Sirolimus for Brain Aneurysm

Overseen by Robert Starke, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: University of Miami

Disqualifiers: Pregnancy, Breastfeeding, HIV, Renal failure, others

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Approved in 4 Jurisdictions

Trial Summary

What is the purpose of this trial?

This trial is investigating the use of Sirolimus, a drug that helps control immune responses and cell growth, in patients with cerebral aneurysms. The goal is to see if Sirolimus can affect the molecular changes in the blood vessels of the brain. By altering how cells grow and repair, Sirolimus may help manage these dangerous bulges in brain blood vessels. Sirolimus has been used in various clinical settings, including kidney and liver transplantation, to reduce the risk of cancer and improve survival rates.

Do I need to stop my current medications for the trial?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug sirolimus for treating brain aneurysms?

Sirolimus, known for its ability to suppress the immune system and prevent organ rejection, has shown effectiveness in reducing acute rejection episodes in kidney transplant patients. Its properties as an mTOR inhibitor, which helps control cell growth and proliferation, suggest potential benefits for conditions involving abnormal cell growth, although direct evidence for brain aneurysms is not provided. ^{1 2 3 4 5}

How is the drug Sirolimus unique in treating brain aneurysms?

Sirolimus (Rapamune) is unique because it works by suppressing specific signaling pathways (mTOR/STAT3) that are involved in inflammation and cell growth, which may help limit aneurysm growth. This mechanism is different from other treatments that may not target these pathways directly. ^{6 7 8 9 10}

Research Team

Robert Starke, MD

Principal Investigator

University of Miami

Eligibility Criteria

This trial is for adults over 18 who are getting surgery or endovascular treatment for unruptured brain aneurysms at Jackson Memorial Hospital and can consent to participate. It's not for those with HIV, certain types of aneurysms, pregnant or breastfeeding women, severe psychiatric conditions, skin cancer history, sirolimus allergy, serious illnesses affecting study results, lung disease called interstitial pneumonitis, or kidney/liver failure.

Inclusion Criteria

I am scheduled for a procedure at Jackson Memorial Hospital to treat an unruptured brain aneurysm.

Willing and able to give informed consent

I am 18 years old or older.

Exclusion Criteria

I have had skin cancer in the past.

I do not have any severe or unstable health conditions that could interfere with the study.

I have kidney or liver failure.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive 2 mg Sirolimus daily for 14-18 consecutive days prior to surgery or procedure

2-3 weeks

Follow-up

Participants are monitored for changes in gene expression and other molecular alterations

4 weeks

Treatment Details

Interventions

• Endovascular treatment (Procedure)
• Microsurgical clipping (Procedure)
• Sirolimus (mTOR inhibitor)

Trial Overview The trial studies the effect of Sirolimus on brain aneurysm molecular changes. Participants will receive either microsurgical clipping or endovascular treatment along with Sirolimus to see how it influences the condition at a molecular level.

Participant Groups

Group I: Microsurgical Clipping Treated with Sirolimus Experimental Treatment 2 Interventions

Participants undergoing standard of care microsurgical clipping of unruptured cerebral aneurysm will be treated with 2 mg Sirolimus daily for 14-18 consecutive days prior to surgery.

Group II: Endovascular Treatment Treated with Sirolimus Experimental Treatment 2 Interventions

Participants undergoing standard of care endovascular treatment of unruptured cerebral aneurysm procedure will be treated with 2 mg Sirolimus daily for 14-18 consecutive days prior to procedure.

Sirolimus is already approved in Canada, Japan for the following indications:

Approved in Canada as Rapamune for:

• Prevention of organ rejection in kidney transplant patients
• Treatment of lymphangioleiomyomatosis (LAM)

Approved in Japan as Rapamune for:

• Prevention of organ rejection in kidney transplant patients

Who Is Running the Clinical Trial?

