Steroid-Free Versus Steroid-Based Immunosuppression in Pediatric Renal (Kidney) Transplantation

Kidney Transplantation Clinical Trial

Official title:

Randomized, Multi-Center Comparative Trial of Tacrolimus w/Steroids and Standard Daclizumab Induction vs a Novel Steroid-Free Tacrolimus Based Immunosuppression Protocol w/ Extended Daclizumab Induction in Pediatric Renal Transplantation

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00141037
• Other study ID #: DAIT SNS01
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: August 1, 2005
• Last updated: July 11, 2013
• Start date: March 2004
• Est. completion date: November 2010

Study information

• Verified date: July 2013
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

Over the last 40 years, corticosteroids (steroids) have been an important part of drug regimens used to prevent organ rejection and to maintain the immune health of individuals who have received organ transplants. Unfortunately, the negative physical effects of steroids can be severe, especially in children. The purpose of this study is to determine the safety and effectiveness of a steroid-free treatment regimen for children and adolescents who have received kidney (renal) transplants.

Description:

Corticosteroids (steroids) have been a cornerstone of immunosuppressive therapy for kidney (renal) transplantation for over 40 years. However, poor growth and bone loss caused by the use of steroids are devastating to pediatric kidney recipients. The negative physical implications of steroid use also greatly impacts patients' compliance to their prescribed steroid-containing regimens.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 130
• Est. completion date: November 2010
• Est. primary completion date: September 2006
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 21 Years

Eligibility

Inclusion Criteria:

• Primary recipient of a kidney transplant

• 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:

• Previous treatment with steroids within 6 months prior to transplantation

• 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

Study Design

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

Related Conditions & MeSH terms

• Kidney Diseases
• Kidney Transplant
• Kidney Transplantation
• Renal Transplant
• Renal Transplantation

Intervention

Drug:
• 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.

Locations

Country	Name	City	State
United States	University of Michigan Medical Center, C.S. Mott Children's Hospital- Division of Nephrology & Transplantation	Ann Arbor	Michigan
United States	University of Alabama - Pediatric Nephrology	Birmingham	Alabama
United States	Children's Hospital Boston - Division of Nephrology	Boston	Massachusetts
United States	University of Florida - Pediatric Nephrology	Gainesville	Florida
United States	Children's Mercy Hospital - Department of Nephrology	Kansas City	Missouri
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	Children's Hospital of New Orleans-Department of Pediatric Nephrology	New Orleans	Louisiana
United States	Stanford University Medical Center, Lucile Packard Children's Hospital	Palo Alto	California
United States	The Children's Hospital of Philadelphia-Department of Nephrology	Philadelphia	Pennsylvania
United States	UCSF Children's Hospital	San Francisco	California
United States	Children's Hospital & Regional Medical Center - Division of Nephrology	Seattle	Washington

Sponsors (3)

Lead Sponsor	Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)	Astellas Pharma Inc, Hoffmann-La Roche

Country where clinical trial is conducted

United States, 

References & Publications (6)

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. — View Citation

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 kidne — View Citation

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 e — View Citation

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. — View Citation

Vidhun JR, Sarwal MM. Corticosteroid avoidance in pediatric renal transplantation. Pediatr Nephrol. 2005 Mar;20(3):418-26. Epub 2005 Feb 3. Review. — View Citation

Vidhun JR, Sarwal MM. Corticosteroid avoidance in pediatric renal transplantation: can it be achieved? Paediatr Drugs. 2004;6(5):273-87. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The Difference in Linear Growth by Treatment Assignment at 1 Year Post Kidney Transplantation	Standardized Z-scores were computed following a formula using an age- and gender-specific calculation provided by the NHANES III 2000 Growth Data set. The Z-score system expresses anthropometric values of height as several standard deviations (SDs) below (e.g., a negative value) or above (a positive value) the reference mean or median value. In this study the measure was used to test whether there is a difference in the change in height between the treatment groups: Steroid-Based versus Steroid-Free	One year post kidney transplantation procedure	No
Primary	Comparison by Treatment Assignment in the Number of Biopsy-Proven Acute Rejections Within 12 Months Post Kidney Transplantation	Biopsy-proven acute renal (kidney) rejection [1, 2].; Diagnosis of acute rejection was made by renal biopsy using the Banff 97 criteria. The Banff 97 diagnostic category for renal allograft biopsies is an international standardized histopathological classification. Acute rejection is defined by a renal biopsy demonstrating a Banff 97 classification of Grade IA or greater, with higher scores indicating more severe rejection[2]; Ref: Racusen LC et al. The Banff 97 working classification of renal allograft pathology. Kidney Int, 55: 713-723, 1999	Up to one year post kidney transplantation procedure	Yes