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Tocilizumab in Cardiac Transplantation

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03644667
Recruitment Status : Recruiting
First Posted : August 23, 2018
Last Update Posted : June 18, 2020
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

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.

Condition or disease Intervention/treatment Phase
Heart Transplant Biological: tocilizumab Biological: Placebo Drug: Standard of Care Triple IS Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 200 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: Targeting Inflammation and Alloimmunity in Heart Transplant Recipients With Tocilizumab (RTB-004)
Actual Study Start Date : December 20, 2018
Estimated Primary Completion Date : August 2022
Estimated Study Completion Date : August 2023

Resource links provided by the National Library of Medicine

Drug Information available for: Tocilizumab

Arm Intervention/treatment
Experimental: 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.

Biological: 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.
Other Name: Actemra®

Drug: 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.
Other Names:
  • calcineurin inhibitor: (tacrolimus (Prograf ®))
  • anti-proliferative treatment: (mycophenolate mofetil ),
  • MMF, CellCept®
  • Myfortic®, enteric-coated mycophenolate sodium
  • steroids: methylprednisolone/prednisone

Placebo Comparator: 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.

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.
Other Names:
  • Placebo for tocilizumab
  • Placebo for Actemra®

Drug: 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.
Other Names:
  • calcineurin inhibitor: (tacrolimus (Prograf ®))
  • anti-proliferative treatment: (mycophenolate mofetil ),
  • MMF, CellCept®
  • Myfortic®, enteric-coated mycophenolate sodium
  • steroids: methylprednisolone/prednisone




Primary Outcome Measures :
  1. Proportion of Participants Positive for Event of dnDSA, ACR, AMR, Hemodynamic Compromise, Death or Re-Transplantation - By Treatment Group [ Time Frame: From transplant through 12 months post transplant surgery (12 months) ]

    This outcome is defined by a composite 1 year post-transplant endpoint of:

    • detection of de novo donor-specific antibodies (dnDSA) (Core Laboratory),
    • acute cellular rejection (ACR) ≥ ISHLT 2R rejection (Core Laboratory),
    • antibody mediated rejection (AMR) ≥ ISHLT AMR 1 (Core Laboratory),
    • hemodynamic compromise rejection in the absence of a biopsy or histological rejection,
    • death, or
    • re-transplantation.


Secondary Outcome Measures :
  1. Freedom of Detection of de Novo Donor-Specific Antibodies (dnDSA) - by Treatment Group [ Time Frame: From transplant through 12 months post transplant surgery (12 months) ]
    A comparison by treatment group of the incidence of freedom from development of de novo donor-specific antibodies (dnDSA). dnDSA is a newly developed alloantibody that is against the donor organ.

  2. Freedom from Acute Cellular Rejection (ACR) ≥ International Society of Heart and Lung Transplantation (ISHLT) 2R Rejection - by Treatment Group [ Time Frame: From transplant through 12 months post transplant surgery (12 months) ]
    A comparison by treatment group of the incidence of freedom from development of acute cellular rejection ≥2R (Reference: International Society of Heart and Lung Transplantation [ISHLT] acute cellular rejection-grade 2R or greater severity).

  3. Freedom from Antibody Mediated Rejection (AMR) ≥ International Society of Heart and Lung Transplantation (ISHLT) AMR 1 - by Treatment Group [ Time Frame: From transplant through 12 months post transplant surgery (12 months) ]
    A comparison by treatment group of the incidence of freedom from development of antibody-mediated rejection defined as ISHLT grade AMR 1 or greater severity.

  4. Freedom from Hemodynamic Compromise Rejection in the Absence of a Biopsy or Histological Rejection - by Treatment Group [ Time Frame: From transplant through 12 months post transplant surgery (12 months) ]

    A comparison by treatment group of the incidence of freedom from development of hemodynamic compromise (HDC).

    Hemodynamic compromise is defined by:

    - Need for inotropic agents due to a Cardiac Index (CI) <2.0 L/min/m^2 or a 25% decrease from baseline, in addition to one of the following:

    • ejection fraction of <40% or a 20% decrease from baseline, and the need for inotropic agents OR
    • fractional shortening of <20% or a 25% decrease from baseline, and the need for inotropic agents.

