Tocilizumab in Cardiac Transplantation

NCT ID: NCT03644667

Last Updated: 2025-04-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 385 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-12-20
• Study Completion Date: 2025-03-21

Brief Summary

The purpose of this research study is to see if a study drug called Tocilizumab will, when given with standard anti-rejection medicines, lead to better heart transplantation outcomes at 1 year after the transplant. Specifically, the investigators will evaluate whether taking tocilizumab leads to less rejection, less development of unwanted antibodies, and better heart function.

Detailed Description

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.

Conditions

Heart Transplant

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Tocilizumab + Standard of Care Triple IS

Tocilizumab plus standard of care triple immunosuppression (IS). Heart transplant recipients will receive tocilizumab (Actemra®) plus standard triple maintenance immunosuppression.

Standard of care triple maintenance immunosuppression includes:

• a calcineurin inhibitor (tacrolimus),
• an anti-proliferative treatment (mycophenolate mofetil) or Myfortic® (enteric-coated mycophenolate sodium), and
• steroids (methylprednisolone/prednisone) as prescribed by site physician investigator.

Participants enrolled in the study will be followed for 24 months after their transplant surgery. Randomization will occur once a participant has weaned from cardiopulmonary bypass and has achieved hemodynamic stability without significant ongoing bleeding within the first 72 hours after transplant.

Group Type: EXPERIMENTAL

tocilizumab

Intervention Type: BIOLOGICAL

6 doses: 8mg/kg (maximum of 800 mg) given once every four weeks by intravenous infusion over a 20-week period, with a minimum of 21 days between each infusion.

Standard of Care Triple IS

Intervention Type: DRUG

Standard of care triple maintenance IS includes:

1. A calcineurin inhibitor-tacrolimus (Prograf ®) per site standards by sublingual, oral or intravenous route to attain target trough levels.

Exception: Should a participant be unable to tolerate tacrolimus, the site physician investigator may choose cyclosporine treatment.

2. An anti-proliferative treatment-mycophenolate mofetil or Myfortic® (enteric-coated mycophenolate sodium) will be administered, per protocol.

Exception: Should a participant be unable to tolerate mycophenolate mofetil, the site physician investigator may choose an alternative treatment.

3. Steroids-methylprednisolone/prednisone dosing will be given according to the local center standard of practice early post transplantation. After 6 months, prednisone may be withdrawn at the discretion of the site physician investigator, per protocol.

Placebo + Standard of Care Triple IS

Placebo plus standard of care triple maintenance immunosuppression (IS). Heart transplant recipients will receive placebo plus standard triple maintenance immunosuppression.

Standard of care triple maintenance immunosuppression includes:

• a calcineurin inhibitor (tacrolimus),
• an anti-proliferative treatment (mycophenolate mofetil) or Myfortic® (enteric-coated mycophenolate sodium), and
• steroids (methylprednisolone/prednisone) as prescribed by site physician investigator.

Participants enrolled in the study will be followed for 24 months after their transplant surgery. Randomization will occur once a participant has weaned from cardiopulmonary bypass and has achieved hemodynamic stability without significant ongoing bleeding within the first 72 hours after transplant.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: BIOLOGICAL

The placebo is 0.9% sterile normal saline. 6 doses: 8mg/kg (maximum of 800 mg) given once every four weeks by intravenous infusion over a 20-week period, with a minimum of 21 days between each infusion.

Standard of Care Triple IS

Intervention Type: DRUG

Standard of care triple maintenance IS includes:

1. A calcineurin inhibitor-tacrolimus (Prograf ®) per site standards by sublingual, oral or intravenous route to attain target trough levels.

Exception: Should a participant be unable to tolerate tacrolimus, the site physician investigator may choose cyclosporine treatment.

2. An anti-proliferative treatment-mycophenolate mofetil or Myfortic® (enteric-coated mycophenolate sodium) will be administered, per protocol.

Exception: Should a participant be unable to tolerate mycophenolate mofetil, the site physician investigator may choose an alternative treatment.

3. Steroids-methylprednisolone/prednisone dosing will be given according to the local center standard of practice early post transplantation. After 6 months, prednisone may be withdrawn at the discretion of the site physician investigator, per protocol.

Interventions

tocilizumab

6 doses: 8mg/kg (maximum of 800 mg) given once every four weeks by intravenous infusion over a 20-week period, with a minimum of 21 days between each infusion.

Intervention Type: BIOLOGICAL

Placebo

The placebo is 0.9% sterile normal saline. 6 doses: 8mg/kg (maximum of 800 mg) given once every four weeks by intravenous infusion over a 20-week period, with a minimum of 21 days between each infusion.

Intervention Type: BIOLOGICAL

Standard of Care Triple IS

Standard of care triple maintenance IS includes:

1. A calcineurin inhibitor-tacrolimus (Prograf ®) per site standards by sublingual, oral or intravenous route to attain target trough levels.

