The Effect and Safety Profile of Thymoglobulin® in Primary Cardiac Transplant Recipients

A Pilot Randomized Study to Assess the Effect and Safety Profile of Thymoglobulin® in Primary Cardiac Transplant Recipients: A 12-month, Single Center, Randomized, Open-label Study of Efficacy Comparing Immediate Treatment With and Without Thymoglobulin® 1.5 mg/kg/d for 5 Consecutive Days in Heart Transplant Recipients

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 Overview

• Status: Enrolling by invitation
• Conditions: Heart Transplantation
• Intervention / Treatment: Drug: Thymoglobulin; Drug: Mycophenolate Mofetil; Drug: Tacrolimus; Drug: Sirolimus; Drug: Corticosteroids

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai Medical Center
    • Los Angeles, California, United States, 90027
      • Kaiser Permanente Los Angeles Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria for Study Entry:

1. Subjects must be undergoing their first allograft transplant
2. Men and non-pregnant women must be 18 to 70 years old
3. Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to transplantation. The sensitivity must be equal to at least 50 mIU/mL. (Urine test is allowed in addition to serum test in patients where serum results are delayed)
4. Men with a female partner of child bearing age and women of childbearing potential must use two reliable forms of contraception simultaneously. Effective contraception must be used before beginning study drug therapy, and for 4 months following discontinuation of study drug therapy.
5. Subjects must be willing and capable of understanding the purpose and risks of the study, and must sign a statement of informed consent
6. Subjects with a Creatinine < 2.0 mg/dl at time of transplant

Exclusion Criteria for Study Entry:

1. Allergy to Thymoglobulin-Thymoglobulin is contraindicated in patients with history of allergy or anaphylaxis to rabbit proteins or to any product excipients, or who have active acute or chronic infections which contraindicate any additional immunosuppression
2. Previous organ transplants
3. Patients receiving multiple organs
4. Patients with a BMI higher than 35
5. Patients with PRA ≥ 25%
6. Patients requiring VAD upon completion of transplantation surgery.
7. HIV-1, HTLV-1, chronic Hepatitis B, or chronic Hepatitis C infection
8. Documented or strong suspicion for pre-operative active infection that has not yet been adequately treated with the recommended course of antimicrobial therapy
9. Presence of any chronic myelosuppressive disease or agent that has resulted in either chronic leucopenia or chronic thrombocytopenia
10. Active peptic ulcer disease and active GI bleeding
11. Patients who have received within the past 30 days or require concomitant treatment with other investigational drugs (except for those listed in section 8.6 "Concomitant treatment")
12. Patients with a history of AL amyloidosis (TTR amyloids) are permitted

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Thymoglobulin®; Thymoglobulin® (Genzyme) [rabbit anti-thymocyte globulin (ATG)] is a purified pasteurized, gamma immune globulin, obtained by immunization of rabbits with human thymocytes. This immunosuppressive product contains polyclonal cytotoxic antibodies directed against antigens expressed on human T-lymphocytes. 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. In addition, there will be maintenance doses of mycophenolate mofetil, tacrolimus, sirolimus, and cumulative dose of corticosteroids at 12 months post-transplantation	Drug: Thymoglobulin; 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.; Drug: Mycophenolate Mofetil; 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; Drug: Tacrolimus; 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.; Drug: Sirolimus; Maintenance doses of sirolimus at 12 months post-transplantation; Drug: Corticosteroids; 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.
No Intervention: No induction therapy; Patients qualifying for the study will be randomized before the transplantation surgery in a 1:1 ratio to either Thymoglobulin® or no treatment.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	12 Months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	12 months
Changes in biomarkers	Correlations between significant changes in biomarkers and their relation to any significant differences in clinical outcomes	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/	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	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	12 months
Time to first rejection	Time to first acute cellular, antibody-mediated, hemodynamic compromise, and any-treated rejection within the first 12 months	12 months
Incidence of primary graft dysfunction (PGD)	The incidence of Primary Graft Dysfunction(PGD) in the first 24 hours post-transplant	first 24 hours post-transplant
Patient and graft survival	Patient and graft survival at 12 months post-transplantation	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	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	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	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	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	12 months
Change in coronary maximal intimal thickness	Change in coronary maximal intimal thickness at matched sites by intravascular ultrasound at 12 months	12 months
Change in coronary intimal area	Change in coronary intimal area at matched sites by intravascular ultrasound at 12 months	12 months
Change in coronary intimal volume	Change in coronary intimal volume at matched sites by intravascular ultrasound at 12 months	12 months
Change in coronary vessel area	Change in coronary vessel area at matched sites by intravascular ultrasound at 12 months	12 months
Change in coronary intimal index	Change in coronary intimal index at matched sites by intravascular ultrasound at 12 months	12 months
Change in coronary percent atheroma volume	Change in coronary percent atheroma volume at matched sites by intravascular ultrasound at 12 months	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	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	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	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	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	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	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	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	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)	12 months
Any treated rejection	To describe between treatment groups any treated rejection at 12 months	12 months

Collaborators and Investigators

• Sponsor: Cedars-Sinai Medical Center
• Collaborators: Genzyme, a Sanofi Company
• Investigators: Principal Investigator: Jon Kobashigawa, MD, Director

Study record dates

Study Major Dates

• Study Start (Actual): September 13, 2018
• Primary Completion (Estimated): March 31, 2026
• Study Completion (Estimated): March 31, 2026

Study Registration Dates

• First Submitted: September 12, 2017
• First Submitted That Met QC Criteria: September 22, 2017
• First Posted (Actual): September 26, 2017

Study Record Updates

• Last Update Posted (Estimated): January 14, 2026
• Last Update Submitted That Met QC Criteria: January 12, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Organic Chemicals; Fatty Acids; Lipids; Acids, Acyclic; Carboxylic Acids; Macrolides; Lactones; Caproates; Sirolimus; Mycophenolic Acid; Tacrolimus; thymoglobulin; Adrenal Cortex Hormones
• Other Study ID Numbers: ATG Pilot Study

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No