Heart Transplant
Conditions
Keywords
heart transplant recipients, alloimmunity, anti-inflammatory, tocilizumab, efficacy clinical trial, immunosuppression (IS)
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.
Interventions
BIOLOGICALtocilizumab
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.
BIOLOGICALPlacebo
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.
DRUGStandard 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.
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
PPD Development, LP
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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. 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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants Positive for Event of dnDSA, ACR, AMR, Hemodynamic Compromise, Death or Re-Transplantation - By Treatment Group | 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
| Measure | Time frame | Description |
|---|---|---|
| Freedom of Detection of de Novo Donor-Specific Antibodies (dnDSA) - by Treatment Group | 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. |
| Freedom from Acute Cellular Rejection (ACR) ≥ International Society of Heart and Lung Transplantation (ISHLT) 2R Rejection - by Treatment Group | 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). |
| Freedom from Antibody Mediated Rejection (AMR) ≥ International Society of Heart and Lung Transplantation (ISHLT) AMR 1 - by Treatment Group | 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. |
| Freedom from Hemodynamic Compromise Rejection in the Absence of a Biopsy or Histological Rejection - by Treatment Group | 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. |
| Freedom from Any-Treated Rejection - by Treatment Group | 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. |
| Freedom from Acute Cellular Rejection (ACR) ≥ International Society of Heart and Lung Transplantation (ISHLT) 2R Per Patient - by Treatment Group | 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). |
| Freedom from Antibody Mediated Rejection (AMR) (≥ International Society of Heart and Lung Transplantation (ISHLT) AMR 1) Per Participant - by Treatment Group | 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 |
| Freedom from Hemodynamic Compromise Rejection in the Absence of a Biopsy or Histological Rejection Per Participant - by Treatment Group | 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 |
| Occurrence of Death - by Treatment Group | From transplant through 12 months post transplant surgery (12 months) | Incidence of all-cause mortality will be compared between the treatment groups. |
| Occurrence of Re-Listed for Transplantation - by Treatment Group | 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. |
| Occurrence of Re-Transplantation - by Treatment Group | From transplant through 12 months post transplant surgery (12 months)] | Incidence of participant(s) re-transplantation will be compared between the treatment groups. |
| Number of Acute Cellular Rejection (≥ International Society of Heart and Lung Transplantation (ISHLT) 2R) Per Patient - by Treatment Group | From transplant through 12 months post transplant surgery (12 months)] | The frequency of events will be compared between the treatment groups. |
| Number of Antibody Mediated Rejection (AMR) (≥ International Society of Heart and Lung Transplantation (ISHLT) AMR 1) Per Participant - by Treatment Group | 12 months post-transplantation | The frequency of events will be compared between the treatment groups. |
| Number of Rejection Episodes Associated with Hemodynamic Compromise (HDC) Per Participant - by Treatment Group | From transplant through 12 months post transplant surgery (12 months)] | The frequency of events will be compared between the treatment groups. |
| Change in Intravascular Ultrasound (IVUS) Measurements From Baseline to 1 Year Post-Transplant- by Treatment Group | Baseline (4 to 8 weeks post-transplant), 1 year post-transplant | Per protocol, per clinical research site standard of care. |
| Angiographic Evidence of Cardiac Allograft Vasculopathy (CAV) - by Treatment Group | 12 months post-transplantation | In accordance with the International Society of Heart and Lung Transplantation (ISHLT) Cardiac Allograft Vasculopathy (CAV) angiographic grading scale. |
| Participant Loss to follow up - by Treatment Group | 12 months post-transplantation | Incidence of participant loss to follow up will be compared between the treatment groups. |
| Occurrence of Serious Infections Requiring Intravenous Antimicrobial Therapy and Need for Hospitalization - by Treatment Group | 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. |
| Incidence of Tuberculosis - by Treatment Group | Through 24 months post transplant surgery | The incidence of tuberculosis will be compared between treatment groups. |
| Incidence of Cytomegalovirus (CMV) Infection - by Treatment Group | Through 24 months post transplant surgery | The incidence of CMV infection will be compared between treatment groups. |
| Incidence of Post-Transplant Lymphoproliferative Disease (PTLD) - by Treatment Group | Through 24 months post transplant surgery | The incidence of PTLD will be compared between treatment groups. |
| Tolerability (Discontinuation of Study Drug) of Tocilizumab (TCZ) - by Treatment Group | Through 24 months post transplant surgery | The number of participants who discontinue study drug, per protocol, will be compared between treatment groups. |
Countries
United States
Contacts
STUDY_CHAIRJon A. Kobashigawa, MD
Cedars Sinai Medical Center: Transplantation
PRINCIPAL_INVESTIGATORJoren C. Madsen, MD, DPHIL
Massachusetts General Hospital: Transplantation
Outcome results
None listed