A Study to Compare Treatment With Sirolimus Versus Standard Treatment in Patients Who Have Received a Kidney Transplant

Phase 3

Terminated

• Conditions: End-Stage Renal Disease; Kidney Transplantation
• Interventions: Drug: Cyclosporine; Drug: Sirolimus; Drug: Tacrolimus

• Registration Number: NCT00005113
• Lead Sponsor: Boston Children's Hospital

Brief Summary

The purpose of this study is to compare treatment with the new drug sirolimus (SRL) versus the standard treatment with cyclosporine (CsA) or tacrolimus in children who have received kidney transplants. SRL is a new medication that may prevent the body's immune system from rejecting organ transplants.

After receiving a kidney transplant, the body recognizes the donated kidney as a foreign invader and triggers the immune system to attack the kidney. This can lead to rejection of the new kidney and a failed transplant. To help reduce the risk of kidney rejection, transplant patients are given immunosuppressant drugs, which reduce the body's normal immune response and allow the transplanted organ to function. CsA or tacrolimus are two drugs that are often given to transplant patients. However, these are powerful drugs, and it can cause serious side effects and put a patient at increased risk for infections. SRL is a new drug that has been shown to reduce a transplant patient's chance of rejecting a new kidney, without serious side effects. This study is necessary to test the safety and effectiveness of SRL in children.

Detailed Description

Successful kidney transplantation has gradually improved over the years; much of the improvement has resulted from the use of CsA. However, adequate and tolerable immunosuppression is difficult to achieve with CsA, and rejection episodes are still frequent. CsA is nephrotoxic, with drug toxicity often masking rejection episodes. Other immunosuppressant therapies can result in a range of complications, including metabolic disturbances, adrenocortical insufficiency, and increased risk for infections. Therefore, more effective drugs with less toxicity are needed to prevent acute rejection, especially in the pediatric population where the overall graft survival rate remains significantly lower when compared with that of adult transplant recipients. SRL is an immunosuppressive agent being developed for the prophylaxis of acute renal allograft rejection. SRL has a unique mechanism of action. It inhibits T and B cell activity. In Phase I and II trials in adults, SRL was generally well tolerated and exhibited no apparent nephrotoxic properties, and significantly lower rates of rejection were seen with SRL when compared to placebo.

Patients receive extensive prestudy screening, which includes a renal core biopsy, chest x-ray, bone density study, blood tests, and glomerular filtration rate (GFR). Patients are then randomly assigned to 1 of 2 study treatment groups in a 2:1 ratio (142 patients receive SRL, CsA/tacrolimus, and corticosteroids and 71 patients receive standard CsA or tacrolimus-based double or triple drug therapy). SRL is administered as an oral dose of 3 mg/m2/day. Patients are followed for 3 years on therapy, and then for 1 month of follow-up. A renal core biopsy is performed at the time of study entry and at Months 6, 18, and at early termination of patient in study. Patients undergo physical examinations and various blood tests at specified time intervals during the 37-month study period. Efficacy is assessed by comparing the composite endpoint of biopsy-proven acute rejection, graft loss, or death after 36 months of treatment. Safety is assessed by comparing the composite endpoint of graft loss or death after 36 months of treatment.

Study Timeline

• Study Start: 1999-07
• Study First Submitted: 2000-04-14
• Study First Submitted QC: 2001-08-30
• Study First Posted: 2001-08-31
• Primary Completion: 2004-07
• Study Completion: 2006-03
• Status Verified: 2012-03
• Last Update Submitted: 2012-03-12
• Last Update Posted: 2012-03-13

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 102

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
1	Cyclosporine	Participants will receive SRL, CsA/tacrolimus, and corticosteroids for up to 36 months
1	Tacrolimus	Participants will receive SRL, CsA/tacrolimus, and corticosteroids for up to 36 months
2	Cyclosporine	Participants will receive standard CsA or tacrolimus-based double or triple drug therapy for up to 36 months
2	Tacrolimus	Participants will receive standard CsA or tacrolimus-based double or triple drug therapy for up to 36 months
1	Sirolimus	Participants will receive SRL, CsA/tacrolimus, and corticosteroids for up to 36 months

Primary Outcome Measures

Name	Time	Method
Safety and efficacy of sirolimus	Throughout study

Secondary Outcome Measures

Name	Time	Method
Rate of change in glomerular filtration rate	At Month 18
Composite endpoint of biopsy proven acute rejection, graft loss, or death	At Months 6, 12, and 24
Rate of clinically diagnosed acute rejection	At months 6, 12, 24, and 36
Mean change in volume of allograft fibrosis	At Months 6 and 18
Intragraft expression of cytokines	Throughout study
Cytokine expression and subsequent development of chronic allograft nephropathy	Throughout study

Trial Locations

Locations (1)

Children's Hospital Boston; 🇺🇸 Boston, Massachusetts, United States