Graft Rejection, Kidney Transplant, Renal Allograft Recipients, Renal Transplant
Conditions
Keywords
renal transplant, immunosuppression, sirolimus/rapamune, planned transition
Brief summary
This study will look at the effect on long-term kidney function using tacrolimus right after a transplant and then switching to sirolimus at 3 to 5 months after the transplant.
Interventions
DRUGTacrolimus
During the screening phase, tacrolimus is provided by the investigator (not the Sponsor) and is dosed to achieve a target trough level determined by the investigator. Therefore, the dosage form, dosage, and frequency are determined by the investigator. Duration of treatment is from transplantation until randomization (from 90 to 150 days).
DRUGSirolimus
Following randomization, sirolimus is provided by the Sponsor in 1 and 2 mg oral tablets. Sirolimus is dosed once daily to achieve a target trough level of 7 to 15 ng/mL in the 1st year post-transplant and 5 - 15 ng/mL in the 2nd year post-transplant. Duration of treatment is from randomization through 2 years post-transplant (19 to 21 months).
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
At Screening: * Male or female subjects aged 18 years or older. * Recipients who are 14 days prior to transplantation up through 14 days after transplantation. * Recipients of a primary, living- or deceased-donor renal allograft. * All female and male subjects who are biologically capable of having children must agree and commit to the use of a reliable method of birth control for the duration of the study and for 3 months after the last dose of test article. A subject is biologically capable of having children even if he or she is using contraceptives or if his or her sexual partner is sterile or using contraceptives. At Randomization: * Ninety (90) to 150 days post-transplantation. * Treatment with tacrolimus and an inosine monophosphate dehydrogenase (IMPDH) inhibitor initiated less than or equal to 30 days of transplantation and has remained on both for the 30 days prior to randomization.
Exclusion criteria
At Screening: * Recipients of multiple organ transplants (i.e., any prior or concurrent transplantation of any organs including prior renal transplant. ) * Recipients of adult or pediatric en bloc kidney transplants. * Recipients who required or will require desensitization protocols. * Known history of focal segmental glomerulosclerosis (FSGS) or membranoproliferative glomerulonephritis (MPGN). * Evidence of active systemic or localized major infection, as determined by the investigator. * Received any investigational drugs or devices less than or equal to 30 days prior to transplantation. * Known or suspected allergy to sirolimus (SRL), tacrolimus (TAC), inosine-monophosphate dehydrogenase (IMPDH) inhibitor, macrolide antibiotics, iothalamate, iodine, iodine-containing products, including contrast media other compounds related to these products/classes of medication, or shellfish. * History of malignancy less than or equal to 3 years of screening (except for adequately treated basal cell or squamous cell carcinoma of the skin). * Recipients who are known to be human immunodeficiency virus (HIV) positive. * Women who are biologically capable of having children with a positive urine or serum pregnancy test at screening. * Breastfeeding women. At Randomization: * Any major illness/condition that, in the investigator's judgment, will substantially increase the risk associated with the subject's participation in and completion of the study, or could preclude the evaluation of the subject's response. * Planned treatment with immunosuppressive therapies other than those described in the protocol. * Subjects who underwent corticosteroids withdrawal or avoidance and did not receive antibody induction at the time of transplantation with anti-thymocyte globulin (rabbit) (rATG) (Thymoglobulin®), anti-thymocyte globulin (equine) (Atgam®), or alemtuzumab (Campath®). * Subjects who have had corticosteroid (CS) discontinued less than or equal to 30 days before randomization. * Calculated glomerular filtration rate (GFR) less than 40 mL/min/1.73m2 using the simplified Modification of Diet in Renal Disease (MDRD) formula less than or equal to 2 weeks prior to randomization. * Spot urine protein to creatinine ratio (UPr/Cr) greater than or equal to 0.5 less than or equal to 2 weeks prior to randomization. * Banff (2007) grade 2 or higher acute T-cell-mediated or any acute antibody-mediated rejection at any time post-transplantation. * Any acute rejection (biopsy-confirmed or presumed) less than or equal to 30 days before randomization. * More than 1 episode of acute rejection (biopsy-confirmed or presumed). * Known Banff (2007) interstitial fibrosis and tubular atrophy (IF/TA) greater than or equal to grade 2 or recurrent/de novo glomerular disease. * Major surgery less than or equal to 2 weeks prior to randomization. * Active post-operative complication, e.g. infection, delayed wound healing. * Total white blood cell count less than 2,000/mm3 or absolute neutrophil count (ANC) less than 1000 or platelet count less than 100,000/mm3 less than or equal to 2 weeks prior to randomization. * Fasting triglycerides greater than 400 mg/dL (greater than 4.5 mmol/L) or fasting total cholesterol greater than 300 mg/dL (greater than 7.8 mmol/L) less than or equal to 2 weeks prior to randomization regardless of whether or not on lipid-lowering therapy. * Women who are biologically capable of having children with a positive urine or serum pregnancy test at randomization. * Breastfeeding women.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Improvement of Greater Than or Equal to [≥]5 Milliliters Per Minute Per 1.73 Square Meters (mL/Min/m^2) in Calculated Glomerular Filtration Rate (GFR) at 24 Months Post-Transplantation (On-Therapy Analysis) | Baseline, Month 24 | GFR was calculated using the Modified Diet in Renal Disease (MDRD) equation using either serum creatinine traceable to isotope dilution mass spectrometry (IDMS) or serum creatinine not traceable to IDMS. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Improvement of ≥5 mL/Min/m^2 in Calculated GFR at 12 Months Post-Transplantation (On-Therapy Analysis) | Baseline, Month 12 | GFR was calculated using the MDRD equation using either serum creatinine traceable to IDMS or serum creatinine not traceable to IDMS. |
| Percentage of Participants With Improvement of ≥5 mL/Min/m^2 in Calculated GFR at 12 and 24 Months Post-Transplantation (Intent-to-Treat [ITT] Analysis) | Baseline, Months 12 and 24 | GFR was calculated using the MDRD equation using either serum creatinine traceable to IDMS or serum creatinine not traceable to IDMS. |
| Percentage of Participants With Improvement of ≥7.5 mL/Min/m^2 in Calculated GFR at 12 and 24 Months Post-Transplantation | Baseline, Months 12 and 24 | GFR was calculated using the MDRD equation using either serum creatinine traceable to IDMS or serum creatinine not traceable to IDMS. |
| Percentage of Participants With Improvement of ≥10 mL/Min/m^2 in Calculated GFR at 12 and 24 Months Post-Transplantation | Baseline, Months 12 and 24 | GFR was calculated using the MDRD equation using either serum creatinine traceable to IDMS or serum creatinine not traceable to IDMS. |
| Calculated GFR Using MDRD (On-Therapy Analysis) | Baseline, Months 6, 12, 18, and 24 | GFR was calculated using the MDRD equation using either serum creatinine traceable to IDMS or serum creatinine not traceable to IDMS. Baseline was defined as the last nonmissing assessment before or on the date of the first dose of test article. |
| Change From Randomization in Calculated GFR Using MDRD (On-Therapy Analysis) | Baseline, Months 6, 12, 18, and 24 | GFR was calculated using the MDRD equation using either serum creatinine traceable to IDMS or serum creatinine not traceable to IDMS. Baseline was defined as the last nonmissing assessment before or on the date of the first dose of test article. |
| Spot and 24 Hour Urine Protein to Creatinine Ratio (UPr/Cr) | Baseline and Months 12 and 24 | Baseline was defined as the last nonmissing assessment before or on the date of the first dose of test article. |
| Slope of Calculated GFR (MDRD) From Randomization to 24 Months Post-Transplantation (On-Therapy Analysis) | Baseline, Month 24 | GFR was calculated using the MDRD equation using either serum creatinine traceable to IDMS or serum creatinine not traceable to IDMS. Timepoints were calculated as study days, relative to the time of randomization of study medication. All available on-therapy values were included. Observed data were multiplied by a scale factor of 365, expressing the slope as an annual change. |
| Serum Creatinine (On-Therapy Analysis) | Baseline, Months 6, 12, 18, and 24 | Serum creatinine was measured in micromillimoles per liter (mcmol/L). Baseline was defined as the last nonmissing assessment before or on the date of the first dose of test article. |
| Change From Randomization in Serum Creatinine (On-Therapy Analysis) | Baseline, Months 6, 12, 18, and 24 | Serum creatinine was measured in mcmol/L. Baseline was defined as the last assessment prior to first administration of study drug. |
| Percentage of Participants With Biopsy-Confirmed Acute Rejection (BCAR), Graft Loss, or Death From Randomization to 24 Months Post-Transplantation | Post-randomization to Month 24 post-transplantation | Biopsy-confirmed acute rejection was defined according to updated Banff criteria (2007) for renal allograft rejection. Graft loss was defined as physical loss (nephrectomy or retransplantation), functional loss (requiring dialysis for greater than or equal to \[≥\]56 days with no return of graft function), or death. |
| Percentage of Participants With Graft Loss (Including Death) at 12 and 24 Months Post-Randomization | Post-randomization to Months 12 and 24 Post-Transplantation | Graft loss was defined as physical loss (nephrectomy or retransplantation), functional loss (requiring dialysis for ≥56 days with no return of graft function), or death. |
| Percentage of Participants With BCAR Post-Randomization to 6, 12, 18, and 24 Months Post-Transplantation | Post-Randomization to 6, 12, 18, and 24 months Post-Transplantation | BCAR was defined according to updated Banff criteria (2007) for renal allograft rejection. |
| Percentage of Participants With First On-Therapy BCAR From Transplantation Occurring at 12 and 24 Months | Months 12 and 24 | Defined as the first BCAR occurring during the On-Therapy period based on the ITT population. Time to first BCAR was the days from transplantation to the date of BCAR. |
| Number of Participants With BCAR by Severity of First BCAR and Time of Onset From Post-Randomization to 6, 12, 18, and 24 Months Post-Transplant | Months 6, 12, 18, and 24 | BCAR was categorized as antibody-mediated (AM) or T-cell. AM BCAR severity was graded as Grade I (mild), Grade II (moderate), and Grade III (severe). T-cell BCAR severity was graded as 'Grade Ia, Ib (mild), Grade IIa, IIb (moderate), and Grade III (severe). If a participant had both T-cell BCAR and antibody-mediated BCAR on the first rejection, the participant was counted in each category. |
| Percentage of Participants With Antibody Use in Treatment of Acute Rejection | On Therapy Period (up to 21 months post-randomization) and Off-Therapy Period (up to 24 months post-transplantation) | Number of participants who experienced an adverse event (AE) of rejection was used as the denominator in the determination of percentage of participants with antibody use in treatment of acute rejection. |
| Percentage of Participants With Anemia, Thrombocytopenia, or Leukopenia | Baseline, Months 12 and 24 | Anemia was defined as hemoglobin less than or equal to (≤)10 grams per deciliter (g/dL); leukopenia was defined as white blood cell (WBC) count ≤2000 per cubic millimeters (/mm\^3); and thrombocytopenia was defined as platelets ≤100,000/mm\^3. Baseline was defined as the last nonmissing assessment before or on the date of the first dose of test article. |
| Percentage of Participants Requiring Anti-Hypertensive Medication, Diabetes Agents, Lipid-Lowering Agents, or Erythropoiesis Stimuating Agents (ESAs) | Baseline, Months 12 and 24 | — |
| Percentage of Participants With Angiotensin Converting Enzyme Inhibitor (ACEI) or Angiotensin II Receptor Block (ARB) Use | Pre-randomization, On-Therapy Period (up to 21 months post-randomization), and Off-Therapy Period (up to 24 months post-transplantation) | Included ACEI or ARB use prior to randomization, during the on-therapy period (up to 19 to 21 months post randomization) and the off-therapy period (up to 24 months post-transplantation). |
| Percentage of Participants With Stomatitis | From randomization up to 24 months after transplantation (On-Therapy) | Includes adverse events based on categorization by the investigator as stomatitis, regardless of the event preferred term in Medical Dictionary for Regulatory Activities (MedDRA) |
| Percentage of Participants Requiring Treatment for Stomatitis by Treatment Type | On-Therapy Period (up to 21 months post-randomization) and Off-Therapy Period (up to 24 months post-transplantation) | Included treatments (analgesics, dental paste, topical antifungal, topical steroids, or other) prior to randomization, during the on-therapy period (up to 19 to 21 months post-randomization) and the off-therapy period (up to 24 months post-transplantation). |
| Change From Pre-Randomization to 12 Months Post-Transplantation in Hemoglobin A1C (Liter Per Liter [L/L]) | Baseline, Month 12 | Ratio of hemoglobin A1c to normal hemoglobin. |
| Change From Pre-Randomization to 12 Months Post-Transplantation in Fasting Glucose (mmol/L) | Baseline, Month 12 | — |
| Change From Pre-Randomization to 12 Months Post-Transplantation in Fasting Insulin (Picomoles Per Liter [Pmol/L]) | Baseline, Month 12 | — |
| Change From Pre-Randomization to 12 Months Post-Transplantation in Weight (Kilograms [kg]) | Baseline, Month 12 | — |
| Change From Pre-Randomization to 12 Months Post-Transplantation in Waist Circumference(Centimeters [cm]) | Baseline, Month 12 | — |
| Change From Pre-Randomization to 12 Months Post-Transplantation in Homeostasis Model Assessment Insulin Resistance (HOMA-IR; Fasting) | Baseline, Month 12 | The HOMA-IR measures insulin resistance based on fasting glucose and insulin measurements: HOMA-IR = fasting plasma glucose (mmol/L) multiplied by (\*) fasting plasma insulin in microunits per liter (µU/L) divided by (/) 22.5. Participants taking insulin within 12 hours were excluded from the analysis. |
| Change From Pre-Randomization to 12 Months Post-Transplantation in HOMA-Beta Cell (HOMA-B; Fasting) | Baseline, Month 12 | The Homeostasis Model Assessment (HOMA) estimates steady state beta cell function (%B) as a percentage of a normal reference population. HOMA-B = 20 \* insulin (µU/L) / fasting plasma glucose (mmol/L) minus (-) 3.5 Participants taking insulin within 12 hours were excluded from the analysis. |
| Change From Pre-Randomization to 12 Months Post-Transplantation in Body Mass Index (BMI; in Kilograms Per Square Meter [kg/m^2]) | Baseline, Month 12 | BMI = Weight (kg)/(Height\*Height) (square meters \[m\^2\]). |
| Percentage of Participants With New-Onset Diabetes | From Baseline to On-Therapy Month 12, from Baseline to On-Therapy Month 24, and from On-Therapy Month 12 up to On-Therapy Month 24 | Participants were considered as having new onset diabetes during the On-therapy period if any of the below events emerged from baseline to Month 24: 1) at least 30 days continuous, or at least 25 days non-stop (without gap) use of any diabetic treatment after randomization; 2) a fasting glucose greater than or equal to (≥)126 milligrams per deciliter (mg/dL) after randomization; or 3) a non-fasting glucose ≥200 mg/dL after randomization, were included in the new-onset diabetes population. Events at Months 12 or 24 occurred from baseline to On-therapy Month 12 and from On-therapy Months 12 to 24, respectively. |
| Percentage of Participants With New-Onset Diabetes Receiving Treatment for Diabetes (Insulin and Non-Insulin) | 12 Months and 24 Months | Participants were considered as having new onset diabetes during the On-therapy period if any of the below events emerged between baseline and Month 12 or Month 24: 1) at least 30 days continuous, or at least 25 days non-stop (without gap) use of any diabetic treatment after randomization; 2) a fasting glucose ≥126 mg/dL after randomization; or 3) a non-fasting glucose ≥200 mg/dL after randomization. |
| Percentage of Participants With Infection | From randomization up to 24 months after transplantation (On-Therapy) | Includes adverse events based on categorization by the investigator as 'infection', regardless of the event preferred term in MedDRA. |
| Percentage of Participants With Cytomegalovirus (CMV) Infection | From randomization up to 24 months after transplantation (On-Therapy) | Includes adverse event terms reported by the investigator to be attributed to the organism 'cytomegalovirus', regardless of the preferred term in MedDRA. |
| Percentage of Participants With Polyomavirus Infection | From randomization up to 24 months after transplantation (On-Therapy) | Includes adverse event terms reported by the investigator to be attributed to the organism 'polyomavirus', regardless of the preferred term in MedDRA. |
| Percentage of Participants With Malignancy | From randomization up to 24 months after transplantation (On-Therapy) | Includes any adverse events based on categorization by the investigator as 'malignancy', regardless of the event preferred term in MedDRA. |
| Change From Baseline (Pre-Randomization) to 12 and 24 Months Post-Transplantation in Fasting Lipid Parameters (Millimoles Per Liter [mmol/L]) | Baseline, Months 12 and 24 | Parameters assessed included total cholesterol (TC), triglycerides, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C); collected when participant was in a fasting state. |
Countries
Argentina, Australia, Brazil, Germany, Italy, Spain, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sirolimus Participants received tacrolimus (extended-release formulation not permitted) within 30 days of transplant, dosed according to center's standard of care. At 3-5 months post-transplant, participants were randomized, tacrolimus was discontinued (withdrawal was to be completed within 2 weeks \[maximum of 4 weeks\] of sirolimus initiation) and participants received sirolimus tablets, orally, at a dose to achieve trough levels of 7-15 nanograms per milliliter (ng/mL) during the first year post-transplant, then 5-15 ng/mL. Participants remained on an inosine monophosphate dehydrogenase (IMPDH) inhibitor (mycophenolate mofetil \[MMF\] or mycophenolate sodium \[MPS\]; switching between the two was permitted). Corticosteroids were maintained at a minimum of 2.5 milligrams per day (mg/day) of prednisone (or equivalent); withdrawal was prohibited after randomization. Participants received study drug during the post-randomization period for up to a maximum of 18 months post-transplant. | 131 |
| Tacrolimus Participants received tacrolimus (extended-release formulation not permitted) within 30 days of transplant, dosed according to center's standard of care. At 3-5 months post-transplant, participants were randomized and tacrolimus continued. Participants remained on an IMPDH inhibitor (MMF or MPS; switching between the two was permitted). Corticosteroids were maintained at a minimum of 2.5 mg/day of prednisone (or equivalent); withdrawal was prohibited after randomization. Participants received study drug during the post-randomization period for up to a maximum of 18 months post-transplant. | 123 |
| Total | 254 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 28 | 4 |
| Overall Study | Death | 2 | 1 |
| Overall Study | Lack of Efficacy | 5 | 0 |
| Overall Study | Lost to Follow-up | 1 | 3 |
| Overall Study | Other | 0 | 1 |
| Overall Study | Physician Decision | 3 | 1 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Withdrawal by Subject | 4 | 2 |
Baseline characteristics
| Characteristic | Sirolimus | Tacrolimus | Total |
|---|---|---|---|
| Age, Continuous | 50.7 years STANDARD_DEVIATION 13.03 | 52.4 years STANDARD_DEVIATION 12.05 | 51.5 years STANDARD_DEVIATION 12.57 |
| Sex: Female, Male Female | 42 Participants | 46 Participants | 88 Participants |
| Sex: Female, Male Male | 89 Participants | 77 Participants | 166 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 116 / 131 | 88 / 123 |
| serious Total, serious adverse events | 50 / 131 | 38 / 123 |
Outcome results
Primary
Percentage of Participants With Improvement of Greater Than or Equal to [≥]5 Milliliters Per Minute Per 1.73 Square Meters (mL/Min/m^2) in Calculated Glomerular Filtration Rate (GFR) at 24 Months Post-Transplantation (On-Therapy Analysis)
GFR was calculated using the Modified Diet in Renal Disease (MDRD) equation using either serum creatinine traceable to isotope dilution mass spectrometry (IDMS) or serum creatinine not traceable to IDMS.
Time frame: Baseline, Month 24
Population: On-Therapy Population (24 Months): all randomized participants who remained on assigned study therapy through 24 months post-transplantation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sirolimus | Percentage of Participants With Improvement of Greater Than or Equal to [≥]5 Milliliters Per Minute Per 1.73 Square Meters (mL/Min/m^2) in Calculated Glomerular Filtration Rate (GFR) at 24 Months Post-Transplantation (On-Therapy Analysis) | 33.7 percentage of participants |
| Tacrolimus | Percentage of Participants With Improvement of Greater Than or Equal to [≥]5 Milliliters Per Minute Per 1.73 Square Meters (mL/Min/m^2) in Calculated Glomerular Filtration Rate (GFR) at 24 Months Post-Transplantation (On-Therapy Analysis) | 42.2 percentage of participants |
p-value: 0.23995% CI: [0.4, 1.3]Fisher Exact
Secondary
Calculated GFR Using MDRD (On-Therapy Analysis)
GFR was calculated using the MDRD equation using either serum creatinine traceable to IDMS or serum creatinine not traceable to IDMS. Baseline was defined as the last nonmissing assessment before or on the date of the first dose of test article.
Time frame: Baseline, Months 6, 12, 18, and 24
Population: On-Therapy Population: all participants who remained on assigned study therapy up to the point of discontinuation. number (n)=number of participants assessed for the specified parameter at a given visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sirolimus | Calculated GFR Using MDRD (On-Therapy Analysis) | Month 6 (n=125,120) | 61.6 mL/min/1.73 m^2 | Standard Deviation 14.9 |
| Sirolimus | Calculated GFR Using MDRD (On-Therapy Analysis) | Month 18 (n=99,111) | 60.0 mL/min/1.73 m^2 | Standard Deviation 15 |
| Sirolimus | Calculated GFR Using MDRD (On-Therapy Analysis) | Month 12 (n=109,116) | 59.6 mL/min/1.73 m^2 | Standard Deviation 16.4 |
| Sirolimus | Calculated GFR Using MDRD (On-Therapy Analysis) | Month 24 (n=86,109) | 59.4 mL/min/1.73 m^2 | Standard Deviation 18 |
| Sirolimus | Calculated GFR Using MDRD (On-Therapy Analysis) | Baseline (n=131,123) | 58.5 mL/min/1.73 m^2 | Standard Deviation 14.3 |
| Tacrolimus | Calculated GFR Using MDRD (On-Therapy Analysis) | Month 24 (n=86,109) | 58.4 mL/min/1.73 m^2 | Standard Deviation 14.9 |
| Tacrolimus | Calculated GFR Using MDRD (On-Therapy Analysis) | Baseline (n=131,123) | 57.4 mL/min/1.73 m^2 | Standard Deviation 14.1 |
| Tacrolimus | Calculated GFR Using MDRD (On-Therapy Analysis) | Month 6 (n=125,120) | 57.6 mL/min/1.73 m^2 | Standard Deviation 14.2 |
| Tacrolimus | Calculated GFR Using MDRD (On-Therapy Analysis) | Month 12 (n=109,116) | 61.3 mL/min/1.73 m^2 | Standard Deviation 14.3 |
| Tacrolimus | Calculated GFR Using MDRD (On-Therapy Analysis) | Month 18 (n=99,111) | 59.8 mL/min/1.73 m^2 | Standard Deviation 17.1 |
Secondary
Change From Baseline (Pre-Randomization) to 12 and 24 Months Post-Transplantation in Fasting Lipid Parameters (Millimoles Per Liter [mmol/L])
Parameters assessed included total cholesterol (TC), triglycerides, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C); collected when participant was in a fasting state.
