Single-stage, three-arm, adaptive test strategies for non-inferiority trials with an unstable reference.

For indications where only unstable reference treatments are available and use of placebo is ethically justified, three-arm "gold standard" designs with an experimental, reference and placebo arm are recommended for non-inferiority trials. In such designs, the demonstration of efficacy of the reference or experimental treatment is a requirement. They have the disadvantage that only little can be concluded from the trial if the reference fails to be efficacious. To overcome this, we investigate novel single-stage, adaptive test strategies where non-inferiority is tested only if the reference shows sufficient efficacy and otherwise δ $$ \delta $$ -superiority of the experimental treatment over placebo is tested. With a properly chosen superiority margin, δ $$ \delta $$ -superiority indirectly shows non-inferiority. We optimize the sample size for several decision rules and find that the natural, data driven test strategy, which tests non-inferiority if the reference's efficacy test is significant, leads to the smallest overall and placebo sample sizes. We proof that under specific constraints on the sample sizes, this procedure controls the family-wise error rate. All optimal sample sizes are found to meet this constraint. We finally show how to account for a relevant placebo drop-out rate in an efficient way and apply the new test strategy to a real life data set.

Simultaneous confidence intervals for ratios with application to the gold standard design with more than one experimental treatment.

Considering a study design with two experimental treatments, a reference treatment and a placebo, we extend a previous approach considering the ratios of effects to a procedure for analyzing multiple ratios. The technical framework for constructing tests and compatible simultaneous confidence intervals is set in a general manner. Besides a single step procedure and its extension to a stepdown procedure, also, an informative stepwise procedure in the spirit of our previous work is developed. The latter is especially interesting, because noninferiority studies require informative confidence intervals to infer more information than just noninferiority at the prespecified margin. Results from a simulation study for the three methods are shown. We also argue that an extension to more than two experimental treatments is straightforward.

Quality of life in persons with dementia using regional dementia care network services in Germany: a one-year follow-up study.

BACKGROUND: The majority of individuals with dementia live in the community; thus, regional dementia care networks are becoming increasingly more important for the provision of care. To date, four different types of dementia care networks have been identified in Germany (stakeholder, organisation, hybrid, mission); however, the effect on the quality of life of persons with dementia using such network services has not yet been examined. Moreover, the possible differences in the effect on the quality of life among the four types of dementia care networks have not been investigated. Therefore, the aim of the present study was to describe the changes over time in the quality of life of persons with dementia, assessing the association with the different types of dementia care networks. METHODS: Within the DemNet-D study, face-to-face interviews with persons with dementia and their primary caregivers were conducted to collect data of typical outcome parameters, such as quality of life (Quality of Life Alzheimers Disease: QoL-AD), sociodemographic data, social index (Scheuch-Winkler), depression (Geriatric Depression Scale: GDS), challenging behaviour (Cohen-Mansfield Agitation Inventory: CMAI), capacities of daily living (Instrumental Activity of Daily Living: IADL), impairment due to dementia (FAST), and caregiver burden. In addition to these parameters, the differences in quality of life scores among the four types of dementia care networks were analysed using multi-level analysis. RESULTS: In total, 407 persons with dementia (79.1 years; 60.1% female) and their caregivers were included in the analysis. Over 75% of the persons with dementia showed moderate to (very) severe impairments of dementia and at least one challenging behaviour. At baseline, 60.6% had a low social index. Quality of life was stable over one-year on a level slightly above average (baseline 29.1; follow-up 28.7). Multi-level analyses (p <  0.001; R2 = 0.183) show that persons with dementia with higher QoL-AD scores at baseline were associated with a decline at follow-up. No significant differences among the types of dementia care networks were found. CONCLUSION: Users of dementia care network services showed a stable QoL-AD score over time at a level slightly above average, indicating no decrease or worsening over time as expected. Therefore, dementia care network services can be considered as a beneficial model of care in terms of the quality of life of persons with dementia, regardless of their special organisational type.

Caregiver burden assessed in dementia care networks in Germany: findings from the DemNet-D study baseline.

OBJECTIVES: This paper aimed to describe the burden experienced by informal caregivers supporting a person with dementia (PwD) who lives at home and utilizes a dementia care network (DCN), to investigate the factors that are associated with caregiver burden, and to identify possible differences in caregiver burden among different types of DCNs. METHOD: This study was part of a multi-center, interdisciplinary evaluation of DCNs in Germany (DemNet-D). Cross-sectional data were collected in face-to-face interviews with people with dementia (PwDs) and their caregivers, and 13 DCNs were represented. Standardized questionnaires were used to assess caregiver burden, challenging PwD behaviors, functional competence and caregiver health status. Based on qualitative data, four DCN governance types were used in a multivariate analysis of burden categories. RESULTS: There were 560 PwD-caregiver dyads enrolled in the study. