Short Term Sirolimus Treatment and MRI of the Brain

Healthy Volunteers Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05386914
• Other study ID #: 2091042
• Status: Recruiting
• Phase: Phase 1
• Start date: March 2, 2023
• Est. completion date: December 2024

Study information

• Verified date: March 2024
• Source: University of Missouri-Columbia
• Contact: Joanne Cassani
• Phone: 573-882-3677
• Email: cassanij[@]health.missouri.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 105
• Est. completion date: December 2024
• Est. primary completion date: July 2024
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 45 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Genetic Predisposition to Disease
• Healthy Volunteers

Intervention

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

Locations

Country	Name	City	State
United States	University of Missouri-Columbia	Columbia	Missouri

Sponsors (1)

Lead Sponsor	Collaborator
University of Missouri-Columbia

Country where clinical trial is conducted

United States, 

References & Publications (14)

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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View Citation

* Note: There are 14 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Assessed at Visit 2 immediately before starting sirolimus and Visit 4 after 4 weeks of continuous sirolimus