Evaluation of Oral Semaglutide Efficacy and Safety in Patients with Early Alzheimer's Disease: A Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of this study is to confirm the **superiority** of oral semaglutide administered once daily compared to placebo, when added to standard care, in terms of changes in cognition and function. This is measured by the Clinical Dementia Rating – Sum of Boxes (CDR-SB) score from baseline to week 104 in patients with mild cognitive impairment (MCI) or mild dementia, both of the Alzheimer's type. This objective is clinically relevant as it aims to assess the potential of semaglutide to improve cognitive and functional outcomes in early Alzheimer's disease, which could significantly impact patient management and quality of life.

Secondary objectives include: - Confirming the superiority of oral semaglutide over placebo in improving activities of daily living, as measured by the Alzheimer's Disease Cooperative Study Activities of Daily Living Scale for MCI (ADCS-ADL-MCI) score from baseline to week 104. - Evaluating the time to progression to a CDR global score ≥1.0 among patients with a baseline CDR global score of 0.5, measured up to week 156. - Comparing the efficacy of semaglutide versus placebo in terms of changes in cognition and function, as measured by CDR-SB and ADCS-ADL-MCI scores, from baseline to week 156. - Assessing the effects of semaglutide on quality of life in subjects with MCI or mild dementia, both of the Alzheimer's type.

The clinical trial involves a total of **1155 participants** diagnosed with **mild cognitive impairment (MCI)** or mild dementia, both of the **Alzheimer's type**. The study population includes both male and female subjects, aged between **55 and 85 years**. Participants were selected based on specific criteria, including a Clinical Dementia Rating (CDR) global score of 0.5 or 1.0, and an RBANS delayed memory index score of 85 or below. Additionally, participants must have demonstrated amyloid positivity through either amyloid PET or CSF A beta 1-42 testing. Those receiving approved Alzheimer's disease treatments were required to maintain a stable dose for at least three months prior to screening. The trial population is characterized by a vulnerable group, with lifestyle considerations such as diet and physical activity not specified. The selection process ensured the inclusion of individuals who met the NIA-AA 2018 criteria for MCI or mild dementia of the Alzheimer's type, with a Mini-Mental State Examination (MMSE) score of 22 or higher.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy and safety of oral **semaglutide** in individuals with early **Alzheimer's disease**, specifically those with mild cognitive impairment (MCI) or mild dementia of the Alzheimer's type. The primary objective is to confirm the superiority of semaglutide over placebo in improving cognition and function, as measured by the Clinical Dementia Rating – Sum of Boxes (CDR-SB) score from baseline to week 104. The trial will involve the administration of semaglutide in tablet form, with dosages of 3 mg, 7 mg, and 14 mg, alongside a placebo group, all administered orally. The trial is expected to last until October 2026, with participant involvement spanning approximately 157 weeks.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age (55-85 years), cognitive status, and amyloid positivity. Following successful screening, participants will be randomized to receive either semaglutide or placebo. Regular follow-up visits will be scheduled to monitor safety, adherence, and efficacy, with assessments including the CDR-SB and the 24-item Alzheimer's Disease Cooperative Study Activities of Daily Living Scale for MCI (ADCS-ADL-MCI). The end-of-study visit will occur at week 104, where final assessments will be conducted to evaluate the primary and secondary endpoints.

Participant involvement may be terminated early if any exclusion criteria are met post-randomization, if there are significant adverse events, or if the participant withdraws consent. The trial will ensure blinding by using tablets without debossment on one face and "M8" debossed on the other, with identical debossment across all strengths to maintain blinding integrity. The trial's design and procedures are structured to rigorously assess the potential benefits of semaglutide in slowing cognitive decline in Alzheimer's disease, with a focus on maintaining participant safety and data integrity throughout the study duration.

The clinical trial involves the administration of **Rybelsus** tablets, which contain the active substance **semaglutide**. The trial includes three different dosages of Rybelsus: 3 mg, 7 mg, and 14 mg. These tablets are manufactured by Novo Nordisk A/S and are administered orally. The tablets are designed for blinding purposes, with no debossment on one face and "M8" debossed on the other. The packaging and labeling are also modified to maintain blinding. The maximum treatment period for each dosage is 157 days. The trial aims to evaluate the efficacy and safety of oral semaglutide in subjects with early Alzheimer's disease.

In addition to the experimental medication, a **placebo** is used as a comparator in the study. The placebo tablets are designed to match the appearance of the semaglutide tablets to ensure blinding. The placebo does not contain any active substance and is administered orally in the same manner as the semaglutide tablets. The use of a placebo allows for a controlled comparison to assess the true effect of the semaglutide treatment on cognitive and functional changes in patients with mild cognitive impairment or mild dementia of the Alzheimer's type.

The efficacy of oral **semaglutide** in subjects with early Alzheimer's disease will be assessed through a randomized, double-blind, placebo-controlled clinical trial. The primary endpoint for evaluating efficacy is the change in the Clinical Dementia Rating – Sum of Boxes (CDR-SB) score from baseline to week 104. This score ranges from 0 to 18, with higher scores indicating greater impairment. Secondary endpoints include the change in the 24-item Alzheimer's Disease Cooperative Study Activities of Daily Living Scale for MCI (ADCS-ADL-MCI) score, which ranges from 0 to 53, and the time to progression to a CDR global score of 1.0 or higher among patients with a baseline CDR global score of 0.5, measured from baseline up to week 156.

Measurements will be collected at specified timepoints, with the primary endpoint assessed from baseline to week 104. The secondary endpoints will also be evaluated over the course of the trial, with the ADCS-ADL-MCI score assessed from baseline to week 104 and the progression to a higher CDR global score monitored up to week 156. The trial aims to confirm the superiority of oral semaglutide over placebo in improving cognition and function in patients with mild cognitive impairment (MCI) or mild dementia of the Alzheimer's type. The trial is designed to ensure blinding, with all tablet strengths having the same debossment and distinct packaging and labeling to maintain the integrity of the study.