Trial Outcomes & Findings for A Study to Assess the Pharmacokinetics of a Modified-release Tacrolimus Based Immunosuppression Regimen in Stable Liver Transplant Patients (NCT NCT00282243)

Last Updated: 2013-09-30

Results Overview

The area under the concentration-time curve was calculated from whole blood tacrolimus concentrations for both the tacrolimus and tacrolimus MR treatment periods at steady state using the linear trapezoidal rule. The AUC0-24 for tacrolimus was calculated as the sum of the AUC0-12 for the morning (0-12 hour) and afternoon (12-24 hour) doses.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

70 participants

Primary outcome timeframe

Days 14 and 42 (tacrolimus) and Days 28 and 56 (tacrolimus MR), pre-dose 0.5, 1, 2, 3, 4, 6, 8, 12 (pre-dose for tacrolimus only), 12.5, 13, 14, 15, 16, 18, 20, and 24 hours post-dose.

Results posted on

2013-09-30

Participant Flow

Stable liver transplant recipients aged 18 to 65 years who were on a stable dose of tacrolimus based immunosuppressive regimen.

Pharmacokinetic (PK) treatment period was 56 days. Participants who completed the PK period were eligible to continue receiving tacrolimus MR in the extended treatment period, from Day 57 up to 60 months.

Participant milestones

Participant milestones
Measure	Tacrolimus MR After enrollment in the pharmacokinetic period, patients were maintained on their usual dose of tacrolimus twice daily on Day 1 through Day 14 and on Day 15 were converted to tacrolimus modified release (MR) once-daily in the morning for 14 days, converted back to tacrolimus twice daily for 14 days and then converted back to tacrolimus MR formulation once-daily in the morning for 14 days, all based on a 1:1 mg for mg total daily dose conversion. The extended treatment period began on day 57 and consisted of a single dose of tacrolimus extended-release formulation once every morning through the end of the study. Dose adjustments were allowed in order to maintain the target tacrolimus trough level within the range of 5 to 20 ng/mL and for clinical reasons.
Pharmacokinetic Treatment Period STARTED	70
Pharmacokinetic Treatment Period Received Tacrolimus	70
Pharmacokinetic Treatment Period Received Tacrolimus MR	69
Pharmacokinetic Treatment Period COMPLETED	65
Pharmacokinetic Treatment Period NOT COMPLETED	5
Extension Treatment Period STARTED	65
Extension Treatment Period COMPLETED	43
Extension Treatment Period NOT COMPLETED	22

Reasons for withdrawal

Reasons for withdrawal
Measure	Tacrolimus MR After enrollment in the pharmacokinetic period, patients were maintained on their usual dose of tacrolimus twice daily on Day 1 through Day 14 and on Day 15 were converted to tacrolimus modified release (MR) once-daily in the morning for 14 days, converted back to tacrolimus twice daily for 14 days and then converted back to tacrolimus MR formulation once-daily in the morning for 14 days, all based on a 1:1 mg for mg total daily dose conversion. The extended treatment period began on day 57 and consisted of a single dose of tacrolimus extended-release formulation once every morning through the end of the study. Dose adjustments were allowed in order to maintain the target tacrolimus trough level within the range of 5 to 20 ng/mL and for clinical reasons.
Pharmacokinetic Treatment Period Adverse Event	3
Pharmacokinetic Treatment Period Withdrawal by Subject	2
Extension Treatment Period Adverse Event	15
Extension Treatment Period Withdrawal by Subject	4
Extension Treatment Period Non-compliance	2
Extension Treatment Period Physician Decision	1

Baseline Characteristics

A Study to Assess the Pharmacokinetics of a Modified-release Tacrolimus Based Immunosuppression Regimen in Stable Liver Transplant Patients

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Tacrolimus MR n=62 Participants After enrollment in the pharmacokinetic period, patients were maintained on their usual dose of tacrolimus twice daily on Day 1 through Day 14 and on Day 15 were converted to tacrolimus modified release (MR) once-daily in the morning for 14 days, converted back to tacrolimus twice daily for 14 days and then converted back to tacrolimus MR formulation once-daily in the morning for 14 days, all based on a 1:1 mg for mg total daily dose conversion. The extended treatment period began on day 57 and consisted of a single dose of tacrolimus extended-release formulation once every morning through the end of the study. Dose adjustments were allowed in order to maintain the target tacrolimus trough level within the range of 5 to 20 ng/mL and for clinical reasons.
Age Continuous	50.3 years STANDARD_DEVIATION 8.97 • n=93 Participants
Sex: Female, Male Female	26 Participants n=93 Participants
Sex: Female, Male Male	36 Participants n=93 Participants
Race/Ethnicity, Customized White	57 participants n=93 Participants
Race/Ethnicity, Customized Black	4 participants n=93 Participants
Race/Ethnicity, Customized Pacific Islander	1 participants n=93 Participants
Reason for End Stage Liver Disease Hepatitis C	15 participants n=93 Participants
Reason for End Stage Liver Disease Alcoholic Liver Disease	11 participants n=93 Participants
Reason for End Stage Liver Disease Autoimmune Disease	4 participants n=93 Participants
Reason for End Stage Liver Disease Primary Biliary Cirrhosis	7 participants n=93 Participants
Reason for End Stage Liver Disease Primary Sclerosing Cholangitis	6 participants n=93 Participants
Reason for End Stage Liver Disease Alpha-1 Anti-Trypsin Deficiency	3 participants n=93 Participants
Reason for End Stage Liver Disease Hepatitis B	2 participants n=93 Participants
Reason for End Stage Liver Disease Non-Alcoholic Steatohepatitis	2 participants n=93 Participants
Reason for End Stage Liver Disease Cryptogenic Cirrhosis	2 participants n=93 Participants
Reason for End Stage Liver Disease Unknown	1 participants n=93 Participants
Reason for End Stage Liver Disease Other	9 participants n=93 Participants
Type of Current Transplant Whole Cadaver	56 participants n=93 Participants
Type of Current Transplant Living related Donor	3 participants n=93 Participants
Type of Current Transplant Split Cadaver	3 participants n=93 Participants
Re-transplant No	56 participants n=93 Participants
Re-transplant Yes	6 participants n=93 Participants

PRIMARY outcome

Timeframe: Days 14 and 42 (tacrolimus) and Days 28 and 56 (tacrolimus MR), pre-dose 0.5, 1, 2, 3, 4, 6, 8, 12 (pre-dose for tacrolimus only), 12.5, 13, 14, 15, 16, 18, 20, and 24 hours post-dose.

Population: Pharmacokinetic evaluable set defined as all patients with four complete pharmacokinetic profiles (two tacrolimus and 2 tacrolimus MR).

Outcome measures

Outcome measures
Measure	Tacrolimus MR n=62 Participants After enrollment in the pharmacokinetic period, patients were maintained on their usual dose of tacrolimus twice daily on Day 1 through Day 14 and on Day 15 were converted to tacrolimus modified release (MR) once-daily in the morning for 14 days, converted back to tacrolimus twice daily for 14 days and then converted back to tacrolimus MR formulation once-daily in the morning for 14 days, all based on a 1:1 mg for mg total daily dose conversion. The extended treatment period began on day 57 and consisted of a single dose of tacrolimus extended-release formulation once every morning through the end of the study. Dose adjustments were allowed in order to maintain the target tacrolimus trough level within the range of 5 to 20 ng/mL and for clinical reasons.
Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) for Tacrolimus Day 14: Tacrolimus	215.6 ng*hr/mL Standard Deviation 77.8
Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) for Tacrolimus Day 28: Tacrolimus MR	184.0 ng*hr/mL Standard Deviation 62.7
Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) for Tacrolimus Day 42: Tacrolimus	202.4 ng*hr/mL Standard Deviation 53.3
Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) for Tacrolimus Day 56: Tacrolimus MR	187.9 ng*hr/mL Standard Deviation 58.1

PRIMARY outcome

Timeframe: Days 14 and 42 at 12 hours post-dose (tacrolimus) and Days 28 and 56 at 24 hours post-dose (for 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=62 Participants After enrollment in the pharmacokinetic period, patients were maintained on their usual dose of tacrolimus twice daily on Day 1 through Day 14 and on Day 15 were converted to tacrolimus modified release (MR) once-daily in the morning for 14 days, converted back to tacrolimus twice daily for 14 days and then converted back to tacrolimus MR formulation once-daily in the morning for 14 days, all based on a 1:1 mg for mg total daily dose conversion. The extended treatment period began on day 57 and consisted of a single dose of tacrolimus extended-release formulation once every morning through the end of the study. Dose adjustments were allowed in order to maintain the target tacrolimus trough level within the range of 5 to 20 ng/mL and for clinical reasons.
Minimum Observed Concentration of Tacrolimus (Cmin) Day 14: Tacrolimus	7.1 ng/mL Standard Deviation 2.5
Minimum Observed Concentration of Tacrolimus (Cmin) Day 28: Tacrolimus MR	5.5 ng/mL Standard Deviation 1.8
Minimum Observed Concentration of Tacrolimus (Cmin) Day 42: Tacrolimus	6.8 ng/mL Standard Deviation 1.8
Minimum Observed Concentration of Tacrolimus (Cmin) Day 56: Tacrolimus MR	5.8 ng/mL Standard Deviation 1.8