Time frame: Baseline, Months 12 and 24
Population: Safety Population; n=number of participants assessed for the specified parameter at a given visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sirolimus | Change From Baseline (Pre-Randomization) to 12 and 24 Months Post-Transplantation in Fasting Lipid Parameters (Millimoles Per Liter [mmol/L]) | TC, Change at Month 12 (n=96,107) | 0.66 mmol/L | Standard Error 0.1 |
| Sirolimus | Change From Baseline (Pre-Randomization) to 12 and 24 Months Post-Transplantation in Fasting Lipid Parameters (Millimoles Per Liter [mmol/L]) | TC, Change at Month 24 (n=74,88) | 0.51 mmol/L | Standard Error 0.14 |
| Sirolimus | Change From Baseline (Pre-Randomization) to 12 and 24 Months Post-Transplantation in Fasting Lipid Parameters (Millimoles Per Liter [mmol/L]) | HDL-C, Change at Month 12 (n=90,99) | -0.00 mmol/L | Standard Error 0.03 |
| Sirolimus | Change From Baseline (Pre-Randomization) to 12 and 24 Months Post-Transplantation in Fasting Lipid Parameters (Millimoles Per Liter [mmol/L]) | HDL-C, Change at Month 24 (n=69,81) | 0.01 mmol/L | Standard Error 0.04 |
| Sirolimus | Change From Baseline (Pre-Randomization) to 12 and 24 Months Post-Transplantation in Fasting Lipid Parameters (Millimoles Per Liter [mmol/L]) | LDL-C, Change at Month 12 (n=87,98) | 0.43 mmol/L | Standard Error 0.09 |
| Sirolimus | Change From Baseline (Pre-Randomization) to 12 and 24 Months Post-Transplantation in Fasting Lipid Parameters (Millimoles Per Liter [mmol/L]) | LDL-C, Change at Month 24 (n=66,78) | 0.34 mmol/L | Standard Error 0.13 |
| Sirolimus | Change From Baseline (Pre-Randomization) to 12 and 24 Months Post-Transplantation in Fasting Lipid Parameters (Millimoles Per Liter [mmol/L]) | Triglycerides, Change at Month 12 (n=94,104) | 0.47 mmol/L | Standard Error 0.11 |
| Sirolimus | Change From Baseline (Pre-Randomization) to 12 and 24 Months Post-Transplantation in Fasting Lipid Parameters (Millimoles Per Liter [mmol/L]) | Triglycerides, Change at Month 24 (n=73,86) | 0.43 mmol/L | Standard Error 0.1 |
| Tacrolimus | Change From Baseline (Pre-Randomization) to 12 and 24 Months Post-Transplantation in Fasting Lipid Parameters (Millimoles Per Liter [mmol/L]) | Triglycerides, Change at Month 24 (n=73,86) | 0.07 mmol/L | Standard Error 0.12 |
| Tacrolimus | Change From Baseline (Pre-Randomization) to 12 and 24 Months Post-Transplantation in Fasting Lipid Parameters (Millimoles Per Liter [mmol/L]) | TC, Change at Month 12 (n=96,107) | -0.12 mmol/L | Standard Error 0.07 |
| Tacrolimus | Change From Baseline (Pre-Randomization) to 12 and 24 Months Post-Transplantation in Fasting Lipid Parameters (Millimoles Per Liter [mmol/L]) | LDL-C, Change at Month 12 (n=87,98) | -0.06 mmol/L | Standard Error 0.07 |
| Tacrolimus | Change From Baseline (Pre-Randomization) to 12 and 24 Months Post-Transplantation in Fasting Lipid Parameters (Millimoles Per Liter [mmol/L]) | TC, Change at Month 24 (n=74,88) | -0.08 mmol/L | Standard Error 0.09 |
| Tacrolimus | Change From Baseline (Pre-Randomization) to 12 and 24 Months Post-Transplantation in Fasting Lipid Parameters (Millimoles Per Liter [mmol/L]) | Triglycerides, Change at Month 12 (n=94,104) | -0.18 mmol/L | Standard Error 0.07 |
| Tacrolimus | Change From Baseline (Pre-Randomization) to 12 and 24 Months Post-Transplantation in Fasting Lipid Parameters (Millimoles Per Liter [mmol/L]) | HDL-C, Change at Month 12 (n=90,99) | 0.01 mmol/L | Standard Error 0.02 |
| Tacrolimus | Change From Baseline (Pre-Randomization) to 12 and 24 Months Post-Transplantation in Fasting Lipid Parameters (Millimoles Per Liter [mmol/L]) | LDL-C, Change at Month 24 (n=66,78) | -0.06 mmol/L | Standard Error 0.08 |
| Tacrolimus | Change From Baseline (Pre-Randomization) to 12 and 24 Months Post-Transplantation in Fasting Lipid Parameters (Millimoles Per Liter [mmol/L]) | HDL-C, Change at Month 24 (n=69,81) | 0.01 mmol/L | Standard Error 0.03 |
Comparison: HDL-C, Month 24p-value: 0.735ANCOVA
Comparison: LDL-C, Month 12p-value: <0.001ANCOVA
Comparison: LDL-C, Month 24p-value: 0.001ANCOVA
Comparison: TC, Month 12p-value: <0.001ANCOVA
Comparison: TC, Month 24p-value: <0.001ANCOVA
Comparison: HDL-C, Month 12p-value: 0.824ANCOVA
Comparison: Triglycerides, Month 12p-value: <0.001ANCOVA
Comparison: Triglycerides, Month 24p-value: 0.028ANCOVA
Secondary
Change From Pre-Randomization to 12 Months Post-Transplantation in Body Mass Index (BMI; in Kilograms Per Square Meter [kg/m^2])
BMI = Weight (kg)/(Height\*Height) (square meters \[m\^2\]).
Time frame: Baseline, Month 12
Population: Safety Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sirolimus | Change From Pre-Randomization to 12 Months Post-Transplantation in Body Mass Index (BMI; in Kilograms Per Square Meter [kg/m^2]) | 0.53 kg/m^2 | Standard Error 0.18 |
| Tacrolimus | Change From Pre-Randomization to 12 Months Post-Transplantation in Body Mass Index (BMI; in Kilograms Per Square Meter [kg/m^2]) | 0.75 kg/m^2 | Standard Error 0.15 |
p-value: 0.337ANCOVA
Secondary
Change From Pre-Randomization to 12 Months Post-Transplantation in Fasting Glucose (mmol/L)
Time frame: Baseline, Month 12
Population: Safety Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sirolimus | Change From Pre-Randomization to 12 Months Post-Transplantation in Fasting Glucose (mmol/L) | -0.50 mmol | Standard Error 0.31 |
| Tacrolimus | Change From Pre-Randomization to 12 Months Post-Transplantation in Fasting Glucose (mmol/L) | -0.23 mmol | Standard Error 0.2 |
p-value: 0.265ANCOVA
Secondary
Change From Pre-Randomization to 12 Months Post-Transplantation in Fasting Insulin (Picomoles Per Liter [Pmol/L])
Time frame: Baseline, Month 12
Population: Safety Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sirolimus | Change From Pre-Randomization to 12 Months Post-Transplantation in Fasting Insulin (Picomoles Per Liter [Pmol/L]) | 27.25 pmol/L | Standard Error 21.97 |
| Tacrolimus | Change From Pre-Randomization to 12 Months Post-Transplantation in Fasting Insulin (Picomoles Per Liter [Pmol/L]) | 17.14 pmol/L | Standard Error 11.85 |
p-value: 0.672ANCOVA
Secondary
Change From Pre-Randomization to 12 Months Post-Transplantation in Hemoglobin A1C (Liter Per Liter [L/L])
Ratio of hemoglobin A1c to normal hemoglobin.
Time frame: Baseline, Month 12
Population: Safety Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sirolimus | Change From Pre-Randomization to 12 Months Post-Transplantation in Hemoglobin A1C (Liter Per Liter [L/L]) | -0.00 L/L | Standard Error 0 |
| Tacrolimus | Change From Pre-Randomization to 12 Months Post-Transplantation in Hemoglobin A1C (Liter Per Liter [L/L]) | 0.00 L/L | Standard Error 0 |
p-value: 0.521ANCOVA
Secondary
Change From Pre-Randomization to 12 Months Post-Transplantation in HOMA-Beta Cell (HOMA-B; Fasting)
The Homeostasis Model Assessment (HOMA) estimates steady state beta cell function (%B) as a percentage of a normal reference population. HOMA-B = 20 \* insulin (µU/L) / fasting plasma glucose (mmol/L) minus (-) 3.5 Participants taking insulin within 12 hours were excluded from the analysis.
Time frame: Baseline, Month 12
Population: Safety Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sirolimus | Change From Pre-Randomization to 12 Months Post-Transplantation in HOMA-Beta Cell (HOMA-B; Fasting) | 230.23 percentage beta cell function | Standard Error 214.68 |
| Tacrolimus | Change From Pre-Randomization to 12 Months Post-Transplantation in HOMA-Beta Cell (HOMA-B; Fasting) | 26.05 percentage beta cell function | Standard Error 21.99 |
p-value: 0.279ANCOVA
Secondary
Change From Pre-Randomization to 12 Months Post-Transplantation in Homeostasis Model Assessment Insulin Resistance (HOMA-IR; Fasting)
The HOMA-IR measures insulin resistance based on fasting glucose and insulin measurements: HOMA-IR = fasting plasma glucose (mmol/L) multiplied by (\*) fasting plasma insulin in microunits per liter (µU/L) divided by (/) 22.5. Participants taking insulin within 12 hours were excluded from the analysis.
Time frame: Baseline, Month 12
Population: Safety Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sirolimus | Change From Pre-Randomization to 12 Months Post-Transplantation in Homeostasis Model Assessment Insulin Resistance (HOMA-IR; Fasting) | 1.14 insulin resistance score | Standard Error 1.37 |
| Tacrolimus | Change From Pre-Randomization to 12 Months Post-Transplantation in Homeostasis Model Assessment Insulin Resistance (HOMA-IR; Fasting) | 1.10 insulin resistance score | Standard Error 0.7 |
p-value: 0.955ANCOVA
Secondary
Change From Pre-Randomization to 12 Months Post-Transplantation in Waist Circumference(Centimeters [cm])
Time frame: Baseline, Month 12
Population: Safety Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sirolimus | Change From Pre-Randomization to 12 Months Post-Transplantation in Waist Circumference(Centimeters [cm]) | 1.13 cm | Standard Error 0.73 |
| Tacrolimus | Change From Pre-Randomization to 12 Months Post-Transplantation in Waist Circumference(Centimeters [cm]) | 2.21 cm | Standard Error 1 |
p-value: 0.637ANCOVA
Secondary
Change From Pre-Randomization to 12 Months Post-Transplantation in Weight (Kilograms [kg])
Time frame: Baseline, Month 12
Population: Safety Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sirolimus | Change From Pre-Randomization to 12 Months Post-Transplantation in Weight (Kilograms [kg]) | 1.61 kg | Standard Error 0.51 |
| Tacrolimus | Change From Pre-Randomization to 12 Months Post-Transplantation in Weight (Kilograms [kg]) | 2.03 kg | Standard Error 0.44 |
p-value: 0.504ANCOVA
Secondary
Change From Randomization in Calculated GFR Using MDRD (On-Therapy Analysis)
GFR was calculated using the MDRD equation using either serum creatinine traceable to IDMS or serum creatinine not traceable to IDMS. Baseline was defined as the last nonmissing assessment before or on the date of the first dose of test article.
Time frame: Baseline, Months 6, 12, 18, and 24
Population: On-Therapy Population; n=number of participants assessed for the specified parameter at a given visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sirolimus | Change From Randomization in Calculated GFR Using MDRD (On-Therapy Analysis) | Month 6 (n=125,120) | 2.7 mL/min/1.73 m^2 | Standard Error 1.1 |
| Sirolimus | Change From Randomization in Calculated GFR Using MDRD (On-Therapy Analysis) | Month 12 (n=109,116) | 1.5 mL/min/1.73 m^2 | Standard Error 1.2 |
| Sirolimus | Change From Randomization in Calculated GFR Using MDRD (On-Therapy Analysis) | Month 18 (n=99,111) | 2.2 mL/min/1.73 m^2 | Standard Error 1.2 |
| Sirolimus | Change From Randomization in Calculated GFR Using MDRD (On-Therapy Analysis) | Month 24 (n=86,109) | 1.2 mL/min/1.73 m^2 | Standard Error 1.6 |
| Tacrolimus | Change From Randomization in Calculated GFR Using MDRD (On-Therapy Analysis) | Month 24 (n=86,109) | 0.6 mL/min/1.73 m^2 | Standard Error 1.3 |
| Tacrolimus | Change From Randomization in Calculated GFR Using MDRD (On-Therapy Analysis) | Month 6 (n=125,120) | 0.0 mL/min/1.73 m^2 | Standard Error 0.8 |
| Tacrolimus | Change From Randomization in Calculated GFR Using MDRD (On-Therapy Analysis) | Month 18 (n=99,111) | 1.5 mL/min/1.73 m^2 | Standard Error 1.3 |
| Tacrolimus | Change From Randomization in Calculated GFR Using MDRD (On-Therapy Analysis) | Month 12 (n=109,116) | 3.4 mL/min/1.73 m^2 | Standard Error 1.1 |
Comparison: Change from randomization at Month 6p-value: 0.01995% CI: [0.5, 5.5]ANCOVA
Comparison: Change from randomization at Month 12p-value: 0.21595% CI: [-4.8, 1.1]ANCOVA
Comparison: Change from randomization at Month 18p-value: 0.72295% CI: [-2.7, 3.9]ANCOVA
Comparison: Change from randomization at Month 24p-value: 0.7195% CI: [-3, 4.4]ANCOVA
Secondary
Change From Randomization in Serum Creatinine (On-Therapy Analysis)
Serum creatinine was measured in mcmol/L. Baseline was defined as the last assessment prior to first administration of study drug.
Time frame: Baseline, Months 6, 12, 18, and 24
Population: On-Therapy Population: all participants who remained on assigned study therapy up to the point of discontinuation. n=number of participants assessed for the specified parameter at a given visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sirolimus | Change From Randomization in Serum Creatinine (On-Therapy Analysis) | Month 18 (n=99,111) | -3.0 mcmol/L | Standard Error 2.5 |
| Sirolimus | Change From Randomization in Serum Creatinine (On-Therapy Analysis) | Month 6 (n=125,120) | -4.1 mcmol/L | Standard Error 2 |
| Sirolimus | Change From Randomization in Serum Creatinine (On-Therapy Analysis) | Month 24 (n=86,109) | 3.2 mcmol/L | Standard Error 4.6 |
| Sirolimus | Change From Randomization in Serum Creatinine (On-Therapy Analysis) | Month 12 (n=109,116) | -0.3 mcmol/L | Standard Error 2.9 |
| Tacrolimus | Change From Randomization in Serum Creatinine (On-Therapy Analysis) | Month 24 (n=86,109) | 0.5 mcmol/L | Standard Error 3.7 |
| Tacrolimus | Change From Randomization in Serum Creatinine (On-Therapy Analysis) | Month 18 (n=99,111) | -1.9 mcmol/L | Standard Error 2.3 |
| Tacrolimus | Change From Randomization in Serum Creatinine (On-Therapy Analysis) | Month 12 (n=109,116) | -7.0 mcmol/L | Standard Error 1.9 |
| Tacrolimus | Change From Randomization in Serum Creatinine (On-Therapy Analysis) | Month 6 (n=125,120) | -0.0 mcmol/L | Standard Error 1.4 |
Comparison: Change from randomization at Month 6p-value: 0.10595% CI: [-8.6, 0.8]ANCOVA
Comparison: Change from randomization at Month 12p-value: 0.02395% CI: [1.1, 14.3]ANCOVA
Comparison: Change from randomization at Month 18p-value: 0.95595% CI: [-6.8, 6.4]ANCOVA
Comparison: Change from randomization at Month 24p-value: 0.58295% CI: [-8.2, 14.6]ANCOVA
Secondary
Number of Participants With BCAR by Severity of First BCAR and Time of Onset From Post-Randomization to 6, 12, 18, and 24 Months Post-Transplant
BCAR was categorized as antibody-mediated (AM) or T-cell. AM BCAR severity was graded as Grade I (mild), Grade II (moderate), and Grade III (severe). T-cell BCAR severity was graded as 'Grade Ia, Ib (mild), Grade IIa, IIb (moderate), and Grade III (severe). If a participant had both T-cell BCAR and antibody-mediated BCAR on the first rejection, the participant was counted in each category.
Time frame: Months 6, 12, 18, and 24
Population: ITT Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sirolimus | Number of Participants With BCAR by Severity of First BCAR and Time of Onset From Post-Randomization to 6, 12, 18, and 24 Months Post-Transplant | Month 12, AM Grade I | 1 participants |
| Sirolimus | Number of Participants With BCAR by Severity of First BCAR and Time of Onset From Post-Randomization to 6, 12, 18, and 24 Months Post-Transplant | Month 6, AM Grade II | 0 participants |
| Sirolimus | Number of Participants With BCAR by Severity of First BCAR and Time of Onset From Post-Randomization to 6, 12, 18, and 24 Months Post-Transplant | Month 6, AM Grade III | 0 participants |
| Sirolimus | Number of Participants With BCAR by Severity of First BCAR and Time of Onset From Post-Randomization to 6, 12, 18, and 24 Months Post-Transplant | Month 6, T-cell Grade Ia, Ib | 2 participants |
| Sirolimus | Number of Participants With BCAR by Severity of First BCAR and Time of Onset From Post-Randomization to 6, 12, 18, and 24 Months Post-Transplant | Month 6, T-cell Grade IIa, IIb | 0 participants |
| Sirolimus | Number of Participants With BCAR by Severity of First BCAR and Time of Onset From Post-Randomization to 6, 12, 18, and 24 Months Post-Transplant | Month 6, T-cell Grade III | 0 participants |
| Sirolimus | Number of Participants With BCAR by Severity of First BCAR and Time of Onset From Post-Randomization to 6, 12, 18, and 24 Months Post-Transplant | Month 6, AM Grade I | 0 participants |
| Sirolimus | Number of Participants With BCAR by Severity of First BCAR and Time of Onset From Post-Randomization to 6, 12, 18, and 24 Months Post-Transplant | Month 12, AM Grade II | 0 participants |
| Sirolimus | Number of Participants With BCAR by Severity of First BCAR and Time of Onset From Post-Randomization to 6, 12, 18, and 24 Months Post-Transplant | Month 12, AM Grade III | 1 participants |
| Sirolimus | Number of Participants With BCAR by Severity of First BCAR and Time of Onset From Post-Randomization to 6, 12, 18, and 24 Months Post-Transplant | Month 12, T-cell Grade Ia, Ib | 5 participants |
| Sirolimus | Number of Participants With BCAR by Severity of First BCAR and Time of Onset From Post-Randomization to 6, 12, 18, and 24 Months Post-Transplant | Month 12, T-cell Grade IIa, IIb | 1 participants |
| Sirolimus | Number of Participants With BCAR by Severity of First BCAR and Time of Onset From Post-Randomization to 6, 12, 18, and 24 Months Post-Transplant | Month 12, T-cell Grade III | 0 participants |
| Sirolimus | Number of Participants With BCAR by Severity of First BCAR and Time of Onset From Post-Randomization to 6, 12, 18, and 24 Months Post-Transplant | Month 18, AM Grade I | 1 participants |
| Sirolimus | Number of Participants With BCAR by Severity of First BCAR and Time of Onset From Post-Randomization to 6, 12, 18, and 24 Months Post-Transplant | Month 18, AM Grade II | 0 participants |
| Sirolimus | Number of Participants With BCAR by Severity of First BCAR and Time of Onset From Post-Randomization to 6, 12, 18, and 24 Months Post-Transplant | Month 18, AM Grade III | 1 participants |
| Sirolimus | Number of Participants With BCAR by Severity of First BCAR and Time of Onset From Post-Randomization to 6, 12, 18, and 24 Months Post-Transplant | Month 18, T-cell Grade Ia, Ib | 7 participants |
| Sirolimus | Number of Participants With BCAR by Severity of First BCAR and Time of Onset From Post-Randomization to 6, 12, 18, and 24 Months Post-Transplant | Month 18, T-cell Grade IIa, IIb | 1 participants |
| Sirolimus | Number of Participants With BCAR by Severity of First BCAR and Time of Onset From Post-Randomization to 6, 12, 18, and 24 Months Post-Transplant | Month 18, T-cell Grade III | 0 participants |
| Sirolimus | Number of Participants With BCAR by Severity of First BCAR and Time of Onset From Post-Randomization to 6, 12, 18, and 24 Months Post-Transplant | Month 24, AM Grade I | 2 participants |
| Sirolimus | Number of Participants With BCAR by Severity of First BCAR and Time of Onset From Post-Randomization to 6, 12, 18, and 24 Months Post-Transplant | Month 24, AM Grade II | 1 participants |
| Sirolimus | Number of Participants With BCAR by Severity of First BCAR and Time of Onset From Post-Randomization to 6, 12, 18, and 24 Months Post-Transplant | Month 24, AM Grade III | 1 participants |
| Sirolimus | Number of Participants With BCAR by Severity of First BCAR and Time of Onset From Post-Randomization to 6, 12, 18, and 24 Months Post-Transplant | Month 24, T-cell Grade Ia, Ib | 8 participants |
| Sirolimus | Number of Participants With BCAR by Severity of First BCAR and Time of Onset From Post-Randomization to 6, 12, 18, and 24 Months Post-Transplant | Month 24, T-cell Grade IIa, IIb | 1 participants |
| Sirolimus | Number of Participants With BCAR by Severity of First BCAR and Time of Onset From Post-Randomization to 6, 12, 18, and 24 Months Post-Transplant | Month 24, T-cell Grade III | 0 participants |
| Tacrolimus | Number of Participants With BCAR by Severity of First BCAR and Time of Onset From Post-Randomization to 6, 12, 18, and 24 Months Post-Transplant | Month 24, T-cell Grade IIa, IIb | 1 participants |
| Tacrolimus | Number of Participants With BCAR by Severity of First BCAR and Time of Onset From Post-Randomization to 6, 12, 18, and 24 Months Post-Transplant | Month 6, AM Grade I | 0 participants |
| Tacrolimus | Number of Participants With BCAR by Severity of First BCAR and Time of Onset From Post-Randomization to 6, 12, 18, and 24 Months Post-Transplant | Month 18, AM Grade I | 1 participants |
| Tacrolimus | Number of Participants With BCAR by Severity of First BCAR and Time of Onset From Post-Randomization to 6, 12, 18, and 24 Months Post-Transplant | Month 6, AM Grade II | 0 participants |
| Tacrolimus | Number of Participants With BCAR by Severity of First BCAR and Time of Onset From Post-Randomization to 6, 12, 18, and 24 Months Post-Transplant | Month 24, AM Grade I | 1 participants |
| Tacrolimus | Number of Participants With BCAR by Severity of First BCAR and Time of Onset From Post-Randomization to 6, 12, 18, and 24 Months Post-Transplant | Month 6, AM Grade III | 0 participants |
| Tacrolimus | Number of Participants With BCAR by Severity of First BCAR and Time of Onset From Post-Randomization to 6, 12, 18, and 24 Months Post-Transplant | Month 18, AM Grade II | 0 participants |
| Tacrolimus | Number of Participants With BCAR by Severity of First BCAR and Time of Onset From Post-Randomization to 6, 12, 18, and 24 Months Post-Transplant | Month 6, T-cell Grade Ia, Ib | 0 participants |
| Tacrolimus | Number of Participants With BCAR by Severity of First BCAR and Time of Onset From Post-Randomization to 6, 12, 18, and 24 Months Post-Transplant | Month 24, T-cell Grade Ia, Ib | 1 participants |
| Tacrolimus | Number of Participants With BCAR by Severity of First BCAR and Time of Onset From Post-Randomization to 6, 12, 18, and 24 Months Post-Transplant | Month 6, T-cell Grade IIa, IIb | 0 participants |
