rATG Induction and Tacrolimus Monotherapy in Pediatric Liver Transplantation

This study is enrolling participants by invitation only.
Sponsor:
Collaborator:
Information provided by:
University of Pittsburgh
ClinicalTrials.gov Identifier:
NCT01207141
First received: September 21, 2010
Last updated: March 24, 2011
Last verified: March 2011
  Purpose

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.


Condition
Liver Transplantation
Thymoglobulin
Rejection

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Prospective
Official Title: Pharmacodynamics, Pharmacogenomics, and Preliminary Safety and Efficacy of rATG Induction and Tacrolimus Monotherapy in Pediatric Liver Transplantation

Resource links provided by NLM:


Further study details as provided by University of Pittsburgh:

Primary Outcome Measures:
  • Incidence and severity of biopsy-proven acute cellular rejection [ Time Frame: 90 days ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Time to Tacrolimus whole blood concentrations <8 ng/ml [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  • Duration of steroid treatment and time to steroid elimination [ Time Frame: 1 year ] [ Designated as safety issue: No ]

Biospecimen Retention:   Samples With DNA

Blood


Estimated Enrollment: 100
Study Start Date: August 2006
Estimated Study Completion Date: December 2011
Estimated Primary Completion Date: December 2010 (Final data collection date for primary outcome measure)
Groups/Cohorts
rATG induction
Liver transplant recipients who receive induction with rATG prior to transplantation.
no rATG induction
Liver transplant recipients who do not receive rATG induction therapy prior to transplantation.

  Hide Detailed Description

Detailed Description:

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, 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:

3. Time to steroid elimination. 4. Duration of steroid treatment. 5. Steroid-resistant rejection. 6. CMV antigenemia (pp5) and CMV disease 7. 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).

10. Time to first rejection

Secondary pharmacodynamic and pharmacogenomic endpoints are 1. Longitudinal evaluation of peripheral lymphocyte subsets prior to and at 1, 4, and 12 months after liver transplantation. This will establish the pattern of lymphocyte reconstitution after depletion with rATG. 2. Inheritance disequilibrium of 100,000 single nucleotide polymorphisms in the major histocompatibility region. This will entail pre-transplant characterization of these single-nucleotide polymorphisms (SNPs) in all children and their biological parents. Preliminary studies lead us to expect identification of outcome-specific patterns of inheritance of SNPs. Such patterns could be used in future studies to allocate appropriate treatment to children based on predicted risk of rejection. For example, the predicted rejector could receive steroids with rATG+Tacrolimus, while the non-rejector could avoid steroids completely.

Research Design and Methods:

Study type: This is a prospective, open-label, evaluation of steroid-free, induction immunosuppression in children receiving liver transplantation.

Study population: Children 0- 21 years receiving liver transplantation.

Informed consent: This will be obtained by the PI or his physician co-investigators.

Randomization: Not applicable.

Control group: Not applicable

Test group: rATG pretreatment.

  1. Premedication with acetaminophen 10 mg/kg orally + diphenhydramine 1 mg/kg intravenously + methylprednisolone 2 mg/kg, intravenously.
  2. rATG 5 mg/kg will be initiated prior to liver transplantation, with half the dose infused over at least 4 hours, prior to reperfusion of the liver graft. Total dose to be infused over 24 hours, but no less than 8 hours. If the requisite amount cannot be infused before LTx, it can be continued through the LTx procedure and afterward.

Procedures:

  1. Tacrolimus will be initiated at 0.01 mg per kg body weight orally. If biopsy-proven rejection does not occur, Tacrolimus will be titrated to whole blood concentrations:

    Month 1 12-15 ng/ml Months 2-3 8-12 ng/ml Month 4-6 5-8 ng/ml Months 6-12 <5 ng/ml

