Landmark trial of T1D-related kidney disease misses primary outcome, but provides valuable lessons

August 10, 2020

In recent years, better ways to control blood sugar levels and blood pressure have led to a decrease in kidney-related complications among the type 1 diabetes (T1D) population. However, kidney disease remains one of the leading complications of diabetes, including the need for dialysis or kidney transplant. Identifying strategies to reduce kidney complications has been a key focus of JDRF’s research strategy. To date, several studies have demonstrated that individuals with higher levels of uric acid in their blood are more susceptible to reduced kidney function. This led to the Preventing Early Renal Loss in Diabetes (PERL) trial, a joint initiative between investigators across North America and Denmark. Partly funded by JDRF, the three-year study involved testing allopurinol – a drug that has been on the market since the 1960s to reduce uric acid levels in gout – in 530 participants with T1D and early to moderate kidney disease. On the basis of years of evidence, including a promising pilot trial supported by JDRF, the hypothesis was that allopurinol would reduce the incidence or severity of kidney disease in people with T1D.

Throughout the placebo-controlled trial, the key measurement of kidney function for patients was the glomerular filtration rate (GFR), which gauges how much blood is filtered every minute by the kidneys – a measure that drops as kidney function gets worse. The study’s findings revealed that levels of uric acid fell about 35 per cent on average among people given allopurinol over the course of three years compared with those who did not receive the drug. However, allopurinol had no impact on GFR leading investigators to conclude that it does not prevent T1D-related kidney disease.

“This is not the result that we wanted,” said Peter Senior*, a researcher at the University of Alberta and PERL collaborator, “but it does give a very clear answer to an important scientific question.” 

Clinical trials that specifically set out to measure kidney outcomes are relatively rare in T1D. The PERL trial was a true landmark by demonstrating that kidney trials can successfully be done in people with the disease. Moreover, the existing trial infrastructure and cohort, as well as learnings from the study, will be leveraged for future trials with other drugs.

“PERL was a textbook example of taking clinical observations and preliminary research findings suggesting the potential for a new use for an old drug, and then designing a study to definitively answer whether or not the drug would prove to be effective as a new treatment,” Senior* noted. “In this case, the drug did not show any of the anticipated benefit. But that is exactly why we do clinical trials, and how our scientific understanding advances. We don’t want to recommend treatments because ‘in theory’ they should work.”

Work to uncover ways to reduce the risk of kidney complications in T1D continues. JDRF is currently funding follow-up studies on biopsies from PERL trial participants, to obtain a better understanding of T1D-related kidney disease. In addition, a JDRF-funded Australian phase 2 trial is testing a completely new drug (referred to as GKT137831) in adults with T1D and early signs of kidney impairment. This drug works by reducing damage to the kidney caused by oxidative stress at the cellular level. The hypothesis is that reduction of oxidative stress by GKT137831 will prevent or slow decline in kidney function in people with T1D involved in the trial. Finally, JDRF Canada is funding a clinical trial of an oral drug called dapagliflozin that can be taken alongside insulin, with the aim of reducing biomarkers of complications, including kidney complications, in adolescents with T1D.

*as quoted in Folio, the University of Alberta’s daily digital magazine

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