Improved Treatment and Monitoring of Alzheimer's Disease

Official title

Improved Treatment and Monitoring of Alzheimer's Disease - a Randomized Controlled Clinical Trial

Overview

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 * Administration of candesartan to patients with biomarker-confirmed initial-stage Alzheimer's disease will decrease levels of amyloid markers, improve cognitive function, and enhance brain connectivity. * Daily multivitamin-mineral, including vitamin D and calcium supplementation, will improve global cognition, episodic memory, and executive functions in older adults. * Alzheimer's disease is associated with certain abnormalities of vision and of the structure of the visual system, both of which can precede the development of symptoms of cognitive decline. Hard drusen are yellow deposits under the retina typically made up of lipids and proteins, which may predict retinal pathology, were more commonly found in the temporal region of Alzheimer's disease retinas compared to retinas of normal older patients. Retinal nerve fiber layer thickness will be measured, retinal drusen, retinal hyper-reflective foci, and foveal avascular zone area in patients with treated Alzheimer's disease compared to controls. * Gait analysis will be performed and may be particularly sensitive to early symptoms of dementia development. * • Biomarkers (p-beta-amyloid, p-tau217 and p-tau181) in cerebrospinal fluid (CSF) will be measured to support suspected Alzheimer's disease.

Interventions

• Drug Semaglutide (Rybelsus®) combined with other interventions
  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®)
• Other Placebo
  A control group treated with placebo and no further intervention
• Drug Semaglutide (Rybelsus®)
  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

Primary outcome measures

• The Montreal Cognitive Assessment [Time frame: At inclusion, and 52 and 78 weeks.]

Secondary outcome measures (12)

• Measurement of β-Amyloid1-42 [Time frame: Performed at inclusion, and 6, 12, and 18 months.]
• Measurement of Tau [Time frame: At inclusion, and 6, 12, and 18 months]
• MRI scan of the brain [Time frame: At inclusion, and 52 and 78 weeks.]
• PET scan of the brain [Time frame: At inclusion, and 52 and 78 weeks.]
• Clinical Dementia Rating scale - Sum of Boxes [Time frame: At inclusion, and 52 and 78 weeks.]
• Symbol Digit Modalities Test [Time frame: At inclusion, and 52 and 78 weeks]
• Quality of Life - Alzheimer's Disease (QoL-AD). [Time frame: At inclusion, and 52 and 78 weeks]
• Patient Global Impression of Change (PGI-C). [Time frame: At inclusion, and 52 and 78 weeks]
• European Quality of Life-5 Dimensions Questionnaire (EuroQol-5D™, EQ-5D) [Time frame: At inclusion, and 52 and 78 weeks]
• The Major Depression Inventory (MDI) [Time frame: At inclusion, and 52 and 78 weeks.]
• The Rey-Osterrieth Complex Figure Test [Time frame: At inclusion, and 52 and 78 weeks.]
• The 12-item Neuropsychiatric Inventory (NPI-12) [Time frame: At inclusion, and 52 and 78 weeks.]

Eligibility criteria

Inclusion criteria

• Decreased cognitive abilities corresponding to 16-25 points in the Mini Mental State Examination (MMSE)
• The cognitive impairment must be supported by the presence of specific levels in cerebrospinal fluid (CSF) of β-Amyloid1-42 (≤1030 pg/ml) and Tau (total and phosphorylated, respectively over 300 pg/ml and 27 pg/ml)
• MRI scan of the brain with coronal sections showing substance loss (atrophy) of the medial part of the temporal lobe compatible with Alzheimer's disease
• PET scan of the brain (18F-FDG PET) with 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

Exclusion criteria

• Patients with active cancer, and in chemo- or radiation therapy
• Severe cardiovascular disease.
• Hepatic insufficiency with ASAT> 2 x upper limit of normal or renal insufficiency with serum creatinine > 200 micromol/l
• Severe epilepsy with frequent tonic-clonic (grand mal) seizures
• Insulin treatment (type 1 diabetes mellitus) and diabetic ketoacidosis
• Severe chronic disease (e.g., cirrhosis, AIDS, chronic kidney failure)
• Severe mental illness e.g., schizophrenia, or physical disabilities leading to inability to participate in intervention or tests, or to provide informed consent
• Evidence for other primary causes of neurodegeneration or dementia, e.g., significant cerebrovascular disease (whose primary cause of dementia was vascular in origin), Lewy Body disease, Parkinson's disease, Fronto-temporal dementia
• Significant ongoing psychiatric or substance abuse problems.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT07135245 · 523376

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