TY - JOUR
T1 - End points for clinical trials in primary hyperoxaluria
AU - Milliner, Dawn S.
AU - McGregor, Tracy L.
AU - Thompson, Aliza
AU - Dehmel, Bastian
AU - Knight, John
AU - Rosskamp, Ralf
AU - Blank, Melanie
AU - Yang, Sixun
AU - Fargue, Sonia
AU - Rumsby, Gill
AU - Groothoff, Jaap
AU - Allain, Meaghan
AU - West, Melissa
AU - Hollander, Kim
AU - Lowther, W. Todd
AU - Lieske, John C.
N1 - Publisher Copyright:
© 2020 by the American Society of Nephrology.
PY - 2020/7
Y1 - 2020/7
N2 - 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, inpartnership 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 functionloss. Urine oxalate is reasonably likely to predict clinicalbenefit,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.
AB - 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, inpartnership 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 functionloss. Urine oxalate is reasonably likely to predict clinicalbenefit,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.
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U2 - 10.2215/CJN.13821119
DO - 10.2215/CJN.13821119
M3 - Article
C2 - 32165440
AN - SCOPUS:85085893569
SN - 1555-9041
VL - 15
SP - 1056
EP - 1065
JO - Clinical Journal of the American Society of Nephrology
JF - Clinical Journal of the American Society of Nephrology
IS - 7
ER -