Sirolimus for Lymphangioleiomyomatosis

(MILED Trial)

Recruiting at 7 trial locations

Overseen By Susan McMahan Sellers, BSN, RN

Age: 18+

Sex: Female

Trial Phase: Phase 3

Sponsor: University of Cincinnati

Must not be taking: Sirolimus, Everolimus, Estrogen

Disqualifiers: Myocardial infarction, Stroke, Pregnancy, Infections, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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: 4

Duration: 2 years

60 Participants Needed

Trial Summary

Do I have to stop taking my current medications for this trial?

The trial requires that you stop using sirolimus, everolimus, investigational treatments for LAM, and estrogen-containing medications at least 30 days before joining. Other medications are not specifically mentioned, so check with the trial team.

Will I have to stop taking my current medications?

The trial requires that you stop using estrogen-containing medications and sirolimus, everolimus, or any investigational treatment for LAM at least 30 days before joining. Other medications are not specifically mentioned, so it's best to discuss with the trial team.

What data supports the idea that Sirolimus for Lymphangioleiomyomatosis is an effective drug?

The available research shows that Sirolimus is effective for treating Lymphangioleiomyomatosis (LAM). It helps stabilize lung function and reduces the size of abnormal growths in the lungs. Patients have shown significant improvements, especially in symptoms outside the lungs. Sirolimus is now considered the first choice for treating LAM, and while it can cause side effects like mouth sores, its benefits in improving lung health and reducing other symptoms make it a valuable treatment option. ^{1 2 3 4 5}

What data supports the effectiveness of the drug Sirolimus for treating lymphangioleiomyomatosis?

Sirolimus has been shown to stabilize lung function and reduce the size of abnormal growths in patients with lymphangioleiomyomatosis, and it is considered the first-line drug for this condition. Patients have experienced significant improvements, especially in symptoms outside the lungs, after treatment with Sirolimus. ^{1 2 3 4 5}

What safety data is available for Sirolimus in treating lymphangioleiomyomatosis?

Sirolimus is the first-line treatment for lymphangioleiomyomatosis and has been shown to stabilize lung function and reduce the size of chylous effusions and lymphangioleiomyomas. The most common adverse event reported is sirolimus-induced stomatitis. The safety and efficacy of sirolimus were evaluated in a phase 3 trial, and ongoing studies continue to assess its long-term effects and optimal dosing. ^{1 2 4 6 7}

Is Sirolimus safe for humans?

Sirolimus is generally safe for humans, but it can cause stomatitis (sore or inflamed mouth) as a common side effect during treatment for lymphangioleiomyomatosis. ^{1 2 4 6 7}

Is the drug Sirolimus a promising treatment for Lymphangioleiomyomatosis?

Yes, Sirolimus is a promising treatment for Lymphangioleiomyomatosis. It has been shown to improve lung function and is considered the first-line drug for this rare lung disease. ^{1 2 3 6 8}

How is the drug Sirolimus unique in treating lymphangioleiomyomatosis?

Sirolimus is unique because it targets the mTOR (mammalian target of rapamycin) pathway, which is involved in the abnormal cell growth seen in lymphangioleiomyomatosis. It is the first-line treatment for this rare lung disease, offering a specific mechanism of action that helps slow down the progression of the condition. ^{1 2 3 6 8}

What is the purpose of this trial?

This is a study to determine if early, long-term low dose sirolimus is effective for preventing progression to more advanced stages.

Research Team

Francis X. McCormack, M.D.

Principal Investigator

University of Cincinnati

Eligibility Criteria

This trial is for women aged 18 or older with Lymphangioleiomyomatosis (LAM), who have certain markers indicating the disease may get worse. They must not be pregnant, planning pregnancy soon, or have used sirolimus recently. Other health conditions and recent surgeries also affect eligibility.

Inclusion Criteria

I have been diagnosed with LAM based on lung CT and other specific tests or conditions.

Your lung function, measured after using a bronchodilator, is better than 70%.

I have signs that my lung condition, LAM, is getting worse.

Exclusion Criteria

I have not had a collapsed lung in the last month.

Your blood oxygen level is below 90% when measured while resting.

Your oxygen level drops below 85% during exercise.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive 1 mg/day sirolimus or placebo for 2 years

2 years

Pulmonary function testing every 4 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Sirolimus

Trial Overview The study tests whether taking a low dose of Sirolimus early on can prevent LAM from progressing to more advanced stages. It's designed as a long-term intervention to see if this treatment makes a difference over time.

Participant Groups

Group I: Treatment Active Control 1 Intervention

Over-encapsulated 1 mg sirolimus tablet

Group II: Placebo Placebo Group 1 Intervention

Overencapsulated matrix

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 Cincinnati

Lead Sponsor

Trials

442

Recruited

639,000+

National Center for Advancing Translational Sciences (NCATS)

Collaborator

Trials

394

Recruited

404,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

The LAM Foundation

Collaborator

Trials

5

Recruited

700+

Findings from Research

In a study of 98 patients with lymphangioleiomyomatosis (LAM), sirolimus therapy led to significant improvements in lung function, with an increase in forced expiratory volume (FEV1) and walking distance after treatment, indicating its efficacy in managing LAM symptoms.

Sirolimus was found to be safe for long-term use, with mild adverse effects reported, and a recommended serum trough level of 5-9.9 ng/mL for optimal results.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Functional improvements in patients with lymphangioleiomyomatosis after sirolimus: an observational study. Zhan, Y., Shen, L., Xu, W., et al.[2019]

In a long-term study of sirolimus for lymphangioleiomyomatosis involving patients over 2 years, stomatitis was the most common side effect, with an incidence rate of 88.9% by 9 months, which is notably higher than in postrenal transplant patients.

