Tocilizumab in Lung Transplantation (ALL IN LUNG)

• ClinicalTrials.gov Identifier: NCT06033196
• Recruitment Status: Recruiting
• First Posted: September 13, 2023
• Last Update Posted: June 24, 2024
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Information provided by (Responsible Party): National Institute of Allergy and Infectious Diseases (NIAID)

Tracking Information

• First Submitted Date: August 24, 2023
• First Posted Date: September 13, 2023
• Last Update Posted Date: June 24, 2024
• Actual Study Start Date: February 13, 2024
• Estimated Primary Completion Date: January 8, 2029 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 8, 2023)

Proportion of subjects who meet any one of the pre-specified events detailed in the outcome description: from Baseline up to 36 months [ Time Frame: Over a period of 3 years after transplantation ]

1. 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.
2. 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
3. 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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: September 8, 2023)

• Time to the onset of CLAD, being listed for re-transplantation, or death [ Time Frame: At 3 years after transplantation ]
• Cumulative incidence of Chronic Lung Allograft Dysfunction (CLAD) [ Time Frame: At 3 years after transplantation ]
• Cumulative incidence listed for re-transplantation [ Time Frame: At 3 years after transplantation ]
• Cumulative incidence of death [ Time Frame: At 3 years after transplantation ]
• Incidence of Primary Graft Dysfunction (PGD) grade 3 [ Time Frame: At any timepoint in the first 72 hours ]
• Freedom from Acute Cellular Rejection (ACR) grade >=A2 [ Time Frame: At 3 years after transplantation ]
  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)
• Proportion of subjects free from Antibody Mediated Rejection (AMR) [ Time Frame: At 3 years after transplantation ]
  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
• Proportion of subjects free from the development of de novo donor specific antibodies (dnDSA) [ Time Frame: At 3 years after transplantation ]
• Incidence of Gastrointestinal (GI) tract perforation [ Time Frame: At 3 years after transplantation ]
• Incidence of serious infections requiring intravenous antimicrobial therapy and need for hospitalization [ Time Frame: At 3 years after transplantation ]
• Incidence of confirmed bacterial infection requiring antimicrobial therapy [ Time Frame: At 3 years after transplantation ]
• Incidence of confirmed Cytomegalovirus (CMV) infection requiring antimicrobial therapy [ Time Frame: At 3 years after transplantation ]
• Incidence of confirmed mold infection requiring antimicrobial therapy [ Time Frame: At 3 years after transplantation ]
• Incidence of confirmed mycobacterial infection requiring antimicrobial therapy [ Time Frame: At 3 years after transplantation ]
• Incidence of confirmed community-acquired respiratory viral infection, including coronavirus disease 2019 (COVID-19) infection [ Time Frame: At 3 years after transplantation ]
• Incidence of discontinuation of Tocilizumab (TCZ) due to an adverse event [ Time Frame: At 3 years after transplantation ]
• Incidence of discontinuation of Tocilizumab (TCZ) due to serious adverse event [ Time Frame: At 3 years after transplantation ]
• Incidence of discontinuation of Tocilizumab (TCZ) placebo due to an adverse event [ Time Frame: At 3 years after transplantation ]
• Incidence of discontinuation of Tocilizumab (TCZ) placebo due to serious adverse event [ Time Frame: At 3 years after transplantation ]
• Incidence of malignancy excluding squamous or basal cell skin cancer [ Time Frame: At 3 years after transplantation ]
• Incidence of Tuberculosis (TB) [ Time Frame: At 3 years after transplantation ]
• Incidence of Post-transplant lymphoproliferative disease (PTLD) [ Time Frame: At 3 years after transplantation ]
• Time to the onset of Chronic Lung Allograft Dysfunction (CLAD) [ Time Frame: At 3 years after transplantation ]
• Time to the onset of being listed for re-transplantation [ Time Frame: At 3 years after transplantation ]
• Time to the onset of death [ Time Frame: At 3 years after transplantation ]

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

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

Brief Summary

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

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Lung Transplant

Intervention

• Drug: Tocilizumab

  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

  Other Name: ACTEMRA
• Drug: Placebo for Tocilizumab

  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

Study Arms

• Experimental: Tocilizumab Group
  Subject in this group will receive ACTEMRA(R) (Tocilizumab) ,(six injections over 20 weeks) plus standard triple maintenance immunosuppression of Tacrolimus, Mycophenolate Mofetil, corticosteroids
  Intervention: Drug: Tocilizumab
• Placebo Comparator: Placebo Group
  Subject in this group will receive placebo for Tocilizumab (sterile normal saline) plus standard triple maintenance immunosuppression of Tacrolimus, Mycophenolate Mofetil, corticosteroids
  Intervention: Drug: Placebo for Tocilizumab

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: September 8, 2023): 350
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: January 8, 2029
• Estimated Primary Completion Date: January 8, 2029 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

Study Entry:

1. Subject and/or parent guardian must be able to understand the purpose of the study and willing to participate and sign informed consent/assent
2. Greater than or equal to 30 kg body weight
3. Listed for a primary lung transplant
4. No previous or planned desensitization therapy prior to transplant
5. 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

6. 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

7. 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
8. 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:

