Tocilizumab in Cardiac Transplantation

This is a prospective, multi-center phase 2 clinical trial in which 200 primary heart transplant recipients will be randomized (1:1) to receive either tocilizumab (Actemra®) or placebo (normal saline) plus standard triple maintenance immunosuppression. Investigators will recruit primary heart transplant recipients from 14 participating centers. Subjects will be screened, consented, and enrolled while on the United Network for Organ Sharing (UNOS) wait list. When the recipient has received the transplant and is deemed hemodynamically stable, randomization will occur.

Study duration: The study duration will be approximately 4 years. There will be a 36-month accrual period, and participants will be followed for a minimum 12-month, and a maximum 24 months after heart transplantation.

*** IMPORTANT NOTICE: *** The National Institute of Allergy and Infectious Diseases does not recommend the discontinuation of immunosuppressive therapy for recipients of cell, organ, or tissue transplants outside of physician-directed, controlled clinical studies. Discontinuation of prescribed immunosuppressive therapy can result in serious health consequences and should only be performed in certain rare circumstances, upon the recommendation and with the guidance of your health care provider.

Inclusion criteria

Inclusion criteria

- Study Entry

• Subject must be able to understand and provide informed consent;
• Is a candidate for a primary heart transplant (listed as a heart transplant only);
• No desensitization therapy prior to 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 the above referenced 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.
• Mechanical support or investigational drug trials where the intervention ends at the time of transplantation are permitted;
• In the absence of contraindication, vaccinations should be up to date for hepatitis B, influenza, pneumococcal, zoster, and Measles, Mumps, & Rubella (MMR); and
• Subjects from areas of endemic coccidioidomycosis are eligible for inclusion but must be treated prophylactically with fluconazole or itraconazole.

Inclusion criteria

- Randomization

• Recipient of a primary heart transplant;
• Negative virtual crossmatch (according to local center criteria);
• No desensitization therapy prior to transplant;
• Female subjects of childbearing potential must have a negative pregnancy test (serum or urine) prior to randomization; and
• 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 the above referenced 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 SARS-CoV-2 real-time reverse transcription polymerase chain reaction (rRT-PCR) test result performed within 48 hours of transplant (SARS-CoV-2 is the virus that causes COVID-19)

Exclusion criteria

Exclusion criteria

Study Entry

• Inability or unwillingness of a participant to give written informed consent or comply with study protocol;
• Candidate for a multiple solid organ or tissue transplants;
• Prior history of organ or cellular transplantation requiring ongoing systemic immunosuppression;
• 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 to tocilizumab (Actemra®);
• Previous treatment with tocilizumab (Actemra®);
• Human Immunodeficiency Virus (HIV) positive;
• Hepatitis B surface antigen positive;
• Hepatitis B core antibody positive;
• Hepatitis C virus antibody positive (anti-HCV Ab+) who are either untreated or, have failed to demonstrate sustained viral remission for more than 12 months (after anti-viral treatment);
• Recipient of a Hepatitis C virus nucleic acid test (NAT) positive donor organ;
• Subjects must be tested for latent TB infection (LTBI) within a year prior to transplant:

--Subjects with a positive test for LTBI must complete appropriate therapy for LTBI.

---A Subject is considered eligible only if they have a negative test for LTBI within one year prior to transplant OR

---- if they have completed appropriate LTBI therapy within one year prior to transplant.

• Subjects with a previous history of active Tuberculosis (TB);
• Subjects with a history of splenectomy;
• Known active current viral, fungal, mycobacterial or other infections not including (left ventricular assist device [LVAD]) driveline infections;
• History of malignancy less than 5 years in remission.

--Any history of adequately treated in-situ cervical carcinoma, low grade prostate carcinoma, or adequately treated basal or squamous cell carcinoma of the skin will be permitted.

• History of hemolytic-uremic syndrome/ thrombotic thrombocytopenia purpura;
• History of demyelinating disorders such as:

• multiple sclerosis,
• chronic inflammation,
• demyelinating polyneuropathy.
• History of gastrointestinal perforations, active inflammatory bowel disease or diverticulitis;
• Any previous treatment with alkylating agents such as chlorambucil or, total lymphoid irradiation;
• Radiation therapy within 3 weeks before enrollment.

--Enrollment of subjects who require concurrent radiotherapy should be deferred until the radiotherapy is completed and 3 weeks have elapsed since the last date of therapy.

• Subjects with a hemoglobin <7.0gm/dL (last measurement within 7 days prior to transplant);
• Subjects with a platelet count of less than 100,000/mm^3 (last measurement within 7 days prior to transplant);
• Subjects with an absolute neutrophil count (ANC) of less than 2,000/mm^3 (last measurement within 7 days prior to transplant);
• Subjects with Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) levels >3 x Upper Limit of Normal (ULN);
• Subjects who are administered or intended to be administered cytolytic or anti-cluster of differentiation 25 (CD25) monoclonal antibody agents as induction therapy in the immediate post-transplant period;
• Intent to give the recipient a live vaccine within 30 days prior to randomization;
• Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may:

• pose additional risks from participation in the study,
• may interfere with the participant's ability to comply with study requirements, or
• that may impact the quality or interpretation of the data obtained from the study.

Exclusion criteria

- Randomization

• Recipient of multiple solid organ or tissue transplants;
• Recipient of ex vivo preserved hearts and hearts donated after cardiac death (DCD);
• Currently breast-feeding a child or plans to become pregnant during the timeframe of the study follow up period;
• History of severe allergic anaphylactic reactions to humanized or murine monoclonal antibodies;
• Known hypersensitivity to tocilizumab (Actemra®);
• Previous treatment with tocilizumab (Actemra®);
• HIV positive;
• Hepatitis B surface antigen positive;
• Hepatitis B core antibody positive;
• Hepatitis B negative transplant recipient that received a transplant from a hepatitis B core antibody positive donor;
• HCV+ subject(s) who are either untreated or have failed to demonstrate sustained viral remission for more than 12 months after anti-viral treatment;
• Recipient of a hepatitis C virus nucleic acid test (NAT) positive donor organ;
• Subject's organ donor tests positive for SARS-CoV-2 by real-time reverse transcription polymerase chain reaction (SARS-CoV-2 is the virus that causes COVID-19).
• Subjects with a previous history of active (TB);
• Subjects must be tested for latent TB infection (LTBI) within a year prior to transplant:

--Subjects with a positive test for LTBI must complete appropriate therapy for LTBI.

---A Subject is considered eligible only if they have a negative test for LTBI within one year prior to transplant OR

---- if they have completed appropriate LTBI therapy within one year prior to transplant.

• Subjects with a history of splenectomy;
• Known active current viral, fungal, mycobacterial or other infections, not including (left ventricular assist device [LVAD]) driveline infections;
• History of malignancy less than 5 years in remission.

--Any history of adequately treated in-situ cervical carcinoma, low grade prostate carcinoma, or adequately treated basal or squamous cell carcinoma of the skin will be permitted.

• History of hemolytic-uremic syndrome/ thrombotic thrombocytopenia purpura;
• History of demyelinating disorders;
• History of gastrointestinal perforations, active inflammatory bowel disease or diverticulitis;
• Any previous treatment with alkylating agents such as chlorambucil, or with total lymphoid irradiation;
• Radiation therapy within 3 weeks before randomization.

--Enrollment of subjects who require concurrent radiotherapy should be deferred until the radiotherapy is completed and 3 weeks have elapsed since the last date of therapy.

• Subjects with a hemoglobin <7.0gm/dL within 7 days prior to randomization;
• Subjects with a platelet count of less than 100,000/mm^3 within 7 days prior to randomization;
• Subjects with an absolute neutrophil count (ANC) of less than 2,000/mm^3 within 7 days prior to randomization;
• Subjects with AST or ALT levels >3 x ULN;
• Subjects who are administered or intended to be administered cytolytic or anti- CD25 monoclonal antibody agents as induction therapy in the immediate post- transplant period;
• Receipt of a live vaccine within 30 days prior to randomization;
• Use of investigational drugs after transplantation;
• Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator,

• may pose additional risks from participation in the study,
• may interfere with the participant's ability to comply with study requirements, or
• that may impact the quality or interpretation of the data obtained from the study.
• Subjects with known donor-specific antibody at the time of evaluation of antibodies for heart transplant surgery (within 6 months).