Trial Outcomes & Findings for Study Of The Safety And Efficacy Of Conversion From A CNI To Sirolimus In Renally-Impaired Heart Transplant Recipients (NCT NCT00369382)

Last Updated: 2011-05-30

Results Overview

Creatinine Clearance (CC) calculated using Cockcroft-Gault equation, adjusted for body surface area. Calculated CC: method to approximate kidney function. It measures rate creatinine (substance formed from metabolism of creatine) is cleared from blood by kidneys. Normal adult creatinine clearance is greater than or equal to (≥) 90 milliliters per minute per 1.73 meters squared (mL/min/1.73m\^2). Change from baseline=CC at Week 52 minus CC at baseline where higher scores represented improved renal function; Least squares mean adjusted for baseline calculated creatinine clearance and center.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

121 participants

Primary outcome timeframe

Baseline and Week 52

Results posted on

2011-05-30

Participant Flow

Actual number of participants randomized was 121; however 5 participants randomized in error. They were withdrawn from study as screen failures, not administered study drug. Participants randomized (121) lower than planned (200); more sites added, time period to enroll extended twice up to 2.5 years. Despite this, final enrollment below planned.

Participant milestones

Participant milestones
Measure	Cyclosporine or Tacrolimus Continuation of Calcineurin inhibitor (CNI) regimen; included cyclosporine (CsA) or tacrolimus (TAC) which were dosed to achieve a target trough level determined by investigator; therefore, form, dosage, and frequency were site and patient specific. CsA therapy could have been switched to TAC therapy and vice versa, as warranted by clinical circumstances.	Sirolimus (SRL) Conversion from CNI therapy to Sirolimus: Sirolimus initiated with oral tablets administered once daily (1 to 5 milligrams per day) to achieve target trough of 8-15 nanograms per milliliter (ng/mL). Protocol was later amended to allow target troughs of 7-15 ng/mL for duration of study. CNI discontinued within 8 weeks post randomization.
Overall Study STARTED	59	57
Overall Study Received Treatment	57	57
Overall Study Completed Assigned Treatment Regimen	48	33
Overall Study COMPLETED	49	54
Overall Study NOT COMPLETED	10	3

Reasons for withdrawal

Reasons for withdrawal
Measure	Cyclosporine or Tacrolimus Continuation of Calcineurin inhibitor (CNI) regimen; included cyclosporine (CsA) or tacrolimus (TAC) which were dosed to achieve a target trough level determined by investigator; therefore, form, dosage, and frequency were site and patient specific. CsA therapy could have been switched to TAC therapy and vice versa, as warranted by clinical circumstances.	Sirolimus (SRL) Conversion from CNI therapy to Sirolimus: Sirolimus initiated with oral tablets administered once daily (1 to 5 milligrams per day) to achieve target trough of 8-15 nanograms per milliliter (ng/mL). Protocol was later amended to allow target troughs of 7-15 ng/mL for duration of study. CNI discontinued within 8 weeks post randomization.
Overall Study Death	0	2
Overall Study Physician Decision	2	1
Overall Study Withdrawal by Subject	5	0
Overall Study Randomized, not treated	2	0
Overall Study Other	1	0

Baseline Characteristics

Study Of The Safety And Efficacy Of Conversion From A CNI To Sirolimus In Renally-Impaired Heart Transplant Recipients

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Cyclosporine or Tacrolimus n=59 Participants Continuation of Calcineurin inhibitor (CNI) regimen; included cyclosporine (CsA) or tacrolimus (TAC) which were dosed to achieve a target trough level determined by investigator; therefore, form, dosage, and frequency were site and patient specific. CsA therapy could have been switched to TAC therapy and vice versa, as warranted by clinical circumstances.	Sirolimus (SRL) n=57 Participants Conversion from CNI therapy to Sirolimus: Sirolimus initiated with oral tablets administered once daily (1 to 5 milligrams per day) to achieve target trough of 8-15 nanograms per milliliter (ng/mL). Protocol was later amended to allow target troughs of 7-15 ng/mL for duration of study. CNI discontinued within 8 weeks post randomization.	Total n=116 Participants Total of all reporting groups
Age Continuous	58.93 years STANDARD_DEVIATION 8.01 • n=5 Participants	57.40 years STANDARD_DEVIATION 9.42 • n=7 Participants	58.18 years STANDARD_DEVIATION 8.73 • n=5 Participants
Sex: Female, Male Female	5 Participants n=5 Participants	12 Participants n=7 Participants	17 Participants n=5 Participants
Sex: Female, Male Male	54 Participants n=5 Participants	45 Participants n=7 Participants	99 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline and Week 52

Population: Intent-to-Treat (ITT) Population: all randomized participants; all available data (on-therapy and off-therapy) included; Last observation carried forward (LOCF) for data missing due to skipped visits or participant withdrawal from study. Number of participants analyzed (N)=those with all measurements required for calculated creatinine clearance.