Patients with low hemoglobin levels (<14.5 g/dL) experienced a significantly higher incidence of stomatitis, indicating that baseline hemoglobin and changes in mean corpuscular volume may be important risk factors for this adverse event during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk factors for stomatitis in patients with lymphangioleiomyomatosis during treatment with sirolimus: A multicenter investigator-initiated prospective study. Kitamura, N., Seyama, K., Inoue, Y., et al.[2018]

In a study of individuals with lymphangioleiomyomatosis (LAM) receiving rapamycin for an average of 35.8 months, the treatment was associated with a significant improvement in lung function, as measured by the change in FEV1, with a mean increase of +11 mL/year.

The effectiveness of rapamycin varied among individuals, with better responses linked to higher pretreatment lung function and shorter disease duration, while side effects were more common at higher serum rapamycin levels but were generally low in prevalence (5% or less) by the end of the study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lung function response and side effects to rapamycin for lymphangioleiomyomatosis: a prospective national cohort study. Bee, J., Fuller, S., Miller, S., et al.[2022]

Sirolimus therapy significantly slowed the decline in lung function in patients with lymphangioleiomyomatosis, with a notable reduction in yearly declines in FEV1 and diffusing capacity of carbon monoxide.

Most patients tolerated sirolimus well despite some adverse events, and the therapy also helped stabilize the size of cystic lesions over time, indicating its potential as a long-term treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sustained effects of sirolimus on lung function and cystic lung lesions in lymphangioleiomyomatosis. Yao, J., Taveira-DaSilva, AM., Jones, AM., et al.[2022]

In a case series of four LAM patients treated with sirolimus for 6 to 12 months, significant improvements were observed in extrapulmonary manifestations, including resolution of chylothorax and reduction in the size of renal angiomyolipomas and lymphangioleiomyomas.

The study supports the efficacy of mTOR inhibitors like sirolimus in treating LAM, but highlights the need for further research to determine optimal dosing, treatment duration, and potential long-term side effects before they can be fully integrated into treatment guidelines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of sirolimus in the treatment of lymphangioleiomyomatosis: favorable responses in patients with different extrapulmonary manifestations. Freitas, CS., Baldi, BG., Araújo, MS., et al.[2022]

In a study of 39 patients with lymphangioleiomyomatosis, low-dose sirolimus showed a trend towards stabilizing lung function decline, but was less effective than conventional-dose sirolimus in improving lung function metrics like FEV1 and DLco.

Both low-dose and conventional-dose sirolimus had similar rates of adverse events, with 89.7% of patients experiencing side effects, the most common being hypercholesterolemia and stomatitis, indicating that safety profiles were comparable between the two dosing strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of low-dose Sirolimus in Lymphangioleiomyomatosis. Yoon, HY., Hwang, JJ., Kim, DS., et al.[2019]

Sirolimus therapy in 25 patients with lymphangioleiomyomatosis (LAM) led to a significant and sustained reduction in serum VEGF-D levels and stabilized lung function over an average of 4.5 years, with improvements in lung function metrics such as FEV1 and diffusion capacity.

While sirolimus effectively reduced VEGF-D levels and improved lung function, the study found no direct correlation between the extent of VEGF-D reduction and lung function improvement, suggesting that other factors may contribute to the therapeutic effects of sirolimus.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Term Effect of Sirolimus on Serum Vascular Endothelial Growth Factor D Levels in Patients With Lymphangioleiomyomatosis. Taveira-DaSilva, AM., Jones, AM., Julien-Williams, P., et al.[2019]

In a one-year study involving seven patients with severe lymphangioleiomyomatosis (LAM), sirolimus therapy was found to stabilize or improve lung function, particularly in terms of forced expiratory volume (FEV1) and forced vital capacity (FVC).

Sirolimus also improved the mean forced expiratory flow (FEF25-75) significantly, indicating enhanced lung function, while showing a trend towards better oxygen saturation levels during rest and exercise.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of Sirolimus on Lung function in patients with Lymphangioleiomyomatosis. Aghaeimeybodi, F., Najafizadeh, K., Razavi-Ratki, SK., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Functional improvements in patients with lymphangioleiomyomatosis after sirolimus: an observational study. [2019]

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

Risk factors for stomatitis in patients with lymphangioleiomyomatosis during treatment with sirolimus: A multicenter investigator-initiated prospective study. [2018]

3. England pubmed.ncbi.nlm.nih.gov

Lung function response and side effects to rapamycin for lymphangioleiomyomatosis: a prospective national cohort study. [2022]

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

Sustained effects of sirolimus on lung function and cystic lung lesions in lymphangioleiomyomatosis. [2022]

5. Brazil pubmed.ncbi.nlm.nih.gov

Use of sirolimus in the treatment of lymphangioleiomyomatosis: favorable responses in patients with different extrapulmonary manifestations. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of low-dose Sirolimus in Lymphangioleiomyomatosis. [2019]

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

Long-Term Effect of Sirolimus on Serum Vascular Endothelial Growth Factor D Levels in Patients With Lymphangioleiomyomatosis. [2019]

8. Iran pubmed.ncbi.nlm.nih.gov

Effects of Sirolimus on Lung function in patients with Lymphangioleiomyomatosis. [2022]