Sirolimus for Lymphangioleiomyomatosis

(MILED Trial)

Not currently 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if taking a low dose of sirolimus (also known as Rapamune) early and for an extended period can prevent the progression of lymphangioleiomyomatosis (LAM), a rare lung disease that primarily affects women and causes breathing difficulties. The study compares sirolimus to a placebo (a pill with no active drug) to evaluate effectiveness. Women diagnosed with LAM who experience symptoms that hinder daily life may be suitable candidates for this trial. As a Phase 3 trial, it represents the final step before FDA approval, offering participants the opportunity to contribute to potentially groundbreaking treatment advancements.

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.

Is there any evidence suggesting that sirolimus is likely to be safe for humans?

Research has shown that sirolimus has been tested for safety in people with lymphangioleiomyomatosis (LAM). In these studies, sirolimus helped maintain stable lung function and improved symptoms. However, some participants experienced side effects; for instance, one study found that a few patients developed lung inflammation. Despite this, sirolimus is generally well-tolerated for LAM. Notably, the FDA has already approved sirolimus for other conditions, indicating its safety. Prospective trial participants should discuss potential side effects with the research team to understand what to expect. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for Lymphangioleiomyomatosis?

Most treatments for lymphangioleiomyomatosis (LAM) primarily aim to manage symptoms and slow disease progression, often using medications like sirolimus or everolimus. However, what makes sirolimus particularly exciting in this study is its potential to specifically target and inhibit the mTOR pathway, which is crucial in LAM progression. This targeted action could mean more effective management of the disease with potentially fewer side effects compared to broader immunosuppressive treatments. Researchers are eager about this treatment because it harnesses a known mechanism with a targeted approach, possibly offering improved outcomes for patients with LAM.

What evidence suggests that sirolimus might be an effective treatment for lymphangioleiomyomatosis?

Research has shown that sirolimus can help people with lymphangioleiomyomatosis (LAM) by slowing the disease's progression. In one study, 59% of patients responded positively after five years of treatment. Sirolimus stabilized lung function and improved quality of life. Patients who took sirolimus for one year also experienced stable lung capacity. Long-term use has generally maintained lung function and oxygen levels. In this trial, participants will receive either sirolimus or a placebo to evaluate its effectiveness further. Overall, sirolimus shows promise for managing LAM symptoms and slowing the disease's progression. ^{1 6 7 8 9}

Who Is on the Research Team?

Francis X. McCormack, M.D.

Principal Investigator

University of Cincinnati

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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 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 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 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]

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]

Citations

1. nature.com nature.com/articles/s41598-021-89562-0

Long-term results of sirolimus treatment in ... After 5 years of sirolimus treatment 59% had a positive response, 30% had a partial response and 11% had a negative response. Our study found ...

2. frontiersin.org frontiersin.org/journals/medicine/articles/10.3389/fmed.2024.1494713/full

Characteristics and outcomes of patients with LAM ... The 5-year survival after sirolimus initiation was 84% (95% CI: 76%; 90%) for probable LAM patients, and 77% (95% CI: 48%; 91%) for TSC-LAM ...

3. nejm.org nejm.org/doi/full/10.1056/NEJMoa1100391

Efficacy and Safety of Sirolimus in ... Our study shows that treatment with sirolimus for 1 year has beneficial effects in patients with LAM, including the stabilization of FEV1 and ...

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/31429781/

Long-term efficacy and safety of sirolimus therapy in ... Sirolimus therapy is effective at improving or stabilizing pulmonary function, oxygen levels, exercise capacity, and quality of life in patients with LAM for ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S2772993124003231

Lung Transplantation Outcomes and Peritransplant ... This study supports lung transplant as a treatment for severe pulmonary LAM and identifies increased mortality associated with pre-LT sirolimus.

6. ojrd.biomedcentral.com ojrd.biomedcentral.com/articles/10.1186/s13023-019-1178-2

Long-term efficacy and safety of sirolimus therapy in patients ... Sirolimus has been confirmed to be effective for lymphangioleiomyomatosis (LAM), a rare multisystem neoplastic disease in women.

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/27513278/

Efficacy and Safety of Long-Term Sirolimus Therapy for ... Although long-term sirolimus treatment of Asian patients with LAM was associated with a large number of adverse events, including three episodes of pneumonitis,

8. sciencedirect.com sciencedirect.com/science/article/abs/pii/S2212534513000403

The efficacy and safety of low-dose sirolimus for treatment ... We conducted a retrospective, observational study of 15 patients with LAM who underwent sirolimus therapy for more than 6 months. The efficacy was evaluated by ...

9. clinicaltrials.gov clinicaltrials.gov/study/NCT02432560

Safety and Durability of Sirolimus for Treatment of LAM This study will help us to refine treatment for patients with LAM and determine if long term suppressive therapy with sirolimus can prevent progression to later ...