Outcome measures

Outcome measures
Measure	Cyclosporine or Tacrolimus n=59 Participants Continuation of Calcineurin inhibitor (CNI) regimen; included cyclosporine (CsA) or tacrolimus (TAC) which were dosed to achieve a target trough level determined by investigator; therefore, form, dosage, and frequency were site and patient specific. CsA therapy could have been switched to TAC therapy and vice versa, as warranted by clinical circumstances.	Sirolimus (SRL) n=56 Participants Conversion from CNI therapy to Sirolimus: Sirolimus initiated with oral tablets administered once daily (1 to 5 milligrams per day) to achieve target trough of 8-15 nanograms per milliliter (ng/mL). Protocol was later amended to allow target troughs of 7-15 ng/mL for duration of study. CNI discontinued within 8 weeks post randomization.
Change From Baseline in Calculated Creatinine Clearance (Cockcroft-Gault Equation) at 52 Weeks Post-randomization	-1.35 mL/min/1.73m^2 Standard Error 1.18	3.03 mL/min/1.73m^2 Standard Error 1.29

PRIMARY outcome

Timeframe: Baseline

Population: ITT; N=participants with all measurements required for calculated creatinine clearance.

Creatinine clearance at baseline calculated using Cockcroft-Gault equation and adjusted for body surface area. Calculated CC: method to approximate kidney function. It measures rate creatinine (substance formed from metabolism of creatine) is cleared from blood by kidneys. Normal adult creatinine clearance is ≥ 90 mL/min/1.73m\^2.

Outcome measures

Outcome measures
Measure	Cyclosporine or Tacrolimus n=59 Participants Continuation of Calcineurin inhibitor (CNI) regimen; included cyclosporine (CsA) or tacrolimus (TAC) which were dosed to achieve a target trough level determined by investigator; therefore, form, dosage, and frequency were site and patient specific. CsA therapy could have been switched to TAC therapy and vice versa, as warranted by clinical circumstances.	Sirolimus (SRL) n=56 Participants Conversion from CNI therapy to Sirolimus: Sirolimus initiated with oral tablets administered once daily (1 to 5 milligrams per day) to achieve target trough of 8-15 nanograms per milliliter (ng/mL). Protocol was later amended to allow target troughs of 7-15 ng/mL for duration of study. CNI discontinued within 8 weeks post randomization.
Calculated Creatinine Clearance (Cockcroft-Gault Equation) at Baseline	57.09 mL/min/1.73m^2 Standard Deviation 11.96	57.75 mL/min/1.73m^2 Standard Deviation 14.04

SECONDARY outcome

Timeframe: Baseline and Weeks 4, 16, 24, 32, and 40

Population: ITT; All available data (on-therapy and off-therapy) were included; LOCF for data points missing due to skipped visits or participant withdrawal from study; N=participants with all measurements required for calculated creatinine clearance.

Creatinine Clearance (CC) calculated using Cockcroft-Gault equation, adjusted for body surface area. Calculated CC: method to approximate kidney function. It measures rate creatinine (substance formed from metabolism of creatine) is cleared from blood by kidneys. Normal adult creatinine clearance is ≥ 90 mL/min/1.73m\^2. Change from baseline=CC at Week X minus CC at baseline where higher scores represented improved renal function; Least squares mean adjusted for baseline calculated creatinine clearance and center.