1. Provide written informed consent for the study participation, and agree to continue in the study
2. Undergoing single or bilateral lung transplant
3. 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
4. Negative physical crossmatch, if the results are available at the time of randomization
5. No desensitization therapy prior to transplant
6. Negative pregnancy test (serum or urine) for women of child-bearing potential within 48 hours prior to transplant
7. Negative severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) Polymerase Chain Reaction (PCR) testing for the recipient prior to transplant as per institutional policy
8. Negative SARS-CoV2 PCR testing for the donor prior to transplant as per institutional policy
9. Recipient of lungs that have been supported with ex vivo lung perfusion (EVLP) devices are permitted

Exclusion Criteria:

Study Entry:

1. Listed for multi-organ transplant (e.g., heart-lung, liver-lung, kidney-lung)
2. Prior history of organ or cellular transplantation
3. Received treatment to deplete Human Leukocyte Antigens (HLA) antibodies before transplantation
4. Currently breast-feeding a child or plans to become pregnant during the timeframe of the study follow up period
5. History of severe allergic and/or anaphylactic reactions to humanized or murine monoclonal antibodies
6. Known hypersensitivity or previous treatment with ACTEMRA(R) (tocilizumab)
7. Infection with human immunodeficiency virus (HIV)
8. Hepatitis B virus surface antigen or core antibody positive
9. 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;
10. Chronic infection with Burkholderia cenocepacia or Burkholderia gladioli
11. Non-tuberculous mycobacterial (NTM) pulmonary disease; if there is a history of NTM pulmonary disease, culture conversion is necessary for eligibility
12. 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
13. History of hemolytic-uremic syndrome/ thrombotic thrombocytopenia purpura
14. History of demyelinating disorders (e.g., multiple sclerosis, chronic inflammation demyelinating polyneuropathy)
15. Current treatment with alkylating agents such as cyclophosphamide
16. History of gastrointestinal (GI) tract perforation
17. History of inflammatory bowel disease except fully excised ulcerative colitis
18. History of diverticulitis (diverticulosis is not an exclusion) or diverticular bleeding;
19. Patients with a platelet count < 100,000/mm^3 (last measurement within 7 days prior to enrollment)
20. Patients with an absolute neutrophil count (ANC) < 2,000/mm^3 (last measurement within 7 days prior to enrollment)
21. Patients with Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) levels >3 times upper limit of normal
22. Patients who use illegal drugs
23. Use of investigational drugs within 4 weeks prior to enrollment
24. Any condition that in the opinion of the site Principal Investigator (PI) introduces undue risk by participating in this study

Randomization:

1. Recipient of multi-organ or tissue transplants
2. Received a live virus vaccine within 30 days prior to randomization
3. Received treatment to deplete HLA antibodies before transplantation to improve the possibility of transplantation
4. Patients with known donor-specific antibody that will require intervention based on local clinical protocols
5. History of GI tract perforation
6. History of inflammatory bowel disease except fully excised ulcerative colitis
7. History of diverticulitis (diverticulosis is not an exclusion) or diverticular bleeding
8. History of severe allergic anaphylactic reactions to humanized or murine monoclonal antibodies
9. Known hypersensitivity or previous treatment with ACTEMRA(R) (tocilizumab)
10. Recipient or donor with infection with human immunodeficiency virus (HIV)
11. Recipient with hepatitis B virus surface antigen or hepatitis B core antibody positive
12. 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
13. Recipient of a hepatitis C virus nucleic acid test (NAT) positive donor organ
14. Latent TB infection (LTBI) and has not completed appropriate therapy
15. Chronic infection with Burkholderia cenocepacia or Burkholderia gladioli
16. Non-tuberculous mycobacterial (NTM) pulmonary disease; if there is a history of NTM pulmonary disease, culture conversion is necessary for eligibility
17. Presence of active malignancy (except for non-melanoma skin cancer)
18. History of hemolytic-uremic syndrome/ thrombotic thrombocytopenia purpura
19. History of demyelinating disorders (e.g., multiple sclerosis, chronic inflammation demyelinating polyneuropathy)
20. Current treatment with alkylating agents such as cyclophosphamide
21. Patients with AST or ALT levels > 1.5 times upper limit of normal (last measurement within 1 day prior to randomization)
22. Patients with platelet count <100,000/mm^3 (last measurement within 1 day prior to randomization)
23. Patients with an absolute neutrophil count (ANC) <2,000/mm^3 (last measurement within 1 day prior to randomization)
24. 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
25. 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
26. Use of an investigational drug after transplant
27. Any condition that in the opinion of the site PI introduces undue risk by participating in this study

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 12 Years to 75 Years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Listed Location Countries: Canada, United States

Administrative Information

• NCT Number: NCT06033196
• Other Study ID Numbers: DAIT CTOT-45
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• Original Responsible Party: Same as current
• Current Study Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Joren Madsen, MD, D.Phil.; Massachusetts General Hospital
• Study Chair: Ramsey Hachem, MD; University of Utah Medical Center
• Study Chair: Daniel Kreisel, M.D.; Washington University School of Medicine

• PRS Account: National Institute of Allergy and Infectious Diseases (NIAID)
• Verification Date: June 2024