Tocilizumab in Lung Transplantation (ALL IN LUNG)

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

Study Description

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

Condition or disease	Intervention/treatment	Phase
Lung Transplant	Drug: Tocilizumab; Drug: Placebo for Tocilizumab	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 350 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Targeting Inflammation and Alloimmunity in Lung Transplant Recipients With Tocilizumab (CTOT-45)
• Actual Study Start Date: February 13, 2024
• Estimated Primary Completion Date: January 8, 2029
• Estimated Study Completion Date: January 8, 2029

Arms and Interventions

Arm	Intervention/treatment
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	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
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	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

Outcome Measures

Primary Outcome Measures :

1. 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.

Secondary Outcome Measures :

1. Time to the onset of CLAD, being listed for re-transplantation, or death [ Time Frame: At 3 years after transplantation ]
2. Cumulative incidence of Chronic Lung Allograft Dysfunction (CLAD) [ Time Frame: At 3 years after transplantation ]
3. Cumulative incidence listed for re-transplantation [ Time Frame: At 3 years after transplantation ]
4. Cumulative incidence of death [ Time Frame: At 3 years after transplantation ]
5. Incidence of Primary Graft Dysfunction (PGD) grade 3 [ Time Frame: At any timepoint in the first 72 hours ]
6. 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)
7. 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
8. Proportion of subjects free from the development of de novo donor specific antibodies (dnDSA) [ Time Frame: At 3 years after transplantation ]
9. Incidence of Gastrointestinal (GI) tract perforation [ Time Frame: At 3 years after transplantation ]
10. Incidence of serious infections requiring intravenous antimicrobial therapy and need for hospitalization [ Time Frame: At 3 years after transplantation ]
11. Incidence of confirmed bacterial infection requiring antimicrobial therapy [ Time Frame: At 3 years after transplantation ]
12. Incidence of confirmed Cytomegalovirus (CMV) infection requiring antimicrobial therapy [ Time Frame: At 3 years after transplantation ]
13. Incidence of confirmed mold infection requiring antimicrobial therapy [ Time Frame: At 3 years after transplantation ]
14. Incidence of confirmed mycobacterial infection requiring antimicrobial therapy [ Time Frame: At 3 years after transplantation ]
15. Incidence of confirmed community-acquired respiratory viral infection, including coronavirus disease 2019 (COVID-19) infection [ Time Frame: At 3 years after transplantation ]
16. Incidence of discontinuation of Tocilizumab (TCZ) due to an adverse event [ Time Frame: At 3 years after transplantation ]
17. Incidence of discontinuation of Tocilizumab (TCZ) due to serious adverse event [ Time Frame: At 3 years after transplantation ]
18. Incidence of discontinuation of Tocilizumab (TCZ) placebo due to an adverse event [ Time Frame: At 3 years after transplantation ]
19. Incidence of discontinuation of Tocilizumab (TCZ) placebo due to serious adverse event [ Time Frame: At 3 years after transplantation ]
20. Incidence of malignancy excluding squamous or basal cell skin cancer [ Time Frame: At 3 years after transplantation ]
21. Incidence of Tuberculosis (TB) [ Time Frame: At 3 years after transplantation ]
22. Incidence of Post-transplant lymphoproliferative disease (PTLD) [ Time Frame: At 3 years after transplantation ]
23. Time to the onset of Chronic Lung Allograft Dysfunction (CLAD) [ Time Frame: At 3 years after transplantation ]
24. Time to the onset of being listed for re-transplantation [ Time Frame: At 3 years after transplantation ]
25. Time to the onset of death [ Time Frame: At 3 years after transplantation ]

Eligibility Criteria

• Ages Eligible for Study: 12 Years to 75 Years (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

