Sirolimus for Post-COVID Fibrosis Prevention

Recruiting in Palo Alto (17 mi)

Overseen by Ayodeji Adegunsoye, MD, MS

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2 & 3

Recruiting

Sponsor: University of Chicago

Must not be taking: CYP3A4 inhibitors

Disqualifiers: Pulmonary fibrosis, Malignancy, Cardiac disease, others

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Approved in 4 Jurisdictions

Trial Summary

What is the purpose of this trial?

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 hospitalized with COVID-19 pneumonia.

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.

What data supports the effectiveness of the drug Sirolimus for preventing post-COVID fibrosis?

Sirolimus, also known as Rapamune, has shown some potential in reducing fibrosis (scarring) in liver transplant patients with hepatitis C, suggesting it might help with fibrosis in other conditions too. Additionally, rapamycin, a component of Sirolimus, has demonstrated anti-fibrotic effects in skin conditions like systemic sclerosis, which might indicate similar benefits for post-COVID fibrosis. ^{1 2 3 4 5}

Is Sirolimus generally safe for humans?

Sirolimus, also known as Rapamune, is generally considered safe for humans, but it can cause some side effects. It has been linked to lung issues like interstitial pneumonitis (lung inflammation) in some transplant patients and may impair wound healing. However, it has a lower risk of kidney and nerve problems compared to other similar drugs. ^{1 3 6 7 8}

How does the drug sirolimus work for post-COVID fibrosis prevention?

Sirolimus is unique because it has an anti-fibrotic effect, meaning it can help prevent or reduce the formation of excess fibrous tissue, which is a key issue in post-COVID fibrosis. This drug works by inhibiting certain proteins that are involved in cell growth and immune response, which can help reduce scarring and improve lung function. ^{1 2 3 9 10}

Research Team

Ayodeji Adegunsoye, MD, MS

Principal Investigator

University of Chicago

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• Sirolimus (mTOR inhibitor)

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.

Participant Groups

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 Canada, Japan for the following indications:

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+

Pete Salzmann

University of Chicago

Chief Executive Officer since 2018

MD from University of Chicago’s Pritzker School of Medicine, MBA from Stanford University’s Graduate School of Business

Anh Nguyen

University of Chicago

Chief Medical Officer

MD from Rutgers New Jersey Medical School, MBA from University of Chicago

Findings from Research

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 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]

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]

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 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]

References

1. Netherlands 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. [2018]

2. Ireland pubmed.ncbi.nlm.nih.gov

Interstitial pneumonitis is a frequent complication in liver transplant recipients treated with sirolimus. [2021]

3. Denmark pubmed.ncbi.nlm.nih.gov

Risk factors for impaired wound healing in sirolimus-treated renal transplant recipients. [2022]

4. England pubmed.ncbi.nlm.nih.gov

A retrospective 15-year review: survival advantage after switching to sirolimus in hepatitis C virus infected liver graft recipients. [2018]

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

Impact of de novo everolimus-based immunosuppression on incisional complications in heart transplantation. [2016]

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

Sirolimus-induced interstitial pneumonitis in a renal transplant patient. [2016]

7. Canada pubmed.ncbi.nlm.nih.gov

Sirolimus: a therapeutic advance for dermatologic disease. [2014]

8. England 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. [2019]

9. China pubmed.ncbi.nlm.nih.gov

[Sirolimus inhibits the expression of type I collagen and fibronectin in cultured renal cortical myofibroblasts]. [2017]

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

Sirolimus-Induced Diffuse Alveolar Hemorrhage: A Case Report. [2017]