Pharmacogenetic Trial of Tacrolimus After Pediatric Transplantation

NCT ID: NCT01655563

Last Updated: 2019-12-13

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 75 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-09-30
• Study Completion Date: 2016-02-29

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.

Conditions

Heart Transplantation; Liver Transplantation; Kidney Transplantation

Keywords

Transplant; Pediatrics; Tacrolimus; Prograf

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

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.

Group Type: ACTIVE_COMPARATOR

Tacrolimus

Intervention Type: DRUG

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.

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. All doses recommended represent clinically acceptable and safe dose ranges used at our institution.

CYP3A5 non-expressor starting dose:

Greater than 6 years of age - 0.075 mg/kg/dose q12 hours; Less than or equal to 6 years of age - 0.1 mg/kg/dose q12 hours

CYP3A5 expressor starting dose:

Greater than 6 years of age - 0.15 mg/kg/dose q12 hours; Less than or equal to 6 years of age - 0.2 mg/kg/dose q12 hours

Group Type: EXPERIMENTAL

Tacrolimus

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: DRUG

Other Intervention Names

Prograf

Eligibility Criteria

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

• Minimum Eligible Age: 1 Day
• Maximum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

The Hospital for Sick Children

OTHER

Sponsor Role: lead

Responsible Party

Seema Mital

Staff Cardiologist

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Seema Mital, MD

Role: PRINCIPAL_INVESTIGATOR

The Hospital for Sick Children

Locations

The Hospital for Sick Children

Toronto, Ontario, Canada

Countries

Canada

References

Min S, Papaz T, Lafreniere-Roula M, Nalli N, Grasemann H, Schwartz SM, Kamath BM, Ng V, Parekh RS, Manlhiot C, Mital S. A randomized clinical trial of age and genotype-guided tacrolimus dosing after pediatric solid organ transplantation. Pediatr Transplant. 2018 Nov;22(7):e13285. doi: 10.1111/petr.13285. Epub 2018 Sep 3.

Reference Type: RESULT

PMID: 30178515 (View on PubMed)

Other Identifiers

1000026524

Identifier Type: -

Identifier Source: org_study_id