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

1. Subject must be able to understand and provide informed consent;

2. Is a candidate for a primary heart transplant (listed as a heart transplant only);

3. No desensitization therapy prior to transplant;

4. 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.

5. Mechanical support or investigational drug trials where the intervention ends at the
time of transplantation are permitted;

6. In the absence of contraindication, vaccinations should be up to date for hepatitis B,
influenza, pneumococcal, haemophilus, Varicella Zoster Virus (VZV), and Measles,
Mumps, & Rubella (MMR); and

7. Subjects from areas of endemic coccidioidomycosis are eligible for inclusion but must
be treated prophylactically with fluconazole.

Inclusion Criteria - Randomization

1. Recipient of a primary heart transplant;

2. Negative virtual crossmatch;

3. No desensitization therapy prior to transplant;

4. Female subjects of childbearing potential must have a negative pregnancy test (serum
or urine) prior to randomization; and

5. 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.

Exclusion Criteria:

Exclusion Criteria Study Entry

1. Inability or unwillingness of a participant to give written informed consent or comply
with study protocol;

2. Candidate for a multiple solid organ or tissue transplants;

3. Prior history of organ or cellular transplantation requiring ongoing systemic
immunosuppression;

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 to tocilizumab (Actemra®);

7. Previous treatment with tocilizumab (Actemra®);

8. Human Immunodeficiency Virus (HIV) positive;

9. Hepatitis B surface antigen positive;

10. Hepatitis B core antibody positive;

11. Hepatitis C virus positive (HCV+) and has failed to demonstrate sustained viral
remission for more than 12 months (after anti-viral treatment);

12. 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.

13. Subjects with a previous history of active Tuberculosis (TB);

14. Known active current viral, fungal, mycobacterial or other infections not including
(left ventricular assist device [LVAD]) driveline infections;

15. 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.

16. History of hemolytic-uremic syndrome/ thrombotic thrombocytopenia purpura;

17. History of demyelinating disorders such as:

- multiple sclerosis,

- chronic inflammation,

- demyelinating polyneuropathy.

18. History of gastrointestinal perforations, active inflammatory bowel disease or
diverticulitis;

19. Any previous treatment with alkylating agents such as chlorambucil or, total lymphoid
irradiation;

20. 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.

21. Subjects with a hemoglobin <7.0gm/dL within 7 days prior to enrollment;

22. Subjects with a platelet count of less than 100,000/mm^3 within 7 days prior to
enrollment;

23. Subjects with an absolute neutrophil count (ANC) of less than 2,000/mm^3 within 7 days
prior to enrollment;

24. Subjects with Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT)
levels >3 x Upper Limit of Normal (ULN);

25. 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;

26. Receipt of a live vaccine within 30 days prior to randomization;

28. 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

1. Recipient of multiple solid organ or tissue transplants;

2. Recipient of ex vivo preserved hearts and hearts donated after cardiac death (DCD);

3. Currently breast-feeding a child or plans to become pregnant during the timeframe of
the study follow up period;

4. History of severe allergic anaphylactic reactions to humanized or murine monoclonal
antibodies;

5. Known hypersensitivity to tocilizumab (Actemra®);

6. Previous treatment with tocilizumab (Actemra®);

7. HIV positive;

8. Hepatitis B surface antigen positive;

9. Hepatitis B core antibody positive;

10. Hepatitis B negative transplant recipient that received a transplant from a hepatitis
B core antibody positive donor;

11. HCV+ subject(s) who are either untreated or have failed to demonstrate sustained viral
remission for more than 12 months after anti-viral treatment;

12. Recipient of a hepatitis C virus nucleic acid test (NAT) positive donor organ;

13. Subjects with a previous history of active (TB);

14. 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.

15. Known active current viral, fungal, mycobacterial or other infections, not including
(left ventricular assist device [LVAD]) driveline infections;

16. 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.

17. History of hemolytic-uremic syndrome/ thrombotic thrombocytopenia purpura;

18. History of demyelinating disorders;

19. History of gastrointestinal perforations, active inflammatory bowel disease or
diverticulitis;

20. Any previous treatment with alkylating agents such as chlorambucil, or with total
lymphoid irradiation;

21. 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.

22. Subjects with a hemoglobin <7.0gm/dL within 7 days prior to randomization;

23. Subjects with a platelet count of less than 100,000/mm^3 within 7 days prior to
randomization;

24. Subjects with an absolute neutrophil count (ANC) of less than 2,000/mm^3 within 7 days
prior to randomization;

25. Subjects with AST or ALT levels >3 x ULN;

26. 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;

27. Receipt of a live vaccine within 30 days prior to randomization;

28. Use of investigational drugs after transplantation;

29. 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.

30. Subjects with known donor-specific antibody at the time of heart transplant surgery.