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Dr. Maddux: Typically, patients with advanced kidney disease are prescribed kidney replacement therapy with three hemodialysis treatments per week. Investigators from Wake Forest University and the Renal Research Institute are conducting a new study funded by the Patient-centered Outcomes Research Institute, also known as PCORI. The research will determine if an incremental hemodialysis treatment plan is safe and effective for patients. Study participants will begin with two hemodialysis treatments a week, and then step up to three hemodialysis treatments per week as residual kidney function declines.
This therapy structure has the potential to reduce hemodialysis treatment related burdens for patients. Dr. Jochen Raimann is the director of Data Analytics at RRI and is here today to discuss this trial and the potential impact on patient quality of life. Welcome, Jo.
Dr. Raimann: Thank you very much Dr. Maddux.
Dr. Maddux: Tell us a little bit about this study called the Two-Plus study.
Dr. Raimann: The Two Plus study is a really wonderful study initiated by Dr. Mariana Murea from Wake Forest University and is conducted in collaboration with the Global Medical Office at Fresenius and is basically starting enrollment at nine health care systems all over the United States. So, it's a multi-center collaborative study. It includes well known universities such as Cleveland Clinic, Johns Hopkins, UNC Chapel Hill,
Indiana University, UCLA, U.C. Irvine, University of Virginia, and also partners with Davita, amongst also other institutions. The data coordinating center is NYU-Langone. So, there are really many partners that came together to answer this immensely important research question. And Dr. Murea actually conducted a pilot study that essentially showed very promising results in terms of many of the primary outcomes that are also being studied now in this study.
We are basically conducting the study to assess non-inferiority in terms of the primary outcomes, which is a composite of hospitalizations, emergency room visits, and mortality. And also in terms of the secondary outcomes that are basically focusing on the quality of life of dialysis patients and on caregiver burden. So, the enrollment target here is essentially 350 patients that are being equally randomized into two treatment arms to start dialysis either on a twice weekly regimen or on this thrice weekly regimen.
And of these 350 patients, 140 caregivers will also be enrolled. So, enrolling also and including also the care partners of these patients. And we are particularly focusing on part of the dialysis population that initiates dialysis still having an appreciable amount of residual renal function, which essentially is 3.5 milliliters per minute, per 1.7, three square meters of urine clearance and 500 milliliters of urine volume per day.
So, estimates say that this should be around a quarter of the dialysis population that initiates dialysis, and these patients are approached and enrolled within the first 60 days of their dialysis treatment. We're hoping to invite them to participate in our research and will then randomized to either arm. We're basically studying these two primary outcomes and the composite of these three primary outcomes and will then also focus on the secondary outcomes.
This also comprises many other outcomes that we also will be collecting data on and that we will be studying. It also will include stakeholder panels and basically assessing from different levels of health care partners. What roadblocks and what benefits the implementation of such an intervention actually will bring along. It's really a multidimensional study focusing in on several levels of the care of dialysis patients.
Dr. Maddux: I'm assuming that acute kidney injury patients are excluded from the study, if we know of them. But how are you going to handle patients, for example, that have recovery of renal function.
Dr. Raimann: Patients that have a recovery of renal function and are not entering a chronic dialysis regiment are not to be included in the study.
Dr. Maddux: You might enroll patients before you know the answer to that because clearly we've seen some of these people have later recovery times than we might have expected. I'll be interested to see if patients end up falling out of the study because of recovery of kidney function. Given that 30% of our new patients come in today with AKI.
Dr. Raimann: Well, that would essentially be very good for the patient, obviously. These patients would then obviously fall out of the study, but that would definitely be considered a dropout of the study. Yes, absolutely.
Dr. Maddux: What's the role that RRI has in the study? Are you all doing any particular component of the study? Other than working to help enroll patients?
Dr. Raimann: The study is conducted, thanks to the support of leadership of the Global Medical Office, as a collaboration with the Global Medical Office, and RRI as being part of the Global Medical Office is on one hand we are representing as the co-P.I. with Peter Kotanko, our research director at RRI, being the co-P.I. of the trial and the trial leadership.
