Immunosuppression, Kidney Failure, Chronic, Kidney Transplantation
Conditions
Keywords
End stage renal disease, Kidney transplantation, Renal transplantation, Kidney failure, Pediatric renal transplant recipients, Alemtuzumab, Campath, Mycophenolate mofetil, MMF, CellCept, Tacrolimus, Prograf, Sirolimus, Rapamycin
Brief summary
The purpose of this study is to evaluate the safety of alemtuzumab after kidney transplantation as part of a multitherapy regimen to prevent kidney graft loss and death and to avoid steroids and chronic use of calcineurin inhibitors in pediatric renal transplant recipients 1 to 20 years of age.
Detailed description
Kidney transplantation is widely considered to be the treatment of choice for children with End Stage Renal Disease (ESRD). Improvements in surgical techniques, donor selection, and immunosuppression practices, as well as the enhanced experience of specialized pediatric transplant teams, have all led to marked improvements in patient and kidney graft survival in infants and young children ages 1 to 10. However, young children now have more infections following transplant previously. Also, improved graft survival is not observed in pediatric renal transplant recipients 11 to 17 years of age. Some studies do indicate that the poor long term outcome of patient and kidney survival observed in this age group may be caused by noncompliance with immunosuppressive medications. Therefore, protocols that minimize the use of immunosuppressive medications while retaining kidney function are necessary for improving graft and patient survival in children. This study will evaluate the safety of a regimen containing alemtuzumab after kidney transplantation, followed by steroid avoidance and calcineurin inhibitor withdrawal in pediatric renal transplant recipients 1 to 20 years of age. The accrual period is scheduled for 18 months. The study follow-up period will last 24 months. All participants enrolled will undergo this treatment schedule: 1.) All participants will receive intravenous alemtuzumab one day before transplantation and 1 day after transplantation. 2.) Mycophenolate mofetil (MMF) will be administered orally no later than 2 days after transplantation. 3.) Participants will begin to take oral tacrolimus twice a day 1 to 3 days after transplantation until Weeks 8 through 12 when 4.) Sirolimus will be initiated. 5.) Sirolimus and MMF will be taken orally until Month 24. Blood collection will occur at baseline, 1 day before transplant, at Days 1 and 3, at Weeks 2, 4, 6, 8, 10, and at Months 3 through 24. Scheduled kidney (renal) biopsies will be performed at transplant, during Weeks 8 through 12, immediately before conversion to sirolimus, and at Months 6 and 24.
Interventions
DRUGAlemtuzumab
Administered intravenously over a period of 2-3 hours. Two doses total, the first will be one day before transplant and the second will be on the day following transplantation. Pre-medication with methylprednisolone, acetaminophen, and Benadryl will be administered before each dose.
DRUGTacrolimus
Administered orally at a dose of 0.05-0.1 mg/kg twice daily, beginning 1-3 days following transplantation and continuing until weeks 8-12. Tacrolimus will be discontinued and a treatment regimen with sirolimus will be initiated between weeks 8-12 but some overlap with these medications is possible.
DRUGMycophenolate mofetil
Per recommendation
DRUGSirolimus
Administered by either liquid or tablet every 12 hours from month 6 until month 24. Dosage will vary throughout the treatment course.
Sponsors
Cooperative Clinical Trials in Pediatric Transplantation
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 20 Years
Healthy volunteers
No
Inclusion criteria
* Between the ages of 1 to 20 (prior to 21st birthday) * End Stage Renal Disease * Necessity of kidney transplant * First kidney transplant received from a living donor * A living kidney donor identified * No known contraindications to therapy with alemtuzumab * Negative pregnancy test before study entry * Willing to use approved methods of contraception for the duration of the study, 6 weeks after discontinuation of MMF, and 12 weeks after discontinuation of sirolimus * Informed consent from participant, parent, or guardian * Current vaccinations, including varicella-zoster (VZV) vaccine, before study enrollment
Exclusion criteria
* Recipient of a deceased donor kidney transplant * Multiorgan transplant * History of prior organ transplantation * Participant sensitized to greater than 0% Panel Reactive Antibody (PRA) within 4 weeks before study enrollment. (If participant receives a blood transfusion status post PRA test, then the PRA must be repeated within 1 week of transplantation) * Participants with human leukocyte antigen (HLA) identical living related donors * History of primary focal segmented glomerulosclerosis * History of other disorders requiring continuous maintenance steroids or calcineurin inhibitors * Active systemic infection at time of transplant * History of malignancy * Infected with human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) * Contraindication to receive tacrolimus, sirolimus, MMF, or monoclonal antibody therapy * Use of investigational drugs within 4 weeks before study enrollment * Recipient of any licensed or investigational live attenuated vaccine(s) within 2 months before study enrollment * Family history of high cholesterol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Proportion of Participants With Graft Loss or Death Within 12 Months Post Kidney Transplantation | Up to one year post kidney transplantation procedure | Graft loss is defined as the need for dialysis for more than 30 days duration, allograft nephrectomy, or the decision to withdraw immunosuppression due to graft failure. |
Countries
United States
Participant flow
Recruitment details
Four centers in the United States recruited 35 subjects between January 2005 and October 2007 who were less than 21 years of age and first time living-donor kidney allograft recipients.
Pre-assignment details
At a screening visit, participants underwent procedures to establish inclusion/exclusion criteria and then sign the informed consent form.
Participants by arm
| Arm | Count |
|---|---|
| Alemtuzumab (Campath) In this open-label, single-arm trial, participants were administered a 0.3 mg/kg dose of alemtuzumab intravenously one day prior to kidney transplantation and one day post kidney transplantation. Participants were then administered a maintenance immunosuppressive regimen of tacrolimus and mycophenolate mofetil (MMF) for 8 to 12 weeks, followed by sirolimus and MMF until 24 months post transplantation. | 35 |
| Total | 35 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Graft failure | 1 |
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | Protocol Violation | 1 |
Baseline characteristics
| Characteristic | Alemtuzumab (Campath) |
|---|---|
| Age, Continuous All Participants (N=35) | 12.6 years STANDARD_DEVIATION 5.5 |
| Age, Continuous Final status: Completed (N=22) | 13.1 years STANDARD_DEVIATION 5 |
| Age, Continuous Final status: Discontinued Study (N=3) | 17.7 years STANDARD_DEVIATION 2.4 |
| Age, Continuous Final status: Discontinued Therapy (N=10) | 9.8 years STANDARD_DEVIATION 6.2 |
| Gender Female | 20 Participants |
| Gender Male | 15 Participants |
| Region of Enrollment United States | 35 participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 34 / 35 |
| serious Total, serious adverse events | 25 / 35 |
Outcome results
Primary
The Proportion of Participants With Graft Loss or Death Within 12 Months Post Kidney Transplantation
Graft loss is defined as the need for dialysis for more than 30 days duration, allograft nephrectomy, or the decision to withdraw immunosuppression due to graft failure.
Time frame: Up to one year post kidney transplantation procedure
Population: Intent-to-treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alemtuzumab (Campath) | The Proportion of Participants With Graft Loss or Death Within 12 Months Post Kidney Transplantation | 0.057 Proportion of participants |
Comparison: The proportion of participants with graft loss or death within 12 months post kidney transplantation is descriptively summarized with a 95% confidence interval using an exact binomial method.95% CI: [0.007, 0.192]95% Confidence Interval