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

Steroid Withdrawal in Pediatric Kidney Transplant Recipients

Sponsors

Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Collaborator: Cooperative Clinical Trials in Pediatric Transplantation

Source National Institute of Allergy and Infectious Diseases (NIAID)
Brief 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 Doctors believe steroids might be safely withdrawn in patients that are receiving other maintenance therapies.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 This study evaluates whether steroid therapy can be withdrawn in a way that does not increase graft rejection.

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.

Overall Status Terminated
Start Date January 2001
Completion Date June 2005
Primary Completion Date June 2005
Phase Phase 2
Study Type Interventional
Primary 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
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
Enrollment 274
Condition
Intervention

Intervention type: Drug

Intervention name: Basiliximab

Description: 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.

Intervention type: Drug

Intervention name: Cyclosporine

Description: 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

Intervention type: Drug

Intervention name: Tacrolimus

Description: 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.

Intervention type: Drug

Intervention name: Sirolimus

Description: 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.

Intervention type: Drug

Intervention name: Methylprednisolone

Description: Administered at 10 mg/kg intravenously perioperatively and on postoperative day 1.

Intervention type: Drug

Intervention name: Prednisone

Description: 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.

Intervention type: Drug

Intervention name: Bactrim

Description: 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).

Eligibility

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

Gender: All

Minimum age: N/A

Maximum age: 20 Years

Healthy volunteers: No

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

Mexico

United States

Verification Date

October 2016

Responsible Party

Responsible party type: Sponsor

Has Expanded Access No
Condition Browse
Number Of Arms 2
Arm Group

Arm group label: Corticosteroid (steroid) withdrawal

Arm group type: Experimental

Description: 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.

Arm group label: Control Treatment

Arm group type: Active Comparator

Description: 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.

Patient Data Yes
Study Design Info

Allocation: Randomized

Intervention model: Parallel Assignment

Primary purpose: Treatment

Masking: Double (Participant, Investigator)

Source: ClinicalTrials.gov