A Phase 2 interventional study of Tacrolimus in Heart Transplantation, Liver Transplantation and Kidney Transplantation, sponsored by The Hospital for Sick Children. Completed at 1 site in Canada. Open to participants aged 1 Day to 18 Years. Per ClinicalTrials.gov, last updated 2019-12-13.
Sponsored by The Hospital for Sick Children · Phase 2, Interventional, and Treatment
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.
The Hospital for Sick Children is the lead sponsor of 568 studies on the registry; 81 are open to participants now.
Of its 7 completed or terminated interventional studies of FDA-regulated products, 0 (0%) have results posted.
Counted across the registry records on this site, refreshed daily.
Exclusion Criteria:
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
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
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
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
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
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
| Milestone | Standard Dosing Arm | Pharmacogenetic Arm |
|---|---|---|
| Started | 18 | 35 |
| Completed | 18 | 35 |
| Not completed | 0 | 0 |
The primary outcome (efficacy) was time to achieve therapeutic tacrolimus trough concentrations
| Days | Standard Dosing Arm | Pharmacogenetic Arm |
|---|---|---|
| Time to Achieve Therapeutic Tacrolimus Drug Concentrations | 4.7 (3.5 to 8.6) | 3.4 (2.5 to 6.6) |
Defined as two consecutive concentrations at least 48 hours apart in the therapeutic range without any changes in tacrolimus dose
| days | Standard Dosing Arm | Pharmacogenetic Arm |
|---|---|---|
| Time to Maintain Stable Therapeutic Trough Concentrations | NA (NA to NA) | 18 (14 to 27) |
The effect of pharmacogenetic dosing of tacrolimus for 48 hours on the frequency clinical adverse effects over 30±3 days.
| adverse events | Standard Dosing Arm | Pharmacogenetic Arm |
|---|---|---|
| Clinical Adverse Events | 71 | 121 |
Collected over Baseline to 30 days post transplant. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Standard Dosing Arm | 0/18 (0%) | 1/18 (5.6%) | 18/18 (100%) |
| Pharmacogenetic Arm | 0/35 (0%) | 4/35 (11.4%) | 34/35 (97.1%) |
| Event | Standard Dosing Arm | Pharmacogenetic Arm |
|---|---|---|
| Pericardial hematomaCardiac disorders | 1/18 | 0/35 |
| IVC thrombosisVascular disorders | 1/18 | 0/35 |
| DiarrheaGastrointestinal disorders | 0/18 | 1/35 |
| Increased LFTsHepatobiliary disorders | 0/18 | 1/35 |
| StrokeNervous system disorders | 0/18 | 1/35 |
| acute kidney injuryRenal and urinary disorders | 0/18 | 1/35 |
| Reactive airway diseaseRespiratory, thoracic and mediastinal disorders | 0/18 | 1/35 |
| Event | Standard Dosing Arm | Pharmacogenetic Arm |
|---|---|---|
| HypertensionVascular disorders | 10/18 | 15/35 |
| AnemiaBlood and lymphatic system disorders | 5/18 | 4/35 |
| Acute kidney injuryRenal and urinary disorders | 4/18 | 4/35 |
| Allergic reactionImmune system disorders | 4/18 | 1/35 |
| Rejection/ suspected rejectionImmune system disorders | 4/18 | 3/35 |
| Urinary tract infectionInfections and infestations | 0/18 | 6/35 |
| DiarrheaGastrointestinal disorders | 3/18 | 5/35 |
| RashSkin and subcutaneous tissue disorders | 1/18 | 5/35 |
| ArrthythmiaCardiac disorders | 2/18 | 4/35 |
| Alanine aminotransferase and/or aspartate aminotransferase increasedInvestigations | 0/18 | 4/35 |
53 patients were randomized, 35 to the pharmacogenetic arm (6 CYP3A5 expressors, 29 CYP3A5 non-expressors) and 18 to the standard dosing arm.
| Age, Continuous(years) | Standard Dosing Arm | Pharmacogenetic Arm | Total |
|---|---|---|---|
| Median | 1.3 (0.8 to 5.9) | 2.8 (0.7 to 13.5) | 2.1 (0.75 to 8.0) |
| Sex: Female, Male(Participants) | Standard Dosing Arm | Pharmacogenetic Arm | Total |
|---|---|---|---|
| Female | 13 | 16 | 29 |
| Male | 5 | 19 | 24 |
| Race (NIH/OMB)(Participants) | Standard Dosing Arm | Pharmacogenetic Arm | Total |
|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 |
| Asian | 4 | 7 | 11 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 |
| Black or African American | 1 | 0 | 1 |
| White | 12 | 26 | 38 |
| More than one race | 1 | 2 | 3 |
| Unknown or Not Reported | 0 | 0 | 0 |
| Region of Enrollment(participants) | Standard Dosing Arm | Pharmacogenetic Arm | Total |
|---|---|---|---|
| Canada | 18 | 35 | 53 |
This study is completed, as verified in Nov 2019. You cannot join it, but the record below documents what was studied.
Get an email when the registry record changes — status, dates, results — or when someone posts here.
Sign in to followQuestions and observations about this study, from anyone following it. Not medical advice, and not a channel to the study team — their contact details are on the registry record.
Sign in to join the discussion. Reading takes no account; posting does. You choose a display name, and a pseudonym is the default.
Nothing here yet. If you are running this trial, taking part in it, or weighing whether to, this is the place to say so.
The Hospital for Sick Children