Futility Boundaries Research Articles

Meta-analysis and trial sequential analysis of local vs. general anaesthesia for carotid endarterectomy.

Controversy exists regarding the best choice of anaesthesia for carotid endarterectomy. We aimed to evaluate the peri-operative outcomes of local vs. general anaesthesia for carotid endarterectomy. We conducted a systematic search of electronic information sources and applied a combination of free text and controlled vocabulary searches adapted to thesaurus headings, search operators and limits in each of the electronic databases. We defined peri-operative stroke, transient ischaemic attack, mortality and myocardial infarction as the primary outcome measures. We identified 12 randomised controlled trials and 21 observational studies reporting a total of 58,212 patients undergoing carotid endarterectomy under local or general anaesthesia. Analysis of observational studies demonstrated that local anaesthesia was associated with a significantly lower incidence of stroke (odds ratio (OR (95% CI) 0.66 (0.55-0.80), p<0.0001), transient ischaemic attack (0.52 (0.38-0.70), p<0.0001), myocardial infarction (0.55 (0.41-0.75), p=0.0002) and mortality (0.72 (0.56-0.94), p=0.01) compared with general anaesthesia. Analysis of randomised controlled trials did not find a significant difference in the risk of stroke (0.92 (0.67-1.28), p=0.63), transient ischaemic attack (2.20 (0.48-10.03), p=0.31), myocardial infarction (1.25 (0.57-2.72), p=0.58) or mortality (0.61 (0.35-1.05), p=0.07) between local and general anaesthesia. On trial sequential analysis of the randomised trials, the Z-curve did not cross the α-spending boundaries or futility boundaries for stroke, mortality and transient ischaemic attack, suggesting that more trials are needed to reach conclusive results. Our meta-analysis of observational studies suggests that local anaesthesia for carotid endarterectomy may be associated with lower peri-operative morbidity and mortality compared with general anaesthesia. Although randomised studies have not confirmed any advantage for local anaesthesia, this may be due to a lack of pooled statistical power in these trials.

Pulmonary artery perfusion versus no perfusion during cardiopulmonary bypass for open heart surgery in adults.

