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Clin J Am Soc Nephrol. 2019 Mar 7;14(3):469-481. doi: 10.2215/CJN.08600718. Epub 2019 Jan 11.

Proteinuria Reduction as a Surrogate End Point in Trials of IgA Nephropathy.

Author information

1
Division of Cardiovascular and Renal Products, Office of New Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland.
2
KJC Statistics Ltd., Bramhall, Cheshire, UK.
3
Tufts Medical Center, Boston, Massachusetts.
4
Division of Nephrology, RWTH University of Aachen, Aachen, Germany.
5
The George Institute for Global Health, University of New South Wales, Sydney, Australia.
6
Service de Néphrologie, Hôpital Pasteur, Centre Hospitalier Universitaire de Nice, Université Nice Sophia-Antipolis, Nice, France; Departments of.
7
Health Sciences and.
8
Infection, Inflammation and Immunity, University of Leicester, Leicester, UK.
9
University Health Network, University of Toronto, Toronto, Ontario, Canada.
10
Covance and University of North Carolina, Chapel Hill, North Carolina.
11
Allena Pharmaceuticals, Inc., Newton, Massachusetts.
12
JAMCO Pharma Consulting AB, Stockholm, Sweden.
13
The Ohio State University Wexner Medical Center, Columbus, Ohio.
14
American Society of Nephrology, Washington, DC; and.
15
Division of Renal Diseases and Hypertension, University of Minnesota, Minneapolis, Minnesota pnachman@umn.edu.

Abstract

IgA nephropathy (IgAN) is an important cause of ESKD for which there are no approved therapies. A challenge for evaluating treatments for IgAN is the usual long time course for progression to ESKD. The aim of this Kidney Health Initiative project was to identify surrogate end points that could serve as reliable predictors of a treatment's effect on long-term kidney outcomes in IgAN and be used as a basis for approval. Proteinuria was identified as the most widely recognized and well studied risk factor for progression to ESKD in IgAN. The workgroup performed a critical review of the data on proteinuria reduction as a surrogate end point for a treatment's effect on progression to ESKD in IgAN. Epidemiologic data indicate a strong and consistent relationship between the level and duration of proteinuria and loss of kidney function. Trial-level analyses of data from 13 controlled trials also show an association between treatment effects on percent reduction of proteinuria and treatment effects on a composite of time to doubling of serum creatinine, ESKD, or death. We conclude that data support the use of proteinuria reduction as a reasonably likely surrogate end point for a treatment's effect on progression to ESKD in IgAN. In the United States, reasonably likely surrogate end points can be used as a basis for accelerated approval of therapies intended to treat serious or life-threatening conditions, such as IgAN. The clinical benefit of products approved under this program would need to be verified in a postmarketing confirmatory trial.

KEYWORDS:

Glomerulonephritis; IGA; IgA nephropathy; Kidney Failure, Chronic; clinical trials; creatinine; kidney; proteinuria; risk factors; surrogate endpoint

PMID:
30635299
PMCID:
PMC6419287
[Available on 2020-03-07]
DOI:
10.2215/CJN.08600718

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