PRIMARY outcome

Timeframe: From enrollment until the end of study (up to 60 months).

Population: Modified full analysis set, defined as all patients who took at least one dose of tacrolimus MR during the extended treatment period of the study.

Patient survival was defined as any participant known to be alive at the time of analysis.

Outcome measures

Outcome measures
Measure	Tacrolimus MR n=65 Participants After enrollment in the pharmacokinetic period, patients were maintained on their usual dose of tacrolimus twice daily on Day 1 through Day 14 and on Day 15 were converted to tacrolimus modified release (MR) once-daily in the morning for 14 days, converted back to tacrolimus twice daily for 14 days and then converted back to tacrolimus MR formulation once-daily in the morning for 14 days, all based on a 1:1 mg for mg total daily dose conversion. The extended treatment period began on day 57 and consisted of a single dose of tacrolimus extended-release formulation once every morning through the end of the study. Dose adjustments were allowed in order to maintain the target tacrolimus trough level within the range of 5 to 20 ng/mL and for clinical reasons.
Patient Survival	92.31 percentage of participants Interval 85.83 to 98.79

PRIMARY outcome

Timeframe: From enrollment until the end of study (up to 60 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=65 Participants After enrollment in the pharmacokinetic period, patients were maintained on their usual dose of tacrolimus twice daily on Day 1 through Day 14 and on Day 15 were converted to tacrolimus modified release (MR) once-daily in the morning for 14 days, converted back to tacrolimus twice daily for 14 days and then converted back to tacrolimus MR formulation once-daily in the morning for 14 days, all based on a 1:1 mg for mg total daily dose conversion. The extended treatment period began on day 57 and consisted of a single dose of tacrolimus extended-release formulation once every morning through the end of the study. Dose adjustments were allowed in order to maintain the target tacrolimus trough level within the range of 5 to 20 ng/mL and for clinical reasons.
Graft Survival	90.77 percentage of participants Interval 83.73 to 97.81

SECONDARY outcome

Timeframe: Days 14 and 42 (tacrolimus) and Days 28 and 56 (tacrolimus MR), pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 (pre-dose for tacrolimus only), 12.5, 13, 14, 15, 16, 18, 20, and 24 hours post-dose.

Population: Pharmacokinetic evaluable set

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

Outcome measures

Outcome measures
Measure	Tacrolimus MR n=62 Participants After enrollment in the pharmacokinetic period, patients were maintained on their usual dose of tacrolimus twice daily on Day 1 through Day 14 and on Day 15 were converted to tacrolimus modified release (MR) once-daily in the morning for 14 days, converted back to tacrolimus twice daily for 14 days and then converted back to tacrolimus MR formulation once-daily in the morning for 14 days, all based on a 1:1 mg for mg total daily dose conversion. The extended treatment period began on day 57 and consisted of a single dose of tacrolimus extended-release formulation once every morning through the end of the study. Dose adjustments were allowed in order to maintain the target tacrolimus trough level within the range of 5 to 20 ng/mL and for clinical reasons.
Maximum Observed Concentration of Tacrolimus (Cmax) Day 14: Tacrolimus	17.9 ng/mL Standard Deviation 9.9
Maximum Observed Concentration of Tacrolimus (Cmax) Day 28: Tacrolimus MR	13.3 ng/mL Standard Deviation 5.6
Maximum Observed Concentration of Tacrolimus (Cmax) Day 42: Tacrolimus	16.0 ng/mL Standard Deviation 6.9
Maximum Observed Concentration of Tacrolimus (Cmax) Day 56: Tacrolimus MR	14.1 ng/mL Standard Deviation 6.0

SECONDARY outcome

Timeframe: Days 14 and 42 (tacrolimus) and Days 28 and 56 (tacrolimus MR), pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 (pre-dose for tacrolimus only), 12.5, 13, 14, 15, 16, 18, 20, and 24 hours post-dose.