| Tacrolimus | Number of Participants With BCAR by Severity of First BCAR and Time of Onset From Post-Randomization to 6, 12, 18, and 24 Months Post-Transplant | Month 18, AM Grade III | 0 participants |
| Tacrolimus | Number of Participants With BCAR by Severity of First BCAR and Time of Onset From Post-Randomization to 6, 12, 18, and 24 Months Post-Transplant | Month 6, T-cell Grade III | 0 participants |
| Tacrolimus | Number of Participants With BCAR by Severity of First BCAR and Time of Onset From Post-Randomization to 6, 12, 18, and 24 Months Post-Transplant | Month 24, AM Grade II | 0 participants |
| Tacrolimus | Number of Participants With BCAR by Severity of First BCAR and Time of Onset From Post-Randomization to 6, 12, 18, and 24 Months Post-Transplant | Month 12, AM Grade I | 0 participants |
| Tacrolimus | Number of Participants With BCAR by Severity of First BCAR and Time of Onset From Post-Randomization to 6, 12, 18, and 24 Months Post-Transplant | Month 18, T-cell Grade Ia, Ib | 1 participants |
| Tacrolimus | Number of Participants With BCAR by Severity of First BCAR and Time of Onset From Post-Randomization to 6, 12, 18, and 24 Months Post-Transplant | Month 12, AM Grade II | 0 participants |
| Tacrolimus | Number of Participants With BCAR by Severity of First BCAR and Time of Onset From Post-Randomization to 6, 12, 18, and 24 Months Post-Transplant | Month 24, T-cell Grade III | 0 participants |
| Tacrolimus | Number of Participants With BCAR by Severity of First BCAR and Time of Onset From Post-Randomization to 6, 12, 18, and 24 Months Post-Transplant | Month 12, AM Grade III | 0 participants |
| Tacrolimus | Number of Participants With BCAR by Severity of First BCAR and Time of Onset From Post-Randomization to 6, 12, 18, and 24 Months Post-Transplant | Month 18, T-cell Grade IIa, IIb | 1 participants |
| Tacrolimus | Number of Participants With BCAR by Severity of First BCAR and Time of Onset From Post-Randomization to 6, 12, 18, and 24 Months Post-Transplant | Month 12, T-cell Grade Ia, Ib | 0 participants |
| Tacrolimus | Number of Participants With BCAR by Severity of First BCAR and Time of Onset From Post-Randomization to 6, 12, 18, and 24 Months Post-Transplant | Month 24, AM Grade III | 0 participants |
| Tacrolimus | Number of Participants With BCAR by Severity of First BCAR and Time of Onset From Post-Randomization to 6, 12, 18, and 24 Months Post-Transplant | Month 12, T-cell Grade IIa, IIb | 1 participants |
| Tacrolimus | Number of Participants With BCAR by Severity of First BCAR and Time of Onset From Post-Randomization to 6, 12, 18, and 24 Months Post-Transplant | Month 18, T-cell Grade III | 0 participants |
| Tacrolimus | Number of Participants With BCAR by Severity of First BCAR and Time of Onset From Post-Randomization to 6, 12, 18, and 24 Months Post-Transplant | Month 12, T-cell Grade III | 0 participants |
Secondary
Percentage of Participants Requiring Anti-Hypertensive Medication, Diabetes Agents, Lipid-Lowering Agents, or Erythropoiesis Stimuating Agents (ESAs)
Time frame: Baseline, Months 12 and 24
Population: ITT Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sirolimus | Percentage of Participants Requiring Anti-Hypertensive Medication, Diabetes Agents, Lipid-Lowering Agents, or Erythropoiesis Stimuating Agents (ESAs) | Month 12, Diabetes agents (insulin) | 26.0 percentage of participants |
| Sirolimus | Percentage of Participants Requiring Anti-Hypertensive Medication, Diabetes Agents, Lipid-Lowering Agents, or Erythropoiesis Stimuating Agents (ESAs) | Month 24, Diabetes agents (non-insulin) | 9.2 percentage of participants |
| Sirolimus | Percentage of Participants Requiring Anti-Hypertensive Medication, Diabetes Agents, Lipid-Lowering Agents, or Erythropoiesis Stimuating Agents (ESAs) | Month 12, Anti-hypertensives | 75.6 percentage of participants |
| Sirolimus | Percentage of Participants Requiring Anti-Hypertensive Medication, Diabetes Agents, Lipid-Lowering Agents, or Erythropoiesis Stimuating Agents (ESAs) | Baseline, Lipid-lowering agents | 46.6 percentage of participants |
| Sirolimus | Percentage of Participants Requiring Anti-Hypertensive Medication, Diabetes Agents, Lipid-Lowering Agents, or Erythropoiesis Stimuating Agents (ESAs) | Month 24, Diabetes agents (insulin) | 18.3 percentage of participants |
| Sirolimus | Percentage of Participants Requiring Anti-Hypertensive Medication, Diabetes Agents, Lipid-Lowering Agents, or Erythropoiesis Stimuating Agents (ESAs) | Month 12, Lipid-lowering agents | 55.7 percentage of participants |
| Sirolimus | Percentage of Participants Requiring Anti-Hypertensive Medication, Diabetes Agents, Lipid-Lowering Agents, or Erythropoiesis Stimuating Agents (ESAs) | Baseline, Diabetes agents (insulin) | 46.6 percentage of participants |
| Sirolimus | Percentage of Participants Requiring Anti-Hypertensive Medication, Diabetes Agents, Lipid-Lowering Agents, or Erythropoiesis Stimuating Agents (ESAs) | Month 24, Lipid-lowering agents | 47.3 percentage of participants |
| Sirolimus | Percentage of Participants Requiring Anti-Hypertensive Medication, Diabetes Agents, Lipid-Lowering Agents, or Erythropoiesis Stimuating Agents (ESAs) | Baseline, Diabetes agents (non-insulin) | 14.5 percentage of participants |
| Sirolimus | Percentage of Participants Requiring Anti-Hypertensive Medication, Diabetes Agents, Lipid-Lowering Agents, or Erythropoiesis Stimuating Agents (ESAs) | Baseline, ESAs | 50.4 percentage of participants |
| Sirolimus | Percentage of Participants Requiring Anti-Hypertensive Medication, Diabetes Agents, Lipid-Lowering Agents, or Erythropoiesis Stimuating Agents (ESAs) | Month 24, Anti-hypertensives | 61.8 percentage of participants |
| Sirolimus | Percentage of Participants Requiring Anti-Hypertensive Medication, Diabetes Agents, Lipid-Lowering Agents, or Erythropoiesis Stimuating Agents (ESAs) | Month 12, ESAs | 7.6 percentage of participants |
| Sirolimus | Percentage of Participants Requiring Anti-Hypertensive Medication, Diabetes Agents, Lipid-Lowering Agents, or Erythropoiesis Stimuating Agents (ESAs) | Month 12, Diabetes agents (non-insulin) | 10.7 percentage of participants |
| Sirolimus | Percentage of Participants Requiring Anti-Hypertensive Medication, Diabetes Agents, Lipid-Lowering Agents, or Erythropoiesis Stimuating Agents (ESAs) | Month 24, ESAs | 3.8 percentage of participants |
| Sirolimus | Percentage of Participants Requiring Anti-Hypertensive Medication, Diabetes Agents, Lipid-Lowering Agents, or Erythropoiesis Stimuating Agents (ESAs) | Baseline, Anti-hypertensives | 95.4 percentage of participants |
| Tacrolimus | Percentage of Participants Requiring Anti-Hypertensive Medication, Diabetes Agents, Lipid-Lowering Agents, or Erythropoiesis Stimuating Agents (ESAs) | Month 24, ESAs | 2.4 percentage of participants |
| Tacrolimus | Percentage of Participants Requiring Anti-Hypertensive Medication, Diabetes Agents, Lipid-Lowering Agents, or Erythropoiesis Stimuating Agents (ESAs) | Baseline, Anti-hypertensives | 92.7 percentage of participants |
| Tacrolimus | Percentage of Participants Requiring Anti-Hypertensive Medication, Diabetes Agents, Lipid-Lowering Agents, or Erythropoiesis Stimuating Agents (ESAs) | Month 12, Anti-hypertensives | 69.9 percentage of participants |
| Tacrolimus | Percentage of Participants Requiring Anti-Hypertensive Medication, Diabetes Agents, Lipid-Lowering Agents, or Erythropoiesis Stimuating Agents (ESAs) | Month 24, Anti-hypertensives | 65.9 percentage of participants |
| Tacrolimus | Percentage of Participants Requiring Anti-Hypertensive Medication, Diabetes Agents, Lipid-Lowering Agents, or Erythropoiesis Stimuating Agents (ESAs) | Baseline, Diabetes agents (insulin) | 47.2 percentage of participants |
| Tacrolimus | Percentage of Participants Requiring Anti-Hypertensive Medication, Diabetes Agents, Lipid-Lowering Agents, or Erythropoiesis Stimuating Agents (ESAs) | Month 12, Diabetes agents (insulin) | 26.0 percentage of participants |
| Tacrolimus | Percentage of Participants Requiring Anti-Hypertensive Medication, Diabetes Agents, Lipid-Lowering Agents, or Erythropoiesis Stimuating Agents (ESAs) | Month 24, Diabetes agents (insulin) | 25.2 percentage of participants |
| Tacrolimus | Percentage of Participants Requiring Anti-Hypertensive Medication, Diabetes Agents, Lipid-Lowering Agents, or Erythropoiesis Stimuating Agents (ESAs) | Baseline, Diabetes agents (non-insulin) | 17.9 percentage of participants |
| Tacrolimus | Percentage of Participants Requiring Anti-Hypertensive Medication, Diabetes Agents, Lipid-Lowering Agents, or Erythropoiesis Stimuating Agents (ESAs) | Month 12, Diabetes agents (non-insulin) | 13.8 percentage of participants |
| Tacrolimus | Percentage of Participants Requiring Anti-Hypertensive Medication, Diabetes Agents, Lipid-Lowering Agents, or Erythropoiesis Stimuating Agents (ESAs) | Month 24, Diabetes agents (non-insulin) | 13.0 percentage of participants |
| Tacrolimus | Percentage of Participants Requiring Anti-Hypertensive Medication, Diabetes Agents, Lipid-Lowering Agents, or Erythropoiesis Stimuating Agents (ESAs) | Baseline, Lipid-lowering agents | 60.2 percentage of participants |
| Tacrolimus | Percentage of Participants Requiring Anti-Hypertensive Medication, Diabetes Agents, Lipid-Lowering Agents, or Erythropoiesis Stimuating Agents (ESAs) | Month 12, Lipid-lowering agents | 54.5 percentage of participants |
| Tacrolimus | Percentage of Participants Requiring Anti-Hypertensive Medication, Diabetes Agents, Lipid-Lowering Agents, or Erythropoiesis Stimuating Agents (ESAs) | Month 24, Lipid-lowering agents | 49.6 percentage of participants |
| Tacrolimus | Percentage of Participants Requiring Anti-Hypertensive Medication, Diabetes Agents, Lipid-Lowering Agents, or Erythropoiesis Stimuating Agents (ESAs) | Baseline, ESAs | 43.1 percentage of participants |
| Tacrolimus | Percentage of Participants Requiring Anti-Hypertensive Medication, Diabetes Agents, Lipid-Lowering Agents, or Erythropoiesis Stimuating Agents (ESAs) | Month 12, ESAs | 2.4 percentage of participants |
Comparison: Anti-hypertensives, Baselinep-value: 0.429Fisher Exact
Comparison: Anti-hypertensives, Month 12p-value: 0.326Fisher Exact
Comparison: Anti-hypertensives, Month 24p-value: 0.517Fisher Exact
Comparison: Diabetes agents (insulin), Baselinep-value: 1Fisher Exact
Comparison: Diabetes agent (insulin), Month 12p-value: 1Fisher Exact
Comparison: Diabetes agent (insulin), Month 24p-value: 0.223Fisher Exact
Comparison: Diabetes agent (non-insulin), Baselinep-value: 0.498Fisher Exact
Comparison: Diabetes agent (non-insulin), Month 12p-value: 0.566Fisher Exact
Comparison: Diabetes agent (non-insulin), Month 24p-value: 0.423Fisher Exact
Comparison: Lipid-lowering agents, Baselinep-value: 0.033Fisher Exact
Comparison: Lipid-lowering agents, Month 12p-value: 0.9Fisher Exact
Comparison: Lipid-lowering agents, Month 24p-value: 0.802Fisher Exact
Comparison: ESAs, Baselinep-value: 0.26Fisher Exact
Comparison: ESAs, Month 12p-value: 0.086Fisher Exact
Comparison: ESAs, Month 24p-value: 0.723Fisher Exact
Secondary
Percentage of Participants Requiring Treatment for Stomatitis by Treatment Type
Included treatments (analgesics, dental paste, topical antifungal, topical steroids, or other) prior to randomization, during the on-therapy period (up to 19 to 21 months post-randomization) and the off-therapy period (up to 24 months post-transplantation).
