Back to results

Short Term Sirolimus Treatment and MRI of the Brain

Primary Purpose

Genetic Predisposition to Disease, Healthy Volunteers

Status

Recruiting

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Sirolimus

About this trial

This is an interventional basic science trial for Genetic Predisposition to Disease

Eligibility Criteria

45 Years - 65 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

1. Age 45-65 y/o
2. Male or female, all ethnic groups
3. Montreal Cognitive Assessment (MoCA) score greater than or equal to 26
4. Clinical Dementia Rating (CDR) Staging Instrument = 0
5. Carrier Cohort: APOE4 homozygous or heterozygous
6. Non-Carrier cohort: no APOE4 gene identified

Exclusion Criteria:

1. Diagnosis of mild cognitive impairment (MCI) or dementia, including Alzheimer's disease
2. BMI ≥35 (based on MRI feasibility)
3. Diabetes (HBA1c≥6.5% or antidiabetic medications)
4. History of skin ulcers or poor wound healing
5. Current tobacco or illicit drug use or alcohol abuse (defined as ≥4 per day or ≥14 per week for men and ≥3 per day or ≥7 per week for women) (Per NIAAA guidelines)
6. Use of anti-platelet or anti-coagulant medications other than aspirin
7. Current medications that affect cytochrome P450 3A4 (CYP3A4)
8. Immunosuppressant therapy within the last year
9. Chemotherapy or radiation treatment within the last year
10. Current or chronic history of liver or kidney disease or known hepatic or biliary abnormalities
11. Untreated hypertriglyceridemia (fasting triglycerides < 300 mg/dl)
12. Current or chronic significant history of pulmonary disease
13. Chronic heart failure
14. Pregnancy or lactation
15. Recent history (past six months) of myocardial infarction, active coronary artery disease, intestinal disorders, stroke, or transient ischemic attack
16. Poorly controlled blood pressure (systolic BP>160 or diastolic BP>100 mmHg)
17.Active inflammatory, Coronavirus (COVID-19), autoimmune, infectious, hepatic, gastrointestinal, malignant, and/or severe mental illness
18. History of, or MRI, or CT positive for, any space occupying brain lesion, including mass effect or abnormal intracranial pressure
19. Organ transplant recipients
20. History of Stroke
21. History of ruptured intracranial aneurysm
22. Any condition for which a MRI procedure is contraindicated. Some examples include: metallic material in the body, such as pacemakers, metallic clips, etc.
23. Likelihood of claustrophobia

Sites / Locations

University of Missouri-ColumbiaRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Other

Arm Label

Carrier APOE4

Non-Carrier APOE4

Arm Description

Outcomes

Primary Outcome Measures

Change in Cerebral blood flow as measured on MRI after 4 weeks of Sirolimus

Rate of blood perfusion expressed as mL/g/min in hippocampus

Secondary Outcome Measures

Full Information

NCT ID

NCT05386914

First Posted

May 16, 2022

Last Updated

March 29, 2023

Sponsor

University of Missouri-Columbia

1. Study Identification

Unique Protocol Identification Number

NCT05386914

Brief Title

Short Term Sirolimus Treatment and MRI of the Brain

Official Title

Short Term Apolipoprotein E (ApoE)-Dependent Cerebral Blood Flow Response to Sirolimus in Cognitively Normal Adults

Study Type

Interventional

2. Study Status

Record Verification Date

March 2023

Overall Recruitment Status

Recruiting

Study Start Date

March 2, 2023 (Actual)

Primary Completion Date

July 2024 (Anticipated)

Study Completion Date

December 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

University of Missouri-Columbia

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

5. Study Description

Brief Summary

Alzheimer's disease is a devastating neurodegenerative disease characterized by accumulation of clumps (also called plaques) and bundles of fibers (also called tangles) in the brain, for which there is currently no cure. Sirolimus is an FDA-approved medication which may improve the blood flow to the brain. This study is designed to see if sirolimus treatment improves MRI blood flow to the brain in individuals with and without a genetic predisposition to Alzheimer's disease.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Genetic Predisposition to Disease, Healthy Volunteers

7. Study Design

Primary Purpose

Basic Science

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

Masking

Investigator

Masking Description

The member of the study team carrying out the MRI imaging and image analysis will be blinded to the APOE genotype of the subject, subject's family history, and treatment category.

Allocation

Non-Randomized

Enrollment

105 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Carrier APOE4

Arm Type

Experimental

Arm Title

Non-Carrier APOE4

Arm Type

Other

Intervention Type

Drug

Intervention Name(s)

Sirolimus

Intervention Description

1 mg of Sirolimus taken orally once a day for 4 weeks.