Outcome measures

Outcome measures
Measure	Cyclosporine or Tacrolimus n=59 Participants Continuation of Calcineurin inhibitor (CNI) regimen; included cyclosporine (CsA) or tacrolimus (TAC) which were dosed to achieve a target trough level determined by investigator; therefore, form, dosage, and frequency were site and patient specific. CsA therapy could have been switched to TAC therapy and vice versa, as warranted by clinical circumstances.	Sirolimus (SRL) n=56 Participants Conversion from CNI therapy to Sirolimus: Sirolimus initiated with oral tablets administered once daily (1 to 5 milligrams per day) to achieve target trough of 8-15 nanograms per milliliter (ng/mL). Protocol was later amended to allow target troughs of 7-15 ng/mL for duration of study. CNI discontinued within 8 weeks post randomization.
Change From Baseline in Calculated Creatinine Clearance (Cockcroft-Gault Equation) at 4, 16, 24, 32, and 40 Weeks Post-randomization Week 4	-0.20 mL/min/1.73m^2 Standard Error 1.06	2.96 mL/min/1.73m^2 Standard Error 1.16
Change From Baseline in Calculated Creatinine Clearance (Cockcroft-Gault Equation) at 4, 16, 24, 32, and 40 Weeks Post-randomization Week 32	-0.76 mL/min/1.73m^2 Standard Error 1.32	2.22 mL/min/1.73m^2 Standard Error 1.45
Change From Baseline in Calculated Creatinine Clearance (Cockcroft-Gault Equation) at 4, 16, 24, 32, and 40 Weeks Post-randomization Week 16	-2.16 mL/min/1.73m^2 Standard Error 1.37	3.79 mL/min/1.73m^2 Standard Error 1.50
Change From Baseline in Calculated Creatinine Clearance (Cockcroft-Gault Equation) at 4, 16, 24, 32, and 40 Weeks Post-randomization Week 24	-1.91 mL/min/1.73m^2 Standard Error 1.28	2.15 mL/min/1.73m^2 Standard Error 1.40
Change From Baseline in Calculated Creatinine Clearance (Cockcroft-Gault Equation) at 4, 16, 24, 32, and 40 Weeks Post-randomization Week 40	0.34 mL/min/1.73m^2 Standard Error 1.39	2.70 mL/min/1.73m^2 Standard Error 1.52

SECONDARY outcome

Timeframe: Baseline and Weeks 4, 16, 24, 32, 40 and 52

Population: ITT; All available data (on-therapy and off-therapy) were included; LOCF for data points missing due to skipped visits or participant withdrawal from study.

Creatinine clearance calculated using MDRD equation. Normal adult creatinine clearance is ≥ 90 mL/min/1.73m\^2. Change from baseline=CC at Week X minus CC at baseline where higher scores represented improved renal function. Least squares mean adjusted for baseline calculated creatinine clearance (MDRD) and center.

Outcome measures

Outcome measures
Measure	Cyclosporine or Tacrolimus n=59 Participants Continuation of Calcineurin inhibitor (CNI) regimen; included cyclosporine (CsA) or tacrolimus (TAC) which were dosed to achieve a target trough level determined by investigator; therefore, form, dosage, and frequency were site and patient specific. CsA therapy could have been switched to TAC therapy and vice versa, as warranted by clinical circumstances.	Sirolimus (SRL) n=57 Participants Conversion from CNI therapy to Sirolimus: Sirolimus initiated with oral tablets administered once daily (1 to 5 milligrams per day) to achieve target trough of 8-15 nanograms per milliliter (ng/mL). Protocol was later amended to allow target troughs of 7-15 ng/mL for duration of study. CNI discontinued within 8 weeks post randomization.
Change From Baseline in Calculated Creatinine Clearance (Modification of Diet in Renal Disease [MDRD] Equation) at 4, 16, 24, 32, 40 and 52 Weeks Post-randomization Week 52	-0.90 mL/min/1.73m^2 Standard Error 1.26	3.26 mL/min/1.73m^2 Standard Error 1.36
Change From Baseline in Calculated Creatinine Clearance (Modification of Diet in Renal Disease [MDRD] Equation) at 4, 16, 24, 32, 40 and 52 Weeks Post-randomization Week 4	-0.00 mL/min/1.73m^2 Standard Error 1.16	3.18 mL/min/1.73m^2 Standard Error 1.25
Change From Baseline in Calculated Creatinine Clearance (Modification of Diet in Renal Disease [MDRD] Equation) at 4, 16, 24, 32, 40 and 52 Weeks Post-randomization Week 16	-1.92 mL/min/1.73m^2 Standard Error 1.40	4.30 mL/min/1.73m^2 Standard Error 1.51
Change From Baseline in Calculated Creatinine Clearance (Modification of Diet in Renal Disease [MDRD] Equation) at 4, 16, 24, 32, 40 and 52 Weeks Post-randomization Week 24	-1.47 mL/min/1.73m^2 Standard Error 1.36	2.54 mL/min/1.73m^2 Standard Error 1.47
Change From Baseline in Calculated Creatinine Clearance (Modification of Diet in Renal Disease [MDRD] Equation) at 4, 16, 24, 32, 40 and 52 Weeks Post-randomization Week 32	-0.15 mL/min/1.73m^2 Standard Error 1.43	2.44 mL/min/1.73m^2 Standard Error 1.54
Change From Baseline in Calculated Creatinine Clearance (Modification of Diet in Renal Disease [MDRD] Equation) at 4, 16, 24, 32, 40 and 52 Weeks Post-randomization Week 40	0.69 mL/min/1.73m^2 Standard Error 1.52	2.69 mL/min/1.73m^2 Standard Error 1.64

SECONDARY outcome

Timeframe: Baseline

Population: ITT.

