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. With the currently available testing procedures, either no testing of hypotheses in interim analyses is possible or there are restrictions on the interim data that can be used in the adaptation decisions as, essentially, only the interim test statistics of the primary endpoint may be used. We propose a general adaptive testing procedure, covering multiarmed and enrichment designs, which does not have these restrictions. An important application are clinical trials, where short-term surrogate endpoints are used as basis for trial adaptations, and we illustrate how such trials can be designed. We propose statistical models to assess the impact of effect sizes, the correlation structure between the short-term and the primary endpoint, the sample size, the timing of interim analyses, and the selection rule on the operating characteristics.

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. Despite, or possibly because of, this controversy, the methodology and its areas of applications grew steadily over the years, with significant contributions from statisticians working in academia, industry and agencies around the world. In the meantime, such type of adaptive designs have become the subject of two major regulatory guidance documents in the US and Europe and the field is still evolving. Developments are particularly noteworthy in the most important applications of adaptive designs, including sample size reassessment, treatment selection procedures, and population enrichment designs. In this article, we summarize the developments over the past 25 years from different perspectives. We provide a historical overview of the early days, review the key methodological concepts and summarize regulatory and industry perspectives on such designs. Then, we illustrate the application of adaptive designs with three case studies, including unblinded sample size reassessment, adaptive treatment selection, and adaptive endpoint selection. We also discuss the availability of software for evaluating and performing such designs. We conclude with a critical review of how expectations from the beginning were fulfilled, and - if not - discuss potential reasons why this did not happen.

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. In this paper the general methodology and designing issues when planning such a design are reviewed. It is shown how to derive overall confidence intervals and p-values. Criteria for assessing the operating characteristics of these designs are given, and the application is illustrated by examples.

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.com/ISRCTN77772144. SETTING: Twenty-eight level 3 German PICUs/neonatal ICUs. PATIENTS: Ventilated newborns and infants: stratum I (1-28 d), stratum II, (29-120 d), and stratum III (121 d to 2 yr). INTERVENTIONS: Patients received clonidine 1 µg/kg/hr or placebo on day 4 after intubation. Fentanyl and midazolam were adjusted to achieve a defined level of analgesia and sedation according to Hartwig score. MEASUREMENTS AND MAIN RESULTS: Two hundred nineteen infants were randomized; 212 received study medication, 69.7% were ventilated in the postoperative care and 30.3% for other reasons. Primary endpoint: consumption of fentanyl and midazolam in the 72 hours following the onset of study medication (main observation period) in the overall study population. The confirmatory analysis of the overall population showed no difference in the consumption of fentanyl and midazolam. Explorative age-stratified analysis demonstrated that in stratum I (n = 112) the clonidine group had a significantly lower consumption of fentanyl (clonidine: 2.1 ± 1.8 µg/kg/hr, placebo: 3.2 ± 3.1 µg/kg/hr; p = 0.032) and midazolam (clonidine: 113.0 ± 100.1 µg/kg/hr, placebo: 180.2 ± 204.0 µg/kg/hr; p = 0.030). Strata II (n = 43) and III (n = 46) showed no statistical difference. Sedation and withdrawal-scores were significantly lower in the clonidine group of stratum I (p < 0.001). Frequency of severe adverse events did not differ between groups. CONCLUSIONS: Clonidine 1 µg/kg/hr in ventilated newborns reduced fentanyl and midazolam demand with deeper levels of analgesia and sedation without substantial side effects. This was not demonstrated in older infants, possibly due to lower clonidine serum levels.

