Steroid Withdrawal in Pediatric Kidney Transplant Recipients - Full Text View

Purpose

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 Doctors believe steroids might be safely withdrawn in patients that are receiving other maintenance therapies.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 This study evaluates whether steroid therapy can be withdrawn in a way that does not increase graft rejection.

Condition	Intervention	Phase
End-Stage Renal Disease	Drug: Basiliximab Drug: Cyclosporine Drug: Tacrolimus Drug: Sirolimus Drug: Methylprednisolone Drug: Prednisone Drug: Bactrim	Phase 2

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Investigator) Primary Purpose: Treatment
Official Title:	A Double-Blind Randomized Trial of Steroid Withdrawal in Sirolimus- and Cyclosporine-Treated Primary Transplant Recipients

Resource links provided by NLM:

MedlinePlus related topics: High Blood Pressure Kidney Failure Kidney Transplantation Steroids

Drug Information available for: Prednisolone Prednisolone acetate Prednisone Methylprednisolone acetate Methylprednisolone Prednisolone sodium phosphate Prednisolone phosphate Sulfamethoxazole Trimethoprim Prednisolone sodium succinate Methylprednisolone sodium succinate Sirolimus Cyclosporine Trimethoprim hydrochloride Tacrolimus Everolimus Temsirolimus Basiliximab

U.S. FDA Resources

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

Primary Outcome Measures:

Growth, measured as change in standardized height from 6 month to 2.5 years post-transplantation [ Time Frame: At 6 months and 2.5 years post-transplant ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Graft and patient survival [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
Biopsy-proven acute rejection [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
Renal function, measured by serum creatinine and the calculated creatinine clearances [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
Hypertension [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
Cushingoid features [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
Systolic and diastolic blood pressure levels [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
Fasting lipid profile [ Time Frame: Throughout study ] [ Designated as safety issue: No ]

Enrollment:	274
Study Start Date:	January 2001
Study Completion Date:	June 2005
Primary Completion Date:	June 2005 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
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 Name: 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: TMP SMX trimethoprim/sulfamethoxazole
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 Name: 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: TMP SMX trimethoprim/sulfamethoxazole

Arms

Assigned Interventions

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 Name: 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:

TMP SMX
trimethoprim/sulfamethoxazole

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 Name: 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:

TMP SMX
trimethoprim/sulfamethoxazole

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.

Eligibility

Ages Eligible for Study:	up to 20 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00023244

Hide Study Locations

Locations

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

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

Cooperative Clinical Trials in Pediatric Transplantation

Investigators

Principal Investigator:

William Harmon, MD

Children's Hospital Boston

More Information

Publications:

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. 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.

Magee JC. Steroids in pediatric kidney transplantation: a balancing act in progress. Am J Transplant. 2010 Jan;10(1):6-7. Epub 2009 Dec 17.

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. Epub 2009 May 13.

Responsible Party:	National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:	NCT00023244 History of Changes
Other Study ID Numbers:	DAIT SW01
Study First Received:	August 29, 2001
Last Updated:	October 26, 2012
Health Authority:	United States: Federal Government United States: Food and Drug Administration

Additional relevant MeSH terms:

Kidney Diseases
Kidney Failure, Chronic
Urologic Diseases
Renal Insufficiency, Chronic
Renal Insufficiency
Antibodies, Monoclonal
Cyclosporins
Cyclosporine
Sirolimus
Everolimus
Tacrolimus
Basiliximab
Trimethoprim
Sulfamethoxazole
Trimethoprim-Sulfamethoxazole Combination

Methylprednisolone acetate
Prednisolone acetate
Methylprednisolone
Methylprednisolone Hemisuccinate
Prednisolone
Prednisone
Prednisolone hemisuccinate
Prednisolone phosphate
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Antifungal Agents

ClinicalTrials.gov processed this record on May 23, 2013