Pharmacogenetic Trial of Tacrolimus After Pediatric Transplantation

This study is currently recruiting participants.
Verified July 2013 by The Hospital for Sick Children
Sponsor:
Information provided by (Responsible Party):
Seema Mital, The Hospital for Sick Children
ClinicalTrials.gov Identifier:
NCT01655563
First received: July 27, 2012
Last updated: July 25, 2013
Last verified: July 2013
  Purpose

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.


Condition Intervention Phase
Heart Transplantation
Lung Transplantation
Kidney Transplantation
Liver Transplantation
Intestinal Transplantation
Drug: Tacrolimus
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Pharmacogenetic Trial of Tacrolimus Dosing After Pediatric Transplantation

Resource links provided by NLM:


Further study details as provided by The Hospital for Sick Children:

Primary Outcome Measures:
  • Time to achieve therapeutic Tacrolimus drug concentrations [ Time Frame: From Baseline to 14 days post-dose ] [ Designated as safety issue: No ]
    The primary objective of this study is to assess the effect of pharmacogenetic starting dose for tacrolimus for 48 hours on achieving and maintaining therapeutic tacrolimus drug concentrations during 14-day follow-ups.


Secondary Outcome Measures:
  • Frequency of Renal dysfunction [ Time Frame: Over 30 days, +/- 3 days ] [ Designated as safety issue: Yes ]
    The effect of pharmacogenetic dosing of tacrolimus for 48 hours on the frequency of renal dysfunction over 30±3 days.

  • Frequency of rejection [ Time Frame: Over 30 days, +/- 3 days ] [ Designated as safety issue: Yes ]
    The effect of pharmacogenetic dosing of tacrolimus for 48 hours on the frequency of rejection over 30±3 days.

  • Clinical adverse events [ Time Frame: Over 30 days, +/- 3 days ] [ Designated as safety issue: Yes ]
    The effect of pharmacogenetic dosing of tacrolimus for 48 hours on the frequency clinical adverse effects over 30±3 days.


Estimated Enrollment: 60
Study Start Date: September 2011
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: 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.
Drug: 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.
Other Name: Prograf
Experimental: 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.
Drug: 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.
Other Name: Prograf

  Eligibility

Ages Eligible for Study:   up to 18 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age < 18 years old
  • Listed for heart, lung, kidney, liver or intestinal 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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01655563

Contacts
Contact: Seema Mital (416)813-7418 seema.mital@sickkids.ca

Locations
Canada, Ontario
The Hospital for Sick Children Recruiting
Toronto, Ontario, Canada, M5G 1X8
Contact: Seema Mital, MD    (416)813-7418    seema.mital@sickkids.ca   
Sub-Investigator: Rulan Parekh, MD         
Sub-Investigator: Binita Kamath, MD         
Sub-Investigator: Hartmut Grasemann, MD         
Principal Investigator: Seema Mital, MD         
Sponsors and Collaborators
The Hospital for Sick Children
Investigators
Principal Investigator: Seema Mital, MD The Hospital for Sick Children
  More Information

No publications provided

Responsible Party: Seema Mital, Staff Cardiologist, The Hospital for Sick Children
ClinicalTrials.gov Identifier: NCT01655563     History of Changes
Other Study ID Numbers: 1000026524
Study First Received: July 27, 2012
Last Updated: July 25, 2013
Health Authority: Canada: Health Canada

Keywords provided by The Hospital for Sick Children:
Transplant
Pediatrics
Tacrolimus
Prograf

Additional relevant MeSH terms:
Tacrolimus
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on April 14, 2014