Primary Outcome Measure Information:

Title

Change in Cerebral blood flow as measured on MRI after 4 weeks of Sirolimus

Description

Rate of blood perfusion expressed as mL/g/min in hippocampus

Time Frame

Assessed at Visit 2 immediately before starting sirolimus and Visit 4 after 4 weeks of continuous sirolimus

10. Eligibility

Sex

All

Minimum Age & Unit of Time

45 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 1. Age 45-65 y/o 2. Male or female, all ethnic groups 3. Montreal Cognitive Assessment (MoCA) score greater than or equal to 26 4. Clinical Dementia Rating (CDR) Staging Instrument = 0 5. Carrier Cohort: APOE4 homozygous or heterozygous 6. Non-Carrier cohort: no APOE4 gene identified Exclusion Criteria: 1. Diagnosis of mild cognitive impairment (MCI) or dementia, including Alzheimer's disease 2. BMI ≥35 (based on MRI feasibility) 3. Diabetes (HBA1c≥6.5% or antidiabetic medications) 4. History of skin ulcers or poor wound healing 5. Current tobacco or illicit drug use or alcohol abuse (defined as ≥4 per day or ≥14 per week for men and ≥3 per day or ≥7 per week for women) (Per NIAAA guidelines) 6. Use of anti-platelet or anti-coagulant medications other than aspirin 7. Current medications that affect cytochrome P450 3A4 (CYP3A4) 8. Immunosuppressant therapy within the last year 9. Chemotherapy or radiation treatment within the last year 10. Current or chronic history of liver or kidney disease or known hepatic or biliary abnormalities 11. Untreated hypertriglyceridemia (fasting triglycerides < 300 mg/dl) 12. Current or chronic significant history of pulmonary disease 13. Chronic heart failure 14. Pregnancy or lactation 15. Recent history (past six months) of myocardial infarction, active coronary artery disease, intestinal disorders, stroke, or transient ischemic attack 16. Poorly controlled blood pressure (systolic BP>160 or diastolic BP>100 mmHg) 17.Active inflammatory, Coronavirus (COVID-19), autoimmune, infectious, hepatic, gastrointestinal, malignant, and/or severe mental illness 18. History of, or MRI, or CT positive for, any space occupying brain lesion, including mass effect or abnormal intracranial pressure 19. Organ transplant recipients 20. History of Stroke 21. History of ruptured intracranial aneurysm 22. Any condition for which a MRI procedure is contraindicated. Some examples include: metallic material in the body, such as pacemakers, metallic clips, etc. 23. Likelihood of claustrophobia

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Joanne Cassani

Phone

573-882-3677

cassanij@health.missouri.edu

First Name & Middle Initial & Last Name or Official Title & Degree

Jessica Overschmidt

Phone

573-884-5372

jlo94y@health.missouri.edu

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Ai-Ling Lin, PhD

Organizational Affiliation

University of Missouri-Columbia

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of Missouri-Columbia

City

Columbia

State/Province

Missouri

ZIP/Postal Code

65212

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Joanne Cassani

Phone

573-882-3677

cassanij@health.missouri.edu

First Name & Middle Initial & Last Name & Degree

Jessica Overschmidt

Phone

573-884-5372

jlo94y@health.missouri.edu

First Name & Middle Initial & Last Name & Degree

Ai-Ling Lin, PhD

First Name & Middle Initial & Last Name & Degree

David Beversdorf, MD

First Name & Middle Initial & Last Name & Degree

Altes Talissa, MD

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

26346644

Citation

Trzepacz PT, Hochstetler H, Wang S, Walker B, Saykin AJ; Alzheimer's Disease Neuroimaging Initiative. Relationship between the Montreal Cognitive Assessment and Mini-mental State Examination for assessment of mild cognitive impairment in older adults. BMC Geriatr. 2015 Sep 7;15:107. doi: 10.1186/s12877-015-0103-3.

Results Reference

background

PubMed Identifier

18695059

Citation

O'Bryant SE, Waring SC, Cullum CM, Hall J, Lacritz L, Massman PJ, Lupo PJ, Reisch JS, Doody R; Texas Alzheimer's Research Consortium. Staging dementia using Clinical Dementia Rating Scale Sum of Boxes scores: a Texas Alzheimer's research consortium study. Arch Neurol. 2008 Aug;65(8):1091-5. doi: 10.1001/archneur.65.8.1091.

Results Reference

background

PubMed Identifier

17708140

Citation

Lynch T, Price A. The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects. Am Fam Physician. 2007 Aug 1;76(3):391-6.

Results Reference

background

PubMed Identifier

29408453

Citation

Kraig E, Linehan LA, Liang H, Romo TQ, Liu Q, Wu Y, Benavides AD, Curiel TJ, Javors MA, Musi N, Chiodo L, Koek W, Gelfond JAL, Kellogg DL Jr. A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort: Immunological, physical performance, and cognitive effects. Exp Gerontol. 2018 May;105:53-69. doi: 10.1016/j.exger.2017.12.026. Epub 2018 Feb 3.

