Study Evaluating A Planned Transition From Tacrolimus To Sirolimus In Kidney Transplant Recipients

Study Overview
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Brief Summary
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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.

Official Title
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Planned Transition To Sirolimus-Based Therapy Versus Continued Tacrolimus-Based Therapy In Renal Allograft Recipients

Conditions
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Graft Rejection, Kidney Transplant, Renal Allograft Recipients, Renal Transplant

Intervention / Treatment
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* Drug: Tacrolimus
* Drug: Sirolimus
* Drug: Tacrolimus


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group I - Planned transition to sirolimus from tacrolimus<br> | Drug: Tacrolimus<br>* 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).<br>* Other names: Prograf, Adagraf;Drug: Sirolimus<br>* 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).<br>* Other names: Rapamune;|
| Active Comparator: Group II - Continuation of tacrolimus<br> | Drug: Tacrolimus<br>* During the study, 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 2 years post-transplant.<br>* Other names: Prograf, adagraf;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline, Month 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline, Month 12 | 
| 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. | Baseline, Months 12 and 24 | 
| 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. | Baseline, Months 12 and 24 | 
| 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. | Baseline, Months 12 and 24 | 
| 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. | Baseline, Months 6, 12, 18, and 24 | 
| 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. | Baseline, Months 6, 12, 18, and 24 | 
| 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. | Baseline, Month 24 | 
| 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. | Baseline, Months 6, 12, 18, and 24 | 
| 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. | Baseline, Months 6, 12, 18, and 24 | 
| 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. | Post-randomization to Month 24 post-transplantation | 
| 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. | Post-randomization to Months 12 and 24 Post-Transplantation | 
| 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. | Post-Randomization to 6, 12, 18, and 24 months Post-Transplantation | 
| 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. | Months 12 and 24 | 
| 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. | Months 6, 12, 18, and 24 | 
| 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. | On Therapy Period (up to 21 months post-randomization) and Off-Therapy Period (up to 24 months post-transplantation) | 
| 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. | Baseline, Months 12 and 24 | 
| 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. | Baseline, Months 12 and 24 | 
| Percentage of Participants Requiring Anti-Hypertensive Medication, Diabetes Agents, Lipid-Lowering Agents, or Erythropoiesis Stimuating Agents (ESAs) |  | Baseline, Months 12 and 24 | 
| 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. | Baseline and Months 12 and 24 | 
| 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). | Pre-randomization, On-Therapy Period (up to 21 months post-randomization), and Off-Therapy Period (up to 24 months post-transplantation) | 
| 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) | From randomization up to 24 months after transplantation (On-Therapy) | 
| 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). | On-Therapy Period (up to 21 months post-randomization) and 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]) | Ratio of hemoglobin A1c to normal hemoglobin. | Baseline, Month 12 | 
| 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) | 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. | Baseline, Month 12 | 
| 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. | Baseline, Month 12 | 
| 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]). | Baseline, Month 12 | 
| 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. | 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 | 
| 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. | 12 Months and 24 Months | 
| Percentage of Participants With Infection | Includes adverse events based on categorization by the investigator as 'infection', regardless of the event preferred term in MedDRA. | From randomization up to 24 months after transplantation (On-Therapy) | 
| 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. | From randomization up to 24 months after transplantation (On-Therapy) | 
| 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. | From randomization up to 24 months after transplantation (On-Therapy) | 
| 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. | From randomization up to 24 months after transplantation (On-Therapy) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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renal transplant, immunosuppression, sirolimus/rapamune, planned transition