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Trial record 1 of 1 for:    NCT03292861
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The Effect and Safety Profile of Thymoglobulin® in Primary Cardiac Transplant Recipients

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ClinicalTrials.gov Identifier: NCT03292861
Recruitment Status : Enrolling by invitation
First Posted : September 26, 2017
Last Update Posted : October 19, 2020
Sponsor:
Collaborator:
Genzyme, a Sanofi Company
Information provided by (Responsible Party):
Jon Kobashigawa, Cedars-Sinai Medical Center

Brief 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.


Condition or disease Intervention/treatment Phase
Heart Transplantation Drug: Thymoglobulin Drug: Mycophenolate Mofetil Drug: Tacrolimus Drug: Sirolimus Drug: Corticosteroids Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
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
Actual Study Start Date : September 13, 2018
Estimated Primary Completion Date : June 22, 2021
Estimated Study Completion Date : June 30, 2021

Resource links provided by the National Library of Medicine


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.



Primary Outcome Measures :
  1. Percentage of Participants With Composite Efficacy Failure at 12 Months [ Time Frame: 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.


Secondary Outcome Measures :
  1. Changes in immune cell profiles [ Time Frame: 12 months ]
    Correlations between significant changes in immune cell profiles and biomarkers, and their relation to any significant differences in clinical outcomes

  2. Changes in biomarkers [ Time Frame: 12 months ]
    Correlations between significant changes in biomarkers and their relation to any significant differences in clinical outcomes

  3. Number of patients who experience rejection [ Time Frame: 12 months ]
    Number of patients who experience acute cellular, antibody-mediated, hemodynamic compromise, and any-treated rejection within first 12 months after transplantation/

  4. Number of episodes per patient [ Time Frame: 12 months ]
    Number of acute cellular, antibody-mediated, hemodynamic compromise and any-treated rejection episodes per patient within the first 12 months post-transplantation

  5. First rejection by ISHLT biopsy grading scale [ Time Frame: 12 months ]
    First acute cellular, antibody-mediated, hemodynamic compromise, and any-treated rejection by the ISHLT biopsy grading scale in the first 12 months post-transplantation

  6. Time to first rejection [ Time Frame: 12 months ]
    Time to first acute cellular, antibody-mediated, hemodynamic compromise, and any-treated rejection within the first 12 months

  7. Incidence of primary graft dysfunction (PGD) [ Time Frame: first 24 hours post-transplant ]
    The incidence of Primary Graft Dysfunction(PGD) in the first 24 hours post-transplant

  8. Patient and graft survival [ Time Frame: 12 months ]
    Patient and graft survival at 12 months post-transplantation

  9. Types of patients with fatal infectious complications [ Time Frame: 12 months ]
    The types of patients with fatal infectious complications (especially CMV infection) within the first 12 months post-transplantation

  10. Number of patients with fatal infectious complications [ Time Frame: 12 months ]
    The number of patients with fatal infectious complications (especially CMV infection) within the first 12 months post-transplantation

  11. Types of patients with non-fatal infectious complications [ Time Frame: 12 months ]
    Types of patients with non-fatal infectious complications (especially CMV infection) within the first 12 months post-transplantation

  12. Number of patients with non-fatal infectious complications [ Time Frame: 12 months ]
    Number of patients with non-fatal infectious complications (especially CMV infection) within the first 12 months post-transplantation

  13. Freedom from development of circulating antibodies [ Time Frame: 12 months ]
    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

  14. Change in coronary maximal intimal thickness [ Time Frame: 12 months ]
    Change in coronary maximal intimal thickness at matched sites by intravascular ultrasound at 12 months

  15. Change in coronary intimal area [ Time Frame: 12 months ]
    Change in coronary intimal area at matched sites by intravascular ultrasound at 12 months

  16. Change in coronary intimal volume [ Time Frame: 12 months ]
    Change in coronary intimal volume at matched sites by intravascular ultrasound at 12 months