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. SEARCH METHODS: We searched CENTRAL (Issue 2 of 4, 2010 on The Cochrane Library), MEDLINE (1950 to May, Week 1 2010), EMBASE (1980 to 2010 Week 19), and the metaRegister of Controlled Trials. Additionally, ongoing trials were searched through the National Research Register, the ClinicalTrials.gov registry and grey literature. Conference indices from relevant scientific meetings (2006-2009) were screened online for eligible trials. No language restrictions were applied. SELECTION CRITERIA: All randomized controlled trials comparing any statin treatment before cardiac surgery, for any given duration and dose, to no preoperative statin therapy (standard of care) or placebo. DATA COLLECTION AND ANALYSIS: Two authors evaluated trial quality and extracted data from titles and abstracts identified from the electronic database searches according to pre-defined criteria. Accordingly, full text articles of potentially relevant studies that met the inclusion criteria were retrieved to assess definite eligibility for inclusion. Effect measures are reported as odds ratios (OR) or weighted mean difference (WMD) with 95% confidence intervals (95%-CI). MAIN RESULTS: Eleven randomized controlled studies including a total of 984 participants undergoing on- or off-pump cardiac surgical procedures were identified. Pooled analysis showed that statin pre-treatment before surgery reduced the incidence of post-operative atrial fibrillation (AF) (OR 0.40; 95%-CI: 0.29 to 0.55; p<0.01), but failed to influence short-term mortality (OR 0.98, 95%-CI: 0.14 to 7.10; p=0.98) or post-operative stroke (OR 0.70, 95%-CI: 0.14 to 3.63; p=0.67). In addition, statin therapy was associated with a shorter length of stay of patients on the intensive care unit (ICU) (WMD: -3.39 hours; 95%-CI: -5.77 to -1.01) and in-hospital (WMD: -0.48 days; 95%-CI: -0.85 to -0.11) where significant heterogeneity was observed. There was no reduction in myocardial infarction (OR 0.52; 95%-CI: 0.2. to 1.30) or renal failure (OR 0.41; 95%-CI: 0.15 to 1.12). These results were unaffected after subgroup analysis. No major or minor perioperative statin side-effects were reported from trials investigating this safety endpoint. AUTHORS' CONCLUSIONS: Preoperative statin therapy reduces the odds of post-operative AF and shortens the stay on the ICU and in the hospital. Statin pretreatment had no influence on perioperative mortality, stroke, myocardial infarction or renal failure. Since analysed studies included mainly patients undergoing myocardial revascularizations the results cannot be extrapolated to patients undergoing other cardiac procedures such as heart valve or aortic surgery.

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. In this paper we consider aspects related to the sample size determination for multi-armed designs. We assess sample size calculations that are based on ad hoc formulas such as the Bonferroni correction. An important aspect will be the choice of the control group sample size. We further consider the weighting scheme in the combination testing approach. Our assessment is restricted to two-stage designs. In general, simulation tools will be necessary to assess the statistical properties of these designs.

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. Trough levels were obtained 24 h after the last voriconazole dose. Median time of voriconazole exposure prior to sample acquisition was 16 days (range 9-21). The mean voriconazole concentration was 486 µg l(-1) and ranged from 136 µg l(-1) to 1257 µg l(-1). Among possible or probable treatment-related adverse events, elevated liver function tests were the most frequent. Five of six patients developed fever during neutropenia, but none of them developed pulmonary infiltrates or other signs of invasive fungal infection while on voriconazole prophylaxis. Future investigations might aim at identifying drug level thresholds that allow for minimum toxicity and optimum efficacy of antifungal prophylaxis.

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. This comment summarizes the discussion within the joint working group "Adaptive Designs and Multiple Testing Procedures" of the Austro-Swiss and German regions of the International Biometric Society held at the 90-day public comment period in spring 2010.

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 19.8 + or - 2.3 years) were taught adult toothbrushing technique (the modified Bass technique) in a project-like manner. After the course, knowledge was tested using a class test, and compliance was evaluated using anonymous quantitative questionnaires. Compliance was defined as a reported degree of change from the easy-to-learn childhood toothbrushing techniques to the more efficient and challenging Bass technique. In Part 2 of the present longitudinal study, the compliance of these students was re-evaluated after having developed and applied themselves a programme of how to tutor peers in oral health. Re-evaluation of compliance was performed after 3 and 9 months. RESULTS: In Part 1, 28.5% of the students were compliant after 1 week. Compared with Part 1, the compliance in Part 2 was significantly higher (P u 0.001), both after 3 months (90%) and after 9 months (82%). CONCLUSIONS: Tutoring peers can significantly enhance the compliance over a period of 9 months. Tutoring can function as a form of empowerment and can establish a strong sustained health engagement. Tutoring peers in health-related subjects can readily be implemented in schools and might be an additional means of oral health promotion with fewer additional costs.

