Two-Year, Randomized, Controlled Trial of Belimumab in Lupus Nephritis.

BACKGROUND: In adults with active lupus nephritis, the efficacy and safety of intravenous belimumab as compared with placebo, when added to standard therapy (mycophenolate mofetil or cyclophosphamide-azathioprine), are unknown. METHODS: In a phase 3, multinational, multicenter, randomized, double-blind, placebo-controlled, 104-week trial conducted at 107 sites in 21 countries, we assigned adults with biopsy-proven, active lupus nephritis in a 1:1 ratio to receive intravenous belimumab (at a dose of 10 mg per kilogram of body weight) or matching placebo, in addition to standard therapy. The primary end point at week 104 was a primary efficacy renal response (a ratio of urinary protein to creatinine of ≤0.7, an estimated glomerular filtration rate [eGFR] that was no worse than 20% below the value before the renal flare (pre-flare value) or ≥60 ml per minute per 1.73 m2 of body-surface area, and no use of rescue therapy), and the major secondary end point was a complete renal response (a ratio of urinary protein to creatinine of <0.5, an eGFR that was no worse than 10% below the pre-flare value or ≥90 ml per minute per 1.73 m2, and no use of rescue therapy). The time to a renal-related event or death was assessed. RESULTS: A total of 448 patients underwent randomization (224 to the belimumab group and 224 to the placebo group). At week 104, significantly more patients in the belimumab group than in the placebo group had a primary efficacy renal response (43% vs. 32%; odds ratio, 1.6; 95% confidence interval [CI], 1.0 to 2.3; P = 0.03) and a complete renal response (30% vs. 20%; odds ratio, 1.7; 95% CI, 1.1 to 2.7; P = 0.02). The risk of a renal-related event or death was lower among patients who received belimumab than among those who received placebo (hazard ratio, 0.51; 95% CI, 0.34 to 0.77; P = 0.001). The safety profile of belimumab was consistent with that in previous trials. CONCLUSIONS: In this trial involving patients with active lupus nephritis, more patients who received belimumab plus standard therapy had a primary efficacy renal response than those who received standard therapy alone. (Funded by GlaxoSmithKline; BLISS-LN ClinicalTrials.gov number, NCT01639339.).

Missing CD4+ cell response in randomized clinical trials of maraviroc and dolutegravir.

BACKGROUND: Missing data can compromise inferences from clinical trials, yet the topic has received little attention in the clinical trial community. Shortcomings in commonly used methods used to analyze studies with missing data (complete case, last- or baseline-observation carried forward) have been highlighted in a recent Food and Drug Administration-sponsored report. This report recommends how to mitigate the issues associated with missing data. We present an example of the proposed concepts using data from recent clinical trials. METHODS: CD4+ cell count data from the previously reported SINGLE and MOTIVATE studies of dolutegravir and maraviroc were analyzed using a variety of statistical methods to explore the impact of missing data. Four methodologies were used: complete case analysis, simple imputation, mixed models for repeated measures, and multiple imputation. We compared the sensitivity of conclusions to the volume of missing data and to the assumptions underpinning each method. RESULTS: Rates of missing data were greater in the MOTIVATE studies (35%-68% premature withdrawal) than in SINGLE (12%-20%). The sensitivity of results to assumptions about missing data was related to volume of missing data. Estimates of treatment differences by various analysis methods ranged across a 61 cells/mm3 window in MOTIVATE and a 22 cells/mm3 window in SINGLE. CONCLUSIONS: Where missing data are anticipated, analyses require robust statistical and clinical debate of the necessary but unverifiable underlying statistical assumptions. Multiple imputation makes these assumptions transparent, can accommodate a broad range of scenarios, and is a natural analysis for clinical trials in HIV with missing data.

A 24-week study to evaluate the effect of rilapladib on cognition and cerebrospinal fluid biomarkers of Alzheimer's disease.

BACKGROUND: The lipoprotein-associated phospholipase A2 inhibitor (Lp-PLA2), rilapladib (SB659032), is being evaluated as a potential treatment to slow the progression of Alzheimer's disease (AD). METHODS: One hundred twenty-four subjects with possible mild AD and with neuroimaging evidence of cerebrovascular disease were randomized to placebo or 250-mg rilapladib once daily, for 24 weeks, in addition to stable background acetylcholinesterase inhibitor and/or memantine. The study assessed the safety and tolerability of rilapladib and its effects on cognition, mechanistic, and disease-related biomarkers. Although the overall intent behind the study was to take a broad exploratory view of the data, two primary end points of interest (cerebrospinal fluid [CSF] amyloid beta peptide 1-42 [Aß1-42] and CogState executive function/working memory [EF/WM] composite score at week 24) were prespecified in the analysis plan for inferential statistical analysis. RESULTS: Rilapladib was well tolerated with no significant safety concerns. A significant difference from placebo was observed for rilapladib on change from baseline in EF/WM (effect size, 0.45; P = .026). There was no significant difference between groups on the change from baseline in CSF Aß1-42 (P = .133). Preliminary evidence of effects was detected on other mechanistic (albumin quotient) and disease-related biomarkers (tau/P-tau and neurofilament light chain). CONCLUSION: These data provide initial evidence supporting Lp-PLA2 inhibition as a novel treatment for dementia. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01428453.

Two randomized controlled trials of SB742457 in mild-to-moderate Alzheimer's disease.

BACKGROUND: Two previous studies of SB742457, a 5-hydroxytryptamine (5-HT6) receptor antagonist, suggested the efficacy of improvements in cognition and global outcome in Alzheimer's disease (AD). METHODS: Two randomized, placebo-controlled trials investigated SB742457 15 and 35 mg daily in subjects with mild-to-moderate AD (Mini-Mental Health State Examination [MMSE] 10-26). Study 1 (n = 576) investigated SB742457 and donepezil (5-10 mg daily) as monotherapy for 6 months. Study 2 (n = 684) investigated SB742457 in subjects who were maintained on donepezil. Coprimary endpoints at 24 weeks assessed cognition (AD Assessment Scale-Cognitive Subscale [ADAS-Cog]) and global outcome (Study 1: Clinician Interview-Based Impression of Change Plus Caregiver Input [CIBIC+]; Study 2: Clinical Dementia Rating-Sum of Boxes [CDR-SB]). Safety was assessed throughout. RESULTS: Both studies failed to achieve formal statistical significance for their primary objectives. Study 1: SB742457 monotherapy was not statistically significantly different from placebo on any endpoint. Donepezil improved CIBIC+ but not ADAS-Cog. Study 2: SB742457 35 mg showed statistically significant differences relative to placebo for ADAS-cog (weeks 12, 24, and 48, but not week 36), ADCS-ADL (weeks 12-36, but not week 48), and CDR-SB (week 12 only). CONCLUSION: Neither study met the overall criteria for success, but as an adjunct to donepezil, SB742457 was associated with sustained improvements for up to 48 weeks in cognition and ADL, compared with donepezil alone.Clinical Trial Registration: Clinicaltrials.gov: Study 1 NCT00708552; Study 2 NCT00710684.

Who is driving continuing medical education for family medicine?

INTRODUCTION: Considerable time and money are invested in continuing medical education (CME) for family physicians (FPs) but the effectiveness is uncertain. The participation of FPs as coordinators and teachers is not well known. The goal of this project was to describe the role of FPs in organizing and teaching CME events that are accredited for FPs. METHODS: Information about accredited CME events occurring in Alberta and Nova Scotia was requested from universities, provincial chapters of the College of Family Physicians of Canada, and pharmaceutical companies. Location, coordinating site, organizing committee members, teaching faculty, and format were recorded from each event. The number and proportion of FPs involved in both organizing and teaching CME events accredited for FPs were calculated and compared. RESULTS: A total of 314 CME events were collected, comprising a total of 1,472 hours of CME. From the CME events collected, there were 1,730 organizing committee members and 1,647 teachers. FPs constitute 59% of the organizing committees and 17% of the teachers. Significant differences in the numbers of FP planners and teachers were related to organizing group, format, location, and expected audience composition. DISCUSSION: The accreditation requirement for FPs on organizing committees likely helps preserve a reasonable proportion of FP organizers but not teachers in FP CME. The proportions of true FP planners and teachers may actually be lower than planning documents indicate. Low level of family physician teachers in CME may be due to FPs' not selecting FP teachers, the FP teaching pool's being inadequate, or the organizing committee's being unaware of FPs who are knowledgeable in particular areas.