Trial Outcomes & Findings for A Study of a Modified-Release Tacrolimus Based Immunosuppression Regimen in Stable Pediatric Liver Transplant Patients (NCT NCT00282256)

Last Updated: 2013-10-17

Results Overview

The area under the concentration-time curve was calculated from whole blood tacrolimus concentrations for both tacrolimus and tacrolimus MR at steady state using the linear trapezoidal rule. The AUC0-24 for tacrolimus was calculated as the sum of the AUC0-12 and AUC 12-24 for the morning and afternoon doses.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

19 participants

Primary outcome timeframe

For tacrolimus, Day 7 at 0 (pre-dose), 0.5, 1, 2, 3, 6, 8, 12 (pre-dose), 13, 14, 15, 18, 20, and 24 hours. For tacrolimus MR, Day 14 at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 15, 18, 20, and 24 hours post-dose.

Results posted on

2013-10-17

Participant Flow

Stable liver transplant recipients aged 12 years or younger receiving tacrolimus based immunosuppression regimen.

Pharmacokinetic (PK) treatment period was 14 days. Participants who completed the PK period were eligible to continue receiving tacrolimus MR in the extended treatment period, from Day 15 through Month 54.

Participant milestones

Participant milestones
Measure	Tacrolimus MR Participants continued to receive their stable twice daily dose of tacrolimus twice daily on Day 1 through Day 7 and on Day 8 were converted to tacrolimus modified release (MR) once-daily in the morning for 7 days on a 1:1 (mg:mg) basis for their total daily dose. Patients who completed the 2-week pharmacokinetic treatment period were eligible to continue receiving tacrolimus MR as part of the extension treatment period of the study. The extended treatment period began on Day 15 and consisted of a single dose of tacrolimus MR once every morning through the end of the study.
Pharmacokinetic Treatment Period STARTED	19
Pharmacokinetic Treatment Period Received Tacrolimus	19
Pharmacokinetic Treatment Period Received Tacrolimus MR	18
Pharmacokinetic Treatment Period COMPLETED	18
Pharmacokinetic Treatment Period NOT COMPLETED	1
Extension Treatment Period STARTED	18
Extension Treatment Period COMPLETED	16
Extension Treatment Period NOT COMPLETED	2

Reasons for withdrawal

Reasons for withdrawal
Measure	Tacrolimus MR Participants continued to receive their stable twice daily dose of tacrolimus twice daily on Day 1 through Day 7 and on Day 8 were converted to tacrolimus modified release (MR) once-daily in the morning for 7 days on a 1:1 (mg:mg) basis for their total daily dose. Patients who completed the 2-week pharmacokinetic treatment period were eligible to continue receiving tacrolimus MR as part of the extension treatment period of the study. The extended treatment period began on Day 15 and consisted of a single dose of tacrolimus MR once every morning through the end of the study.
Pharmacokinetic Treatment Period Poor venous access	1
Extension Treatment Period Adverse Event	2

Baseline Characteristics

A Study of a Modified-Release Tacrolimus Based Immunosuppression Regimen in Stable Pediatric Liver Transplant Patients

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Tacrolimus MR n=18 Participants Participants continued to receive their stable twice daily dose of tacrolimus twice daily on Day 1 through Day 7 and on Day 8 were converted to tacrolimus modified release (MR) once-daily in the morning for 7 days on a 1:1 (mg:mg) basis for their total daily dose. Patients who completed the 2-week pharmacokinetic treatment period were eligible to continue receiving tacrolimus MR as part of the extension treatment period of the study. The extended treatment period began on Day 15 and consisted of a single dose of tacrolimus MR once every morning through the end of the study.
Age Continuous	8.6 years STANDARD_DEVIATION 2.28 • n=5 Participants
Sex: Female, Male Female	13 Participants n=5 Participants
Sex: Female, Male Male	5 Participants n=5 Participants
Reason for End Stage Liver Disease Biliary Atresia	5 participants n=5 Participants
Reason for End Stage Liver Disease Acute Fulminant (Hepatic) Failure	2 participants n=5 Participants
Reason for End Stage Liver Disease Fulminant Hepatitis	2 participants n=5 Participants
Reason for End Stage Liver Disease Tyrosinemia	2 participants n=5 Participants
Reason for End Stage Liver Disease Unknown	1 participants n=5 Participants
Reason for End Stage Liver Disease Other	6 participants n=5 Participants
Type of Current Transplant Whole Cadaver	10 participants n=5 Participants
Type of Current Transplant Split Cadaver	4 participants n=5 Participants
Type of Current Transplant Living Donor	4 participants n=5 Participants
Re-transplant No	16 participants n=5 Participants
Re-transplant Yes	2 participants n=5 Participants

PRIMARY outcome

Timeframe: For tacrolimus, Day 7 at 0 (pre-dose), 0.5, 1, 2, 3, 6, 8, 12 (pre-dose), 13, 14, 15, 18, 20, and 24 hours. For tacrolimus MR, Day 14 at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 15, 18, 20, and 24 hours post-dose.

