#KidneyWk 2017: Late-Breaking and High-Impact Clinical Trial Session

Kidney Week does a lot of reviewing and integrating during the week. The best sessions present old data with a new interpretation so that you can use the information to take better care of patients. But the Late-Breaking and High-Impact Trials Session is different. This session is the biggest moment on the biggest stage in nephrology. This is where the big dogs come to present their latest data to an excited but skeptical audience. Getting on stage for the late-breaking and high-impact session is the center ring of the Kidney Week Circus.

My review of the session leans heavily on the tweets of the people in the audience. It was amazing to see the number of people and perspectives engaged on Twitter.

This year, seven investigators presented data.

Tolvaptan for ADPKD. Again.

Up first was Vicente Torres with REPRISE: A trial of tolvaptan in ADPKD. COI: My practice was a big enroller for this trial.

The TEMPO 3:4 trial showed decreased progression of CKD in ADPKD with tolvaptan but the primary outcome was reduction in growth of total kidney volume. REPRISE had change in GFR as the primary outcome.

The investigators enrolled patients with more severe kidney disease than in TEMPO, GFR 25-65 ml/min.

One of the problems that the FDA had with the TEMPO trial was the high degree of dropout. To prevent this, REPRISE had a 5 week run-in where patients were titrated up to goal dosage. Here is the dosage plan:

They randomized 683 patients to placebo and 687 to tolvaptan.

Fully 20% of the patients had CKD stage 4. Remarkably, 85% of the tolvaptan patients were still on tolvaptan at the end of the study. The GFR plot can be seen in this slide. Note the acute drop in GFR with starting tolvaptan. This was presumed to be a hemodynamic effect.

Topline result: tolvaptan reduced the rate of GFR decline from 3.6 ml/min/yr to 2.3 ml/min/year.

TEMPO 3:4 was the first tolvaptan trial to identify liver damage. This was carefully monitored in REPRISE. The hazard ratio for increased aminotransferase levels > 3 times the upper limit of normal (ULN) was 4.9 with tolvaptan, but it was still pretty rare with a cumulative rate of 6% at 390 days and all patients returned to below 2x ULN within 3 months of stopping the drug.

This is a major win. I hope to see quick approval by the FDA. Let’s provide these patients with the same effective drug they can get everywhere else in the world. 

Bardoxolone and GFR. Again.

Next up was a study of GFR changes with Bardoxolone using inulin clearance.

One of the early findings with bardoxolone, a Nrf2 activator, in diabetic kidney disease was an improvement in GFR as measured by MDRD. However, this drug also caused volume overload so there was some concern that what was actually measured was dilution of creatinine from excess volume and no real change in GFR. The TSUBAKI trial was done to answer that question.

 

 

The trial randomized patients to bardoxolone or matching placebo. The GFR was checked at time zero, after patients had titrated to a maximal dose of 15 mg, and after they stopped study drug for four weeks.

Special care was taken to exclude patients at risk for volume overload and then they did careful monitoring to avoid volume overload.

The study showed a nice improvement in measured and estimated GFR. The improvement in GFR from the earlier studies is real.

There was an excess number of study withdrawals in the patients randomized to bardoxolone but the investigators thought this was more likely due to random chance than due to the drug. Yeah, color me skeptical.

There was also increased BNP and liver enzymes. The investigators are charging ahead with a phase 3 trial in 2018. With patient dropout, increased BNP, and liver toxicity, plus the weight loss and hypomagnesemia from BEACON, the investigators may be playing with fire.

After the presentation, the authors got some challenging questions from the floor:

Contrast nephropathy, intra-arterial versus intravenous contrast

The next trial is a contrast nephropathy trial, pitting intracoronary contrast against intravenous contrast. This presentation was a secondary outcome of the CAD-man trial.

They were able to randomize patients to IV versus intracoronary contrast by randomizing patients to CT angiogram versus coronary angiography for the evaluation of chest pain. The intravenous (CTA) had a much lower risk of contrast nephropathy.

The increase in AKI was driven by contrast volume (stop doing LVGrams!) and a femoral approach, opening up the possibility that what we are actually seeing is atheroembolic disease.

He also presented data on the rate of CKD after 1.9 years of follow up. Unfortunately, he did not present intention to treat data (CTA vs Cath) but based the analysis on whether the people had developed AKI or not. And yes, just like in every other study, getting AKI puts you at much higher risk of subsequent CKD.

In the end, the study was thin on details. I mean, how can a radiologist come into a nephrology meeting without the average GFR in his back pocket? The authors did say that contrast nephropathy prophylaxis was not balanced between groups. This trial deserved a bit more color. We will have to wait for publication of this before a final thumbs up or thumbs down can be declared.

 

Novel AKI therapy

Next up QPI-1002 (QPI) for the treatment of AKI after cardiac surgery.

