Rapamycin - Effects on Alzheimer's and Cognitive Health

Phase 2

Recruiting

• Conditions: Alzheimer Disease; Mild Cognitive Impairment
• Interventions: Other: Placebo; Drug: Rapamycin

• Registration Number: NCT04629495
• Lead Sponsor: The University of Texas Health Science Center at San Antonio

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2020-11-09
• Study First Submitted QC: 2020-11-09
• Study First Posted: 2020-11-16
• Study Start: 2021-08-11
• Status Verified: 2024-08
• Last Update Submitted: 2024-08-12
• Last Update Posted: 2024-08-13
• Primary Completion: 2026-03
• Study Completion: 2026-03

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 40

Inclusion Criteria

1. Both genders and all ethnic groups
2. Ages 55 to 89 years
3. 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)
4. Amyloid positivity based on Amyloid PET Imaging
5. 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
6. 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
7. Stable dose of AD medications (Donepezil, rivastigmine, Memantine, galantamine) for at least three months is allowed

Exclusion Criteria

1. Diabetes (HBA1c≥6.5% or antidiabetic medications)
2. History of skin ulcers or poor wound healing
3. Current tobacco or illicit drug use or alcohol abuse
4. Use of anti-platelet or anti-coagulant medications other than aspirin
5. Current medications that affect cytochrome 450 3A4 (CYP3A4)
6. Immunosuppressant therapy within the last year
7. Chemotherapy or radiation treatment within the last year
8. Current or chronic history of liver or kidney disease or known hepatic or biliary abnormalities
9. Untreated hypertriglyceridemia (fasting triglycerides < 250 mg/dl)
10. Current or chronic history of pulmonary disease or abnormal pulse oximetry (<90%)
11. Chronic heart failure
12. Pregnancy or lactation
13. Recent history (past six months) of myocardial infarction, active coronary artery disease, intestinal disorders, stroke, or transient ischemic attack
14. Significant neurological conditions other than AD or MCI
15. Poorly controlled blood pressure (systolic BP>160, diastolic BP>90 mmHg - based on two readings)
16. Active inflammatory, COVID-19, autoimmune, infectious, hepatic, gastrointestinal, malignant, and/or severe mental illness
17. 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
18. Organ transplant recipients

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo group	Placebo	Subjects will receive placebo
RAPA (rapamycin) treatment group	Rapamycin	Subjects will receive active drug

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
Change in Gait Speed	Baseline to 12 months	Gait speed will be evaluated with an electronic gait mat
Change in Brain Volumetry	Baseline to 12 months	Measure of brain volumetry using MRI
Change in Cognition using preclinical Alzheimer's Cognitive Composite 5 (PACC5)	Baseline to 12 months	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.
Change in Cognition using Clinical Dementia Rating Scale sum of Boxes (CDR-SOB)	Baseline to 12 months	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.
Change in Grip Strength	Baseline to 12 months	Grip strength will be evaluated with a hand dynamometer
Change in Functional status	Baseline to 12 months	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.
Change in Neuropsychiatric symptoms	Baseline to 12 months	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.
Central nervous system penetration of rapamycin	Baseline and 12 months	A lumbar puncture and blood draw will be used to evaluate levels of study drug
Change in CSF amyloid beta	Baseline to 12 months	Cerebrospinal fluid (CSF) levels of amyloid beta
Change in cerebral glucose metabolism	Baseline to 12 months	Cerebral glucose metabolism is measured using fluorodeoxyglucose-Positron emission tomography (FDG-PET)

Trial Locations

Locations (1)

Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases; 🇺🇸 San Antonio, Texas, United States