Population: The pharmacokinetic evaluable set was defined as all patients who completed both pharmacokinetic profiles: one for tacrolimus, and one for tacrolimus MR. A complete pharmacokinetic profile was considered to be a profile that was adequate to determine AUC0-24, Cmax, and Cmin.

Outcome measures

Outcome measures
Measure	Tacrolimus MR n=18 Participants Participants continued to receive their stable twice daily dose of tacrolimus twice daily on Day 1 through Day 7 and on Day 8 were converted to tacrolimus modified release (MR) once-daily in the morning for 7 days on a 1:1 (mg:mg) basis for their total daily dose. Patients who completed the 2-week pharmacokinetic treatment period were eligible to continue receiving tacrolimus MR as part of the extension treatment period of the study. The extended treatment period began on Day 15 and consisted of a single dose of tacrolimus MR once every morning through the end of the study.
Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) for Tacrolimus Day 7: Tacrolimus	198.2 ng*hr/mL Standard Deviation 99.2
Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) for Tacrolimus Day 14: Tacrolimus MR	193.0 ng*hr/mL Standard Deviation 78.0

PRIMARY outcome

Timeframe: Day 7 at 12 hours post-dose (tacrolimus) and Day 14 at 24 hours post-dose (tacrolimus MR).

Population: Pharmacokinetic evaluable set.

The trough (minimum) concentration of tacrolimus determined from the tacrolimus whole blood concentration value at the 12 hour post-dose concentration based on the evening dose (i.e., the 8 am concentration) for tacrolimus and the 24-hour time point post-dose for tacrolimus MR, prior to receiving the next dose.

Outcome measures

Outcome measures
Measure	Tacrolimus MR n=18 Participants Participants continued to receive their stable twice daily dose of tacrolimus twice daily on Day 1 through Day 7 and on Day 8 were converted to tacrolimus modified release (MR) once-daily in the morning for 7 days on a 1:1 (mg:mg) basis for their total daily dose. Patients who completed the 2-week pharmacokinetic treatment period were eligible to continue receiving tacrolimus MR as part of the extension treatment period of the study. The extended treatment period began on Day 15 and consisted of a single dose of tacrolimus MR once every morning through the end of the study.
Minimum Observed Concentration of Tacrolimus (Cmin) Day 7: Tacrolimus	5.9 ng/mL Standard Deviation 2.9
Minimum Observed Concentration of Tacrolimus (Cmin) Day 14: Tacrolimus MR	5.3 ng/mL Standard Deviation 2.6

PRIMARY outcome

Timeframe: From enrollment until the end of study (up to 54 months).

Population: The Modified Full Analysis Set included all patients who took at least 1 dose of tacrolimus MR formulation during the extended treatment period.

Patient survival was defined as any participant known to be alive at the end of the study.

Outcome measures

Outcome measures
Measure	Tacrolimus MR n=18 Participants Participants continued to receive their stable twice daily dose of tacrolimus twice daily on Day 1 through Day 7 and on Day 8 were converted to tacrolimus modified release (MR) once-daily in the morning for 7 days on a 1:1 (mg:mg) basis for their total daily dose. Patients who completed the 2-week pharmacokinetic treatment period were eligible to continue receiving tacrolimus MR as part of the extension treatment period of the study. The extended treatment period began on Day 15 and consisted of a single dose of tacrolimus MR once every morning through the end of the study.
Patient Survival	94.44 percentage of participants Interval 83.86 to 100.0

PRIMARY outcome

Timeframe: From enrollment until the end of study (up to 54 months).

Population: Modified full analysis set.

Graft survival was defined as any participant who did not meet the definition of graft loss, where graft loss was defined as graft failure (re-transplant) or participant death.

Outcome measures

Outcome measures
Measure	Tacrolimus MR n=18 Participants Participants continued to receive their stable twice daily dose of tacrolimus twice daily on Day 1 through Day 7 and on Day 8 were converted to tacrolimus modified release (MR) once-daily in the morning for 7 days on a 1:1 (mg:mg) basis for their total daily dose. Patients who completed the 2-week pharmacokinetic treatment period were eligible to continue receiving tacrolimus MR as part of the extension treatment period of the study. The extended treatment period began on Day 15 and consisted of a single dose of tacrolimus MR once every morning through the end of the study.
Graft Survival	94.44 percentage of participants Interval 83.86 to 100.0

SECONDARY outcome

Population: Pharmacokinetic evaluable set.

The maximum concentration was calculated from whole blood tacrolimus concentrations for both the tacrolimus and tacrolimus MR at steady state, without interpolation.

Outcome measures

Outcome measures
Measure	Tacrolimus MR n=18 Participants Participants continued to receive their stable twice daily dose of tacrolimus twice daily on Day 1 through Day 7 and on Day 8 were converted to tacrolimus modified release (MR) once-daily in the morning for 7 days on a 1:1 (mg:mg) basis for their total daily dose. Patients who completed the 2-week pharmacokinetic treatment period were eligible to continue receiving tacrolimus MR as part of the extension treatment period of the study. The extended treatment period began on Day 15 and consisted of a single dose of tacrolimus MR once every morning through the end of the study.
Maximum Observed Concentration of Tacrolimus (Cmax) Day 7: Tacrolimus	20.7 ng/mL Standard Deviation 13.3
Maximum Observed Concentration of Tacrolimus (Cmax) Day 14: Tacrolimus MR	15.2 ng/mL Standard Deviation 5.7

SECONDARY outcome

Population: Pharmacokinetic evaluable set.

Time to reach the first observed maximum concentration of tacrolimus was calculated from whole blood tacrolimus concentrations for both tacrolimus and tacrolimus MR at steady state, without interpolation.

Outcome measures

Outcome measures
Measure	Tacrolimus MR n=18 Participants Participants continued to receive their stable twice daily dose of tacrolimus twice daily on Day 1 through Day 7 and on Day 8 were converted to tacrolimus modified release (MR) once-daily in the morning for 7 days on a 1:1 (mg:mg) basis for their total daily dose. Patients who completed the 2-week pharmacokinetic treatment period were eligible to continue receiving tacrolimus MR as part of the extension treatment period of the study. The extended treatment period began on Day 15 and consisted of a single dose of tacrolimus MR once every morning through the end of the study.
Time to Maximum Observed Concentration of Tacrolimus (Tmax) Day 7: Tacrolimus	1.0 hours Interval 0.5 to 19.7
Time to Maximum Observed Concentration of Tacrolimus (Tmax) Day 14: Tacrolimus MR	2.0 hours Interval 0.9 to 6.0

SECONDARY outcome

Timeframe: From enrollment until the end of study (up to 54 months).

Population: Modified full analysis set.

Biopsy-confirmed acute rejection (BCAR) is defined as an episode of acute liver allograft rejection that was confirmed by biopsy results and was Banff grade ≥ I. Biopsies were graded by the pathologist at the clinical site according to the 1997 Banff criteria for grading of acute liver allograft rejection: Indeterminate: Portal inflammatory infiltrate that fails to meet the criteria for diagnosis of acute rejection; Grade I (Mild): Rejection infiltrate in a minority of the triads that is generally mild and confined within the portal spaces; Grade II (Moderate): Rejection infiltrate, expanding to most or all of the triads; Grade III (Severe): Rejection infiltrate, expanding to most or all of the triads, with spillover into periportal areas and moderate to severe perivenular inflammation that extends into the hepatic parenchyma and is associated with perivenular hepatocyte. necrosis

Outcome measures

Outcome measures
Measure	Tacrolimus MR n=18 Participants Participants continued to receive their stable twice daily dose of tacrolimus twice daily on Day 1 through Day 7 and on Day 8 were converted to tacrolimus modified release (MR) once-daily in the morning for 7 days on a 1:1 (mg:mg) basis for their total daily dose. Patients who completed the 2-week pharmacokinetic treatment period were eligible to continue receiving tacrolimus MR as part of the extension treatment period of the study. The extended treatment period began on Day 15 and consisted of a single dose of tacrolimus MR once every morning through the end of the study.
Percentage of Participants With Biopsy-confirmed Acute Rejection	16.67 percentage of participants

SECONDARY outcome

Timeframe: From enrollment until the end of study (up to 54 months).

Population: Participants in the modified full analysis set who died on study.

For participants who died on study, the median number of days from first dose of study drug to death due to any cause.

Outcome measures

Outcome measures
Measure	Tacrolimus MR n=1 Participants Participants continued to receive their stable twice daily dose of tacrolimus twice daily on Day 1 through Day 7 and on Day 8 were converted to tacrolimus modified release (MR) once-daily in the morning for 7 days on a 1:1 (mg:mg) basis for their total daily dose. Patients who completed the 2-week pharmacokinetic treatment period were eligible to continue receiving tacrolimus MR as part of the extension treatment period of the study. The extended treatment period began on Day 15 and consisted of a single dose of tacrolimus MR once every morning through the end of the study.
Time to Event for Patient Non-survival	1204.00 days Interval 1204.0 to 1204.0

SECONDARY outcome

Timeframe: From enrollment until the end of study (up to 54 months).

Population: Participants in the modified full analysis set with graft loss.

For participants with graft loss, the median number of days from the first dose of study drug to graft loss. Graft loss was defined as graft failure (re-transplant) or participant death.

Outcome measures

Outcome measures
Measure	Tacrolimus MR n=1 Participants Participants continued to receive their stable twice daily dose of tacrolimus twice daily on Day 1 through Day 7 and on Day 8 were converted to tacrolimus modified release (MR) once-daily in the morning for 7 days on a 1:1 (mg:mg) basis for their total daily dose. Patients who completed the 2-week pharmacokinetic treatment period were eligible to continue receiving tacrolimus MR as part of the extension treatment period of the study. The extended treatment period began on Day 15 and consisted of a single dose of tacrolimus MR once every morning through the end of the study.
Time to Event for Graft Non-survival	1203.00 days Interval 1203.0 to 1203.0

SECONDARY outcome

Timeframe: From enrollment until the end of study (up to 54 months).

Population: Participants in the modified full analysis set with a biopsy-confirmed acute rejection.

For participants with a biopsy-confirmed acute rejection (BCAR), the median number of days from the first dose of study drug to the date of biopsy confirmation. BCAR is defined as an episode of acute liver allograft rejection that was confirmed by biopsy results and was Banff grade ≥ I. Biopsies were graded by the clinical site pathologist according to the 1997 Banff criteria for grading acute liver allograft rejection: Indeterminate: Portal inflammatory infiltrate that fails to meet the criteria for diagnosis of acute rejection; Grade I: Rejection infiltrate in a minority of the triads that is generally mild and confined within the portal spaces; Grade II: Rejection infiltrate, expanding to most or all of the triads; Grade III: Rejection infiltrate, expanding to most or all of the triads, with spillover into periportal areas and moderate to severe perivenular inflammation that extends into the hepatic parenchyma and is associated with perivenular hepatocyte necrosis.

Outcome measures

Outcome measures
Measure	Tacrolimus MR n=3 Participants Participants continued to receive their stable twice daily dose of tacrolimus twice daily on Day 1 through Day 7 and on Day 8 were converted to tacrolimus modified release (MR) once-daily in the morning for 7 days on a 1:1 (mg:mg) basis for their total daily dose. Patients who completed the 2-week pharmacokinetic treatment period were eligible to continue receiving tacrolimus MR as part of the extension treatment period of the study. The extended treatment period began on Day 15 and consisted of a single dose of tacrolimus MR once every morning through the end of the study.
Time to First Biopsy-confirmed Acute Rejection	748.00 days Interval 729.0 to 773.0

SECONDARY outcome

Timeframe: From enrollment until the end of study (up to 54 months).

Population: Participants in the modified full analysis set with a biopsy-confirmed acute rejection.

Biopsy-confirmed acute rejection (BCAR) is defined as an episode of acute liver allograft rejection that was confirmed by biopsy results and was Banff grade ≥ I. Biopsies were graded by the clinical site pathologist according to the 1997 Banff criteria for grading of acute liver allograft rejection: Indeterminate: Portal inflammatory infiltrate that fails to meet the criteria for diagnosis of acute rejection; Grade I (Mild): Rejection infiltrate in a minority of the triads that is generally mild and confined within the portal spaces; Grade II (Moderate): Rejection infiltrate, expanding to most or all of the triads; Grade III (Severe): Rejection infiltrate, expanding to most or all of the triads, with spillover into periportal areas and moderate to severe perivenular inflammation that extends into the hepatic parenchyma and is associated with perivenular hepatocyte necrosis. For participants with more than one biopsy-confirmed acute rejection episode, the worst case grade is reported.

Outcome measures

Outcome measures
Measure	Tacrolimus MR n=3 Participants Participants continued to receive their stable twice daily dose of tacrolimus twice daily on Day 1 through Day 7 and on Day 8 were converted to tacrolimus modified release (MR) once-daily in the morning for 7 days on a 1:1 (mg:mg) basis for their total daily dose. Patients who completed the 2-week pharmacokinetic treatment period were eligible to continue receiving tacrolimus MR as part of the extension treatment period of the study. The extended treatment period began on Day 15 and consisted of a single dose of tacrolimus MR once every morning through the end of the study.
Grade of Biopsy-confirmed Acute Rejection Episodes Grade I	2 participants
Grade of Biopsy-confirmed Acute Rejection Episodes Grade II	1 participants
Grade of Biopsy-confirmed Acute Rejection Episodes Grade III	0 participants

SECONDARY outcome

Timeframe: From enrollment until the end of study (up to 54 months).

Population: Modified full analysis set.

Steroid-resistant rejection episodes were treated with anti-lymphocyte antibodies. If a participant had a histologically proven Banff Grade II or III rejection, they could be initiated on anti-lymphocyte antibody treatment per institutional practice.

Outcome measures

Outcome measures
Measure	Tacrolimus MR n=18 Participants Participants continued to receive their stable twice daily dose of tacrolimus twice daily on Day 1 through Day 7 and on Day 8 were converted to tacrolimus modified release (MR) once-daily in the morning for 7 days on a 1:1 (mg:mg) basis for their total daily dose. Patients who completed the 2-week pharmacokinetic treatment period were eligible to continue receiving tacrolimus MR as part of the extension treatment period of the study. The extended treatment period began on Day 15 and consisted of a single dose of tacrolimus MR once every morning through the end of the study.
Number of Participants Receiving Anti-lymphocyte Antibody Therapy for Acute Rejection	0 participants

SECONDARY outcome

Timeframe: From enrollment until the end of study (up to 54 months).

Population: Modified full analysis set.

This analysis includes rejection episodes that were either confirmed by biopsy by the clinical site pathologist or were clinically treated.

Outcome measures

Outcome measures
Measure	Tacrolimus MR n=18 Participants Participants continued to receive their stable twice daily dose of tacrolimus twice daily on Day 1 through Day 7 and on Day 8 were converted to tacrolimus modified release (MR) once-daily in the morning for 7 days on a 1:1 (mg:mg) basis for their total daily dose. Patients who completed the 2-week pharmacokinetic treatment period were eligible to continue receiving tacrolimus MR as part of the extension treatment period of the study. The extended treatment period began on Day 15 and consisted of a single dose of tacrolimus MR once every morning through the end of the study.
Number of Participants With Multiple Rejection Episodes	1 participants

SECONDARY outcome

Timeframe: From enrollment until the end of study (up to 54 months).

Population: Modified full analysis set.

A clinically treated acute rejection episode was any biopsy-confirmed or suspected rejection episode that was treated with immunosuppressive therapy.

Outcome measures

Outcome measures
Measure	Tacrolimus MR n=18 Participants Participants continued to receive their stable twice daily dose of tacrolimus twice daily on Day 1 through Day 7 and on Day 8 were converted to tacrolimus modified release (MR) once-daily in the morning for 7 days on a 1:1 (mg:mg) basis for their total daily dose. Patients who completed the 2-week pharmacokinetic treatment period were eligible to continue receiving tacrolimus MR as part of the extension treatment period of the study. The extended treatment period began on Day 15 and consisted of a single dose of tacrolimus MR once every morning through the end of the study.
Number of Participants With Clinically Treated Acute Rejection Episodes	3 participants

SECONDARY outcome

Timeframe: From enrollment until the end of study (up to 54 months).

Due to the low number of participants with biopsy-confirmed acute rejection episodes, chronic rejection was not analyzed.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From enrollment until the end of study (up to 54 months).

Treatment failure was defined as discontinuation of study drug for any reason. Due to discontinuation of the study by the sponsor, treatment failure was not analyzed.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From enrollment until the end of study (up to 54 months).

Population: Participants in the modified full analysis set with graft loss.

The primary reason for graft loss was recorded by the Investigator. Graft loss was defined as graft failure (re-transplant) or participant death.

Outcome measures

Outcome measures
Measure	Tacrolimus MR n=1 Participants Participants continued to receive their stable twice daily dose of tacrolimus twice daily on Day 1 through Day 7 and on Day 8 were converted to tacrolimus modified release (MR) once-daily in the morning for 7 days on a 1:1 (mg:mg) basis for their total daily dose. Patients who completed the 2-week pharmacokinetic treatment period were eligible to continue receiving tacrolimus MR as part of the extension treatment period of the study. The extended treatment period began on Day 15 and consisted of a single dose of tacrolimus MR once every morning through the end of the study.
Primary Reason for Graft Loss Recurrent disease	0 participants
Primary Reason for Graft Loss Death	1 participants

SECONDARY outcome

Timeframe: From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 54 months).

Population: Modified safety analysis set defined as all participants who took at least 1 dose of both tacrolimus and tacrolimus MR formulation during the pharmacokinetic period of the study.

An adverse event (AE) is defined as any reaction, side effect or other untoward medical occurrence, regardless of the relationship to study drug which occurred during the conduct of a clinical study. Clinically significant adverse changes in clinical status, routine laboratory studies or physical examinations were considered adverse events. A serious adverse event was any adverse event occurring at any dose that resulted in any of the following outcomes: * Death * Life-threatening adverse event * Inpatient hospitalization or prolongation of existing hospitalization * Persistent or significant disability or incapacity * Congenital abnormality or birth defect * Important medical event.

Outcome measures

Outcome measures
Measure	Tacrolimus MR n=18 Participants Participants continued to receive their stable twice daily dose of tacrolimus twice daily on Day 1 through Day 7 and on Day 8 were converted to tacrolimus modified release (MR) once-daily in the morning for 7 days on a 1:1 (mg:mg) basis for their total daily dose. Patients who completed the 2-week pharmacokinetic treatment period were eligible to continue receiving tacrolimus MR as part of the extension treatment period of the study. The extended treatment period began on Day 15 and consisted of a single dose of tacrolimus MR once every morning through the end of the study.
Safety as Assessed by Clinical Signs and Symptoms, Laboratory Parameters and Diagnostic Tests Any adverse event	12 participants
Safety as Assessed by Clinical Signs and Symptoms, Laboratory Parameters and Diagnostic Tests Any death	1 participants
Safety as Assessed by Clinical Signs and Symptoms, Laboratory Parameters and Diagnostic Tests Any serious adverse event	6 participants
Safety as Assessed by Clinical Signs and Symptoms, Laboratory Parameters and Diagnostic Tests Any AE leading to a change in study drug dose	3 participants
Safety as Assessed by Clinical Signs and Symptoms, Laboratory Parameters and Diagnostic Tests AE leading to study drug discontinuation	1 participants

Adverse Events

Tacrolimus MR

Serious events: 6 serious events

Other events: 11 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Tacrolimus MR n=18 participants at risk Participants continued to receive their stable twice daily dose of tacrolimus twice daily on Day 1 through Day 7 and on Day 8 were converted to tacrolimus modified release (MR) once-daily in the morning for 7 days on a 1:1 (mg:mg) basis for their total daily dose. Patients who completed the 2-week pharmacokinetic treatment period were eligible to continue receiving tacrolimus MR as part of the extension treatment period of the study. The extended treatment period began on Day 15 and consisted of a single dose of tacrolimus MR once every morning through the end of the study.
Infections and infestations Bacteraemia	5.6% 1/18 • From the first dose of tacrolimus MR through the last dose day plus 10 days (approximately 54 months). Adverse events are reported for the modified safety analysis set defined as all participants who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Infections and infestations Pneumonia mycoplasmal	5.6% 1/18 • From the first dose of tacrolimus MR through the last dose day plus 10 days (approximately 54 months). Adverse events are reported for the modified safety analysis set defined as all participants who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Infections and infestations Pneumonia streptococcal	5.6% 1/18 • From the first dose of tacrolimus MR through the last dose day plus 10 days (approximately 54 months). Adverse events are reported for the modified safety analysis set defined as all participants who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Infections and infestations Urinary tract infection	5.6% 1/18 • From the first dose of tacrolimus MR through the last dose day plus 10 days (approximately 54 months). Adverse events are reported for the modified safety analysis set defined as all participants who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Gastrointestinal disorders Abdominal pain	5.6% 1/18 • From the first dose of tacrolimus MR through the last dose day plus 10 days (approximately 54 months). Adverse events are reported for the modified safety analysis set defined as all participants who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Gastrointestinal disorders Gastroenteritis eosinophilic	5.6% 1/18 • From the first dose of tacrolimus MR through the last dose day plus 10 days (approximately 54 months). Adverse events are reported for the modified safety analysis set defined as all participants who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Hepatobiliary disorders Cholangitis	5.6% 1/18 • From the first dose of tacrolimus MR through the last dose day plus 10 days (approximately 54 months). Adverse events are reported for the modified safety analysis set defined as all participants who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Investigations Liver function test abnormal	5.6% 1/18 • From the first dose of tacrolimus MR through the last dose day plus 10 days (approximately 54 months). Adverse events are reported for the modified safety analysis set defined as all participants who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Musculoskeletal and connective tissue disorders Back pain	5.6% 1/18 • From the first dose of tacrolimus MR through the last dose day plus 10 days (approximately 54 months). Adverse events are reported for the modified safety analysis set defined as all participants who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Musculoskeletal and connective tissue disorders Neck pain	5.6% 1/18 • From the first dose of tacrolimus MR through the last dose day plus 10 days (approximately 54 months). Adverse events are reported for the modified safety analysis set defined as all participants who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.

Other adverse events

Other adverse events
Measure	Tacrolimus MR n=18 participants at risk Participants continued to receive their stable twice daily dose of tacrolimus twice daily on Day 1 through Day 7 and on Day 8 were converted to tacrolimus modified release (MR) once-daily in the morning for 7 days on a 1:1 (mg:mg) basis for their total daily dose. Patients who completed the 2-week pharmacokinetic treatment period were eligible to continue receiving tacrolimus MR as part of the extension treatment period of the study. The extended treatment period began on Day 15 and consisted of a single dose of tacrolimus MR once every morning through the end of the study.
Infections and infestations Pneumonia	11.1% 2/18 • From the first dose of tacrolimus MR through the last dose day plus 10 days (approximately 54 months). Adverse events are reported for the modified safety analysis set defined as all participants who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Infections and infestations Sinusitis	11.1% 2/18 • From the first dose of tacrolimus MR through the last dose day plus 10 days (approximately 54 months). Adverse events are reported for the modified safety analysis set defined as all participants who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Infections and infestations Tinea capitis	11.1% 2/18 • From the first dose of tacrolimus MR through the last dose day plus 10 days (approximately 54 months). Adverse events are reported for the modified safety analysis set defined as all participants who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Infections and infestations Viral upper respiratory tract infection	11.1% 2/18 • From the first dose of tacrolimus MR through the last dose day plus 10 days (approximately 54 months). Adverse events are reported for the modified safety analysis set defined as all participants who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Infections and infestations Bronchitis	5.6% 1/18 • From the first dose of tacrolimus MR through the last dose day plus 10 days (approximately 54 months). Adverse events are reported for the modified safety analysis set defined as all participants who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Infections and infestations Cat scratch disease	5.6% 1/18 • From the first dose of tacrolimus MR through the last dose day plus 10 days (approximately 54 months). Adverse events are reported for the modified safety analysis set defined as all participants who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Infections and infestations Ear infection	5.6% 1/18 • From the first dose of tacrolimus MR through the last dose day plus 10 days (approximately 54 months). Adverse events are reported for the modified safety analysis set defined as all participants who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Infections and infestations Epstein-barr virus infection	5.6% 1/18 • From the first dose of tacrolimus MR through the last dose day plus 10 days (approximately 54 months). Adverse events are reported for the modified safety analysis set defined as all participants who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Infections and infestations Escherichia urinary tract infection	5.6% 1/18 • From the first dose of tacrolimus MR through the last dose day plus 10 days (approximately 54 months). Adverse events are reported for the modified safety analysis set defined as all participants who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Infections and infestations Gastroenteritis	5.6% 1/18 • From the first dose of tacrolimus MR through the last dose day plus 10 days (approximately 54 months). Adverse events are reported for the modified safety analysis set defined as all participants who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Infections and infestations Herpes simplex	5.6% 1/18 • From the first dose of tacrolimus MR through the last dose day plus 10 days (approximately 54 months). Adverse events are reported for the modified safety analysis set defined as all participants who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Infections and infestations Influenza	5.6% 1/18 • From the first dose of tacrolimus MR through the last dose day plus 10 days (approximately 54 months). Adverse events are reported for the modified safety analysis set defined as all participants who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Infections and infestations Otitis media	5.6% 1/18 • From the first dose of tacrolimus MR through the last dose day plus 10 days (approximately 54 months). Adverse events are reported for the modified safety analysis set defined as all participants who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Infections and infestations Pharyngitis streptococcal	5.6% 1/18 • From the first dose of tacrolimus MR through the last dose day plus 10 days (approximately 54 months). Adverse events are reported for the modified safety analysis set defined as all participants who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Infections and infestations Upper respiratory tract infection	5.6% 1/18 • From the first dose of tacrolimus MR through the last dose day plus 10 days (approximately 54 months). Adverse events are reported for the modified safety analysis set defined as all participants who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Infections and infestations Urinary tract infection	5.6% 1/18 • From the first dose of tacrolimus MR through the last dose day plus 10 days (approximately 54 months). Adverse events are reported for the modified safety analysis set defined as all participants who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Infections and infestations Urinary tract infection staphylococcal	5.6% 1/18 • From the first dose of tacrolimus MR through the last dose day plus 10 days (approximately 54 months). Adverse events are reported for the modified safety analysis set defined as all participants who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Infections and infestations Viral infection	5.6% 1/18 • From the first dose of tacrolimus MR through the last dose day plus 10 days (approximately 54 months). Adverse events are reported for the modified safety analysis set defined as all