Available evidence has been inconclusive on whether pulmonary artery perfusion during cardiopulmonary bypass (CPB) is associated with decreased or increased mortality, pulmonary events, and serious adverse events (SAEs) after open heart surgery. To our knowledge, no previous systematic reviews have included meta-analyses of these interventions. To assess the benefits and harms of single-shot or continuous pulmonary artery perfusion with blood (oxygenated or deoxygenated) or a preservation solution compared with no perfusion during cardiopulmonary bypass (CPB) in terms of mortality, pulmonary events, serious adverse events (SAEs), and increased inflammatory markers for adult surgical patients. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Science Citation Index Expanded, and advanced Google for relevant studies. We handsearched retrieved study reports and scanned citations of included studies and relevant reviews to ensure that no relevant trials were missed. We searched for ongoing trials and unpublished trials in the World Health Organization International Clinical Trials Registry Platform (ICTRP) and at clinicaltrials.gov (4 July 2017). We contacted medicinal firms producing preservation solutions to retrieve additional studies conducted to examine relevant interventions. We included randomized controlled trials (RCTs) that compared pulmonary artery perfusion versus no perfusion during CPB in adult patients (≧ 18 years). Two independent review authors extracted data, conducted fixed-effect and random-effects meta-analyses, and calculated risk ratios (RRs) or odds ratios (ORs) for dichotomous outcomes. For continuous data, we have presented mean differences (MDs) and 95% confidence intervals (CIs) as estimates of the intervention effect. To minimize the risk of systematic error, we assessed risk of bias of included trials. To reduce the risk of random errors caused by sparse data and repetitive updating of cumulative meta-analyses, we applied Trial Sequential Analyses (TSAs). We used GRADE principles to assess the quality of evidence. We included in this review four RCTs (210 participants) reporting relevant outcomes. Investigators randomly assigned participants to pulmonary artery perfusion with blood versus no perfusion during CPB. Only one trial included the pulmonary artery perfusion intervention with a preservation solution; therefore we did not perform meta-analysis. Likewise, only one trial reported patient-specific data for the outcome "pulmonary events"; therefore we have provided no results from meta-analysis. Instead, review authors added two explorative secondary outcomes for this version of the review: the ratio of partial pressure of oxygen in arterial blood (PaO2) to fraction of inspired oxygen (FiO2); and intubation time. Last, review authors found no comparable data for the secondary outcome inflammatory markers.The effect of pulmonary artery perfusion on all-cause mortality was uncertain (Peto OR 1.78, 95% CI 0.43 to 7.40; TSA adjusted CI 0.01 to 493; 4 studies, 210 participants; GRADE: very low quality). Sensitivity analysis of one trial with overall low risk of bias (except for blinding of personnel during the surgical procedure) yielded no evidence of a difference for mortality (Peto OR 1.65, 95% CI 0.27 to 10.15; 1 study, 60 participants). The TSA calculated required information size was not reached and the futility boundaries did not cross; thus this analysis cannot refute a 100% increase in mortality.The effect of pulmonary artery perfusion with blood on SAEs was likewise uncertain (RR 1.12, 95% CI 0.66 to 1.89; 3 studies, 180 participants; GRADE: very low quality). Data show an association between pulmonary artery perfusion with blood during CPB and a higher postoperative PaO2/FiO2 ratio (MD 27.80, 95% CI 5.67 to 49.93; 3 studies, 119 participants; TSA adjusted CI 5.67 to 49.93; GRADE: very low quality), although TSA could not confirm or refute a 10% increase in the PaO2/FiO2 ratio, as the required information size was not reached. The effects of pulmonary artery perfusion with blood during cardiopulmonary bypass (CPB) are uncertain owing to the small numbers of participants included in meta-analyses. Risks of death and serious adverse events may be higher with pulmonary artery perfusion with blood during CPB, and robust evidence for any beneficial effects is lacking. Future randomized controlled trials (RCTs) should provide long-term follow-up and patient stratification by preoperative lung function and other documented risk factors for mortality. One study that is awaiting classification (epub abstract with preliminary results) may change the results of this review when full study details have been published.

Choice of futility boundaries for group sequential designs with two endpoints

BackgroundIn clinical trials, the opportunity for an early stop during an interim analysis (either for efficacy or for futility) may relevantly save time and financial resources. This is especially important, if the planning assumptions required for power calculation are based on a low level of evidence. For example, when including two primary endpoints in the confirmatory analysis, the power of the trial depends on the effects of both endpoints and on their correlation. Assessing the feasibility of such a trial is therefore difficult, as the number of parameter assumptions to be correctly specified is large. For this reason, so-called ‘group sequential designs’ are of particular importance in this setting. Whereas the choice of adequate boundaries to stop a trial early for efficacy has been broadly discussed in the literature, the choice of optimal futility boundaries has not been investigated so far, although this may have serious consequences with respect to performance characteristics.MethodsIn this work, we propose a general method to construct ‘optimal’ futility boundaries according to predefined criteria. Further, we present three different group sequential designs for two endpoints applying these futility boundaries. Our methods are illustrated by a real clinical trial example and by Monte-Carlo simulations.ResultsBy construction, the provided method of choosing futility boundaries maximizes the probability to correctly stop in case of small or opposite effects while limiting the power loss and the probability of stopping the study ‘wrongly’. Our results clearly demonstrate the benefit of using such ‘optimal’ futility boundaries, especially compared to futility boundaries commonly applied in practice.ConclusionsAs the properties of futility boundaries are often not considered in practice and unfavorably chosen futility boundaries may imply bad properties of the study design, we recommend assessing the performance of these boundaries according to the criteria proposed in here.

Early Versus Late Initiation of Renal Replacement Therapy in Critically Ill Patients: Systematic Review and Meta-Analysis.

Early initiation of renal replacement therapy (RRT) effect on survival and renal recovery of critically ill patients is still uncertain. We aimed to systematically review current evidence comparing outcomes of early versus late initiation of RRT in critically ill patients. We searched the Medline (via Pubmed), LILACS, Science Direct, and CENTRAL databases from inception until November 2016 for randomized clinical trials (RCTs) or observational studies comparing early versus late initiation of RRT in critically ill patients. The primary outcome was mortality. Duration of mechanical ventilation, intensive care unit (ICU) length of stay (LOS), hospital LOS, and renal function recovery were secondary outcomes. Meta-analysis and trial sequential analysis (TSA) were used for the primary outcome. Sixty-two studies were retrieved and analyzed, including 11 RCTs. There was no difference in mortality between early and late initiation of RRT among RCTs (odds ratio [OR] = 0.78; 95% confidence interval [CI]: 0.52-1.19; I2 = 63.1%). Trial sequential analysis of mortality across all RCTs achieved futility boundaries at both 1% and 5% type I error rates, although a subgroup analysis of studies including only acute kidney injury patients was not conclusive. There was also no difference in time on mechanical ventilation, ICU and hospital LOS, or renal recovery among studies. Early initiation of RRT was associated with reduced mortality among prospective (OR = 0.69; 95% CI: 0.49-0.96; I2 = 85.9%) and retrospective (OR = 0.61; 95% CI: 0.41-0.92; I2 = 90.9%) observational studies, both with substantial heterogeneity. However, subgroup analysis excluding low-quality observational studies did not achieve statistical significance. Pooled analysis of randomized trials indicates early initiation of RRT is not associated with lower mortality rates. The potential benefit of reduced mortality associated with early initiation of RRT was limited to low-quality observational studies.

Planned interim analysis of PATRICIA: An open-label, single-arm, phase II study of pertuzumab (P) with high-dose trastuzumab (H) for the treatment of central nervous system (CNS) progression post radiotherapy (RT) in patients (pts) with HER2-positive metastatic breast cancer (MBC).

2074 Background: There is currently no clear standard of care to address the management of recurring/multiple intracranial metastases post RT in HER2-positive MBC. The ongoing PATRICIA study (NCT02536339) is evaluating the safety and efficacy of P in combination with high-dose h for patients with HER2-positive MBC with CNS metastases who have CNS progression following RT. Reported herein are results from the protocol-specified interim analysis of PATRICIA. Methods: All eligible patients must have measurable (≥10 mm) CNS progression post RT, and stable non-CNS disease. Patients receive P (840-mg loading dose, then 420 mg every 3 weeks) and high-dose h (6 mg/kg weekly). The primary efficacy endpoint is objective response rate (ORR) in the CNS per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. The interim analysis was planned after 15 patients were enrolled and had ≥2 left ventricular ejection fraction (LVEF) measurements, 2 cycles of study drugs, and 2 response measurements. The study would proceed to full enrollment (n=40) if objective response or stable disease in the CNS was observed in ≥1 of 15 patients and &lt;2 of 15 patients develop congestive heart failure (CHF) related to P or H. Results: As of Sept 6, 2016, 15 patients had been enrolled across 9 sites. Median treatment duration was 4.4 (range 1.2−8.3) months. Six patients discontinued treatment (5 for disease progression; 1 for symptomatic deterioration). Range for duration of response was 1.4−3.3 months. There were no new safety signals for P combined with high-dose h treatment. No patients had CHF or a clinically significant drop in LVEF. Conclusions: Based on early evidence of clinical benefit (ORR 20%) and a lack of new safety signals, the safety and futility boundaries for PATRICIA have been passed and study enrollment continues. Clinical trial information: NCT02536339. [Table: see text]

Screening for coronary artery disease in patients with type 2 diabetes: a meta-analysis and trial sequential analysis

ObjectiveTo evaluate the efficacy of coronary artery disease screening in asymptomatic patients with type 2 diabetes and assess the statistical reliability of the findings.MethodsElectronic databases (MEDLINE, EMBASE, Cochrane Library and...

Design and monitoring of multi-arm multi-stage clinical trials.

Two-arm group sequential designs have been widely used for over 40 years, especially for studies with mortality endpoints. The natural generalization of such designs to trials with multiple treatment arms and a common control (MAMS designs) has, however, been implemented rarely. While the statistical methodology for this extension is clear, the main limitation has been an efficient way to perform the computations. Past efforts were hampered by algorithms that were computationally explosive. With the increasing interest in adaptive designs, platform designs, and other innovative designs that involve multiple comparisons over multiple stages, the importance of MAMS designs is growing rapidly. This article provides break-through algorithms that can compute MAMS boundaries rapidly thereby making such designs practical. For designs with efficacy-only boundaries the computational effort increases linearly with number of arms and number of stages. For designs with both efficacy and futility boundaries the computational effort doubles with successive increases in number of stages.

Gemox versus surveillance following surgery of localized biliary tract cancer: Results of the PRODIGE 12-ACCORD 18 (UNICANCER GI) phase III trial.

225 Background: No standard post-surgery adjuvant treatment is currently recommended in localized biliary tract cancer (BTC). Gemcitabine combined with platinum is the standard chemotherapy for advanced BTC. The aim of this phase III randomized trial was to assess whether GEMOX would increase relapse-free survival (RFS) while maintaining health-related quality of life (HrQoL). Methods: We performed a multicenter randomized phase III trial. Patients were randomized, within 3 months of R0 or R1 resection of a localized BTC (intra-hepatic, perihilar, extra-hepatic cholangiocarcinoma or gallbladder cancer), to receive either GEMOX 85 for 12 cycles (Experimental Arm A) or surveillance (Standard Arm B). Co-primary objectives were RFS and HrQoL. 190 patients and 126 RFS events were required to show an increase of median RFS from 18 to 30 months. Results: Between July 2009 and February 2014, 196 patients were included in 33 French centers. Baseline characteristics were balanced, with similar primary sites, R0 resection rates were 86.2% (Arm A) vs 87.9% (Arm B), lymph node invasion present in 37.2% vs 36.4%. In Arm A, a median of 12 cycles was delivered (mean: 9.3, range: 0-12). Maximal grade of adverse events were grade 3 in 57.5% vs 22.2%, and grade 4 in 17.0% vs 9.1%. During treatment one patient died in each arm. The main grade ≥ 3 adverse events in the year following inclusion were peripheral neuropathy (50.0% vs 1.1%), and neutropenia (22.3% vs 0%). Median follow-up was 44.3 months, with 54 and 64 RFS events in arms A vs B. There was no significant difference in RFS between the arms (log-rank p = 0.31), with a hazard ratio of 0.83 [95% CI: 0.58-1.19], p = 0.31 (futility boundaries were crossed). Median RFS was 30.4 [95% CI: 15.4-45.8] vs 22.0 months [95%CI: 13.6-38.3] in arms A &amp; B respectively, and 4-years RFS was 39.3% [95%CI: 28.4%-50.0%] vs 33.2% [95%CI: 23.1-43.7%]. Global Health HrQoL scores were not different at 12 months (70.8 vs 83.3, p = 0.18) and at 24 months (75.0 vs 83.3, p = 0.50). Conclusions: Adjuvant chemotherapy in BTC with GEMOX was feasible and associated with expected toxicities and no deterioration of HrQoL. There was no significant difference in RFS between GEMOX and surveillance. Clinical trial information: NCT01313377.

MTE06.01 Radiotherapy Techniques in Lung Cancer

MTE06.01 Radiotherapy Techniques in Lung Cancer

Pressure RElieving Support SUrfaces: a Randomised Evaluation 2 (PRESSURE 2): study protocol for a randomised controlled trial.

BackgroundPressure ulcers represent a major burden to patients, carers and the healthcare system, affecting approximately 1 in 17 hospital and 1 in 20 community patients. They impact greatly on an individual’s functional status and health-related quality of life. The mainstay of pressure ulcer prevention practice is the provision of pressure redistribution support surfaces and patient repositioning. The aim of the PRESSURE 2 study is to compare the two main mattress types utilised within the NHS: high-specification foam and alternating pressure mattresses, in the prevention of pressure ulcers.Methods/DesignPRESSURE 2 is a multicentre, open-label, randomised, double triangular, group sequential, parallel group trial. A maximum of 2954 ‘high-risk’ patients with evidence of acute illness will be randomised on a 1:1 basis to receive either a high-specification foam mattress or alternating-pressure mattress in conjunction with an electric profiling bed frame. The primary objective of the trial is to compare mattresses in terms of the time to developing a new Category 2 or above pressure ulcer by 30 days post end of treatment phase. Secondary endpoints include time to developing new Category 1 and 3 or above pressure ulcers, time to healing of pre-existing Category 2 pressure ulcers, health-related quality of life, cost-effectiveness, incidence of mattress change and safety. Validation objectives are to determine the responsiveness of the Pressure Ulcer Quality of Life-Prevention instrument and the feasibility of having a blinded endpoint assessment using photography. The trial will have a maximum of three planned analyses with unequally spaced reviews at event-driven coherent cut-points. The futility boundaries are constructed as non-binding to allow a decision for stopping early to be overruled by the Data Monitoring and Ethics Committee.DiscussionThe double triangular, group sequential design of the PRESSURE 2 trial will provide an efficient design through the possibility of early stopping for demonstrating either superiority, inferiority of mattresses or futility of the trial. The trial optimises the potential for producing robust clinical evidence on the effectiveness of two commonly used mattresses in clinical practice earlier than in a conventional design.Trial registration ISRCTN01151335. Registered on 14 May 2013. Protocol version: 5.0, dated 25 September 2015Trial sponsor: Clare Skinner, Faculty Head of Research Support, University of Leeds, Leeds, LS2 9JT; 0113 343 4897; C.E.Skinner@leeds.ac.uk.

Interim evaluation of efficacy or futility in group-sequential trials with multiple co-primary endpoints.

We discuss group-sequential designs in superiority clinical trials with multiple co-primary endpoints, that is, when trials are designed to evaluate if the test intervention is superior to the control on all primary endpoints. We consider several decision-making frameworks for evaluating efficacy or futility, based on boundaries using group-sequential methodology. We incorporate the correlations among the endpoints into the calculations for futility boundaries and sample sizes as a function of other design parameters, including mean differences, the number of analyses, and efficacy boundaries. We investigate the operating characteristics of the proposed decision-making frameworks in terms of efficacy/futility boundaries, power, the Type I error rate, and sample sizes, while varying the number of analyses, the correlations among the endpoints, and the mean differences. We provide an example to illustrate the methods and discuss practical considerations when designing efficient group-sequential designs in clinical trials with co-primary endpoints.

Simultaneous sequential monitoring of efficacy and safety led to masking of effects

ObjectiveUsually, sequential designs for clinical trials are applied on the primary (=efficacy) outcome. In practice, other outcomes (e.g., safety) will also be monitored and influence the decision whether to stop a trial early. Implications of simultaneous monitoring on trial decision making are yet unclear. This study examines what happens to the type I error, power, and required sample sizes when one efficacy outcome and one correlated safety outcome are monitored simultaneously using sequential designs. Study Design and SettingWe conducted a simulation study in the framework of a two-arm parallel clinical trial. Interim analyses on two outcomes were performed independently and simultaneously on the same data sets using four sequential monitoring designs, including O'Brien-Fleming and Triangular Test boundaries. Simulations differed in values for correlations and true effect sizes. ResultsWhen an effect was present in both outcomes, competition was introduced, which decreased power (e.g., from 80% to 60%). Futility boundaries for the efficacy outcome reduced overall type I errors as well as power for the safety outcome. ConclusionMonitoring two correlated outcomes, given that both are essential for early trial termination, leads to masking of true effects. Careful consideration of scenarios must be taken into account when designing sequential trials. Simulation results can help guide trial design.

Initial results from ASSURE (E2805): Adjuvant sorafenib or sunitinib for unfavorable renal carcinoma, an ECOG-ACRIN-led, NCTN phase III trial.

