Rapamycin - Effects on Alzheimer's and Cognitive Health

Study Overview
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Brief Summary
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This study will evaluate the safety, tolerability, and feasibility of 12 month oral rapamycin treatment in older adults with amnestic mild cognitive impairment (aMCI) and early stage Alzheimer's disease (AD).

Detailed Description
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The study will consist of a screening/baseline period of up to 90 days pre-study drug, with a 12-month (+3 day) treatment period with rapamycin, followed by a post-treatment assessment completed within 14 days of the final study drug dose, and a final assessment conducted 6-months (+14 days) after the final study drug dose. The study duration is not expected to exceed 90 weeks for participants.

Official Title
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Rapamycin - Effects on Alzheimer's and Cognitive Health (REACH)

Conditions
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Mild Cognitive Impairment, Alzheimer Disease

Intervention / Treatment
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* Drug: Rapamycin
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Both genders and all ethnic groups Ages 55 to 89 years Diagnosis of MCI or AD (Mini Mental Status Examination (MMSE): 18-30; Clinical Dementia Rating Scale (CDR) = 0.5 - 1; California Verbal Learning Test III (CVLT-III) Delayed Recall ≤16% based on age-adjusted norms, clinician approval) Amyloid positivity based on Amyloid PET Imaging Labs: Normal blood cell counts without clinically significant excursions; normal liver and renal function; and glucose control (HbA1c < 6.5%). Fasting lipid panel and prothrombin time/prothrombin time test/international normalized ration (PT/PTT/INR) within normal limits A legally authorized representative (LAR) designated to sign informed consent (if necessary) must attend the Screening visit and accompany the participant to all remaining visits to provide reported outcomes Stable dose of AD medications (Donepezil, rivastigmine, Memantine, galantamine) for at least three months is allowed Exclusion Criteria: Diabetes (HBA1c≥6.5% or antidiabetic 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 450 3A4 (CYP3A4) Immunosuppressant therapy within the last year Chemotherapy or radiation treatment within the last year Current or chronic history of liver or kidney disease or known hepatic or biliary abnormalities Untreated hypertriglyceridemia (fasting triglycerides < 250 mg/dl) Current or chronic history of pulmonary disease or abnormal pulse oximetry (<90%) Chronic heart failure Pregnancy or lactation Recent history (past six months) of myocardial infarction, active coronary artery disease, intestinal disorders, stroke, or transient ischemic attack Significant neurological conditions other than AD or MCI Poorly controlled blood pressure (systolic BP>160, diastolic BP>90 mmHg - based on two readings) Active inflammatory, COVID-19, autoimmune, infectious, hepatic, gastrointestinal, malignant, and/or severe mental illness History of, or MRI, or CT positive for, any space occupying lesion, including mass effect or abnormal intracranial pressure, which would indicate contraindications to lumbar puncture Organ transplant recipients

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 89 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: placebo controlled study
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: RAPA (rapamycin) treatment group<br>Subjects will receive active drug | Drug: Rapamycin<br>* RAPA will be administered orally 1mg daily<br>* Other names: Sirolimus, RAPA;|
| Placebo Comparator: Placebo group<br>Subjects will receive placebo | Other: Placebo<br>* Placebo will be administered orally once daily<br>* Other names: Placebo capsule;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of adverse events | Development or worsening of medical symptoms or problems | Baseline to 12 months | 
| Change in glucose level | A comprehensive metabolic panel is used to measure change in glucose level | Baseline to 12 months | 
| Change in albumin | A comprehensive metabolic panel is used to measure change in albumin level | Baseline to 12 months | 
| Change in carbon dioxide or bicarbonate (CO2) | A comprehensive metabolic panel is used to measure change in CO2 | Baseline to 12 months | 
| Change in calcium | A comprehensive metabolic panel is used to measure change in calcium levels | Baseline to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Central nervous system penetration of rapamycin | A lumbar puncture and blood draw will be used to evaluate levels of study drug | Baseline and 12 months | 
| Change in Cognition using preclinical Alzheimer's Cognitive Composite 5 (PACC5) | Cognition will be measured using the PACC5 scale. The PACC5 is a composite score comprised of measures of global cognition, memory, and executive function. The score reflects an averaged z-score. Scores range from -3 to +3 with higher scores indicating better cognitive performance. | Baseline to 12 months | 
| Change in Cognition using Clinical Dementia Rating Scale sum of Boxes (CDR-SOB) | CDR is obtained through semistructured interviews of patients and informants, and cognitive functioning is rated in 6 domains of functioning: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. Each domain is rated on a 5-point scale of functioning as follows: 0, no impairment; 0.5, questionable impairment; 1, mild impairment; 2, moderate impairment; and 3, severe impairment. Domain scores are entered into an online algorithm and CDR-SOB score obtained by summing each of the domain box scores, ranging from 0 to 18. A lower score indicates better cognition. | Baseline to 12 months | 
| Change in Functional status | Functional status will be measured using the functional assessment scale (FAS). The FAS is completed by a collateral source and assesses ability to complete instrumental activities of daily living. The scale has 10-items and responses range from 0-3. The total score is a sum of the individual items. The total score ranges from 0 to 30 with higher scores indicating more assistance needed. | Baseline to 12 months | 
| Change in Neuropsychiatric symptoms | Symptoms will be evaluated using the Geriatric Depression Scale 15 Item (GDS-15). The GDS-15 is a self-report questionnaire with 15 items that have response options of 0 or 1. The total score is the sum of the individual items. The total score on the measure ranges between 0 to 15 with higher scores indicating more depressive symptoms. | Baseline to 12 months | 
| Change in Gait Speed | Gait speed will be evaluated with an electronic gait mat | Baseline to 12 months | 
| Change in Grip Strength | Grip strength will be evaluated with a hand dynamometer | Baseline to 12 months | 
| Change in CSF amyloid beta | Cerebrospinal fluid (CSF) levels of amyloid beta | Baseline to 12 months | 
| Change in cerebral glucose metabolism | Cerebral glucose metabolism is measured using fluorodeoxyglucose-Positron emission tomography (FDG-PET) | Baseline to 12 months | 
| Change in Brain Volumetry | Measure of brain volumetry using MRI | Baseline to 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cognition, Alzheimer's disease biomarkers, Neuroimaging