Time frame: On-Therapy Period (up to 21 months post-randomization) and Off-Therapy Period (up to 24 months post-transplantation)
Population: ITT Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sirolimus | Percentage of Participants Requiring Treatment for Stomatitis by Treatment Type | On-Therapy Period, any treatment | 17.6 percentage of participants |
| Sirolimus | Percentage of Participants Requiring Treatment for Stomatitis by Treatment Type | Off-Therapy Period, any treatment | 3.1 percentage of participants |
| Sirolimus | Percentage of Participants Requiring Treatment for Stomatitis by Treatment Type | On-Therapy, analgesics | 0.8 percentage of participants |
| Sirolimus | Percentage of Participants Requiring Treatment for Stomatitis by Treatment Type | On-Therapy, dental paste | 3.8 percentage of participants |
| Sirolimus | Percentage of Participants Requiring Treatment for Stomatitis by Treatment Type | On-Therapy, topical steroids | 5.3 percentage of participants |
| Sirolimus | Percentage of Participants Requiring Treatment for Stomatitis by Treatment Type | On-Therapy, other | 10.7 percentage of participants |
| Sirolimus | Percentage of Participants Requiring Treatment for Stomatitis by Treatment Type | Off-Therapy, topical steroids | 1.5 percentage of participants |
| Sirolimus | Percentage of Participants Requiring Treatment for Stomatitis by Treatment Type | Off-Therapy, other | 1.5 percentage of participants |
| Tacrolimus | Percentage of Participants Requiring Treatment for Stomatitis by Treatment Type | Off-Therapy, other | 1.6 percentage of participants |
| Tacrolimus | Percentage of Participants Requiring Treatment for Stomatitis by Treatment Type | On-Therapy Period, any treatment | 2.4 percentage of participants |
| Tacrolimus | Percentage of Participants Requiring Treatment for Stomatitis by Treatment Type | On-Therapy, topical steroids | 0.0 percentage of participants |
| Tacrolimus | Percentage of Participants Requiring Treatment for Stomatitis by Treatment Type | Off-Therapy Period, any treatment | 1.6 percentage of participants |
| Tacrolimus | Percentage of Participants Requiring Treatment for Stomatitis by Treatment Type | Off-Therapy, topical steroids | 0.0 percentage of participants |
| Tacrolimus | Percentage of Participants Requiring Treatment for Stomatitis by Treatment Type | On-Therapy, analgesics | 0.0 percentage of participants |
| Tacrolimus | Percentage of Participants Requiring Treatment for Stomatitis by Treatment Type | On-Therapy, other | 2.4 percentage of participants |
| Tacrolimus | Percentage of Participants Requiring Treatment for Stomatitis by Treatment Type | On-Therapy, dental paste | 0.8 percentage of participants |
Comparison: On-Therapy Period, any treatmentp-value: <0.001Fisher Exact
Comparison: Off-Therapy Period, any treatmentp-value: 0.685Fisher Exact
Secondary
Percentage of Participants With Anemia, Thrombocytopenia, or Leukopenia
Anemia was defined as hemoglobin less than or equal to (≤)10 grams per deciliter (g/dL); leukopenia was defined as white blood cell (WBC) count ≤2000 per cubic millimeters (/mm\^3); and thrombocytopenia was defined as platelets ≤100,000/mm\^3. Baseline was defined as the last nonmissing assessment before or on the date of the first dose of test article.
Time frame: Baseline, Months 12 and 24
Population: Safety Population; n=number of participants assessed for the specified parameter at a given visit.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sirolimus | Percentage of Participants With Anemia, Thrombocytopenia, or Leukopenia | Baseline (n=131,122) | 4.6 percentage of participants |
| Sirolimus | Percentage of Participants With Anemia, Thrombocytopenia, or Leukopenia | Month 12 (n=110,116) | 9.1 percentage of participants |
| Sirolimus | Percentage of Participants With Anemia, Thrombocytopenia, or Leukopenia | Month 24 (n=89,112) | 3.4 percentage of participants |
| Tacrolimus | Percentage of Participants With Anemia, Thrombocytopenia, or Leukopenia | Baseline (n=131,122) | 1.6 percentage of participants |
| Tacrolimus | Percentage of Participants With Anemia, Thrombocytopenia, or Leukopenia | Month 12 (n=110,116) | 2.6 percentage of participants |
| Tacrolimus | Percentage of Participants With Anemia, Thrombocytopenia, or Leukopenia | Month 24 (n=89,112) | 4.5 percentage of participants |
Comparison: Baselinep-value: 0.284Fisher Exact
Comparison: Month 12p-value: 0.046Fisher Exact
Comparison: Month 24p-value: 1Fisher Exact
Secondary
Percentage of Participants With Angiotensin Converting Enzyme Inhibitor (ACEI) or Angiotensin II Receptor Block (ARB) Use
Included ACEI or ARB use prior to randomization, during the on-therapy period (up to 19 to 21 months post randomization) and the off-therapy period (up to 24 months post-transplantation).
Time frame: Pre-randomization, On-Therapy Period (up to 21 months post-randomization), and Off-Therapy Period (up to 24 months post-transplantation)
Population: ITT Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sirolimus | Percentage of Participants With Angiotensin Converting Enzyme Inhibitor (ACEI) or Angiotensin II Receptor Block (ARB) Use | Pre-randomization | 46.6 percentage of participants |
| Sirolimus | Percentage of Participants With Angiotensin Converting Enzyme Inhibitor (ACEI) or Angiotensin II Receptor Block (ARB) Use | On-Therapy Period | 43.5 percentage of participants |
| Sirolimus | Percentage of Participants With Angiotensin Converting Enzyme Inhibitor (ACEI) or Angiotensin II Receptor Block (ARB) Use | Off-Therapy Period | 32.1 percentage of participants |
| Tacrolimus | Percentage of Participants With Angiotensin Converting Enzyme Inhibitor (ACEI) or Angiotensin II Receptor Block (ARB) Use | Pre-randomization | 46.3 percentage of participants |
| Tacrolimus | Percentage of Participants With Angiotensin Converting Enzyme Inhibitor (ACEI) or Angiotensin II Receptor Block (ARB) Use | On-Therapy Period | 29.3 percentage of participants |
| Tacrolimus | Percentage of Participants With Angiotensin Converting Enzyme Inhibitor (ACEI) or Angiotensin II Receptor Block (ARB) Use | Off-Therapy Period | 18.7 percentage of participants |
Comparison: Pre-randomizationp-value: 1Fisher Exact
Comparison: On-Therapy Periodp-value: 0.02Fisher Exact
Comparison: Off-Therapy Periodp-value: 0.021Fisher Exact
Secondary
Percentage of Participants With Antibody Use in Treatment of Acute Rejection
Number of participants who experienced an adverse event (AE) of rejection was used as the denominator in the determination of percentage of participants with antibody use in treatment of acute rejection.
Time frame: On Therapy Period (up to 21 months post-randomization) and Off-Therapy Period (up to 24 months post-transplantation)
Population: Safety Population; only participants with an AE of rejection were included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sirolimus | Percentage of Participants With Antibody Use in Treatment of Acute Rejection | On-therapy Period | 60.0 percentage of participants |
| Sirolimus | Percentage of Participants With Antibody Use in Treatment of Acute Rejection | Off-therapy Period | 40.0 percentage of participants |
| Tacrolimus | Percentage of Participants With Antibody Use in Treatment of Acute Rejection | On-therapy Period | 75.0 percentage of participants |
| Tacrolimus | Percentage of Participants With Antibody Use in Treatment of Acute Rejection | Off-therapy Period | 25.0 percentage of participants |
Comparison: On-therapy Periodp-value: 1Fisher Exact
Comparison: Off-therapy Periodp-value: 1Fisher Exact
Secondary
Percentage of Participants With BCAR Post-Randomization to 6, 12, 18, and 24 Months Post-Transplantation
BCAR was defined according to updated Banff criteria (2007) for renal allograft rejection.