University of Miami

Lead Sponsor

Trials

976

Recruited

423,000+

Sylvia Daunert

University of Miami

Chief Executive Officer since 2011

PhD in Biochemistry and Molecular Biology, University of Kentucky

Bahar Motlagh

University of Miami

Chief Medical Officer since 2021

PhD in Biomedical Engineering, Ecole Polytechnique Montreal

National Institute of Neurological Disorders and Stroke (NINDS)

Collaborator

Trials

1,403

Recruited

655,000+

Jordan Gladman

National Institute of Neurological Disorders and Stroke (NINDS)

Chief Medical Officer

MD from Harvard Medical School

Walter J. Koroshetz

National Institute of Neurological Disorders and Stroke (NINDS)

Chief Executive Officer since 2007

MD from the University of Chicago

Findings from Research

Sirolimus (rapamycin) is an effective immunosuppressant approved for preventing graft rejection in kidney transplants, with a lower risk of complications compared to other immunosuppressants.

Recent findings suggest that sirolimus may also have potential in treating skin disorders and extending lifespan, making it a promising candidate for addressing age-related diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sirolimus: a therapeutic advance for dermatologic disease. Peters, T., Traboulsi, D., Tibbles, LA., et al.[2014]

Sirolimus is a powerful immunosuppressant used in kidney transplantation that works by inhibiting the mTOR pathway, which is crucial for cell growth and proliferation, leading to reduced rates of acute rejection episodes to less than 10% when combined with cyclosporin A (CsA).

In clinical trials, using sirolimus at doses of 2 or 5 mg/day alongside CsA and steroids resulted in acute rejection rates of only 19% and 14% within 12 months, while also potentially reducing the need for nephrotoxic calcineurin inhibitors, although it may cause side effects like myelosuppression and increased lipid levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sirolimus: a comprehensive review. Kahan, BD.[2019]

Rapamune (Sirolimus) is an important immunosuppressant used in solid organ transplants for various purposes, including induction therapy and managing refractory rejection.

Understanding the pharmacodynamics and side effects of Rapamune is crucial for critical care nurses to enhance patient education and improve outcomes in transplant care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Update on transplant pharmacology: sirolimus. Hoffmann, RL., Roesch, T.[2021]

Sirolimus (RAPA) treatment in renal transplant patients significantly increases plasma triglyceride levels and VLDL-apoB100 concentrations due to a reduced catabolic rate of these lipoproteins, rather than increased production.

The study found that RAPA-induced hyperlipidemia is linked to decreased clearance of apoB100-containing lipoproteins, highlighting a metabolic pathway that could be targeted to manage lipid levels in patients undergoing immunosuppression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of sirolimus on the metabolism of apoB100- containing lipoproteins in renal transplant patients. Hoogeveen, RC., Ballantyne, CM., Pownall, HJ., et al.[2019]

In a phase II trial involving 149 kidney transplant recipients, sirolimus (SRL) significantly reduced the incidence of acute renal allograft rejection from 32.0% in the control group to 8.5% in those receiving SRL with full-dose cyclosporine (CsA).

SRL allowed for a reduction in CsA dosage without increasing the risk of rejection, and while it caused some reversible side effects, it did not worsen CsA-related kidney damage or increase the risk of opportunistic infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sirolimus reduces the incidence of acute rejection episodes despite lower cyclosporine doses in caucasian recipients of mismatched primary renal allografts: a phase II trial. Rapamune Study Group. Kahan, BD., Julian, BA., Pescovitz, MD., et al.[2022]

In a study using an apolipoprotein E-deficient mouse model, the mTOR inhibitor everolimus was found to significantly inhibit the growth of abdominal aortic aneurysms induced by angiotensin II infusion.

Everolimus works by reducing the development and circulation of CCR2 monocytes, which are linked to aortic dilation, suggesting a potential mechanism for its protective effects against aneurysm formation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Everolimus limits aortic aneurysm in the apolipoprotein E-deficient mouse by downregulating C-C chemokine receptor 2 positive monocytes. Moran, CS., Jose, RJ., Moxon, JV., et al.[2022]

In a study using male mice with induced abdominal aortic aneurysms (AAAs), treatment with rapamycin significantly reduced aortic enlargement by 38% and 53% at 3 and 10 days, respectively, compared to the control group.

