Steroid-Free Versus Steroid-Based Immunosuppression in Pediatric Renal (Kidney) Transplantation
NCT ID: NCT00141037
Last Updated: 2016-11-29
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE1/PHASE2
130 participants
INTERVENTIONAL
2004-03-31
2010-11-30
Brief Summary
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Detailed Description
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The development of a steroid-free regimen for post-transplant pediatric patients is sorely needed. This study will evaluate the safety and efficacy of a steroid-free based treatment regimen in children and adolescents who have received kidney transplants, compared to a standard of care steroid-based regimen. Participants in this study will be pediatric patients with end-stage kidney disease who will undergo kidney transplantation at the start of the study.
Patients will participate in this study for 3 years. Participants will be randomized (1:1) to one of two groups. The study includes 23 study visits over 3 years. A physical exam, medication history, adverse events reporting, blood pressure readings, growth assessment, and blood collection will occur at most visits. At the time of transplantation, participants will have a kidney biopsy. Participants will also undergo cataract screening within 4 months of transplantation.
Conditions
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Keywords
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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Steroid-Based Immunosuppression
Subjects will receive prednisone immunosuppression (10 mg/kg peri-operatively followed by 2 mg/kg/day in subjects weighing \<40kg and 1.5 mg/kg/day in subjects weighing \>40 kg) and proceed with a prednisone taper according to the trial's protocol.
Daclizumab
Steroid-Based Immunosuppression(Prednisone) arm: 1 mg/kg pre-transplant followed by 1 mg/kg at weeks 2, 4, 6, and 8 (e.g., standard dose of daclizumab induction until the second month post-transplant)
Steroid-Free Immunosuppression (Extended daclizumab induction) arm: 2 mg/kg pre-transplant followed by 1 mg/kg at weeks 2, 4, 6, 8, 11, and months 4, 5, and 6 (e.g., extended daclizumab induction until the sixth month post-transplant)
Mycophenolate mofetil (MMF)
Intravenous MMF was dosed at 1200 mg/m\^2/day in two divided doses preoperatively and for the first 48 hours postoperatively. Oral MMF was dosed at 600 to 900 mg/m\^2/day in two divided doses; the dose range allowed for dose titration according to tolerability and side effects of MMF. This regimen was used in both arms.
Prednisone
Administered as 10 mg/kg peri-operatively followed by 2 mg/kg/day in subjects weighing \<40 kg and 1.5 mg/kg/day in subjects weighing \>40 kg. The prednisone dosing was tapered as follows: by the end of wks 1, 2, 4,6,12 and 16, dosages were 0.5, 0.4, 0.3, 0.2, 0.15 and 0.1 mg/kg/day, respectively. The prednisone dose of 0.1 mg/kg was achieved by no later than 6 months post-transplant.
Tacrolimus
Taken orally from immediately preoperatively to those\>age 5 yrs. (starting dose= 0.1 mg/kg/dose twice daily (BID) for living donor recipients; 0.1 mg/kg/dose daily for deceased donor recipients).Subjects \<age 5 yrs. received drug from immediately preoperatively at 0.15 mg/kg/dose BID (two preoperative doses) for living donor recipients and 0.15 mg/kg/dose daily (one preoperative dose) for deceased donor recipients. Postoperatively: 0.07 mg/kg/dose BID w/adjustment to achieve target levels of 12-14 ng/mL (days 0-7), 10-12 ng/mL (wks. 2-8), 7-10 ng/mL (wks. 9-12) \&5-7 ng/mL \>= 12 wks. Evidence of drug toxicity on any protocol biopsy resulted in a further lowering of the drug target level to 4-6 ng/mL before yr 1 \& 3-5 ng/mL after yr 1 post-transplant. This regimen was used in both arms.
Ganciclovir
Cytomegalovirus (CMV) and Epstein-Barr Virus (EBV) Prophylaxis: All participants will receive intravenous ganciclovir 5 mg/kg/day beginning after transplantation until tolerating oral medications, at which time oral valganciclovir will be initiated and continued for a minimum of 100 days.
Valganciclovir
Cytomegalovirus (CMV) and Epstein-Barr Virus (EBV) Prophylaxis: All participants will receive intravenous ganciclovir 5 mg/kg/day beginning after transplantation until tolerating oral medications, at which time oral valganciclovir will be initiated and continued for a minimum of 100 days.
