Steroid Withdrawal in Pediatric Kidney Transplant Recipients

A Double-Blind Randomized Trial of Steroid Withdrawal in Sirolimus- and Cyclosporine-Treated Primary Transplant Recipients

The purpose of this study is to examine the effects of withdrawing steroids on graft rejection and kidney functions in kidney transplant recipients between the ages of 0 and 20 years (prior to their 21st birthday).

Graft survival has improved in recent years in children with kidney transplants. One bad side effect of steroid maintenance therapy has been growth retardation. Doctors believe steroids might be safely withdrawn in patients that are receiving other maintenance therapies. If steroids are removed, children might catch up in their growth and also might have fewer side effects of other kinds. This study evaluates whether steroid therapy can be withdrawn in a way that does not increase graft rejection.

Study Overview

• Status: Terminated
• Conditions: End-Stage Renal Disease
• Intervention / Treatment: Drug: Basiliximab; Drug: Cyclosporine; Drug: Tacrolimus; Drug: Sirolimus; Drug: Methylprednisolone; Drug: Prednisone; Drug: Bactrim

Detailed Description

Children receiving kidney (renal) transplantation face distressing issues in post-transplantation including but not limited to growth retardation directly attributable to corticosteroids (steroids). It is hypothesized that robust immunosuppression with sirolimus and calcineurin inhibitors (cyclosporine or tacrolimus) in conjunction with induction therapy should enable successful steroid withdrawal. A steroid-free environment could lessen side effects by enabling a child to achieve catch-up growth, reducing the need for anti-hypertensive therapy, and reducing the risk of cardiovascular disease. This trial tests the objective of providing a steroid-free state without incurring the risk of increased incidence of acute transplant rejections.

Patients are enrolled prior to kidney transplantation and receive standard evaluations. Patients receive induction therapy with basiliximab preoperatively and on Day 4 after surgery. Immunosuppressive therapy begins with sirolimus and either cyclosporine or tacrolimus on Day 1 following surgery, and with corticosteroids the day of surgery. Infection prophylaxis with Bactrim is begun on Day 1 after surgery and center-specific anti-cytomegalovirus (CMV) therapy is given for all recipients of a CMV positive kidney. At 6 months post-transplantation, all patients who have not had an episode of acute rejection undergo a renal graft biopsy. Patients who are confirmed to be free of subclinical rejection are randomized to either undergo complete steroid withdrawal or continue maintenance on daily steroids. Patients receive either steroids or placebo, while continuing other immunosuppressive medications. Patients are segregated into weight groups for steroid withdrawal that occurs over months 7 to 13. Any acute rejection event during withdrawal is confirmed by renal biopsy and managed with methylprednisolone treatment. Patients are followed for 3 years post-transplantation for analysis of growth rate, blood pressure, lipid profile and renal function as measured by serum creatinine and calculated creatinine clearances. Post-transplantation clinic visits are weekly for the first 2 months, every 2 weeks until 13 months, weekly during Month 13, every 2 weeks through Month 18, and monthly until the study ends.

Patients who exhibit evidence of acute or subclinical rejection do not continue the steroid withdrawal trial and care is managed by their pediatric renal transplant center physicians.

• Study Type: Interventional
• Enrollment (Actual): 274
• Phase: Phase 2

Contacts and Locations

Study Locations

• Mexico
  • Distrito Federal
    • Mexico City, Distrito Federal, Mexico, 06720
      • Hospital Infantil de Mexico
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama
  • California
    • San Diego, California, United States, 92103
      • UCSD Medical Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Denver Children's Hospital
  • Florida
    • Jacksonville, Florida, United States, 32209
      • University of Florida Health Science Center
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory Children's Center
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Tulane University Medical Center
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Children's Hospital of Boston
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131
      • University of New Mexico Health Science Center
  • New York
    • Buffalo, New York, United States, 14222
      • The Children's Hospital of Buffalo
    • Valhalla, New York, United States, 10595
      • Westchester Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Rainbow Babies and Childrens Hospital
    • Cleveland, Ohio, United States, 44106
      • University Hospitals of Cleveland
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State College of Medicine
  • Tennessee
    • Memphis, Tennessee, United States, 38103
      • LeBonheur Children's Medical Center
  • Texas
    • San Antonio, Texas, United States, 78207
      • Christopher Goldsbury Center
  • Washington
    • Seattle, Washington, United States, 98105
      • Children's Hospital and Regional Medical Center
  • Wisconsin
    • Madison, Wisconsin, United States, 53705
      • University of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 day to 20 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Patients may be eligible for this study if they:

• Are between the ages of 0 and 20 years (prior to their 21st birthday)
• Are receiving their first living related (e.g.,kidney from a relative or unrelated donor) or cadaver donor transplant
• Are willing to practice an acceptable method of birth control during the study, if women able to have children

Exclusion Criteria:

Patients will not be eligible for this study if they:

• Have received multiple organs
• Have received 2 or more transplants
• Have an active infection (including tuberculosis), or cancer
• Have used an experimental agent within 4 weeks of transplantation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Corticosteroid (steroid) withdrawal; All enrolled subjects who have not experienced an episode of acute rejection or other event resulting in removal from the study in the first 6 months after transplantation will undergo a protocol-driven biopsy at 6 months. Subjects with no clinical or histologic evidence of rejection will be eligible to be randomized and treated in a double-blinded (e.g., masked-neither subject nor health care providers will know treatment being received) fashion while continuing other immunosuppressive medications. Subjects in this arm will undergo complete steroid withdrawal by the end of 12 months post-transplant.	Drug: Basiliximab; Administered as a bolus intravenous injection. The first dose is given pre-operatively, the second dose is given on post-transplant day four. Dosage is determined by individual weight.; Other Names: Simulect; Anti-CD25 monoclonal antibody, chimeric; Drug: Cyclosporine; Participants receiving cyclosporine microemulsion formula (in lieu of tacrolimus) will have the dose adjusted to maintain a whole blood trough Abbott TDx assay monoclonal level of 175-400 ng/mL (or an equivalent high pressure liquid chromatography (HPLC) level) for the first 2 weeks after transplant. The dose will subsequently be tapered to maintain a trough level of 175-300 ng/mL from week 3 to month 3, and 50-250 ng/mL from month 3 through the end of the study at month 36 (year 3).; Other Names: CsA; Drug: Tacrolimus; Participants receiving tacrolimus (in lieu of Cyclosporine) will have the dose adjusted to maintain a whole blood trough level between 10 and 15 ng/mL for the first 4weeks after transplant. Trough levels will be maintained between 5 and 10 ng/mL thereafter throughout the duration of the study.; Drug: Sirolimus; Participants take daily (orally, either as tablets or as liquid) starting on postoperative day 1 at a dose of 6 mg/m2 and will be adjusted to maintain a trough level of 10-20 ng/mL throughout the study.; Drug: Methylprednisolone; Administered at 10 mg/kg intravenously perioperatively and on postoperative day 1.; Drug: Prednisone; Administered orally beginning on Post-Op Day 2 and maintained for all participants until day 180. Randomization will determine whether patients will maintain this treatment following day 180.; Drug: Bactrim; All subjects will receive TMP SMX (Bactrim), pneumocystis jiroveci (carinii) prophylaxis, beginning on postoperative day 1 and continuing for 6 months following transplant. Dosage: 10 mg/kg taken orally three times weekly (maximum dose 160 mg).; Other Names: trimethoprim/sulfamethoxazole; TMP SMX
Active Comparator: Control Treatment; All enrolled subjects who have not experienced an episode of acute rejection or other event resulting in removal from the study in the first 6 months after transplantation will undergo a protocol-driven biopsy at 6 months. Subjects with no clinical or histologic evidence of rejection will be eligible to be randomized and treated in a double-blinded (e.g., masked-neither subject nor health care providers will know treatment being received) fashion while continuing other immunosuppressive medications. Subjects in this arm will be maintained on low-dose (0.15 mg/kg/day) daily steroids.	Drug: Basiliximab; Administered as a bolus intravenous injection. The first dose is given pre-operatively, the second dose is given on post-transplant day four. Dosage is determined by individual weight.; Other Names: Simulect; Anti-CD25 monoclonal antibody, chimeric; Drug: Cyclosporine; Participants receiving cyclosporine microemulsion formula (in lieu of tacrolimus) will have the dose adjusted to maintain a whole blood trough Abbott TDx assay monoclonal level of 175-400 ng/mL (or an equivalent high pressure liquid chromatography (HPLC) level) for the first 2 weeks after transplant. The dose will subsequently be tapered to maintain a trough level of 175-300 ng/mL from week 3 to month 3, and 50-250 ng/mL from month 3 through the end of the study at month 36 (year 3).; Other Names: CsA; Drug: Tacrolimus; Participants receiving tacrolimus (in lieu of Cyclosporine) will have the dose adjusted to maintain a whole blood trough level between 10 and 15 ng/mL for the first 4weeks after transplant. Trough levels will be maintained between 5 and 10 ng/mL thereafter throughout the duration of the study.; Drug: Sirolimus; Participants take daily (orally, either as tablets or as liquid) starting on postoperative day 1 at a dose of 6 mg/m2 and will be adjusted to maintain a trough level of 10-20 ng/mL throughout the study.; Drug: Methylprednisolone; Administered at 10 mg/kg intravenously perioperatively and on postoperative day 1.; Drug: Prednisone; Administered orally beginning on Post-Op Day 2 and maintained for all participants until day 180. Randomization will determine whether patients will maintain this treatment following day 180.; Drug: Bactrim; All subjects will receive TMP SMX (Bactrim), pneumocystis jiroveci (carinii) prophylaxis, beginning on postoperative day 1 and continuing for 6 months following transplant. Dosage: 10 mg/kg taken orally three times weekly (maximum dose 160 mg).; Other Names: trimethoprim/sulfamethoxazole; TMP SMX

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Growth, measured as change in standardized height from 6 month to 2.5 years post-transplantation	At 6 months and 2.5 years post-transplant

Secondary Outcome Measures

Outcome Measure	Time Frame
Graft and patient survival	Throughout study
Biopsy-proven acute rejection	Throughout study
Renal function, measured by serum creatinine and the calculated creatinine clearances	Throughout study
Hypertension	Throughout study
Cushingoid features	Throughout study
Systolic and diastolic blood pressure levels	Throughout study
Fasting lipid profile	Throughout study

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: Cooperative Clinical Trials in Pediatric Transplantation

Publications and helpful links

General Publications

• Magee JC. Steroids in pediatric kidney transplantation: a balancing act in progress. Am J Transplant. 2010 Jan;10(1):6-7. doi: 10.1111/j.1600-6143.2009.02923.x. Epub 2009 Dec 17. No abstract available.
• Li L, Chang A, Naesens M, Kambham N, Waskerwitz J, Martin J, Wong C, Alexander S, Grimm P, Concepcion W, Salvatierra O, Sarwal MM. Steroid-free immunosuppression since 1999: 129 pediatric renal transplants with sustained graft and patient benefits. Am J Transplant. 2009 Jun;9(6):1362-72. doi: 10.1111/j.1600-6143.2009.02640.x. Epub 2009 May 13.
• Benfield MR, Bartosh S, Ikle D, Warshaw B, Bridges N, Morrison Y, Harmon W. A randomized double-blind, placebo controlled trial of steroid withdrawal after pediatric renal transplantation. Am J Transplant. 2010 Jan;10(1):81-8. doi: 10.1111/j.1600-6143.2009.02767.x. Epub 2009 Jul 28.
• McDonald RA, Smith JM, Ho M, Lindblad R, Ikle D, Grimm P, Wyatt R, Arar M, Liereman D, Bridges N, Harmon W; CCTPT Study Group. Incidence of PTLD in pediatric renal transplant recipients receiving basiliximab, calcineurin inhibitor, sirolimus and steroids. Am J Transplant. 2008 May;8(5):984-9. doi: 10.1111/j.1600-6143.2008.02167.x.

Helpful Links

• National Institute of Allergy and Infectious Diseases (NIAID)
• Division of Allergy, Immunology, and Transplantation (DAIT)

Study record dates

Study Major Dates

• Study Start: January 1, 2001
• Primary Completion (Actual): June 1, 2005
• Study Completion (Actual): June 1, 2005

Study Registration Dates

• First Submitted: August 29, 2001
• First Submitted That Met QC Criteria: August 30, 2001
• First Posted (Estimate): August 31, 2001

Study Record Updates

• Last Update Posted (Estimate): October 21, 2016
• Last Update Submitted That Met QC Criteria: October 19, 2016
• Last Verified: October 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Renal Insufficiency; Renal Insufficiency, Chronic; Kidney Failure, Chronic; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Neuroprotective Agents; Protective Agents; Dermatologic Agents; Anti-Bacterial Agents; Cytochrome P-450 Enzyme Inhibitors; Antibiotics, Antineoplastic; Antifungal Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Folic Acid Antagonists; Calcineurin Inhibitors; Anti-Dyskinesia Agents; Anti-Infective Agents, Urinary; Renal Agents; Cytochrome P-450 CYP2C8 Inhibitors; Methylprednisolone; Prednisone; Tacrolimus; Sirolimus; Basiliximab; Cyclosporine; Cyclosporins; Trimethoprim; Sulfamethoxazole; Trimethoprim, Sulfamethoxazole Drug Combination
• Other Study ID Numbers: DAIT SW01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Participant level data and additional relevant materials are available to the public in the Immunology Database and Analysis Portal (ImmPort). ImmPort is a long-term archive of clinical and mechanistic data from DAIT-funded grants and contracts.

Study Data/Documents

1. Individual Participant Data Set
   Information identifier: SDY133
   Information comments: ImmPort study identifier is SDY133
2. Study Protocol
   Information identifier: SDY133
   Information comments: ImmPort study identifier is SDY133
3. Study summary, -design,-demographics, -files et al.
   Information identifier: SDY133
   Information comments: ImmPort study identifier is SDY133