Population: Pharmacokinetic evaluable set

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

Outcome measures

Outcome measures
Measure	Tacrolimus MR n=62 Participants After enrollment in the pharmacokinetic period, patients were maintained on their usual dose of tacrolimus twice daily on Day 1 through Day 14 and on Day 15 were converted to tacrolimus modified release (MR) once-daily in the morning for 14 days, converted back to tacrolimus twice daily for 14 days and then converted back to tacrolimus MR formulation once-daily in the morning for 14 days, all based on a 1:1 mg for mg total daily dose conversion. The extended treatment period began on day 57 and consisted of a single dose of tacrolimus extended-release formulation once every morning through the end of the study. Dose adjustments were allowed in order to maintain the target tacrolimus trough level within the range of 5 to 20 ng/mL and for clinical reasons.
Time to Maximum Observed Concentration of Tacrolimus (Tmax) Day 42: Tacrolimus	3.0 hours Standard Deviation 4.4
Time to Maximum Observed Concentration of Tacrolimus (Tmax) Day 56: Tacrolimus MR	2.7 hours Standard Deviation 2.1
Time to Maximum Observed Concentration of Tacrolimus (Tmax) Day 14: Tacrolimus	2.8 hours Standard Deviation 4.2
Time to Maximum Observed Concentration of Tacrolimus (Tmax) Day 28: Tacrolimus MR	3.0 hours Standard Deviation 3.1

SECONDARY outcome

Timeframe: From enrollment until the end of study (up to 60 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=65 Participants After enrollment in the pharmacokinetic period, patients were maintained on their usual dose of tacrolimus twice daily on Day 1 through Day 14 and on Day 15 were converted to tacrolimus modified release (MR) once-daily in the morning for 14 days, converted back to tacrolimus twice daily for 14 days and then converted back to tacrolimus MR formulation once-daily in the morning for 14 days, all based on a 1:1 mg for mg total daily dose conversion. The extended treatment period began on day 57 and consisted of a single dose of tacrolimus extended-release formulation once every morning through the end of the study. Dose adjustments were allowed in order to maintain the target tacrolimus trough level within the range of 5 to 20 ng/mL and for clinical reasons.
Percentage of Participants With Biopsy-confirmed Acute Rejection	9.23 percentage of participants Interval 2.19 to 16.27

SECONDARY outcome

Timeframe: From enrollment until the end of study (up to 60 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=5 Participants After enrollment in the pharmacokinetic period, patients were maintained on their usual dose of tacrolimus twice daily on Day 1 through Day 14 and on Day 15 were converted to tacrolimus modified release (MR) once-daily in the morning for 14 days, converted back to tacrolimus twice daily for 14 days and then converted back to tacrolimus MR formulation once-daily in the morning for 14 days, all based on a 1:1 mg for mg total daily dose conversion. The extended treatment period began on day 57 and consisted of a single dose of tacrolimus extended-release formulation once every morning through the end of the study. Dose adjustments were allowed in order to maintain the target tacrolimus trough level within the range of 5 to 20 ng/mL and for clinical reasons.
Time to Event for Patient Non-survival	1561.00 days Interval 720.0 to 1881.0

SECONDARY outcome

Timeframe: From enrollment until the end of study (up to 60 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=6 Participants After enrollment in the pharmacokinetic period, patients were maintained on their usual dose of tacrolimus twice daily on Day 1 through Day 14 and on Day 15 were converted to tacrolimus modified release (MR) once-daily in the morning for 14 days, converted back to tacrolimus twice daily for 14 days and then converted back to tacrolimus MR formulation once-daily in the morning for 14 days, all based on a 1:1 mg for mg total daily dose conversion. The extended treatment period began on day 57 and consisted of a single dose of tacrolimus extended-release formulation once every morning through the end of the study. Dose adjustments were allowed in order to maintain the target tacrolimus trough level within the range of 5 to 20 ng/mL and for clinical reasons.
Time to Event for Graft Non-survival	1529.50 days Interval 720.0 to 1881.0