Creatinine clearance calculated using MDRD equation. Calculated CC: method to approximate kidney function. It measures rate creatinine (substance formed from metabolism of creatine) is cleared from blood by kidneys. Normal adult creatinine clearance is ≥ 90 mL/min/1.73m\^2.

Outcome measures

Outcome measures
Measure	Cyclosporine or Tacrolimus n=59 Participants Continuation of Calcineurin inhibitor (CNI) regimen; included cyclosporine (CsA) or tacrolimus (TAC) which were dosed to achieve a target trough level determined by investigator; therefore, form, dosage, and frequency were site and patient specific. CsA therapy could have been switched to TAC therapy and vice versa, as warranted by clinical circumstances.	Sirolimus (SRL) n=57 Participants Conversion from CNI therapy to Sirolimus: Sirolimus initiated with oral tablets administered once daily (1 to 5 milligrams per day) to achieve target trough of 8-15 nanograms per milliliter (ng/mL). Protocol was later amended to allow target troughs of 7-15 ng/mL for duration of study. CNI discontinued within 8 weeks post randomization.
Calculated Creatinine Clearance (Modification of Diet in Renal Disease [MDRD] Equation) at Baseline	55.39 mL/min/1.73m^2 Standard Deviation 12.84	54.47 mL/min/1.73m^2 Standard Deviation 14.14

SECONDARY outcome

Timeframe: Baseline and Weeks 4, 16, 24, 32, 40, and 52

Population: ITT, All available data (on-therapy and off-therapy) were included; LOCF for data points missing due to skipped visits or participant withdrawal from study.

Serum creatinine is an indicator of kidney function. Creatinine is a substance formed from the metabolism of creatine, commonly found in blood, urine, and muscle tissue. It is removed from the blood by the kidneys and excreted in urine. Normal adult blood levels of creatinine=45 to 90 micromoles per liter (mcmol/L) for females, 60 to 110 mcmol/L for males, however normal values are age-dependent. Change from baseline=creatinine level at Week x minus baseline level where higher scores represented decreased kidney function. Least squares mean adjusted for treatment group and center.

Outcome measures

Outcome measures
Measure	Cyclosporine or Tacrolimus n=59 Participants Continuation of Calcineurin inhibitor (CNI) regimen; included cyclosporine (CsA) or tacrolimus (TAC) which were dosed to achieve a target trough level determined by investigator; therefore, form, dosage, and frequency were site and patient specific. CsA therapy could have been switched to TAC therapy and vice versa, as warranted by clinical circumstances.	Sirolimus (SRL) n=57 Participants Conversion from CNI therapy to Sirolimus: Sirolimus initiated with oral tablets administered once daily (1 to 5 milligrams per day) to achieve target trough of 8-15 nanograms per milliliter (ng/mL). Protocol was later amended to allow target troughs of 7-15 ng/mL for duration of study. CNI discontinued within 8 weeks post randomization.
Change From Baseline in Serum Creatinine Level at 4, 16, 24, 32, 40, and 52 Weeks Post-randomization Week 4	1.68 mcmol/L Standard Error 2.00	-4.95 mcmol/L Standard Error 2.15
Change From Baseline in Serum Creatinine Level at 4, 16, 24, 32, 40, and 52 Weeks Post-randomization Week 16	7.96 mcmol/L Standard Error 2.62	-5.52 mcmol/L Standard Error 2.82
Change From Baseline in Serum Creatinine Level at 4, 16, 24, 32, 40, and 52 Weeks Post-randomization Week 24	8.02 mcmol/L Standard Error 2.21	-0.89 mcmol/L Standard Error 2.37
Change From Baseline in Serum Creatinine Level at 4, 16, 24, 32, 40, and 52 Weeks Post-randomization Week 32	4.08 mcmol/L Standard Error 2.52	-2.80 mcmol/L Standard Error 2.71
Change From Baseline in Serum Creatinine Level at 4, 16, 24, 32, 40, and 52 Weeks Post-randomization Week 40	2.44 mcmol/L Standard Error 2.70	2.81 mcmol/L Standard Error 2.90
Change From Baseline in Serum Creatinine Level at 4, 16, 24, 32, 40, and 52 Weeks Post-randomization Week 52	4.76 mcmol/L Standard Error 2.22	-4.39 mcmol/L Standard Error 2.39

SECONDARY outcome

Timeframe: Baseline

Population: ITT.

