Evaluation of Safety and Efficacy of PRI-002 in Patients with Mild Cognitive Impairment or Mild Dementia Due to Alzheimer's Disease: A Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of this study is to evaluate the **safety** and **efficacy** of multiple doses of PRI-002 in subjects with mild cognitive impairment (MCI) or mild dementia due to **Alzheimer's disease** (AD). Safety assessment is based on the incidence of drug-related adverse events (AEs), which is crucial for determining the tolerability of the treatment. Efficacy is evaluated using the Clinical Dementia Rating-Sum of Boxes (CDR-SB), a standard measure for assessing the severity of dementia, which is clinically relevant for understanding the potential therapeutic benefits of PRI-002.

Secondary objectives include: - Evaluating the safety and tolerability of multiple doses of PRI-002 based on AEs, amyloid-related imaging abnormalities oedema (ARIA-E) and haemosiderin (ARIA-H), and treatment discontinuations due to AEs. - Assessing clinical outcome measures and biomarkers associated with multiple doses of PRI-002. - Monitoring drug levels of PRI-002 during the administration of multiple doses in the target population. These objectives aim to provide a comprehensive understanding of the drug's safety profile, its impact on clinical outcomes, and pharmacokinetics, which are essential for the development of effective treatments for AD.

The clinical trial involves participants diagnosed with **Alzheimer's disease**, specifically those with mild cognitive impairment (MCI) or mild dementia due to Alzheimer's. The study population includes both male and female subjects aged between 55 and 80 years. Participants are required to have a body mass index (BMI) ranging from 18.5 to 30.0 kg/m². The trial does not include a vulnerable population. Participants were selected based on specific criteria, including a Mini-Mental State Examination (MMSE) score of 22 to 30 and a Repeatable Battery for the Assessment of Neuropsychological Status - Delayed Memory Index (RBANS-DMI) score of 85 or less. Additionally, a Clinical Dementia Rating (CDR) global score of 0.5 or 1 with a memory score of at least 0.5 is required. Confirmation of Alzheimer's diagnosis is necessary, either through cerebrospinal fluid (CSF) biomarker profile or positive amyloid positron emission tomography (PET) evidence. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the safety and efficacy of the investigational product, PRI-002, in patients with mild cognitive impairment (MCI) or mild dementia due to **Alzheimer's disease**. The trial will involve multiple doses of PRI-002, administered orally in capsule form, with a maximum daily dose of 600 mg and a total treatment period of 96 weeks. The primary objectives are to assess the safety and tolerability of PRI-002 based on the incidence of drug-related adverse events (AEs) and to evaluate its efficacy using the Clinical Dementia Rating-Sum of Boxes (CDR-SB) as a measure of global outcome.

The trial will commence with a screening visit to confirm eligibility, which includes criteria such as age between 55 and 80 years, a body mass index (BMI) between 18.5 and 30.0 kg/m², and a diagnosis of MCI or mild dementia due to Alzheimer's disease according to NIA-AA criteria. Participants must also have a Mini Mental State Examination (MMSE) score of 22 to 30 and a CDR global score of 0.5 or 1. Following successful screening, participants will be randomized to receive either PRI-002 or a placebo.

Study visits will occur at regular intervals throughout the trial to monitor safety and efficacy outcomes. These visits will include assessments of AEs, serious adverse events (SAEs), and changes in cognitive and functional measures. Biomarker analyses will be conducted to evaluate changes in cerebrospinal fluid (CSF) and plasma concentrations of relevant biomarkers. The trial will conclude with an end-of-study visit to assess final outcomes and ensure participant safety.

The expected duration of participant involvement is up to 48 weeks, with conditions for early termination including the occurrence of significant AEs or SAEs, or if a participant withdraws consent. The trial is anticipated to end by May 2026, with recruitment starting in October 2023. The study is categorized as a Phase II trial, focusing on both safety and efficacy endpoints.

The clinical trial involves the administration of an **experimental medication** known as PRI-002, which is a synthetic peptide. The active substance in PRI-002 is **D-prolyl-D-threonyl-D-leucyl-D-histidyl-D-threonyl-D-histidyl-D-asparaginyl-D-arginyl-D-arginyl-D-arginyl-D-arginyl-D-arginine amide acetate**. This medication is provided in the form of a capsule and is administered orally. The maximum daily dose of PRI-002 is 600 mg, with a total maximum dose of 300 mg per administration. The treatment period for this medication is up to 96 days. The trial aims to evaluate the safety and efficacy of PRI-002 in patients with mild cognitive impairment (MCI) or mild dementia due to Alzheimer's disease.

In addition to the experimental medication, a **placebo** is used as a comparator treatment in this study. The placebo is designed to match the experimental medication in appearance but does not contain any active pharmaceutical ingredients. The placebo is administered in the same manner as PRI-002, ensuring that the study remains double-blind. This means that neither the participants nor the investigators know who is receiving the experimental medication or the placebo, which helps to eliminate bias in the assessment of the treatment's efficacy and safety.

The efficacy of the investigational product PRI-002 in the clinical trial will be assessed using the **Clinical Dementia Rating-Sum of Boxes (CDR-SB)** as the primary endpoint. This measure will evaluate changes in global outcomes from baseline to week 48. Secondary endpoints include changes in additional cognitive and functional assessments such as the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) and the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog 13) from baseline to week 48. Biomarker analysis will also be conducted, assessing changes in cerebrospinal fluid (CSF) and plasma biomarker concentrations, including the ratio of Aβ 1-42/1-40, phosphorylated tau (p-tau), total tau (t-tau), Aβ oligomers, tau oligomers, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP). Additionally, PRI-002 plasma concentrations will be monitored over time, and Mini Mental State Examination (MMSE) scores will be evaluated.

The collection and analysis of these efficacy parameters will be conducted at specified timepoints, with the primary endpoint being assessed at week 48. The trial is designed as a randomized, double-blind, placebo-controlled study, ensuring rigorous evaluation of the efficacy of PRI-002 in patients with mild cognitive impairment (MCI) or mild dementia due to Alzheimer's disease. The study will adhere to validated scales and laboratory tests to ensure the accuracy and reliability of the efficacy assessments.