REmoval Of Tacrolimus For Sirolimus Following Thymoglobulin Induction On The Development of REgulatory T Cells in Kidney Transplant Patients
A prospective, open label, controlled, multicentre trial to assess the effect of an induction regimen of Thymoglobulin (Registered Trademark) compared with Simulect (Registered Trademark) with Tacrolimus, Mycophenolic acid and corticosteroids, followed by withdrawal of Tacrolimus for Sirolimus on the development of regulatory T cells in kidney transplant recipients of donation after cardiac death donor kidneys
Department of Health
30 participants
Apr 1, 2012
Interventional
Conditions
Summary
The introduction of induction transplant medications (i.e. given before transplantation) such as Thymoglobulin and Basiliximab has led to a major reduction in acute kidney rejection and enhanced early kidney transplant survival. Despite improvement in short-term outcomes, there has been minimal improvement in longer-term kidney transplant survival due to progressive scarring and damage of transplanted kidneys, partly attributed to the use of other transplant medications such as tacrolimus (a form of calcienurin-inhibitor). In addition, renal transplant recipients receiving marginal donor kidneys (poorer quality kidneys) have more damage/scarring and have reduced graft survival compared to standard donor kidneys. A population of circulating rare cells known as regulatory T cells, have been shown to be beneficial in kidney transplantation, possibly by reducing patients’ immune responses (therefore may reduce rejection risk) and prevent inflammation and scarring (which may improve long-term outcome of kidney transplants). Thymoglobulin and sirolimus (another type of transplant medication) have been shown independently to promote the development of regulatory T cells and may possibly prevent scarring in the transplanted kidney. However, the combination of thymoglobulin with sirolimus on transplant outcomes have not been evaluated. The aims of this study will be to compare recipients of donation after cardiac death donor kidneys receiving Thymoglobulin compared to basiliximab induction with low-dose tacrolimus, mycophenolic acid and steroids (other transplant medications) for at least months, changing to sirolimus in appropriate recipients up to 12 months post-transplant. The following outcomes will be assessed: proportion of circulating regulatory T cells, transplant kidney injury and scarring, metabolic and inflammatory outcomes as well as efficacy and tolerability between the two treatment groups.
Eligibility
Inclusion Criteria6
- Males and females aged >18 years inclusive.
- Primary and subsequent DCD renal transplant recipients.
- Females capable of becoming pregnant must have a negative serum pregnancy test within 7 days prior to or at screening, and are required to practice a medically accepted effective method of birth control for the duration of the study and for a period of 6 weeks following discontinuation of study medication, even where there has been a history of infertility.
- Patients who are willing and able to participate in the study and from whom written informed consent has been obtained.
- Day 90-135 post-kidney transplantation.
- Continuously maintained on Tacrolimus and Mycophenolic acid during the last 30 days.
Exclusion Criteria21
- Patients who are recipients of multiple organ transplants, kidney and pancreas, or previous transplant with any organ other than kidney but recipients receiving two kidneys from DCD donor can be included in study.
- Patients at high immunological risk of graft loss, indicated by the presence of donor-specific antibody or loss of a previous renal allograft within the first 6 months of transplantation due to acute rejection.
- Presence of any severe allergy or hypersensitivity to drugs similar to sirolimus (e.g. macrolides), tacrolimus, thymoglobulin, basiliximab or mycophenolic acid.
- Patients who are recipients of A-B-O incompatible transplants or T or B cell allogeneic cross-match positive transplants.
- Patients who are known to have chronic active Hepatitis C, or who are HIV or Hepatitis B surface antigen positive. Laboratory results obtained within 6 months prior to randomization are acceptable. Recipients of organs from donors who test positive for Hepatitis B surface antigen or Hepatitis C are excluded.
- Patients with symptoms of significant somatic or mental illness, or inability to co-operate or communicate with the investigator.
- Unresolved history of drug or alcohol abuse.
- Patients with clinically significant infections requiring continued therapy, severe diarrhea, active peptic ulcer disease, or uncontrolled diabetes mellitus that in the opinion of the investigator would interfere with the appropriate conduct of the study.
- Patients with a history of malignancy within 3 years of transplant (other than excised basal cell carcinoma of the skin).
- Breastfeeding women.
- Abnormal physical or laboratory findings of clinical significance, which at investigator discretion would interfere with the objectives of the study.
- Patients receiving drugs known to interact with tacrolimus and/or sirolimus, where exposure to the interacting drug is unstable/variable or may lead to difficulties attaining stable target levels of tacrolimus or sirolimus.