Time frame: Post-Randomization to 6, 12, 18, and 24 months Post-Transplantation
Population: ITT Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sirolimus | Percentage of Participants With BCAR Post-Randomization to 6, 12, 18, and 24 Months Post-Transplantation | Month 6 | 1.5 percentage of participants |
| Sirolimus | Percentage of Participants With BCAR Post-Randomization to 6, 12, 18, and 24 Months Post-Transplantation | Month 12 | 5.3 percentage of participants |
| Sirolimus | Percentage of Participants With BCAR Post-Randomization to 6, 12, 18, and 24 Months Post-Transplantation | Month 18 | 6.9 percentage of participants |
| Sirolimus | Percentage of Participants With BCAR Post-Randomization to 6, 12, 18, and 24 Months Post-Transplantation | Month 24 | 8.4 percentage of participants |
| Tacrolimus | Percentage of Participants With BCAR Post-Randomization to 6, 12, 18, and 24 Months Post-Transplantation | Month 24 | 1.6 percentage of participants |
| Tacrolimus | Percentage of Participants With BCAR Post-Randomization to 6, 12, 18, and 24 Months Post-Transplantation | Month 6 | 0.0 percentage of participants |
| Tacrolimus | Percentage of Participants With BCAR Post-Randomization to 6, 12, 18, and 24 Months Post-Transplantation | Month 18 | 1.6 percentage of participants |
| Tacrolimus | Percentage of Participants With BCAR Post-Randomization to 6, 12, 18, and 24 Months Post-Transplantation | Month 12 | 0.8 percentage of participants |
Comparison: Month 6p-value: 0.499Fisher Exact
Comparison: Month 12p-value: 0.067Fisher Exact
Comparison: Month 18p-value: 0.061Fisher Exact
Comparison: Month 24p-value: 0.02Fisher Exact
Secondary
Percentage of Participants With Biopsy-Confirmed Acute Rejection (BCAR), Graft Loss, or Death From Randomization to 24 Months Post-Transplantation
Biopsy-confirmed acute rejection was defined according to updated Banff criteria (2007) for renal allograft rejection. Graft loss was defined as physical loss (nephrectomy or retransplantation), functional loss (requiring dialysis for greater than or equal to \[≥\]56 days with no return of graft function), or death.
Time frame: Post-randomization to Month 24 post-transplantation
Population: ITT Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sirolimus | Percentage of Participants With Biopsy-Confirmed Acute Rejection (BCAR), Graft Loss, or Death From Randomization to 24 Months Post-Transplantation | 11.5 percentage of participants |
| Tacrolimus | Percentage of Participants With Biopsy-Confirmed Acute Rejection (BCAR), Graft Loss, or Death From Randomization to 24 Months Post-Transplantation | 2.4 percentage of participants |
p-value: 0.006Fisher Exact
Secondary
Percentage of Participants With Cytomegalovirus (CMV) Infection
Includes adverse event terms reported by the investigator to be attributed to the organism 'cytomegalovirus', regardless of the preferred term in MedDRA.
Time frame: From randomization up to 24 months after transplantation (On-Therapy)
Population: Safety Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sirolimus | Percentage of Participants With Cytomegalovirus (CMV) Infection | 3.1 percentage of participants |
| Tacrolimus | Percentage of Participants With Cytomegalovirus (CMV) Infection | 3.3 percentage of participants |
p-value: 1Fisher Exact
Secondary
Percentage of Participants With First On-Therapy BCAR From Transplantation Occurring at 12 and 24 Months
Defined as the first BCAR occurring during the On-Therapy period based on the ITT population. Time to first BCAR was the days from transplantation to the date of BCAR.
Time frame: Months 12 and 24
Population: ITT Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sirolimus | Percentage of Participants With First On-Therapy BCAR From Transplantation Occurring at 12 and 24 Months | Month 12 | 5.1 percentage of participants |
| Sirolimus | Percentage of Participants With First On-Therapy BCAR From Transplantation Occurring at 12 and 24 Months | Month 24 | 9.3 percentage of participants |
| Tacrolimus | Percentage of Participants With First On-Therapy BCAR From Transplantation Occurring at 12 and 24 Months | Month 12 | 0.0 percentage of participants |
| Tacrolimus | Percentage of Participants With First On-Therapy BCAR From Transplantation Occurring at 12 and 24 Months | Month 24 | 0.9 percentage of participants |
Secondary
Percentage of Participants With Graft Loss (Including Death) at 12 and 24 Months Post-Randomization
Graft loss was defined as physical loss (nephrectomy or retransplantation), functional loss (requiring dialysis for ≥56 days with no return of graft function), or death.
Time frame: Post-randomization to Months 12 and 24 Post-Transplantation
Population: ITT Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sirolimus | Percentage of Participants With Graft Loss (Including Death) at 12 and 24 Months Post-Randomization | Month 12 | 0.8 percentage of participants |
| Sirolimus | Percentage of Participants With Graft Loss (Including Death) at 12 and 24 Months Post-Randomization | Month 24 | 3.8 percentage of participants |
| Tacrolimus | Percentage of Participants With Graft Loss (Including Death) at 12 and 24 Months Post-Randomization | Month 12 | 0.0 percentage of participants |
| Tacrolimus | Percentage of Participants With Graft Loss (Including Death) at 12 and 24 Months Post-Randomization | Month 24 | 0.8 percentage of participants |
Comparison: Post-randomization to Month 12 Post-transplantationp-value: 1Fisher Exact
Comparison: Post-randomization to Month 24 post-transplantationp-value: 0.215Fisher Exact
Secondary
Percentage of Participants With Improvement of ≥10 mL/Min/m^2 in Calculated GFR at 12 and 24 Months Post-Transplantation
GFR was calculated using the MDRD equation using either serum creatinine traceable to IDMS or serum creatinine not traceable to IDMS.
Time frame: Baseline, Months 12 and 24
Population: ITT Population. Missing GFR was imputed as follows: 1) GFR=0 after graft loss and 2) last observed value prior to missing was carried forward for death (with functioning graft), early termination or skipped assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sirolimus | Percentage of Participants With Improvement of ≥10 mL/Min/m^2 in Calculated GFR at 12 and 24 Months Post-Transplantation | Month 12 | 19.8 percentage of participants |
| Sirolimus | Percentage of Participants With Improvement of ≥10 mL/Min/m^2 in Calculated GFR at 12 and 24 Months Post-Transplantation | Month 24 | 22.1 percentage of participants |
| Tacrolimus | Percentage of Participants With Improvement of ≥10 mL/Min/m^2 in Calculated GFR at 12 and 24 Months Post-Transplantation | Month 12 | 23.6 percentage of participants |
| Tacrolimus | Percentage of Participants With Improvement of ≥10 mL/Min/m^2 in Calculated GFR at 12 and 24 Months Post-Transplantation | Month 24 | 22.0 percentage of participants |
Comparison: Month 12p-value: 0.54395% CI: [0.4, 1.5]Fisher Exact
Comparison: Month 24p-value: 195% CI: [0.6, 1.8]Fisher Exact
Secondary
Percentage of Participants With Improvement of ≥5 mL/Min/m^2 in Calculated GFR at 12 and 24 Months Post-Transplantation (Intent-to-Treat [ITT] Analysis)
GFR was calculated using the MDRD equation using either serum creatinine traceable to IDMS or serum creatinine not traceable to IDMS.
Time frame: Baseline, Months 12 and 24
Population: ITT Population: all randomized participants who received at least 1 dose of the assigned therapy after randomization. Missing GFR was imputed as follows: 1) GFR equals (=)0 after graft loss and 2) last observed value prior to missing was carried forward for death (with functioning graft), early termination or skipped assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sirolimus | Percentage of Participants With Improvement of ≥5 mL/Min/m^2 in Calculated GFR at 12 and 24 Months Post-Transplantation (Intent-to-Treat [ITT] Analysis) | Month 12 | 38.2 percentage of participants |
| Sirolimus | Percentage of Participants With Improvement of ≥5 mL/Min/m^2 in Calculated GFR at 12 and 24 Months Post-Transplantation (Intent-to-Treat [ITT] Analysis) | Month 24 | 33.6 percentage of participants |
| Tacrolimus | Percentage of Participants With Improvement of ≥5 mL/Min/m^2 in Calculated GFR at 12 and 24 Months Post-Transplantation (Intent-to-Treat [ITT] Analysis) | Month 12 | 42.3 percentage of participants |
| Tacrolimus | Percentage of Participants With Improvement of ≥5 mL/Min/m^2 in Calculated GFR at 12 and 24 Months Post-Transplantation (Intent-to-Treat [ITT] Analysis) | Month 24 | 40.7 percentage of participants |
Comparison: Month 12p-value: 0.52495% CI: [0.5, 1.4]Fisher Exact
Comparison: Month 24p-value: 0.29895% CI: [0.4, 1.2]Fisher Exact
Secondary
Percentage of Participants With Improvement of ≥5 mL/Min/m^2 in Calculated GFR at 12 Months Post-Transplantation (On-Therapy Analysis)
GFR was calculated using the MDRD equation using either serum creatinine traceable to IDMS or serum creatinine not traceable to IDMS.
Time frame: Baseline, Month 12
Population: On-Therapy Population (12 Months): all randomized participants who remained on assigned study therapy through 12 months post-transplantation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sirolimus | Percentage of Participants With Improvement of ≥5 mL/Min/m^2 in Calculated GFR at 12 Months Post-Transplantation (On-Therapy Analysis) | 39.4 percentage of participants |
| Tacrolimus | Percentage of Participants With Improvement of ≥5 mL/Min/m^2 in Calculated GFR at 12 Months Post-Transplantation (On-Therapy Analysis) | 44.8 percentage of participants |
p-value: 0.42295% CI: [0.5, 1.4]Fisher Exact
Secondary
Percentage of Participants With Improvement of ≥7.5 mL/Min/m^2 in Calculated GFR at 12 and 24 Months Post-Transplantation
GFR was calculated using the MDRD equation using either serum creatinine traceable to IDMS or serum creatinine not traceable to IDMS.
Time frame: Baseline, Months 12 and 24
Population: ITT Population. Missing GFR was imputed as follows: 1) GFR=0 after graft loss and 2) last observed value prior to missing was carried forward for death (with functioning graft), early termination or skipped assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sirolimus | Percentage of Participants With Improvement of ≥7.5 mL/Min/m^2 in Calculated GFR at 12 and 24 Months Post-Transplantation | Month 12 | 24.4 percentage of participants |
| Sirolimus | Percentage of Participants With Improvement of ≥7.5 mL/Min/m^2 in Calculated GFR at 12 and 24 Months Post-Transplantation | Month 24 | 25.2 percentage of participants |
| Tacrolimus | Percentage of Participants With Improvement of ≥7.5 mL/Min/m^2 in Calculated GFR at 12 and 24 Months Post-Transplantation | Month 12 | 35.8 percentage of participants |
| Tacrolimus | Percentage of Participants With Improvement of ≥7.5 mL/Min/m^2 in Calculated GFR at 12 and 24 Months Post-Transplantation | Month 24 | 30.9 percentage of participants |
Comparison: Month 12p-value: 0.05595% CI: [0.3, 1]Fisher Exact
Comparison: Month 24p-value: 0.3395% CI: [0.4, 1.3]Fisher Exact
Secondary
Percentage of Participants With Infection
Includes adverse events based on categorization by the investigator as 'infection', regardless of the event preferred term in MedDRA.
Time frame: From randomization up to 24 months after transplantation (On-Therapy)
Population: Safety Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sirolimus | Percentage of Participants With Infection | 61.8 percentage of participants |
| Tacrolimus | Percentage of Participants With Infection | 52.0 percentage of participants |
p-value: 0.129Fisher Exact
Secondary
Percentage of Participants With Malignancy
Includes any adverse events based on categorization by the investigator as 'malignancy', regardless of the event preferred term in MedDRA.