Outcome measures

Outcome measures
Measure	Cyclosporine or Tacrolimus n=59 Participants Continuation of Calcineurin inhibitor (CNI) regimen; included cyclosporine (CsA) or tacrolimus (TAC) which were dosed to achieve a target trough level determined by investigator; therefore, form, dosage, and frequency were site and patient specific. CsA therapy could have been switched to TAC therapy and vice versa, as warranted by clinical circumstances.	Sirolimus (SRL) n=57 Participants Conversion from CNI therapy to Sirolimus: Sirolimus initiated with oral tablets administered once daily (1 to 5 milligrams per day) to achieve target trough of 8-15 nanograms per milliliter (ng/mL). Protocol was later amended to allow target troughs of 7-15 ng/mL for duration of study. CNI discontinued within 8 weeks post randomization.
Serum Creatinine Level at Baseline	125.42 mcmol/L Standard Deviation 23.15	126.21 mcmol/L Standard Deviation 29.63

SECONDARY outcome

Timeframe: Baseline to discontinuation (up to Week 52)

Population: ITT; N=participants with all measurements required for calculated creatinine clearance. All observed data up to the point of discontinuation of the study were used.

The change in creatinine clearance over time assessed using the random coefficient slope of the regression line with creatinine clearance as the dependent variable and study day as the independent variable. Time points calculated as study days, relative to time of randomization of study medication. Observed data multiplied by a scale factor of 365 to express an annual change.

Outcome measures

Outcome measures
Measure	Cyclosporine or Tacrolimus n=59 Participants Continuation of Calcineurin inhibitor (CNI) regimen; included cyclosporine (CsA) or tacrolimus (TAC) which were dosed to achieve a target trough level determined by investigator; therefore, form, dosage, and frequency were site and patient specific. CsA therapy could have been switched to TAC therapy and vice versa, as warranted by clinical circumstances.	Sirolimus (SRL) n=56 Participants Conversion from CNI therapy to Sirolimus: Sirolimus initiated with oral tablets administered once daily (1 to 5 milligrams per day) to achieve target trough of 8-15 nanograms per milliliter (ng/mL). Protocol was later amended to allow target troughs of 7-15 ng/mL for duration of study. CNI discontinued within 8 weeks post randomization.
Annual Change in Calculated Creatinine Clearance (Cockcroft-Gault Equation)	-0.740 mL/min/1.73m^2 Interval -2.921 to 1.441	1.571 mL/min/1.73m^2 Interval -0.447 to 3.588

SECONDARY outcome

Timeframe: Baseline until death (up to Week 56)

Population: Safety population: all randomized participants who received at least 1 dose of study medication; not analyzed by Kaplan-Meier because number of events limited to 2 deaths in the sirolimus group.

Survival time from the start of study treatment to date of death due to any cause, censored at the last visit if no death. Death was determined from the Death report. The distribution of time to death was to be estimated using Kaplan-Meier method and compared between treatment groups with a proportional hazard model. The number and percent of survival at 6 and 12 months were to be reported.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline to Week 52

Population: Safety population; n=number of participants analyzed for the specified type of biopsy.

Based on International Society for Heart and Lung Transplantation \[ISHLT\] 1990 criteria: rejections Grade 3A or higher, rejection accompanied by hemodynamic compromise or requiring treatment. Grade 3A or higher included: multifocal aggressive infiltrates and/or myocyte damage, diffuse inflammatory process with necrosis, diffuse aggressive polymorphus with necrosis, increased infiltrates, and changes in edema, hemorrhage, or vasculitis. Biopsies performed for clinically suspected rejection (for cause), site's standard of care (site protocol biopsy), or protocol mandated.

Outcome measures

Outcome measures
Measure	Cyclosporine or Tacrolimus n=57 Participants Continuation of Calcineurin inhibitor (CNI) regimen; included cyclosporine (CsA) or tacrolimus (TAC) which were dosed to achieve a target trough level determined by investigator; therefore, form, dosage, and frequency were site and patient specific. CsA therapy could have been switched to TAC therapy and vice versa, as warranted by clinical circumstances.	Sirolimus (SRL) n=57 Participants Conversion from CNI therapy to Sirolimus: Sirolimus initiated with oral tablets administered once daily (1 to 5 milligrams per day) to achieve target trough of 8-15 nanograms per milliliter (ng/mL). Protocol was later amended to allow target troughs of 7-15 ng/mL for duration of study. CNI discontinued within 8 weeks post randomization.
Number of Participants With Acute Rejection For cause biopsies (n=57, 57)	1 Participants	5 Participants
Number of Participants With Acute Rejection Standard of Care biopsies (n=11, 11)	0 Participants	2 Participants
Number of Participants With Acute Rejection Protocol mandated biopsies (n=0, 39)	NA Participants Only participants randomized to sirolimus had protocol mandated biopsies 2 to 6 weeks after conversion to sirolimus.	7 Participants