403 Background: Patients (pts) with locally advanced renal cell carcinoma (RCC) are not uniformly cured by resection. The pursuit of tolerable and effective adjuvant therapies led to this investigation of two oral agents that are widely effective in the metastatic setting. Methods: 1,943 pts with completely resected RCC (pT1b high grade to pT4 any grade N any) were stratified on risk (intermediate-high or very high), clear/non-clear histology, ECOG PS, and resection approach, and randomized equally to sunitinib daily for 4 of 6 wk cycle, sorafenib daily, or placebo, then treated for up to 1 year. The primary endpoint was disease-free survival (DFS). The study was designed to detect a 25% reduction in the hazard rate, corresponding to an improvement from 5.8 to 7.7 years median DFS. After accrual of 1322 pts, the starting dose was reduced and then individually titrated to mitigate the effect of pt discontinuation from treatment intolerance. Results: At an interim analysis conducted with 62% information, although no efficacy or futility boundaries were crossed, the Data Safety Monitoring Committee recommended release of results. Using a stratified log-rank test, there were no significant differences in DFS or overall survival between either of the experimental arms and placebo. The redesign reduced the discontinuation rate on the experimental arms from about 26% in pts starting at full dose to about 14% in pts starting at reduced dose. Most common grade ≥3 adverse events were hypertension (16%/16%/4%), hand-foot reaction (15%/33%/1%), Rash (2%/15%/&lt;1%), and fatigue (17%/7%/3%) on sunitinib, sorafenib and placebo, respectively. (See Table.) Conclusions: In pts with locally advanced, resected RCC, adjuvant treatment with sorafenib or sunitinib should not be pursued. Dose titration reduced the treatment discontinuation rate; this finding may have relevance in other settings. Clinical trial information: NCT00326898. [Table: see text]

Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study

We aimed to compare overall survival after standard-dose versus high-dose conformal radiotherapy with concurrent chemotherapy and the addition of cetuximab to concurrent chemoradiation for patients with inoperable stage III non-small-cell lung cancer. In this open-label randomised, two-by-two factorial phase 3 study in 185 institutions in the USA and Canada, we enrolled patients (aged ≥ 18 years) with unresectable stage III non-small-cell lung cancer, a Zubrod performance status of 0-1, adequate pulmonary function, and no evidence of supraclavicular or contralateral hilar adenopathy. We randomly assigned (1:1:1:1) patients to receive either 60 Gy (standard dose), 74 Gy (high dose), 60 Gy plus cetuximab, or 74 Gy plus cetuximab. All patients also received concurrent chemotherapy with 45 mg/m(2) paclitaxel and carboplatin once a week (AUC 2); 2 weeks after chemoradiation, two cycles of consolidation chemotherapy separated by 3 weeks were given consisting of paclitaxel (200 mg/m(2)) and carboplatin (AUC 6). Randomisation was done with permuted block randomisation methods, stratified by radiotherapy technique, Zubrod performance status, use of PET during staging, and histology; treatment group assignments were not masked. Radiation dose was prescribed to the planning target volume and was given in 2 Gy daily fractions with either intensity-modulated radiation therapy or three-dimensional conformal radiation therapy. The use of four-dimensional CT and image-guided radiation therapy were encouraged but not necessary. For patients assigned to receive cetuximab, 400 mg/m(2) cetuximab was given on day 1 followed by weekly doses of 250 mg/m(2), and was continued through consolidation therapy. The primary endpoint was overall survival. All analyses were done by modified intention-to-treat. The study is registered with ClinicalTrials.gov, number NCT00533949. Between Nov 27, 2007, and Nov 22, 2011, 166 patients were randomly assigned to receive standard-dose chemoradiotherapy, 121 to high-dose chemoradiotherapy, 147 to standard-dose chemoradiotherapy and cetuximab, and 110 to high-dose chemoradiotherapy and cetuximab. Median follow-up for the radiotherapy comparison was 22.9 months (IQR 27.5-33.3). Median overall survival was 28.7 months (95% CI 24.1-36.9) for patients who received standard-dose radiotherapy and 20.3 months (17.7-25.0) for those who received high-dose radiotherapy (hazard ratio [HR] 1.38, 95% CI 1.09-1.76; p=0.004). Median follow-up for the cetuximab comparison was 21.3 months (IQR 23.5-29.8). Median overall survival in patients who received cetuximab was 25.0 months (95% CI 20.2-30.5) compared with 24.0 months (19.8-28.6) in those who did not (HR 1.07, 95% CI 0.84-1.35; p=0.29). Both the radiation-dose and cetuximab results crossed protocol-specified futility boundaries. We recorded no statistical differences in grade 3 or worse toxic effects between radiotherapy groups. By contrast, the use of cetuximab was associated with a higher rate of grade 3 or worse toxic effects (205 [86%] of 237 vs 160 [70%] of 228 patients; p<0.0001). There were more treatment-related deaths in the high-dose chemoradiotherapy and cetuximab groups (radiotherapy comparison: eight vs three patients; cetuximab comparison: ten vs five patients). There were no differences in severe pulmonary events between treatment groups. Severe oesophagitis was more common in patients who received high-dose chemoradiotherapy than in those who received standard-dose treatment (43 [21%] of 207 patients vs 16 [7%] of 217 patients; p<0.0001). 74 Gy radiation given in 2 Gy fractions with concurrent chemotherapy was not better than 60 Gy plus concurrent chemotherapy for patients with stage III non-small-cell lung cancer, and might be potentially harmful. Addition of cetuximab to concurrent chemoradiation and consolidation treatment provided no benefit in overall survival for these patients. National Cancer Institute and Bristol-Myers Squibb.