- 3-month biopsy demonstrating subclinical/grade I rejection, recurrent glomerular disease and/or transplant glomerulopathy (patients with subclinical rejection or with grade I rejection may still be included provided they have a normal repeat biopsy within the conversion period. The repeat biopsy should occur at least 14 days after the last dose of methylprednisolone and at least 7 days prior to the conversion to sirolimus).
- Any vascular or antibody-mediated or = grade 2 rejection according to Banff criteria at any time prior to conversion.
- Patients treated with other immunosuppressive agents not described in this protocol (e.g. cyclosporine, everolimus).
- Significant proteinuria (defined as equivalent to protein/creatinine ratio >80mg/mmol) within 1 week prior to randomization.
- eGFR (4-point MDRD) of <35ml/min.
- Patients with thrombocytopenia (platelets <75,000/mm3), with an absolute neutrophil count of <1,500/mm3 or leucopenia (leucocytes <2,500/mm3), or hemoglobin <8g/dL.
- Evidence of severe liver disease (including abnormal liver enzyme profile, i.e. AST, ALT or total bilirubin >3 times ULN).
- Patients with fasting total cholesterol >8mmol/L and/or triglyceride >4.5mmol/L despite lipid-lowering agents.
- Recent major surgery within 2 weeks prior to conversion to sirolimus.
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Interventions
Induction therapy with thymoglobulin with tacrolimus (0.15-0.20mg/kg/day in divided doses orally), mycophenolic acid (mycophenolate mofetil 1g twice daily or myfortic 720mg twice daily orally) and prednisolone (30mg daily orally), followed by changing from tacrolimus to sirolimus (2-5mg daily orally) in eligible patients (i.e. tacrolimus ceased and sirolimus commenced). Thymoglobulin given as 6mg/kg over 4 days as a 4-6 hour intravenous infusion, starting at time of transplant. Mycophenolic acid will be given pre-transplant and tacrolimus and prednisolone given within 12 hours post-transplant. The combination of tacrolimus (or sirolimus), mycophenolic acid and prednisolone will be given for at least 12 months following transplantation. In more details: Induction: Thymoglobulin 6mg/kg in 4 divided doses. Dose 1 – 1.5mg/kg given within 6 hours pre-transplant or at or around time of transplant as at least a 6 hour infusion (see appendix 2). Dose 2 – 1.5mg/kg day +1 post-transplant as a 4-6 hours infusion. Dose 3 – 1.5mg/kg day +2 post-transplant as a 4-6 hours infusion. Dose 4 – 1.5mg/kg day +3 post-transplant as a 4-6 hours infusion. Standard pre-transplant methylprednisolone (500-1000mg), day +1 methylprednisolone (500-1000mg) and day +2 oral prednisolone (30mg daily) to be given at least 30 minutes prior to thymoglobulin infusion with 1g paracetamol and 25mg oral/IM phernergan. If the WCC is between 2-3x109/L and/or platelet count between 50-70x109/L, it is recommended that the dose of thymoglobulin is reduced by one-half. If the WCC is less than 2x109/L and/or platelet count is less than 50x109/L, it is recommended that thymoglobulin is stopped until the WCC and/or platelet counts recover. Day 1 – Day 90-135: Tacrolimus with dose adjusted to levels as per local institution protocol (recommended trough level 5-10ug/L). Cellcept or myfortic - recommended dosing at least 1g bd or 720mg bd respectively for the first 2 weeks, then dosing according to local institutional protocol . Prednisolone 30mg daily and dose reduce according to local institutional protocol to not less than 10mg daily. Day 90 – Day 135 (conversion period): Sirolimus: Recommendation is to stop tacrolimus on day before introducing sirolimus at 2-5mg daily. Target sirolimus trough level as per local protocol (recommendation: 8-12ug/L up to day 180). An overlap between tacrolimus and sirolimus is allowed and recommended regimen is to reduce tacrolimus by 50% and initiating sirolimus at 2mg daily. Tacrolimus must be ceased when sirolimus level reaches target level. Cellcept or myfortic according to local institutional protocol. Prednisolone as per local institution protocol. Day 135 – month 12: Sirolimus dose adjustment to achieve trough level as per local protocol (recommendation: target 8-12ug/L to day 180, then 5-10ug/L till month 12). Cellcept or myfortic according to local institutional protocol. Prednisolone as per local institution protocol.
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ACTRN12611001224910