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| Name | Class |
|---|---|
| Herlev Hospital | OTHER |
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In the world's high-income countries, Alzheimer's disease and other dementia diseases are currently the second most common cause of death. This is a recent change, as strokes in the form of blood clots or bleedings in the brain previously were the second most common cause of death.
In Denmark 90,000 live with dementia and life expectancy after dementia diagnosis is 5 to 8 years. Of these, 50,000 have Alzheimer's disease. By 2040 due to a steep increase of the elderly population, the number of people with dementia in Denmark is expected to profoundly increase to 120,000-146,000. This is a concerning forecast which calls for action for several reasons. First and foremost, for the sake of the many thousands of persons who will experience dementia. Every three hours, a Dane dies of dementia. There is currently no cure for Alzheimer's disease and there is a need for the development of an effective therapy. The use of cholinesterase inhibitors, such as donepezil, galantamine and rivastigmine, and the NMDA receptor antagonist memantine, may relieve symptoms, but cannot stop disease progression.
Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are among the promising therapies for repurposing as a treatment for Alzheimer's disease. Dementia rate was significantly lower both in type 2 diabetic patients randomized to GLP-1 RAs versus placebo (hazard ratio: 0.47) and in a nationwide Danish registry-based cohort (HR: 0.89) with yearly increased exposure to GLP-1 RAs in a publication on pooled data from three randomized double-blind placebo-controlled trials (15,820 patients) and the cohort (120,054 patients). It is not known whether treatment with GLP-1 RAs may reduce the incidence of dementia in patients without diabetes. There are ongoing studies of whether the GLP-1 RA semaglutide (Rybelsus®), which has a 94% similarity to the naturally occurring human GLP-1 hormone, has a positive effect on early Alzheimer's disease, namely the EVOKE and EVOKE Plus clinical trials.
In this present placebo-controlled clinical trial, the effect of semaglutide (Rybelsus®) on cognitive impairment in Alzheimer's disease will be investigated. The primary hypothesis is that treatment with semaglutide (Rybelsus®) in combination with other treatments will reduce the progression of the cognitive impairment compared to the control group. In comparison with the EVOKE trials focusing on semaglutide as monotherapy, this present trial will investigate the effect of semaglutide both alone and combined with other treatments.
The secondary hypothesis is that patients with mild cognitive impairment and Alzheimer's disease have a more frequent incidence of gingivitis and periodontitis, especially with the bacterium Porphyromonas gingivalis producing its toxins in the oral cavity. Recent research has indicated that this bacteria from the mouth and gingiva through the bloodstream can spread to the brain and be a trigger for Alzheimer's disease. Lactobacillus rhamnosus (LGG) has demonstrated to decrease the level of Porphyromonas gingivalis in plaque along with reduction in gingivitis.
Further hypotheses tested in this trial
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Intervention - semaglutide only | Experimental | An intervention group treated with semaglutide (Rybelsus®) 3 mg daily for 4 weeks followed by 7 mg daily for 4 weeks, hereafter 14 mg daily and placebo. |
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| Control | Placebo Comparator | A control group treated with placebo and no further intervention. |
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| Intervention - combination | Experimental | An intervention group will be treated with semaglutide (Rybelsus®) 3 mg daily for 4 weeks, followed by 7 mg daily for 4 weeks, and subsequently 14 mg daily. The intervention will also include candesartan up to 32 mg daily, a multivitamin-mineral tablet containing vitamin D and calcium, increased oral hygiene and a tooth lozenge (CariGuard®). |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Semaglutide (Rybelsus®) combined with other interventions | Drug | The full intervention includes treatment with semaglutide (Rybelsus®) 3 mg daily for 4 weeks, followed by 7 mg daily for 4 weeks, and subsequently 14 mg daily. The intervention will also include candesartan up to 32 mg daily, a multivitamin-mineral tablet containing vitamin D and calcium, increased oral hygiene and a tooth lozenge (CariGuard®) |
| Measure | Description | Time Frame |
|---|---|---|
| The Montreal Cognitive Assessment | The Montreal Cognitive Assessment is a cognitive screening instrument which provides an estimate of the level of intellectual functioning. Scores are from 0 to 30, where a score of 26 or higher is considered normal. Montreal Cognitive Assessment is moreover sensitive to mild cognitive problems as well as dementia. Studies have shown that Montreal Cognitive Assessment is more sensitive than Mini Mental State Examination to detecting mild cognitive changes and is as effective in identifying the incidence of Alzheimer's disease. | At inclusion, and 52 and 78 weeks. |