Trimethoprim and sulfamethoxazole
Pneumocystis pneumonia (PCP)/Urinary Tract Infection (UTI) Prophylaxis: Trimethoprim/sulfamethoxazole (Septra®) 2 mg/kg by mouth will be administered daily at bedtime for a minimum period of the first 6 months post-transplant. If unable to tolerate Septra®, inhaled pentamidine (8 mg/kg to a maximum dose of 300 mg monthly) or Dapsone (2 mg/kg PO to a maximum dose of 100 mg/day) may be substituted for a minimum of the first 6 months post-transplant. For UTI prophylaxis, if Septra® is not tolerated, nitrofurantoin (Macrodantin®), 2.5 mg/kg/day, may be given at bedtime up to a maximum dose of 100 mg/day.
Steroid-Free Immunosuppression
Subjects will receive extended daclizumab induction until the sixth month post-transplant (2 mg/kg pre-transplant followed by 1 mg/kg at weeks 2, 4, 6, 8, 11 and months 4, 5, and 6).
Daclizumab
Steroid-Based Immunosuppression(Prednisone) arm: 1 mg/kg pre-transplant followed by 1 mg/kg at weeks 2, 4, 6, and 8 (e.g., standard dose of daclizumab induction until the second month post-transplant)
Steroid-Free Immunosuppression (Extended daclizumab induction) arm: 2 mg/kg pre-transplant followed by 1 mg/kg at weeks 2, 4, 6, 8, 11, and months 4, 5, and 6 (e.g., extended daclizumab induction until the sixth month post-transplant)
Mycophenolate mofetil (MMF)
Intravenous MMF was dosed at 1200 mg/m\^2/day in two divided doses preoperatively and for the first 48 hours postoperatively. Oral MMF was dosed at 600 to 900 mg/m\^2/day in two divided doses; the dose range allowed for dose titration according to tolerability and side effects of MMF. This regimen was used in both arms.
Tacrolimus
Taken orally from immediately preoperatively to those\>age 5 yrs. (starting dose= 0.1 mg/kg/dose twice daily (BID) for living donor recipients; 0.1 mg/kg/dose daily for deceased donor recipients).Subjects \<age 5 yrs. received drug from immediately preoperatively at 0.15 mg/kg/dose BID (two preoperative doses) for living donor recipients and 0.15 mg/kg/dose daily (one preoperative dose) for deceased donor recipients. Postoperatively: 0.07 mg/kg/dose BID w/adjustment to achieve target levels of 12-14 ng/mL (days 0-7), 10-12 ng/mL (wks. 2-8), 7-10 ng/mL (wks. 9-12) \&5-7 ng/mL \>= 12 wks. Evidence of drug toxicity on any protocol biopsy resulted in a further lowering of the drug target level to 4-6 ng/mL before yr 1 \& 3-5 ng/mL after yr 1 post-transplant. This regimen was used in both arms.
Ganciclovir
Cytomegalovirus (CMV) and Epstein-Barr Virus (EBV) Prophylaxis: All participants will receive intravenous ganciclovir 5 mg/kg/day beginning after transplantation until tolerating oral medications, at which time oral valganciclovir will be initiated and continued for a minimum of 100 days.
Valganciclovir
Cytomegalovirus (CMV) and Epstein-Barr Virus (EBV) Prophylaxis: All participants will receive intravenous ganciclovir 5 mg/kg/day beginning after transplantation until tolerating oral medications, at which time oral valganciclovir will be initiated and continued for a minimum of 100 days.
Trimethoprim and sulfamethoxazole
Pneumocystis pneumonia (PCP)/Urinary Tract Infection (UTI) Prophylaxis: Trimethoprim/sulfamethoxazole (Septra®) 2 mg/kg by mouth will be administered daily at bedtime for a minimum period of the first 6 months post-transplant. If unable to tolerate Septra®, inhaled pentamidine (8 mg/kg to a maximum dose of 300 mg monthly) or Dapsone (2 mg/kg PO to a maximum dose of 100 mg/day) may be substituted for a minimum of the first 6 months post-transplant. For UTI prophylaxis, if Septra® is not tolerated, nitrofurantoin (Macrodantin®), 2.5 mg/kg/day, may be given at bedtime up to a maximum dose of 100 mg/day.
Interventions
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Daclizumab
Steroid-Based Immunosuppression(Prednisone) arm: 1 mg/kg pre-transplant followed by 1 mg/kg at weeks 2, 4, 6, and 8 (e.g., standard dose of daclizumab induction until the second month post-transplant)
Steroid-Free Immunosuppression (Extended daclizumab induction) arm: 2 mg/kg pre-transplant followed by 1 mg/kg at weeks 2, 4, 6, 8, 11, and months 4, 5, and 6 (e.g., extended daclizumab induction until the sixth month post-transplant)
Mycophenolate mofetil (MMF)
Intravenous MMF was dosed at 1200 mg/m\^2/day in two divided doses preoperatively and for the first 48 hours postoperatively. Oral MMF was dosed at 600 to 900 mg/m\^2/day in two divided doses; the dose range allowed for dose titration according to tolerability and side effects of MMF. This regimen was used in both arms.
Prednisone
Administered as 10 mg/kg peri-operatively followed by 2 mg/kg/day in subjects weighing \<40 kg and 1.5 mg/kg/day in subjects weighing \>40 kg. The prednisone dosing was tapered as follows: by the end of wks 1, 2, 4,6,12 and 16, dosages were 0.5, 0.4, 0.3, 0.2, 0.15 and 0.1 mg/kg/day, respectively. The prednisone dose of 0.1 mg/kg was achieved by no later than 6 months post-transplant.
Tacrolimus
Taken orally from immediately preoperatively to those\>age 5 yrs. (starting dose= 0.1 mg/kg/dose twice daily (BID) for living donor recipients; 0.1 mg/kg/dose daily for deceased donor recipients).Subjects \<age 5 yrs. received drug from immediately preoperatively at 0.15 mg/kg/dose BID (two preoperative doses) for living donor recipients and 0.15 mg/kg/dose daily (one preoperative dose) for deceased donor recipients. Postoperatively: 0.07 mg/kg/dose BID w/adjustment to achieve target levels of 12-14 ng/mL (days 0-7), 10-12 ng/mL (wks. 2-8), 7-10 ng/mL (wks. 9-12) \&5-7 ng/mL \>= 12 wks. Evidence of drug toxicity on any protocol biopsy resulted in a further lowering of the drug target level to 4-6 ng/mL before yr 1 \& 3-5 ng/mL after yr 1 post-transplant. This regimen was used in both arms.
Ganciclovir
Cytomegalovirus (CMV) and Epstein-Barr Virus (EBV) Prophylaxis: All participants will receive intravenous ganciclovir 5 mg/kg/day beginning after transplantation until tolerating oral medications, at which time oral valganciclovir will be initiated and continued for a minimum of 100 days.
Valganciclovir
Cytomegalovirus (CMV) and Epstein-Barr Virus (EBV) Prophylaxis: All participants will receive intravenous ganciclovir 5 mg/kg/day beginning after transplantation until tolerating oral medications, at which time oral valganciclovir will be initiated and continued for a minimum of 100 days.
Trimethoprim and sulfamethoxazole
Pneumocystis pneumonia (PCP)/Urinary Tract Infection (UTI) Prophylaxis: Trimethoprim/sulfamethoxazole (Septra®) 2 mg/kg by mouth will be administered daily at bedtime for a minimum period of the first 6 months post-transplant. If unable to tolerate Septra®, inhaled pentamidine (8 mg/kg to a maximum dose of 300 mg monthly) or Dapsone (2 mg/kg PO to a maximum dose of 100 mg/day) may be substituted for a minimum of the first 6 months post-transplant. For UTI prophylaxis, if Septra® is not tolerated, nitrofurantoin (Macrodantin®), 2.5 mg/kg/day, may be given at bedtime up to a maximum dose of 100 mg/day.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* Meets site-specific transplant criteria
* Panel Reactive Antibody (PRA) of 20% or less
* Willing to use acceptable forms of contraception
* Parent or guardian willing to provide informed consent, if applicable
Exclusion Criteria
* Received en-bloc kidney or other kidney that does not meet protocol-specified requirements
* Received an organ from an human leukocyte antigen (HLA) identical donor or a non-heart-beating donor
* Received a solid organ other than a kidney
* Received a bone marrow or hematopoietic stem cell transplant
* Received a repeat kidney transplant
* Currently receiving an investigational pharmacologic or biologic agent
* Human Immunodeficiency virus (HIV) infected or infected with another immunodeficiency virus
* Hypersensitivity to murine products or the study drugs or their formulations
* Inability to measure height accurately
* Pregnant or breastfeeding
21 Years
ALL
No
Sponsors
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Astellas Pharma Inc
INDUSTRY
Hoffmann-La Roche
INDUSTRY
National Institute of Allergy and Infectious Diseases (NIAID)
NIH
Responsible Party
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Principal Investigators
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Minnie Sarwal, MD, PhD
Role: STUDY_CHAIR
California Pacific Medical Center
Oscar Salvatierra, MD
Role: PRINCIPAL_INVESTIGATOR
Pediatric Kidney Transplant Program, Stanford University Medical Center, Stanford Hospital and Clinics
Locations
