End Point Considerations for Clinical Trials in Enteric Hyperoxaluria.

Enteric hyperoxaluria is a medical condition characterized by elevated urinary oxalate excretion due to increased gastrointestinal oxalate absorption. Causative features include fat malabsorption and/or increased intestinal permeability to oxalate. Enteric hyperoxaluria has long been known to cause nephrolithiasis and nephrocalcinosis, and, more recently, an association with chronic kidney disease and kidney failure has been shown. Currently, there are no FDA approved therapies for enteric hyperoxaluria, and it is unclear what end points should be used to evaluate the efficacy of new drugs and biologics for this condition. This paper represents work of a multidisciplinary group convened by the Kidney Health Initiative (KHI) to review the evidence supporting potential end points for clinical trials in enteric hyperoxaluria. A potential clinical outcome is symptomatic kidney stone events. Potential surrogate end points include: (1) an irreversible loss of kidney function as a surrogate for progression to kidney failure; (2) asymptomatic kidney stone growth/new stone formation observed on imaging as a surrogate for symptomatic kidney stone events; (3) urinary oxalate and urinary calcium oxalate supersaturation as surrogates for the development of symptomatic kidney stone events; and (4) plasma oxalate as a surrogate for the development of the clinical manifestations of systemic oxalosis. Unfortunately, because of gaps in the data, this KHI workgroup was unable to provide definitive recommendations. Work is underway to obtain robust information that can be used to inform trial design and medical product development in this space.