SECONDARY outcome

Timeframe: Baseline to Week 52

Population: Safety population

Severity of acute rejection summarized using revised 2005 ISHLT criteria. Grade 0R: no rejection, Grade 1R: Focal (perivascular or interstitial) infiltrate without necrosis, diffuse but sparse infiltrate without necrosis, or one focus only with aggressive infiltration and/or focal myocyte damage, Grade 2R:Multifocal aggressive infiltrates and/or myocyte damage, and Grade 3R:Diffuse inflammatory process with necrosis, or diffuse aggressive polymorphous with necrosis, increased infiltrate, changes in edema, hemorrhage and vasculitis.

Outcome measures

Outcome measures
Measure	Cyclosporine or Tacrolimus n=57 Participants Continuation of Calcineurin inhibitor (CNI) regimen; included cyclosporine (CsA) or tacrolimus (TAC) which were dosed to achieve a target trough level determined by investigator; therefore, form, dosage, and frequency were site and patient specific. CsA therapy could have been switched to TAC therapy and vice versa, as warranted by clinical circumstances.	Sirolimus (SRL) n=57 Participants Conversion from CNI therapy to Sirolimus: Sirolimus initiated with oral tablets administered once daily (1 to 5 milligrams per day) to achieve target trough of 8-15 nanograms per milliliter (ng/mL). Protocol was later amended to allow target troughs of 7-15 ng/mL for duration of study. CNI discontinued within 8 weeks post randomization.
Number of Participants With Biopsy-confirmed Acute Rejection by Severity Grade 0R site protocol	0 Participants	0 Participants
Number of Participants With Biopsy-confirmed Acute Rejection by Severity Grade 1R protocol mandated	NA Participants Only participants randomized to the Sirolimus group were required to have protocol mandated biopsies.	0 Participants
Number of Participants With Biopsy-confirmed Acute Rejection by Severity Grade 2R protocol mandated	NA Participants Only participants randomized to the Sirolimus group were required to have protocol mandated biopsies.	6 Participants
Number of Participants With Biopsy-confirmed Acute Rejection by Severity Grade 0R protocol mandated	NA Participants Only participants randomized to the Sirolimus group were required to have protocol mandated biopsies.	0 Participants
Number of Participants With Biopsy-confirmed Acute Rejection by Severity Grade 0R for cause	0 Participants	0 Participants
Number of Participants With Biopsy-confirmed Acute Rejection by Severity Grade 1R for cause	0 Participants	0 Participants
Number of Participants With Biopsy-confirmed Acute Rejection by Severity Grade 1R site protocol	0 Participants	0 Participants
Number of Participants With Biopsy-confirmed Acute Rejection by Severity Grade 2R for cause	0 Participants	4 Participants
Number of Participants With Biopsy-confirmed Acute Rejection by Severity Grade 2R site protocol	0 Participants	1 Participants
Number of Participants With Biopsy-confirmed Acute Rejection by Severity Grade 3R protocol mandated	NA Participants Only participants randomized to the Sirolimus group were required to have protocol mandated biopsies.	1 Participants
Number of Participants With Biopsy-confirmed Acute Rejection by Severity Grade 3R for cause	1 Participants	1 Participants
Number of Participants With Biopsy-confirmed Acute Rejection by Severity Grade 3R site protocol	0 Participants	1 Participants

SECONDARY outcome

Timeframe: Baseline to Week 52

Population: Safety population; not analyzed because actual start date of rejection was unknown for those diagnosed by site protocol (SOC) biopsy and protocol-required biopsy.

Time from baseline to first biopsy-confirmed acute rejection defined as any of the following (based on ISHLT 1990 criteria): all rejections Grade 3A or higher, any rejection accompanied by hemodynamic compromise, or any rejection requiring treatment. ISHLT Grade 3A or higher included: Multifocal aggressive infiltrates and/or myocyte damage, diffuse inflammatory process with necrosis, diffuse aggressive polymorphus with necrosis, increased infiltrates, and changes in edema, hemorrhage, or vasculitis.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline to Week 52

Population: Safety population; N=participants who had biopsy-confirmed acute rejection.

Number of participants requiring antilymphocyte antibody therapy with suspected or biopsy-proven, steroid-resistant, acute rejection with or without hemodynamic compromise. Acute rejection based on ISHLT 1990 criteria: all rejections Grade 3A or higher, any rejection accompanied by hemodynamic compromise, or any rejection requiring treatment. ISHLT Grade 3A or higher included: Multifocal aggressive infiltrates and/or myocyte damage, diffuse inflammatory process with necrosis, diffuse aggressive polymorphus with necrosis, increased infiltrates, and changes in edema, hemorrhage, or vasculitis.

