Impact of Conversion From Tacrolimus to Sirolimus in African American Renal Transplant Recipients

Chronic Allograft Nephropathy Clinical Trial

Official title:

Prospective Trial of Conversion From Tacrolimus to Sirolimus in African American Renal Transplant Recipients With Chronic Allograft Nephropathy

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT00999258
• Other study ID #: 0468X1-4504
• Status: Recruiting
• Phase: Phase 4
• First received: October 20, 2009
• Last updated: October 20, 2009
• Start date: September 2009
• Est. completion date: June 2011

Study information

• Verified date: October 2009
• Source: Temple University
• Contact: Serban Constantinescu, MD, PhD
• Phone: 215-707-9171
• Email: serban.constantinescu[@]tuhs.temple.edu
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

The objective of this study is to examine the effect on allograft function and histology of converting African American renal transplant recipients with chronic allograft nephropathy (CAN) from a tacrolimus-based regimen to a sirolimus-based maintenance immunosuppression regimen.

The investigators hypothesize that the conversion from tacrolimus to sirolimus in African American renal recipients will stabilize or improve renal allograft function, and stabilize the histological progression of CAN. This conversion will have the potential to prolong long-term graft survival in African American renal transplant patients.

GFR measurements, histological parameters on the allograft biopsy, as well as patient and graft survival, incidence of acute rejection, and specific side effects will be monitored and compared between the sirolimus conversion group and the patients who will be maintained on tacrolimus.

Description:

All African American renal transplant recipients (>3months and <5 years post-transplant) at our institution that are currently on a tacrolimus based regimen will be screened. Subjects with 10% or more decrease in glomerular filtration rate (GFR) from baseline, estimated by the MDRD formula,65 and who meet all inclusion criteria will be consented to be enrolled in the study. Baseline will be defined as the highest GFR estimated by MDRD formula, within 3 months of transplant.

Subjects who consent to participate in the study will undergo allograft biopsy and GFR measurement by Gd-DTPA, and will be randomly assigned (2:1) to undergo conversion from tacrolimus to sirolimus or to continue to receive tacrolimus.

The subjects assigned to the sirolimus conversion group will be initiated on sirolimus 5mg po daily at which time their tacrolimus dose will be decreased by 50%. Sirolimus levels will be checked within a week and adjusted in a linear fashion to achieve a trough goal of 12-15ng/ml in subjects within 1 year post-transplant, and 8-12 ng/ml in subjects more than 1 year post-transplant. Tacrolimus will be continued in these subjects until sirolimus target trough levels are achieved. Thereafter, tacrolimus will be discontinued indefinitely. Sirolimus trough levels will be monitored in the study as follows: weekly for the first month, monthly from 1 - 6 months, every 3 months from 6 months - 1 year post conversion. Subjects will continue to receive maintenance immunosuppression consisting of mycophenolate mofetil 500mg to 1000 mg po bid as tolerated and corticosteroid taper per protocol (maintenance of 2.5mg - 5mg po daily at 6 months post-transplant and then indefinitely). GFR measurement by DTPA will be repeated at 6 months, and 1 year post conversion. The second allograft biopsy will be performed at 1 year after sirolimus conversion.

The subjects assigned to the tacrolimus maintenance group (control group) represent our present standard of care. The subjects will continue to receive prednisone, and mycophenolate mofetil, similarly to the subjects assigned to the sirolimus conversion group. In the tacrolimus maintenance group, the subjects will be monitored according to our current clinic protocol, monthly between 3 months - 1 year post transplant, every two months in the second year post-transplant and every 3 months after 2 years. The tacrolimus dose will be adjusted to achieve a trough of 5-10ng/ml in subjects randomized to the control group which is standard of care per protocol. GFR measurement by DTPA will be repeated at 6 months, and 1 year post randomization. The second allograft biopsy will be performed at 1 year post randomization.

Patient and graft survival, and the incidence of acute rejection, proteinuria, hyperlipidemia, anemia, leucopenia, thrombocytopenia, and other clinical parameters will be monitored and compared between the sirolimus conversion group and the subjects who will be maintained on tacrolimus.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 50
• Est. completion date: June 2011
• Est. primary completion date: June 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• African American (self-identified) renal transplant recipients.

• Primary or re-transplant kidney-only recipients.

• Recipients on tacrolimus-based immunosuppression regimen.

• Time interval after transplant: at least 3 months but not greater than 5 years.

• Renal transplant recipients with 10% decrease in GFR from baseline.

• Women of childbearing potential must have a negative pregnancy test upon enrollment, and must consent to receive contraceptive counseling and to use effective contraception while enrolled in the study. Two reliable forms of contraception must be used simultaneously unless abstinence is the chosen method.

Exclusion Criteria:

• GFR <40ml/min.

• Urine protein-to-creatinine ratio >0.5.

• Significant chronic allograft nephropathy grade 3 Banff score.

• Evidence of acute rejection episodes within the past 3 months.

• Evidence of active infection within the past month.

• Any malignancy except treated non-melanoma skin cancer within the past 3 years.

• Leucopenia <2,000/mm3 within the past month.

• Thrombocytopenia <100,000/mm3 within the past month.

• Total cholesterol >300mg/dl, despite adequate treatment.

• Triglycerides >500mg/dl, despite adequate treatment.

• Non-healed post-surgical or non-surgical wound.

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Chronic Allograft Nephropathy
• Glomerular Filtration Rate
• Kidney Diseases

Intervention

Drug:
• sirolimus
The subjects assigned to the sirolimus conversion group will be initiated on sirolimus 5mg po daily at which time their tacrolimus dose will be decreased by 50%. Sirolimus levels will be checked within a week and adjusted in a linear fashion to achieve a trough goal of 12-15ng/ml in subjects within 1 year post-transplant, and 8-12 ng/ml in subjects more than 1 year post-transplant. Tacrolimus will be continued in these subjects until sirolimus target trough levels are achieved. Thereafter, tacrolimus will be discontinued indefinitely. The subjects assigned to the tacrolimus maintenance group (control group) represent our present standard of care.

Locations

Country	Name	City	State
United States	Temple University	Philadelphia	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
Temple University	Wyeth is now a wholly owned subsidiary of Pfizer

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Glomerular filtration rate measured by Gd-DTPA		6 months, and 1 year	No
Secondary	Quantification the histological markers on renal allograft biopsy		1 year	No
Secondary	Patient survival, graft survival, and incidence of acute rejection		1 year	No