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. This presents a number of challenges associated with considerable uncertainty over the natural history of the disease and the number and characteristics of patients affected, and the emergence of new potential therapies. These challenges make adaptive designs for clinical trials a particularly attractive option. Such designs allow a trial to be modified on the basis of interim analysis data or stopped as soon as sufficiently strong evidence has been observed to answer the research question, without compromising the trial's scientific validity or integrity. In this article, we describe some of the adaptive design approaches that are available and discuss particular issues and challenges associated with their use in the pandemic setting. Our discussion is illustrated by details of four ongoing COVID-19 trials that have used adaptive designs.

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. Odds ratio (OR) with 95% confidence intervals (95%CI) were reported using fixed or random effect models and publication bias was assessed. Preoperative statin therapy resulted in a 1.5% absolute risk reduction (2.2 vs. 3.7%; P < 0.0001) and 43% odds reduction for early all-cause mortality (OR 0.57; 95%CI: 0.49-0.67). A significant reduction (P < 0.01) in statin pretreated patients was also observed for AF (24.9 vs. 29.3%; OR 0.67, 95%CI: 0.51-0.88), stroke (2.1 vs. 2.9%, OR 0.74, 95%CI: 0.60-0.91), but not for MI (OR 1.11; 95%CI: 0.93-1.33) or renal failure (OR 0.78, 95%CI: 0.46-1.31). Funnel plot and Egger's regression analysis (P = 0.60) excluded relevant publication bias. CONCLUSION: Our meta-analysis provides evidence that preoperative statin therapy exerts substantial clinical benefit on early postoperative adverse outcomes in cardiac surgery patients, but underscores the need for RCT trials.

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). PARTICIPANTS: 12-year-old schoolchildren. METHOD: A trained and calibrated dentist examined a representative, random sample of schoolchildren under the same standardised conditions. Social class was recorded using the 'Goldthorpe-Social-Class-Schema'. Dental caries was recorded using WHO criteria. RESULTS: Atotal of 567 schoolchildren were examined, 332 in Ireland and 249 in Germany. For Ireland the mean DMFT in SC-1 (highest social class) was 0.28, in SC-2 (middle social class) it was 1.1 and in SC-3 (lowest social class) it was 0.94. For Germany the mean DMFT in SC-1 was 0.31, in SC-2 it was 0.61 and in SC-3 it was 1.33. CONCLUSIONS: This study demonstrated the existence of social gradients in dental caries levels in both samples but the magnitude of the difference varied across the two populations and appeared to be smaller in the needs-based dental service.

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. If there is insufficient information on the dependence structure of the outcome on the biomarker, several thresholds may be investigated. The nested structure of such subpopulations is similar to the structure in group sequential trials. Therefore, it has been proposed to use the corresponding critical boundaries to test such nested subpopulations. We show that for biomarkers with a prognostic effect that is not adjusted for in the statistical model, the variability of the outcome may vary across subpopulations which may lead to an inflation of the family-wise type 1 error rate. Using simulations we quantify the potential inflation of testing procedures based on group sequential designs. Furthermore, alternative hypotheses tests that control the family-wise type 1 error rate under minimal assumptions are proposed. The methodological approaches are illustrated by a trial in depression.

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. This paper summarizes the main results of the project, which was completed in 2017.The InSPiRe project has led to development of novel statistical methodology for clinical trials in small populations in four areas. We have explored new decision-making methods for small population clinical trials using a Bayesian decision-theoretic framework to compare costs with potential benefits, developed approaches for targeted treatment trials, enabling simultaneous identification of subgroups and confirmation of treatment effect for these patients, worked on early phase clinical trial design and on extrapolation from adult to pediatric studies, developing methods to enable use of pharmacokinetics and pharmacodynamics data, and also developed improved robust meta-analysis methods for a small number of trials to support the planning, analysis and interpretation of a trial as well as enabling extrapolation between patient groups. In addition to scientific publications, we have contributed to regulatory guidance and produced free software in order to facilitate implementation of the novel methods.

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). Regimens containing tenofovir provided effective control of HIV-1 infection, with stable CD4+ cell counts and continued suppression of plasma HIV-1 level following the treatment switch from stavudine.

Randomized comparison of mounted versus unmounted stents: the multicenter COMUS trial.