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University of Alabama - Pediatric Nephrology
Birmingham, Alabama, United States
Maxine Dunitz Children's Health Center Cedars-Sinai
Los Angeles, California, United States
UCLA - Department of Pediatrics, Division of Nephrology
Los Angeles, California, United States
Stanford University Medical Center, Lucile Packard Children's Hospital
Palo Alto, California, United States
UCSF Children's Hospital
San Francisco, California, United States
University of Florida - Pediatric Nephrology
Gainesville, Florida, United States
Children's Hospital of New Orleans-Department of Pediatric Nephrology
New Orleans, Louisiana, United States
Children's Hospital Boston - Division of Nephrology
Boston, Massachusetts, United States
University of Michigan Medical Center, C.S. Mott Children's Hospital- Division of Nephrology & Transplantation
Ann Arbor, Michigan, United States
Children's Mercy Hospital - Department of Nephrology
Kansas City, Missouri, United States
The Children's Hospital of Philadelphia-Department of Nephrology
Philadelphia, Pennsylvania, United States
Children's Hospital & Regional Medical Center - Division of Nephrology
Seattle, Washington, United States
Countries
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References
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Cole E, Landsberg D, Russell D, Zaltzman J, Kiberd B, Caravaggio C, Vasquez AR, Halloran P. A pilot study of steroid-free immunosuppression in the prevention of acute rejection in renal allograft recipients. Transplantation. 2001 Sep 15;72(5):845-50. doi: 10.1097/00007890-200109150-00018.
Sarwal MM, Vidhun JR, Alexander SR, Satterwhite T, Millan M, Salvatierra O Jr. Continued superior outcomes with modification and lengthened follow-up of a steroid-avoidance pilot with extended daclizumab induction in pediatric renal transplantation. Transplantation. 2003 Nov 15;76(9):1331-9. doi: 10.1097/01.TP.0000092950.54184.67.
Vidhun JR, Sarwal MM. Corticosteroid avoidance in pediatric renal transplantation. Pediatr Nephrol. 2005 Mar;20(3):418-26. doi: 10.1007/s00467-004-1786-4. Epub 2005 Feb 3.
Vidhun JR, Sarwal MM. Corticosteroid avoidance in pediatric renal transplantation: can it be achieved? Paediatr Drugs. 2004;6(5):273-87. doi: 10.2165/00148581-200406050-00002.
Sarwal MM, Ettenger RB, Dharnidharka V, Benfield M, Mathias R, Portale A, McDonald R, Harmon W, Kershaw D, Vehaskari VM, Kamil E, Baluarte HJ, Warady B, Tang L, Liu J, Li L, Naesens M, Sigdel T, Waskerwitz J, Salvatierra O. Complete steroid avoidance is effective and safe in children with renal transplants: a multicenter randomized trial with three-year follow-up. Am J Transplant. 2012 Oct;12(10):2719-29. doi: 10.1111/j.1600-6143.2012.04145.x. Epub 2012 Jun 13.
Naesens M, Salvatierra O, Benfield M, Ettenger RB, Dharnidharka V, Harmon W, Mathias R, Sarwal MM; SNS01-NIH-CCTPT Multicenter Trial. Subclinical inflammation and chronic renal allograft injury in a randomized trial on steroid avoidance in pediatric kidney transplantation. Am J Transplant. 2012 Oct;12(10):2730-43. doi: 10.1111/j.1600-6143.2012.04144.x. Epub 2012 Jun 13.
Li L, Khatri P, Sigdel TK, Tran T, Ying L, Vitalone MJ, Chen A, Hsieh S, Dai H, Zhang M, Naesens M, Zarkhin V, Sansanwal P, Chen R, Mindrinos M, Xiao W, Benfield M, Ettenger RB, Dharnidharka V, Mathias R, Portale A, McDonald R, Harmon W, Kershaw D, Vehaskari VM, Kamil E, Baluarte HJ, Warady B, Davis R, Butte AJ, Salvatierra O, Sarwal MM. A peripheral blood diagnostic test for acute rejection in renal transplantation. Am J Transplant. 2012 Oct;12(10):2710-8. doi: 10.1111/j.1600-6143.2012.04253.x.
Related Links
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National Institute of Allergy and Infectious Diseases (NIAID)
Division of Allergy, Immunology, and Transplantation (DAIT)
Other Identifiers
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DAIT SNS01
Identifier Type: -
Identifier Source: org_study_id