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

Kidney Transplant Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00895583
• Other study ID #: 0468E8-4500
• Secondary ID: B1741007
• Status: Completed
• Phase: Phase 4
• First received: April 29, 2009
• Last updated: September 15, 2014
• Start date: June 2009
• Est. completion date: August 2013

Study information

• Verified date: September 2014
• Source: Pfizer
• Contact: n/a
• Is FDA regulated: No
• Health authority: Argentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia MedicaAustralia: Depart
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 254
• Est. completion date: August 2013
• Est. primary completion date: August 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Prevention

Related Conditions & MeSH terms

• Graft Rejection
• Kidney Transplant
• Renal Allograft Recipients
• Renal Transplant

Intervention

Drug:
• Tacrolimus
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).
• Sirolimus
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).
• Tacrolimus
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.

Locations

Country	Name	City	State
Argentina	Pfizer Investigational Site	Ciudad de Buenos Aires	Buenos Aires
Australia	Pfizer Investigational Site	Adelaide	South Australia
Australia	Pfizer Investigational Site	Nedlands	Western Australia
Australia	Pfizer Investigational Site	Randwick	New South Wales
Brazil	Pfizer Investigational Site	Bela Vista	Sao Paulo
Brazil	Pfizer Investigational Site	Porto Alegre	RS
Brazil	Pfizer Investigational Site	Sao Paulo	SP
Brazil	Pfizer Investigational Site	Sao Paulo	SP
Brazil	Pfizer Investigational Site	Sao Paulo	SP
Brazil	Pfizer Investigational Site	Sao Paulo	SP
Germany	Pfizer Investigational Site	Berlin
Italy	Pfizer Investigational Site	Milano
Italy	Pfizer Investigational Site	Milano
Spain	Pfizer Investigational Site	Barcelona
Spain	Pfizer Investigational Site	Barcelona
Spain	Pfizer Investigational Site	Madrid
Spain	Pfizer Investigational Site	Madrid
Spain	Pfizer Investigational Site	Santander
Spain	Pfizer Investigational Site	Valencia
United States	Pfizer Investigational Site	Atlanta	Georgia
United States	Pfizer Investigational Site	Aurora	Colorado
United States	Pfizer Investigational Site	Boston	Massachusetts
United States	Pfizer Investigational Site	Chapel Hill	North Carolina
United States	Pfizer Investigational Site	Charleston	South Carolina
United States	Pfizer Investigational Site	Charlottesville	Virginia
United States	Pfizer Investigational Site	Charlottesville	Virginia
United States	Pfizer Investigational Site	Chicago	Illinois
United States	Pfizer Investigational Site	Cincinnati	Ohio
United States	Pfizer Investigational Site	Cincinnati	Ohio
United States	Pfizer Investigational Site	Cleveland	Ohio
United States	Pfizer Investigational Site	Denver	Colorado
United States	Pfizer Investigational Site	Detroit	Michigan
United States	Pfizer Investigational Site	Detroit	Michigan
United States	Pfizer Investigational Site	Durham	North Carolina
United States	Pfizer Investigational Site	Houston	Texas
United States	Pfizer Investigational Site	La Jolla	California
United States	Pfizer Investigational Site	Lexington	Kentucky
United States	Pfizer Investigational Site	New York	New York
United States	Pfizer Investigational Site	Philadelphia	Pennsylvania
United States	Pfizer Investigational Site	Portland	Oregon
United States	Pfizer Investigational Site	Portland	Maine
United States	Pfizer Investigational Site	Richmond	Virginia
United States	Pfizer Investigational Site	Rochester	New York
United States	Pfizer Investigational Site	San Francisco	California

Sponsors (1)

Lead Sponsor	Collaborator
Pfizer

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Brazil,  Germany,  Italy,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	Baseline, Month 24	No
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.	Baseline, Month 12	No
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.	Baseline, Months 12 and 24	No
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.	Baseline, Months 12 and 24	No
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.	Baseline, Months 12 and 24	No
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.	Baseline, Months 6, 12, 18, and 24	No
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.	Baseline, Months 6, 12, 18, and 24	No
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.	Baseline, Month 24	No
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.	Baseline, Months 6, 12, 18, and 24	No
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.	Baseline, Months 6, 12, 18, and 24	No
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.	Post-randomization to Month 24 post-transplantation	Yes
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.	Post-randomization to Months 12 and 24 Post-Transplantation	Yes
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.	Post-Randomization to 6, 12, 18, and 24 months Post-Transplantation	Yes
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.	Months 12 and 24	Yes
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.	Months 6, 12, 18, and 24	Yes
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.	On Therapy Period (up to 21 months post-randomization) and Off-Therapy Period (up to 24 months post-transplantation)	No
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.	Baseline, Months 12 and 24	No
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.	Baseline, Months 12 and 24	No
Secondary	Percentage of Participants Requiring Anti-Hypertensive Medication, Diabetes Agents, Lipid-Lowering Agents, or Erythropoiesis Stimuating Agents (ESAs)		Baseline, Months 12 and 24	No
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.	Baseline and Months 12 and 24	No
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).	Pre-randomization, On-Therapy Period (up to 21 months post-randomization), and Off-Therapy Period (up to 24 months post-transplantation)	No
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)	From randomization up to 24 months after transplantation (On-Therapy)	No
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).	On-Therapy Period (up to 21 months post-randomization) and Off-Therapy Period (up to 24 months post-transplantation)	No
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.	Baseline, Month 12	No
Secondary	Change From Pre-Randomization to 12 Months Post-Transplantation in Fasting Glucose (mmol/L)		Baseline, Month 12	No
Secondary	Change From Pre-Randomization to 12 Months Post-Transplantation in Fasting Insulin (Picomoles Per Liter [Pmol/L])		Baseline, Month 12	No
Secondary	Change From Pre-Randomization to 12 Months Post-Transplantation in Weight (Kilograms [kg])		Baseline, Month 12	No
Secondary	Change From Pre-Randomization to 12 Months Post-Transplantation in Waist Circumference(Centimeters [cm])		Baseline, Month 12	No
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.	Baseline, Month 12	No
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.	Baseline, Month 12	No
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]).	Baseline, Month 12	No
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.	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	No
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.	12 Months and 24 Months	No
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.	From randomization up to 24 months after transplantation (On-Therapy)	No
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.	From randomization up to 24 months after transplantation (On-Therapy)	No
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.	From randomization up to 24 months after transplantation (On-Therapy)	No
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.	From randomization up to 24 months after transplantation (On-Therapy)	No

External Links

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