Sirolimus for Post-COVID Fibrosis Prevention

Overseen By Spring Maleckar

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: University of Chicago

Must not be taking: CYP3A4 inhibitors

Disqualifiers: Pulmonary fibrosis, Malignancy, Cardiac disease, 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: 2

Duration: 2 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether the drug sirolimus (Rapamune) can prevent lung scarring (pulmonary fibrosis) in people hospitalized with COVID-19 pneumonia. Participants will take one of three different doses of sirolimus daily for 14 days to determine if it reduces the risk of developing lung issues after recovering from COVID-19. The trial is suitable for those currently hospitalized with COVID-19 pneumonia who require extra oxygen and have little to no existing lung scarring. As a Phase 2, Phase 3 trial, this research measures the treatment's effectiveness in an initial, smaller group and represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

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

You may need to stop taking certain medications to join the trial, especially if you are currently on drugs that strongly inhibit CYP3A4, such as clarithromycin or ritonavir. The trial does not specify a washout period, but you should discuss your current medications with the trial team.

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

Research has shown that sirolimus, also known as Rapamune, is generally safe for people, though it can cause some side effects. Some individuals have reported lung problems and other issues when using sirolimus. Notably, the FDA has already approved sirolimus for other uses, indicating prior safety studies. Prospective trial participants should discuss any concerns with a healthcare provider to understand how these side effects might affect them. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatment?

Unlike the standard treatments for post-COVID fibrosis, which often focus on symptom management and supportive care, Sirolimus targets the underlying pathways involved in fibrosis formation. Researchers are excited about Sirolimus because it works by inhibiting the mTOR pathway, which plays a crucial role in cell growth and immune response, potentially preventing or reducing the development of fibrotic tissue in the lungs. The trial explores three different doses—0.5mg, 1mg, and 2mg—offering a tailored approach to optimizing efficacy and minimizing side effects. This unique mechanism and dosing flexibility make Sirolimus a promising candidate for altering the course of post-COVID fibrosis, offering hope for a more effective treatment option.

What evidence suggests that sirolimus might be an effective treatment for post-COVID fibrosis?

Research has shown that sirolimus might help prevent lung scarring in people who have had COVID-19 pneumonia. Sirolimus affects cell growth, which can reduce swelling and scarring. Early results suggest it might lower the risk of developing lung scarring after COVID-19. This trial will test different dosages of sirolimus to determine the most effective amount for reducing this risk. Although more information is needed, early research is promising for sirolimus as a potential treatment. ^{2 3 5 6 7}

Who Is on the Research Team?

Ayodeji Adegunsoye, MD, MS

Principal Investigator

University of Chicago

Are You a Good Fit for This Trial?

Adults over 18 with COVID-19 pneumonia, needing oxygen support, and showing less than 10% lung fibrosis on a CT scan can join. They must be hospitalized, able to consent or have someone who can for them. Those with recent severe heart issues, sirolimus allergies, other serious health conditions, or women who are pregnant/lactating cannot participate.

Inclusion Criteria

Your chest CT scan shows less than 10% lung scarring.

Approval from the patient's primary inpatient service

I need extra oxygen of at least 5 liters per minute or 40% oxygen concentration.

Exclusion Criteria

I have not had worsening or unstable brain or nerve conditions.

I have cancer or an active infection that is not COVID-19, including untreated TB.

I have not had serious heart problems or treatments in the last 6 months.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

1 visit (in-person)

Treatment

Participants receive Sirolimus orally daily for 14 days while hospitalized or at home if discharged early

2 weeks

Daily monitoring (in-person) while hospitalized

Follow-up

Participants return to clinic at 12 weeks for routine lab work and imaging to assess for pulmonary fibrosis

12 weeks

1 visit (in-person)

Long-term monitoring

Optional use of leftover blood samples for research up to 1 year after enrollment

1 year

What Are the Treatments Tested in This Trial?

Interventions

• Sirolimus

Trial Overview

The trial is testing if Sirolimus can prevent lung scarring (pulmonary fibrosis) in patients hospitalized with COVID-19 pneumonia. It aims to see whether this drug reduces the chances of developing long-term lung damage after recovery from the virus.

How Is the Trial Designed?

Group I: Sirolimus 0.5mg Active Control 1 Intervention

Subject will take Sirolimus 0.5mg orally daily for 14 days.

Group II: Sirolimus 1mg Active Control 1 Intervention

Subject will take Sirolimus 1mg orally daily for 14 days.

Group III: Sirolimus 2mg Active Control 1 Intervention

Subject will take Sirolimus 2mg orally daily for 14 days.

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 Chicago

Lead Sponsor

Trials

1,086

Recruited

844,000+

Published Research Related to This Trial

Rapamycin effectively reduces type I collagen production while increasing matrix metalloproteinase 1 (MMP1) levels in both normal and systemic sclerosis (SSc) dermal fibroblasts, indicating its potential as an anti-fibrotic treatment.

The drug's effects are more pronounced in SSc fibroblasts, where it regulates collagen and MMP1 gene expression through different mechanisms, suggesting a targeted approach for treating skin fibrosis in SSc patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of the immunosuppressant rapamycin on the expression of human α2(I) collagen and matrix metalloproteinase 1 genes in scleroderma dermal fibroblasts. Tamaki, Z., Asano, Y., Kubo, M., et al.[2018]

In a study of 194 renal transplant recipients treated with sirolimus, the overall incidence of wound complications was 36% within the first year, with infections, lymphocele formation, and incisional hernias being the most common issues.

Key risk factors for developing wound complications included being over 40 years old, having a BMI over 26 (especially over 30), using thymoglobulin for immunosuppression, and receiving a cumulative sirolimus dose of at least 35 mg by day 4 post-transplant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk factors for impaired wound healing in sirolimus-treated renal transplant recipients. Knight, RJ., Villa, M., Laskey, R., et al.[2022]

In a study of 522 liver transplant patients, 6.7% of those switched to sirolimus developed interstitial pneumonitis, highlighting this as a notable side effect of the drug.

Pneumonitis symptoms, such as cough and dyspnea, were reversible upon discontinuation of sirolimus, emphasizing the importance of early recognition to avoid unnecessary complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interstitial pneumonitis is a frequent complication in liver transplant recipients treated with sirolimus. Morcos, A., Nair, S., Keane, MP., et al.[2021]

Sirolimus, an immunosuppressive drug used in renal transplant patients, can cause interstitial pneumonitis, a rare but serious adverse effect that presents with symptoms like cough and fever.

In this case, a renal transplant patient developed drug-induced hypersensitivity pneumonitis, which only improved after stopping sirolimus, highlighting the importance of monitoring for respiratory symptoms in patients on this medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sirolimus-induced interstitial pneumonitis in a renal transplant patient. Mingos, MA., Kane, GC.[2016]

In a study involving 209 kidney transplant recipients in Korea, Rapamune (Sirolimus) demonstrated an acceptable safety profile, with 54.07% of subjects reporting adverse events, most of which were mild and resolved by the end of the study.

The efficacy of Rapamune was notable, with a low incidence of biopsy-proven acute rejection at 2.87% and a high graft survival rate of 99.51%, indicating its effectiveness in preventing kidney allograft rejection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of Rapamune® (Sirolimus) in kidney transplant recipients: results of a prospective post-marketing surveillance study in Korea. Jeon, HJ., Lee, HE., Yang, J.[2019]

Sirolimus (rapamycin) significantly reduced the expression of collagen type I (Col-I) and fibronectin (FN) in cultured rat renal myofibroblasts, suggesting its potential anti-fibrotic effects at the cellular level.

The reduction in procollagen-I mRNA levels indicates that sirolimus may inhibit collagen production early on, although this effect diminishes after 4 hours, highlighting a time-dependent response in its mechanism of action.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Sirolimus inhibits the expression of type I collagen and fibronectin in cultured renal cortical myofibroblasts]. Zhang, L., Huang, HC., Li, JZ., et al.[2017]

Sirolimus, a drug used to inhibit T and B cell proliferation, can cause serious lung-related side effects, including diffuse alveolar hemorrhage, as seen in a case involving a 33-year-old renal transplant recipient.

