Cognition, Age, and RaPamycin Effectiveness - DownregulatIon of thE mTor Pathway

Study Overview
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Brief Summary
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Evaluation of central nervous system penetration of orally administered Rapamune (RAPA) in older adults with Mild Cognitive Impairment (MCI) or early Alzheimer's disease (AD) and investigate associated safety, tolerability, target engagement, cognition, and functional status as initial proof-of-concept study

Detailed Description
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This study is an open-label pilot study of orally administered RAPA to measure its target engagement in Cerebrospinal Fluid (CSF) and blood, and to establish the feasibility and safety of RAPA treatment in older adults with MCI and early stage AD as initial proof-of-concept for a larger Phase 2 clinical trial.

Official Title
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Cognition, Age, and RaPamycin Effectiveness - DownregulatIon of thE mTor Pathway (CARPE DIEM)

Conditions
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Cognitive Impairment, Mild, Alzheimer Disease

Intervention / Treatment
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* Drug: Rapamune


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of Mild Cognitive Impairment (MCI), Clinical Dementia Rating Scale (CDR)=0.5-1; Hopkins Verbal Learning Test-Revised (HVLT-R) Delayed Recall ≤5% based on age-adjusted normal values, clinician approved Normal blood cell counts without clinically significant excursions A Legally Authorized Representative (LAR) if necessary for consent An LAR or study partner to accompany participant to all visits Availability for all study visits Stable dose of AD medications) Donepezil, rivastigmine, memantine, galantamine) for at least 3 months Exclusion Criteria: Diabetes (HbA1c≥6.5% or anti-diabetic medications) History of skin ulcers or poor wound healing Current tobacco or illicit drug use or alcohol abuse Use of anti-platelet or anti-coagulant medications other than aspirin Current medications that affect cytochrome P450 3A4 Immunosuppressant therapy within the last year Chemotherapy or radiation treatment within the last year Current or chronic history of liver disease or known hepatic or biliary abnormalities Current or chronic history of pulmonary disease or abnormal pulse oximetry (<90%) Chronic heart failure Pregnancy Recent history (past 6 months) of myocardial infarction, active coronary artery disease, intestinal disorders, stroke, or transient ischemic attack significant neurological conditions other than AD Poorly controlled blood pressure (systolic BP>160, diastolic BP>90mmHg) Active inflammatory, autoimmune, infectious, hepatic, gastrointestinal, malignant, and/or psychiatric disease History of, or Magnetic Resonance Imaging (MRI) positive for any space occupying lesion, including mass effect and/or abnormal intracranial pressure, which would indicate contraindication to lumbar puncture

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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: RAPA intervention<br>Sirolimus 1mg orally once a day for 8 weeks | Drug: Rapamune<br>* Sirolimus 1mg capsules<br>* Other names: Sirolimus;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood Brain Barrier Penetration of RAPA | Lumbar punctures will be performed at baseline and after the final RAPA dose, to assess CSF levels of the drug. Change is calculated as value at 8 weeks minus the value at baseline. | Change from Baseline to 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events | Number of adverse events experienced across all 10 subjects after they were enrolled and randomized to treatment, regardless of relatedness to intervention. | Baseline to 8 weeks | 
| Change in CSF A Beta-42 Levels From Baseline to 8 Weeks | Evaluation of relevant AD biomarkers.Change is calculated as value at 8 weeks minus the value at baseline. | Baseline to 8 weeks | 
| Electronic Gait Mapping | Assessment of physical functioning under single and dual task conditions | Change from Baseline to 8 weeks | 
| Grip Strength | Assessment of physical function using grip strength | Change from Baseline to 8 weeks | 
| Clinical Dementia Rating (CDR) Global Score | A 5 point scale used to characterize six domains of cognitive and functional performance to give a possible score of 0-18. Each domain is rated on a score of 0 to 3 (0, 0.5, 1, 2 or 3) and the global score is derived based on the Washington University logarithm. Higher scores indicate worse cognitive and functional status. | Change from Baseline to 8 weeks | 
| Benson Figure Copy | A scale used to score a test of visuoconstructional abilities. Scores range from 0-16 with higher scores indicating better performance. Change is calculated as performance at 8 weeks minus baseline. | Change from Baseline to 8 weeks | 
| Neuropsychiatric Inventory (NPI) | A scale to assess dementia-related behavioral symptoms. The score represents the sum of 12 items, each scored 0-3. The total score can range from 0 to 36. Higher scores indicated greater neuropsychiatric severity. Change is calculated as the 8-week score minus baseline. | Change from Baseline to 8 weeks | 
| Functional Activities Questionnaire (FAQ) | An informant rates the subject's ability using a scoring system. The measure consists of 10 items with scoring ranging from 0-3 and the total score represents the sum of the items. The scores range from 0 to 30 with higher scores indicating more functional impairment. Change is calculated as the 8-week score minus baseline. | Change from Baseline to 8 weeks |