A Pilot Study Comparing the Use of Low-target Versus Conventional Target Advagraf

NCT ID: NCT01265537

Last Updated: 2025-01-23

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 30 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-06-24
• Study Completion Date: 2019-10-11

Brief Summary

While the incidence of acute rejection and early graft loss have improved dramatically with the advent of newer immunosuppressant medications, improvements in long-term patient and allograft survival after kidney transplantation have not been achieved. The specific drug combination that provides the best outcomes with the least amount of side effects is not known. Each kidney transplant center uses the combination of drugs that they believe is optimal. This study is about identifying whether drugs that are currently approved for use in kidney transplantation can be used in a new combination safely and with potentially fewer side effects than the drug combinations that are currently used at St. Paul's Hospital and other transplant centres.

Detailed Description

Purpose This study has been designed to test whether using Thymoglobulin with low dose tacrolimus and early steroid withdrawal will minimize both kidney rejection and the development of new onset diabetes after transplant (NODAT).

Justification Experimental treatment is low target tacrolimus with thymoglobulin. Standard treatment is a standard target (higher dose) tacrolimus and basiliximab, instead of thymoglobulin.

The investigators hypothesize, that a combined approach of early steroid withdrawal and low dose tacrolimus in low immunologic risk transplant recipients will be effective in reducing the incidence of new onset diabetes mellitus, while maintaining a low risk of acute rejection.

Objective

The objective of this study is to compare early post-transplant outcomes with the use of low target versus standard target Advagraf in de novo kidney allograft recipients of low immunologic risk undergoing early corticosteroid withdrawal.

Research Method

This is a pilot study. Primary and secondary outcomes are as follows:

Primary Outcome Composite endpoint of biopsy proven acute rejection and NODAT at 6 months post transplantation.

Secondary Outcomes

• Patient survival
• Graft survival
• Frequency, severity, and treatment of hypertension
• Frequency, severity, and treatment of hyperlipidemia (serum total cholesterol, (high density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides)
• Weight gain
• Infections (cytomegalovirus (CMV), opportunistic infections including urinary tract infections requiring treatment, pneumonia)
• Malignancy, including post-transplant lymphoproliferative disease (PTLD)
• Leukopenia
• Renal function as measured by serum creatinine and estimated Glomerular Filtration Rate (eGFR)

The primary endpoint will be evaluated by time-to-event Kaplan Meier analysis and by Chi-squared analysis of final 6 month data.

Statistical Analysis

Sample size and power:

In the setting of early steroid withdrawal, Woodle et al. reported an acute rejection rate of 14% with rATG and 24% with an interleukin-2 receptor antibody induction(10). The incidence of NODAT was reported at 21% by Woodle, et al., and was reported 10% in the low dose tacrolimus arm of the ELITE-Symphony trial. The investigators, therefore expect a combined event rate of 24% in Group A and 45% in group B. With a power of 0.80 and alpha error of 0.05, the investigators determined that the investigators need 72 subjects in each arm to demonstrate a 20% difference in our composite primary outcome. For this initial pilot study, the investigators aim to recruit a total of 30 subjects After receiving informed consent, subjects will be randomized on a 1:1 basis to one of the two treatment groups. Subjects who discontinue the study prematurely will not be replaced.

Conditions

Acute Graft Rejection; Diabetes

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Low target tacrolimus (Advagraf)

This group will receive rabbit anti-thymocyte globulin (rATG) induction (3 -4 doses of 1.5 mg/kg during the first post transplant week) with IV solumedrol, MPA (Mycophenolate Mofetil or Mycophenolate Sodium), and "low-target" Advagraf.

Group Type: EXPERIMENTAL

Tacrolimus

Intervention Type: DRUG

Low target tacrolimus Advagraf (0.25mg/kg) orally once daily dosed as per manufacturer's recommendation to target trough levels as per Table 1

Table 1

Months post tx:

0-1 month, level 5-7; 1-3 months, level 4-5; and 3-6 months, level 3-4

Standard target tacrolimus (Advagraf)

This group will receive basiliximab induction (40 mg total) with IV solumedrol, MPA (Mycophenolate Mofetil or Mycophenolate Sodium), and "standard target" Advagraf.

Group Type: ACTIVE_COMPARATOR

Tacrolimus

Intervention Type: DRUG

Standard dose of tacrolimus Advagraf (0.25mg/kg) orally once daily dosed as per manufacturer's recommendation to target trough levels as per Table 1

Table 1

Months post tx

0-1 month; level 8-12; 1-3 months, level 6-9; and 3-6 months, level 5-8.

Interventions

Tacrolimus

Low target tacrolimus Advagraf (0.25mg/kg) orally once daily dosed as per manufacturer's recommendation to target trough levels as per Table 1

Table 1

Months post tx:

0-1 month, level 5-7; 1-3 months, level 4-5; and 3-6 months, level 3-4

Intervention Type: DRUG

Tacrolimus

Standard dose of tacrolimus Advagraf (0.25mg/kg) orally once daily dosed as per manufacturer's recommendation to target trough levels as per Table 1

Table 1

Months post tx

0-1 month; level 8-12; 1-3 months, level 6-9; and 3-6 months, level 5-8.

Intervention Type: DRUG

Other Intervention Names

Advagraf; Advagraf

Eligibility Criteria

Inclusion Criteria

1. Male or female patients over 18 years of age who receive a deceased, living unrelated or living related donor renal transplant

2. No history of pre-existing diabetes mellitus

3. Not using diabetic medications (insulin, hypoglycemic agents) at the time of transplantation

4. Random plasma glucose level <11.1 at the time of transplantation

5. Peak PRA (panel reactive antibody) <30%

6. Females capable of becoming pregnant must have a negative pregnancy test at baseline and are required to practice an approved method of birth control for the duration of the study and for a period of three months following discontinuation of study medication

7. The patient has given written informed consent to participate in the study

Exclusion Criteria

1. Patients with primary non-function

2. Peak PRA>=30%

3. Multiple organ transplants

4. HLA (human leukocyte antigen) identical living donor transplant recipients

5. Cold ischemia time over 36 hours

6. Nonheart beating donor kidney recipients

7. Pediatric donor kidney recipients

8. Donor age>=65 years

9. Patients who are known to have a positive hepatitis C serology, who are human immunodeficiency virus (HIV) or Hepatitis B surface antigen positive. Laboratory results obtained within 6 months prior to study entry are acceptable. Recipients of organs from donors who test positive for Hepatitis B surface antigen or Hepatitis C will be excluded.

10. Patients who are Epstein-Barr virus (EBV) negative and are receiving a transplant from an EBV-positive donor (mismatch).

11. Presence of any severe allergy requiring acute (within 4 weeks of baseline) or chronic treatment, or hypersensitivity to drugs similar to those used in the study

12. Patients with systemic infections

13. Existence of any surgical or medical condition, other than the current transplant, which in the opinion of the investigator, preclude enrollment in this trial

14. Inability to cooperate or communicate with the investigator

• Minimum Eligible Age: 19 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Astellas Pharma Canada, Inc.

INDUSTRY

Sponsor Role: collaborator

University of British Columbia

OTHER

Sponsor Role: lead

Responsible Party

Jagbir Gill

Assistant Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Jagbir Gill, MD

Role: PRINCIPAL_INVESTIGATOR

UBC / Dept of Medicine / Nephrology

Locations

St. Paul's Hospital

Vancouver, British Columbia, Canada

Countries

Canada

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

H10-03047

Identifier Type: -

Identifier Source: org_study_id