Tocilizumab in Lung Transplantation

Study Overview
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Brief Summary
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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

Official Title
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Targeting Inflammation and Alloimmunity in Lung Transplant Recipients With Tocilizumab (CTOT-45)

Conditions
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Lung Transplant

Intervention / Treatment
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* Drug: Tocilizumab
* Drug: Placebo for Tocilizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Study Entry: Subject and/or parent guardian must be able to understand the purpose of the study and willing to participate and sign informed consent/assent Greater than or equal to 30 kg body weight Listed for a primary lung transplant No previous or planned desensitization therapy prior to transplant Serum Immunoglobulin G (IgG) level greater than 400 mg/dL. Patients treated with intravenous immune globulin (IVIG) for hypogammaglobulinemia are eligible for enrollment if their serum IgG level is greater than 400 mg/dL 14 or more days after the most recent IVIG treatment For women of child-bearing potential, willingness to use highly-effective contraception; according to the Food and Drug Administration (FDA) Office of Women's Health (http://www.fda.gov/birthcontrol). Female participants of child-bearing potential must consult with their physician and determine the most suitable method(s) from this list to be used for the duration of the study. Those who choose oral contraception must agree to use a second form of contraception after administration of study drug for a period of 1 year after the last dose of study drug Tested negative for latent TB infection (LTBI) using a PPD or interferon-gamma release assay (i.e., QuantiFERON-TB, T-SPOT.TB) within 1 year prior to transplant or has completed appropriate LTBI therapy within the 1 year prior to transplant In the absence of contraindication, vaccinations must be up to date per the Division of Allergy, Immunology, and Transplantation (DAIT) Guidance for Patients in Transplant Trials Randomization: Provide written informed consent for the study participation, and agree to continue in the study Undergoing single or bilateral lung transplant Agreement to use contraception; according to the FDA Office of Women's Health (http://www.fda.gov/birthcontrol), there are a number of birth control methods that are more than 80% effective. Female participants of child-bearing potential must consult with their physician and determine the most suitable method(s) from this list to be used for the duration of the study. Those who choose oral contraception must agree to use a second form of contraception after administration of study drug for a period of 1 year after the last dose of study drug Negative physical crossmatch, if the results are available at the time of randomization No desensitization therapy prior to transplant Negative pregnancy test (serum or urine) for women of child-bearing potential within 48 hours prior to transplant Negative severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) Polymerase Chain Reaction (PCR) testing for the recipient prior to transplant as per institutional policy Negative SARS-CoV2 PCR testing for the donor prior to transplant as per institutional policy Recipient of lungs that have been supported with ex vivo lung perfusion (EVLP) devices are permitted Exclusion Criteria: Study Entry: Listed for multi-organ transplant (e.g., heart-lung, liver-lung, kidney-lung) Prior history of organ or cellular transplantation Received treatment to deplete Human Leukocyte Antigens (HLA) antibodies before transplantation Currently breast-feeding a child or plans to become pregnant during the timeframe of the study follow up period History of severe allergic and/or anaphylactic reactions to humanized or murine monoclonal antibodies Known hypersensitivity or previous treatment with ACTEMRA(R) (tocilizumab) Infection with human immunodeficiency virus (HIV) Hepatitis B virus surface antigen or core antibody positive