And secondly, we are also a contributing site to the trial. So, we are participating in five clinics here in Manhattan. And I do have the privilege and the honor to be site P.I. for RRI. And together with my team, Erika Trenberth and Dr. Laura Rosales, will be recruiting patients within our five clinics here in Manhattan. We're a liaison between Wake Forest and the site P.I.s in terms of contractual agreement with facility use agreements with data flow.
So, we have worked together with our wonderful legal team and the privacy team and compliance team. We have worked and supported the development of contractual agreements. We have also helped with establishing together with our DTI team and the clinical advanced analytics team will be working towards setting up service accounts that will facilitate recruitment, that basically will automatically pull screening lists and will also support the work and the data flow from our database essentially to the data coordinating center and will facilitate the work and reduce the work bourdon on the clinical research coordinators. So we are doing that not only for RRI sites, we are also supporting the site P.I.s and respective contributing partners.
Dr. Maddux: For a long time, we've been dissatisfied with sort of the incident mortality that we have in our patients that start hemodialysis. It's quite a bit higher than the baseline annualized mortality. Do you think, considering an incremental start offers an opportunity to avoid some of that early mortality and morbidity? Or is the thought that this will teach us something different that we need to do simply to try to preserve residual renal function?
Dr. Raimann: The study is designed and powered essentially to an analyticly approach, a non-inferiority design compared to a thrice weekly regimen. Once this has been analyzed sufficiently, there will also be an analysis in the direction to see whether there's a reduction in those outcomes. To what extent this can be anticipated, this is very hard to say. There had been data published that looks promising in terms of benefits of incremental dialysis.
There was a meta-analysis, for example, that was suggesting an improvement in terms of mortality. There's signals from pilot trials that were conducted by Dr. Murea in Wake Forest that suggests that benefits in terms of hospitalizations. So, there are also data published that suggests that prolonged preservation of residual renal function, which also may come with benefits of urine removal, better fluid management, better acid-based status, also a better quality of life.
You may also think of vascular access complications. So, this may also be improved with less often canulations required. So many potential benefits may be found in our data.
Dr. Maddux: In the protocol, is there a defined way to determine what the algorithm is for when to go from two treatments a week to three or more? And how will we assess dose of dialysis per week? Will we include residual kidney function as part of the overall calculation?
Dr. Raimann: There are criteria defined at what point a patient will need to transition from a twice weekly to a thrice weekly regimen. So there's a quite diligently designed algorithm at what point patients would need to transition over, the decision is then made by the caregiver, by the actual treating physician in conjunction with the leadership of the trial, with the site P.I.s, as well as the leadership and the Data Safety Monitoring board that will also be overseeing all aspects of the study.
There’s definitely a collaborative decision that will be made once at what point the patient will need to transition over to a thrice weekly regimen.
Dr. Maddux: When would you expect that the study might readout?
Dr. Raimann: We're concluding enrollment by 2027. So, we hope that results will be available very soon after. I'm hesitant to give an exact timeline, but I would assume sometime after 2027, that's a realistic timeline for first results to be published in the literature.
Dr. Maddux: When I was looking at the hemodiafiltration study, the CONVINCE study. One of the things that struck me when they looked at subgroup analysis, the one group of patients that didn't look like it either trended to or had a distinct advantage for hemodiafiltration were those people with significant residual renal function.
And I found that a really interesting result because I think it actually probably supports the original hypothesis that you have in this particular study in that residual renal function can play a significant role in how a patient responds to their kidney replacement therapy.
Dr. Raimann: I think residual renal function is definitely an aspect of dialysis treatment that wasn't sufficiently studied from many angles. I think there's definitely a lot of benefit of residual renal function, and it's going to be on the scientific level, very, very interesting to see what the preservation of residual renal function that is one of the expected, hoped for outcomes of the trial will basically bring along in terms of other outcomes.
The subset analysis you're referring to is definitely of great interest and, and we hopefully will also see associated positive benefits in the Two Plus study.