  17. Change in coronary vessel area [ Time Frame: 12 months ]
    Change in coronary vessel area at matched sites by intravascular ultrasound at 12 months

  18. Change in coronary intimal index [ Time Frame: 12 months ]
    Change in coronary intimal index at matched sites by intravascular ultrasound at 12 months

  19. Change in coronary percent atheroma volume [ Time Frame: 12 months ]
    Change in coronary percent atheroma volume at matched sites by intravascular ultrasound at 12 months

  20. Maintenance doses of mycophenolate mofetil, tacrolimus, sirolimus, and dose of corticosteroids [ Time Frame: 12 months ]
    Maintenance doses of mycophenolate mofetil, tacrolimus, sirolimus, and cumulative dose of corticosteroids at 12 months post-transplantation

  21. Number of hospital days per patient [ Time Frame: 3 months, 6 months, 12 months ]
    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

  22. Number of patients requiring hospitalization [ Time Frame: 3 months, 6 months, 12 months ]
    Number of patients requiring hospitalization by 3 months, by 6 months, or by 1 year post-transplantation

  23. Death/Re-transplant [ Time Frame: 12 months ]
    To describe between treatment groups the incidence of the composite primary endpoint of death/re-transplant at 12 months post-transplantation

  24. Hemodynamic compromise rejection [ Time Frame: 12 months ]
    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

  25. Graft dysfunction [ Time Frame: 12 months ]
    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

  26. Cellular rejection [ Time Frame: 12 months ]
    To describe between treatment groups the incidence of the composite primary endpoint of biopsy proven cellular rejection ≥2R at 12 months post-transplantation

  27. Antibody mediated rejected [ Time Frame: 12 months ]
    To describe between treatment groups the incidence of the composite primary endpoint of biopsy proven antibody mediated rejection ≥AMR1 at 12 months post-transplantation

  28. Cardiac Allograft Vasculopathy (CAV) [ Time Frame: 12 months ]
    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)

  29. Any treated rejection [ Time Frame: 12 months ]
    To describe between treatment groups any treated rejection at 12 months



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  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:

  1. Allergy to Thymoglobulin-Thymglobulin 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 > 250 lbs or 114 kgs
  5. Patients with PRA ≥ 25%
  6. Patients requiring VAD upon completion of transplantation surgery.
  7. History of a psychological illness or condition which would interfere with the patient's ability to understand the requirements of the study
  8. White blood cell count ≤ 300/mm3, or platelets ≤ 75,000/mm3, or hemoglobin ≤ 6g/dL
  9. HIV-1, HTLV-1, chronic Hepatitis B, or chronic Hepatitis C infection
  10. Documented or strong suspicion for pre-operative active infection that has not yet been adequately treated with the recommended course of antimicrobial therapy
  11. Presence of any chronic myelosuppressive disease or agent that has resulted in either chronic leucopenia or chronic thrombocytopenia
  12. Active peptic ulcer disease
  13. 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")

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03292861


Locations
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United States, California
Kaiser Permanente Los Angeles Medical Center
Los Angeles, California, United States, 90027
Cedars-Sinai Medical Center
Los Angeles, California, United States, 90048
Sponsors and Collaborators
Cedars-Sinai Medical Center
Genzyme, a Sanofi Company
Investigators
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Principal Investigator: Jon Kobashigawa, MD Director
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Responsible Party: Jon Kobashigawa, Director of Advanced Heart Disease Program, Cedars-Sinai Medical Center
ClinicalTrials.gov Identifier: NCT03292861    
Other Study ID Numbers: ATG Pilot Study
First Posted: September 26, 2017    Key Record Dates
Last Update Posted: October 19, 2020
Last Verified: August 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Mycophenolic Acid
Sirolimus
Tacrolimus
Thymoglobulin
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Calcineurin Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antibiotics, Antineoplastic
Antineoplastic Agents
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents
Antifungal Agents