Exact sequential test of equivalence hypothesis based on bivariate non-central [formula omitted]-statistics

A critical step in group sequential designs is computation of the appropriate critical values for rejecting H0 at the interim look to keep the overall type I error rate at a prespecified level. When applying the sequential test in a study with an equivalence hypothesis, calculation of the critical values is complicated by the dependency between the dual test statistics at each interim look. Current methods for calculating critical values apply two primary approximations: z-statistics assuming a large sample size, and ignorance of the contribution to the overall type I error rate from rejecting one out of the two one-sided hypotheses under a null value. In the sequential testing, with smaller stagewise sample size and type I error rate, the first approximation would result in unsatisfactory inflation of the type I error rate, and the second approximation could lead to excessive conservatism. We establish a mathematical and computational framework of the exact sequential test based on bivariate non-central t statistics and propose several numerical approaches for computing the exact equivalence boundaries and futility boundaries. Examples and simulation studies are used to compare the operating characteristics between the exact test procedure and three other approximate test procedures.

Gset: An R Package for Exact Sequential Test of Equivalence Hypothesis Based on Bivariate Non-Central t-Statistics

The R package gset calculates equivalence and futility boundaries based on the exact bivariate non-central t test statistics. It is the first R package that targets specifically at the group sequential test of equivalence hypotheses. The exact test approach adopted by gset neither assumes the large-sample normality of the test statistics nor ignores the contribution to the overall Type I error rate from rejecting one out of the two one-sided hypotheses under a null value. The features of gset include: error spending functions, computation of equivalence boundaries and futility boundaries, either binding or nonbinding, depiction of stagewise boundary plots, and operating characteristics of a given group sequential design including empirical Type I error rate, empirical power, expected sample size, and probability of stopping at an interim look due to equivalence or futility.

A generalized Dunnett test for multi-arm multi-stage clinical studies with treatment selection

We generalize the Dunnett test to derive efficacy and futility boundaries for a flexible multi-arm multi-stage clinical trial for a normally distributed endpoint with known variance. We show that the boundaries control the familywise error rate in the strong sense. The method is applicable for any number of treatment arms, number of stages and number of patients per treatment per stage. It can be used for a wide variety of boundary types or rules derived from α-spending functions. Additionally, we show how sample size can be computed under a least favourable configuration power requirement and derive formulae for expected sample sizes.

Phase III trial of sunitinib (Su) versus sorafenib (So) in advanced hepatocellular carcinoma (HCC).

4000 Background: The oral multitargeted tyrosine kinase inhibitor Su had antitumor activity in phase II HCC trials, leading to a phase III open-label trial comparing the efficacy and safety of Su with So. Methods: Patients (pts) with advanced HCC, Child-Pugh A, ECOG PS 0/1 and no prior systemic chemotherapy were stratified by geographic region, prior TACE and tumor invasion. Pts were randomized 1:1 to Su 37.5 mg/day or So 400 mg BID. The primary endpoint was overall survival (OS; 1-sided log-rank test; α=0.025, 90% power) with 600 pts/arm required in this superiority/non-inferiority trial design. Secondary endpoints were progression-free survival (PFS), time to progression (TTP) and safety. Efficacy and futility boundaries were set using the Lan-DeMets and O’Brien–Fleming methods for interim analyses. Results: 1,073 pts were randomized (Su 529/So 544) from July 2008 to May 2010. An Independent Data Monitoring Committee stopped the trial early for futility and safety concerns. Pts were notified. Su discont...

Mortality Risk in Dialysis Patients with Naturally Higher Hemoglobins

Pioneering studies by Eshbach[1][1] demonstrated the effectiveness of treating the anemia of ESRD with erythropoietin-stimulating agents (ESAs). These results led to more aggressive treatment of anemia in an effort to improve quality of life and survival for dialysis and predialysis patients.

Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial

Observational data and non-human primate challenge studies suggest that cell-mediated immune responses might provide control of HIV replication. The Step Study directly assessed the efficacy of a cell-mediated immunity vaccine to protect against HIV-1 infection or change in early plasma HIV-1 levels. We undertook a double-blind, phase II, test-of-concept study at 34 sites in North America, the Caribbean, South America, and Australia. We randomly assigned 3000 HIV-1-seronegative participants by computer-generated assignments to receive three injections of MRKAd5 HIV-1 gag/pol/nef vaccine (n=1494) or placebo (n=1506). Randomisation was prestratified by sex, adenovirus type 5 (Ad5) antibody titre at baseline, and study site. Primary objective was a reduction in HIV-1 acquisition rates (tested every 6 months) or a decrease in HIV-1 viral-load setpoint (early plasma HIV-1 RNA measured 3 months after HIV-1 diagnosis). Analyses were per protocol and modified intention to treat. The study was stopped early because it unexpectedly met the prespecified futility boundaries at the first interim analysis. This study is registered with ClinicalTrials.gov, number NCT00095576. In a prespecified interim analysis in participants with baseline Ad5 antibody titre 200 or less, 24 (3%) of 741 vaccine recipients became HIV-1 infected versus 21 (3%) of 762 placebo recipients (hazard ratio [HR] 1.2 [95% CI 0.6-2.2]). All but one infection occurred in men. The corresponding geometric mean plasma HIV-1 RNA was comparable in infected male vaccine and placebo recipients (4.61 vs 4.41 log(10) copies per mL, one tailed p value for potential benefit 0.66). The vaccine elicited interferon-gamma ELISPOT responses in 75% (267) of the 25% random sample of all vaccine recipients (including both low and high Ad5 antibody titres) on whose specimens this testing was done (n=354). In exploratory analyses of all study volunteers, irrespective of baseline Ad5 antibody titre, the HR of HIV-1 infection between vaccine and placebo recipients was higher in Ad5 seropositive men (HR 2.3 [95% CI 1.2-4.3]) and uncircumcised men (3.8 [1.5-9.3]), but was not increased in Ad5 seronegative (1.0 [0.5-1.9]) or circumcised (1.0 [0.6-1.7]) men. This cell-mediated immunity vaccine did not prevent HIV-1 infection or reduce early viral level. Mechanisms for insufficient efficacy of the vaccine and the increased HIV-1 infection rates in subgroups of vaccine recipients are being explored.