Clinical trial NCT00895583: Study Evaluating A Planned Transition From Tacrolimus To Sirolimus In Kidney Transplant Recipients
Official title: Planned Transition To Sirolimus-Based Therapy Versus Continued Tacrolimus-Based Therapy In Renal Allograft Recipients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Graft Rejection
Kidney Transplant
Renal Allograft Recipients
Renal Transplant
Keywords: renal transplant
immunosuppression
sirolimus/rapamune
planned transition
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2009-05-08
Enrollment: 254
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.


Eligibility criteria: 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.

Primary outcomes:
measure: 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)
timeFrame: Baseline, Month 24
Secondary outcomes:
measure: Percentage of Participants With Improvement of ≥5 mL/Min/m^2 in Calculated GFR at 12 Months Post-Transplantation (On-Therapy Analysis)
timeFrame: Baseline, Month 12
measure: 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)
timeFrame: Baseline, Months 12 and 24
measure: Percentage of Participants With Improvement of ≥7.5 mL/Min/m^2 in Calculated GFR at 12 and 24 Months Post-Transplantation
timeFrame: Baseline, Months 12 and 24
measure: Percentage of Participants With Improvement of ≥10 mL/Min/m^2 in Calculated GFR at 12 and 24 Months Post-Transplantation
timeFrame: Baseline, Months 12 and 24
measure: Calculated GFR Using MDRD (On-Therapy Analysis)
timeFrame: Baseline, Months 6, 12, 18, and 24
measure: Change From Randomization in Calculated GFR Using MDRD (On-Therapy Analysis)
timeFrame: Baseline, Months 6, 12, 18, and 24
measure: Slope of Calculated GFR (MDRD) From Randomization to 24 Months Post-Transplantation (On-Therapy Analysis)
timeFrame: Baseline, Month 24
measure: Serum Creatinine (On-Therapy Analysis)
timeFrame: Baseline, Months 6, 12, 18, and 24
measure: Change From Randomization in Serum Creatinine (On-Therapy Analysis)
timeFrame: Baseline, Months 6, 12, 18, and 24
measure: Percentage of Participants With Biopsy-Confirmed Acute Rejection (BCAR), Graft Loss, or Death From Randomization to 24 Months Post-Transplantation
timeFrame: Post-randomization to Month 24 post-transplantation
measure: Percentage of Participants With Graft Loss (Including Death) at 12 and 24 Months Post-Randomization
timeFrame: Post-randomization to Months 12 and 24 Post-Transplantation
measure: Percentage of Participants With BCAR Post-Randomization to 6, 12, 18, and 24 Months Post-Transplantation
timeFrame: Post-Randomization to 6, 12, 18, and 24 months Post-Transplantation
measure: Percentage of Participants With First On-Therapy BCAR From Transplantation Occurring at 12 and 24 Months
timeFrame: Months 12 and 24
measure: 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
timeFrame: Months 6, 12, 18, and 24
measure: Percentage of Participants With Antibody Use in Treatment of Acute Rejection
timeFrame: On Therapy Period (up to 21 months post-randomization) and Off-Therapy Period (up to 24 months post-transplantation)
measure: Percentage of Participants With Anemia, Thrombocytopenia, or Leukopenia
timeFrame: Baseline, Months 12 and 24
measure: Change From Baseline (Pre-Randomization) to 12 and 24 Months Post-Transplantation in Fasting Lipid Parameters (Millimoles Per Liter [mmol/L])
timeFrame: Baseline, Months 12 and 24
measure: Percentage of Participants Requiring Anti-Hypertensive Medication, Diabetes Agents, Lipid-Lowering Agents, or Erythropoiesis Stimuating Agents (ESAs)
timeFrame: Baseline, Months 12 and 24
measure: Spot and 24 Hour Urine Protein to Creatinine Ratio (UPr/Cr)
timeFrame: Baseline and Months 12 and 24
measure: Percentage of Participants With Angiotensin Converting Enzyme Inhibitor (ACEI) or Angiotensin II Receptor Block (ARB) Use
timeFrame: Pre-randomization, On-Therapy Period (up to 21 months post-randomization), and Off-Therapy Period (up to 24 months post-transplantation)
measure: Percentage of Participants With Stomatitis
timeFrame: From randomization up to 24 months after transplantation (On-Therapy)
measure: Percentage of Participants Requiring Treatment for Stomatitis by Treatment Type
timeFrame: On-Therapy Period (up to 21 months post-randomization) and Off-Therapy Period (up to 24 months post-transplantation)
measure: Change From Pre-Randomization to 12 Months Post-Transplantation in Hemoglobin A1C (Liter Per Liter [L/L])
timeFrame: Baseline, Month 12
measure: Change From Pre-Randomization to 12 Months Post-Transplantation in Fasting Glucose (mmol/L)
timeFrame: Baseline, Month 12
measure: Change From Pre-Randomization to 12 Months Post-Transplantation in Fasting Insulin (Picomoles Per Liter [Pmol/L])
timeFrame: Baseline, Month 12
measure: Change From Pre-Randomization to 12 Months Post-Transplantation in Weight (Kilograms [kg])
timeFrame: Baseline, Month 12
measure: Change From Pre-Randomization to 12 Months Post-Transplantation in Waist Circumference(Centimeters [cm])
timeFrame: Baseline, Month 12
measure: Change From Pre-Randomization to 12 Months Post-Transplantation in Homeostasis Model Assessment Insulin Resistance (HOMA-IR; Fasting)
timeFrame: Baseline, Month 12
measure: Change From Pre-Randomization to 12 Months Post-Transplantation in HOMA-Beta Cell (HOMA-B; Fasting)
timeFrame: Baseline, Month 12
measure: Change From Pre-Randomization to 12 Months Post-Transplantation in Body Mass Index (BMI; in Kilograms Per Square Meter [kg/m^2])
timeFrame: Baseline, Month 12
measure: Percentage of Participants With New-Onset Diabetes
timeFrame: 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
measure: Percentage of Participants With New-Onset Diabetes Receiving Treatment for Diabetes (Insulin and Non-Insulin)
timeFrame: 12 Months and 24 Months
measure: Percentage of Participants With Infection
timeFrame: From randomization up to 24 months after transplantation (On-Therapy)
measure: Percentage of Participants With Cytomegalovirus (CMV) Infection
timeFrame: From randomization up to 24 months after transplantation (On-Therapy)
measure: Percentage of Participants With Polyomavirus Infection
timeFrame: From randomization up to 24 months after transplantation (On-Therapy)
measure: Percentage of Participants With Malignancy
timeFrame: From randomization up to 24 months after transplantation (On-Therapy)
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: Pfizer Investigational Site
state: California
city: San Francisco
country: United States
facility: Pfizer Investigational Site
state: California
city: Aurora
country: United States
facility: Pfizer Investigational Site
state: Colorado
city: Denver
country: United States
facility: Pfizer Investigational Site
state: Colorado
city: Atlanta
country: United States
facility: Pfizer Investigational Site
state: Georgia
city: Chicago
country: United States
facility: Pfizer Investigational Site
state: Illinois
city: Lexington
country: United States
facility: Pfizer Investigational Site
state: Kentucky
city: Portland
country: United States
facility: Pfizer Investigational Site
state: Maine
city: Boston
country: United States
facility: Pfizer Investigational Site
state: Massachusetts
city: Detroit
country: United States
facility: Pfizer Investigational Site
state: Michigan
city: Detroit
country: United States
facility: Pfizer Investigational Site
state: Michigan
city: New York
country: United States
facility: Pfizer Investigational Site
state: New York
city: Rochester
country: United States
facility: Pfizer Investigational Site
state: New York
city: Chapel Hill
country: United States
facility: Pfizer Investigational Site
state: North Carolina
city: Durham
country: United States
facility: Pfizer Investigational Site
state: North Carolina
city: Cincinnati
country: United States
facility: Pfizer Investigational Site
state: Ohio
city: Cincinnati
country: United States
facility: Pfizer Investigational Site
state: Ohio
city: Cleveland
country: United States
facility: Pfizer Investigational Site
state: Ohio
city: Portland
country: United States
facility: Pfizer Investigational Site
state: Oregon
city: Philadelphia
country: United States
facility: Pfizer Investigational Site
state: Pennsylvania
city: Charleston
country: United States
facility: Pfizer Investigational Site
state: South Carolina
city: Houston
country: United States
facility: Pfizer Investigational Site
state: Texas
city: Charlottesville
country: United States
facility: Pfizer Investigational Site
state: Virginia
city: Charlottesville
country: United States
facility: Pfizer Investigational Site
state: Virginia
city: Richmond
country: United States
facility: Pfizer Investigational Site
state: Virginia
city: Ciudad de Buenos Aires
country: Argentina
facility: Pfizer Investigational Site
state: Buenos Aires
city: Randwick
country: Australia
facility: Pfizer Investigational Site
state: New South Wales
city: Adelaide
country: Australia
facility: Pfizer Investigational Site
state: South Australia
city: Nedlands
country: Australia
facility: Pfizer Investigational Site
state: Western Australia
city: Porto Alegre
country: Brazil
facility: Pfizer Investigational Site
state: RS
city: Bela Vista
country: Brazil
facility: Pfizer Investigational Site
state: Sao Paulo
city: Sao Paulo
country: Brazil
facility: Pfizer Investigational Site
state: SP
city: Sao Paulo
country: Brazil
facility: Pfizer Investigational Site
state: SP
city: Sao Paulo
country: Brazil
facility: Pfizer Investigational Site
state: SP
city: Sao Paulo
country: Brazil
facility: Pfizer Investigational Site
state: SP
city: Berlin
country: Germany
facility: Pfizer Investigational Site
city: Milano
country: Italy
facility: Pfizer Investigational Site
city: Milano
country: Italy
facility: Pfizer Investigational Site
city: Barcelona
country: Spain
facility: Pfizer Investigational Site
city: Barcelona
country: Spain
facility: Pfizer Investigational Site
city: Madrid
country: Spain
facility: Pfizer Investigational Site
city: Madrid
country: Spain
facility: Pfizer Investigational Site
city: Santander
country: Spain
facility: Pfizer Investigational Site
city: Valencia
country: Spain
facility: Pfizer Investigational Site
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References: