Assessment of Hazard Ratios in Oncology Clinical Trials Terminated Early for Superiority: A Systematic Review.

Importance: Group sequential designs allow potential early trial termination at the interim analysis, before study completion. Traditional maximum likelihood estimate is commonly used to quantify the treatment effect in group sequential design trials; however, in published clinical trials, a bias-adjusted estimator has rarely been reported. Objective: To emphasize the need for considering overestimation of treatment effect by applying 2 bias-adjusted estimators to previously published, early-terminated oncology clinical trials. Evidence Review: Trials published from 2013 to 2017 were identified by searching MEDLINE and Embase on February 23, 2018. This review was restricted to oncology clinical trials using group sequential designs with a single preplanned interim analysis as well as 2-arm randomized clinical trials that were subsequently stopped for efficacy reasons. Each article was independently reviewed by 3 biostatisticians during text screening, and differences in opinion were resolved by discussion. This report presents the unadjusted hazard ratio (HR) of an experimental arm to a reference arm and 2 bias-adjusted HRs calculated by using the conditional mean-adjusted estimator (CMAE) and weighted CMAE (WCMAE). Findings: In total, 198 abstracts were screened for eligibility, of which, 19 eligible clinical trials were identified as applicable to the bias-adjusted estimators. Unadjusted HRs ranged from 0.203 (95% CI, 0.150-0.276) to 0.71 (95% CI, 0.60-0.84), number of events at the interim analysis from 58 to 540, and information time from 48% to 82%. In each study, the HRs adjusted by CMAE and WCMAE were higher than the unadjusted HR. Bias-adjusted estimates in large trials (243 and 414 events at the interim analysis) were similar to the unadjusted HR. However, in small trials (eg, with 58 events at the interim analysis), bias-adjusted estimates were highly disparate from the unadjusted HR. In trials with large treatment effects (eg, HRs of 0.20 and 0.22), the difference between unadjusted and bias-adjusted HRs was small even though the number of events at the interim analysis was small; larger differences were observed when the unadjusted HR was greater than 0.5. Conclusions and Relevance: In this systematic review of oncology clinical trials that were stopped for efficacy at the interim analysis, relatively large differences were noted between the unadjusted and adjusted HRs when the number of events at the interim analysis was small or when the unadjusted HR was close to the boundaries. These findings suggest presenting the 2 bias-adjusted HRs along with the unadjusted HR in the data monitoring committee meeting.

Assessment of the Efficacy of ReoGo-J Robotic Training Against Other Rehabilitation Therapies for Upper-Limb Hemiplegia After Stroke: Protocol for a Randomized Controlled Trial.

Background: Stroke patients experience chronic hemiparesis in their upper extremities leaving negative effects on quality of life. Robotic therapy is one method to recover arm function, but its research is still in its infancy. Research questions of this study is to investigate how to maximize the benefit of robotic therapy using ReoGo-J for arm hemiplegia in chronic stroke patients. Methods: Design of this study is a multi-center parallel group trial following the prospective, randomized, open-label, blinded endpoint (PROBE) study model. Participants and setting will be 120 chronic stroke patients (over 6 months post-stroke) will be randomly allocated to three different rehabilitation protocols. In this study, the control group will receive 20 min of standard rehabilitation (conventional occupational therapy) and 40 min of self-training (i.e., sanding, placing and stretching). The robotic therapy group will receive 20 min of standard rehabilitation and 40 min of robotic therapy using ReoGo®-J device. The combined therapy group will receive 40 min of robotic therapy and 20 min of constraint-induced movement therapy (protocol to improve upper-limb use in ADL suggests). This study employs the Fugl-Meyer Assessment upper-limb score (primary outcome), other arm function measures and the Stroke Impact Scale score will be measured at baseline, 5 and 10 weeks of the treatment phase. In analysis of this study, we use the mixed effects model for repeated measures to compare changes in outcomes between groups at 5 and 10 Weeks. The registration number of this study is UMIN000022509. Conclusions: This study is a feasible, multi-site randomized controlled trial to examine our hypothesis that combined training protocol could maximize the benefit of robotic therapy and best effective therapeutic strategy for patients with upper-limb hemiparesis.

Bartlett-type corrections and bootstrap adjustments of likelihood-based inference methods for network meta-analysis.

In network meta-analyses that synthesize direct and indirect comparison evidence concerning multiple treatments, multivariate random effects models have been routinely used for addressing between-studies heterogeneities. Although their standard inference methods depend on large sample approximations (eg, restricted maximum likelihood estimation) for the number of trials synthesized, the numbers of trials are often moderate or small. In these situations, standard estimators cannot be expected to behave in accordance with asymptotic theory; in particular, confidence intervals cannot be assumed to exhibit their nominal coverage probabilities (also, the type I error probabilities of the corresponding tests cannot be retained). The invalidity issue may seriously influence the overall conclusions of network meta-analyses. In this article, we develop several improved inference methods for network meta-analyses to resolve these problems. We first introduce 2 efficient likelihood-based inference methods, the likelihood ratio test-based and efficient score test-based methods, in a general framework of network meta-analysis. Then, to improve the small-sample inferences, we developed improved higher-order asymptotic methods using Bartlett-type corrections and bootstrap adjustment methods. The proposed methods adopt Monte Carlo approaches using parametric bootstraps to effectively circumvent complicated analytical calculations of case-by-case analyses and to permit flexible application to various statistical models network meta-analyses. These methods can also be straightforwardly applied to multivariate meta-regression analyses and to tests for the evaluation of inconsistency. In numerical evaluations via simulations, the proposed methods generally performed well compared with the ordinary restricted maximum likelihood-based inference method. Applications to 2 network meta-analysis datasets are provided.

