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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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. |
|
| 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 |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| Clinical Adverse Events | The effect of pharmacogenetic dosing of tacrolimus for 48 hours on the frequency clinical adverse effects over 30±3 days. | Over 30 days, +/- 3 days |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Seema Mital, MD | The Hospital for Sick Children | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| The Hospital for Sick Children | Toronto | Ontario | M5G 1X8 | Canada |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 30178515 | Result | 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. |
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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.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | 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 |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
53 patients were randomized, 35 to the pharmacogenetic arm (6 CYP3A5 expressors, 29 CYP3A5 non-expressors) and 18 to the standard dosing arm.
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Age at transplant was collected |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Time to Achieve Therapeutic Tacrolimus Drug Concentrations | The primary outcome (efficacy) was time to achieve therapeutic tacrolimus trough concentrations | 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. | Posted | Median | Inter-Quartile Range | Days | From Baseline to 30 days post-dose |
|
Baseline to 30 days post transplant
AEs were classified by intensity, severity, relationship to investigational agent, expectedness of the event, treatment or action taken, and clinical outcome. All serious, unexpected adverse drug reactions to the study medication were reported to Health Canada within 15 calendar days or for death or life-threatening events, within 7 calendar days. A copy of any serious, unexpected adverse drug reaction reports was sent to the Data and Safety Monitoring Committee.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Pericardial hematoma | Cardiac disorders | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Hypertension | Vascular disorders | Systematic Assessment |
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.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Seema Mital | Hospital for Sick Children | 416-813-7418 | 207418 | seema.mital@sickkids.ca |
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| ID | Term |
|---|---|
| D016559 | Tacrolimus |
| ID | Term |
|---|---|
| D018942 | Macrolides |
| D007783 | Lactones |
| D009930 | Organic Chemicals |
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|
|
| BG001 | 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. |
| BG002 | Total | Total of all reporting groups |
| Median |
| Inter-Quartile Range |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 | 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 |
|
|
| 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 | 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. | Posted | Median | Inter-Quartile Range | days | From Baseline to 30 days post-dose |
|
|
|
| Secondary | Clinical Adverse Events | The effect of pharmacogenetic dosing of tacrolimus for 48 hours on the frequency clinical adverse effects over 30±3 days. | 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. | Posted | Number | adverse events | Over 30 days, +/- 3 days |
|
|
|
| 0 |
| 18 |
| 1 |
| 18 |
| 18 |
| 18 |
| EG001 | 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. | 0 | 35 | 4 | 35 | 34 | 35 |
| Diarrhea | Gastrointestinal disorders | Systematic Assessment |
|
| Increased LFTs | Hepatobiliary disorders | Systematic Assessment |
|
| Stroke | Nervous system disorders | Systematic Assessment |
|
| acute kidney injury | Renal and urinary disorders | Systematic Assessment |
|
| Reactive airway disease | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| IVC thrombosis | Vascular disorders | Systematic Assessment |
|
| Superficial thrombophlebitis | Vascular disorders | Systematic Assessment |
|
| Arrthythmia | Cardiac disorders | Systematic Assessment |
|
| Pericardial effusion | Cardiac disorders | Systematic Assessment |
|
| Anemia | Blood and lymphatic system disorders | Systematic Assessment |
|
| Neutropenia | Blood and lymphatic system disorders | Systematic Assessment |
|
| Neutrophilia | Blood and lymphatic system disorders | Systematic Assessment |
|
| Thrombocytopenia | Blood and lymphatic system disorders | Systematic Assessment |
|
| Abdominal pain | Gastrointestinal disorders | Systematic Assessment |
|
| Diarrhea | Gastrointestinal disorders | Systematic Assessment |
|
| Acute kidney injury | Renal and urinary disorders | Systematic Assessment |
|
| Proteinuria | Renal and urinary disorders | Systematic Assessment |
|
| Atelectasis | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Pleural effusion | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Pneumothorax | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Pulmonary edema | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Respiratory distress | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| irritability | Psychiatric disorders | Systematic Assessment |
|
| Seizure | Nervous system disorders | Systematic Assessment |
|
| Tremor | Nervous system disorders | Systematic Assessment |
|
| Rash | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Viremia | Infections and infestations | Systematic Assessment |
|
| Urinary tract infection | Infections and infestations | Systematic Assessment |
|
| Abdominal infection | Infections and infestations | Systematic Assessment |
|
| Lung infection | Infections and infestations | Systematic Assessment |
|
| Allergic reaction | Immune system disorders | Systematic Assessment |
|
| Rejection/ suspected rejection | Immune system disorders | Systematic Assessment |
|
| Hyperglycemia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Hypomagnesemia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Blood tacrolimus level increased | Investigations | Systematic Assessment |
|
| Alanine aminotransferase and/or aspartate aminotransferase increased | Investigations | Systematic Assessment |
|
| Postoperative thoracic procedure complication | Injury, poisoning and procedural complications | Systematic Assessment |
|
| Fever | General disorders | Systematic Assessment |
|
| Edema face/limbs/ trunk | General disorders | Systematic Assessment |
|
| pain in extremity | General disorders | Systematic Assessment |
|
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