Trial Outcomes & Findings for Pharmacogenetic Trial of Tacrolimus After Pediatric Transplantation (NCT NCT01655563)

NCT ID: NCT01655563

Last Updated: 2019-12-13

Results Overview

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

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

75 participants

Primary outcome timeframe

From Baseline to 30 days post-dose

Results posted on

2019-12-13

Participant Flow

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.

Participant milestones

Participant milestones
Measure	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.	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
Overall Study STARTED	18	35
Overall Study COMPLETED	18	35
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Pharmacogenetic Trial of Tacrolimus After Pediatric Transplantation

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Standard Dosing Arm n=18 Participants 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.	Pharmacogenetic Arm n=35 Participants 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.	Total n=53 Participants Total of all reporting groups
Age, Continuous	1.3 years n=5 Participants	2.8 years n=7 Participants	2.1 years n=5 Participants
Sex: Female, Male Female	13 Participants n=5 Participants	16 Participants n=7 Participants	29 Participants n=5 Participants
Sex: Female, Male Male	5 Participants n=5 Participants	19 Participants n=7 Participants	24 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	4 Participants n=5 Participants	7 Participants n=7 Participants	11 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) White	12 Participants n=5 Participants	26 Participants n=7 Participants	38 Participants n=5 Participants
Race (NIH/OMB) More than one race	1 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment Canada	18 participants n=5 Participants	35 participants n=7 Participants	53 participants n=5 Participants

PRIMARY outcome

Timeframe: From Baseline to 30 days post-dose

Population: 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.

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

Outcome measures

Outcome measures
Measure	Standard Dosing Arm n=18 Participants 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.	Pharmacogenetic Arm n=35 Participants 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
Time to Achieve Therapeutic Tacrolimus Drug Concentrations	4.7 Days Interval 3.5 to 8.6	3.4 Days Interval 2.5 to 6.6

PRIMARY outcome

Timeframe: From Baseline to 30 days post-dose

Defined as two consecutive concentrations at least 48 hours apart in the therapeutic range without any changes in tacrolimus dose

Outcome measures

Outcome measures
Measure	Standard Dosing Arm n=18 Participants 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.	Pharmacogenetic Arm n=35 Participants 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
Time to Maintain Stable Therapeutic Trough Concentrations	NA days Median time could not be generated for the standard dosing arm because \<50% participants achieved stable therapeutic concentration during study follow-up leading to an insufficient number of participants with events.	18 days Interval 14.0 to 27.0

SECONDARY outcome

Timeframe: Over 30 days, +/- 3 days

The effect of pharmacogenetic dosing of tacrolimus for 48 hours on the frequency clinical adverse effects over 30±3 days.

Outcome measures

Outcome measures
Measure	Standard Dosing Arm n=18 Participants 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.	Pharmacogenetic Arm n=35 Participants 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
Clinical Adverse Events	71 adverse events	121 adverse events

Adverse Events

Standard Dosing Arm

Serious events: 1 serious events

Other events: 18 other events

Deaths: 0 deaths

Pharmacogenetic Arm

Serious events: 4 serious events

Other events: 34 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Standard Dosing Arm n=18 participants at risk 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.	Pharmacogenetic Arm n=35 participants at risk 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.
Cardiac disorders Pericardial hematoma	5.6% 1/18 • Number of events 1 • 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.	0.00% 0/35 • 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.
Gastrointestinal disorders Diarrhea	0.00% 0/18 • 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.	2.9% 1/35 • Number of events 1 • 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.
Hepatobiliary disorders Increased LFTs	0.00% 0/18 • 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.	2.9% 1/35 • Number of events 1 • 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.
Nervous system disorders Stroke	0.00% 0/18 • 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.	2.9% 1/35 • Number of events 1 • 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.
Renal and urinary disorders acute kidney injury	0.00% 0/18 • 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.	2.9% 1/35 • Number of events 1 • 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.
Respiratory, thoracic and mediastinal disorders Reactive airway disease	0.00% 0/18 • 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.	2.9% 1/35 • Number of events 1 • 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.
Vascular disorders IVC thrombosis	5.6% 1/18 • Number of events 1 • 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.	0.00% 0/35 • 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.

Other adverse events

Additional Information

Dr. Seema Mital

Hospital for Sick Children

Phone: 416-813-7418

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place