  5. Freedom from Any-Treated Rejection - by Treatment Group [ Time Frame: From transplant through 12 months post transplant surgery (12 months) ]
    A comparison by treatment group of the incidence of freedom from development of episode of rejection requiring treatment. Reference: Acute cellular rejection as defined by the 2004 International Society of Heart and Lung Transplantation (ISHLT) grading scale.

  6. Freedom from Acute Cellular Rejection (ACR) ≥ International Society of Heart and Lung Transplantation (ISHLT) 2R Per Patient - by Treatment Group [ Time Frame: From transplant through 12 months post transplant surgery (12 months) ]
    A comparison by treatment group of the incidence of freedom from acute cellular rejection (ACR) ≥ ISHLT 2R rejection. Reference: 2004 International Society of Heart and Lung Transplantation [ISHLT [ grading scale).

  7. Freedom from Antibody Mediated Rejection (AMR) (≥ International Society of Heart and Lung Transplantation (ISHLT) AMR 1) Per Participant - by Treatment Group [ Time Frame: From transplant through 12 months post transplant surgery (12 months)] ]

    Time from transplant, free of antibody mediated rejection, defined as ISHLT grade AMR 1 or greater will be compared between the treatment groups. Hemodynamic compromise is defined as the need for inotropic agents due to a Cardiac Index (CI) <2.0 L/min/m2 or a 25% decrease from baseline in addition to one of the following:

    • Ejection fraction of <40% or a 20% decrease from baseline, and the need for inotropic agents
    • Fractional shortening of <20% or a 25% decrease from baseline, and the need for inotropic agents

  8. Freedom from Hemodynamic Compromise Rejection in the Absence of a Biopsy or Histological Rejection Per Participant - by Treatment Group [ Time Frame: From transplant through 12 months post transplant surgery (12 months) ]
    Time from transplant, free of antibody mediated rejection, defined as ISHLT grade AMR 1 or greater will be compared between the treatment groups

  9. Occurrence of Death - by Treatment Group [ Time Frame: From transplant through 12 months post transplant surgery (12 months) ]
    Incidence of all-cause mortality will be compared between the treatment groups.

  10. Occurrence of Re-Listed for Transplantation - by Treatment Group [ Time Frame: From transplant through 12 months post transplant surgery (12 months) ]
    Incidence of participant(s) being re-listed for transplant will be compared between the treatment groups.

  11. Occurrence of Re-Transplantation - by Treatment Group [ Time Frame: From transplant through 12 months post transplant surgery (12 months)] ]
    Incidence of participant(s) re-transplantation will be compared between the treatment groups.

  12. Number of Acute Cellular Rejection (≥ International Society of Heart and Lung Transplantation (ISHLT) 2R) Per Patient - by Treatment Group [ Time Frame: From transplant through 12 months post transplant surgery (12 months)] ]
    The frequency of events will be compared between the treatment groups.

  13. Number of Antibody Mediated Rejection (AMR) (≥ International Society of Heart and Lung Transplantation (ISHLT) AMR 1) Per Participant - by Treatment Group [ Time Frame: 12 months post-transplantation ]
    The frequency of events will be compared between the treatment groups.

  14. Number of Rejection Episodes Associated with Hemodynamic Compromise (HDC) Per Participant - by Treatment Group [ Time Frame: From transplant through 12 months post transplant surgery (12 months)] ]
    The frequency of events will be compared between the treatment groups.

  15. Change in Intravascular Ultrasound (IVUS) Measurements From Baseline to 1 Year Post-Transplant- by Treatment Group [ Time Frame: Baseline (4 to 8 weeks post-transplant), 1 year post-transplant ]
    Per protocol, per clinical research site standard of care.

  16. Angiographic Evidence of Cardiac Allograft Vasculopathy (CAV) - by Treatment Group [ Time Frame: 12 months post-transplantation ]
    In accordance with the International Society of Heart and Lung Transplantation (ISHLT) Cardiac Allograft Vasculopathy (CAV) angiographic grading scale.

