Oral semaglutide versus placebo in early Alzheimer’s disease: a randomized double-blind trial in patients with mild cognitive impairment or mild dementia

The primary objective is to confirm the superiority of semaglutide versus placebo on the change in cognition and function in subjects with mild cognitive impairment or mild dementia of the Alzheimer’s type. This is clinically relevant because it evaluates whether treatment can modify the combined cognitive-functional trajectory of early Alzheimer’s disease. The secondary objectives are to confirm superiority versus placebo for change in function as measured by the ADCS-ADL-MCI score from baseline to week 104; to assess time to progression to CDR global score ≥1.0 in participants with baseline CDR global score of 0.5 up to week 156b; to compare changes in cognition and function as measured by CDR-SB and ADCS-ADL-MCI from baseline to week 156; and to compare effects on quality of life.

The trial enrolled 982 male and female participants aged 55 to 85 years with mild cognitive impairment or mild dementia of the Alzheimer’s type. The population consisted of patients with generally preserved global cognitive status, defined by a Clinical Dementia Rating global score of 0.5 or 1.0, and required amyloid positivity confirmed by amyloid PET or cerebrospinal fluid biomarkers. Participants were selected according to predefined clinical criteria, including a Mini-Mental State Examination score of at least 22 and evidence of impaired delayed memory performance. If receiving approved Alzheimer’s disease treatment, the dose had to be stable for at least 3 months before screening. No additional information on lifestyle factors such as diet, physical activity, or habits was provided.

This is a randomized, double-blind, placebo-controlled phase 3 clinical trial evaluating oral semaglutide in subjects with early Alzheimer’s disease. The trial is designed to assess superiority of semaglutide versus placebo on change in cognition and function. Study participation begins with a screening visit to confirm eligibility, including diagnosis, cognitive criteria, amyloid positivity, and other required baseline conditions. Eligible participants then enter the treatment period and undergo scheduled follow-up visits for assessment of efficacy and safety endpoints, including the primary outcome at week 104. An end-of-study visit is performed at the end of the trial period, with secondary follow-up extending to week 156 for progression-related assessment. The overall trial duration is approximately 5 years, from May 2021 to October 2026. Expected participant involvement may last up to 156 weeks. Early termination may occur if eligibility criteria are no longer met, if discontinuation is required for medical reasons, or if treatment must be changed because of clinical necessity.

The investigational treatment consisted of semaglutide administered as oral tablets. The study products included Rybelsus 3 mg tablets, 7 mg tablets, and 14 mg tablets. The pharmaceutical form was tablet, and the route of administration was oral. The dosing regimen used these strengths as part of the study treatment schedule, with administration frequency not specified in the source data.

The non-experimental treatment was placebo tablets matching semaglutide tablets. The placebo arm was used as the comparator in this randomised, double-blind, placebo-controlled clinical trial. No additional information on dosing schedule, dose escalation, or compliance monitoring was provided in the source data.

Efficacy will be assessed by the change in Clinical Dementia Rating – Sum of Boxes (CDR-SB) score from baseline (week 0) to week 104. The score is measured on a 0 to 18 scale. A secondary efficacy assessment will evaluate the change in the 24-item Alzheimer’s Disease Cooperative Study Activities of Daily Living Scale for MCI (ADCS-ADL-MCI) score from baseline (week 0) to week 104. The score is measured on a 0 to 53 scale. Another secondary endpoint will assess time to progression to CDR global score ≥1.0 among participants with a CDR global score of 0.5 at baseline, from baseline (week 0) up to week 156b.