ERAP: Evaluating Rapamycin Treatment in Alzheimer's Disease Using Positron Emission Tomography
Study Details
Study Description
Brief Summary
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1/Phase 2 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Rapamycin Sirolimus tablets will be administered orally, 7 mg once per week during 26 weeks |
Drug: Sirolimus
7 mg taken once per week during 26 weeks.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Change in cerebral glucose metabolism [From baseline to six months]
Cerebral glucose uptake measured through [18F]FDG positron emission tomography
Secondary Outcome Measures
- Incidence of Treatment-Emergent Adverse Events [From baseline to six months]
Safety and tolerability of intermittent sirolimus treatment
- Change in Cerebrospinal fluid (CSF) concentration of amyloid beta 42 [From baseline to six months]
CSF biomarker for Alzheimers disease
- Change in CSF concentration of phosphorylated tau [From baseline to six months]
CSF biomarker for Alzheimers disease
- Change in CSF concentration of total tau [From baseline to six months]
CSF biomarker for Alzheimers disease
- Change in cerebral blood flow [From baseline to six months]
Cerebral blood flow measured with MRI using arterial spin labeling
- Area under the concentration versus time curve (AUC) of sirolimus [Tested at one occasion between baseline to six months]
Whole blood measurements of sirolimus concentration.
- Peak Plasma Concentration (Cmax) of sirolimus [Tested at one occasion between baseline to six months]
Whole blood measurements of sirolimus concentration.
- Trough Plasma Concentration (Cmin) of sirolimus [Tested at one occasion between baseline to six months]
Whole blood measurements of sirolimus concentration.
- Change in Montreal Cognitive Assessment (MoCA) rating [From baseline to six months]
Cognition assessed using the MoCA rating scale (0-30 points, higher scores indicating better cognitive performance)
Other Outcome Measures
- Change in composite z-score of neuropsychological tests [From baseline to six months]
Cognition assessed with a composite score of the following tests: Rey Auditory Verbal Learning Test; Rey-Osterrieth Complex Figure; Hagman test; Trail Making Test A + B; Wechsler Adult Intelligence Scale (subtest to assess processing speed/attention). A composite score will be calculated using z-score approach..
- Change in concentration of neurofilament light in CSF [From baseline to six months]
Neuronal damage assessed using concentraion of neurofilament light in CSF.
- Change in quotient of albumin concentration in serum and CSF [From baseline to six months]
Blood-brain barrier integrity assessed using quotient of concentration albumin in serum and CSF
- Change in hand-grip strength [From baseline to six months]
Measured using a hand-grip dynamometer
- Change in chair stand test [From baseline to six months]
Number of completed chair stands in 30 seconds
- Change in walking speed [From baseline to six months]
Timed 10-metre dual task walking test
- Change in ratio of CSF concentration of amyloid beta 42 and 40 [From baseline to six months]
CSF biomarker for Alzheimers disease
Eligibility Criteria
Criteria
Inclusion Criteria:
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Clinical diagnosis of mild cognitive impairment (MCI), or dementia of Alzheimer's type
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Amyloid positivity established with either amyloid positron emission tomography or cerebrospinal fluid analysis.
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For subjects with dementia, the disease should be in an early stage, operationalized as:
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Stage 4 (Mild dementia) or lower, according to the National Institute on Aging - Alzheimer's Association 2018 clinical staging criteria, AND
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Clinical Dementia Rating Scale (CDR) global score of 1 or lower, AND
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Montreal Cognitive Assessment (MoCA) score of ≥ 18 OR Rey Auditory Verbal Learning Test (RAVLT) >4 words after 30 minutes
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Capable of giving, and has the capacity to give informed consent
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Availability of a responsible study partner who can accompany the subject to all planned visits
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Male or female between 50 and 80 years
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Normal or clinically acceptable medical history, physical examination, and vital signs
Exclusion Criteria:
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History of any major disease that may interfere with safe engagement in the intervention (especially severe liver or kidney disease, or uncontrolled diabetes).
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Central nervous system infarct, infection, or focal lesions of clinical significance on MRI scans.
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Fulfills any contraindication for the use of sirolimus as per the summary of product characteristics, including but not restricted to:
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Current or planned medication with a strong inhibitor of CYP3A4 or P-gp
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Current or planned medication with a strong inducer of CYP3A4 or P-gp
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Other current medications with known serious interaction risks with sirolimus
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Known allergy or hypersensitivity to sirolimus
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Significant obesity
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Untreated and clinically significant hyperlipidemia
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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
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Major surgery within 3 months prior to the planned start of sirolimus treatment, OR has major surgery planned during the period of the trial.
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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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Karolinska University Hospital Memory clinic | Solna | Stockholm | Sweden | 171 64 |
Sponsors and Collaborators
- Karolinska Institutet
- Karolinska University Hospital
Investigators
- Principal Investigator: Jonas Svensson, MD, PhD, Karolinska Institutet
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 2023-00611-01