Clinical trials with interim analyses: standardizing terminology to increase clarity.

Interim analyses for group-sequential decision-making are prevalent in clinical trials. Methodology is well established and has been routinely implemented over the last decades. Still, confusions and uncertainties on aspects of how to operationalize and interpret interim analyses exist for many stakeholders.

Two-stage group-sequential designs with delayed responses - what is the point of applying corresponding methods?

Background: In group-sequential designs, it is typically assumed that there is no time gap between patient enrollment and outcome measurement in clinical trials. However, in practice, there is usually a lag between the two time points. This can affect the statistical analysis of the data, especially in trials with interim analyses.

Efficient Adaptive Designs for Clinical Trials of Interventions for COVID-19.

The COVID-19 pandemic has led to an unprecedented response in terms of clinical research activity. An important part of this research has been focused on randomized controlled clinical trials to evaluate potential therapies for COVID-19. The results from this research need to be obtained as rapidly as possible.

Nested combination tests with a time-to-event endpoint using a short-term endpoint for design adaptations.

Adaptive trial methodology for multiarmed trials and enrichment designs has been extensively discussed in the past. A general principle to construct test procedures that control the family-wise Type I error rate in the strong sense is based on combination tests within a closed test. Using survival data, a problem arises when using information of patients for adaptive decision making, which are under risk at interim.

Recent advances in methodology for clinical trials in small populations: the InSPiRe project.

Where there are a limited number of patients, such as in a rare disease, clinical trials in these small populations present several challenges, including statistical issues. This led to an EU FP7 call for proposals in 2013. One of the three projects funded was the Innovative Methodology for Small Populations Research (InSPiRe) project.

Robustness of testing procedures for confirmatory subpopulation analyses based on a continuous biomarker.

With the advent of personalized medicine, clinical trials studying treatment effects in subpopulations are receiving increasing attention. The objectives of such studies are, besides demonstrating a treatment effect in the overall population, to identify subpopulations, based on biomarkers, where the treatment has a beneficial effect. Continuous biomarkers are often dichotomized using a threshold to define two subpopulations with low and high biomarker levels.

Twenty-five years of confirmatory adaptive designs: opportunities and pitfalls.

'Multistage testing with adaptive designs' was the title of an article by Peter Bauer that appeared 1989 in the German journal Biometrie und Informatik in Medizin und Biologie. The journal does not exist anymore but the methodology found widespread interest in the scientific community over the past 25 years. The use of such multistage adaptive designs raised many controversial discussions from the beginning on, especially after the publication by Bauer and Köhne 1994 in Biometrics: Broad enthusiasm about potential applications of such designs faced critical positions regarding their statistical efficiency.

Designing Issues in Confirmatory Adaptive Population Enrichment Trials.

Adaptive population enrichment designs enable the data-driven selection of one or more pre-specified subpopulations in an interim analysis, and the confirmatory proof of efficacy in the selected subset at the end of the trial. Sample size reassessment and other adaptive design changes can be performed as well. Strong control of the experimentwise Type I error rate is guaranteed by use of the combination testing principle together with the closed testing argument.

Continuous infusion of clonidine in ventilated newborns and infants: a randomized controlled trial.

Objectives: To assess the influence of an infusion of clonidine 1 μg/kg/hr on fentanyl and midazolam requirement in ventilated newborns and infants.

Design: Prospective, double-blind, randomized controlled multicenter trial. Controlled trials.

Preoperative statin therapy for patients undergoing cardiac surgery.

Background: Patients referred to cardiac surgery for cardiovascular disease are at significant risk for the development of post-operative major adverse events despite significant advances in surgical techniques and perioperative care. Statins (HMG-CoA reductase inhibitors) have gained a pivotal role in the primary and secondary prevention of coronary artery disease, and are thought to improve perioperative outcomes in patients undergoing cardiac surgery.

Objectives: To determine the effectiveness of a preoperative statin therapy in patients undergoing cardiac surgery.

Efficacy and safety of moxifloxacin as antibacterial prophylaxis for patients receiving autologous haematopoietic stem cell transplantation: a randomised trial.

Patients receiving high-dose chemotherapy with autologous peripheral blood stem cell transplantation (PBSCT) are at high risk of infections, especially bacteraemia. A prospective, double-blind, randomised, placebo-controlled, single-centre, pilot study was performed on oral moxifloxacin 400mg versus placebo for preventing bacteraemia in PBSCT recipients. Patients received moxifloxacin or placebo for the duration of neutropenia or until emergence of fever or other infections necessitating intravenous antibiotic treatment.

On sample size determination in multi-armed confirmatory adaptive designs.

An important application of confirmatory adaptive designs is the data-driven selection of treatment arms in multi-armed trials. A general methodology for adaptive designs is based on the combination testing principle. Using this principle, selection of treatment arms in multi-armed designs, recalculation of sample size, and more general data-driven changes to the design are possible without undermining type I error control.

Comments on the draft guidance on "adaptive design clinical trials for drugs and biologics" of the U.S. Food and Drug Administration.

