Clinical trial NCT06033196: Tocilizumab in Lung Transplantation
Official title: Targeting Inflammation and Alloimmunity in Lung Transplant Recipients With Tocilizumab (CTOT-45)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Lung Transplant
Keywords: Lung Transplant
Tocilizumab
Immunosuppression
ACTEMRA
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2023-09-13
Enrollment: 350
Sex: ALL
Minimum age (years): 12
Maximum age (years): 75
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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


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 or received 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. 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. Received a 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 at the time of transplant or a crossmatch result that did not require specific treatment per the site's clinical protocol
5. Underwent bronchoscopy and found to have satisfactory bronchial anastomotic healing
6. No desensitization therapy prior to transplant
7. Negative pregnancy test (serum or urine) for women of child-bearing potential within 48 hours prior to randomization
8. 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 allogeneic 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) within the last 3 months
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. Any history of diverticulitis (event if not perforated) or confirmed diverticular bleeding. (Diverticulosis is not an exclusion).
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. Smoking or vaping within 6 months of listing for transplant
24. Use of investigational drugs within 4 weeks prior to enrollment
25. 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. Clinically stable, without clinical evidence of untreated infection
3. Received a live virus vaccine within 30 days prior to randomization
4. Received treatment to deplete HLA antibodies before transplantation to improve the possibility of transplantation
5. Patients with known donor-specific antibody that will require intervention based on local clinical protocols
6. History of GI tract perforation
7. History of inflammatory bowel disease except fully excised ulcerative colitis
8. History of diverticulitis (diverticulosis is not an exclusion) or diverticular bleeding
9. History of severe allergic anaphylactic reactions to humanized or murine monoclonal antibodies
10. Known hypersensitivity to ACTEMRA® (tocilizumab)
11. Previous treatment with ACTEMRA® (tocilizumab) within the last 3 months.
12. Recipient or donor with infection with human immunodeficiency virus (HIV)
13. Recipient with hepatitis B virus surface antigen or hepatitis B core antibody positive
14. 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
15. Recipient of a hepatitis C virus nucleic acid test (NAT) positive donor organ
16. Latent TB infection (LTBI) and has not completed appropriate therapy
17. Chronic infection with Burkholderia cenocepacia or Burkholderia gladioli
18. Non-tuberculous mycobacterial (NTM) pulmonary disease; if there is a history of NTM pulmonary disease, culture conversion is necessary for eligibility
19. Presence of active malignancy (except for non-melanoma skin cancer)
20. History of hemolytic-uremic syndrome/ thrombotic thrombocytopenia purpura
21. History of demyelinating disorders (e.g., multiple sclerosis, chronic inflammation demyelinating polyneuropathy)
22. Current treatment with alkylating agents such as cyclophosphamide
23. Patients with AST or ALT levels \> 1.5 times upper limit of normal (last measurement within 1 day prior to randomization)
24. Patients with platelet count \<100,000/mm\^3 (last measurement within 1 day prior to randomization)
25. Patients with an absolute neutrophil count (ANC) \<2,000/mm\^3 (last measurement within 1 day prior to randomization)
26. Patients who are administered anti-thymocyte globulin as induction therapy in the immediate post- transplant period
27. 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
28. Use of an investigational drug after transplant
29. Smoking or vaping since enrollment
30. Any condition that in the opinion of the site PI introduces undue risk by participating in this study

Primary outcomes:
measure: Proportion of subjects who meet any one of the pre-specified events detailed in the outcome description: from Baseline up to 36 months
timeFrame: Over a period of 3 years after transplantation
Secondary outcomes:
measure: Time to the onset of CLAD, being listed for re-transplantation, or death
timeFrame: At 3 years after transplantation
measure: Cumulative incidence of Chronic Lung Allograft Dysfunction (CLAD)
