Sirolimus for Aplastic Anemia

Overseen By Bhavisha A Patel, M.D.

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

Must be taking: Cyclosporine

Must not be taking: CYP3A4 inhibitors

Disqualifiers: Myelodysplastic syndrome, Pregnancy, Cancer, 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: 5

Duration: 3 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether sirolimus, an immune-suppressing drug, can prevent aplastic anemia from returning after stopping cyclosporine treatment. Aplastic anemia occurs when the body doesn't produce enough blood cells, often due to the immune system interfering with bone marrow function. Participants will either take sirolimus or be monitored without it after stopping cyclosporine. The trial seeks individuals aged 2 and older with severe aplastic anemia who have responded to cyclosporine-based treatment and are not currently on other blood-affecting medications. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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

The trial requires you to stop taking cyclosporine. You cannot participate if you are taking drugs with hematologic effects or certain CYP3A4 inhibitors unless you can replace them with equivalent medications. The protocol does not specify other medication restrictions, but you should discuss your current medications with the study team.

Will I have to stop taking my current medications?

The trial requires participants to stop taking cyclosporine, but it does not specify if you need to stop other medications. However, you cannot participate if you are taking certain drugs like CYP3A4 inhibitors and cannot switch to alternatives.

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

Research has shown that sirolimus is generally safe for treating blood-related conditions. One study demonstrated that sirolimus, when combined with another drug, was effective and well-tolerated in patients with pure red cell aplasia, a condition where the body stops making red blood cells. Another study found that sirolimus could be used safely in patients with primary aplastic anemia, a condition similar to severe aplastic anemia, which is the focus of the current trial.

While all treatments have risks, previous studies suggest that sirolimus is usually well-tolerated. Common side effects include mouth sores, diarrhea, and higher levels of fats in the blood. Serious side effects are less common but can include a higher risk of infections due to immune system weakening.

Overall, past research provides some reassurance about the safety of sirolimus in people, especially those with conditions affecting blood cell production. Prospective participants should consider these findings and discuss any concerns with the trial team. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Sirolimus is unique because it offers a different approach to treating aplastic anemia compared to the standard immunosuppressive treatments, such as antithymocyte globulin and cyclosporine. Unlike these traditional treatments, sirolimus works by inhibiting a specific pathway known as mTOR, which plays a role in cell growth and survival. Researchers are excited about sirolimus because it has the potential to improve blood cell production in patients with aplastic anemia, possibly offering a more effective and targeted treatment option.

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

Research suggests that sirolimus, which participants in this trial may receive, might help prevent the recurrence of aplastic anemia. One study showed that patients with conditions similar to aplastic anemia responded well to sirolimus, with many experiencing full or partial improvement. Sirolimus has also benefited patients who did not respond to other treatments. It calms the immune system, which may help prevent the disease from returning after stopping cyclosporine. While these early results are promising, more research is needed to confirm its effectiveness specifically for aplastic anemia. ^{1 2 3 4 6}

Who Is on the Research Team?

Bhavisha A Patel, M.D.

Principal Investigator

National Heart, Lung, and Blood Institute (NHLBI)

Are You a Good Fit for This Trial?

This trial is for people aged 2 and older who weigh more than 12 kg, have severe aplastic anemia (SAA) previously treated with immunosuppressive therapy including cyclosporine, and show a positive response to treatment. They must not be pregnant or breastfeeding, should agree to use birth control if of childbearing potential, haven't used sirolimus or similar drugs recently, aren't on certain medications that affect the study drug's action, don't have other blood disorders like leukemia or myelodysplastic syndrome, and are generally healthy enough to participate.

Inclusion Criteria

I am at least 2 years old.

Weight greater than 12 kg

I have been on cyclosporine consistently for the last 6 months.

Exclusion Criteria

My infection is not improving despite treatment.

I am taking medications that affect liver enzyme levels and cannot switch them.

Anaphylactic or hypersensitivity reaction to sirolimus

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants in Group 1 take sirolimus daily for 3 months with close monitoring; Group 2 is monitored without sirolimus

3 months

Weekly blood tests, monthly fasting blood tests, sirolimus measurements every 1-2 weeks for Group 1

Follow-up

Participants are monitored for safety and effectiveness after treatment, with clinic visits at 3 months, 12 months, and annually for 5 years

5 years

Clinic visits at 3 months, 12 months, and annually

What Are the Treatments Tested in This Trial?

Interventions

• Sirolimus

Trial Overview The trial tests whether taking Sirolimus orally can prevent SAA from returning after stopping cyclosporine treatment. Participants will either receive Sirolimus daily for three months while being closely monitored (Group 1), or they'll stop cyclosporine without receiving Sirolimus but still under close observation (Group 2). The effectiveness will be measured through regular blood tests and bone marrow biopsies over five years.

How Is the Trial Designed?

Group I: Sirolimus Experimental Treatment 1 Intervention

sirolimus

Group II: Standard of Care Active Control 1 Intervention

no intervention

Who Is Running the Clinical Trial?