Time frame: From randomization up to 24 months after transplantation (On-Therapy)
Population: Safety Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sirolimus | Percentage of Participants With Malignancy | 3.1 percentage of participants |
| Tacrolimus | Percentage of Participants With Malignancy | 7.3 percentage of participants |
p-value: 0.158Fisher Exact
Secondary
Percentage of Participants With New-Onset Diabetes
Participants were considered as having new onset diabetes during the On-therapy period if any of the below events emerged from baseline to Month 24: 1) at least 30 days continuous, or at least 25 days non-stop (without gap) use of any diabetic treatment after randomization; 2) a fasting glucose greater than or equal to (≥)126 milligrams per deciliter (mg/dL) after randomization; or 3) a non-fasting glucose ≥200 mg/dL after randomization, were included in the new-onset diabetes population. Events at Months 12 or 24 occurred from baseline to On-therapy Month 12 and from On-therapy Months 12 to 24, respectively.
Time frame: From Baseline to On-Therapy Month 12, from Baseline to On-Therapy Month 24, and from On-Therapy Month 12 up to On-Therapy Month 24
Population: Safety Population; participants at risk of new-onset diabetes mellitus at the beginning of the analysis interval were included and those with pre-existing diabetes were excluded from the analysis. n=number of participants assessed for the specified parameter at a given visit.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sirolimus | Percentage of Participants With New-Onset Diabetes | New onset (n=82,72) | 18.3 percentage of participants |
| Sirolimus | Percentage of Participants With New-Onset Diabetes | New onset at 1 year (n=82,72) | 14.6 percentage of participants |
| Sirolimus | Percentage of Participants With New-Onset Diabetes | New onset at 2 years (n=70,70) | 4.3 percentage of participants |
| Tacrolimus | Percentage of Participants With New-Onset Diabetes | New onset (n=82,72) | 5.6 percentage of participants |
| Tacrolimus | Percentage of Participants With New-Onset Diabetes | New onset at 1 year (n=82,72) | 2.8 percentage of participants |
| Tacrolimus | Percentage of Participants With New-Onset Diabetes | New onset at 2 years (n=70,70) | 2.9 percentage of participants |
Comparison: New onset (from baseline up to On-Therapy Month 24)p-value: 0.025Fisher Exact
Comparison: New onset at 1 year (from baseline up to On-Therapy Month 12)p-value: 0.012Fisher Exact
Comparison: New onset at 2 years (from On-Therapy Month 12 to On-Therapy Month 24)p-value: 1Fisher Exact
Secondary
Percentage of Participants With New-Onset Diabetes Receiving Treatment for Diabetes (Insulin and Non-Insulin)
Participants were considered as having new onset diabetes during the On-therapy period if any of the below events emerged between baseline and Month 12 or Month 24: 1) at least 30 days continuous, or at least 25 days non-stop (without gap) use of any diabetic treatment after randomization; 2) a fasting glucose ≥126 mg/dL after randomization; or 3) a non-fasting glucose ≥200 mg/dL after randomization.
Time frame: 12 Months and 24 Months
Population: Safety Population. Only participants with new-onset diabetes mellitus at the beginning of the analysis interval were included; those with pre-existing diabetes were excluded from the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sirolimus | Percentage of Participants With New-Onset Diabetes Receiving Treatment for Diabetes (Insulin and Non-Insulin) | Insulin (12-Month) | 13.3 percentage of participants |
| Sirolimus | Percentage of Participants With New-Onset Diabetes Receiving Treatment for Diabetes (Insulin and Non-Insulin) | Insulin (24-Month) | 6.7 percentage of participants |
| Sirolimus | Percentage of Participants With New-Onset Diabetes Receiving Treatment for Diabetes (Insulin and Non-Insulin) | Non-insulin (12-Month) | 13.3 percentage of participants |
| Sirolimus | Percentage of Participants With New-Onset Diabetes Receiving Treatment for Diabetes (Insulin and Non-Insulin) | Non-Insulin (24-Month) | 13.3 percentage of participants |
| Tacrolimus | Percentage of Participants With New-Onset Diabetes Receiving Treatment for Diabetes (Insulin and Non-Insulin) | Non-Insulin (24-Month) | 0.0 percentage of participants |
| Tacrolimus | Percentage of Participants With New-Onset Diabetes Receiving Treatment for Diabetes (Insulin and Non-Insulin) | Insulin (12-Month) | 0.0 percentage of participants |
| Tacrolimus | Percentage of Participants With New-Onset Diabetes Receiving Treatment for Diabetes (Insulin and Non-Insulin) | Non-insulin (12-Month) | 0.0 percentage of participants |
| Tacrolimus | Percentage of Participants With New-Onset Diabetes Receiving Treatment for Diabetes (Insulin and Non-Insulin) | Insulin (24-Month) | 25.0 percentage of participants |
Comparison: Insulin (12-Month)p-value: 1Fisher Exact
Comparison: Non-insulin (12-Month)p-value: 1Fisher Exact
Comparison: Non-insulin (24-Month)p-value: 0.386Fisher Exact
Comparison: Insulin (24-Month)p-value: 1Fisher Exact
Secondary
Percentage of Participants With Polyomavirus Infection
Includes adverse event terms reported by the investigator to be attributed to the organism 'polyomavirus', regardless of the preferred term in MedDRA.
Time frame: From randomization up to 24 months after transplantation (On-Therapy)
Population: Safety Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sirolimus | Percentage of Participants With Polyomavirus Infection | 3.8 percentage of participants |
| Tacrolimus | Percentage of Participants With Polyomavirus Infection | 7.3 percentage of participants |
p-value: 0.276Fisher Exact
Secondary
Percentage of Participants With Stomatitis
Includes adverse events based on categorization by the investigator as stomatitis, regardless of the event preferred term in Medical Dictionary for Regulatory Activities (MedDRA)
Time frame: From randomization up to 24 months after transplantation (On-Therapy)
Population: Safety Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sirolimus | Percentage of Participants With Stomatitis | 28.2 percentage of participants |
| Tacrolimus | Percentage of Participants With Stomatitis | 1.6 percentage of participants |
p-value: <0.001Fisher Exact
Secondary
Serum Creatinine (On-Therapy Analysis)
Serum creatinine was measured in micromillimoles per liter (mcmol/L). Baseline was defined as the last nonmissing assessment before or on the date of the first dose of test article.
Time frame: Baseline, Months 6, 12, 18, and 24
Population: On-Therapy Population: all participants who remained on assigned study therapy up to the point of discontinuation. n=number of participants assessed for the specified parameter at a given visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sirolimus | Serum Creatinine (On-Therapy Analysis) | Month 6 (n=125,120) | 113.9 mcmol/L | Standard Deviation 27.6 |
| Sirolimus | Serum Creatinine (On-Therapy Analysis) | Month 18 (n=99,111) | 116.9 mcmol/L | Standard Deviation 33.1 |
| Sirolimus | Serum Creatinine (On-Therapy Analysis) | Month 12 (n=109,116) | 119.6 mcmol/L | Standard Deviation 37.5 |
| Sirolimus | Serum Creatinine (On-Therapy Analysis) | Month 24 (n=86,109) | 122.9 mcmol/L | Standard Deviation 48.8 |
| Sirolimus | Serum Creatinine (On-Therapy Analysis) | Baseline (n=131,123) | 118.3 mcmol/L | Standard Deviation 24.8 |
| Tacrolimus | Serum Creatinine (On-Therapy Analysis) | Month 24 (n=86,109) | 117.5 mcmol/L | Standard Deviation 42.8 |
| Tacrolimus | Serum Creatinine (On-Therapy Analysis) | Baseline (n=131,123) | 117.7 mcmol/L | Standard Deviation 27.9 |
| Tacrolimus | Serum Creatinine (On-Therapy Analysis) | Month 6 (n=125,120) | 117.0 mcmol/L | Standard Deviation 28.2 |
| Tacrolimus | Serum Creatinine (On-Therapy Analysis) | Month 12 (n=109,116) | 109.4 mcmol/L | Standard Deviation 24.6 |
| Tacrolimus | Serum Creatinine (On-Therapy Analysis) | Month 18 (n=99,111) | 114.2 mcmol/L | Standard Deviation 30.4 |
Secondary
Slope of Calculated GFR (MDRD) From Randomization to 24 Months Post-Transplantation (On-Therapy Analysis)
GFR was calculated using the MDRD equation using either serum creatinine traceable to IDMS or serum creatinine not traceable to IDMS. Timepoints were calculated as study days, relative to the time of randomization of study medication. All available on-therapy values were included. Observed data were multiplied by a scale factor of 365, expressing the slope as an annual change.
Time frame: Baseline, Month 24
Population: On-Therapy analysis of the slope comprised the data collected from the on-therapy evaluations for all the participants in the ITT population; data collected from participants receiving sirolimus during the first 3 weeks post-randomization for safety monitoring were excluded from the analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Sirolimus | Slope of Calculated GFR (MDRD) From Randomization to 24 Months Post-Transplantation (On-Therapy Analysis) | -0.9 mL/min/1.73 m^2 per year |
| Tacrolimus | Slope of Calculated GFR (MDRD) From Randomization to 24 Months Post-Transplantation (On-Therapy Analysis) | 0.9 mL/min/1.73 m^2 per year |
Comparison: Slope difference (sirolimus \[SRL\] minus tacrolimus \[TAC\])p-value: 0.13195% CI: [-4.2, 0.5]Random coefficient model
Secondary
Spot and 24 Hour Urine Protein to Creatinine Ratio (UPr/Cr)
Baseline was defined as the last nonmissing assessment before or on the date of the first dose of test article.
Time frame: Baseline and Months 12 and 24
Population: Safety Population; n=number of participants assessed for the specified parameter at a given visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sirolimus | Spot and 24 Hour Urine Protein to Creatinine Ratio (UPr/Cr) | Baseline (n=127,120) | 0.180 UPr/Cr | Standard Deviation 0.1413 |
| Sirolimus | Spot and 24 Hour Urine Protein to Creatinine Ratio (UPr/Cr) | Month 12 (n=112,108) | 0.353 UPr/Cr | Standard Deviation 0.3677 |
| Sirolimus | Spot and 24 Hour Urine Protein to Creatinine Ratio (UPr/Cr) | Month 24 (n=102,106) | 0.510 UPr/Cr | Standard Deviation 0.7887 |
| Tacrolimus | Spot and 24 Hour Urine Protein to Creatinine Ratio (UPr/Cr) | Baseline (n=127,120) | 0.195 UPr/Cr | Standard Deviation 0.1477 |
| Tacrolimus | Spot and 24 Hour Urine Protein to Creatinine Ratio (UPr/Cr) | Month 12 (n=112,108) | 0.208 UPr/Cr | Standard Deviation 0.2234 |
| Tacrolimus | Spot and 24 Hour Urine Protein to Creatinine Ratio (UPr/Cr) | Month 24 (n=102,106) | 0.300 UPr/Cr | Standard Deviation 0.6154 |
Comparison: Change from pre-randomization at Month 12; treatment ratio (SRC/TAC) in adjusted geometric mean fold-change from baseline.p-value: <0.00195% CI: [1.38, 2.11]ANCOVA
Comparison: Change from pre-randomization at Month 24; treatment ratio (SRC/TAC) in adjusted geometric mean fold-change from baseline.p-value: <0.00195% CI: [1.39, 2.26]ANCOVA