Hepatitis C virus PCR positive (HCV+) patients who have failed to demonstrate sustained viral remission (2 consecutive PCR or Nucleic Acid Tests (NAT) negative tests at least 24 weeks apart), with or without anti-viral treatment; Chronic infection with Burkholderia cenocepacia or Burkholderia gladioli Non-tuberculous mycobacterial (NTM) pulmonary disease; if there is a history of NTM pulmonary disease, culture conversion is necessary for eligibility Presence of active malignancy or history of malignancy less than 5 years in remission, excluding adequately treated in-situ cervical carcinoma, low grade prostate carcinoma, or adequately treated basal or squamous cell carcinoma of the skin History of hemolytic-uremic syndrome/ thrombotic thrombocytopenia purpura History of demyelinating disorders (e.g., multiple sclerosis, chronic inflammation demyelinating polyneuropathy) Current treatment with alkylating agents such as cyclophosphamide History of gastrointestinal (GI) tract perforation History of inflammatory bowel disease except fully excised ulcerative colitis History of diverticulitis (diverticulosis is not an exclusion) or diverticular bleeding; 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) Patients with Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) levels >3 times upper limit of normal Patients who use illegal drugs Use of investigational drugs within 4 weeks prior to enrollment Any condition that in the opinion of the site Principal Investigator (PI) introduces undue risk by participating in this study Randomization: Recipient of multi-organ or tissue transplants Received a live virus vaccine within 30 days prior to randomization Received treatment to deplete HLA antibodies before transplantation to improve the possibility of transplantation Patients with known donor-specific antibody that will require intervention based on local clinical protocols History of GI tract perforation History of inflammatory bowel disease except fully excised ulcerative colitis History of diverticulitis (diverticulosis is not an exclusion) or diverticular bleeding History of severe allergic anaphylactic reactions to humanized or murine monoclonal antibodies Known hypersensitivity or previous treatment with ACTEMRA(R) (tocilizumab) Recipient or donor with infection with human immunodeficiency virus (HIV) Recipient with hepatitis B virus surface antigen or hepatitis B core antibody positive Hepatitis B negative transplant recipient that received a transplant from a Hepatitis B core antibody positive donor unless the recipient has a Hepatitis B Surface Antigen (HBsAb) titer >10U/L Recipient of a hepatitis C virus nucleic acid test (NAT) positive donor organ Latent TB infection (LTBI) and has not completed appropriate therapy Chronic infection with Burkholderia cenocepacia or Burkholderia gladioli Non-tuberculous mycobacterial (NTM) pulmonary disease; if there is a history of NTM pulmonary disease, culture conversion is necessary for eligibility Presence of active malignancy (except for non-melanoma skin cancer) History of hemolytic-uremic syndrome/ thrombotic thrombocytopenia purpura History of demyelinating disorders (e.g., multiple sclerosis, chronic inflammation demyelinating polyneuropathy) Current treatment with alkylating agents such as cyclophosphamide Patients with AST or ALT levels > 1.5 times upper limit of normal (last measurement within 1 day prior to randomization) Patients with platelet count <100,000/mm^3 (last measurement within 1 day prior to randomization) Patients with an absolute neutrophil count (ANC) <2,000/mm^3 (last measurement within 1 day prior to randomization) Patients who are administered or intended to be administered cytolytic (such as anti-thymocyte globulin) or anti-CD25 monoclonal antibody agents as induction therapy in the immediate post- transplant period Patients who have been treated in the past 3 months, or for whom it is anticipated that treatment with any immunomodulatory biological agents post-transplant are excluded Use of an investigational drug after transplant Any condition that in the opinion of the site PI introduces undue risk by participating in this study

