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

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

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

Study Overview

• Status: Completed
• Conditions: Alzheimer Disease; Cognitive Impairment, Mild
• Intervention / Treatment: Drug: Rapamune

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.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • San Antonio, Texas, United States, 78229
      • UTHSA McDermott Clinical Sciences Building

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 55 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: RAPA intervention; Sirolimus 1mg orally once a day for 8 weeks	Drug: Rapamune; Sirolimus 1mg capsules; Other Names: Sirolimus

What is the study measuring?

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
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
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
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

Collaborators and Investigators

• Sponsor: The University of Texas Health Science Center at San Antonio
• Collaborators: National Center for Advancing Translational Sciences (NCATS)
• Investigators: Principal Investigator: Mitzi Gonzales, PhD, UT Health San Antonio

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2020
• Primary Completion (Actual): January 13, 2022
• Study Completion (Actual): January 13, 2022

Study Registration Dates

• First Submitted: December 6, 2019
• First Submitted That Met QC Criteria: December 12, 2019
• First Posted (Actual): December 16, 2019

Study Record Updates

• Last Update Posted (Actual): December 22, 2023
• Last Update Submitted That Met QC Criteria: December 20, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Cognition Disorders; Alzheimer Disease; Cognitive Dysfunction; Physiological Effects of Drugs; Anti-Infective Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Sirolimus
• Other Study ID Numbers: HSC20190850H; UL1TR002645 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The Institution, Sponsor or respective designees may review results prior to presenting or publishing the results of a scientific investigation involving this Study in accordance with ICJME guidelines and institutional requirements.
• IPD Sharing Time Frame: After publication in a peer reviewed journal
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes