Comparison of alternative primary outcome measures for use in lupus nephritis clinical trials

Abstract

Objective: Clinical trials of therapies for lupus nephritis have used many different primary outcome measures, ranging from complete response to time to end-stage renal disease. The objective of this study was to compare several possible outcome measures, using data from a large, multicenter trial of abatacept in lupus nephritis, to gain insight into which outcome measure, if any, was best able to discern differences among treatment groups.

Methods: Study patients received either abatacept or placebo, on a background of mycophenolate mofetil and glucocorticoids. Using data from this trial, the following primary outcome measures at 24 and 52 weeks were compared: complete response rate, major clinical response rate, total response rate (complete plus partial response), improvement in proteinuria, improvement in estimated glomerular filtration rate, and frequency of treatment failure. Time to complete response was also evaluated.

Results: Complete response rate, major clinical response rate, and time to complete response were the measures that best discriminated between the abatacept groups and placebo, and the sensitivities of these 3 measures were comparable. For these measures, sample sizes of 50 patients would have been sufficient to demonstrate a statistically significant difference between treatment and control at 52 weeks. Each of the other measures also discriminated between treatment and control, but much larger group sizes would have been required to determine statistical significance.

Conclusion: The choice of primary outcome measure can substantially influence the ability to detect therapeutic benefit in lupus nephritis trials. This study suggests that complete response rate, major clinical response rate at 52 weeks, and time to complete response may be the most sensitive outcome measures for detecting differences among therapeutic regimens.

Trial registration: ClinicalTrials.gov NCT00430677.

Copyright © 2013 by the American College of Rheumatology.

Figures

Figure 1

Complete response (CR) rates, major clinical response (MCR) rates, and total response (CR plus partial response [PR]) rates at week 52 (A) and week 24 (B) in each abatacept treatment group compared with the standard-of-care placebo control group. For the treatment groups, one group received abatacept infusions on days 1, 15, and 29, and every 28 days thereafter for 12 months at a fixed, weight-tiered dose of ~10 mg/kg (abatacept 10/10), while the other group received a higher dose of abatacept for the first 5 infusions (30 mg/kg), followed by a fixed, weight-tiered dose of ~10 mg/kg every 28 days thereafter (abatacept 30/10).

Figure 2

Frequency of improved urine protein:creatinine ratio (UPCR) (reduction in UPCR of ≥75%), improved estimated glomerular filtration rate (eGFR) (increase in eGFR of ≥25%), and treatment failure at week 52 in each abatacept treatment group (as described in Figure 1) compared with the standard-of-care placebo control group.

Figure 3

Time to complete response (CR) among patients who met the CR criteria at week 52 in the abatacept treatment groups (as described in Figure 1) compared with the placebo control group. This outcome measure was based on the principle that the concept of time to CR is meaningful only for patients who maintained the CR status and not for those whose CR was evanescent. Therefore, only the data for the patients who met the CR criteria at week 52 are shown. Values below the plot are the number of patients evaluated at each time point.

Figure 4

Group sizes representing the approximate number of patients per group that would have been sufficient to demonstrate a statistically significant difference between treatment and control, based on the observed response rates. For the 2 treatment groups, the mean value was used. Values for approximated group sizes are shown over the bars. CR = complete response; MCR = major clinical response; UPCR = urine protein:creatinine ratio; PR = partial response; eGFR = estimated glomerular filtration rate.