Sirolimus for Brain Aneurysm

Overseen By Jayro Toledo, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Miami

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

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 2-3 weeks

80 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether Sirolimus, a medication, can affect brain changes that cause cerebral aneurysms—bulges in blood vessels that can lead to serious problems if they burst. Participants will take Sirolimus for about two weeks before undergoing a standard procedure to treat their unruptured aneurysm, either through surgery or a less invasive method. The trial seeks individuals scheduled for these specific procedures at Jackson Memorial Hospital who can provide informed consent. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that Sirolimus has been studied for safety in various situations. The FDA has approved Sirolimus for other uses, indicating it is generally safe.

For patients undergoing microsurgical clipping, direct safety data on Sirolimus is unavailable. However, its presence in a Phase 2 trial implies that earlier studies have demonstrated some level of safety, suggesting it might be well-tolerated, though specific safety details remain unclear.

For those receiving endovascular treatment, Sirolimus has been used in similar treatments, such as stents, where it has shown a trend toward safety. However, specific information on side effects or adverse reactions for brain aneurysms is not available.

Overall, while Sirolimus is generally considered safe for other conditions, further research is needed to understand its safety for brain aneurysms. Participants should consult their healthcare providers about potential risks. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about using Sirolimus for treating brain aneurysms because it offers a unique approach compared to standard treatments like microsurgical clipping and endovascular procedures. Sirolimus is an immunosuppressive drug that targets specific pathways to potentially reduce inflammation and improve healing before these surgical procedures. This is different from traditional treatments that focus solely on physically repairing the aneurysm. By administering Sirolimus prior to surgery, it's hoped to enhance outcomes and minimize complications, providing a new layer of protection that current options don't offer.

What evidence suggests that this trial's treatments could be effective for brain aneurysms?

Research has shown that Sirolimus might improve treatment outcomes for brain aneurysms. In this trial, participants undergoing microsurgical clipping of an aneurysm will receive Sirolimus, which reduces swelling and could enhance the surgery's effectiveness by decreasing inflammation around the aneurysm.

Sirolimus is also being tested for participants undergoing endovascular treatment. It shows promise in preventing blood vessels from narrowing after the procedure. Research has found that stents releasing a similar drug, rapamycin, effectively prevent blood vessels from narrowing again in other conditions. This suggests that Sirolimus could help keep blood vessels open and reduce complications during endovascular treatment. ^{3 4 5 6 7}

Who Is on the Research Team?

Robert Starke, MD

Principal Investigator

University of Miami

Are You a Good Fit for This Trial?

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

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Endovascular treatment
• Microsurgical clipping
• Sirolimus

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.

How Is the Trial Designed?

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 United States, European Union, Canada, Japan for the following indications:

Approved in United States as Rapamune for:

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

Approved in European Union as Rapamune for:

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

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+

National Institute of Neurological Disorders and Stroke (NINDS)

Collaborator

Trials

1,403

Recruited

655,000+

Published Research Related to This Trial

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]

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]

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]

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 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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10474558/

Outcomes Associated With Intracranial Aneurysm Treatments ... Outcomes associated with intracranial aneurysm treatments reported as safe, effective, or durable: a systematic review and meta-analysis.

2. frontiersin.org frontiersin.org/journals/neurology/articles/10.3389/fneur.2021.649426/full

Safety and Efficacy of Rapamycin-Eluting Vertebral Stents ... The placement of rapamycin-eluting stents in patients with symptomatic extracranial VAS yields favorable ISR results and showed a trend of favorable safety ...

3. j-stroke.org j-stroke.org/journal/view.php?viewtype=pubreader&number=601

Time to Consider Pharmacologic Management ... Systematic review and meta-analysis of endovascular therapy effectiveness for unruptured saccular intracranial aneurysms. Stroke Vasc Interv ...

4. ahajournals.org ahajournals.org/doi/10.1161/STROKEAHA.124.046725

Most Promising Approaches to Improve Brain AVM ... Although SRS may follow embolization, some studies have suggested that SRS is less effective after embolization due to the presence of the ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12356742/

Repeated recurrence after endovascular treatment for ... In terms of therapeutic outcomes, repeat EVT sessions provided favorable long-term clinical outcomes (aneurysm stabilization, 85.0%; favorable ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3465008/

Endovascular minimally invasive treatment of the ... The treatment of cerebral aneurysms with coils is a safe and durable option with a mortality rate of 2,6% and a risk of recanalization in our cohort of 4,3%.

7. ninds.nih.gov ninds.nih.gov/health-information/clinical-trials/effect-sirolimus-molecular-alterations-cerebral-aneurysms

Effect of Sirolimus on Molecular Alterations in Cerebral ... The objective of this study is to explore the effects of Sirolimus on the underlying molecular alterations of cerebral aneurysms.