PERL Study: A Trial on the Use of Allopurinol to Preserve Kidney Function in Type 1 Diabetes

By Leda Espinoza and Alexander Wolf

Twitter summary: Can a drug for gout also help with #t1d kidney function? A new trial on allopurinol looks to find the answer.

Clinical Trial Identifier: NCT02017171

This three year Preventing Early Renal Loss (PERL) study is testing a new approach to prevent kidney disease in type 1 patients – using a generic drug called allopurinol that has been used for decades to treat gout. For background, gout is a type of arthritis that causes sudden attacks of burning pain, stiffness, and swelling in a joint. Gout is caused by elevated levels of uric acid in the blood, which at high levels can form hard crystals in joints. All people have some uric acid in their blood, but in people with diabetes, even slightly elevated levels of uric acid (but lower than those that cause gout) can predispose to kidney function loss. Kidney disease affects almost 30% of type 1 patients, and its most advanced form, diabetic kidney disease (also called nephropathy), can require the use of dialysis treatments or kidney transplant. 

While many have studied various treatments in an effort to reduce the growing burden of diabetic kidney disease, there are currently no other trials investigating the effect of an intervention at such an early stage, when it can be most beneficial. According to PERL's principal investigators – Drs. Alessandro Doria and Michael Mauer – this research has the potential to delay the onset of dialysis or end stage renal disease (ESRD) by as many as 10 to 15 years, and perhaps even prevent them from happening. Also, the trial is using a drug (allopurinol) that is already available, inexpensive, and known to be safe; if successful, there could be substantial support for the wide-spread use of allopurinol for the prevention of diabetic nephropathy.

What are the trial’s details and who is eligible?

The primary outcome of the PERL trial is to measure the glomerular filtration rate (eGFR), a test used to check how well the kidneys are working by estimating how much blood is filtered through the kidneys’ filter system each minute, and urinary albumin excretion (AER), a measure of the amount of the protein albumin in the urine used to estimate kidney membrane damage. Promising results have been seen in a few small studies for using allopurinol for kidney disease in general in a few small studies, and it will be exciting to see if the larger and longer PERL study confirms these early findings specifically for diabetes.

This trial aims to enroll 480 participants with type 1 diabetes. Volunteers will be treated with allopurinol or a placebo for three years, during which their kidney function will be tested be repeated GFR measurements. In order to participate, volunteers must be between the ages of 18 and 70, have had type 1 diabetes for at least eight years, and have early signs of decreased kidney function or increased risk of diabetic kidney disease on blood and/or urine tests. Often people do not know that they have these early findings, so it may be helpful to get these tests results from your doctor or to contact the study personnel for guidance. Exclusion criteria include a history of gout, a renal transplant, non-diabetic kidney disease, cancer treatment within two years before screening, alcohol or drug abuse in the past six months, breastfeeding or pregnancy, hepatitis B or C, and HIV. For a full list of inclusion and exclusion criteria, please visit the trial’s posting on ClinicalTrials.gov. The PERL study is currently recruiting at 13 (soon to be 14) sites in the US, Canada, and Denmark; US sites include places in CO, GA, IL, MA, MI, MN, MO, NY, and WA – these studies involve some of the most prominent diabetes research institutions, such as the Joslin Diabetes Center and the University of Washington. A complete list of locations can be found at the trial’s posting on ClinicalTrials.gov and on the PERL website at perl-study.org.

Although the PERL study currently operates out of 13 core sites, investigators are attempting to expand recruitment to a nationwide level. Through a “remote site strategy,” the trial would be able to enroll patients even if they live far away from these sites. Participants would be able to do most visits locally and would only need to travel to one of the main trial sites about five times over the course of the three-year study (e.g., a participant from California traveling five times to the site in Seattle). The PERL trial is actively seeking ways to involve the entire country and is prepared to finance travel expenses for patients in more remote locations – we applaud this innovative approach, which we have never heard of in such a big trial – type 1 diabetes community, this is a big opportunity!

Affecting future diabetes research:

While the NIH and the JDRF are funding the PERL study, the funding also stems directly from Congress through the Special Diabetes Program. The funding is specifically mandated for type 1 diabetes research and was renewed last year until September 2015. If the PERL study is successful, there is a higher chance that Congress may supply additional funding for diabetes research. And although this trial is targeted for people with type 1 diabetes (largely as a result of the above funding sources), a positive outcome could potentially translate to an effective intervention for type 2 patients.  As a nation, we are spending so much on the medical costs of diabetic nephropathy (totaling $22 billion in 2010 – a fourteen-fold increase since 1993) that this therapy could translate into huge savings down the road. Of course, success is never a given with drugs – many drug therapies have failed in larger studies despite early promise. We are optimistic that allopurinol will not be dangerous for people with diabetes, mainly because it is already known to be safe for gout. And of course, it is imperative that we continue to identify more ways to address diabetic kidney disease.