This is a randomized, controlled, single center study to evaluate the efficacy of Thymoglobulin induction therapy in combination with Mycophenolate Mofetil, tacrolimus, and steroids in the prevention of CAV. Approximately half of the patients will be randomized to receive a total of 5 doses of Thymoglobulin during the study. The first dose of Thymoglobulin will be administered at 1.5 mg/kg via intravenous infusion over 6 hours immediately upon arrival to the ICU post-operation (day 1). Subsequent doses of 1.5 mg/kg will be administered on days 2, 3, 4, and 5 via IV infusion over 4 hours. Mechanistic assays (T-reg cells, Lym subsets, B cell subsets, IL-1b, cytokines, TGFb, IL-21 to be drawn at Pre-transplant, 3, 6, 12 months post-transplant) will also be performed. All patients will be followed and monitored according to standard of care protocols for heart transplant recipients at our center.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
60
Approximately half of the patients will be randomized to receive a total of 5 doses of Thymoglobulin during the study. The first dose of Thymoglobulin will be administered at 1.5 mg/kg via intravenous infusion over 8 hours immediately upon arrival to the ICU post-operation (day 1). Subsequent doses of 1.5 mg/kg will be administered on days 2, 3, 4, and 5 via IV infusion over 4-8 hours.
3.0 grams divided bid begun post-transplant, either IV or po as tolerated by patient. Initial dose must be given within 24 hours post-transplant. Dosing will be titrated based on recipient's body size and any adverse side effects
Doses of 1-4 mg bid either IV or po will be prescribed to achieve a target trough level of 10-15 ng/mL before post-operative day number 5. Target trough levels are 10-15 ng/mL for post-operative days #1-30, 8-12ng/mL days#31-60 and 5-10 ng/mL thereafter.
Maintenance doses of sirolimus at 12 months post-transplantation
125 mg IV methylprednisolone immediately post-operatively x 3 doses q12hrs, then switching to oral prednisone at 1.0 mg/kg/day po divided into bid doses that are rounded off to the next higher 5 mg increment. For example, a 76 kg person would should be dosed at 38 mg po bid, which rounded off to the next 5 mg increment would be 40 mg po bid. (Equivalent dosing via an alternative route may be used if pos not tolerated or contraindicated). Prednisone will be tapered by 10 mg qd until the dose of 10 mg po bid is reached.
Kaiser Permanente Los Angeles Medical Center
Los Angeles, California, United States
Cedars-Sinai Medical Center
Los Angeles, California, United States
Percentage of Participants With Composite Efficacy Failure at 12 Months
Composite efficacy failure is defined as development of de novo donor specific antibodies (measured by standardized alloantibody testing by Luminex and control sera, characterizing kinetics, specificities and relative binding strength) and ischemia on endomyocardial biopsy (characterized on biopsy by myocyte necrosis and/or regions of myocyte dropout) at 12 months post-transplant.
Time frame: 12 Months
Changes in immune cell profiles
Correlations between significant changes in immune cell profiles and biomarkers, and their relation to any significant differences in clinical outcomes
Time frame: 12 months
Changes in biomarkers
Correlations between significant changes in biomarkers and their relation to any significant differences in clinical outcomes
Time frame: 12 months
Number of patients who experience rejection
Number of patients who experience acute cellular, antibody-mediated, hemodynamic compromise, and any-treated rejection within first 12 months after transplantation/
Time frame: 12 months
Number of episodes per patient
Number of acute cellular, antibody-mediated, hemodynamic compromise and any-treated rejection episodes per patient within the first 12 months post-transplantation
Time frame: 12 months
First rejection by ISHLT biopsy grading scale
First acute cellular, antibody-mediated, hemodynamic compromise, and any-treated rejection by the ISHLT biopsy grading scale in the first 12 months post-transplantation
Time frame: 12 months
Time to first rejection
Time to first acute cellular, antibody-mediated, hemodynamic compromise, and any-treated rejection within the first 12 months
Time frame: 12 months
Incidence of primary graft dysfunction (PGD)
The incidence of Primary Graft Dysfunction(PGD) in the first 24 hours post-transplant
Time frame: first 24 hours post-transplant
Patient and graft survival
Patient and graft survival at 12 months post-transplantation
Time frame: 12 months
Types of patients with fatal infectious complications
The types of patients with fatal infectious complications (especially CMV infection) within the first 12 months post-transplantation
Time frame: 12 months
Number of patients with fatal infectious complications
The number of patients with fatal infectious complications (especially CMV infection) within the first 12 months post-transplantation
Time frame: 12 months
Types of patients with non-fatal infectious complications
Types of patients with non-fatal infectious complications (especially CMV infection) within the first 12 months post-transplantation
Time frame: 12 months
Number of patients with non-fatal infectious complications
Number of patients with non-fatal infectious complications (especially CMV infection) within the first 12 months post-transplantation
Time frame: 12 months
Freedom from development of circulating antibodies
Freedom from the development of circulating antibodies within the first 12 months post transplantation, where circulating antibodies include donor specific antibodies (DSA), non-specific antibodies, and non-human leukocyte antigen antibodies
Time frame: 12 months
Change in coronary maximal intimal thickness
Change in coronary maximal intimal thickness at matched sites by intravascular ultrasound at 12 months
Time frame: 12 months
Change in coronary intimal area
Change in coronary intimal area at matched sites by intravascular ultrasound at 12 months
Time frame: 12 months
Change in coronary intimal volume
Change in coronary intimal volume at matched sites by intravascular ultrasound at 12 months
Time frame: 12 months
Change in coronary vessel area
Change in coronary vessel area at matched sites by intravascular ultrasound at 12 months
Time frame: 12 months
Change in coronary intimal index
Change in coronary intimal index at matched sites by intravascular ultrasound at 12 months
Time frame: 12 months
Change in coronary percent atheroma volume
Change in coronary percent atheroma volume at matched sites by intravascular ultrasound at 12 months
Time frame: 12 months
Maintenance doses of mycophenolate mofetil, tacrolimus, sirolimus, and dose of corticosteroids
Maintenance doses of mycophenolate mofetil, tacrolimus, sirolimus, and cumulative dose of corticosteroids at 12 months post-transplantation
Time frame: 12 months
Number of hospital days per patient
Number of hospital days per patient, both during the transplant period and during the post-transplant period at 3 months, 6 months, and 1 year
Time frame: 3 months, 6 months, 12 months
Number of patients requiring hospitalization
Number of patients requiring hospitalization by 3 months, by 6 months, or by 1 year post-transplantation
Time frame: 3 months, 6 months, 12 months
Death/Re-transplant
To describe between treatment groups the incidence of the composite primary endpoint of death/re-transplant at 12 months post-transplantation
Time frame: 12 months
Hemodynamic compromise rejection
To describe between treatment groups the incidence of the composite primary endpoint of hemodynamic compromise rejection at 12 months post-transplantation. This is an ejection fraction of ≤ 30% or a 0.20 absolute decrease from baseline, and the need for inotropic agents OR a fractional shortening ≤ 20% or a 25% decrease from baseline, and the need for inotropic agents PLUS need for inotropic agents due to a Cardiac Index (CI) \< 2.0 L/min/m2 or a 25% decrease from baseline
Time frame: 12 months
Graft dysfunction
To describe between treatment groups the incidence of the composite primary endpoint of graft dysfunction (ejection fraction less than or equal to 40% by echocardiography)at 12 months post-transplantation
Time frame: 12 months
Cellular rejection
To describe between treatment groups the incidence of the composite primary endpoint of biopsy proven cellular rejection ≥2R at 12 months post-transplantation
Time frame: 12 months
Antibody mediated rejected
To describe between treatment groups the incidence of the composite primary endpoint of biopsy proven antibody mediated rejection ≥AMR1 at 12 months post-transplantation
Time frame: 12 months
Cardiac Allograft Vasculopathy (CAV)
To describe between treatment groups the incidence of cardiac allograft vasculopathy (CAV) (defined as a change ≥0.5mm in maximal intimal thickness (MIT) of the coronary arteries by intravascular ultrasound at 12 months as compared to baseline)
Time frame: 12 months
Any treated rejection
To describe between treatment groups any treated rejection at 12 months
Time frame: 12 months
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