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

Conditions

Acute Graft Rejection, Diabetes

Keywords

Transplant, Tacrolimus, Diabetes after transplant, Acute rejection prevention, New onset diabetes after transplant

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.

Related papers

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Interventions

DRUGTacrolimus

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

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

19 Years to No maximum

Healthy volunteers

No

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

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants With New Onset Diabetes After Transplant (NODAT) or Acute Rejection	6 months post transplant	Composite endpoint of biopsy proven acute rejection and NODAT at 6 months post transplantation. NODAT will be defined as either FPG \>7.0mmol/L OR symptoms of hyperglycemia and a random plasma glucose of \>11.1 OR 2-h plasma glucose \>11.1 during an oral glucose tolerance test(OGTT).

Secondary

Measure	Time frame	Description
Number of Participants With Graft Failure	6 months post transplant	Any graft failure by the end of the study.
Number of Participants With Dialysis Events	6 months post transplant	Any dialysis required by end of study.
Number of Participants With Infection Events	6 months post transplant	Any infection (CMV, opportunistic infections including urinary tract infections requiring treatment, pneumonia) by end of study.
Number of Participants With Hospitalization Events	6 months post transplant	Any hospitalization by end of study.
Number of Participants With Malignancy Events	6 months post transplant	Any malignancy (including post-transplant lymphoproliferative disease) by end of study.
Number of Participant Deaths	6 months post transplant	Death of any participant by end of study.
Number of Any Leukopenia Events	6 months post transplant	Any leukopenia by end of study.
Number of Leukopenia Events on ≥2 Occasions	6 months post transplant	Any leukopenia on ≥2 occasions by end of study.
Change From Baseline in Weight	baseline to 6 months post transplant	Any changes in weight by end of study.
eGFR at 6 Months	6 months post transplant	Participant eGFR value by end of study.
Number of Participants With Cardiovascular Event	6 months post transplant	Any cardiovascular events by end of study.

Countries

Canada

Participant flow

Participants by arm

Arm	Count
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. 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	14
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. 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.	14
Total	28

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	2	1
Overall Study	Physician Decision	0	1

Baseline characteristics

Characteristic	Low Target Tacrolimus (Advagraf)	Standard Target Tacrolimus (Advagraf)	Total
Age, Continuous	61.8 years	50.4 years	54.3 years
Body Mass Index	25.1 kg/m^2 STANDARD_DEVIATION 3	27.5 kg/m^2 STANDARD_DEVIATION 6.3	26.4 kg/m^2 STANDARD_DEVIATION 5.1
Cholesterol Medications No	10 Participants	12 Participants	22 Participants
Cholesterol Medications Yes	4 Participants	2 Participants	6 Participants
Cholestoral	4.56 mmol/L STANDARD_DEVIATION 0.97	4.43 mmol/L STANDARD_DEVIATION 0.6	4.49 mmol/L STANDARD_DEVIATION 0.78
Diastolic Blood Pressure	81 mmHg STANDARD_DEVIATION 9	87 mmHg STANDARD_DEVIATION 9	84 mmHg STANDARD_DEVIATION 9
Donor Age	41 years	34 years	39 years
Donor Type Deceased	3 participants	11 participants	14 participants
Donor Type Living	11 participants	3 participants	14 participants
Family History of Diabetes	6 participants	6 participants	12 participants
Fasting Glucose	5.6 mmol/L STANDARD_DEVIATION 0.8	5.2 mmol/L STANDARD_DEVIATION 0.6	5.4 mmol/L STANDARD_DEVIATION 0.7
High-Density Lipoproteins	1.21 mmol/L STANDARD_DEVIATION 0.28	1.37 mmol/L STANDARD_DEVIATION 0.62	1.30 mmol/L STANDARD_DEVIATION 0.49
Human Leukocyte Antigen (HLA) Matches 0 matches	3 Participants	6 Participants	9 Participants
Human Leukocyte Antigen (HLA) Matches 1 match	4 Participants	3 Participants	7 Participants
Human Leukocyte Antigen (HLA) Matches 2 matches	3 Participants	0 Participants	3 Participants
Human Leukocyte Antigen (HLA) Matches 3 matches	1 Participants	1 Participants	2 Participants
Human Leukocyte Antigen (HLA) Matches 4 matches	1 Participants	0 Participants	1 Participants
Human Leukocyte Antigen (HLA) Matches 5 matches	1 Participants	0 Participants	1 Participants
Human Leukocyte Antigen (HLA) Matches Missing	1 Participants	4 Participants	5 Participants
Low-Density Lipoproteins	2.72 mmol/L STANDARD_DEVIATION 0.82	2.68 mmol/L STANDARD_DEVIATION 0.76	2.70 mmol/L STANDARD_DEVIATION 0.77
Peak Panel-Reactive Antibody (PRA) before transplant	0 %	0 %	0 %
Race/Ethnicity, Customized Asian	0 Participants	4 Participants	4 Participants
Race/Ethnicity, Customized Caucasian/White	13 Participants	9 Participants	22 Participants
Race/Ethnicity, Customized Other/Multiracial	1 Participants	0 Participants	1 Participants
Race/Ethnicity, Customized Pacific Islander	0 Participants	1 Participants	1 Participants
Random Glucose	5.5 mmol/L STANDARD_DEVIATION 1.3	5.7 mmol/L STANDARD_DEVIATION 1.1	5.6 mmol/L STANDARD_DEVIATION 1.2
Sex: Female, Male Female	4 Participants	4 Participants	8 Participants
Sex: Female, Male Male	10 Participants	10 Participants	20 Participants
Systolic Blood Pressure	150 mmHg STANDARD_DEVIATION 21	159 mmHg STANDARD_DEVIATION 27	154 mmHg STANDARD_DEVIATION 24
Triglycerides	1.38 mmol/L STANDARD_DEVIATION 0.36	1.52 mmol/L STANDARD_DEVIATION 1.08	1.46 mmol/L STANDARD_DEVIATION 0.82

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 14	0 / 14
other Total, other adverse events	0 / 14	0 / 14
serious Total, serious adverse events	7 / 14	7 / 14

Outcome results

Primary

Number of Participants With New Onset Diabetes After Transplant (NODAT) or Acute Rejection

Composite endpoint of biopsy proven acute rejection and NODAT at 6 months post transplantation. NODAT will be defined as either FPG \>7.0mmol/L OR symptoms of hyperglycemia and a random plasma glucose of \>11.1 OR 2-h plasma glucose \>11.1 during an oral glucose tolerance test(OGTT).

Time frame: 6 months post transplant