participants who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Investigations Alanine aminotransferase increased	11.1% 2/18 • From the first dose of tacrolimus MR through the last dose day plus 10 days (approximately 54 months). Adverse events are reported for the modified safety analysis set defined as all participants who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Investigations Aspartate aminotransferase increased	11.1% 2/18 • From the first dose of tacrolimus MR through the last dose day plus 10 days (approximately 54 months). Adverse events are reported for the modified safety analysis set defined as all participants who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Investigations Blood triglycerides increased	5.6% 1/18 • From the first dose of tacrolimus MR through the last dose day plus 10 days (approximately 54 months). Adverse events are reported for the modified safety analysis set defined as all participants who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Investigations Hepatic enzyme increased	5.6% 1/18 • From the first dose of tacrolimus MR through the last dose day plus 10 days (approximately 54 months). Adverse events are reported for the modified safety analysis set defined as all participants who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Investigations Low density lipoprotein increased	5.6% 1/18 • From the first dose of tacrolimus MR through the last dose day plus 10 days (approximately 54 months). Adverse events are reported for the modified safety analysis set defined as all participants who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Investigations Weight increased	5.6% 1/18 • From the first dose of tacrolimus MR through the last dose day plus 10 days (approximately 54 months). Adverse events are reported for the modified safety analysis set defined as all participants who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Gastrointestinal disorders Vomiting	11.1% 2/18 • From the first dose of tacrolimus MR through the last dose day plus 10 days (approximately 54 months). Adverse events are reported for the modified safety analysis set defined as all participants who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Nervous system disorders Headache	5.6% 1/18 • From the first dose of tacrolimus MR through the last dose day plus 10 days (approximately 54 months). Adverse events are reported for the modified safety analysis set defined as all participants who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Nervous system disorders Tremor	5.6% 1/18 • From the first dose of tacrolimus MR through the last dose day plus 10 days (approximately 54 months). Adverse events are reported for the modified safety analysis set defined as all participants who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
General disorders Pyrexia	5.6% 1/18 • From the first dose of tacrolimus MR through the last dose day plus 10 days (approximately 54 months). Adverse events are reported for the modified safety analysis set defined as all participants who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Hepatobiliary disorders Hyperbilirubinaemia	5.6% 1/18 • From the first dose of tacrolimus MR through the last dose day plus 10 days (approximately 54 months). Adverse events are reported for the modified safety analysis set defined as all participants who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Injury, poisoning and procedural complications Contusion	5.6% 1/18 • From the first dose of tacrolimus MR through the last dose day plus 10 days (approximately 54 months). Adverse events are reported for the modified safety analysis set defined as all participants who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Metabolism and nutrition disorders Glucose tolerance impaired	5.6% 1/18 • From the first dose of tacrolimus MR through the last dose day plus 10 days (approximately 54 months). Adverse events are reported for the modified safety analysis set defined as all participants who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Renal and urinary disorders Glomerulosclerosis	5.6% 1/18 • From the first dose of tacrolimus MR through the last dose day plus 10 days (approximately 54 months). Adverse events are reported for the modified safety analysis set defined as all participants who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Respiratory, thoracic and mediastinal disorders Maxillary sinusitis	5.6% 1/18 • From the first dose of tacrolimus MR through the last dose day plus 10 days (approximately 54 months). Adverse events are reported for the modified safety analysis set defined as all participants who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Skin and subcutaneous tissue disorders Urticaria	5.6% 1/18 • From the first dose of tacrolimus MR through the last dose day plus 10 days (approximately 54 months). Adverse events are reported for the modified safety analysis set defined as all participants who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Vascular disorders Hypertension	5.6% 1/18 • From the first dose of tacrolimus MR through the last dose day plus 10 days (approximately 54 months). Adverse events are reported for the modified safety analysis set defined as all participants who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Renal and urinary disorders Renal impairment	5.6% 1/18 • From the first dose of tacrolimus MR through the last dose day plus 10 days (approximately 54 months). Adverse events are reported for the modified safety analysis set defined as all participants who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.

Additional Information

Vice President, Therapeutic Area Head, Transplantation

Astellas Pharma Global Development, Inc.

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Institute and/or Principal Investigator may publish trial data generated at their specific study site after Sponsor publication of the multi-center data or until 18 months have elapsed following study completion. Sponsor must receive a site's manuscript at least 30 days prior to publication to ensure that no confidential information of Sponsor is included in the document.
Publication restrictions are in place

Restriction type: OTHER