Kidney & Renal Failure Research in the Phase 1 Setting

Posted by: DaVita Clinical Research

Getting people with Chronic Kidney Disease (CKD) in on the ground floor.

At DaVita Clinical Research, our specialty is performing research in people with chronic kidney disease (CKD). From the outset, it’s probably worth stepping back and asking the question, “Why is it even necessary to do kidney research in people with CKD?”

To begin with, most drugs (estimated as high as 98% of all drugs) are excreted by the kidney in some way or another. While not every drug may require a detailed renal pharmacokinetic study, knowledge of how a drug behaves in relation to kidney function is essential to assure the proper dosage and safe use of new and existing medications.

But more importantly, people with CKD need treatment for chronic disease just like anyone else. They are more likely to have or develop comorbid conditions such as diabetes, heart attack and stroke than the general population. Traditional risk factors for cardiovascular disease such as increased cholesterol, diabetes and hypertension are highly prevalent in the CKD population. With such high risk, they potentially stand to benefit the most from research into the treatments for many of the common chronic diseases in the population.

Yet, they have historically been systematically excluded from kidney research into therapies for those conditions. A recent systematic review in JAMA Internal Medicine of 371 large trials, published in major journals, showed that 65% of American and Canadian trials excluded subjects with renal disease, sometimes subjects with relatively minor dysfunction.

In order to change this trend, research into new therapies ought to increasingly include people with kidney disease early in the process. In drug development, that means the Phase I trial. While studying people with kidney disease may pose challenges not typically found in the normal healthy population, if the investigator has the right knowledge and experience, Phase I trials can give vital information regarding a medication early in development.

As mentioned above, the CKD population is affected by other common health conditions such as diabetes, hypertension and cardiovascular disease. Frailty can be an issue as well. Often these conditions do not preclude Phase I evaluation, provided careful assessment of the clinical stability of these conditions is taken into account. “Pure” CKD populations are difficult to find to be sure, but, more importantly, investigating medications in those with comorbidities early on sets the stage for allowing generalizable populations to participate in clinical trials further along the spectrum of drug development.

Medications for Treatment

Along with these comorbidities come chronic medications. Such concomitant medications can and are continued in many Phase I trials. Knowledge of the hepatic metabolism of the investigational product, for instance, is often available in early phase. This information can allow appropriate medications to continue during the study.

People who require dialysis as treatment for kidney failure provide both unique challenges and opportunities. It is easy to understand why the dialyzability of an investigational product is essential so that it may be used safely in those on dialysis. Conducting the studies in subjects on dialysis requires logistical planning beyond the already complex nature of the Phase I trial. Many questions have to be answered when planning a Phase I trial that includes subjects on dialysis. How should dosing occur in relation to dialysis? How do we transport the subject to his or her dialysis? Which medications for treatment of the subject’s phosphorus or anemia need to be adjusted or held?  Are the changes seen on laboratory parameters an adverse event, or are they just the variation one would expect in someone on dialysis? Answering these questions in the planning process can only be accomplished with an experienced and trained team.

Adverse Reactions to Treatment

While we all wish it were not the case, adverse events are inevitably encountered in early drug development. Determining whether an adverse event is related to the study medication in a normal, healthy population can be difficult. In people with chronic kidney disease, especially those on dialysis, this process can be even more challenging. Adverse event rates will typically be higher in those with chronic disease due to the natural history of their conditions. A team who is familiar with the CKD population is valuable in the process of fettering out what may or may not be related to the study medication.

We think the day will come when clinical trials will include people with chronic kidney disease, much as those with cardiovascular disease and diabetes are included today. Getting to that point will require keeping it a high priority to include people with CKD in all phases of research. It will also require research teams with the necessary skills and knowledge in order to get it accomplished.

If you’d like to learn more about our capabilities for Phase I renal trials, reach out to our VP of Commercial Development, Kevin.Goudreau@DaVita.com.

Jeffrey Connaire, MD

Medical Director, Nephrology Services

Jeffrey Connaire, MD, completed medical school and adult and pediatric nephrology fellowships at the University of Minnesota Medical School, and served as medical director of the Hennepin County Medical Center Kidney Transplant Program.  He is experienced in the treatment of glomerular disease with cytotoxic agents and biologics, the diagnosis and management of complicated hypertension, and the treatment and management of acute rejection using mono/polyclonal preparations, biologics, plasmapharesis and IV immunoglobulin.  He was responsible for protocol selection and management of kidney transplant anti-rejection medications, including therapeutic monitoring of mTOR and calcineurin inhibitors.  Dr. Connaire has authored more than a dozen publications and is a two-time recipient of a Nephrology Fellowship Teaching Award, the University of Minnesota Pediatric Resident Teaching Award, and in 2015 was selected as a Top Doctor in nephrology by Mpls.St.Paul magazine.

Dr. Connaire oversees scientific and investigator functions across DCR’s two clinical pharmacology units in Minneapolis, MN and Denver, CO.  His extensive nephrology experience will help inform your protocol design, trial execution, and patient management.