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

Early Phase 1

Completed

Conditions: Cognitive Impairment, Mild
Alzheimer Disease

Interventions: Drug: Rapamune

Registration Number: NCT04200911

Lead Sponsor: The University of Texas Health Science Center at San Antonio

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 10

Inclusion Criteria

Diagnosis of Mild Cognitive Impairment (MCI) or Alzheimer's disease, Global Clinical Dementia Rating Scale (CDR)=0.5-1
Normal blood cell counts without clinically significant excursions; ; normal liver and renal function; and glucose control (HbA1c < 6.5%). Lipid panel and PT/PTT/INR within normal limits
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 prior to the baseline visit

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; current or recent medications for hypertriglyceridemia (eg, Gemfibrozil)
Hypersensitivity or history of allergy to Rapamycin
Immunosuppressant therapy within the last year; current treatment with hydroxychloroquine and chloroquine (requires "washout period" of 14 days)
Chemotherapy or radiation treatment within the last year
Current or chronic history of liver disease or known hepatic or biliary abnormalities
History of primary hypertriglyceridemia. Abnormal triglycerides >200 or LDL cholesterol >193, or other abnormal labs deemed clinically significant upon investigator review
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, COVID-19, 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
Organ transplant recipients

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
RAPA intervention	Rapamune	Sirolimus 1mg orally once a day for 8 weeks

Primary Outcome Measures

Name	Time	Method
Blood Brain Barrier Penetration of RAPA	Change from Baseline to 8 weeks	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.

Secondary Outcome Measures

Name	Time	Method
Safety Labs - Change in Monocytes	8 weeks	Evaluation of of safety labs - monocytes. Change is calculated as value at 8 weeks minus the value at baseline.
Safety Labs - Change in Hematocrit	8 weeks	Evaluation of of safety labs - hematocrit. Change is calculated as value at 8 weeks minus the value at baseline.
Adverse Events	Baseline to 8 weeks	Number of adverse events experienced across all 10 subjects after they were enrolled and randomized to treatment, regardless of relatedness to intervention.
Change in Vitals From Baseline to 8 Weeks	Baseline to 8 weeks	Evaluation of vitals. Change is calculated as value at 8 weeks minus the value at baseline.
Percentage of Study Drug Pills Taken	Baseline to 8 weeks	Average percentage of study drug pills taken across all 10 subjects after they were enrolled and randomized to treatment. The percentage of study drug pills taken was evaluated by having participants return any leftover study drug pills at each visit during the active treatment period.
Change in CSF AD Biomarkers From Baseline to 8 Weeks	Baseline to 8 weeks	Evaluation of CSF AD biomarkers. Change is calculated as value at 8 weeks minus the value at baseline.
Change in Plasma AD Biomarkers From Baseline to 8 Weeks	Baseline to 8 weeks	Evaluation of plasma AD biomarkers. Change is calculated as value at 8 weeks minus the value at baseline.
Change in CSF Inflammatory Markers From Baseline to 8 Weeks	Baseline to 8 weeks	Evaluation of CSF inflammatory markers. Change is calculated as value at 8 weeks minus the value at baseline.
Change in Plasma Inflammatory Markers From Baseline to 8 Weeks	Baseline to 8 weeks	Evaluation of plasma inflammatory markers. Change is calculated as value at 8 weeks minus the value at baseline.
Safety Labs - Change in White Blood Cell and Platelet Counts From Baseline to 8 Weeks	Baseline to 8 weeks	Evaluation of safety labs - white blood cell and platelet counts. Change is calculated as value at 8 weeks minus the value at baseline.
Safety Labs - Change in Red Blood Cell Count	Baseline to 8 weeks	Evaluation of safety labs - red blood cell counts. Change in red blood cell count calculated as value at 8 weeks minus the value at baseline.
Safety Labs - Change in Mean Corpuscular Volume	8 weeks	Evaluation of safety labs - Change in Mean Corpuscular volume. Change is calculated as value at 8 weeks minus the value at baseline
Safety Labs - Change in Mean Corpuscular Hemoglobin	8-weeks	safety labs - Mean Corpuscular Hemoglobin. Change is calculated as value at 8 weeks minus the value at baseline.
Safety Labs - Change in Metabolic Parameters (g/dl)	8 weeks	Evaluation of safety labs - metabolic parameters. Change is calculated as value at 8 weeks minus the value at baseline.
Safety Labs - Change in Red Cell Distribution Width	8 weeks	Evaluation of of safety labs - Red cell distribution width. Change is calculated as value at 8 weeks minus the value at baseline. The value reported is % of red blood cell size and volume variability.
Safety Labs - Change in Hemoglobin A1c	8 weeks	Evaluation of of safety labs - hemoglobin A1c. Change is calculated as value at 8 weeks minus the value at baseline.
Safety Labs - Change in Metabolic and Lipid Parameters (mg/dl)	8 weeks	Evaluation of safety labs - metabolic and lipid parameters. Change is calculated as value at 8 weeks minus the value at baseline.
Safety Labs - Change in Sodium and Potassium (mmol/L)	8 weeks	Evaluation of safety labs - sodium and potassium. Change is calculated as value at 8 weeks minus the value at baseline.
Safety Labs - Change in Liver Panel (iU/L)	8 weeks	Evaluation of safety labs - liver panel. Change is calculated as value at 8 weeks minus the value at baseline.
Cognition/Functional Status - Change in Montreal Cognitive Assessment (MoCA)	8 weeks	The Montreal Cognitive Assessment (MoCA) assesses global cognition with scores ranging from 0 to 30 points. Higher scores indicate better performance.Change is calculated as value at 8 weeks minus the value at baseline.
Cognition/Functional Status - Change on the Clinical Rating Scale Global Score	8 weeks	The Clinical Rating Scale Global Score assesses cognition and daily functioning with scores ranging from 0 to 3 points. Higher scores indicate worse cognition and/or functional status.Change is calculated as value at 8 weeks minus the value at baseline.
Cognition/Functional Status - Change on the Clinical Rating Scale Sum of Boxes Score	8 weeks	The Clinical Rating Scale Sum of Boxes assesses cognition and daily functioning with scores ranging from 0 to 18 points. Higher scores indicate worse cognition and/or functional status.Change is calculated as value at 8 weeks minus the value at baseline.
Cognition/Functional Status - Change on the Hopkins Verbal Learning Test - Revised Immediate Recall	8 weeks	The Hopkins Verbal Learning Test - Revised Immediate Recall assesses verbal list learning with scores ranging from 0 to 36 points. Higher scores indicate better performance. Change is calculated as value at 8 weeks minus the value at baseline.
Cognition/Functional Status - Change on the Hopkins Verbal Learning Test - Revised Delayed Recall	8 weeks	The Hopkins Verbal Learning Test - Revised Delayed Recall assesses verbal list learning with scores ranging from 0 to 12 points. Higher scores indicate better performance. Change is calculated as value at 8 weeks minus the value at baseline.