National Heart, Lung, and Blood Institute (NHLBI)

Lead Sponsor

Trials

3,987

Recruited

47,860,000+

Published Research Related to This Trial

Sirolimus was successfully used to treat a 55-year-old patient with severe aplastic anemia and chronic kidney disease, leading to a gradual increase in blood cell counts and achieving transfusion independence.

The treatment was well-tolerated and demonstrated lower nephrotoxicity compared to traditional therapies like cyclosporine, making sirolimus a promising option for patients with similar conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful sirolimus therapy of an aplastic anemia patient with chronic kidney disease: A case report. Niu, H., Qi, W., Wang, Y., et al.[2022]

In mouse models of acquired aplastic anemia, rapamycin effectively improved blood cell counts and bone marrow health, showing comparable efficacy to cyclosporine, a standard treatment.

Rapamycin works through unique mechanisms, such as increasing regulatory T cells and reducing harmful CD8+ T cells, suggesting it could be a promising alternative therapy for patients with aplastic anemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapamycin is highly effective in murine models of immune-mediated bone marrow failure. Feng, X., Lin, Z., Sun, W., et al.[2019]

In a study of 84 heart transplant patients treated with sirolimus, the prevalence of anemia increased from 71% to 75% after starting the medication, indicating a significant impact on hemoglobin levels.

A quarter of the patients experienced a drop in hemoglobin of 20 g/L or more, and the hematologic profile suggested that the anemia was related to chronic disease and functional iron deficiency, highlighting the need for monitoring and management in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sirolimus is associated with impaired hematopoiesis in heart transplant patients? A retrospective analysis. McDonald, MA., Gustafsson, F., Almasood, A., et al.[2013]

In two cases of aplastic anemia (AA) that relapsed after standard immunosuppressive therapy (IST) with anti-thymocyte globulin (ATG) and cyclosporine (CsA), patients achieved transfusion independence after being treated with sirolimus combined with CsA.

Sirolimus works by inhibiting the mTOR pathway, which may provide an effective alternative treatment for patients who do not respond to traditional IST, highlighting its potential role in managing refractory AA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Relapse of aplastic anemia responsive to sirolimus combined with cyclosporine. He, G., Zhang, X., Wu, D., et al.[2013]

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]

In a study of 25 stable renal transplant patients, switching from sirolimus to enteric coated mycophenolate sodium resulted in an increase in hemoglobin levels in 86% of patients, indicating improved anemia management.

The conversion also led to a significant decrease in endogenous erythropoietin levels and reduced erythropoietin resistance, suggesting that sirolimus may contribute to anemia by making the body less responsive to erythropoietin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduction in erythropoietin resistance after conversion from sirolimus to enteric coated mycophenolate sodium. Augustine, JJ., Rodriguez, V., Padiyar, A., et al.[2013]

In a study of 77 patients with severe aplastic anemia, the addition of sirolimus to standard treatment (h-ATG and cyclosporine) did not improve the hematologic response rate at 3 or 6 months compared to the standard treatment alone.

The overall response rates were 37% for the h-ATG/CsA/sirolimus group and 50% for the h-ATG/CsA group at 3 months, indicating that sirolimus did not provide the expected benefits despite its theoretical advantages.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of severe aplastic anemia with a combination of horse antithymocyte globulin and cyclosporine, with or without sirolimus: a prospective randomized study. Scheinberg, P., Wu, CO., Nunez, O., et al.[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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT00319878

Study Details | NCT00319878 | Sirolimus and Cyclosporine ... This study will evaluate the safety and efficacy of sirolimus in combination with cyclosporine for treating individuals with aplastic anemia that has not ...

2. nature.com nature.com/articles/s41408-023-00845-3

Sirolimus versus cyclosporine A in patients with primary ... We recently demonstrated that sirolimus is an effective treatment for patients with refractory /relapsed/intolerant aPRCA [7]. Even patients who ...

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0006497124065960

Sirolimus Plus Roxadustat in Patients with Pure Red Cell ... Sirolimus plus roxadustat produced an overall response (OR) in 65/72 patients (90.3%), including 39/72 (54.2%) CR and 26/72 (36.1%) partial ...

4. centerwatch.com centerwatch.com/clinical-trials/listings/NCT02979873/sirolimus-rapamune-for-relapse-prevention-in-people-with-severe-aplastic-anemia-responsive-to-immunosuppressive-therapy

Sirolimus (Rapamune ) for Relapse Prevention in People ... We hypothesize that CSA to SRL conversion will significantly decrease the relapse rate after immunosuppressive therapy for acquired aplastic ...

5. ashpublications.org ashpublications.org/bloodadvances/article/7/21/6451/497485/Treatment-strategy-for-acquired-pure-red-cell

Treatment strategy for acquired pure red cell aplasia Sirolimus is effective for refractory/relapsed/intolerant acquired pure red cell aplasia: results of a prospective single-institutional trial.

6. connect.careboxhealth.com connect.careboxhealth.com/en-US/trial/listing/589455

Efficacy and Safety of Sirolimus With or Without Cyclosporin A ... This is a single center, randomized, open-label, phase II study to compare the efficacy of sirolimus combined with cyclosporin A (CsA) to sirolimus alone in ...