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tocilizumab Group<br>Subject in this group will receive ACTEMRA(R) (Tocilizumab) ,(six injections over 20 weeks) plus standard triple maintenance immunosuppression of Tacrolimus, Mycophenolate Mofetil, corticosteroids | Drug: Tocilizumab<br>* The initial dose of tocilizumab will be administered in the operating room before reperfusion of the first lung during the lung transplant surgery. 6 doses will be given once every four weeks over a 20-week period. The dose is approved for pediatric patients who weigh 30 kg or more<br>* Other names: ACTEMRA;|
| Placebo Comparator: Placebo Group<br>Subject in this group will receive placebo for Tocilizumab (sterile normal saline) plus standard triple maintenance immunosuppression of Tacrolimus, Mycophenolate Mofetil, corticosteroids | Drug: Placebo for Tocilizumab<br>* Placebo 0.9% Sodium Chloride Injection USP (Normal Saline) Placebo will be given as a single intravenous dose, volume matched to tocilizumab. Placebo will be administered over a period of approximately 60 minutes; once every four weeks over a 20-week period. The first placebo dose will be during the transplant surgery before reperfusion of the first lung allograft, with 5 subsequent monthly doses<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of subjects who meet any one of the pre-specified events detailed in the outcome description: from Baseline up to 36 months | The development of Chronic Lung Allograft Dysfunction (CLAD) The development of any form of CLAD will be defined according to the standard 2019 The International Society for Heart and Lung Transplantation (ISHLT) criteria. Listed for re-transplantation Re-transplantation defined as the subject has been formally registered on the United Network for Organ Sharing (UNOS) waiting list to undergo a second lung transplant surgery Death Primary analysis will be conducted according to an Intent-to-treat (ITT) principle and therefore will include all randomized subjects who receive Tocilizumab(TCZ) or placebo. The time from randomization to development of CLAD will be compared between the two treatment groups (TCZ vs. placebo) using a Pearson's chi-square test. | Over a period of 3 years after transplantation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to the onset of CLAD, being listed for re-transplantation, or death |  | At 3 years after transplantation | 
| Cumulative incidence of Chronic Lung Allograft Dysfunction (CLAD) |  | At 3 years after transplantation | 
| Cumulative incidence listed for re-transplantation |  | At 3 years after transplantation | 
| Cumulative incidence of death |  | At 3 years after transplantation | 
| Incidence of Primary Graft Dysfunction (PGD) grade 3 |  | At any timepoint in the first 72 hours | 
| Freedom from Acute Cellular Rejection (ACR) grade >=A2 | Transbronchial lung biopsies will be performed according to the local center standard of care using the 2007 International Society for Heart and Lung Transplantation (ISHLT) criteria. Acute Cellular Rejection (A grade Rejection) Scale: None (A0) Minimal (A1) Mild (A2) Moderate (A3) Severe (A4) Ungradable (AX) | At 3 years after transplantation | 
| Proportion of subjects free from Antibody Mediated Rejection (AMR) | Antibody mediated rejection studies will be performed using original H&E stained slides, trichrome/elastic trichrome stain, and C4d immunostain (5 slides per case), along with positive controls | At 3 years after transplantation | 
| Proportion of subjects free from the development of de novo donor specific antibodies (dnDSA) |  | At 3 years after transplantation | 
| Incidence of Gastrointestinal (GI) tract perforation |  | At 3 years after transplantation | 
| Incidence of serious infections requiring intravenous antimicrobial therapy and need for hospitalization |  | At 3 years after transplantation | 
| Incidence of confirmed bacterial infection requiring antimicrobial therapy |  | At 3 years after transplantation | 
| Incidence of confirmed Cytomegalovirus (CMV) infection requiring antimicrobial therapy |  | At 3 years after transplantation | 
| Incidence of confirmed mold infection requiring antimicrobial therapy |  | At 3 years after transplantation | 
| Incidence of confirmed mycobacterial infection requiring antimicrobial therapy |  | At 3 years after transplantation | 
| Incidence of confirmed community-acquired respiratory viral infection, including coronavirus disease 2019 (COVID-19) infection |  | At 3 years after transplantation | 
| Incidence of discontinuation of Tocilizumab (TCZ) due to an adverse event |  | At 3 years after transplantation | 
| Incidence of discontinuation of Tocilizumab (TCZ) due to serious adverse event |  | At 3 years after transplantation | 
| Incidence of discontinuation of Tocilizumab (TCZ) placebo due to an adverse event |  | At 3 years after transplantation | 
| Incidence of discontinuation of Tocilizumab (TCZ) placebo due to serious adverse event |  | At 3 years after transplantation | 
| Incidence of malignancy excluding squamous or basal cell skin cancer |  | At 3 years after transplantation | 
| Incidence of Tuberculosis (TB) |  | At 3 years after transplantation | 
| Incidence of Post-transplant lymphoproliferative disease (PTLD) |  | At 3 years after transplantation | 
| Time to the onset of Chronic Lung Allograft Dysfunction (CLAD) |  | At 3 years after transplantation | 
| Time to the onset of being listed for re-transplantation |  | At 3 years after transplantation | 
| Time to the onset of death |  | At 3 years after transplantation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lung Transplant, Tocilizumab, Immunosuppression, ACTEMRA