United States, Arizona

St. Joseph's Hospital and Medical Center (Site #: 71192); Not yet recruiting

Phoenix, Arizona, United States, 85013

Contact: Brian Mutoff, BSHN, MHA 602-406-3825 Brian.Mutoff@commonspirit.org

United States, California

Cedars Sinai Medical Center (Site #: 71146); Not yet recruiting

Los Angeles, California, United States, 90048

Contact: Emine Gholian 424-314-0585 Emine.Gholian@cshs.org

David Geffen School of Medicine at UCLA (Site #: 71123); Not yet recruiting

Los Angeles, California, United States, 90095

Contact: Paul Lopez, LVN 310-794-8595 plopez@mednet.ucla.edu

United States, Maryland

University of Maryland Medical Center (Site #: 71138); Recruiting

Baltimore, Maryland, United States, 21201

Contact: Toye Jenkins, PT, CCRP 410-328-6366 toye.jenkins@som.umaryland.edu

United States, Massachusetts

Massachusetts General Hospital (Site #: 71107); Recruiting

Boston, Massachusetts, United States, 02114

Contact: Idrisa Saad 617-726-1082 Isaad1@mgh.harvard.edu

Boston Children's Hospital (Site #: 71001); Recruiting

Boston, Massachusetts, United States, 02215

Contact: Jennifer Arruda, RN 617-355-6665 Jennifer.arruda@childrens.harvard.edu

Brigham & Women's Hospital (Site #: 71106); Recruiting

Boston, Massachusetts, United States, 02215

Contact: Sam Wong 404-661-3615 swong1@bwh.harvard.edu

United States, Missouri

Barnes Jewish Hospital/ Washington University SOM (Site #: 71191); Recruiting

Saint Louis, Missouri, United States, 63110

Contact: Brigitte Mittler, CCRC 314-747-1931 b.mittler@wustl.edu

St. Louis Children's Hospital of Washington University (Site #: 71006); Recruiting

Saint Louis, Missouri, United States, 63110

Contact: Brigitte Mittler, BA 314-747-1931 b.mittler@wustl.edu

United States, New York

Columbia University Medical Center (Site #: 71113); Recruiting

New York, New York, United States, 10032

Contact: Shreena Patel, BA, LPN 973-722-6835 sp3646@cumc.columbia.edu

United States, North Carolina

Duke University Medical Center (Site #: 71139); Recruiting

Durham, North Carolina, United States, 27710

Contact: Kathy Lane 919-684-2037 Kathleen.rohrback@duke.edu

United States, Ohio

Cleveland Clinic Lerner College Medicine (Site #: 71101); Not yet recruiting

Cleveland, Ohio, United States, 44195

Contact: Stacy Shoemaker, BSN 216-554-4956 Shoemas2@ccf.org

United States, Texas

University of Texas Southwestern (Site #: 71187); Not yet recruiting

Dallas, Texas, United States, 75390

Contact: Rhoda Annoh-Gordon 214-645-7108 Rhoda.Annoh-Gordon@UTSouthwestern.edu

Houston Methodist Hospital (Site #: 71120); Not yet recruiting

Houston, Texas, United States, 77030

Contact: Darrel Cleere 713-441-6232 DWCleere@houstonmethodist.org

United States, Utah

University of Utah Medical Center (Site #: 71126); Recruiting

Salt Lake City, Utah, United States, 84132

Contact: Macy Barrios, BS 801-581-5811 Macy.barrios@hsc.utah.edu

Canada, Ontario

University Health Network/ Toronto General Hospital (Site #: 71121); Not yet recruiting

Toronto, Ontario, Canada, M5G 2C4

Contact: Sharaniyaa Balachandran, BSc, CCRP 416-340-4800 ext 6549 Sharaniyaa.balachandran@uhn.ca

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

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

More Information

Additional Information:

NIAID Transplant Programs website 

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT06033196
• Other Study ID Numbers: DAIT CTOT-45
• First Posted: September 13, 2023
• Last Update Posted: May 6, 2024
• Last Verified: May 2024

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

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):

Lung Transplant; Tocilizumab; Immunosuppression; ACTEMRA