Evaluating Rapamycin Treatment in Alzheimer's Disease Using Positron Emission Tomography

Study Overview
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Brief Summary
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This single-center, uncontrolled pilot study aims to evaluate the efficacy, safety, and tolerability of six months of intermittently dosed oral rapamycin (sirolimus) in subjects with early-stage Alzheimer's disease. Fifteen participants will be recruited. Following a set of baseline measurements, all participants will receive a weekly oral dose of 7 mg rapamycin for six months. Participants will be continuously monitored for safety and side effects. At the termination of the treatment, follow-up measurements will be taken. The primary endpoint will be change in cerebral glucose metabolism, measured using 18F labeled fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET). In addition to the registered outcome measures this pilot trial will explore the feasibility of acquiring data on the effect of sirolimus treatment on age-related tissue changes in the body using a variety of imaging modalities, such as bone mineral density assessed using quantitative computed tomography, retinal structures assessed using optical coherence tomography, periodontal tissue assessed using MRI and FDG-PET, cardiac function assessed using MRI, vessel wall in large arteries using MRI and [18F]FDG PET.

Official Title
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Evaluating Rapamycin Treatment in Alzheimer's Disease Using Positron Emission Tomography (ERAP)

Conditions
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Alzheimer Disease

Intervention / Treatment
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* Drug: Sirolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinical diagnosis of mild cognitive impairment (MCI), or dementia of Alzheimer's type Amyloid positivity established with either amyloid positron emission tomography or cerebrospinal fluid analysis. For subjects with dementia, the disease should be in an early stage, operationalized as: Stage 4 (Mild dementia) or lower, according to the National Institute on Aging - Alzheimer's Association 2018 clinical staging criteria, AND Clinical Dementia Rating Scale (CDR) global score of 1 or lower, AND Montreal Cognitive Assessment (MoCA) score of ≥ 18 OR Rey Auditory Verbal Learning Test (RAVLT) >4 words after 30 minutes Capable of giving, and has the capacity to give informed consent Availability of a responsible study partner who can accompany the subject to all planned visits Male or female between 50 and 80 years Normal or clinically acceptable medical history, physical examination, and vital signs Exclusion Criteria: History of any major disease that may interfere with safe engagement in the intervention (especially severe liver or kidney disease, or uncontrolled diabetes). Central nervous system infarct, infection, or focal lesions of clinical significance on MRI scans. Fulfills any contraindication for the use of sirolimus as per the summary of product characteristics, including but not restricted to: Current or planned medication with a strong inhibitor of CYP3A4 or P-gp Current or planned medication with a strong inducer of CYP3A4 or P-gp Other current medications with known serious interaction risks with sirolimus Known allergy or hypersensitivity to sirolimus Significant obesity Untreated and clinically significant hyperlipidemia Treatment with immunosuppressive medications within the last 90 days (topical and nasal corticosteroids and inhaled corticosteroids for asthma are permitted), or chemotherapeutic agents for malignancy within the last 3 years Major surgery within 3 months prior to the planned start of sirolimus treatment, OR has major surgery planned during the period of the trial. Use of experimental medications for Alzheimer's or any other investigational medication or device within 60 days. Participants who have been involved in a monoclonal antibody study are excluded unless it is known that they were receiving placebo in that trial

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rapamycin<br>Sirolimus tablets will be administered orally, 7 mg once per week during 26 weeks | Drug: Sirolimus<br>* 7 mg taken once per week during 26 weeks.<br>* Other names: Rapamycin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in cerebral glucose metabolism | Cerebral glucose uptake measured through [18F]FDG positron emission tomography | From baseline to six months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-Emergent Adverse Events | Safety and tolerability of intermittent sirolimus treatment | From baseline to six months | 
| Change in Cerebrospinal fluid (CSF) concentration of amyloid beta 42 | CSF biomarker for Alzheimers disease | From baseline to six months | 
| Change in CSF concentration of phosphorylated tau | CSF biomarker for Alzheimers disease | From baseline to six months | 
| Change in CSF concentration of total tau | CSF biomarker for Alzheimers disease | From baseline to six months | 
| Change in cerebral blood flow | Cerebral blood flow measured with MRI using arterial spin labeling | From baseline to six months | 
| Area under the concentration versus time curve (AUC) of sirolimus | Whole blood measurements of sirolimus concentration. | Tested at one occasion between baseline to six months | 
| Peak Plasma Concentration (Cmax) of sirolimus | Whole blood measurements of sirolimus concentration. | Tested at one occasion between baseline to six months | 
| Trough Plasma Concentration (Cmin) of sirolimus | Whole blood measurements of sirolimus concentration. | Tested at one occasion between baseline to six months | 
| Change in Montreal Cognitive Assessment (MoCA) rating | Cognition assessed using the MoCA rating scale (0-30 points, higher scores indicating better cognitive performance) | From baseline to six months |