Blog entry by Meguid El Nahas
BEACON, the Phase III RCT launched by Abbot in 2011 to study the effect of Bardoxolone on the progression of diabetic nephropathy has been terminated by the sponsor due to serious adverse events including increased death rate.
BEACON was launched in mid-2011 and involved 1,600 patients with type 2 diabetes and stage 4 CKD. It built on the apparent, and I stress apparent...(see below), success of BEAM, the phase II study that claimed improved kidney function on those treated with Bardoxolone over a 12 months period. BEACON was designed to assess whether bardoxolone could delay progression to the first event of end-stage renal disease, such as dialysis or death from cardiovascular causes.
Bardoxolone, a drug designed by Reata, activates Nrf2, a protein believed to be a principal regulator of cellular antioxidation and detoxification enzymes, while suppressing NFkB, a primary regulator of inflammatory genes. NFkB is thought to play a major role in the progression of renal inflammation associated with progressive CKD. In fact, many of the putative mediators of CKD progression, such as angiotensin II and endothelin1, are known activators of NFkB. Inflammation mediated by NFkB is thought to play an important role in the progression of diabetic nephropathy (1).
At the ASN in Denver 2010, the BEAM investigators revealed with great aplomb that Bardoxolone improves kidney function and slows the progression of diabetic nephropathy. I remember that I was compelled to stand up and draw the attention of the author/presenter of the data that what he presented is that Bardoxolone decreases serum creatinine acutely, within weeks, and subsequently increases estimated GFR (eGFR). I stressed to the author that eGFR does NOT equate to measured GFR. He seemded surprised....and the Chair of the session (Drs Agarwal and De Zeeuw) came to his defence...?! It was also noted by Dr Parving that the low level of proteinuria observed in the patients studied made diabetic nephropathy most unlikely at this advanced stage (CKD3) of renal impairment. Also of note, the control group did not progress; most unusual for CKD3 diabetic nephropathy....
In 2011, the prestigious NEJM published the results of BEAM study and showed all its limitations. Mainly, that this agent primarily lowered serum creatinine and was associated with weight loss. But also may have a potential toxic effect on renal tubules with changes in serum magnesium, uric acid and phosphorus denoting a potential tubular effect/toxicity. The conclusion, and excitement that followed that publication...., once more revealed the influence of Pharma on Nephrology, Nephrologists and how the latter are not capable of critical thinking. Phase III was planned, BEACON was launched with the same limitations: USING eGFR TO ESTIMATE PROGRESSION OF DIABETIC KIDNEY DISEASE....WHEN ANY NEPHROLOGIST WORTH ITS SALT WOULD KNOW THAT eGFR DOES NOT EQUATE WITH MEASURED GFR!!!!
Once more, most Nephrologists enthusiastically embraced the BEAM findings, thus relinquishing critical thinking and even plain thinking that changes in serum creatinine could have been affected by:
1. Weight loss (observed), 2. Changes in tubular handling of creatinine, along with uric acid and magnesium (Observed) as well as 3. Loss of appetite and decreased protein intake.
Some didnt, as shown by their sharp and perceptive letters to the NEJM Editor (3)!
The story of BEAM and BEACON should once and for all draw our attention to a number of facts related to RCT in Nephrology:
1. The power of the Pharmaceutical Industry that dictates to clinical investigators the conduct and often interpretation of clinical trials and their results (interestingly enough, I am currently reading "Bad Pharma: How Drug companies mislead doctors and harm patients" the book just published by Ben Goldacre that makes precisely that point...).
2. The all too enthusiastic willingness of Clinical Investigators to embrace positive results related to new interventions without dwelling on their potential side effects and harm...
3. The all too enthusiastic and non-critical acceptance of published data by the nephrology community, specially when featuring in a prestigious medical journal.
4. That prestigious medical journals have reviewers who may be less than critical in their appraisal of publications?!
5. That eGFR is USELESS if we want to ascertain the effect of an intervention on the progression of CKD; it is a poor surrogate endpoint as is serum creatinine. The true hard endpoint to study progression of CKD is MEASURED GFR!
Finally, I recommend to all nephrologists to read Bad Pharma! It is an eye opener...
Like many examples quoted in this book....Reata/Abbot took a potentially dangerous drug through phases 1 and 2 clinical research overlooking its harm...and focusing on its potential commercial and financial benefits....doctors went along...?!
It is high time, that we as nephrologists and as a medical profession become more critical of published data and sponsored research.
It is high time we remember our Hippocratic Oath: FIRST DO NO HARM!