Steroid Withdrawal in Pediatric Kidney Transplant Recipients

End-Stage Renal Disease Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00023244
• Other study ID #: DAIT SW01
• Status: Terminated
• Phase: Phase 2
• First received: August 29, 2001
• Last updated: October 19, 2016
• Start date: January 2001
• Est. completion date: June 2005

Study information

• Verified date: October 2016
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal GovernmentUnited States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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 Doctors believe steroids might be safely withdrawn in patients that are receiving other maintenance therapies.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 This study evaluates whether steroid therapy can be withdrawn in a way that does not increase graft rejection.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 274
• Est. completion date: June 2005
• Est. primary completion date: June 2005
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 20 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• End-Stage Renal Disease
• Kidney Failure, Chronic

Intervention

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.
• 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).
• 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.
• 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.
• Methylprednisolone
Administered at 10 mg/kg intravenously perioperatively and on postoperative day 1.
• 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.
• 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).

Locations

Country	Name	City	State
Mexico	Hospital Infantil de Mexico	Mexico City	Distrito Federal
United States	University of New Mexico Health Science Center	Albuquerque	New Mexico
United States	Emory Children's Center	Atlanta	Georgia
United States	Denver Children's Hospital	Aurora	Colorado
United States	University of Maryland Medical Center	Baltimore	Maryland
United States	University of Alabama	Birmingham	Alabama
United States	Children's Hospital of Boston	Boston	Massachusetts
United States	The Children's Hospital of Buffalo	Buffalo	New York
United States	Rainbow Babies and Childrens Hospital	Cleveland	Ohio
United States	University Hospitals of Cleveland	Cleveland	Ohio
United States	Penn State College of Medicine	Hershey	Pennsylvania
United States	University of Florida Health Science Center	Jacksonville	Florida
United States	University of Wisconsin	Madison	Wisconsin
United States	LeBonheur Children's Medical Center	Memphis	Tennessee
United States	Tulane University Medical Center	New Orleans	Louisiana
United States	Christopher Goldsbury Center	San Antonio	Texas
United States	UCSD Medical Center	San Diego	California
United States	Children's Hospital and Regional Medical Center	Seattle	Washington
United States	Westchester Medical Center	Valhalla	New York

Sponsors (2)

Lead Sponsor	Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)	Cooperative Clinical Trials in Pediatric Transplantation

Countries where clinical trial is conducted

United States,  Mexico, 

References & Publications (4)

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.1600-6143.200 — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	Graft and patient survival		Throughout study	Yes
Secondary	Biopsy-proven acute rejection		Throughout study	No
Secondary	Renal function, measured by serum creatinine and the calculated creatinine clearances		Throughout study	No
Secondary	Hypertension		Throughout study	No
Secondary	Cushingoid features		Throughout study	No
Secondary	Systolic and diastolic blood pressure levels		Throughout study	No
Secondary	Fasting lipid profile		Throughout study	No

External Links

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