After stopping sirolimus and initiating a 6-month tapering steroid therapy, the patient's lung condition improved significantly, leading to full recovery of pulmonary functions without any remaining symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sirolimus-Induced Diffuse Alveolar Hemorrhage: A Case Report. Balcan, B., Simsek, E., Ugurlu, AO., et al.[2017]

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]

Switching to low-dose sirolimus monotherapy in HCV-infected liver transplant recipients significantly improved survival rates and slowed the progression to cirrhosis, based on a retrospective study of 190 patients over 15 years.

Patients with hepatocellular carcinoma (HCC) who were switched to sirolimus had a longer time to HCC recurrence, and those with renal dysfunction showed improved kidney function, indicating that sirolimus may offer multiple clinical benefits in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A retrospective 15-year review: survival advantage after switching to sirolimus in hepatitis C virus infected liver graft recipients. Shah, M., Shankar, A., Gee, I., et al.[2018]

In a study of 1009 heart transplant recipients, everolimus was associated with a low incidence of incision-related wound complications, with 12.3% of patients experiencing such issues, which is slightly higher than the 7.2% for mycophenolate mofetil (MMF).

The analysis indicated that while everolimus had a higher rate of serious incisional complications compared to azathioprine and MMF, it was not conclusively an independent risk factor; instead, a higher body mass index (BMI) was significantly linked to increased risk of complications, with a 12.9% increase in risk for each kg increase in BMI.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of de novo everolimus-based immunosuppression on incisional complications in heart transplantation. Zuckermann, A., Arizon, JM., Dong, G., et al.[2016]

Citations

1.

clinicaltrials.gov

clinicaltrials.gov/study/NCT04948203

Assessing the Efficacy of Sirolimus in Patients With COVID ...

Assessing the Efficacy of Sirolimus in Patients With COVID-19 Pneumonia for Prevention of Post-COVID Fibrosis. ClinicalTrials.gov ID NCT04948203.

2.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC10410516/

Pharmacotherapy and pulmonary fibrosis risk after SARS- ...

Treatment with rituximab considerably increases the risk of developing severe post-COVID-19 outcomes (risk ratios 1.7–5.5). Similar to ...

3.

withpower.com

withpower.com/trial/phase-2-and-3-pneumonia-6-2021-08189

Sirolimus for Post-COVID Fibrosis Prevention · Info for Participants

The primary purpose of this study is to determine whether the drug sirolimus reduces the likelihood of developing of pulmonary fibrosis in patients who are ...

4.

centerwatch.com

centerwatch.com/clinical-trials/listings/NCT04948203/assessing-the-efficacy-of-sirolimus-in-patients-with-covid-19-pneumonia-for-prevention-of-post-covid-fibrosis

Assessing the Efficacy of Sirolimus in Patients With COVID ...

The primary purpose of this study is to determine whether the drug sirolimus reduces the likelihood of developing of pulmonary fibrosis in ...

5.

mdpi.com

mdpi.com/2075-4426/14/1/51

Perspectives on Post-COVID-19 Pulmonary Fibrosis ...

An ongoing study aims to explore the effectiveness of sirolimus therapy in reducing pulmonary fibrosis in COVID-19 hospitalized patients [98]. Sirolimus, an ...

6.

clinicaltrials.gov

clinicaltrials.gov/ct2/show/NCT04948203?cond=Covid19+fibrosis&draw=2&rank=6

Assessing the Efficacy of Sirolimus in Patients With COVID- ...

A group of independent scientists who monitor the safety and scientific integrity of a clinical trial. The DMC can recommend to the sponsor that the trial be ...

7.

clinicaltrials.gov

clinicaltrials.gov/study/NCT04948203

Assessing the Efficacy of Sirolimus in Patients With COVID ...

The primary purpose of this study is to determine whether the drug sirolimus reduces the likelihood of developing of pulmonary fibrosis in patients who are ...