Fluctuations in routine blood count might signal severe immune-related adverse events in melanoma patients treated with nivolumab.

BACKGROUND: Although nivolumab significantly prolongs survival of metastatic melanoma, about 10% of patients experience severe, even fatal immune-related adverse events (irAEs). Biomarkers to predict irAEs are, therefore, of great interest. OBJECTIVE: We aimed to correlate changes in routine blood count parameters to the occurrence of serious irAEs (grade 3/4 [G3/4] or lung/gastrointestinal [lung/GI] irAEs) in patients with melanoma who were treated with nivolumab. METHODS: We retrospectively analyzed data from 101 patient with melanoma treated with nivolumab from 8 institutes in Japan. We used logistic regression analyses to investigate associations between severe irAEs and fluctuations in routine blood count parameters (total white blood cell [WBC] count, relative neutrophil, monocyte, lymphocyte, and eosinophil count) during the treatment. Receiver-operating characteristic curve was used to determine a cutoff value for the blood count parameters and area under the curve (AUC). RESULTS: Univariate analysis revealed that G3/4 irAEs were associated with increased total WBC count (P=0.034, cutoff value=+27%, AUC=0.68, odds ratio [OR]=1.58) and decreased relative lymphocyte count (RLC, P=0.042, cutoff value=-23%, AUC=0.65, OR=1.65). However, multivariate analysis showed that the same factors, increased WBC count (P=0.014, cutoff value=+59.1%, AUC=0.79, OR=6.04) and decreased RLC (P=0.012, cutoff value=-32.3%, AUC=0.81, OR=5.01) were independent factors associated with lung/GI irAEs. CONCLUSIONS: Our results suggest that increased WBC count and decreased RLC are associated with G3/4 and lung/GI irAEs. Our analysis was based on the data point at which irAE occurrence was noticed and, therefore, these factors are not predictive, however, they could be a "signal" of severe irAE occurrence in patients with melanoma treated with nivolumab.

Randomized study of granulocyte colony stimulating factor for childhood B-cell non-Hodgkin lymphoma: a report from the Japanese pediatric leukemia/lymphoma study group B-NHL03 study.

The objective of this study was to assess the impact of the primary prophylaxis of granulocyte colony-stimulating factor (G-CSF) in the management of childhood B-cell non-Hodgkin lymphoma (B-NHL). Patients with advanced-stage mature B-NHL were randomized to receive prophylactic G-CSF (G-CSF+) or not receive G-CSF (G-CSF-) based on protocols of the B-NHL03 study. The G-CSF group received 5 µg/kg/d Lenograstim from day 2 after each course of six chemotherapy courses. Fifty-eight patients were assessable, 29 G-CSF + and 29 G-CSF-. G-CSF + patients showed a positive impact on the meantime to neutrophil recovery and hospital stay. On the other hand, they had no impact in the incidences of febrile neutropenia, serious infections, stomatitis and total cost. Our study showed that administration of prophylactic G-CSF through all six chemotherapy courses for childhood B-NHL showed no clinical and economic benefits for the management of childhood B-NHL treatment.

Non-invasive assessment of functionally significant coronary stenoses through mathematical analysis of spectral ECG components.

OBJECTIVES: The aim of this study was to evaluate the accuracy of the Multifunction CardioGram (MCG) in detecting the presence of functionally significant coronary ischaemia. METHODS AND RESULTS: This prospective study evaluated the accuracy of the MCG, a new ECG analysis device used to diagnose ischaemic coronary artery disease (CAD). A consecutive 112 participants suspected to have CAD who were scheduled for elective coronary angiography (CAG) from October 2012 to December 2013 were examined. Their predictive values of relevant ischaemia were measured by MCG, standard ECG and Framingham Risk Score (FRS) and compared. Five levels of ischaemia based on CAG findings adjusted by fractional flow reserve (FFR) values and three levels of MCG score of high, borderline or low were used. The MCG (OR=2.67 (1.60 to 4.44), p<0.001) was the only test significantly associated with ischaemia level. The FFR values for individual MCG scores with low, borderline and high were 0.77 (0.70 to 0.86), 0.78 (0.71 to 0.82) and 0.69 (0.65 to 0.77), respectively, p=0.042. A high MCG score had a specificity of 90.4% (87.0% to 93.9%) in model 1 adjusted by FFR≤0.8 threshold and of 87.0% (83.2% to 90.8%) in model 2 adjusted by FFR≤0.75 threshold, and a negative predictive value of 82.5% (78.3% to 86.7%) in model 1 and of 83.8% (79.6% to 87.9%) in model 2 for the prediction of severe ischaemia. CONCLUSIONS: The MCG showed high specificity with a high negative predictive value, suggesting that the MCG could be used not only to identify functionally significant ischaemia but to reduce unnecessary CAGs. TRIAL REGISTRATION NUMBER: UMIN ID: 000009992.