This clinical trial is studying early Alzheimer’s disease, including mild cognitive impairment and mild dementia of the Alzheimer’s type. The treatment being tested is semaglutide, taken as an oral tablet under the brand names Rybelsus 3 mg, Rybelsus 7 mg, and Rybelsus 14 mg. Some people in the study receive placebo tablets instead of the active medicine.
The purpose of the study is to see whether oral semaglutide can help slow worsening of memory, thinking, and daily function in people with early Alzheimer’s disease, and to check its safety. The study is randomised, which means the treatment is assigned by chance, and double-blind, which means neither the participants nor the study team knows who receives semaglutide or placebo during the study. Treatment is taken by mouth over a long period, and the study follows changes over time.
Participants take the study tablets regularly and are seen at planned visits during the trial. These visits are used to monitor health, review how the person is doing, and record any changes in memory, daily activities, or side effects. The study compares how people do over time in the semaglutide and placebo groups.
1study treatment begins
You start the trial by taking oral semaglutide tablets or placebo tablets. A placebo is a tablet that looks like the study medicine but does not contain the active drug.
The study uses three semaglutide tablet strengths: 3 mg, 7 mg, and 14 mg. The tablets are taken by mouth.
The trial is randomised, which means the treatment is assigned by chance, and double-blind, which means neither you nor the study team knows which treatment you receive during the trial.
2treatment period
You continue taking the assigned tablets during the study period. The medicine is given once daily by mouth.
The main treatment period lasts until week 104. This is the time point used to measure the main study result.
The main result is the change in thinking and daily function from the start of the study to week 104. Thinking and function are measured with the clinical dementia rating – sum of boxes (CDR-SB) score. This is a scale used to show how much help is needed in different areas of daily life and thinking.
3follow-up assessments during treatment
During the trial, you have study assessments to check changes in your condition over time.
One assessment measures daily functioning with the 24-item alzheimer’s disease cooperative study activities of daily living scale for mild cognitive impairment (ADCS-ADL-MCI). This is a questionnaire that measures how well you manage everyday activities.
This daily function measure is compared from week 0 to week 104.
4extended observation period
Some patients are followed for a longer period to see how long it takes for the condition to become more severe.
For patients who have a CDR global score of 0.5 at the start of the study, the trial checks the time to progression to a CDR global score of 1.0 or higher. A CDR global score is a general rating of the level of memory and daily-life problems.
This longer observation can continue from week 0 up to week 156b.
Who Can Join the Study?
Be a man or woman between 55 and 85 years old, including both ages, when signing the informed consent form.
Have mild cognitive impairment (a mild problem with memory or thinking) or mild dementia of the Alzheimer’s type, based on the NIA-AA 2018 criteria (standard medical rules used to diagnose these conditions).
Have a Clinical Dementia Rating (CDR) global score of 0.5 and a score of 0.5 or higher in at least one of these daily life areas: personal care, home and hobbies, or community affairs; or have a CDR global score of 1.0. The CDR is a scale that measures how much memory and thinking problems affect daily life.
Have a Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) delayed memory index score of 85 or lower. This is a test score that measures delayed memory, meaning how well a person remembers information after some time has passed.
Have a Mini-Mental State Examination (MMSE) score of 22 or higher. This is a short test that measures thinking skills such as memory, attention, and language.
Have amyloid positivity, meaning signs of amyloid buildup in the brain, shown by either an amyloid PET scan or cerebrospinal fluid (CSF) testing. CSF is the fluid around the brain and spinal cord. The CSF test must show either A beta 1-42 or A beta 1-42/A beta 1-40 results that meet the study’s requirements.
If already taking an approved Alzheimer’s disease treatment, such as acetylcholinesterase inhibitors, memantine, or aducanumab, the dose must have been stable for at least 3 months before screening, and it should not be changed during the study unless it is medically necessary.
Who Cannot Join the Study?
A brain MRI (magnetic resonance imaging) or CT scan showing a serious structural brain problem, such as a large stroke, a past major brain bleed, abnormal blood vessels, a brain aneurysm, a brain tumor, or signs of normal pressure hydrocephalus (a buildup of fluid in the brain).
A brain MRI or CT scan showing important small vessel disease (damage to the tiny blood vessels in the brain), such as more than one small stroke-like area called a lacunar infarct, or too much white matter damage in the deep or around the fluid spaces of the brain.
A brain MRI or CT scan showing certain strategic infarcts (small brain tissue injuries in important locations), including both thalamus areas being affected or a single infarct in a specific thalamus area.
Any other important neurological disorder at screening, meaning a disease of the brain or nervous system, other than mild cognitive impairment or mild Alzheimer-type dementia. This includes conditions such as Parkinson’s disease, Lewy body disease, frontotemporal dementia, Huntington’s disease, amyotrophic lateral sclerosis (a disease that weakens muscles), multiple sclerosis, systemic lupus erythematosus, progressive supranuclear palsy, neurosyphilis, HIV, learning disability, intellectual disability, brain damage from lack of oxygen, or serious head injury with loss of consciousness that caused lasting memory or thinking problems.
A serious or unstable psychiatric disorder at screening, meaning a mental health condition that is not well controlled. This includes schizophrenia or another psychotic disorder (a condition that can affect a person’s contact with reality), or bipolar disorder. A past history of major depression does not automatically exclude a person if there has been no episode in the last 24 months and the depression is in remission or well controlled with treatment.
Rybelsus is an oral tablet that contains semaglutide. In this trial, it is the active treatment being tested to see whether it can help slow changes in thinking and daily function in people with early Alzheimer’s disease. Participants take it by mouth, and the study compares its effects with placebo to check both how well it works and how safe it is.
Semaglutide placebo tablet is an inactive tablet that looks like the study medicine but does not contain the active drug. It is used so researchers can compare results fairly and see whether any changes are really caused by the active treatment rather than by expectation or chance.
Alzheimer’s disease – Alzheimer’s disease is a brain disorder that causes a gradual decline in memory, thinking, and the ability to carry out everyday activities. It usually begins with mild problems such as forgetfulness or reduced attention and slowly worsens over time. In some people, it first appears as mild cognitive impairment, where thinking changes are present but daily function is mostly preserved. As it progresses, more aspects of memory, reasoning, and daily living become affected, leading to mild dementia and then more advanced stages.
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