Outcome measures

Outcome measures
Measure	Cyclosporine or Tacrolimus n=1 Participants Continuation of Calcineurin inhibitor (CNI) regimen; included cyclosporine (CsA) or tacrolimus (TAC) which were dosed to achieve a target trough level determined by investigator; therefore, form, dosage, and frequency were site and patient specific. CsA therapy could have been switched to TAC therapy and vice versa, as warranted by clinical circumstances.	Sirolimus (SRL) n=14 Participants Conversion from CNI therapy to Sirolimus: Sirolimus initiated with oral tablets administered once daily (1 to 5 milligrams per day) to achieve target trough of 8-15 nanograms per milliliter (ng/mL). Protocol was later amended to allow target troughs of 7-15 ng/mL for duration of study. CNI discontinued within 8 weeks post randomization.
Number of Participants Requiring Antibody Use in Treatment of Acute Rejection	1 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline up to Week 52

Population: Safety population.

Outcome measures

Outcome measures
Measure	Cyclosporine or Tacrolimus n=57 Participants Continuation of Calcineurin inhibitor (CNI) regimen; included cyclosporine (CsA) or tacrolimus (TAC) which were dosed to achieve a target trough level determined by investigator; therefore, form, dosage, and frequency were site and patient specific. CsA therapy could have been switched to TAC therapy and vice versa, as warranted by clinical circumstances.	Sirolimus (SRL) Conversion from CNI therapy to Sirolimus: Sirolimus initiated with oral tablets administered once daily (1 to 5 milligrams per day) to achieve target trough of 8-15 nanograms per milliliter (ng/mL). Protocol was later amended to allow target troughs of 7-15 ng/mL for duration of study. CNI discontinued within 8 weeks post randomization.
Number of Participants in Sirolimus Treatment Group Requiring Conversion Back to CNI Therapy	21 Participants	—

Adverse Events

Cyclosporine or Tacrolimus

Serious events: 13 serious events

Other events: 40 other events

Deaths: 0 deaths

Sirolimus (SRL)

Serious events: 30 serious events

Other events: 54 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Pfizer ClinicalTrials.gov Call Center

Pfizer, Inc.

Phone: 1-800-718-1021

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.
Publication restrictions are in place

Restriction type: OTHER

Serious adverse events
Measure	Cyclosporine or Tacrolimus n=57 participants at risk Continuation of Calcineurin inhibitor (CNI) regimen; included cyclosporine (CsA) or tacrolimus (TAC) which were dosed to achieve a target trough level determined by investigator; therefore, form, dosage, and frequency were site and patient specific. CsA therapy could have been switched to TAC therapy and vice versa, as warranted by clinical circumstances.	Sirolimus (SRL) n=57 participants at risk Conversion from CNI therapy to Sirolimus: Sirolimus initiated with oral tablets administered once daily (1 to 5 milligrams per day) to achieve target trough of 8-15 nanograms per milliliter (ng/mL). Protocol was later amended to allow target troughs of 7-15 ng/mL for duration of study. CNI discontinued within 8 weeks post randomization.
General disorders Abdominal pain	1.8% 1/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.8% 1/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
General disorders Asthenia	0.00% 0/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.8% 1/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
General disorders Fever	0.00% 0/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.8% 1/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
General disorders Lab test abnormal	1.8% 1/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
General disorders Sudden death	0.00% 0/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.8% 1/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
General disorders Transplant rejection	1.8% 1/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	22.8% 13/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Cardiac disorders Angina pectoris	1.8% 1/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Cardiac disorders Arrhythmia	0.00% 0/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.8% 1/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Cardiac disorders Cerebral ischemia	0.00% 0/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.8% 1/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Cardiac disorders Endocarditis	0.00% 0/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.8% 1/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Cardiac disorders Hypertension	0.00% 0/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.8% 1/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Cardiac disorders Hypotension	0.00% 0/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.8% 1/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Cardiac disorders Pericardial effusion	0.00% 0/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.8% 1/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Cardiac disorders Sick sinus syndrome	0.00% 0/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.8% 1/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Cardiac disorders Syncope	1.8% 1/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Biliary pain	0.00% 0/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.8% 1/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Cholelithiasis	3.5% 2/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Constipation	1.8% 1/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Diarrhea	1.8% 1/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.8% 1/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Gastroenteritis	0.00% 0/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.8% 1/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Gastrointestinal carcinoma	0.00% 0/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.8% 1/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Gastrointestinal disorder	0.00% 0/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.8% 1/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Liver function tests abnormal	0.00% 0/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.8% 1/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Rectal hemorrhage	0.00% 0/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.8% 1/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Blood and lymphatic system disorders Anemia	0.00% 0/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.8% 1/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Arthrosis	1.8% 1/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Myalgia	0.00% 0/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	5.3% 3/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Nervous system disorders Confusion	0.00% 0/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.8% 1/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Bronchitis	0.00% 0/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.8% 1/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Dyspnea	1.8% 1/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.8% 1/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Pharyngitis	0.00% 0/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.8% 1/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Pneumonia	0.00% 0/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	7.0% 4/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Upper respiratory infection	1.8% 1/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	3.5% 2/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Skin and subcutaneous tissue disorders Herpes zoster	1.8% 1/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Skin and subcutaneous tissue disorders Skin carcinoma	5.3% 3/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	3.5% 2/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.

