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
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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