Navdeep Tangri, MD
Dr. Tangri is an Associate Professor in the Department of Medicine at the University of Manitoba. He is interested in the trajectory of patients with moderate to severe CKD as they transition to dialysis, and is generating the evidence to help clinicians and patients make risk based shared decisions around CKD care. He loves all things Arsenal FC. Follow him @NavTangri.
Competitors for the Trial Outcomes Region
It’s time to double down on 40% decline.
As long as there have been clinical trials in nephrology, there have been complaints about not having enough clinical trials in nephrology. At the recent annual meeting of the American College of Cardiology, I couldn’t help but be jealous of my cardiology colleagues who look forward to multiple landmark clinical trials every year which provide level 1 evidence to inform their clinical practice.
We must do better, and we are trying. In the last few years, the FDA is finally listening. In 2016, the FDA asked a group of scientists including Lesley Inker, Tom Greene, Hiddo Heerspink, and Joe Coresh to produce evidence for alternative GFR-based endpoints for CKD progression. The team presented a series of analyses which tackled this important question using different yet complementary methods. The CKD Prognosis Consortium presented observational data from 1.2 million individuals, Lesley and Hiddo presented data from previously conducted clinical trials, and Tom Greene presented a simulation study.
The findings from these analyses were consistent. In nearly every scenario, a 40% Reduction in eGFR when substituted for the more traditional Doubling of Creatinine endpoint resulted in a meaningful (20-35% ) sample size reduction while having a minimal effect on the false positive or type 1 error rate.
When translated to numbers, this meant 2,000 patients and a $50 million trial vs 3,000 patients or an almost $80 million trial. Dollars aside, smaller trials also require fewer countries, fewer sites, shorter recruitment periods, and are ultimately more feasible.
Why should we care?
1) It makes sense. For the patient with an eGFR of 50 ml/min who enrolls in a nephrology trial, a decline down to 30 ml/min is meaningful. It changes how they feel and it changes their prognosis.
2) It predicts downstream kidney failure. When eGFR declines by 40% over 12 months or longer, the risk of eventually requiring dialysis or transplant goes up nearly 10-fold. While that’s not 50-fold or 100-fold, it’s good enough for me.
3) Acute effects are not enough to cause false positive errors. Some of you may be thinking “What if I put my patient on a RAAS inhibitor and their eGFR declines by 40 % before stabilizing – Are they not protected from kidney failure?” NO! Large acute declines are uncommon and a terrible prognostic marker. This is more of an issue for 30 % decline as an endpoint, and did not affect the results for RAASi trials and the 40 % endpoint.
4) We want more trials. We certainly need them. So, let’s make it feasible and attractive for industry and academics to do more CKD trials. It will help us, help them, and above all, help our patients.
– Post written by Navdeep Tangri. Follow him @NavTangri.
As with all content on the AJKD Blog, the opinions expressed are those of the author of each post, and are not necessarily shared or endorsed by the AJKD Blog, AJKD, the National Kidney Foundation, Elsevier, or any other entity unless explicitly stated.