Results Reference

background

PubMed Identifier

23667480

Citation

Ozcelik S, Fraser G, Castets P, Schaeffer V, Skachokova Z, Breu K, Clavaguera F, Sinnreich M, Kappos L, Goedert M, Tolnay M, Winkler DT. Rapamycin attenuates the progression of tau pathology in P301S tau transgenic mice. PLoS One. 2013 May 7;8(5):e62459. doi: 10.1371/journal.pone.0062459. Print 2013.

Results Reference

background

PubMed Identifier

20376313

Citation

Spilman P, Podlutskaya N, Hart MJ, Debnath J, Gorostiza O, Bredesen D, Richardson A, Strong R, Galvan V. Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of Alzheimer's disease. PLoS One. 2010 Apr 1;5(4):e9979. doi: 10.1371/journal.pone.0009979. Erratum In: PLoS One. 2011;6(11). doi:10.1371/annotation/05c1b976-7eab-4154-808d-0526e604b8eb.

Results Reference

background

PubMed Identifier

26568298

Citation

Ross C, Salmon A, Strong R, Fernandez E, Javors M, Richardson A, Tardif S. Metabolic consequences of long-term rapamycin exposure on common marmoset monkeys (Callithrix jacchus). Aging (Albany NY). 2015 Nov;7(11):964-73. doi: 10.18632/aging.100843.

Results Reference

background

PubMed Identifier

25038772

Citation

Tardif S, Ross C, Bergman P, Fernandez E, Javors M, Salmon A, Spross J, Strong R, Richardson A. Testing efficacy of administration of the antiaging drug rapamycin in a nonhuman primate, the common marmoset. J Gerontol A Biol Sci Med Sci. 2015 May;70(5):577-87. doi: 10.1093/gerona/glu101. Epub 2014 Jul 19.

Results Reference

background

PubMed Identifier

30311681

Citation

Sills AM, Artavia JM, DeRosa BD, Ross CN, Salmon AB. Long-term treatment with the mTOR inhibitor rapamycin has minor effect on clinical laboratory markers in middle-aged marmosets. Am J Primatol. 2019 Feb;81(2):e22927. doi: 10.1002/ajp.22927. Epub 2018 Oct 12.

Results Reference

background

PubMed Identifier

27341957

Citation

Lelegren M, Liu Y, Ross C, Tardif S, Salmon AB. Pharmaceutical inhibition of mTOR in the common marmoset: effect of rapamycin on regulators of proteostasis in a non-human primate. Pathobiol Aging Age Relat Dis. 2016 Jun 23;6:31793. doi: 10.3402/pba.v6.31793. eCollection 2016.

Results Reference

background

PubMed Identifier

32173556

Citation

Lin AL, Parikh I, Yanckello LM, White RS, Hartz AMS, Taylor CE, McCulloch SD, Thalman SW, Xia M, McCarty K, Ubele M, Head E, Hyder F, Sanganahalli BG. APOE genotype-dependent pharmacogenetic responses to rapamycin for preventing Alzheimer's disease. Neurobiol Dis. 2020 Jun;139:104834. doi: 10.1016/j.nbd.2020.104834. Epub 2020 Mar 12.

Results Reference

background

PubMed Identifier

26721390

Citation

Lin AL, Jahrling JB, Zhang W, DeRosa N, Bakshi V, Romero P, Galvan V, Richardson A. Rapamycin rescues vascular, metabolic and learning deficits in apolipoprotein E4 transgenic mice with pre-symptomatic Alzheimer's disease. J Cereb Blood Flow Metab. 2017 Jan;37(1):217-226. doi: 10.1177/0271678X15621575. Epub 2015 Dec 31.

Results Reference

background

PubMed Identifier

23801246

Citation

Lin AL, Zheng W, Halloran JJ, Burbank RR, Hussong SA, Hart MJ, Javors M, Shih YY, Muir E, Solano Fonseca R, Strong R, Richardson AG, Lechleiter JD, Fox PT, Galvan V. Chronic rapamycin restores brain vascular integrity and function through NO synthase activation and improves memory in symptomatic mice modeling Alzheimer's disease. J Cereb Blood Flow Metab. 2013 Sep;33(9):1412-21. doi: 10.1038/jcbfm.2013.82. Epub 2013 Jun 26.

Results Reference

background

PubMed Identifier

25540326

Citation

Mannick JB, Del Giudice G, Lattanzi M, Valiante NM, Praestgaard J, Huang B, Lonetto MA, Maecker HT, Kovarik J, Carson S, Glass DJ, Klickstein LB. mTOR inhibition improves immune function in the elderly. Sci Transl Med. 2014 Dec 24;6(268):268ra179. doi: 10.1126/scitranslmed.3009892.

Results Reference

background

Learn more about this trial

Short Term Sirolimus Treatment and MRI of the Brain

We'll reach out to this number within 24 hrs