Dr. Maddux: Any other comments you want to make regarding the collaboration or the work that we as a company need to do to be strong participants of this PCORI study?
Dr. Raimann: The collaboration is just wonderful to see how it now develops. It's really wonderful that Fresenius and the Global Medical Office steps up to really support such an important scientific contribution, which is essentially it is a question that really is asked for by the community. So, there's great interest there, very strong opinions that the incremental dialysis is of great importance and is something that will need to be understood in more detail.
It's increasing in popularity all over the world. So, you hear strong opinions that actually are promoting incremental dialysis. So, I personally think it's just absolutely wonderful that Fresenius and the Global Medical Office is supporting this study and really helping to answer this important question and all the preliminary data that you see, it will definitely make a difference in patients’ life if they have this possibility, this choice to make.
In a collaborative setting, as we're currently envisioning it, it's really great that Fresenius is supporting this study. And Fresenius is essentially providing half of the clinics that are being part of the trial. So, there's really strong support, which really is just wonderful.
Dr. Maddux: Are you aware of any countries that have adopted this routinely this method of starting patients?
Dr. Raimann: Essentially, it is all over the world, quite a common practice. You actually see the many countries in Asia-Pacific. You see it in Central America, you see it in Latin America, admittedly to some extent there for economic reasons. But nevertheless, it's like when you when one, for example, looks for the study that was published by the dialysis outcomes and practice study, which was published a couple of years ago, this study suggested that almost a quarter of all patients in China did actually start dialysis on the twice weekly regimen, and they actually were they failed to see differences in terms of adverse outcomes between these two groups. And when they further stratify that, they also failed to see differences in terms of in terms of presence of residual kidney function. It’s really very interesting to see these different practices and see how this will translate into the outcomes of our study.
Dr. Maddux: It strikes me that one of the opportunities we have given the launch of the Apollo database is to go look at where in the world we are caring for patients in which this has already been adopted and determine whether we could propensity match a different cohort and actually try to, in silico, look at a retrospective study of whether there are any distinctions that might support more of what the study is going to either prove or disprove.
Dr. Raimann: Absolutely. That would be a very interesting study, indeed. We definitely could look at that. I think dialysis frequency is definitely recorded in all aspects and seeing regional variability and comparing the actual signals then from these different regions will definitely be very supportive of either frequency chosen at the initiation. And with a database like the Apollo database, which is such a high granularity and, such a detailed collection of data, one could envision very advanced methods to employ essentially to answer various research questions.
In addition to adverse outcomes, one could think of different outcomes to study, which are not only hard outcomes but also soft outcomes, like, for example, vascular access complications. That could be a very interesting outcome. So, there's definitely a plethora of research questions one could think of.
Dr. Maddux: I do think the opportunity exists since it's going to be til 2027 before we get results from the Two-Plus study, there is some groundwork we could do that might actually be supportive of looking at this and understanding it better by the time that definitive data really comes out.
Dr. Raimann: I think that's a wonderful idea. I definitely put it on my list.
Dr. Maddux: Any other thoughts or concluding comments about this and the focus that we need to have on our new patients to dialysis and what's safest for them, I know we struggle with transplant patients that come back to kidney replacement therapies, and we obviously struggle with patients that come in that are unplanned and not well prepared for their options.
Any final thoughts before we end?
Dr. Raimann: Individualizing treatment and individualizing therapy for the respective patient is definitely the right way to go. And conducting research in the direction to determine what's the most optimal treatment for the respective patient will be, Is of greatest importance. So, studies like the Two-Plus study will inform what actually the most optimal treatment is. And I think personalization will be the way to go for the future.
Dr. Maddux: I'm here today speaking with Dr. Jochem Raimann, and Jochen and the RRI team have been heavily involved in the support and development of the two-plus study. Looking at our incident population of patients on hemodialysis. So, I want to thank you so much Jo for joining us and helping everybody understand what this study's about and how you're executing it.
Dr. Raimann: Thank you very much. Dr. Maddux.