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Clinical Trial Details — Status: Enrolling by invitation

Administrative data

NCT number NCT03292861
Other study ID # ATG Pilot Study
Secondary ID
Status Enrolling by invitation
Phase Phase 2
First received
Last updated
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
Health authority
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

Study Design


Related Conditions & MeSH terms


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
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