Choice of futility boundaries for group sequential designs with two endpoints

Background: In 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. Methods: In 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. Results: By 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. Conclusions: As 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

Vascular Impulse Technology versus elevation in the treatment of posttraumatic swelling of extremity fractures: study protocol for a randomized controlled trial

Background: Fractures of the extremities are often complicated by a variable degree of swelling secondary to hemorrhage and soft tissue injury. Patients typically require up to 7 days of inpatient bed rest and elevation to reduce swelling to an acceptable level for operative treatment with internal fixation. Alternatively, an intermittent pneumatic compression device, such as the Vascular Impulse Technology (VIT) system, can be used at the injured extremity to reduce the posttraumatic swelling. The VIT system consists of a pneumatic compressor that intermittently rapidly inflates a bladder positioned under the arch of the hand or the foot, which results in compression of the venous hand or foot plexus. That intermittent compression induces an increased venous velocity and aims to reduce the soft tissue swelling of the affected extremity. Methods/design: The VIT study is a prospective, monocenter, randomized controlled trial to compare the VIT system with elevation in the treatment of posttraumatic swelling in the case of a fracture of the upper and lower extremity. This study will include 280 patients with fractures of the upper and the lower extremity with nine different injury types. For each of the nine injury types a separate randomization to the two intervention groups (VIT group or control group) will be performed. The primary outcome parameter is the time taken for the swelling to resolve sufficiently to permit surgery. A separate analysis for each of the nine injury types will be performed. Discussion: In the proposed study, the effectiveness of the VIT system in the treatment of posttraumatic swelling of upper and lower extremity fractures will be evaluated. Trial registration: German Clinical Trial Register, No. DRKS00010510. Registered on 17 July 2016

Development and validation of a novel questionnaire for self-determination of the range of motion of wrist and elbow

Background: The aim of this study was to develop and validate a novel self-administered questionnaire for assessing the patient’s own range of motion (ROM) of the wrist and the elbow. Methods: In a prospective clinical study from January 2015 to June 2015, 101 consecutive patients were evaluated with a novel, self-administered, diagram-based, wrist motion assessment score (W-MAS) and elbow motion assessment score (E-MAS). The questionnaire was statistically evaluated for test-retest reliability, patient-physician agreement, comparison with healthy population, and influence of covariates (age, gender, affected side and involvement in workers’ compensation cases). Results: Assessment of patient-physician agreement demonstrated almost perfect agreement (k > 0.80) with regard to six out of eight items. There was substantial agreement with regard to two items: elbow extension (k = 0.76) and pronation (k = 0.75). The assessment of the test-retest reliability revealed at least substantial agreement (k = 0.70). The questionnaire revealed a high discriminative power when comparing the healthy population with the study group (p = 0.007 or lower for every item). Age, gender, affected side and involvement in workers’ compensation cases did not in general significantly influence the patient-physician agreement for the questionnaire. Conclusion: The W-MAS and E-MAS are valid and reliable self-administered questionnaires that provide a high level of patient-physician agreement for the assessments of wrist and elbow ROM. Level of evidence: Diagnostic study, Level I

Interobserver and intraobserver agreement of ligamentous injuries on conventional MRI after simple elbow dislocation

Background: The primary objective of this study was to assess the interobserver and intraobserver agreement on ligamentous injuries on conventional magnetic resonance imaging (MRI) in acute simple elbow dislocation. The secondary objectives were to determine the interobserver agreement on the assessment of joint congruity, joint effusion, loose bodies and chondral lesions on conventional MRI. Methods: Conventional MRIs (1.5 Tesla, elbow specific surface coil) of 30 patients (40.7 years; range 14–72) with simple elbow dislocations were evaluated by four blinded examiners. An analysis of the interobserver agreement of all raters and for several subgroups (radiologists, orthopaedics, experienced, non-experienced) was performed. The examiners assessed the integrity (intact, partial tear, complete tear) of the lateral collateral ligament (LCL), medial collateral ligament (MCL), extensor and flexor tendons, as well as the presence of joint congruity, joint effusion, loose bodies and chondral lesions. Agreement strength, correlation and proportion of exact agreement were determined for interobserver agreement, and intraobserver agreement analyses. Results: Interobserver agreement of all examiners was fair to moderate for collateral ligaments (LCL: 0.441, MCL: 0.275). Exact agreement of all raters was found in 33.3% for the LCL and in 26.7% for the MCL. The both experienced examiners showed highest agreement strength for the LCL (0.619) and the radiologists showed highest agreement strength for the MCL (0.627), the proportion of exact agreement was 60.0% in both categories. A high proportion of exact agreement regarding joint congruity (90%), joint effusion (100%), loose bodies (96.7%) and chondral lesion (80%) was found among the radiologists. The evaluation of the intraobserver agreement revealed slight to substantial agreement (0.227 to 0.718) for the collateral ligaments. Conclusions: This study shows difficulties in the evaluation of ligaments by conventional MRI technique as demonstrated by a weak inter- and intraobserver agreement. This should be the basis to develop new MRI quality standards with special focus on coronal oblique reconstructions to improve the evaluation of ligament injuries after simple elbow dislocations

Adverse Events Following International Normalized Ratio Reversal in Intracerebral Hemorrhage

Background: Prothrombin complex concentrates (PCCs) are frequently used to reverse the effect of vitamin Kantagonists (VKAs) in patients with non-traumatic intracerebral hemorrhage (ICH). However, information on the rate of thromboembolic events (TEs) and allergic events after PCC therapy in VKA-ICH patients is limited. Methods: Consecutive VKA-ICH patients treated with PCC at our institution between December 2004 and June 2014 were included into this retrospective observational study. We recorded international normalized ratio (INR) values before and after PCC treatment, baseline clinical characteristics including the premorbid modified Rankin Scale (pmRS) score, TE and allergic event that occurred during the hospital stay. All events were classified by 3 reviewers as being ‘related’, ‘probably related’, ‘possibly related’, ‘unlikely related’ or ‘not related’ to treatment with PCC. To identify factors associated with TEs, logrank analyses were applied. Results: Two hundred and five patients were included. Median INR was 2.8 (interquartile range (IQR) 2.2–3.8) before and 1.3 (IQR 1.2–1.4) after PCC treatment and a median of 1,500 IU PCC (IQR 1,000–2,500) was administered. Nineteen TEs were observed (9.3%); none were classified ‘related’ but 9 were classified as ‘possibly’ or ‘probably related’ to PCC infusion (4.4%). One allergic reaction (0.5%), ‘unlikely related’ to PCC, was observed. In the whole cohort, PCC doses >2,000–3,000 IU, ICH volumes >40 ml, National Institute of Health Stroke Scale values >10 and a pmRS >2 were associated with the development of TEs (p = 0.031, p = 0.034, p = 0.050 and p = 0.036, respectively). Conclusions: Overall, INR reversal with PCC appears safe. Though no clear relationship between higher PCC dosing and TEs was observed, PCC doses between >2,000 and 3,000 IU and higher morbidity at ICH onset were associated with TEs. Hence, individual titration of PCC to avoid exposure to unnecessarily high doses using point-of-care devices should be prospectively explored

Medienkompetenz und selbstorganisiertes Lernen – Ergebnisse einer Evaluation

Dieser Beitrag beschreibt Erkenntnisse bezüglich studentischer Medienkompetenz und selbstorganisiertem Lernen auf Basis einer qualitativen Evaluation an der Fachhochschule Osnabrück. Gegenstand der Untersuchung war ein medial gestütztes Vorlesungskonzept, das Vorlesungsaufzeichnungen, Coaching-Sitzungen, Online-Tests und Praktika als integrale Bestandteile einer Lehrveranstaltung kombiniert. Die Vorlesungsaufzeichnungen ersetzen dabei die bisherige, klassische Frontalvorlesung. Die Ergebnisse der Analyse bestätigen, dass die durch das Konzept eingeräumten Freiheitsgrade sowie das damit verbundene, geförderte selbstorganisierte Lernen auf Seiten der Studierenden auf Akzeptanz stoßen. Gleichzeitig wurde aber belegt, dass Selbstlern- und Medienkompetenz bei vielen Studierenden nicht vorausgesetzt werden kann. Dieses Spannungsfeld wird anhand der Evaluationsergebnisse kritisch reflektiert. (DIPF/ Orig.

Planning and analyzing clinical trials with composite endpoints

This book addresses the most important aspects of how to plan and evaluate clinical trials with a composite primary endpoint to guarantee a clinically meaningful and valid interpretation of the results. Composite endpoints are often used as primary efficacy variables for clinical trials, particularly in the fields of oncology and cardiology. These endpoints combine several variables of interest within a single composite measure, and as a result, all variables that are of major clinical relevance can be considered in the primary analysis without the need to adjust for multiplicity. Moreover, composite endpoints are intended to increase the size of the expected effects thus making clinical trials more powerful. The book offers practical advice for statisticians and medical experts involved in the planning and analysis of clinical trials. For readers who are mainly interested in the application of the methods, all the approaches are illustrated with real-world clinical trial examples, and the software codes required for fast and easy implementation are provided. The book also discusses all the methods in the context of relevant guidelines related to the topic. To benefit most from the book, readers should be familiar with the principles of clinical trials and basic statistical methods

Adaptive Designs for Two Candidate Primary Time-to-Event Endpoints

<p>In clinical trials, the choice of an adequate primary endpoint is often difficult. Besides its clinical relevance, the endpoint must be measurable within reasonable time and must allow differentiating between the treatments. Often, the most relevant endpoint is ‘’time-to-death,” but if the overall survival prognosis is good, only a few deaths are observed during the study duration. A possible solution is to use surrogate endpoints instead. However, various examples from the literature demonstrate that surrogates do not always perform as intended. Sometimes, the surrogate effect is smaller than for the original endpoint, or the latter shows a higher effect than anticipated so using the surrogate is not reasonable. In this work, different adaptive design strategies for two candidate endpoints are proposed to solve these problems. The idea is to base the efficacy proof on the significance of at least one endpoint. At an interim analysis, both candidates are evaluated. If it is not possible to stop the study early, the sample size is recalculated based on the more promising endpoint. The new methods are illustrated by a clinical study example and compared in terms of power and sample size using Monte Carlo simulations. The software code is provided as supplementary material.</p