Other adverse events
Measure	Cyclosporine or Tacrolimus n=57 participants at risk Continuation of Calcineurin inhibitor (CNI) regimen; included cyclosporine (CsA) or tacrolimus (TAC) which were dosed to achieve a target trough level determined by investigator; therefore, form, dosage, and frequency were site and patient specific. CsA therapy could have been switched to TAC therapy and vice versa, as warranted by clinical circumstances.	Sirolimus (SRL) n=57 participants at risk Conversion from CNI therapy to Sirolimus: Sirolimus initiated with oral tablets administered once daily (1 to 5 milligrams per day) to achieve target trough of 8-15 nanograms per milliliter (ng/mL). Protocol was later amended to allow target troughs of 7-15 ng/mL for duration of study. CNI discontinued within 8 weeks post randomization.
General disorders Abdominal pain	5.3% 3/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	12.3% 7/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
General disorders Accidental injury	0.00% 0/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	7.0% 4/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
General disorders Asthenia	8.8% 5/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	8.8% 5/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
General disorders Back pain	3.5% 2/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	7.0% 4/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
General disorders Chest pain	0.00% 0/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	5.3% 3/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
General disorders Face edema	1.8% 1/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	8.8% 5/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
General disorders Fever	1.8% 1/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	7.0% 4/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
General disorders Generalized edema	1.8% 1/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	5.3% 3/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
General disorders Headache	3.5% 2/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	14.0% 8/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
General disorders Pain	1.8% 1/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	8.8% 5/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
General disorders Transplant rejection	1.8% 1/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	7.0% 4/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Cardiac disorders Hypertension	3.5% 2/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	12.3% 7/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Cardiac disorders Tachycardia sinus	1.8% 1/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	5.3% 3/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Anorexia	0.00% 0/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	5.3% 3/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Aphthous stomatitis	0.00% 0/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	14.0% 8/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Diarrhea	10.5% 6/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	26.3% 15/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Liver function tests abnormal	0.00% 0/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	5.3% 3/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Mouth ulceration	0.00% 0/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	10.5% 6/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Nausea	8.8% 5/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	8.8% 5/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Stomatitis	1.8% 1/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	5.3% 3/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Blood and lymphatic system disorders Anemia	0.00% 0/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	8.8% 5/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Blood and lymphatic system disorders Ecchymosis	0.00% 0/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	8.8% 5/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Blood and lymphatic system disorders Leukopenia	1.8% 1/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	7.0% 4/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Metabolism and nutrition disorders Creatinine increased	5.3% 3/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Metabolism and nutrition disorders Gout	1.8% 1/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	7.0% 4/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Metabolism and nutrition disorders Healing abnormal	1.8% 1/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	5.3% 3/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Metabolism and nutrition disorders Hypercholesteremia	1.8% 1/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	10.5% 6/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Metabolism and nutrition disorders Hyperlipemia	1.8% 1/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	10.5% 6/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Metabolism and nutrition disorders Peripheral edema	15.8% 9/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	31.6% 18/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Arthralgia	3.5% 2/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	10.5% 6/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Myalgia	8.8% 5/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	7.0% 4/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Nervous system disorders Anxiety	0.00% 0/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	5.3% 3/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Nervous system disorders Depression	0.00% 0/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	5.3% 3/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Nervous system disorders Dizziness	7.0% 4/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	8.8% 5/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Nervous system disorders Insomnia	1.8% 1/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	7.0% 4/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Nervous system disorders Somnolence	1.8% 1/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	8.8% 5/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Cough increased	10.5% 6/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	8.8% 5/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Dyspnea	8.8% 5/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	10.5% 6/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Epistaxis	0.00% 0/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	7.0% 4/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Pharyngitis	0.00% 0/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	5.3% 3/57 • Baseline up to Week 56 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.