Histological analysis showed that rapamycin preserved important structural components of the aorta, such as elastin and smooth muscle cells, while also reducing inflammation and new blood vessel formation, suggesting it may be a promising treatment to limit AAA progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapamycin limits the growth of established experimental abdominal aortic aneurysms. Rouer, M., Xu, BH., Xuan, HJ., et al.[2014]

In a rat model of chronic subdural hematoma (CSDH), treatment with rapamycin significantly reduced hematoma development and improved neurological function, especially when combined with atorvastatin, indicating its potential as an effective therapeutic option.

Rapamycin works by suppressing the mTOR and STAT3 signaling pathways, which enhances endothelial cell function and promotes hematoma resorption, suggesting a specific mechanism of action in managing CSDH.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapamycin promotes hematoma resorption and enhances endothelial cell function by suppressing the mTOR/STAT3 signaling in chronic subdural hematoma. Shen, J., Zhang, Y., Wu, X.[2023]

In a study using an experimental rat model of abdominal aortic aneurysm (AAA), rapamycin treatment resulted in significantly smaller aneurysm diameters (3.3 mm vs 4.5 mm) and reduced the rate of aneurysm expansion by 40%.

The mechanism behind rapamycin's effectiveness appears to involve the suppression of inflammatory signaling, as indicated by a 64% reduction in NF kappa B levels and a 54% decrease in matrix metalloproteinase-9 (MMP-9) levels in treated rats.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapamycin suppresses experimental aortic aneurysm growth. Lawrence, DM., Singh, RS., Franklin, DP., et al.[2019]

A novel nanoparticle delivery system effectively targets and delivers rapamycin to the damaged areas of aortic aneurysms in a rat model, showing significant accumulation in the affected tissues.

Treatment with rapamycin nanoparticles not only suppressed the formation of abdominal aortic aneurysms but also reduced inflammation and the activity of harmful enzymes, indicating a promising approach for targeted therapy in aortic aneurysm management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nanoparticles Effectively Target Rapamycin Delivery to Sites of Experimental Aortic Aneurysm in Rats. Shirasu, T., Koyama, H., Miura, Y., et al.[2018]

References

1. Canada pubmed.ncbi.nlm.nih.gov

Sirolimus: a therapeutic advance for dermatologic disease. [2014]

2. England pubmed.ncbi.nlm.nih.gov

Sirolimus: a comprehensive review. [2019]

3. United States pubmed.ncbi.nlm.nih.gov

Update on transplant pharmacology: sirolimus. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

Effect of sirolimus on the metabolism of apoB100- containing lipoproteins in renal transplant patients. [2019]

5. United States pubmed.ncbi.nlm.nih.gov

Sirolimus reduces the incidence of acute rejection episodes despite lower cyclosporine doses in caucasian recipients of mismatched primary renal allografts: a phase II trial. Rapamune Study Group. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Everolimus limits aortic aneurysm in the apolipoprotein E-deficient mouse by downregulating C-C chemokine receptor 2 positive monocytes. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Rapamycin limits the growth of established experimental abdominal aortic aneurysms. [2014]

8. United States pubmed.ncbi.nlm.nih.gov

Rapamycin promotes hematoma resorption and enhances endothelial cell function by suppressing the mTOR/STAT3 signaling in chronic subdural hematoma. [2023]

9. United States pubmed.ncbi.nlm.nih.gov

Rapamycin suppresses experimental aortic aneurysm growth. [2019]

10. United States pubmed.ncbi.nlm.nih.gov

Nanoparticles Effectively Target Rapamycin Delivery to Sites of Experimental Aortic Aneurysm in Rats. [2018]