  17. Participant Loss to follow up - by Treatment Group [ Time Frame: 12 months post-transplantation ]
    Incidence of participant loss to follow up will be compared between the treatment groups.

  18. Occurrence of Serious Infections Requiring Intravenous Antimicrobial Therapy and Need for Hospitalization - by Treatment Group [ Time Frame: Through 24 months post transplant surgery ]
    The frequency of serious infections requiring intravenous antimicrobial therapy and need for hospitalization will be compared between treatment groups.

  19. Incidence of Tuberculosis - by Treatment Group [ Time Frame: Through 24 months post transplant surgery ]
    The incidence of tuberculosis will be compared between treatment groups.

  20. Incidence of Cytomegalovirus (CMV) Infection - by Treatment Group [ Time Frame: Through 24 months post transplant surgery ]
    The incidence of CMV infection will be compared between treatment groups.

  21. Incidence of Post-Transplant Lymphoproliferative Disease (PTLD) - by Treatment Group [ Time Frame: Through 24 months post transplant surgery ]
    The incidence of PTLD will be compared between treatment groups.

  22. Tolerability (Discontinuation of Study Drug) of Tocilizumab (TCZ) - by Treatment Group [ Time Frame: Through 24 months post transplant surgery ]
    The number of participants who discontinue study drug, per protocol, will be compared between treatment groups.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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, 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.

Inclusion Criteria - Randomization

  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.

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. Subjects with a history of splenectomy;
  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 such as:

    • multiple sclerosis,
    • chronic inflammation,
    • demyelinating polyneuropathy.
  19. History of gastrointestinal perforations, active inflammatory bowel disease or diverticulitis;
  20. Any previous treatment with alkylating agents such as chlorambucil or, total lymphoid irradiation;
  21. 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.

  22. Subjects with a hemoglobin <7.0gm/dL (last measurement within 7 days prior to transplant);
  23. Subjects with a platelet count of less than 100,000/mm^3 (last measurement within 7 days prior to transplant);
  24. Subjects with an absolute neutrophil count (ANC) of less than 2,000/mm^3 (last measurement within 7 days prior to transplant);
  25. Subjects with Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) levels >3 x Upper Limit of Normal (ULN);
  26. 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;
  27. Intent to give the recipient 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. 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;
  20. History of gastrointestinal perforations, active inflammatory bowel disease or diverticulitis;
  21. Any previous treatment with alkylating agents such as chlorambucil, or with total lymphoid irradiation;
  22. 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.

  23. Subjects with a hemoglobin <7.0gm/dL within 7 days prior to randomization;
  24. Subjects with a platelet count of less than 100,000/mm^3 within 7 days prior to randomization;
  25. Subjects with an absolute neutrophil count (ANC) of less than 2,000/mm^3 within 7 days prior to randomization;
  26. Subjects with AST or ALT levels >3 x ULN;
  27. 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;
  28. Receipt of a live vaccine within 30 days prior to randomization;
  29. Use of investigational drugs after transplantation;
  30. 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.
  31. Subjects with known donor-specific antibody at the time of evaluation of antibodies for heart transplant surgery (within 6 months).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03644667


Locations
Show Show 19 study locations
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
Investigators
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Study Chair: Jon A. Kobashigawa, MD Cedars Sinai Medical Center: Transplantation
Principal Investigator: Joren Madsen, MD, DPHIL Massachusetts General Hospital: Transplantation
Additional Information:
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Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT03644667    
Other Study ID Numbers: DAIT RTB-004
ALL IN ( Other Identifier: Study Team )
First Posted: August 23, 2018    Key Record Dates
Last Update Posted: June 18, 2020
Last Verified: June 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
heart transplant recipients
alloimmunity
anti-inflammatory
tocilizumab
efficacy clinical trial
immunosuppression (IS)
Additional relevant MeSH terms:
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Mycophenolic Acid
Prednisone
Methylprednisolone
Tacrolimus
Calcineurin Inhibitors
Anti-Inflammatory Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antibiotics, Antineoplastic
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Gastrointestinal Agents
Neuroprotective Agents
Protective Agents