| Measure | Description | Time Frame |
|---|---|---|
| Measurement of β-Amyloid1-42 | Measurement in CSF of β-Amyloid1-42 using the Elecsys System Cobas® provided by Roche Diagnostics, Denmark, where more pronounced changes in markers for positive identification of Alzheimer's disease in the control group will be expected. Measurements of beta-amyloid, vitamin D and Herpes Simplex Virus (HSV-1) will be carried out by the medical investigator. | Performed at inclusion, and 6, 12, and 18 months. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Karsten OVergaard, MD, Specialist in Neurology | Contact | +4526172611 | karsten.overgaard@regionh.dk | |
| Rune S Rasmussen, MSc (neuropsychology), PhD | Contact | +4528757500 | rsr@sund.ku.dk |
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| ID | Term |
|---|---|
| D000544 | Alzheimer Disease |
| ID | Term |
|---|---|
| D003704 | Dementia |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
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| ID | Term |
|---|---|
| C000591245 | semaglutide |
| C081643 | candesartan |
| D002118 | Calcium |
| ID | Term |
|---|---|
| D008673 | Metals, Alkaline Earth |
| D004602 | Elements |
| D007287 | Inorganic Chemicals |
| D008670 | Metals |
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180 participants with mild cognitive impairments are randomized into 3 groups of 60 participants each and treated for 1.5 years (78 weeks):
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Treatment with medications will be double blinded and oral hygiene treatment will be single blinded, as it is impossible to blind patients to increased oral hygiene. The evaluators of a patient do not know the patient's treatment group, or if it is a baseline evaluation or a final evaluation.
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| Placebo | Other | A control group treated with placebo and no further intervention |
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| Semaglutide (Rybelsus®) | Drug | An intervention group treated with semaglutide (Rybelsus®) 3 mg daily for 4 weeks followed by 7 mg daily for 4 weeks, hereafter 14 mg daily and placebo |
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| Measurement of Tau | Measurement in CSF of Tau (total and phosphorylated) using the Elecsys System Cobas® provided by Roche Diagnostics, Denmark, where more pronounced changes in markers for positive identification of Alzheimer's disease in the control group will be expected. CSF levels of phosphorylated p-tau217 and p-tau181 are measured at inclusion and thereafter every 6 months. | At inclusion, and 6, 12, and 18 months |
| MRI scan of the brain | Registration of substance loss (atrophy) of the medial part of the temporal lobe demonstrated in coronal sections, compatible with Alzheimer's disease, will be performed, and patients will be monitored for other kinds of brain pathologies. We will use resting state fMRI data to analyze trends of functional connectivity alterations in the patients. | At inclusion, and 52 and 78 weeks. |
| PET scan of the brain | PET scans will be performed using (18F-FDG PET) to identify any decreased regional glucose metabolism in the temporal and parietal regions and PiB (PiB-PET scan) with amyloid plaques in the brain compatible with Alzheimer's disease. | At inclusion, and 52 and 78 weeks. |
| Clinical Dementia Rating scale - Sum of Boxes | Clinical Dementia Rating scale - Sum of Boxes (CDR-SB) scores reliably discriminated between mild cognitive impairment (MCI) and very early Alzheimer disease.The CDR-SB provides a more quantitative measure than the single "Global CDR Score." It is considered more sensitive to early cognitive changes and is useful for tracking changes over time, especially in clinical trials. General guidelines for interpreting the CDR-SB score are as follows: 0: Normal 0.5 - 4.0: Questionable cognitive impairment to very mild dementia 4.5 - 9.0: Suggests mild dementia 9.5 - 15.5: Suggests moderate dementia 16.0 - 18.0: Suggests severe dementia | At inclusion, and 52 and 78 weeks. |
| Symbol Digit Modalities Test | Danish norms exists. Participants are given a key showing a set of geometric symbols and their corresponding digits (e.g., a "]" symbol corresponds to the number "4"). They then have a grid of symbols and must quickly write or say the correct digit for each symbol. The test is timed, with a standard duration of 90 seconds. The raw score is simply the total number of correct substitutions made within that 90-second interval. Incorrect or omitted responses do not count. Higher scores are better. | At inclusion, and 52 and 78 weeks |