Exception: Should a participant be unable to tolerate tacrolimus, the site physician investigator may choose cyclosporine treatment.

2. An anti-proliferative treatment-mycophenolate mofetil or Myfortic® (enteric-coated mycophenolate sodium) will be administered, per protocol.

Exception: Should a participant be unable to tolerate mycophenolate mofetil, the site physician investigator may choose an alternative treatment.

3. Steroids-methylprednisolone/prednisone dosing will be given according to the local center standard of practice early post transplantation. After 6 months, prednisone may be withdrawn at the discretion of the site physician investigator, per protocol.

Intervention Type: DRUG

Other Intervention Names

Actemra®; Placebo for tocilizumab; Placebo for Actemra®; calcineurin inhibitor: (tacrolimus (Prograf ®)); anti-proliferative treatment: (mycophenolate mofetil ),; MMF, CellCept®; Myfortic®, enteric-coated mycophenolate sodium; steroids: methylprednisolone/prednisone

Eligibility Criteria

Inclusion Criteria

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, zoster, and Measles, Mumps, & Rubella (MMR); and

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

1. Recipient of a primary heart transplant;

2. Negative virtual crossmatch (according to local center criteria);

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.

6. 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

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 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);

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

13. 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.

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

15. Subjects with a history of splenectomy;

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

17. 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.

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

19. History of demyelinating disorders such as:

• multiple sclerosis,
• chronic inflammation,
• demyelinating polyneuropathy.

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

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

22. 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.

23. Subjects with a hemoglobin <7.0gm/dL (last measurement within 7 days prior to transplant);

24. Subjects with a platelet count of less than 100,000/mm^3 (last measurement within 7 days prior to transplant);

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

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

27. 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;

28. Intent to give the recipient a live vaccine within 30 days prior to randomization;

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.

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. 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).

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

15. 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.

16. Subjects with a history of splenectomy;

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

18. 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.

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

20. History of demyelinating disorders;

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

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

23. 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.

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

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

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

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

28. 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;

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

30. Use of investigational drugs after transplantation;

31. 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.

32. Subjects with known donor-specific antibody at the time of evaluation of antibodies for heart transplant surgery (within 6 months).

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

PPD Development, LP

INDUSTRY

Sponsor Role: collaborator

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Jon A. Kobashigawa, MD

Role: STUDY_CHAIR

Cedars Sinai Medical Center: Transplantation

Joren C. Madsen, MD, DPHIL

Role: PRINCIPAL_INVESTIGATOR

Massachusetts General Hospital: Transplantation

Locations

Cedars Sinai Medical Center (CACS)

Beverly Hills, California, United States

University of California, San Diego: Sulpizio Cardiovascular Center (CASD)

La Jolla, California, United States

Stanford Health Care (CASU)

Stanford, California, United States

Tampa General Hospital (FLTG)

Tampa, Florida, United States

Northwestern Memorial Hospital (INLM)

Chicago, Illinois, United States

Tufts Medical Center (MANM)

Boston, Massachusetts, United States

Massachusetts General Hospital (MAMG)

Boston, Massachusetts, United States

St. Luke's Hospital of Kansas City (MOLH)

Kansas City, Missouri, United States

University of Nebraska Medical Center (NEUN)

Omaha, Nebraska, United States

Mount Sinai Medical Center (NYMS)

New York, New York, United States

Columbia University Medical Center (NYCP)

New York, New York, United States

Montefiore Medical Center (NYMA)

The Bronx, New York, United States

Duke University Medical Center (NCDU)

Durham, North Carolina, United States

Cleveland Clinic Foundation (OHCC)

Cleveland, Ohio, United States

Penn State Health: Milton S. Hershey Medical Center (PAHE)

Hershey, Pennsylvania, United States

Hospital of the University of Pennsylvania (PAUP)

Philadelphia, Pennsylvania, United States

Allegheny General Hospital (PAAG)

Pittsburgh, Pennsylvania, United States

Vanderbilt University Medical Center (TNVU)

Nashville, Tennessee, United States

Baylor University Medical Center (TXTX)

Dallas, Texas, United States

University of Utah (UTMC)

Salt Lake City, Utah, United States

Countries

United States

Related Links

https://www.niaid.nih.gov/

National Institute of Allergy and Infectious Diseases (NIAID)

https://www.niaid.nih.gov/about/dait

The Division of Allergy, Immunology, and Transplantation (DAIT)

Other Identifiers

ALL IN

Identifier Type: OTHER

Identifier Source: secondary_id

U01AI136816

Identifier Type: NIH

Identifier Source: secondary_id

View Link

DAIT RTB-004

Identifier Type: -

Identifier Source: org_study_id