Risk factors for heart failure in patients with type 2 diabetes mellitus and stage 4 chronic kidney disease treated with bardoxolone methyl

Background: A phase 3 randomized clinical trial was designed to test whether bardoxolone methyl, a nuclear factor erythroid-2–related factor 2 (Nrf2) activator, slows progression to end-stage renal disease in patients with stage 4 chronic kidney disease and type 2 diabetes mellitus. The trial was terminated because of an increase in heart failure in the bardoxolone methyl group; many of the events were clinically associated with fluid retention.<p></p> Methods and Results: We randomized 2,185 patients with type 2 diabetes mellitus (T2DM) and stage 4 chronic kidney disease (CKD) (estimated glomerular filtration rate 15 to <30 mL min−1 1.73 m−2) to once-daily bardoxolone methyl (20 mg) or placebo. We used classification and regression tree analysis to identify baseline factors predictive of heart failure or fluid overload events. Elevated baseline B-type natriuretic peptide and previous hospitalization for heart failure were identified as predictors of heart failure events; bardoxolone methyl increased the risk of heart failure by 60% in patients with these risk factors. For patients without these baseline characteristics, the risk for heart failure events among bardoxolone methyl– and placebo-treated patients was similar (2%). The same risk factors were also identified as predictors of fluid overload and appeared to be related to other serious adverse events.<p></p> Conclusions: Bardoxolone methyl contributed to events related to heart failure and/or fluid overload in a subpopulation of susceptible patients with an increased risk for heart failure at baseline. Careful selection of participants and vigilant monitoring of the study drug will be required in any future trials of bardoxolone methyl to mitigate the risk of heart failure and other serious adverse events.<p></p&gt

Protecting Clinical Trial Participants and Protecting Data Integrity: Are We Meeting the Challenges?

Susan Ellenberg discusses alternative approaches towards evaluating data as it accumulates in clinical trials, and to protecting the integrity and preventing undue risks to participants, as the trial continues

Through the looking glass: understanding non-inferiority

Non-inferiority trials test whether a new product is not unacceptably worse than a product already in use. This paper introduces concepts related to non-inferiority, and discusses the regulatory views of both the European Medicines Agency and the United States Food and Drug Administration

The Effectiveness of Alcohol Screening and Brief Intervention in Emergency Departments: A Multicentre Pragmatic Cluster Randomized Controlled Trial

BACKGROUND: Alcohol misuse is common in people attending emergency departments (EDs) and there is some evidence of efficacy of alcohol screening and brief interventions (SBI). This study investigated the effectiveness of SBI approaches of different intensities delivered by ED staff in nine typical EDs in England: the SIPS ED trial. METHODS AND FINDINGS: Pragmatic multicentre cluster randomized controlled trial of SBI for hazardous and harmful drinkers presenting to ED. Nine EDs were randomized to three conditions: a patient information leaflet (PIL), 5 minutes of brief advice (BA), and referral to an alcohol health worker who provided 20 minutes of brief lifestyle counseling (BLC). The primary outcome measure was the Alcohol Use Disorders Identification Test (AUDIT) status at 6 months. Of 5899 patients aged 18 or more presenting to EDs, 3737 (63·3%) were eligible to participate and 1497 (40·1%) screened positive for hazardous or harmful drinking, of whom 1204 (80·4%) gave consent to participate in the trial. Follow up rates were 72% (n?=?863) at six, and 67% (n?=?810) at 12 months. There was no evidence of any differences between intervention conditions for AUDIT status or any other outcome measures at months 6 or 12 in an intention to treat analysis. At month 6, compared to the PIL group, the odds ratio of being AUDIT negative for brief advice was 1·103 (95% CI 0·328 to 3·715). The odds ratio comparing BLC to PIL was 1·247 (95% CI 0·315 to 4·939). A per protocol analysis confirmed these findings. CONCLUSIONS: SBI is difficult to implement in typical EDs. The results do not support widespread implementation of alcohol SBI in ED beyond screening followed by simple clinical feedback and alcohol information, which is likely to be easier and less expensive to implement than more complex interventions

A randomised controlled trial and cost-effectiveness evaluation of "booster" interventions to sustain increases in physical activity in middle-aged adults in deprived urban neighbourhoods

Background: Systematic reviews have identified a range of brief interventions which increase physical activity in previously sedentary people. There is an absence of evidence about whether follow up beyond three months can maintain long term physical activity. This study assesses whether it is worth providing motivational interviews, three months after giving initial advice, to those who have become more active. Methods/Design: Study candidates (n = 1500) will initially be given an interactive DVD and receive two telephone follow ups at monthly intervals checking on receipt and use of the DVD. Only those that have increased their physical activity after three months (n = 600) will be randomised into the study. These participants will receive either a "mini booster" (n = 200), "full booster" (n = 200) or no booster (n = 200). The "mini booster" consists of two telephone calls one month apart to discuss physical activity and maintenance strategies. The "full booster" consists of a face-to-face meeting with the facilitator at the same intervals. The purpose of these booster sessions is to help the individual maintain their increase in physical activity. Differences in physical activity, quality of life and costs associated with the booster interventions, will be measured three and nine months from randomisation. The research will be conducted in 20 of the most deprived neighbourhoods in Sheffield, which have large, ethnically diverse populations, high levels of economic deprivation, low levels of physical activity, poorer health and shorter life expectancy. Participants will be recruited through general practices and community groups, as well as by postal invitation, to ensure the participation of minority ethnic groups and those with lower levels of literacy. Sheffield City Council and Primary Care Trust fund a range of facilities and activities to promote physical activity and variations in access to these between neighbourhoods will make it possible to examine whether the effectiveness of the intervention is modified by access to community facilities. A one-year integrated feasibility study will confirm that recruitment targets are achievable based on a 10% sample.Discussion: The choice of study population, study interventions, brief intervention preceding the study, and outcome measure are discussed

Statistical design of personalized medicine interventions: The Clarification of Optimal Anticoagulation through Genetics (COAG) trial

<p>Abstract</p> <p>Background</p> <p>There is currently much interest in pharmacogenetics: determining variation in genes that regulate drug effects, with a particular emphasis on improving drug safety and efficacy. The ability to determine such variation motivates the application of personalized drug therapies that utilize a patient's genetic makeup to determine a safe and effective drug at the correct dose. To ascertain whether a genotype-guided drug therapy improves patient care, a personalized medicine intervention may be evaluated within the framework of a randomized controlled trial. The statistical design of this type of personalized medicine intervention requires special considerations: the distribution of relevant allelic variants in the study population; and whether the pharmacogenetic intervention is equally effective across subpopulations defined by allelic variants.</p> <p>Methods</p> <p>The statistical design of the Clarification of Optimal Anticoagulation through Genetics (COAG) trial serves as an illustrative example of a personalized medicine intervention that uses each subject's genotype information. The COAG trial is a multicenter, double blind, randomized clinical trial that will compare two approaches to initiation of warfarin therapy: genotype-guided dosing, the initiation of warfarin therapy based on algorithms using clinical information and genotypes for polymorphisms in <it>CYP2C9 </it>and <it>VKORC1</it>; and clinical-guided dosing, the initiation of warfarin therapy based on algorithms using only clinical information.</p> <p>Results</p> <p>We determine an absolute minimum detectable difference of 5.49% based on an assumed 60% population prevalence of zero or multiple genetic variants in either <it>CYP2C9 </it>or <it>VKORC1 </it>and an assumed 15% relative effectiveness of genotype-guided warfarin initiation for those with zero or multiple genetic variants. Thus we calculate a sample size of 1238 to achieve a power level of 80% for the primary outcome. We show that reasonable departures from these assumptions may decrease statistical power to 65%.</p> <p>Conclusions</p> <p>In a personalized medicine intervention, the minimum detectable difference used in sample size calculations is not a known quantity, but rather an unknown quantity that depends on the genetic makeup of the subjects enrolled. Given the possible sensitivity of sample size and power calculations to these key assumptions, we recommend that they be monitored during the conduct of a personalized medicine intervention.</p> <p>Trial Registration</p> <p>clinicaltrials.gov: NCT00839657</p

Efficacy, Safety, and Durability of Voretigene Neparvovec-rzyl in RPE65 Mutation–Associated Inherited Retinal Dystrophy: Results of Phase 1 and 3 Trials

Purpose: To report the durability of voretigene neparvovec-rzyl (VN) adeno-associated viral vector–based gene therapy for RPE65 mutation–associated inherited retinal dystrophy (IRD), including results of a phase 1 follow-on study at year 4 and phase 3 study at year 2. Design: Open-label phase 1 follow-on clinical trial and open-label, randomized, controlled phase 3 clinical trial. Participants: Forty subjects who received 1.5×1011 vector genomes (vg) of VN per eye in at least 1 eye during the trials, including 11 phase 1 follow-on subjects and 29 phase 3 subjects (20 original intervention [OI] and 9 control/intervention [CI]). Methods: Subretinal injection of VN in the second eye of phase 1 follow-on subjects and in both eyes of phase 3 subjects. Main Outcome Measures: End points common to the phase 1 and phase 3 studies included change in performance on the Multi-Luminance Mobility Test (MLMT) within the illuminance range evaluated, full-field light sensitivity threshold (FST) testing, and best-corrected visual acuity (BCVA). Safety end points included adverse event reporting, ophthalmic examination, physical examination, and laboratory testing. Results: Mean (standard deviation) MLMT lux score change was 2.4 (1.3) at 4 years compared with 2.6 (1.6) at 1 year after administration in phase 1 follow-on subjects (n = 8), 1.9 (1.1) at 2 years, and 1.9 (1.0) at 1 year post-administration in OI subjects (n = 20), and 2.1 (1.6) at 1 year post-administration in CI subjects (n = 9). All 3 groups maintained an average improvement in FST, reflecting more than a 2 log10(cd.s/m2) improvement in light sensitivity at 1 year and subsequent available follow-up visits. The safety profile was consistent with vitrectomy and the subretinal injection procedure, and no deleterious immune responses occurred. Conclusions: After VN gene augmentation therapy, there was a favorable benefit-to-risk profile with similar improvement demonstrated in navigational ability and light sensitivity among 3 groups of subjects with RPE65 mutation–associated IRD, a degenerative disease that progresses to complete blindness. The safety profile is consistent with the administration procedure. These data suggest that this effect, which is nearly maximal by 30 days after VN administration, is durable for 4 years, with observation ongoing

Health services changes: is a run-in period necessary before evaluation in randomised clinical trials?

Background Most randomised clinical trials (RCTs) testing a new health service do not allow a run-in period of consolidation before evaluating the new approach. Consequently, health professionals involved may feel insufficiently familiar or confident, or that new processes or systems that are integral to the service are insufficiently embedded in routine care prior to definitive evaluation in a RCT. This study aimed to determine the optimal run-in period for a new physiotherapy-led telephone assessment and treatment service known as PhysioDirect and whether a run-in was needed prior to evaluating outcomes in an RCT. Methods The PhysioDirect trial assessed whether PhysioDirect was as effective as usual care. Prior to the main trial, a run-in of up to 12 weeks was permitted to facilitate physiotherapists to become confident in delivering the new service. Outcomes collected from the run-in and main trial were length of telephone calls within the PhysioDirect service and patients’ physical function (SF-36v2 questionnaire) and Measure Yourself Medical Outcome Profile v2 collected at baseline and six months. Joinpoint regression determined how long it had taken call times to stabilise. Analysis of covariance determined whether patients’ physical function at six months changed from the run-in to the main trial. Results Mean PhysioDirect call times (minutes) were higher in the run-in (31 (SD: 12.6)) than in the main trial (25 (SD: 11.6)). Each physiotherapist needed to answer 42 (95% CI: 20,56) calls for their mean call time to stabilise at 25 minutes per call; this took a minimum of seven weeks. For patients’ physical function, PhysioDirect was equally clinically effective as usual care during both the run-in (0.17 (95% CI: -0.91,1.24)) and main trial (-0.01 (95% CI: -0.80,0.79)). Conclusions A run-in was not needed in a large trial testing PhysioDirect services in terms of patient outcomes. A learning curve was evident in the process measure of telephone call length. This decreased during the run-in and stabilised prior to commencement of the main trial. Future trials should build in a run-in if it is anticipated that learning would have an effect on patient outcome