timeFrame: At 3 years after transplantation
measure: Cumulative incidence listed for re-transplantation
timeFrame: At 3 years after transplantation
measure: Cumulative incidence of death
timeFrame: At 3 years after transplantation
measure: Freedom from Acute Cellular Rejection (ACR) grade >=A2
timeFrame: At 3 years after transplantation
measure: Proportion of subjects free from Antibody Mediated Rejection (AMR)
timeFrame: At 3 years after transplantation
measure: Proportion of subjects free from the development of de novo donor specific antibodies (dnDSA)
timeFrame: At 3 years after transplantation
measure: Incidence of Gastrointestinal (GI) tract perforation
timeFrame: At 3 years after transplantation
measure: Incidence of serious infections requiring intravenous antimicrobial therapy and need for hospitalization
timeFrame: At 3 years after transplantation
measure: Incidence of confirmed bacterial infection requiring antimicrobial therapy
timeFrame: At 3 years after transplantation
measure: Incidence of confirmed Cytomegalovirus (CMV) infection requiring antimicrobial therapy
timeFrame: At 3 years after transplantation
measure: Incidence of confirmed mold infection requiring antimicrobial therapy
timeFrame: At 3 years after transplantation
measure: Incidence of confirmed mycobacterial infection requiring antimicrobial therapy
timeFrame: At 3 years after transplantation
measure: Incidence of confirmed community-acquired respiratory viral infection, including coronavirus disease 2019 (COVID-19) infection
timeFrame: At 3 years after transplantation
measure: Incidence of discontinuation of Tocilizumab (TCZ) due to an adverse event
timeFrame: At 3 years after transplantation
measure: Incidence of discontinuation of Tocilizumab (TCZ) due to serious adverse event
timeFrame: At 3 years after transplantation
measure: Incidence of discontinuation of Tocilizumab (TCZ) placebo due to an adverse event
timeFrame: At 3 years after transplantation
measure: Incidence of discontinuation of Tocilizumab (TCZ) placebo due to serious adverse event
timeFrame: At 3 years after transplantation
measure: Incidence of malignancy excluding squamous or basal cell skin cancer
timeFrame: At 3 years after transplantation
measure: Incidence of Tuberculosis (TB)
timeFrame: At 3 years after transplantation
measure: Incidence of Post-transplant lymphoproliferative disorder (PTLD)
timeFrame: At 3 years after transplantation
measure: Time to the onset of Chronic Lung Allograft Dysfunction (CLAD)
timeFrame: At 3 years after transplantation
measure: Time to the onset of being listed for re-transplantation
timeFrame: At 3 years after transplantation
measure: Time to the onset of death
timeFrame: At 3 years after transplantation
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: St. Joseph's Hospital and Medical Center (Site #: 71192)
state: Arizona
city: Los Angeles
country: United States
facility: Cedars Sinai Medical Center (Site #: 71146)
state: California
city: Los Angeles
country: United States
facility: David Geffen School of Medicine at UCLA (Site #: 71123)
state: California
city: Baltimore
country: United States
facility: University of Maryland Medical Center (Site #: 71138)
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital (Site #: 71107)
state: Massachusetts
city: Boston
country: United States
facility: Boston Children's Hospital and Harvard Medical School (Site #: 71001)
state: Massachusetts
city: Saint Louis
country: United States
facility: Barnes Jewish Hospital/ Washington University SOM (Site #: 71191)
state: Missouri
city: Saint Louis
country: United States
facility: St. Louis Children's Hospital of Washington University (Site #: 71006)
state: Missouri
city: New York
country: United States
facility: Columbia University Medical Center (Site #: 71113)
state: New York
city: Durham
country: United States
facility: Duke University Medical Center (Site #: 71139)
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic (Site #: 71101)
state: Ohio
city: Dallas
country: United States
facility: University of Texas Southwestern (Site #: 71187)
state: Texas
city: Houston
country: United States
facility: Houston Methodist Hospital (Site #: 71120)
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah Medical Center (Site #: 71126)
state: Utah
Study officials:
affiliation: Massachusetts General Hospital
name: Joren Madsen, MD, D.Phil.
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Utah Medical Center
name: Ramsey Hachem, MD
role: STUDY_CHAIR
affiliation: Washington University School of Medicine
name: Daniel Kreisel, M.D.
role: STUDY_CHAIR
References: