Idarucizumab for Dabigatran Reversal - Full Cohort Analysis.

BACKGROUND: Idarucizumab, a monoclonal antibody fragment, was developed to reverse the anticoagulant effect of dabigatran. METHODS: We performed a multicenter, prospective, open-label study to determine whether 5 g of intravenous idarucizumab would be able to reverse the anticoagulant effect of dabigatran in patients who had uncontrolled bleeding (group A) or were about to undergo an urgent procedure (group B). The primary end point was the maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours after the administration of idarucizumab, on the basis of the diluted thrombin time or ecarin clotting time. Secondary end points included the restoration of hemostasis and safety measures. RESULTS: A total of 503 patients were enrolled: 301 in group A, and 202 in group B. The median maximum percentage reversal of dabigatran was 100% (95% confidence interval, 100 to 100), on the basis of either the diluted thrombin time or the ecarin clotting time. In group A, 137 patients (45.5%) presented with gastrointestinal bleeding and 98 (32.6%) presented with intracranial hemorrhage; among the patients who could be assessed, the median time to the cessation of bleeding was 2.5 hours. In group B, the median time to the initiation of the intended procedure was 1.6 hours; periprocedural hemostasis was assessed as normal in 93.4% of the patients, mildly abnormal in 5.1%, and moderately abnormal in 1.5%. At 90 days, thrombotic events had occurred in 6.3% of the patients in group A and in 7.4% in group B, and the mortality rate was 18.8% and 18.9%, respectively. There were no serious adverse safety signals. CONCLUSIONS: In emergency situations, idarucizumab rapidly, durably, and safely reversed the anticoagulant effect of dabigatran. (Funded by Boehringer Ingelheim; RE-VERSE AD ClinicalTrials.gov number, NCT02104947 .)

Continued use of afatinib with the addition of cetuximab after progression on afatinib in patients with EGFR mutation-positive non-small-cell lung cancer and acquired resistance to gefitinib or erlotinib

Objectives: In a phase Ib trial, afatinib plus cetuximab demonstrated promising clinical activity (objective response rate [ORR]: 29%; median progression-free survival [PFS]: 4.7 months) in patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) with acquired resistance to erlotinib or gefitinib. Here, a separate cohort exploring afatinib plus cetuximab after progression on afatinib is reported. Materials and methods: Patients with EGFR mutation-positive NSCLC who progressed on erlotinib or gefitinib received afatinib 40 mg daily until progression, followed by afatinib daily plus cetuximab 500 mg/m(2) every 2 weeks until progression or intolerable adverse events (AEs). Endpoints included safety, ORR, and PFS. Results: Thirty-seven patients received afatinib monotherapy. Two (5%) patients responded; median PFS was 2.7 months. Thirty-six patients transitioned to afatinib plus cetuximab. Four (11%) patients responded; median PFS was 2.9 months. Median PFS with afatinib plus cetuximab for patients who received afatinib monotherapy for >= 12 versus <12 weeks was 4.9 versus 1.8 months (p = 0.0354), and for patients with T790M-positive versus T790M-negative tumors was 4.8 versus 1.8 months (p = 0.1306). Fifty percent of patients receiving afatinib plus cetuximab experienced drug-related grade 3/4 AEs. The most frequent drug-related AEs (any grade) were diarrhea (70%), rash (49%), and fatigue (35%) with afatinib monotherapy and rash (69%), paronychia (39%), and dry skin (36%) with afatinib plus cetuximab. Conclusion: Sequential EGFR blockade with afatinib followed by afatinib plus cetuximab had a predictable safety profile and demonstrated modest activity in patients with EGFR mutation-positive NSCLC with resistance to erlotinib or gefitinib

Solving Consistency Problems in Multiple Hypotheses Testing with Consonant Likelihood Ratio Test

In the past century, several multiple testing procedures have been developed based on the closure principle. Procedures following the closure principle are called closed test and they find individual tests for intersection hypotheses in the family and collates the results to control the familywise error rate. Almost all popular closed tests use the union-intersection method for their intersection hypotheses. However, due to computational issue, likelihood ratio test has not yet received much attention in closed testing. Moreover, not being a union-intersection method, the likelihood ratio test will not satisfy the logical consistency requirement of consonance.In this dissertation, a general solution (consonance adjustment) to the consistency problem in multiple hypotheses testing is proposed under the framework of closure principle and partitioning principle. Simulation examples are used to show its advantages.Besides a general framework, also provided in this dissertation is a special form of the consonant test in the context of multiple comparisons with a control. Using likelihood ratio test with the closure principle and a consonance adjustment step, the consonant closed likelihood ratio test is introduced. The rejection region, shortcut and steps in critical constants calculation are discussed. Extensive simulation studies and pre-clinical trial example are provided.More recently, testing for efficacy in multiple endpoints has emerged as a challenging statistical problem in clinical trials. Current approaches to this problem are based on closed testing or partition testing, which test the efficacy in certain dose-endpoint combinations and collate the results. Partition testing is in general a more powerful approach since it tests fewer hypotheses to avoid unnecessary power loss. However, all current approaches are still based on various union-intersection tests. In my dissertation, I generalize the decision path principle proposed by Liu and Hsu (2009) to the cases with multiple primary endpoints. Then propose a new partition testing approach based on consonance adjusted likelihood ratio test. The new procedure provides consistent inferences and yet it is still conservative and does not rely on the estimation of endpoint correlations or independence assumption which might be challenged by the regulatory agencies

Solving Consistency Problems in Multiple Hypotheses Testing with Consonant Likelihood Ratio Test

In the past century, several multiple testing procedures have been developed based on the closure principle. Procedures following the closure principle are called closed test and they find individual tests for intersection hypotheses in the family and collates the results to control the familywise error rate. Almost all popular closed tests use the union-intersection method for their intersection hypotheses. However, due to computational issue, likelihood ratio test has not yet received much attention in closed testing. Moreover, not being a union-intersection method, the likelihood ratio test will not satisfy the logical consistency requirement of consonance.In this dissertation, a general solution (consonance adjustment) to the consistency problem in multiple hypotheses testing is proposed under the framework of closure principle and partitioning principle. Simulation examples are used to show its advantages.Besides a general framework, also provided in this dissertation is a special form of the consonant test in the context of multiple comparisons with a control. Using likelihood ratio test with the closure principle and a consonance adjustment step, the consonant closed likelihood ratio test is introduced. The rejection region, shortcut and steps in critical constants calculation are discussed. Extensive simulation studies and pre-clinical trial example are provided.More recently, testing for efficacy in multiple endpoints has emerged as a challenging statistical problem in clinical trials. Current approaches to this problem are based on closed testing or partition testing, which test the efficacy in certain dose-endpoint combinations and collate the results. Partition testing is in general a more powerful approach since it tests fewer hypotheses to avoid unnecessary power loss. However, all current approaches are still based on various union-intersection tests. In my dissertation, I generalize the decision path principle proposed by Liu and Hsu (2009) to the cases with multiple primary endpoints. Then propose a new partition testing approach based on consonance adjusted likelihood ratio test. The new procedure provides consistent inferences and yet it is still conservative and does not rely on the estimation of endpoint correlations or independence assumption which might be challenged by the regulatory agencies

2015 ICSA/Graybill Applied Statistics Symposium

The papers in this volume represent a broad, applied swath of advanced contributions to the 2015 ICSA/Graybill Applied Statistics Symposium of the International Chinese Statistical Association, held at Colorado State University in Fort Collins. The contributions cover topics that range from statistical applications in business and finance to applications in clinical trials and biomarker analysis. Each papers was peer-reviewed by at least two referees and also by an editor. The conference was attended by over 400 participants from academia, industry, and government agencies around the world, including from North America, Asia, and Europe. Focuses on statistical applications from clinical trials, biomarker analysis, and personalized medicine to applications in finance and business analytics A unique selection of papers from broad and multi-disciplinary critical hot topics - from academic, government, and industry perspectives - to appeal to a wide variety of applied research interests All papers feature original, peer-reviewed content

Phase 3, single-arm, multicenter study of dabigatran etexilate for secondary prevention of venous thromboembolism in children: Rationale and design

Background: Anticoagulant therapy for venous thromboembolism (VTE) in children is largely based on treatment recommendations for adults. However, differences in both physiology (ie, renal maturation and drug excretion) and developmental hemostasis must be considered when treating children, as such differences could affect dose appropriateness, safety and efficacy. Objectives: To address these concerns, a study was designed to evaluate the safety of dabigatran etexilate in children requiring secondary thrombus prevention in whom an initial VTE was associated with an identified risk factor that persisted after the acute VTE treatment period. We report herein the rationale and design of the study. Patients/Methods: This phase 3, open-label, single-arm, multicenter, multinational, prospective cohort study will be conducted in ≥100 children aged 0 to <18 years at ~100 specialist sites worldwide. Children will be treated with dabigatran etexilate for 12 months, or for a shorter duration if their identified VTE risk factor resolves, as per current American College of Chest Physicians recommendations. A nomogram will be used to determine starting doses for each patient. Results: The primary outcomes of the study will be VTE recurrence, bleeding events, overall mortality, and VTE-related mortality. Secondary outcomes will include occurrence of post-thrombotic syndrome, the pharmacokinetics of dabigatran, and the need for dose adjustments during treatment. Data on adverse events during the study will also be collected. Conclusion: This study will evaluate the safety of dabigatran etexilate for the secondary prevention of VTE in children, in addition to providing further data to guide pediatric dosing with dabigatran