| Quality of Life - Alzheimer's Disease (QoL-AD). | The Quality of Life-Alzheimer's Disease (QoL-AD) scale is a widely used tool for assessing the subjective well-being of individuals with Alzheimer's and other forms of dementia. It is scored in a straightforward manner, but its key feature is that it can be completed by both participants and caregivers (proxy), which allows for a more comprehensive view of their quality of life. The QoL-AD consists of 13 items covering various life domains, such as physical health, energy, mood, living situation, memory, family, friends, and the ability to do things for fun. Each of the 13 items is rated on a 4-point scale:
The total score is the sum of the ratings for all 13 items. The minimum possible score is 13 (1 point for each of the 13 items), and the maximum is 52 (4 points for each item). A higher score indicates a better quality of life. | At inclusion, and 52 and 78 weeks |
| Patient Global Impression of Change (PGI-C). | The Patient Global Impression of Change (PGI-C) is a single-item, patient-reported outcome measure used to evaluate a patient's overall perception of how their condition has changed since the start of a treatment or study. Scoring is based on a simple, usually 7-point, Likert scale. The PGI-C is a self-administered questionnaire that asks the patient to rate the change in their condition. The scale ranges from "very much worse" to "very much improved," with "no change" as the midpoint. Instead of a total score like other scales, the PGI-C result is a single number corresponding to the patient's selected response. The interpretation is often dichotomous, meaning it's used to classify patients into "improved" or "not improved." The PGI-C is considered a "gold standard" for assessing a subjective experience of change because it directly asks them what participants think. This is useful in clinical trials to complement objective measures and provide participant-centered perspectives. | At inclusion, and 52 and 78 weeks |
| European Quality of Life-5 Dimensions Questionnaire (EuroQol-5D™, EQ-5D) | The EuroQol-5 Dimensions (EQ-5D) is a widely used, standardized instrument for measuring health-related quality of life. It is scored in two main parts, which are often used independently or together: the descriptive system and the EQ Visual Analogue Scale (EQ VAS). The responses to the five dimensions are combined into a 5-digit code or "health profile." For example, a response of "no problems," "slight problems," "moderate problems," "severe problems," and "extreme problems" would be represented by the health profile 12345 on the EQ-5D-5L. A score of 11111 represents perfect health. A descriptive health profile (e.g., 11123), which can be converted into a single index value (utility score) using a country-specific value set. The EQ Visual Analogue Scale (EQ VAS) is a separate, single-item component of the EQ-5D, where participants are asked to rate their overall health "today" on a vertical scale from 0 to 100. The score is simply the number the respondent marks on the scale.. | At inclusion, and 52 and 78 weeks |
| The Major Depression Inventory (MDI) | The Major Depression Inventory (MDI) is a self-report questionnaire used to assess depressive symptoms and the severity of depression. As a severity scale, MDI provides a total score that indicates the degree of depressive symptoms. Total Score: The scores from all 10 items are summed up. The theoretical range of the total score is from 0 (no depression) to 50 (maximum depression). | At inclusion, and 52 and 78 weeks. |
| The Rey-Osterrieth Complex Figure Test | The Rey-Osterrieth Complex Figure (ROCF) test is a neuropsychological assessment used to evaluate visuospatial abilities, memory, and executive functions. Participants copy an advanced visual figure (without later recall). Rey-Osterrieth Complex Figure is scored by a trained clinician who systematically evaluates the accuracy and placement of 18 specific components, with a maximum possible score of 36, higher scores are best. This process provides a quantitative measure of visuospatial and memory skills and a qualitative understanding of the individual's cognitive strategy. Danish norms exist. The test is sensitive to Alzheimer's disease. | At inclusion, and 52 and 78 weeks. |
| The 12-item Neuropsychiatric Inventory (NPI-12) | The 12-item Neuropsychiatric Inventory (NPI-12) is scored based on a structured interview with a caregiver who knows the patient well. Only the Caregiver Distress Scale will be used. For each of 12 symptom domain where a behavior is present, the caregiver is asked to rate how distressing the behavior is for them personally. Distress Rating: This is rated on a scale from 0 to 5: 0: Not distressing at all
The Total Caregiver Distress Score range from 0 (best) to 60 (worst). This score helps researchers understand the impact of the patient's behaviors on their caregivers. | At inclusion, and 52 and 78 weeks. |
| D024801 |
| Tauopathies |
| D019636 | Neurodegenerative Diseases |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |
| D001779 |
| Blood Coagulation Factors |
| D001685 | Biological Factors |