Pharmacogenetic Trial of Tacrolimus After Pediatric Transplantation

NCT01655563 | Completed Phase 2 Results DMC

• 1 other identifier: 1000026524
• Study Type: interventional
• Target: 75
• Locations: 1 country
• Sites: 1

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

Outcome Measures

Primary Outcomes (2)

• Time to Achieve Therapeutic Tacrolimus Drug Concentrations

  The primary outcome (efficacy) was time to achieve therapeutic tacrolimus trough concentrations

  From Baseline to 30 days post-dose

• 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

  From Baseline to 30 days post-dose

Secondary Outcomes (1)

• Clinical Adverse Events

  Over 30 days, +/- 3 days

Study Arms (2)

Standard Dosing Arm

ACTIVE COMPARATOR

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.

Drug: Tacrolimus

Pharmacogenetic Arm

EXPERIMENTAL

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

Drug: Tacrolimus

Interventions

Tacrolimus 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.

Also known as: Prograf

Pharmacogenetic Arm; Standard Dosing Arm

Eligibility Criteria

• Age: 1 Day - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• The Hospital for Sick Children: lead

Study Sites (1)

The Hospital for Sick Children

Toronto, Ontario, M5G 1X8, Canada

Location

Related Publications (1)

• 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.

  PMID: 30178515 RESULT

MeSH Terms

Interventions

Tacrolimus

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals

Limitations and Caveats

The current trial was a pilot trial for feasibility, safety and preliminary efficacy. It was not powered to study confounding influence of other recipient factors and of donor genotype on outcomes.

Results Point of Contact

• Title: Dr. Seema Mital
• Organization: Hospital for Sick Children

seema.mital@sickkids.ca

416-813-7418

Study Officials

• Seema Mital, MD

  The Hospital for Sick Children

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Staff Cardiologist

Study Record Dates

• First Submitted: July 27, 2012
• First Posted: August 2, 2012
• Study Start: September 1, 2011
• Primary Completion: February 1, 2016
• Study Completion: February 1, 2016
• Last Updated: December 13, 2019
• Results First Posted: August 28, 2019

Record last verified: 2019-11

Locations

CA (1)