Wednesday, January 29, 2014

IMAGINE trial for Transplant Immunosuppression: Dream RCT in Nephrology

I thought I would throw in my two cents on the Dream RCT in Nephrology poll being co-ordinated at UKidney. My choice focuses on transplant immunosuppression and you can see the entry by Joel Topf on PB Fluids here.

There is no standardization of immunosuppression post kidney transplant and before I’m attacked on the blogosphere, I do think that’s a good thing. Each transplant operation is unique with differing immunological risks based on donor & recipient factors. A non-sensitized, white, living donor transplant recipient should be managed different to a deceased-donor, African American, re-transplant. However, there are almost as many different protocols as there are transplant centers and new immunosuppressive agents are becoming available for clinical use. Therefore the transplant community is far from certain which exact agents should be employed for different risk groups. My pick for dream RCT in Nephrology is admittedly a tricky one. If I could have 2 or 3 dream RCTs that would certainly make things easier for me.

Before I start I would like to justify why I feel we need this. The ELITE-Symphony study was a landmark RCT in kidney transplant immunosuppression. Briefly, a regimen of low dose tacrolimus together with MMF, steroids and induction with daclizumab was more beneficial regarding eGFR, allograft survival and acute rejection (AR) at 1 year. Comparison regimens were low dose cyclosporine, low dose sirolimus (both instead of tacrolimus above) plus an additional arm without induction but with standard dose cyclosporine, MMF & steroids. Note that the patients were overall low risk: predominantly white, 35% living donors, mean PRA 20%. This trial solidified the current standard of care for most patients as low dose, triple immunosuppression based around tacrolimus. However since then we have a new kid on the block in belatacept, follow up in SYMPHONY was only 1 year and the issue of induction therapy is not resolved.

Belatacept is a T-cell co-stimulatory blocker and has demonstrated efficacy as a maintenance agent for both standard and expanded criteria donor kidneys. The belatacept studies (BENEFIT & BENEFIT-EXT) used cyclosporine as the comparator and both demonstrated an improvement in eGFR at 3 years despite more early AR.

Let us consider these 2 points which will simplify my imaginary trials:
1. Firstly, no mTOR inhibitors. They’re out! Why do we keep trying to find a mainstream role for mTOR inhibitors in renal transplantation?. I will admit that they have a (limited) role in renal transplantation, mostly when malignancy is an issue or in certain cases of calcineurin inhibitor toxicity (when no proteinuria and preserved GFR). In the ELITE-Symphony study, they had the worst allograft survival & the most adverse events with almost half of patients withdrawing from the sirolimus group. They will never be the cornerstone of immunosuppression post-transplant, especially early post transplant, so they will not be considered.

2. Why is cyclosporine always the control group for new immunosuppressive drugs post transplant? The FDA has traditional mandated that the control arm be a cyclosporine based regimen, despite this not being the standard of care anymore. Tacrolimus is now the leading agent used for >85% of patients as per the SRTR Report 2011 (versus about 4% for cyclosporine). Therefore, cyclosporine is also out. Transplant centers will be more willing to participate as their patients in the control arm will be getting current standard of care.

Immunuosuppression MAnagement for Graft survival IN the current Era (IMAGINE) will be a multi-center randomized controlled trial comparing 2 immunosuppression regimes in general real-world kidney transplant recipients (living & deceased donors, calculated PRA <50%, re-transplants with cPRA <30%). The trial will have a 2x2 factorial design based on 2 induction and 2 subsequent maintenance arms.
1. Induction arm: Basiliximab (daclizumab no longer available) versus rATG. There is an argument for including Alemtuzumab here but this trial is already getting messy so we’ll leave that for IMAGINE-2.
2. Maintenance arm: tacrolimus V belatacept, both with MMF (1g BID)/steroids. It is an open-label design given that belatacept is administered IV and therapeutic drug monitoring is needed with tacrolimus. Maintenance trough levels will be 4-7ng/ml. Note that actual achieved levels in SYMPHONY were close to 7ng/ml despite target being 3-7ng/ml.

Induction: I have included an induction arm as I feel this is another area which needs clarity. For highly sensitized patients there is more consensus that lymphocyte-depleting agents are the way to go (with rATG being more favourable to ATGAM & OKT3). For general low-to-moderate risk recipients, the optimal induction agent is less clear. There is evidence that again rATG is more efficacious but with infection risk and logistical reasons perhaps being important, basiliximab use is common (approximately 1/3 of transplants in 2011).
The sister trial Immunuosuppression MAnagement for Graft survival IN A RiskY population (IMAGINARY) will include highly sensitized recipients with cPRA>50% and re-transplants with prior graft loss due to AR or cPRA >30%. This study will use rATG as induction.
Outcomes: Primary outcome is allograft & patient survival (hard outcomes) at 5 years. Secondary outcome are eGFR and early AR (a relatively soft outcome in my opinion post transplant). Most trials report one year follow-ups which has less relevance for an organ you hope to last >10 years.

Therefore notable features of these trials include hard endpoints, longer follow-up, comparison to the current standard of care and induction arms. That’s my trial design which will form the template for further imaginary studies of newer immunosuppressive agents currently in development. I apologize for the protracted post but these issues couldn’t be dealt with any more briefly! I realize that my dream RCTs may leave me open to criticism but the point of this exercise is to provoke discussion and challenge us to think about what we do and why we do it. And yes, I came up with the trial acronyms before I even wrote the post!

1 comment:

Paul Phelan said...

I have amended the 'protocol' to a 2 x 2 factorial design rather than 1:1:1:1. Thanks to Joel Topf for pointing that out.