BACKGROUND: Although the use of premounted stents on a delivery balloon has almost completely eliminated the initially used hand-crimping procedure, no data are available that prove the superiority of one or the other approach on a randomized basis. Therefore, this study was designed to examine whether the use of premounted stents is comparable with the hand-crimping procedure. METHODS: A total of 123 patients (64 treated with unmounted stents, 59 treated with premounted stents) were examined in a multicenter, randomized, prospective study. There were no significant differences in patient characteristics between groups. RESULTS: Primary end points (acute, postinterventional [within 72 hours], and late complications related to the stenting procedure) were reached in 1 patient treated with an unmounted stent versus 2 patients with mounted stents (P = not significant). In patients with angiographic follow up (n = 84, mean follow-up period 6 +/- 1 months), the total rate of restenosis was 27% (unmounted 12, mounted 11, P = not significant). Secondary end points were procedural success of stenting and maximal balloon inflation pressure needed for optimal stenting results by use of angiography. There were no differences in secondary end points for both techniques. The mean balloon pressure was 12.56 +/- 2.1 atmospheres (unmounted) and 12.12 +/- 1.92 atmospheres (mounted, P = not significant). CONCLUSION: Stenting with premounted devices was demonstrated to have a similar clinical and angiographic outcome as the hand-crimping approach for maximal inflation pressure, procedural success, major cardiac events, and rate of restenosis after 6 months of follow up. Thus, the more convenient use of a premounted stent provides procedural safety and efficacy comparable with a hand-crimped system.

Efficacy of extract of Pelargonium sidoides in children with acute non-group A beta-hemolytic streptococcus tonsillopharyngitis: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Clinical trial data suggest that antibiotics are not indicated for the treatment of acute non-group A beta hemolytic strep (non-GABHS) tonsillopharyngitis. Nevertheless patients are symptomatic and effective alternatives for its treatment are needed that have been evaluated in clinical trials. OBJECTIVE: To confirm that treatment with an extract of Pelargonium sidoides (EPs 7630) is superior to placebo for the treatment of non-GABHS tonsillopharyngitis in children. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Six study sites in 4 pediatric and ENT primary care outpatient clinics. PATIENTS: One hundred forty-three children aged 6-10 years with non-GABHS tonsillopharyngitis present < or = 48 h, a negative rapid strep screen, a Tonsillopharyngitis Severity Score (TSS) > or = 8 points, and informed consent. INTERVENTION: EPs 7630 or placebo (20 drops tid) for 6 days. MEASUREMENT: The primary outcome criterion was the decrease of the TSS from baseline (day 0) to day 4. RESULTS: The decrease of the TSS from baseline (day 0) to day 4 was 7.1 +/- 2.1 points under EPs 7630 (n = 73), and 2.5 +/- 3.6 points under placebo (n = 70). The covariate adjusted decrease was 7.0 +/- 2.4 points under EPs 7630, and 2.9 +/- 2.4 points under placebo. The 95% RCI for the difference between the groups was [2.7; 4.9] demonstrating a significant difference in efficacy of EPs 7630 compared to placebo (P < 0.0001). Adverse events (AEs) occurred in 15/143 patients (EPs 7630: 4/73 patient, placebo: 44/70) and were not related to the investigational medication. CONCLUSIONS: EPs 7630 was superior compared to placebo for the treatment of acute non-GABHS tonsillopharyngitis in children. Treatment with EPs 7630 reduced the severity of symptoms and shortened the duration of illness by at least 2 days.

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. Of 68 patients included in the trial, 2 were excluded from the trial before taking their first dose. The remaining 66 patients were eligible for evaluation in the intention-to-treat analysis set. Neutropenia with an absolute neutrophil count of <500cells/µL developed in 30 moxifloxacin-treated patients (88.2%) and 21 patients in the placebo group (65.6%) (P<0.03). Nine patients (26.5%) and eight patients (25.0%), respectively, were prematurely discontinued from study treatment. Breakthrough bacteraemia occurred in 3 moxifloxacin-treated patients (8.8%) and 9 patients in the placebo group (28.1%) (P=0.042). The time period until fever was 9.5 days [95% confidence interval (CI) 8.06-10.94 days) and 7.69 days (95% CI 6.51-8.85 days), respectively (P=0.0499). There was no difference in adverse events or toxicities between the groups. Moxifloxacin prevented bacteraemia and shortened febrile episodes in patients receiving autologous PBSCT. No significant increase of adverse events in the moxifloxacin arm was observed, possibly due to the rather small sample size.