Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT01207141 |
| Other study ID # |
0608006 |
| Secondary ID |
1R01AI073895-01 |
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
August 2006 |
| Est. completion date |
May 2019 |
Study information
| Verified date |
March 2023 |
| Source |
University of Pittsburgh |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
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.
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
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:
3. 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).
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 a SNP array
and 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 subsetsas well as dendritic cells types 1 and 2 are shown in the
following table (table 8). Concentration of rATG will also be measured in 0.1 ml human
plasma obtained from the same blood sample. Concentration associated with half-maximal
depletion of each subset will be determined by pharmacodynamic models based on Hill
equations.
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