Cognition/Functional Status - Change on the Craft Story Immediate Recall Verbatim	8 weeks	The Craft Story Immediate Recall Verbatim assesses verbal narrative learning with scores ranging from 0 to 44 points. Higher scores indicate better performance. Change is calculated as value at 8 weeks minus the value at baseline.
Cognition/Functional Status - Change on the Craft Story Delayed Recall Verbatim	8 weeks	The Craft Story Delayed Recall Verbatim assesses verbal memory recall with scores ranging from 0 to 44 points. Higher scores indicate better performance. Change is calculated as value at 8 weeks minus the value at baseline.
Cognition/Functional Status - Change on the Benson Figure Copy	8 weeks	The Benson Figure Copy assesses visuoconstructional skills with scores ranging from 0 to 17points. Higher scores indicate better performance. Change is calculated as value at 8 weeks minus the value at baseline.
Cognition/Functional Status - Change on the Benson Figure Delayed Recall	8 weeks	The Benson Figure Delayed Recall assesses visual memory with scores ranging from 0 to 17 points. Higher scores indicate better performance.Change is calculated as value at 8 weeks minus the value at baseline.
Cognition/Functional Status - Change on the Number Span Forward	8 weeks	The Number Span Forward test assesses basic attention with scores ranging from 0 to 16 points. Higher scores indicate better performance. Change is calculated as value at 8 weeks minus the value at baseline.
Cognition/Functional Status - Change on the Number Span Backward	8 weeks	The Number Span Backward test assesses working memory with scores ranging from 0 to 14 points. Higher scores indicate better performance. Change is calculated as value at 8 weeks minus the value at baseline.
Cognition/Functional Status - Change on the Trail Making Test Part A, Time to Completion	8 weeks	The Trail Making Test Part A, time to completion assesses psychomotor speed and visual scanning with scores ranging from 1 to 150 seconds. Higher scores indicate worse performance. Change is calculated as value at 8 weeks minus the value at baseline.
Cognition/Functional Status - Change Trail Making Test Part B, Time to Completion	8 weeks	The Trail Making Test Part B, time to completion assesses attentional shifting with scores ranging from 1 to 300 seconds. Higher scores indicate worse performance. Change is calculated as value at 8 weeks minus the value at baseline.
Cognition/Functional Status - Change on Phonemic Fluency	8 weeks	The Phonemic fluency test assesses speeded word generation to a phonemic cue. Scores begin at 0 with no upper limit. Higher scores indicate better performance. Change is calculated as value at 8 weeks minus the value at baseline.
Cognition/Functional Status - Change on Semantic Fluency	8 weeks	The Semantic fluency test assesses speeded word generation to a semantic cue. Scores begin at 0 with no upper limit. Higher scores indicate better performance. Change is calculated as value at 8 weeks minus the value at baseline.
Cognition/Functional Status - Change on the Multilingual Naming Test	8 weeks	The Multilingual Naming Test assesses confrontation naming. Scores range from 0 to 32 and higher scores indicate better performance. Change is calculated as value at 8 weeks minus the value at baseline.
Cognition/Functional Status - Change on the Hayling, Total Errors	8 weeks	The Hayling assesses response inhibition errors. Scores range from 0 to 30 and higher scores indicate worse performance. Change is calculated as value at 8 weeks minus the value at baseline.
Cognition/Functional Status - Change on Grip Strength, Dominant Hand	8 weeks	The grip strength, dominant hand assesses grip strength in kilograms. Values begin at 0 with no upper limit. Higher scores indicate better performance Change is calculated as value at 8 weeks minus the value at baseline.
Cognition/Functional Status - Change on Grip Strength, Non-dominant Hand	8 weeks	The grip strength, non-dominant hand assesses grip strength in kilograms. Values begin at 0 with no upper limit. Higher scores indicate better performance. Change is calculated as value at 8 weeks minus the value at baseline.
Cognition/Functional Status - Change on the Geriatric Depression Scale 15-item	8 weeks	The Geriatric Depression Scale 15-item assesses depressive symptomatology. Scores range from 0 to 15 and higher scores indicate worse outcomes. Change is calculated as value at 8 weeks minus the value at baseline.
Cognition/Functional Status - Change on the Functional Activities Questionnaire	8 weeks	The Functional Activities Questionnaire assesses functional status for independent activities of daily living. Scores range from 0 to 30 and higher scores indicate worse outcomes. Change is calculated as value at 8 weeks minus the value at baseline.
Cognition/Functional Status - Change on the Neuropsychiatric Inventory Questionnaire	8 weeks	The Neuropsychiatric Inventory Questionnaire assesses neuropsychiatric symptoms. Scores range from 0 to 12 and higher scores indicate worse outcomes. Change is calculated as value at 8 weeks minus the value at baseline.