QPI is a small interfering RNA (siRNA) that targets the p53 gene. This is supposed to decrease the apoptosis that is part of the AKI phenotype (I’ll take their word for it). QPI-1002 is the first siRNA to be administered to humans. Nice overview can be found on the company website.

This trial looked at high risk cardiac surgery. All of the patients were on bypass, many of them had two procedures (valve and bypass). They randomized 341 in a double blind fashion. QPI was given x 1 dose four hours after surgery. Primary outcome was development of AKIN and defines AKI with a secondary outcome of degree of AKI (AKIN stage 1, 2, or 3).

And it worked. They found a 12% absolute and 28% relative risk reduction with a p value of 0.012.

They found lower rates of an AKI stages 1, 2, and 3.

They looked at hard(ish) outcomes, a composite of death, RRT, or a 25% drop in GFR. They didn’t reach significance for the whole cohort, but did in the highest risk patients. Promising.

Of note this is the second AKI trial to show improvement with QPI. The first trial looked at delayed graft function.

Impressive trial.

The question everyone asks about Nephrocheck, is “What do you do with a positive finding?” Well, maybe QPI is the answer to that question. Skeptics will argue that p53 inhibition may have adverse effects that we don’t know about yet.

Make a fistula with an incision

Next up was how to make a non-invasive fistula.

This technique uses nanotechnology to weld blood vessels together and create a fistula entirely endovascularly. The product is called The Ellipsys Anastomosis. The procedure was taught to interventional nephrologists and is similar to endovascular creation as was seen in the NEAT trial. The trial end-point was fraction of usable fistulas at 90 days. The trial was up against historic controls. The goal was more than 49%.

The device is designed to build a proximal radial artery fistula. They had 95% technical success at building the fistula and the procedure took only 23 minutes.

Nearly all of the fistulas required a subsequent intervention but after that turned into a pretty good fistula. Secondary patency was 87% at 12 months.

The final and most important points about this non-invasive fistula option was that many of these successful fistulas were placed by interventional nephrologists with limited training in an office setting. This has the potential to be a game changer.

 

Give us more TiME

Next up is Laura Dember to present the TiME trial.

This was a pragmatic trial where dialysis centers were the unit of randomization and were randomized to either standard care or increased duration of dialysis (target time of 4:15). The primary outcome was mortality. Only incident patients were enrolled.

Hint: when the presenter spends a lot of time talking about the methods and how successful they were at collecting all of the data and randomizing units without presenting results, this is a warning sign that a negative result (or worse) is coming.

And then the rubber meets the road: they were only able to achieve 9 minutes of separation between usual care and the extended dialysis groups. Their Data Safety Monitoring Board recommended terminating the study.

The study does serve as a compelling proof of concept. They were able to rapidly enroll a huge cohort, 7,035 patients, relatively quickly (less than 3 years). They also enrolled a cohort that looked much like a typical dialysis patients, making the results (if there had been any) much more applicable to a general dialysis population.

Dember was asked what was the reason for the lack of separation between the two groups. The answer, “Patient resistance to the longer treatment.” I had patients who were in a TiME unit randomized to prolonged dialysis. My patients often started dialysis with significant residual renal function and I felt that they needed quite a bit less dialysis than 4:15. On at least one occasion, I overruled the standard orders for 4:15 to give a dialysis prescription that better fit my patient’s need. I was part of the problem.

Someone asked about the decision not to get informed consent from each patient. The questioner thought that getting informed consent would have resulted in a more motivated patient, but Dember said that would also have resulted in a population much less representative of the overall dialysis population.

 

 

Rituximab in idiopathic membranous (yet another non-inferiority study)

The last session of the Late-Breaking and High-Impact Clinical Trials Session was the MENTOR trial.

Primary outcome was primary or secondary outcome at 24 months after randomization.

The intervention

 

Honestly, has any drug been studied more with a non-inferiority design than rituximab?

 

The entry criteria were designed to eliminate people in the process of spontaneous remission and excluded people with a GFR < 40 mL/min.

They enrolled patients with pretty severe disease, 10 grams of proteinuria at randomization.

The results showed that patients went into remission quicker with cyclosporine but were better able to remain in remission with rituximab.

In conclusion, MENTOR showed that rituximab was equivalent to cyclosporine at inducing remission but like in many other cyclosporine trials, when the cyclosporine was stopped, the proteinuria returned. The same thing happened here so that rituximab was better at maintaining remission.

Of note, Swapnil Hiremath provided a rationale for looking at per protocol analysis of a non-inferiority trial rather than the presumed gold-standard of intention-to-treat analysis.

Someone asked about a trial of rituximab versus cyclophosphamide and apparently there was resistance to using the first line agent suggested by KDIGO because of toxicity.

…And that’s it. Seven trials in 2 hours!

 

– Post prepared by Joel Topf, AJKD Social Media Advisory Board member. Follow him @kidney_boy.

Check out more AJKDBlog coverage of Kidney Week 2017! 

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