samples from plasma and CSF, and conduct pharmacodynamic assessments including amyloid PET imaging. The end-of-study visit marks the completion of the assigned treatment period, with comprehensive safety and efficacy evaluations performed. Conditions that may lead to early termination from the study include the occurrence of significant adverse events, dose-limiting toxicities, withdrawal of consent, protocol deviations, or investigator discretion based on participant safety considerations. The structured visit schedule ensures systematic data collection to support the evaluation of Trontinemab's therapeutic potential in Alzheimer's disease.

The experimental medication **Trontinemab** (also known as RO-7126209, sponsor product code 712-6209/F01-01) is a **protein-based therapeutic agent** manufactured by F. Hoffmann-La Roche Ltd. The active substance is trontinemab, classified as a protein of other origin. The product is formulated as a **solution for injection/infusion** and is administered via **intravenous infusion**. The study investigates multiple-ascending doses of trontinemab in patients with prodromal or mild to moderate **Alzheimer's disease**. The trial is designed to evaluate the safety, tolerability, **pharmacokinetics**, and **pharmacodynamics** of trontinemab following intravenous administration across multiple study parts, including long-term administration phases.

**Placebo Trontinemab** serves as the **comparator treatment** in this randomized, double-blind, placebo-controlled study. The placebo is matched to the experimental medication to maintain blinding throughout the trial. Specific details regarding the pharmaceutical form, route of administration, and dosage specifications for the placebo are not provided in the available documentation. The placebo is administered in parallel groups to allow for direct comparison with the active treatment arms.

**Flortaucipir F18** (also known as LY3191748, 18F-AV-1451, or T807 F-18) is utilized as an **auxiliary medicinal product** in this clinical trial. This radiopharmaceutical agent is manufactured by Eli Lilly and Company Limited and contains the active substance **flortaucipir (18F)**, a chemical compound. The product is formulated as a **solution for injection** and is administered via **intravenous bolus injection or intravenous infusion**. Flortaucipir F18 is a **positron emission tomography (PET) imaging agent** used for diagnostic purposes to assess tau protein distribution in the brain, supporting the evaluation of pharmacodynamic effects in study participants.

Efficacy will be assessed through multiple parameters across the study parts. The primary efficacy endpoint for Part 3 is the change from baseline in brain amyloid load, as measured by amyloid PET scan. Secondary efficacy endpoints include the change from baseline in brain amyloid load, as measured by amyloid PET scan, for Parts 1, 2, and 4. Additional secondary endpoints comprise plasma concentration of Trontinemab at specified timepoints, cerebrospinal fluid concentration of Trontinemab, and the incidence and titer of anti-Trontinemab antibodies over time. The study utilizes amyloid PET scanning as a key imaging tool for quantifying amyloid burden, with a positive amyloid PET scan defined as greater than 50 Centiloid units at baseline. Clinical assessments at screening and baseline include the Mini-Mental State Examination with scores ranging from 18 to 28 points and the Clinical Dementia Rating-Global Score of 0.5, 1, or 2, both conducted within 84 days before baseline.