The U.S. FDA has published a draft guidance on "Adaptive Design Clinical Trials for Drugs and Biologics", which gives regulatory guidance on methodological issues in exploratory and confirmatory clinical trials planned with an adaptive design.

A strategy for encouraging young adults' adoption of a preferred oral hygiene technique.

Purpose: Adherence to dental preventive programmes in young adults is low. The aim of the present longitudinal study was to evaluate whether tutoring peers can be a compliance-enhancing tool or not.

Methods: In Part 1, two randomly selected classes (49 female students, mean age 19.

Interventional therapy of bifurcation lesions: a TIMI flow-guided concept to treat side branches in bifurcation lesions--a prospective randomized clinical study (Thueringer bifurcation study, THUEBIS study as pilot trial).

Background: Treatment of bifurcations is a complex problem. The clinical value of treating side branches is an unsolved problem in the field of interventional cardiology.

Methods And Results: We initiated a prospective randomized controlled trial.

Voriconazole serum concentrations in prophylactically treated acute myelogenous leukaemia patients.

Antifungal prophylaxis during first remission induction chemotherapy for acute myelogenous leukaemia requires broad spectrum azoles. In a clinical trial, therapeutic drug monitoring (TDM) of antifungal prophylaxis with voriconazole 200 mg bid was evaluated in a population of six patients. High pressure liquid chromatography was applied.

Statins for prevention of atrial fibrillation after cardiac surgery: a systematic literature review.

Objective: To determine the strength of evidence of preoperative statin therapy for prevention of atrial fibrillation after cardiac surgery.

Methods: A meta-analysis was performed of randomized controlled trials and observational trials reporting the impact of preoperative statin therapy on the incidence of any type and new-onset atrial fibrillation after cardiac surgery. Unadjusted and adjusted treatment effects (odds ratio, 95% confidence intervals) were pooled using a random-effects model, and publication bias was assessed.

Dental caries experience of schoolchildren of two different oral health care delivery systems.

Objectives: To report on the dental caries experience in schoolchildren from a region with a needs-based dental service compared with a region with a demand-led dental service.

Design: Cross-sectional study with clustered sampling.

Setting: Urban primary schools in Dublin (Ireland) and Freiburg (Germany).

Inefficacy of different strategies to improve guideline awareness - 5-year follow-up of the hypertension evaluation project (HEP).

Background: In spite of numerous guidelines for evidence based diagnostic and therapy adequate knowledge of current recommendations is disappointingly low. In the Hypertension Evaluation Project (HEP I) we showed that awareness of national hypertension guidelines under German practitioners was less than 25% in the year 2000. This indicates the need for efficient strategies to relevantly improve guideline awareness.

Impact of preoperative statin therapy on adverse postoperative outcomes in patients undergoing cardiac surgery: a meta-analysis of over 30,000 patients.

Aims: To determine the strength of evidence for preoperative statin use for prevention of adverse postoperative outcomes in patients undergoing cardiac surgery.

Methods And Results: After literature search in major databases, 19 studies were identified [three RCT (randomized prospective clinical trials), 16 observational] that reported outcomes of 31 725 cardiac surgery patients with (n = 17 201; 54%) or without (n = 14 524; 46%) preoperative statin therapy. Outcomes that were analysed included early all-cause mortality (30-day mortality), myocardial infarction (MI), atrial fibrillation (AF), stroke and renal failure.

A double-blind trial on prophylactic voriconazole (VRC) or placebo during induction chemotherapy for acute myelogenous leukaemia (AML).

Objectives: Invasive fungal infections remain a frequent cause of morbidity and mortality in long-term neutropenic patients. The availability of tolerable broad-spectrum antifungals like voriconazole stimulated the discussion about optimal timing of antifungal therapy. We conducted a trial to analyze the efficacy and safety of voriconazole in the prevention of lung infiltrates during induction chemotherapy for acute myelogenous leukaemia (AML).

A brief review on software developments for group sequential and adaptive designs.

In this paper the currently available software we know for group sequential and adaptive designs is briefly reviewed. Stand-alone packages as well as modules within software packages or programming languages exist. New software developments for adaptive designs enable the user to perform data dependent design adaptations while controlling the Type I error rate.

Planning and analyzing adaptive group sequential survival trials.

The use of adaptive methods has experienced increasing interest in the current literature on group sequential designs. Group sequential analysis in survival trials usually apply the error spending function approach due to the unpredictable amount of information available in an interim analysis. An alternative way is to apply adaptive methods where additionally the maximum amount of information and other designing parameters can be changed based on the information available at the interim stage.

Improved lipid profiles and maintenance of virologic control in heavily pretreated HIV-infected patients who switched from stavudine to tenofovir treatment.

A retrospective chart analysis of 66 human immunodeficiency virus type 1 (HIV-1)-infected patients whose treatment was switched from stavudine to tenofovir without any other treatment changes was conducted. The mean total cholesterol values decreased significantly within 3 months after the tenofovir substitution and remained significantly less than baseline values during 18 months of follow-up (mean decrease, 36 mg/dL; P = .002).