Presenters Have Hope for the Future of Trial Design in Pediatric Chronic Kidney Disease

Clinician Presenting Kidneys | image credit: Pixel-Shot - stock.adobe.com

A group of presenters at the American Society of Nephrology's Kidney Week 2023 discussed important aspects surrounding the state of pediatric nephrology, including the challenges of conducting pediatric trials for children with chronic kidney disease (CKD), a first-hand patient and family perspective on CKD, and current evidence research has gathered about sodium-glucose cotransporter-2 (SGLT2) inhibitors.

Designing Trials in Pediatric CKD: Hurdles and Solutions

William E. Smoyer, MD, Nationwide Children's Hospital, kicked off the session with his presentation on trial designs for pediatric CKD. He explored the obstacles and potential solutions that coincide with these efforts, beginning with the essential question: Why include children at all?

CKD is a global disease affecting an estimated 50 to 75 per 1 million children. Smoyer points out that nearly half of these cases are caused by congenital abnormalities of the kidney and urinary tract, while another third are caused by glomerular diseases.

“This is dramatically different than the causes of CKD in adults, where 40% of the cases are diabetic nephropathy and another quarter of them are hypertensive. Said another way, three-quarters of the causes of CKD in children have nothing to do with three-quarters of the causes in adults. So these diseases are very different in their origins," Moyer noted.

Designing pediatric trials has not been easy. Recruitment numbers for these studies is very low across the United States; the national average is 0.3 subjects per investigation site, and many of these trials feature zero subjects.

Identifying eligible patients poses a challenge because CKD can be silent in children; furthermore, parents may understandably hesitate to enroll their children because of the possibility they will be assigned to a placebo group. However, Smoyer posits that raising awareness about the unmet medical needs in pediatric cases and the opportunity for children to receive novel, affordable care may help persuade participation. Especially because, currently, drug approvals in this realm can take upwards of 10 years.

He continued by emphasizing the need to design trials that meet both pediatric and site investigators’ needs, offering solutions that include working better with patient and parent schedules around work and school, addressing any barriers with travel, experimenting with remote communication, and shorting the intervals between communication to keep engagement high. As for site investigators, confronting issues with administrative or clinical research infrastructure—including legal and contracting barriers, as well as qualified staff shortages—and ensuring adequate spaces, funding, and time are available for researchers could help mitigate the challenges they face.

Journey Through CKD: A Family’s Perspective

Following Smoyer’s presentation, Austin and Clarissa Lee took the stage to give insights into their family’s experience with CKD. Austin received a diagnosis of posterior urethral valves before he was born; at age 18 months, he was starting home peritoneal dialysis; and he had undergone 2 kidney transplants by early adulthood.

Throughout their talk, Clarissa expressed great appreciation for the nephrologists working to expand care options for children with kidney disease. She emphasizes how a diagnosis like theirs can really alter the dynamics of a family, a marriage, or one's employment. Her story included strict coordination with her spouse to ensure one of them was home to administer Austin’s dialysis throughout his childhood, teaching their other 4 children how to administer it themselves, and how managing CKD can keep parents busy in doctors’ offices and away from the rest of the family at times. Clarissa also mentioned that throughout their journey with CKD, she was never once made aware of clinical trials or experimental options available for her child.

Austin is now a kindergarten teacher who volunteers in his community. One thing he has taken away from his experience is that he now has the tools to educate children and teens in similar situations about the choices they have ahead of them, especially during a time when pediatric trials are gaining momentum.

“His second transplant, it changed his life. It changed our life, and it changed the life of children and families that he impacts as a volunteer and in his community. ... I'm just hoping that you all will be helping children in these studies, in all these clinical trials, and that they will allow other kids the same type of chance to have a great life,” Clarissa concluded.

SGLT2 Inhibitors and Kidneys: What We Know So Far

Marva Moxey-Mims, MD, FASN, Children's National Hospital, continued the session with updates on current evidence surrounding the efficacy of SGLT2 inhibitors. She admitted that the mechanisms at play in SGLT2 inhibitors are not fully understood; however, researchers know they work effectively and improve outcomes in patients with CKD. At large, the hemodynamic effect of this class od medications is suggested to preserve kidney function, and other benefits appear to exist independently of blood glucose-lowering effects.

Her presentation featured data from multiple adult trials on the demonstrated success of SGLT2 inhibitors in CKD. Each of these studies was ended prematurely because they had met their primacy efficacy outcomes by interim analysis. The CREDENCE trial, utilizing canagliflozin; the DAPA-CKD trial, utilizing dapagliflozin; and the EMPA-KIDNEY trial, utilizing empagliflozin, all showcased SGLT2 inhibitors significantly affecting the progression of kidney disease.

In the wake of these adult studies, empagliflozin exhibited benefits for reducing hemoglobin A_1C levels in adolescents with type 2 diabetes (T2D). Subsequently, empagliflozin was approved for the treatment of T2D in children 10 years and younger in June of this year.

Moxey-Mims highlighted that the adverse effects are generally accepted in this treatment. Data shows an increased risk for hyperkalemia (HR, 1.06); however, the overall benefits are still in favor of SGLT2 inhibitors despite this possibility.

“The question is,” she concluded, “can we harness knowledge from all of these findings for pediatric kidney trials?”

Conceptual Model for Pediatric Trials: SGLT2 Inhibitors in Children With CKD

To close the session, Zubin Modi, MD, MS, C.S. Mott Children's Hospital, discussed what the next steps look like for SGLT2 inhibitors and pediatric nephrology trials. He echoed a point from DSmoyer’s talk that mentioned that people and children are already using this medication.

“I find that within pediatric nephrology clinics in particular, however, that number remains very small. And so I think we are kind of in that moment of an opportunity, where if we don't study them now, we lose our ability to study them in an effective way,” Modi stated in light of data showing SGLT2 inhibitor use is almost 5 times more prevalent in endocrinology and cardiology compared with nephrology.

Looking toward the future, Modi conceptualized solutions for extrapolating data to benefit trial designs in pediatric nephrology. In his conceptual model, he began by suggesting the benefits of comparing pediatric and adult populations. Concentrating on etiological similarities such as glomerular disease and diabetic nephropathy, or differences such as congenital anomalies in the urinary and kidney tract, present a potentially fruitful opportunity, by his assessment. Building on this option, Modi explored the benefits of bridging biomarkers from adult trials, posing the question: Could biomarkers discovered in adults be brought into pediatric trials?

Among his other suggestions, Bayesian statistical strategies were mentioned as a method for including known information from previous SGLT2 inhibitor trials to develop probability distributions. Additionally, Modi emphasized the importance of deciding which populations to study further—such as those with glomerular disease or specific age groups.

“The children with congenital anomalies really, I think, are a group that needs some kind of additional study; maybe that's in conjunction with that lower age group in the way that you go about testing them,” he adds.

Furthermore, he mentioned that evaluating patients with higher likelihoods of progression could allow researchers to analyze outcomes in reduced timeframes because reaching clinical end points can take longer when studying pediatric populations.

Bringing the session to a conclusion, Modi took time to reemphasize points from the previous speakers, including the need to reduce burdens on investigators, implement flexible trial designs, limit long-term follow-up, and believe in the value of real-world data.