AASK: a cautionary tale for bardoxolone?

Robert Leversee had some questions regarding my presentation on diabetic nephropathy. You can see his concerns in the comments after the post. he was specifically concerned about this slide.

Robert felt it minimized the GFR gains found with bardoxolone. What is not clear from the deck is that 56 weeks, represents the GFR one month after stopping the drug. In the lecture, I pointed out that patients that were on bardoxolone all had a higher GFR than at baseline, while patients randomized to placebo had a lower GFR.

As a reminder, the primary end-point of the study was the change in GFR at 24 weeks and that was dramatic.

The reason I included the slide showing the 56 week data was my concern that bardoxolone may be pulling a creatinine slight of hand. My personal concern is that the changes in GFR are due to simple hemodynamic changes like were seen with amlodipine in AASK.

AASK was a trial of hypertension therapy in African Americans with a renal end-point rather than a cardiovascular end-point that are more common in hypertension trials. The trial is a two by three design with two blood pressure targets (MAP 102-107 vs <92) and three blood pressure medications (amlodipine, ramipril, metoprolol).

The data is difficult to interpret because the amlodipine caused an acute hemodynamic-related bump in the GFR, but after 12 months the loss of GFR in the amlodipine group was faster than with ramipril. The study designers designated co-primary end points, a total change in GFR and a chronic change in GFR that ignored the initial 3 months.

Ramipril was superior to amlodipine in the chronic phase but not in the total change in GFR. Though this ambiguity was not represented in the conclusions of the trial:

The fact that amlodipine improved renal function for one year makes me nervous about the one year duration of the bardoxolone study. Thankfully BEACON is in full swing enrolling patients so a definitive answer is just ahead.

11 Replies to “AASK: a cautionary tale for bardoxolone?”

  1. Thanks for expanding on this point – the AASK trial is certainly a cautionary tale. Maybe Bardoxolone's overall GFR curve will look similar when the BEACON data is compiled in 2013, just with a slower time to GFR decline. I would just note that in the AASK paper the authors talk about "a large acute increase in GFR for amlodipine in the 3 months after randomization", and thus far in the Bardoxolone trial, the GFR increase seems to be holding for at least 12 months, without a similar decline. But your point is well taken, and certainly it is too early in the story to proclaim a lasting benefit for Bardoxolone.
    Again, thanks!

  2. Homer,

    In AASK the renal function was measured with iothalamate clearance so there is no tubular secretion issue. In BEAM 2 they used serum creatinine so enhanced tubular secretion of creatinine is on the table but off the top of my head I'm unable to think of a drug or disease that causes increased secretion of creatinine. Do you have something in mind?

  3. I hope that this drug is fully studied before it is out in the market, otherwise I belive we may going down the path of ESA all over again, where it was enthusiastically embraced by the nephrology community without knowledge of what we know today.
    Also I note on the BEACON inclusion criteria, that the patients should be on ACE- AND/or ARB. Given the recent data on combined use of RAS blockade, the investigators may need to exclude this subset of patients who were on the combination. I only hope that this is a small number now.

  4. I have a post coming up on combining ACE and ARB from a lecture at Kidney Week. I don't fear a rehash of the ESA conundrum with bardoxolone because the drug is currently undergoing a large study with an appropriate end-point, something that was never done with EPO until TREAT.

    If bardoxolone works I hope the company does not delay selling it. We all have clinics full of patients who could benefit.

  5. I'm not sure about the appropriateness of the endpoint of BEACON. They're recruiting Stage 4 CKD and using time to ESRD or death as the primary endpoint. In the setting of a drug that causes Cr to fall, perhaps hemodynamically (or via other mechansisms that may not involve a change in GFR), the study is designed to bias against placebo. It'd be a much better design to recruit patients with lesser degrees of renal impairment and look at the typical doubling of sCr, ESRD, or death. Initiation of ESRD is quite subjective, making for a soft endpoint for a trial that's recruiting patients near-ESRD at baseline.

