Pharmacodynamics, Pharmacogenomics, and Preliminary Safety and Efficacy of rATG Induction and Tacrolimus Monotherapy in Pediatric Liver Transplantation
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 110
- 试验地点
- 1
- 主要终点
- Incidence and severity of biopsy-proven acute cellular rejection
研究概览
简要总结
This open-label clinical trial will evaluate the pharmacodynamics, pharmacogenomics and early efficacy and safety of steroid-free Tacrolimus (TAC) monotherapy and its minimization after induction with rabbit, anti-human thymocyte globulin (rATG, Genzyme, Cambridge, MA) in children and adults with pediatric liver transplantation. Eighty subjects (0-21 years) receiving liver transplantation will be enrolled. Incidence and severity of biopsy-proven acute cellular rejection (ACR) is a primary endpoint as well as time to Tacrolimus whole blood concentrations <8 ng/ml The expected incidence of ACR is 50% and is derived from a non-consecutive subject population (n=40) who received an identical regimen in IND 64555. This incidence is acceptable because the long term sequel of rejection reported with other allografts have not been observed in liver grafts during IND 64555. These risks are further negated by the unique regenerative capacity of the liver allograft. An OBSERVATIONAL arm is being included in this trial. Because the numbers of pediatric liver transplants (LTx) are small in any single center setting, no information is known about relative outcomes on a conventional protocol, in children receiving conventional protocol of steroids+Tacrolimus. The PURPOSE of this additional recruitment is OBSERVATIONAL, only. Therefore, these subjects will NOT be randomized. Rather, by studying all types of patients, the investigators hope to utilize maximally, all available subjects, to understand the relative place of monotherapeutic induction. In turn, this will be the basis for a follow-up comparative, randomized trial.
详细描述
This open-label clinical trial will evaluate the pharmacodynamics, pharmacogenomics and early efficacy and safety of steroid-free Tacrolimus (TAC) monotherapy and its minimization after induction with rabbit, anti-human thymocyte globulin (rATG, Genzyme, Cambridge, MA) in children and adults with pediatric liver transplantation. Eighty subjects (0-21 years) receiving liver transplantation will be enrolled. Incidence and severity of biopsy-proven acute cellular rejection (ACR) is a primary endpoint as well as time to Tacrolimus whole blood concentrations <8 ng/ml The expected incidence of ACR is 50% and is derived from a non-consecutive subject population (n=40) who received an identical regimen in Investigational New Drug (IND) 64555. This incidence is acceptable because the long term sequel of rejection reported with other allografts have not been observed in liver grafts during IND 64555. These risks are further negated by the unique regenerative capacity of the liver allograft. An OBSERVATIONAL arm is being included in this trial. Because the numbers of pediatric liver transplants (LTx) are small in any single center setting, no information is known about relative outcomes on a conventional protocol, in children receiving conventional protocol of steroids+Tacrolimus. The PURPOSE of this additional recruitment is OBSERVATIONAL, only. Therefore, these subjects will NOT be randomized. Rather, by studying all types of patients, we hope to utilize maximally, all available subjects, to understand the relative place of monotherapeutic induction. In turn, this will be the basis for a follow-up comparative, randomized trial.
The protocol also incorporates a clearly defined schedule to minimize Tacrolimus (TAC) maintenance therapy in each subject, based on presence or absence of early biopsy-proven rejection.
Secondary clinical endpoints are:
-
Time to steroid elimination. 4. Duration of steroid treatment. 5. Steroid-resistant rejection. 6. Cytomegalovirus (CMV) antigenemia (pp5) and CMV disease 7. Epstein-barr virus (EBV) viremia 8. Post-transplant lymphoproliferative disorder (PTLD) 9. Frequency of use of Non-immunosuppressive co-medications - antihypertensives, magnesium and bicarbonate supplements, hypokalemic agents (safety endpoint).
-
Time to first rejection
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- — 至 21 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age 0-21 years, male and female
- •Primary OLTx, Whole/segmental, cadaveric/live, Re-LTx, and LTx in the setting of a previous or simultaneous kidney transplant.
- •All children receiving the types of LTx described above, but on conventional immunosuppression, will be enrolled in an observational arm, with the same treatment and monitoring protocols.
排除标准
- •Multiorgan transplants (liver-intestine, liver intestine with stomach and other organs)
- •Documented non-compliance
- •Donor: Age >60, macrovesicular steatosis > 30%, Hepatitis C and B infections defined as anti-HCV antibody positive, and anti-Hepatitis B surface antigen or Hepatitis B core antibody positive, malignancy, cold ischemia time >16 hours
- •Children of child-bearing age receive pregnancy testing at the time of transplantation. Pregnancy is a contraindication to liver transplantation and therefore to enrollment in this clinical trial.
结局指标
主要结局
Incidence and severity of biopsy-proven acute cellular rejection
时间窗: 90 days
次要结局
- Duration of steroid treatment and time to steroid elimination(1 year)
- Time to Tacrolimus whole blood concentrations <8 ng/ml(1 year)
研究者
Rakesh Sindhi
Professor of Surgery
University of Pittsburgh