Tocilizumab for Lung Transplant

(ALL IN LUNG Trial)

Recruiting at 32 trial locations

Overseen By Yvonne Morrison, MS

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Must be taking: Triple immunosuppression

Must not be taking: Alkylating agents

Disqualifiers: HIV, Hepatitis B, Malignancy, others

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 6 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 20 weeks

350 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a trial in which 350 primary lung transplant recipients will be randomized (1:1) to receive either Tocilizumab (six doses over 20 weeks) plus standard triple maintenance immunosuppression or placebo (sterile normal saline) plus standard triple maintenance immunosuppression (Tacrolimus, Mycophenolate Mofetil, corticosteroids). The primary objective is to test the hypothesis that treatment with triple maintenance immunosuppression plus Tocilizumab (TCZ) is superior to triple maintenance immunosuppression plus placebo (saline) as defined by a composite endpoint of a) CLAD, b) listed for re-transplantation, and c) death

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, it mentions that you cannot be on certain treatments like alkylating agents or investigational drugs. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug Tocilizumab for lung transplant patients?

Tocilizumab, an IL-6 inhibitor, has shown promise in treating antibody-mediated rejection in lung transplant patients by reducing donor-specific antibodies and lowering graft failure rates, as seen in a study comparing its use to treatments without it. ^{1 2 3 4 5}

Is tocilizumab generally safe for humans?

Tocilizumab, also known as Actemra or RoActemra, is generally well tolerated in humans, but it can cause some side effects like infections and, in rare cases, leukoencephalopathy (a brain condition). It has been used safely for conditions like arthritis, but long-term safety data is limited. ^{4 6 7 8 9}

How is the drug Tocilizumab unique for lung transplant patients?

Tocilizumab is unique for lung transplant patients because it targets interleukin-6 (IL-6), helping to clear donor-specific antibodies and reduce graft failure, which is not commonly addressed by other treatments for antibody-mediated rejection in lung transplants. ^{1 3 4 8 10}

Research Team

Ramsey Hachem, MD

Principal Investigator

University of Utah Medical Center

Daniel Kreisel, M.D.

Principal Investigator

Washington University School of Medicine

Joren Madsen, MD, D.Phil.

Principal Investigator

Massachusetts General Hospital

Eligibility Criteria

This trial is for individuals over 30 kg awaiting their first lung transplant, who understand the study and consent to participate. They must not be pregnant, use effective contraception if applicable, have up-to-date vaccinations, no prior desensitization therapy or organ transplants, a negative TB test within a year or completed LTBI treatment, and an adequate level of IgG.

Inclusion Criteria

I am on the waiting list for my first lung transplant.

I have not had, nor am I planning to have, desensitization therapy before a transplant.

My vaccinations are up to date according to transplant trial guidelines.

Exclusion Criteria

You have had serious allergic reactions to certain types of antibody medications.

Patients with a platelet count < 100,000/mm^3 (last measurement within 7 days prior to enrollment)

Patients with an absolute neutrophil count (ANC) < 2,000/mm^3 (last measurement within 7 days prior to enrollment)

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either Tocilizumab (six doses over 20 weeks) plus standard triple maintenance immunosuppression or placebo plus standard triple maintenance immunosuppression

20 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment, with primary and secondary outcomes measured up to 3 years

36 months

Treatment Details

Interventions

• Placebo for Tocilizumab
• Tocilizumab

Trial Overview The trial tests whether Tocilizumab (six doses over 20 weeks) combined with standard immunosuppression is more effective than placebo plus standard care in preventing complications like CLAD, re-transplantation listing or death in primary lung transplant recipients.

Participant Groups

Group I: Tocilizumab Group Experimental Treatment 1 Intervention

Subject in this group will receive ACTEMRA(R) (Tocilizumab) ,(six injections over 20 weeks) plus standard triple maintenance immunosuppression of Tacrolimus, Mycophenolate Mofetil, corticosteroids

Group II: Placebo Group Placebo Group 1 Intervention

Subject in this group will receive placebo for Tocilizumab (sterile normal saline) plus standard triple maintenance immunosuppression of Tacrolimus, Mycophenolate Mofetil, corticosteroids

Tocilizumab is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Actemra for:

• Rheumatoid Arthritis
• Systemic Juvenile Idiopathic Arthritis
• Polyarticular Juvenile Idiopathic Arthritis
• Giant Cell Arteritis
• Cytokine Release Syndrome
• COVID-19

Approved in United States as Actemra for:

• Rheumatoid Arthritis
• Systemic Juvenile Idiopathic Arthritis
• Polyarticular Juvenile Idiopathic Arthritis
• Giant Cell Arteritis
• Cytokine Release Syndrome
• COVID-19

Approved in Canada as Actemra for:

• Rheumatoid Arthritis
• Systemic Juvenile Idiopathic Arthritis
• Polyarticular Juvenile Idiopathic Arthritis
• Giant Cell Arteritis
• Cytokine Release Syndrome
• COVID-19

Approved in Japan as Actemra for:

• Rheumatoid Arthritis
• Systemic Juvenile Idiopathic Arthritis
• Polyarticular Juvenile Idiopathic Arthritis
• Giant Cell Arteritis
• Cytokine Release Syndrome
• COVID-19

Who Is Running the Clinical Trial?

National Institute of Allergy and Infectious Diseases (NIAID)

Lead Sponsor

Trials

3,361

Recruited

5,516,000+

Findings from Research

In a study of 9 lung transplant recipients treated with tocilizumab (TCZ), the drug was associated with better outcomes in managing antibody-mediated rejection (AMR), including more effective clearance of donor-specific antibodies (DSA) and lower rates of graft failure compared to 18 patients treated without TCZ.

The safety profile of TCZ was comparable to standard AMR treatments, with similar rates of infusion reactions, liver enzyme elevation, and infections, suggesting it is a safe option for lung transplant patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tocilizumab for antibody-mediated rejection treatment in lung transplantation. January, SE., Fester, KA., Halverson, LP., et al.[2023]

Eculizumab, a monoclonal antibody that inhibits complement protein C5, shows promise in preventing and treating antibody-mediated rejection (AMR) in lung transplant recipients, with three case reports indicating successful outcomes.

Despite limited robust data, early experiences suggest that eculizumab could be a valuable alternative treatment option for managing AMR, which is crucial for improving long-term lung transplant success and patient survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Complement to Traditional Treatments for Antibody-Mediated Rejection? Use of Eculizumab in Lung Transplantation: A Review and Early Center Experience. Kleiboeker, HL., Prom, A., Paplaczyk, K., et al.[2023]

Tocilizumab is an effective treatment for adults with moderate to severe rheumatoid arthritis (RA), showing beneficial effects on disease symptoms and quality of life, based on several large clinical trials and studies.

Long-term use of tocilizumab (up to 9 years) is generally well tolerated, with infections being the most common side effect, and it has been shown to be more effective than adalimumab in patients who cannot continue methotrexate.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravenous tocilizumab: a review of its use in adults with rheumatoid arthritis. Dhillon, S.[2022]

Tocilizumab is a humanized monoclonal antibody that targets the interleukin-6 receptor, showing efficacy in treating conditions like Castleman disease and various types of arthritis, with approval in Japan and the European Union for these uses.

The drug is currently under review by the US FDA for moderate-to-severe rheumatoid arthritis and has potential applications for other IL-6 related disorders, such as Crohn's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tocilizumab. Venkiteshwaran, A.[2021]

In a study of 53 patients with rheumatoid arthritis, tocilizumab (TCZ) demonstrated high effectiveness, with 75.5% achieving remission or low disease activity at 24 weeks and 87.3% at 52 weeks.

The switch from intravenous to subcutaneous administration of TCZ did not affect its effectiveness, and the treatment was found to be safe with a low adverse event rate of 13.6 events per 100 patient-years.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analysis of effectiveness, safety and optimization of tocilizumab in a cohort of patients with rheumatoid arthritis in clinical practice. Mena-Vázquez, N., Manrique-Arija, S., Rojas-Giménez, M., et al.[2022]

Biologic agents for asthma and allergic diseases, including omalizumab and anti-IL5 medications, are generally safe with most adverse effects being mild and manageable, although long-term safety data is still limited.

Omalizumab and reslizumab carry a slightly increased risk of anaphylaxis, leading to a black box warning that emphasizes the need for patient monitoring after injection and the availability of epinephrine autoinjectors for emergencies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hypersensitivity and adverse reactions to biologics for asthma and allergic diseases. Jackson, K., Bahna, SL.[2021]

In a study of 188 patients aged 2-17 with polyarticular-course juvenile idiopathic arthritis (JIA), tocilizumab (TCZ) demonstrated high efficacy over 2 years, with JIA-ACR50/70/90 response rates of 80.3%, 77.1%, and 59.6% respectively, and over half of the patients achieving inactive disease by week 104.

The safety profile of TCZ was consistent with previous reports, with adverse event rates of 406.5 per 100 patient-years and serious infections at 5.2 per 100 patient-years, indicating that TCZ is a relatively safe option for long-term treatment of JIA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Tocilizumab for Polyarticular-Course Juvenile Idiopathic Arthritis in the Open-Label Two-Year Extension of a Phase III Trial. Brunner, HI., Ruperto, N., Zuber, Z., et al.[2021]

Tocilizumab is an effective treatment for systemic and polyarticular juvenile idiopathic arthritis (JIA) in children aged 2 years and older, showing significant improvement in patient responses compared to placebo in two phase III trials involving patients aged 2-17 years.

The drug was generally well tolerated, with infections being the most common adverse events; however, there was an approximately 11% annual risk of serious infections, indicating the need for monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tocilizumab: a review of its use in the treatment of juvenile idiopathic arthritis. Frampton, JE.[2021]

A 63-year-old woman with rheumatoid arthritis experienced cognitive impairment after 34 months of treatment with tocilizumab (TCZ), an anti-IL-6 receptor antibody, indicating a potential side effect of long-term use.

Discontinuing TCZ led to improvements in her cognitive function and brain MRI results within 3 months, suggesting that leukoencephalopathy may occur with prolonged TCZ administration and highlighting the importance of monitoring and possibly stopping the drug for better outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tocilizumab-induced Leukoencephalopathy with a Reversible Clinical Course. Sasaki, R., Hishikawa, N., Nomura, E., et al.[2023]

Tocilizumab (TCZ) administered subcutaneously (TCZ-SC) has been shown to be as effective and safe as the intravenous (TCZ-IV) form in treating rheumatoid arthritis, based on three phase III randomized controlled trials and additional real-world studies.

For patients with higher body weight, TCZ-SC 162 mg every two weeks may be less effective, but switching to a weekly dose (TCZ-SC 162 mg qw) can improve drug concentration without introducing new safety concerns, making TCZ-SC a flexible treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Subcutaneous tocilizumab: recent advances for the treatment of rheumatoid arthritis. Ogata, A., Kato, Y., Higa, S., et al.[2020]

References

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

Tocilizumab for antibody-mediated rejection treatment in lung transplantation. [2023]

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

A Complement to Traditional Treatments for Antibody-Mediated Rejection? Use of Eculizumab in Lung Transplantation: A Review and Early Center Experience. [2023]

3. New Zealand pubmed.ncbi.nlm.nih.gov

Intravenous tocilizumab: a review of its use in adults with rheumatoid arthritis. [2022]

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

Tocilizumab. [2021]

5. Spain pubmed.ncbi.nlm.nih.gov

Analysis of effectiveness, safety and optimization of tocilizumab in a cohort of patients with rheumatoid arthritis in clinical practice. [2022]

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

Hypersensitivity and adverse reactions to biologics for asthma and allergic diseases. [2021]

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

Efficacy and Safety of Tocilizumab for Polyarticular-Course Juvenile Idiopathic Arthritis in the Open-Label Two-Year Extension of a Phase III Trial. [2021]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Tocilizumab: a review of its use in the treatment of juvenile idiopathic arthritis. [2021]

9. Japan pubmed.ncbi.nlm.nih.gov

Tocilizumab-induced Leukoencephalopathy with a Reversible Clinical Course. [2023]

10. England pubmed.ncbi.nlm.nih.gov

Subcutaneous tocilizumab: recent advances for the treatment of rheumatoid arthritis. [2020]