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

This study has been completed.
Sponsor:
Collaborators:
Astellas Pharma Inc
Hoffmann-La Roche
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT00141037
First received: August 1, 2005
Last updated: July 11, 2013
Last verified: July 2013
  Purpose

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.


Condition Intervention Phase
Kidney Diseases
Kidney Transplantation
Kidney Transplant
Renal Transplantation
Renal Transplant
Drug: Daclizumab
Drug: Mycophenolate mofetil (MMF)
Drug: Prednisone
Drug: Tacrolimus
Drug: Ganciclovir
Drug: Valganciclovir
Drug: Trimethoprim and sulfamethoxazole
Phase 1
Phase 2

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

Resource links provided by NLM:


Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:
  • The Difference in Linear Growth by Treatment Assignment at 1 Year Post Kidney Transplantation [ Time Frame: One year post kidney transplantation procedure ] [ Designated as safety issue: No ]
    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

  • Comparison by Treatment Assignment in the Number of Biopsy-Proven Acute Rejections Within 12 Months Post Kidney Transplantation [ Time Frame: Up to one year post kidney transplantation procedure ] [ Designated as safety issue: Yes ]

    Biopsy-proven acute renal (kidney) rejection [1, 2].

    1. 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]
    2. Ref: Racusen LC et al. The Banff 97 working classification of renal allograft pathology. Kidney Int, 55: 713-723, 1999


Enrollment: 130
Study Start Date: March 2004
Study Completion Date: November 2010
Primary Completion Date: September 2006 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: 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.
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)

Other Names:
  • ZENAPAX®
  • Humanised Anti-Tac Antibody
  • Ro-24-7375
Drug: 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.
Other Name: CellCept®
Drug: 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.
Drug: 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.
Other Name: Prograf®
Drug: 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.
Other Name: Cytovene
Drug: 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.
Other Name: Valcyte
Drug: 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 Name: Septra®)
Experimental: 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).
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)

Other Names:
  • ZENAPAX®
  • Humanised Anti-Tac Antibody
  • Ro-24-7375
Drug: 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.
Other Name: CellCept®
Drug: 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.
Other Name: Prograf®
Drug: 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.
Other Name: Cytovene
Drug: 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.
Other Name: Valcyte
Drug: 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 Name: Septra®)

Detailed 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.

  Eligibility

Ages Eligible for Study:   up to 21 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00141037

Locations
United States, Alabama
University of Alabama - Pediatric Nephrology
Birmingham, Alabama, United States, 35233
United States, California
UCLA - Department of Pediatrics, Division of Nephrology
Los Angeles, California, United States, 90095-1752
Maxine Dunitz Children's Health Center Cedars-Sinai
Los Angeles, California, United States, 90048
Stanford University Medical Center, Lucile Packard Children's Hospital
Palo Alto, California, United States, 94304
UCSF Children's Hospital
San Francisco, California, United States, 94143
United States, Florida
University of Florida - Pediatric Nephrology
Gainesville, Florida, United States, 32610-0296
United States, Louisiana
Children's Hospital of New Orleans-Department of Pediatric Nephrology
New Orleans, Louisiana, United States, 70118
United States, Massachusetts
Children's Hospital Boston - Division of Nephrology
Boston, Massachusetts, United States, 02115
United States, Michigan
University of Michigan Medical Center, C.S. Mott Children's Hospital- Division of Nephrology & Transplantation
Ann Arbor, Michigan, United States, 48109
United States, Missouri
Children's Mercy Hospital - Department of Nephrology
Kansas City, Missouri, United States, 64108
United States, Pennsylvania
The Children's Hospital of Philadelphia-Department of Nephrology
Philadelphia, Pennsylvania, United States, 19104
United States, Washington
Children's Hospital & Regional Medical Center - Division of Nephrology
Seattle, Washington, United States, 98105
Sponsors and Collaborators
Astellas Pharma Inc
Hoffmann-La Roche
Investigators
Study Chair: Minnie Sarwal, MD, PhD California Pacific Medical Center
Principal Investigator: Oscar Salvatierra, MD Pediatric Kidney Transplant Program, Stanford University Medical Center, Stanford Hospital and Clinics
  More Information

Publications:

Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT00141037     History of Changes
Other Study ID Numbers: DAIT SNS01
Study First Received: August 1, 2005
Results First Received: May 21, 2013
Last Updated: July 11, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
Organ Rejection
Corticosteroids
Child
Adolescent
Immunosuppression
Steroids

Additional relevant MeSH terms:
Kidney Diseases
Urologic Diseases
Ganciclovir
Valganciclovir
Sulfamethoxazole
Trimethoprim
Mycophenolate mofetil
Tacrolimus
Daclizumab
Mycophenolic Acid
Prednisone
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antibiotics, Antineoplastic
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Anti-Inflammatory Agents
Anti-Infective Agents, Urinary
Renal Agents
Antimalarials

ClinicalTrials.gov processed this record on July 28, 2014