SECONDARY outcome

Timeframe: From enrollment until the end of study (up to 60 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=6 Participants After enrollment in the pharmacokinetic period, patients were maintained on their usual dose of tacrolimus twice daily on Day 1 through Day 14 and on Day 15 were converted to tacrolimus modified release (MR) once-daily in the morning for 14 days, converted back to tacrolimus twice daily for 14 days and then converted back to tacrolimus MR formulation once-daily in the morning for 14 days, all based on a 1:1 mg for mg total daily dose conversion. The extended treatment period began on day 57 and consisted of a single dose of tacrolimus extended-release formulation once every morning through the end of the study. Dose adjustments were allowed in order to maintain the target tacrolimus trough level within the range of 5 to 20 ng/mL and for clinical reasons.
Time to First Biopsy-confirmed Acute Rejection	802.50 days Interval 153.0 to 1871.0

SECONDARY outcome

Timeframe: From enrollment until the end of study (up to 60 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=6 Participants After enrollment in the pharmacokinetic period, patients were maintained on their usual dose of tacrolimus twice daily on Day 1 through Day 14 and on Day 15 were converted to tacrolimus modified release (MR) once-daily in the morning for 14 days, converted back to tacrolimus twice daily for 14 days and then converted back to tacrolimus MR formulation once-daily in the morning for 14 days, all based on a 1:1 mg for mg total daily dose conversion. The extended treatment period began on day 57 and consisted of a single dose of tacrolimus extended-release formulation once every morning through the end of the study. Dose adjustments were allowed in order to maintain the target tacrolimus trough level within the range of 5 to 20 ng/mL and for clinical reasons.
Grade of Biopsy-confirmed Acute Rejection Episodes Grade I	4 participants
Grade of Biopsy-confirmed Acute Rejection Episodes Grade II	2 participants
Grade of Biopsy-confirmed Acute Rejection Episodes Grade III	0 participants

SECONDARY outcome

Timeframe: From enrollment until the end of study (up to 60 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=65 Participants After enrollment in the pharmacokinetic period, patients were maintained on their usual dose of tacrolimus twice daily on Day 1 through Day 14 and on Day 15 were converted to tacrolimus modified release (MR) once-daily in the morning for 14 days, converted back to tacrolimus twice daily for 14 days and then converted back to tacrolimus MR formulation once-daily in the morning for 14 days, all based on a 1:1 mg for mg total daily dose conversion. The extended treatment period began on day 57 and consisted of a single dose of tacrolimus extended-release formulation once every morning through the end of the study. Dose adjustments were allowed in order to maintain the target tacrolimus trough level within the range of 5 to 20 ng/mL and for clinical reasons.
Number of Participants Receiving Anti-lymphocyte Antibody Therapy for Acute Rejection	1 participants

SECONDARY outcome

Timeframe: From enrollment until the end of study (up to 60 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=65 Participants After enrollment in the pharmacokinetic period, patients were maintained on their usual dose of tacrolimus twice daily on Day 1 through Day 14 and on Day 15 were converted to tacrolimus modified release (MR) once-daily in the morning for 14 days, converted back to tacrolimus twice daily for 14 days and then converted back to tacrolimus MR formulation once-daily in the morning for 14 days, all based on a 1:1 mg for mg total daily dose conversion. The extended treatment period began on day 57 and consisted of a single dose of tacrolimus extended-release formulation once every morning through the end of the study. Dose adjustments were allowed in order to maintain the target tacrolimus trough level within the range of 5 to 20 ng/mL and for clinical reasons.
Number of Participants With Multiple Rejection Episodes	2 participants

SECONDARY outcome

Timeframe: From enrollment until the end of study (up to 60 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=65 Participants After enrollment in the pharmacokinetic period, patients were maintained on their usual dose of tacrolimus twice daily on Day 1 through Day 14 and on Day 15 were converted to tacrolimus modified release (MR) once-daily in the morning for 14 days, converted back to tacrolimus twice daily for 14 days and then converted back to tacrolimus MR formulation once-daily in the morning for 14 days, all based on a 1:1 mg for mg total daily dose conversion. The extended treatment period began on day 57 and consisted of a single dose of tacrolimus extended-release formulation once every morning through the end of the study. Dose adjustments were allowed in order to maintain the target tacrolimus trough level within the range of 5 to 20 ng/mL and for clinical reasons.
Number of Participants With Clinically Treated Acute Rejection Episodes	5 participants

SECONDARY outcome

Timeframe: From enrollment until the end of study (up to 60 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 60 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 60 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=6 Participants After enrollment in the pharmacokinetic period, patients were maintained on their usual dose of tacrolimus twice daily on Day 1 through Day 14 and on Day 15 were converted to tacrolimus modified release (MR) once-daily in the morning for 14 days, converted back to tacrolimus twice daily for 14 days and then converted back to tacrolimus MR formulation once-daily in the morning for 14 days, all based on a 1:1 mg for mg total daily dose conversion. The extended treatment period began on day 57 and consisted of a single dose of tacrolimus extended-release formulation once every morning through the end of the study. Dose adjustments were allowed in order to maintain the target tacrolimus trough level within the range of 5 to 20 ng/mL and for clinical reasons.
Primary Reason for Graft Loss Recurrent disease	1 participants
Primary Reason for Graft Loss Death	5 participants

SECONDARY outcome

Timeframe: Baseline (the last day of tacrolimus on Day 14 prior to the first conversion to tacrolimus MR), Day 56 (end of the pharmacokinetic phase) and end of treatment (EOT; the last observed value during treatment, maximum time on study was 60 months).

Population: Modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and at least one dose of tacrolimus MR during the pharmacokinetic portion of the study. "N" indicates the number of participants with available data at each time point.

Hepatic function was assessed by measuring alanine aminotransferase levels over the course of the study.

Outcome measures

Outcome measures
Measure	Tacrolimus MR n=69 Participants After enrollment in the pharmacokinetic period, patients were maintained on their usual dose of tacrolimus twice daily on Day 1 through Day 14 and on Day 15 were converted to tacrolimus modified release (MR) once-daily in the morning for 14 days, converted back to tacrolimus twice daily for 14 days and then converted back to tacrolimus MR formulation once-daily in the morning for 14 days, all based on a 1:1 mg for mg total daily dose conversion. The extended treatment period began on day 57 and consisted of a single dose of tacrolimus extended-release formulation once every morning through the end of the study. Dose adjustments were allowed in order to maintain the target tacrolimus trough level within the range of 5 to 20 ng/mL and for clinical reasons.
Change From Baseline in Alanine Aminotransferase (ALT) Baseline [N= 69]	38.5 U/L Standard Deviation 22.38
Change From Baseline in Alanine Aminotransferase (ALT) Change from Baseline at Day 56 [N=67]	14.4 U/L Standard Deviation 79.16
Change From Baseline in Alanine Aminotransferase (ALT) Change from Baseline at EOT [N=68]	13.3 U/L Standard Deviation 60.60

SECONDARY outcome

Population: Modified safety analysis set. "N" indicates the number of participants with available data at each time point.

Hepatic function was assessed by measuring aspartate aminotransferase levels over the course of the study.

Outcome measures

Outcome measures
Measure	Tacrolimus MR n=69 Participants After enrollment in the pharmacokinetic period, patients were maintained on their usual dose of tacrolimus twice daily on Day 1 through Day 14 and on Day 15 were converted to tacrolimus modified release (MR) once-daily in the morning for 14 days, converted back to tacrolimus twice daily for 14 days and then converted back to tacrolimus MR formulation once-daily in the morning for 14 days, all based on a 1:1 mg for mg total daily dose conversion. The extended treatment period began on day 57 and consisted of a single dose of tacrolimus extended-release formulation once every morning through the end of the study. Dose adjustments were allowed in order to maintain the target tacrolimus trough level within the range of 5 to 20 ng/mL and for clinical reasons.
Change From Baseline in Aspartate Aminotransferase (AST) Baseline [N= 69]	33.4 U/L Standard Deviation 17.94
Change From Baseline in Aspartate Aminotransferase (AST) Change from Baseline at Day 56 [N=67]	3.6 U/L Standard Deviation 23.32
Change From Baseline in Aspartate Aminotransferase (AST) Change from Baseline at EOT [N=68]	10.6 U/L Standard Deviation 55.05

SECONDARY outcome

Population: Modified safety analysis set. "N" indicates the number of participants with available data at each time point.

Hepatic function was assessed by measuring total bilirubin over the course of the study.

Outcome measures

Outcome measures
Measure	Tacrolimus MR n=69 Participants After enrollment in the pharmacokinetic period, patients were maintained on their usual dose of tacrolimus twice daily on Day 1 through Day 14 and on Day 15 were converted to tacrolimus modified release (MR) once-daily in the morning for 14 days, converted back to tacrolimus twice daily for 14 days and then converted back to tacrolimus MR formulation once-daily in the morning for 14 days, all based on a 1:1 mg for mg total daily dose conversion. The extended treatment period began on day 57 and consisted of a single dose of tacrolimus extended-release formulation once every morning through the end of the study. Dose adjustments were allowed in order to maintain the target tacrolimus trough level within the range of 5 to 20 ng/mL and for clinical reasons.
Change From Baseline in Total Bilirubin Baseline [N= 69]	0.74 mg/dL Standard Deviation 0.604
Change From Baseline in Total Bilirubin Change from Baseline at Day 56 [N=67]	0.03 mg/dL Standard Deviation 0.657
Change From Baseline in Total Bilirubin Change from Baseline at EOT [N=68]	1.04 mg/dL Standard Deviation 5.948

SECONDARY outcome

Timeframe: From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months).

