Heart Transplantation, Kidney Transplantation, Liver Transplantation
Conditions
Keywords
Transplant, Pediatrics, Tacrolimus, Prograf
Brief summary
Tacrolimus is a standard and widely used maintenance immunosuppressive agent after solid organ transplantation.The purpose of this trial is to determine if dosing of tacrolimus through genetics will help in early attainment and maintenance of the correct dosage level in the early post-transplant period. This pilot dose-finding trial will help to determine a dosing strategy guided by genotypes and age for solid organ transplant recipients that will be further validated through a multi-centre trial as an immediate next step. The study hypothesizes that dosage levels determined through age and genotype will be attained faster and more accurately than the standard dosing procedures in the 14-days after the transplant. Further, this study hypothesizes that a genotype and age dosing strategy will cause a faster recovery (tested through the kidneys' ability to clear creatine from the blood) and result in lower frequencies of adverse effects and rejection of the transplant.
Interventions
DRUGTacrolimus
Tacrolimus, a calcineurin inhibitor, is the commonest immunosuppressive agent used for maintenance immunosuppression after solid organ transplantation. The mechanism of action involves binding to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin and calcineurin is then formed and the phosphatase activity of calcineurin is inhibited. This prevents the generation of nuclear factor of activated T-cells, a nuclear component, resulting in inhibition of transcription of lymphokines (interleukin-2, γ-interferon). The net result is the inhibition of T-lymphocyte activation.Tacrolimus is metabolized primarily by the CYP3A enzymes in the liver particularly the CYP3A5.
Sponsors
The Hospital for Sick Children
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
1 Days to 18 Years
Healthy volunteers
No
Inclusion criteria
* Age \< 18 years old * Assessed and/or listed for heart, kidney, liver transplantation * Planned oral or enteral maintenance immunosuppression with tacrolimus post transplant * Informed consent of legal guardian
Exclusion criteria
* Contra-indications to oral or enteral tacrolimus * Co-morbidities that preclude standard dosing e.g. significant renal or hepatic insufficiency * Participation in other investigational drug trials within 30 days of study initiation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Achieve Therapeutic Tacrolimus Drug Concentrations | From Baseline to 30 days post-dose | The primary outcome (efficacy) was time to achieve therapeutic tacrolimus trough concentrations |
| Time to Maintain Stable Therapeutic Trough Concentrations | From Baseline to 30 days post-dose | Defined as two consecutive concentrations at least 48 hours apart in the therapeutic range without any changes in tacrolimus dose |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Adverse Events | Over 30 days, +/- 3 days | The effect of pharmacogenetic dosing of tacrolimus for 48 hours on the frequency clinical adverse effects over 30±3 days. |
Countries
Canada
Participant flow
Pre-assignment details
22 participants were excluded after enrollment due to the following reasons: 8 developed ineligibility criteria for randomization, 2 withdrew, 4 were delisted for transplant, 4 died and 4 had still not received a transplant.
Participants by arm
| Arm | Count |
|---|---|
| Standard Dosing Arm Patients in the standard arm will receive standard starting dose of tacrolimus that is clinically used i.e. 0.1 mg/kg/dose twice a day.
Tacrolimus: Tacrolimus, a calcineurin inhibitor, is the commonest immunosuppressive agent used for maintenance immunosuppression after solid organ transplantation. The mechanism of action involves binding to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin and calcineurin is then formed and the phosphatase activity of calcineurin is inhibited. This prevents the generation of nuclear factor of activated T-cells, a nuclear component, resulting in inhibition of transcription of lymphokines (interleukin-2, γ-interferon). The net result is the inhibition of T-lymphocyte activation.Tacrolimus is metabolized primarily by the CYP3A enzymes in the liver particularly the CYP3A5. | 18 |
| Pharmacogenetic Arm Patients in the pharmacogenetic arm will receive a starting dose that is assigned based on age and CYP3A5 expressor status. Patients that are CYP3A5 expressors will receive the higher end of the dose range compared to non-expressors as described in Table 1. All doses recommended in Table 1 represent clinically acceptable and safe dose ranges used at our institution. This proposed pharmacogenetic dosing algorithm is derived from a validated algorithm published in pediatric renal transplant patients. | 35 |
| Total | 53 |
Baseline characteristics
| Characteristic | Standard Dosing Arm | Total | Pharmacogenetic Arm |
|---|---|---|---|
| Age, Continuous | 1.3 years | 2.1 years | 2.8 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 11 Participants | 7 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 12 Participants | 38 Participants | 26 Participants |
| Region of Enrollment Canada | 18 participants | 53 participants | 35 participants |
| Sex: Female, Male Female | 13 Participants | 29 Participants | 16 Participants |
| Sex: Female, Male Male | 5 Participants | 24 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 18 | 0 / 35 |
| other Total, other adverse events | 18 / 18 | 34 / 35 |
| serious Total, serious adverse events | 1 / 18 | 4 / 35 |
Outcome results
Primary
Time to Achieve Therapeutic Tacrolimus Drug Concentrations
The primary outcome (efficacy) was time to achieve therapeutic tacrolimus trough concentrations
Time frame: From Baseline to 30 days post-dose
Population: The overall number of participants analyzed was 53. A total of 7 patients (4 from genotype-guided dosing arm and 3 from standard dosing arm) began but did not complete 36- 48 hours of study dosing and were analyzed in their original assigned groups in an intention-to- treat model.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Standard Dosing Arm | Time to Achieve Therapeutic Tacrolimus Drug Concentrations | 4.7 Days |
| Pharmacogenetic Arm | Time to Achieve Therapeutic Tacrolimus Drug Concentrations | 3.4 Days |
Primary
Time to Maintain Stable Therapeutic Trough Concentrations
Defined as two consecutive concentrations at least 48 hours apart in the therapeutic range without any changes in tacrolimus dose
Time frame: From Baseline to 30 days post-dose
Population: The overall number of participants analyzed was 53. A total of 7 patients (4 from genotype-guided dosing arm and 3 from standard dosing arm) began but did not complete 36- 48 hours of study dosing and were analyzed in their original assigned groups in an intention-to- treat model.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Standard Dosing Arm | Time to Maintain Stable Therapeutic Trough Concentrations | NA days |
| Pharmacogenetic Arm | Time to Maintain Stable Therapeutic Trough Concentrations | 18 days |
Secondary
Clinical Adverse Events
The effect of pharmacogenetic dosing of tacrolimus for 48 hours on the frequency clinical adverse effects over 30±3 days.
Time frame: Over 30 days, +/- 3 days
Population: The overall number of participants analyzed was 53. A total of 7 patients (4 from genotype-guided dosing arm and 3 from standard dosing arm) began but did not complete 36- 48 hours of study dosing and were analyzed in their original assigned groups in an intention-to- treat model.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Standard Dosing Arm | Clinical Adverse Events | 71 adverse events |
| Pharmacogenetic Arm | Clinical Adverse Events | 121 adverse events |