  2. This minimization protocol will be delayed by 3 months if biopsy proven acute cellular rejection occurs. For example, if rejection occurs, Tacrolimus is increased to month 1 levels of 12-15 ng/ml, and steroids added to the regimen. Steroids will be eliminated within 3 months of rejection, and Tacrolimus minimization resumed as described above. These protocols are our standards of care in the event of rejection, whether we use the rATG induction approach with steroid-free Tacrolimus, or Tacrolimus with steroids.
  3. Laboratory tests per clinical protocol. The clinical standard of care will be followed in performing post-LTx monitoring labs consisting of complete blood count with differential count, serum sodium, potassium, chloride, bicarbonate, BUN, creatinine and glucose, and liver function tests consisting of Total bilirubin, aspartate alanine transaminase (ALT), aspartate glutamine transaminase (AST), and glutamyl galactosyl transaminase (GGT), and TAC whole blood concentrations. These laboratory tests are performed at least weekly in the first and second months, twice monthly in month 3, and monthly thereafter to the sixth month. The extra 5 ml needed for pharmacodynamic and pharmacogenomic studies is discussed further in items 5 and 6, and in Table 7.
  4. Pharmacogenomic studies will consist of characterizing 100,000 SNPs using the Infineum chip (Illumina, Dan Diego, CA) in DNA extracted from 3 ml of whole blood obtained pre-LTx, from each of 80 children.
  5. Table 7 (located in . Blood sampling strategy for: pharmacodynamic studies which will measure the lymphocyte subsets CD3+, CD4+, CD8+, CD19+, CD16/56+, αβ and γδ subsets as well as dendritic cells types 1 and 2 are shown in the following table (table 8). Concentration of rabbit IgG will also be measured by ELISA in 0.1 ml human plasma obtained from the same blood sample. Concentration of rabbit IgG associate with half-maximal depletion of each subset will be determined by Emax pharmacodynamic models based on Hill equations using the WINNONLIN software (Pharsight Inc, Palo Alto, CA.)

    This assay will be carried out in the laboratories of Dr. Rakesh Sindhi at the Rangos Research Center at 530 45th St, Pittsburgh, Pa 15201. Specimens will be stored in the transplant laboratory indefinitely, and will be under the control of the principal investigator, Dr. Rakesh Sindhi. The specimens will be stored to include assigned code numbers and the information linking these code numbers to the corresponding subjects' identities will be kept in a separate, secure location. The specimens will be shared with secondary investigators without identifiers.

  6. Liver biopsy will be performed per clinical standard of care, to rule out acute cellular rejection. No protocol biopsies will be performed.
  7. The treatment of rejection consists of steroids taper per standard of care. This standard includes methylprednisolone, total dose up to 30 mg/kg, or its equivalent.

    If this occurs, TAC whole blood concentrations will be titrated starting with 12-15 ng/ml during month 1 following the rejection event. Thereafter, the timing of downward titration of TAC concentrations will follow the schema outlined in item 3.

  8. Steroid-resistant rejection is defined as biopsy-proven acute cellular rejection not responsive to methylprednisolone or its equivalent.
  9. Follow-up for each patient is 12 months.
  10. All children will receive standard of care for antiviral and antipneumocystic prophylaxis
  Eligibility

Ages Eligible for Study:   up to 21 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population

Children 0- 21 years receiving liver transplantation

Criteria

Inclusion Criteria:

  • 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.

Exclusion Criteria:

  • 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01207141

Locations
United States, Pennsylvania
Children's Hospital of Pittsburgh of UPMC
Pittsburgh, Pennsylvania, United States, 15213
Sponsors and Collaborators
University of Pittsburgh
Investigators
Principal Investigator: Rakesh Sindhi, MD Children's Hospital of Pittsburgh of UPMC
  More Information

No publications provided

Responsible Party: Rakesh Sindhi, MD, Children's Hospital of Pittsburgh of UPMC
ClinicalTrials.gov Identifier: NCT01207141     History of Changes
Other Study ID Numbers: 0608006, 1R01AI073895-01
Study First Received: September 21, 2010
Last Updated: March 24, 2011
Health Authority: United States: Institutional Review Board

Keywords provided by University of Pittsburgh:
Liver Transplantation
Thymoglobulin
Rejection

ClinicalTrials.gov processed this record on October 19, 2014