Population: Modified safety analysis set.

An adverse event 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=69 Participants After enrollment in the pharmacokinetic period, patients were maintained on their usual dose of tacrolimus twice daily on Day 1 through Day 14 and on Day 15 were converted to tacrolimus modified release (MR) once-daily in the morning for 14 days, converted back to tacrolimus twice daily for 14 days and then converted back to tacrolimus MR formulation once-daily in the morning for 14 days, all based on a 1:1 mg for mg total daily dose conversion. The extended treatment period began on day 57 and consisted of a single dose of tacrolimus extended-release formulation once every morning through the end of the study. Dose adjustments were allowed in order to maintain the target tacrolimus trough level within the range of 5 to 20 ng/mL and for clinical reasons.
Safety as Assessed by Adverse Events, Laboratory Parameters and Vital Signs Serious adverse event	37 participants
Safety as Assessed by Adverse Events, Laboratory Parameters and Vital Signs Any adverse event	63 participants
Safety as Assessed by Adverse Events, Laboratory Parameters and Vital Signs Adverse event leading to discontinuation	18 participants
Safety as Assessed by Adverse Events, Laboratory Parameters and Vital Signs Adverse event leading to dose changes	37 participants
Safety as Assessed by Adverse Events, Laboratory Parameters and Vital Signs Death	5 participants

Adverse Events

Tacrolimus MR

Serious events: 37 serious events

Other events: 51 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Tacrolimus MR n=69 participants at risk After enrollment in the pharmacokinetic period, patients were maintained on their usual dose of tacrolimus twice daily on Day 1 through Day 14 and on Day 15 were converted to tacrolimus modified release (MR) once-daily in the morning for 14 days, converted back to tacrolimus twice daily for 14 days and then converted back to tacrolimus MR formulation once-daily in the morning for 14 days, all based on a 1:1 mg for mg total daily dose conversion. The extended treatment period began on day 57 and consisted of a single dose of tacrolimus extended-release formulation once every morning through the end of the study. Dose adjustments were allowed in order to maintain the target tacrolimus trough level within the range of 5 to 20 ng/mL and for clinical reasons.
Infections and infestations Pneumonia	7.2% 5/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients 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	2.9% 2/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Infections and infestations Bronchiectasis	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Infections and infestations Clostridial infection	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Infections and infestations Enterobacter sepsis	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients 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 bacteraemia	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients 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	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients 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 salmonella	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients 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 zoster	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Infections and infestations Perianal abscess	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Infections and infestations Sepsis	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients 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	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Infections and infestations Urosepsis	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients 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	2.9% 2/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Gastrointestinal disorders Diarrhea	2.9% 2/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients 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 lower	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Gastrointestinal disorders Abdominal strangulated hernia	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Gastrointestinal disorders Colitis ulcerative	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Gastrointestinal disorders Diverticulitis	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Gastrointestinal disorders Haematemesis	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Gastrointestinal disorders Nausea	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Gastrointestinal disorders Rectal haemorrhage	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Gastrointestinal disorders Vomiting	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Hepatobiliary disorders Cholangitis	2.9% 2/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Hepatobiliary disorders Cholestasis	2.9% 2/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Hepatobiliary disorders Autoimmune hepatitis	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Hepatobiliary disorders Bile duct obstruction	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Hepatobiliary disorders Bile duct stenosis	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Hepatobiliary disorders Haemobilia	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Hepatobiliary disorders Hepatitis granulomatous	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Hepatobiliary disorders Ischaemic hepatitis	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients 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 Incisional hernia	5.8% 4/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients 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 Postoperative haematoma	2.9% 2/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients 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 Anastomotic stenosis	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients 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 Humerus fracture	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients 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 Post procedural bile leak	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients 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 Post procedural complication	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients 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 Postoperative heterotopic calcification	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Squamous cell carcinoma of skin	2.9% 2/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Basal cell carcinoma	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Colon cancer	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Colorectal cancer	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Diffuse large B-cell lymphoma	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Diffuse large B-cell lymphoma recurrent	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Hepatic cancer metastatic	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Hepatic neoplasm malignant	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung adenocarcinoma	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung nodule	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung squamous cell carcinoma stage	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Unspecified malignant melanoma	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to lung	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumor lysis syndrome	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Cardiac disorders Atrial fibrillation	2.9% 2/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Cardiac disorders Acute myocardial infarction	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Cardiac disorders Angina pectoris	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Cardiac disorders Cardio-respiratory arrest	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Cardiac disorders Coronary artery disease	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Cardiac disorders Myocardial infarction	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients 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 Fluid overload	2.9% 2/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients 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 Hyperglycaemia	2.9% 2/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients 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 Dehydration	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients 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 Hyperkalaemia	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients 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 Hypolycaemia	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients 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 failure acute	8.7% 6/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients 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 Acute prerenal failure	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients 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 failure chronic	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients 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	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients 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 insufficiency	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
General disorders Pyrexia	5.8% 4/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
General disorders Asthenia	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
General disorders Chest pain	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
General disorders Hernia	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
General disorders Rigors	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients 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 Dyspnoea	2.9% 2/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients 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 Pleural effusion	2.9% 2/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients 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 Acute respiratory failure	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients 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 Atelectasis	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients 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 Cough	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Immune system disorders Graft loss	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Immune system disorders Liver transplant rejection	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Immune system disorders Transplant rejection	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients 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 Musculoskeletal chest pain	2.9% 2/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients 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 Intervertebral disc protrusion	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Investigations Blood creatinine increased	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Investigations International normalized ratio increased	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients 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	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Nervous system disorders Aphasia	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Nervous system disorders Cerebrovascular accident	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Nervous system disorders Leukoencephalopathy	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Nervous system disorders Neurotoxicity	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Psychiatric disorders Disorientation	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Psychiatric disorders Drug dependence	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Vascular disorders Hypotension	2.9% 2/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Blood and lymphatic system disorders Febrile neutropenia	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Ear and labyrinth disorders Vestibular disorder	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Pregnancy, puerperium and perinatal conditions Pregnancy	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Surgical and medical procedures Spinal laminectomy	1.4% 1/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients 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=69 participants at risk After enrollment in the pharmacokinetic period, patients were maintained on their usual dose of tacrolimus twice daily on Day 1 through Day 14 and on Day 15 were converted to tacrolimus modified release (MR) once-daily in the morning for 14 days, converted back to tacrolimus twice daily for 14 days and then converted back to tacrolimus MR formulation once-daily in the morning for 14 days, all based on a 1:1 mg for mg total daily dose conversion. The extended treatment period began on day 57 and consisted of a single dose of tacrolimus extended-release formulation once every morning through the end of the study. Dose adjustments were allowed in order to maintain the target tacrolimus trough level within the range of 5 to 20 ng/mL and for clinical reasons.
Infections and infestations Upper respiratory tract infection	11.6% 8/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients 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	11.6% 8/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients 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	8.7% 6/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients 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	5.8% 4/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients 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 Hyperlipidaemia	11.6% 8/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients 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 Diabetes mellitus	7.2% 5/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients 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 Hyperkalaemia	5.8% 4/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients 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 Hypomagnesaemia	5.8% 4/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients 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	13.0% 9/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients 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 insufficiency	10.1% 7/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Investigations Blood creatinine increased	8.7% 6/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients 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	8.7% 6/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients 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	5.8% 4/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients 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	18.8% 13/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Gastrointestinal disorders Diarrhea	10.1% 7/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Gastrointestinal disorders Nausea	7.2% 5/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients 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 Arthralgia	5.8% 4/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients 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 Pain in extremity	5.8% 4/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
Vascular disorders Hypertension	11.6% 8/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients who took at least 1 dose of tacrolimus and one dose of tacrolimus MR during the pharmacokinetic period of the study.
General disorders Fatigue	8.7% 6/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients 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 Pharyngolaryngeal pain	7.2% 5/69 • From the first dose of tacrolimus MR formulation through the last dose day plus 10 days (approximately 60 months). Adverse events are reported for the modified safety analysis set defined as all patients 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