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Early change in proteinuria as a surrogate end point for kidney disease progression: an individual patient meta-analysis.

ABSTRACT: It is controversial whether proteinuria is a valid surrogate end point for randomized trials in chronic kidney disease.Meta-analysis of individual patient-level data.Individual patient data for 9,008 patients from 32 randomized trials evaluating 5 intervention types.Randomized controlled trials of kidney disease progression until 2007 with measurements of proteinuria both at baseline and during the first year of follow-up, with at least 1 further year of follow-up for the clinical outcome.Early change in proteinuria.Doubling of serum creatinine level, end-stage renal disease, or death.Early decline in proteinuria was associated with lower risk of the clinical outcome (pooled HR, 0.74 per 50% reduction in proteinuria); this association was stronger at higher levels of baseline proteinuria. Pooled estimates for the proportion of treatment effect on the clinical outcome explained by early decline in proteinuria ranged from -7.0% (95%CI, -40.6% to 26.7%) to 43.9% (95%CI, 25.3% to 62.6%) across 5 intervention types. The direction of the pooled treatment effects on early change in proteinuria agreed with the direction of the treatment effect on the clinical outcome for all 5 intervention types, with the magnitudes of the pooled treatment effects on the 2 end points agreeing for 4 of the 5 intervention types. The pooled treatment effects on both end points were simultaneously stronger at higher levels of proteinuria. However, statistical power was insufficient to determine whether differences in treatment effects on the clinical outcome corresponded to differences in treatment effects on proteinuria between individual studies.Limited variety of interventions tested and low statistical power for many chronic kidney disease clinical trials.These results provide new evidence supporting the use of an early reduction in proteinuria as a surrogate end point, but do not provide sufficient evidence to establish its validity in all settings.

SUBMITTER: Inker LA

PROVIDER: S-EPMC4070618 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Early change in proteinuria as a surrogate end point for kidney disease progression: an individual patient meta-analysis.

Inker Lesley A LA Levey Andrew S AS Pandya Kruti K Stoycheff Nicholas N Okparavero Aghogho A Greene Tom T

American journal of kidney diseases : the official journal of the National Kidney Foundation 20140429 1

<h4>Background</h4>It is controversial whether proteinuria is a valid surrogate end point for randomized trials in chronic kidney disease.<h4>Study design</h4>Meta-analysis of individual patient-level data.<h4>Setting & population</h4>Individual patient data for 9,008 patients from 32 randomized trials evaluating 5 intervention types.<h4>Selection criteria for studies</h4>Randomized controlled trials of kidney disease progression until 2007 with measurements of proteinuria both at baseline and d ...[more]

PMID: 24787763

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Project description:Purpose Overall survival (OS) is the definitive and best-established primary efficacy end point to evaluate diffuse large B-cell lymphoma (DLBCL) therapies, but it requires prolonged follow-up. An earlier end point assessed post-treatment would expedite clinical trial conduct and accelerate patient access to effective new therapies. Our objective was to formally evaluate progression-free survival (PFS) and PFS at 24 months (PFS24) as surrogate end points for OS in first-line DLBCL. Patients and Methods Individual patient data were analyzed from 7,507 patients from 13 multicenter randomized controlled trials of active treatment in previously untreated DLBCL, published after 2002, with sufficient PFS data to predict treatment effects on OS. Trial-level surrogacy examining the correlation of treatment effect estimates of PFS/PFS24 and OS was evaluated using both linear regression ( R2WLS) and Copula bivariable ( R2Copula) models. Prespecified criteria for surrogacy required either R2WLS or R2Copula ? 0.80 and neither < 0.7, with lower-bound 95% CI > 0.60. Results Trial-level surrogacy for PFS was strong ( R2WLS = 0.83; R2Copula = 0.85) and met the predefined criteria for surrogacy. At the patient level, PFS strongly correlated with OS. The surrogate threshold effect had a hazard ratio of 0.89. Surrogacy was consistent across comparisons with or without rituximab and with rituximab maintenance trials. Trial-level surrogacy for PFS24 was relatively strong ( R2WLS = 0.77; R2Copula = 0.78) but did not meet prespecified criteria. At the patient level, PFS24 significantly correlated with OS. The surrogate threshold effect had an odds ratio of 1.51. Conclusion This large pooled analysis of individual patient data supports PFS as a surrogate end point for OS in future randomized controlled trials evaluating chemoimmunotherapy in DLBCL. Use of this end point may expedite therapeutic development with the intent of bringing novel therapies to this patient population years before OS results are mature.

Dataset Information

Early change in proteinuria as a surrogate end point for kidney disease progression: an individual patient meta-analysis.

Publications

Early change in proteinuria as a surrogate end point for kidney disease progression: an individual patient meta-analysis.

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