  6. Oh, and just because we can't think of a drug or disease that increases tubular secretion of Cr doesn't mean that the possibility doesn't exist. Bardoxolone could also inhibit creatinine generation in some way. It just would've been nice for them to show some iGFR data instead of relying on only Cr-based measures for a brand new drug. Hopefully they have iGFR data.

  7. Dr. Smith, I respectfully disagree.

    The use of hard end-points like dialysis and death are absolutely the best practices available. A doubling of serum creatinine is a factor much more able to be fudged especially given the possibility of a hemodynamic effect on GFR. And I am skeptical of your argument that starting dialysis is a soft, subjective end-point and given that the study is a placebo controlled trial, it becomes even more valid. Did you discount the results of CREATE that showed an increase in dialysis with higher hemoglobins? That wasn't even blinded.

    Lastly, I would argue with your statement that CKD stage 4 patient are that close to dialysis. Look at Keith's data (Keith et al. Longitudinal follow-up and outcomes among a population with chronic kidney disease in a large managed care organization. Arch Intern Med (2004) vol. 164 (6) pp. 659-63) from Kaiser Permanente.

    Keith showed that over a 5.5 year period 45% of CKD stage 4 patients died and only 17% started dialysis, 3 percent a year. With those odds, if someone told you there was a drug that decreased the likelihood of those end-points would you be interested? I would and I'm sure most of my patients would also.

  8. Let me give you an example. For the sake of example, suppose that bardoxolone has NO effect on preventing renal fibrosis, which is really what "renoprotection" is. Let's just say that its effect on eGFR is entirely hemodynamic.

    Suppose you recruit two identical patients with an eGFR of 15 ml/min. Suppose study drug increases eGFR by 10 mL/min, approximately the mean increase observed in the phase 2 study. You now have 2 patients: one with eGFR 25 ml/min (bard.) and the other with an eGFR of 15 ml/min (placebo). Since we're hypothetically saying that the study drug has no effect on renal progression, both otherwise-identical patients will progress at the same rate. Let's fast-forward a year, and you could have a patient with an eGFR of 20 ml/min and another with 10 ml/min.

    If these are patients with uncontrolled type 2 diabetes and they come in with some occasional nausea/vomiting, a bit of dysguesia, some loss of appetite, I find it very hard to believe that the probability of initiating dialysis would be equal between these two patients. A treating nephrologist, I speculate, would be far more likely to initiate the patient with 10 ml/min than the patient with 20 ml/min.

    I realize this is a hypothetical example, but it illustrates that you could very easily have a drug that "delays dialysis" intiation without having one iota of an effect on the underlying pathophysiology of renal progression, which is renal fibrosis.

    If one were to argue that this time difference to initiate dialysis is important regardless of the mechanism (i.e., even if it was entirely driven by hemodynamic changes in eGFR), then there are a multitude of "bardoxolones" out there already.

    Don't get me wrong. I sincerely hope that bardoxolone modulates the progression to renal disease. I simply disagree with the way the phase 3 trial was designed.

  9. (I admit my penultimate paragraph is over the top. I realize that there is not a multitude of drugs that have been shown to delay the initiation of dialysis. I was just referring to the fact that there are several drugs that will increase GFR by mechanisms other than true renoprotection. This may or may not be the case with bardoxolone…I'd just like to see it studied with more rigor than the current plan appears.)

  10. Sorry for late response but did u guys observe more CV events in bardoxalone treatement arm?

    I was going through the Supplementary Table 5 and there is something funny there. if u look under the section of Cardiac disorders it gives u the adverse events as 4 (7) 5 (9) 5 (9) 4 (7) (for placebo and increasing doses of drug respectively). BUT if u look the subdivided section, the totals dont add up at all. THE CV outcomes are much worse in active drug group, about 3 times placebo at any drug dose.

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