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

Phase 4

Completed

• Conditions: Graft Rejection; Kidney Transplant; Renal Transplant; Renal Allograft Recipients
• Interventions: Drug: Tacrolimus; Drug: Sirolimus

• Registration Number: NCT00895583
• Lead Sponsor: Pfizer

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2009-04-29
• Study First Submitted QC: 2009-05-07
• Study First Posted: 2009-05-08
• Study Start: 2009-06
• Primary Completion: 2013-08
• Study Completion: 2013-08
• Results First Submitted: 2014-07-23
• Status Verified: 2014-09
• Results First Submitted QC: 2014-09-15
• Last Update Submitted: 2014-09-15
• Results First Posted: 2014-09-18
• Last Update Posted: 2014-09-18

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 254

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group I - Planned transition to sirolimus from tacrolimus	Tacrolimus	-
Group I - Planned transition to sirolimus from tacrolimus	Sirolimus	-
Group II - Continuation of tacrolimus	Tacrolimus	-

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.
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.
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.
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 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.
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.

Trial Locations

Locations (1)

Pfizer Investigational Site; 🇪🇸 Valencia, Spain