End Points for Clinical Trials in Primary Hyperoxaluria

Abstract

Patients with primary hyperoxaluria experience kidney stones from a young age and can develop progressive oxalate nephropathy. Progression to kidney failure often develops over a number of years, and is associated with systemic oxalosis, intensive dialysis, and often combined kidney and liver transplantation. There are no therapies approved by the Food and Drug Association. Thus, the Kidney Health Initiative, in partnership with the Oxalosis and Hyperoxaluria Foundation, initiated a project to identify end points for clinical trials. A workgroup of physicians, scientists, patients with primary hyperoxaluria, industry, and United States regulators critically examined the published literature for clinical outcomes and potential surrogate end points that could be used to evaluate new treatments. Kidney stones, change in eGFR, urine oxalate, and plasma oxalate were the strongest candidate end points. Kidney stones affect how patients with primary hyperoxaluria feel and function, but standards for measurement and monitoring are lacking. Primary hyperoxaluria registry data suggest that eGFR decline in most patients is gradual, but can be unpredictable. Epidemiologic data show a strong relationship between urine oxalate and long-term kidney function loss. Urine oxalate is reasonably likely to predict clinical benefit, due to its causal role in stone formation and kidney damage in CKD stages 1-3a, and plasma oxalate is likely associated with risk of systemic oxalosis in CKD 3b-5. Change in slope of eGFR could be considered the equivalent of a clinically meaningful end point in support of traditional approval. A substantial change in urine oxalate as a surrogate end point could support traditional approval in patients with primary hyperoxaluria type 1 and CKD stages 1-3a. A substantial change in markedly elevated plasma oxalate could support accelerated approval in patients with primary hyperoxaluria and CKD stages 3b-5. Primary hyperoxaluria type 1 accounts for the preponderance of available data, thus heavily influences the conclusions. Addressing gaps in data will further facilitate testing of promising new treatments, accelerating improved outcomes for patients with primary hyperoxaluria.

Keywords: biomarkers; chronic; clinical trial end points; hyperoxaluria; kidney; kidney calculi; kidney stones; liver transplantation; oxalate; primary; primary hyperoxaluria type 1; rare kidney disease; registries; renal dialysis; renal insufficiency.

Figure 1.

Clinical manifestations observed in primary hyperoxaluria and candidate markers of progression vary by kidney disease stage. The consequences of hepatic oxalate overproduction (upper bars) are shaded to reflect high (purple) to low (gray) relative frequency, as best is known at this time. The clinical and biochemical markers (lower bars) are shaded to indicate those supported by clinical and experimental evidence (purple), while those with insufficient data and need for further research are shaded lighter (gray). Figure modified from the original provided courtesy of S. Hulton.

Figure 2.

Plasma oxalate increases exponentially as eGFR declines below 60 ml/min per 1.73 m². Plasma oxalate values and eGFR taken from the latest visit of 128 patients with primary hyperoxaluria (PH) who were >2 years of age (PH type 1, n=96; PH2, n=14; PH3, n=18) were plotted. Plasma oxalate values are relatively stable in the eGFR range of >60 ml/min per 1.73 m², and then they increase exponentially as eGFR declines. Plasma oxalate concentration was measured by ion chromatography. The CKD Epidemiology Collaboration (CKD-EPI) equation was used to calculate eGFR in adults, and the modified Schwartz equation at <18 years of age. The model was fit using a third degree polynomial regression (plotted as a black line). Both quadratic and cubic terms were statistically significant by the likelihood ratio test (P<0.001 for both). The 95% confidence interval of the regression model is indicated by the shaded region. Data shown is from the Rare Kidney Stone Consortium Primary Hyperoxaluria Registry.