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

Heart Transplantation Clinical Trial

Official title:

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

Clinical Trial Details — Status: Enrolling by invitation

Administrative data

• NCT number: NCT03292861
• Other study ID #: ATG Pilot Study
• Status: Enrolling by invitation
• Phase: Phase 2
• Start date: September 13, 2018
• Est. completion date: October 31, 2025

Study information

• Verified date: November 2023
• Source: Cedars-Sinai Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Enrolling by invitation
• Enrollment: 60
• Est. completion date: October 31, 2025
• Est. primary completion date: October 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

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

Related Conditions & MeSH terms

• Heart Transplantation

Intervention

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.
• 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
• 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.
• Sirolimus
Maintenance doses of sirolimus at 12 months post-transplantation
• 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.

Locations

Country	Name	City	State
United States	Cedars-Sinai Medical Center	Los Angeles	California
United States	Kaiser Permanente Los Angeles Medical Center	Los Angeles	California

Sponsors (2)

Lead Sponsor	Collaborator
Cedars-Sinai Medical Center	Genzyme, a Sanofi Company

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	Changes in biomarkers	Correlations between significant changes in biomarkers and their relation to any significant differences in clinical outcomes	12 months
Secondary	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
Secondary	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
Secondary	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
Secondary	Time to first rejection	Time to first acute cellular, antibody-mediated, hemodynamic compromise, and any-treated rejection within the first 12 months	12 months
Secondary	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
Secondary	Patient and graft survival	Patient and graft survival at 12 months post-transplantation	12 months
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Change in coronary maximal intimal thickness	Change in coronary maximal intimal thickness at matched sites by intravascular ultrasound at 12 months	12 months
Secondary	Change in coronary intimal area	Change in coronary intimal area at matched sites by intravascular ultrasound at 12 months	12 months
Secondary	Change in coronary intimal volume	Change in coronary intimal volume at matched sites by intravascular ultrasound at 12 months	12 months
Secondary	Change in coronary vessel area	Change in coronary vessel area at matched sites by intravascular ultrasound at 12 months	12 months
Secondary	Change in coronary intimal index	Change in coronary intimal index at matched sites by intravascular ultrasound at 12 months	12 months
Secondary	Change in coronary percent atheroma volume	Change in coronary percent atheroma volume at matched sites by intravascular ultrasound at 12 months	12 months
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Any treated rejection	To describe between treatment groups any treated rejection at 12 months	12 months