Number and Frequency of Albuminuria Measurements in Clinical Trials in Diabetic Nephropathy

Abstract

Background and objectives Albuminuria change is often used to assess drug efficacy in intervention trials in nephrology. The change is often calculated using a variable number of urine samples collected at baseline and end of treatment. Yet more albuminuria measurements usually occur. Because albuminuria shows a large day-to-day variability, this study assessed to what extent the average and the precision of the antialbuminuric drug effect varies with the number of urine collections at each visit and the number of follow-up visits.Design, setting, participants, & measurements This study used data from three randomized intervention trials (Aliskiren Combined with Losartan in Type 2 Diabetes and Nephropathy, Selective Vitamin D Receptor Activation for Albuminuria Lowering, and Residual Albuminuria Lowering with Endothelin Antagonist Atrasentan) including patients with type 2 diabetes and macroalbuminuria. Albuminuria-lowering drug effects were estimated from one, two, or three urine collections at consecutive days before each study visit and reported as albuminuria change from baseline to end of treatment or the change over time considering an average of all follow-up albuminuria measurements.Results Increasing the number of urine collections for an albuminuria measurement at baseline and end of treatment or using all study visits during follow-up did not alter the average drug effect. The precision of the drug effect increased (decreased SEM) when the number of study visits and the number of urine collections per visit were increased. Using all albuminuria measurements at all study visits led to a 4-to 6-fold reduction in sample size to detect a 30% albuminuria-lowering treatment effect with 80% power compared with using baseline and end-of-treatment albuminuria measurements alone.Conclusions Increasing the number of urine collections per study visit and the number of visits over time does not change the average drug effect estimate but markedly increases the precision, thereby enhancing statistical power. Thus, clinical trial designs in diabetic nephropathy using albuminuria as an end point can be significantly improved, leading to smaller sample sizes and less complex trials.

Determining the Optimal Protocol for Measuring an Albuminuria Class Transition in Clinical Trials in Diabetic Kidney Disease

“…These results may, at first sight, contrast our previous findings, in which we concluded that increasing the frequency of urine collections during follow-up of a clinical trial increases the precision and statistical power to detect an albuminuria-lowering drug effect. 15 However, there are important differences between these studies. First, the end points between the studies were different.…”

Proteomic prediction and Renin angiotensin aldosterone system Inhibition prevention Of early diabetic nephRopathy in TYpe 2 diabetic patients with normoalbuminuria (PRIORITY): essential study design and rationale of a randomised clinical multicentre trial

“…This surrogate end point was chosen instead of using hard end points, as the trial is conducted in a normoalbuminuric population. Development of hard renal end points can take up to 20 years12 in such populations, hence, persistent microalbuminuria, which is considered a valid surrogate end point will be a feasible and acceptable outcome for our study 39. The aim to replace albuminuria as a biomarker, by designing a study based on albuminuria as outcome, may appear suboptimal at first glance.…”

“…Development of hard renal end points can take up to 20 years 12 in such populations, hence, persistent microalbuminuria, which is considered a valid surrogate end point will be a feasible and acceptable outcome for our study. 39 The aim to replace albuminuria as a biomarker, by designing a study based on albuminuria as outcome, may appear suboptimal at first glance. However, despite all criticisms, microalbuminuria has consistently found its way into clinical guidelines and is the key event in a diabetes patient's clinical course that triggers the initiation of renoprotective therapy.…”

Effect of Processing Delay and Storage Conditions on Urine Albumin-to-Creatinine Ratio

“…Therefore, randomized trials usually need to be large to detect moderate effects on uACR. To reduce sample sizes, collection of three sequential spot urine samples from each participant has been recommended, because the uncertainty in the estimate of an individual's average 24-hour albuminuria excretion is reduced (12). However, the collection of multiple FMV spot samples in an outpatient clinic is inconvenient for both participants and study staff and increases study costs.…”