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
试验速览
- 阶段
- 2 期
- 状态
- Enrolling By Invitation
- 入组人数
- 60
- 试验地点
- 2
- 主要终点
- Percentage of Participants With Composite Efficacy Failure at 12 Months
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •for Study Entry:
- •Subjects must be undergoing their first allograft transplant
- •Men and non-pregnant women must be 18 to 70 years old
- •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)
- •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.
- •Subjects must be willing and capable of understanding the purpose and risks of the study, and must sign a statement of informed consent
- •Subjects with a Creatinine < 2.0 mg/dl at time of transplant
排除标准
- •for Study Entry:
- •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
- •Previous organ transplants
- •Patients receiving multiple organs
- •Patients with a BMI higher than 35
- •Patients with PRA ≥ 25%
- •Patients requiring VAD upon completion of transplantation surgery.
- •HIV-1, HTLV-1, chronic Hepatitis B, or chronic Hepatitis C infection
- •Documented or strong suspicion for pre-operative active infection that has not yet been adequately treated with the recommended course of antimicrobial therapy
- •Presence of any chronic myelosuppressive disease or agent that has resulted in either chronic leucopenia or chronic thrombocytopenia
- •Active peptic ulcer disease and active GI bleeding
- •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")
- •Patients with a history of AL amyloidosis (TTR amyloids) are permitted
研究组 & 干预措施
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
干预措施: Thymoglobulin (Drug)
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
干预措施: Mycophenolate Mofetil (Drug)
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
干预措施: Tacrolimus (Drug)
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
干预措施: Sirolimus (Drug)
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
干预措施: Corticosteroids (Drug)
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.
结局指标
主要结局
Percentage of Participants With Composite Efficacy Failure at 12 Months
时间窗: 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.
次要结局
- Changes in biomarkers(12 months)
- Number of patients who experience rejection(12 months)
- First rejection by ISHLT biopsy grading scale(12 months)
- Time to first rejection(12 months)
- Incidence of primary graft dysfunction (PGD)(first 24 hours post-transplant)
- Patient and graft survival(12 months)
- Types of patients with fatal infectious complications(12 months)
- Number of patients with fatal infectious complications(12 months)
- Types of patients with non-fatal infectious complications(12 months)
- Number of patients with non-fatal infectious complications(12 months)
- Freedom from development of circulating antibodies(12 months)
- Change in coronary maximal intimal thickness(12 months)
- Changes in immune cell profiles(12 months)
- Number of episodes per patient(12 months)
- Change in coronary intimal area(12 months)
- Change in coronary intimal volume(12 months)
- Change in coronary vessel area(12 months)
- Change in coronary intimal index(12 months)
- Change in coronary percent atheroma volume(12 months)
- Maintenance doses of mycophenolate mofetil, tacrolimus, sirolimus, and dose of corticosteroids(12 months)
- Number of hospital days per patient(3 months, 6 months, 12 months)
- Number of patients requiring hospitalization(3 months, 6 months, 12 months)
- Death/Re-transplant(12 months)
- Hemodynamic compromise rejection(12 months)
- Graft dysfunction(12 months)
- Cellular rejection(12 months)
- Antibody mediated rejected(12 months)
- Cardiac Allograft Vasculopathy (CAV)(12 months)
- Any treated rejection(12 months)
研究者
Jon Kobashigawa
Director of Advanced Heart Disease Program
Cedars-Sinai Medical Center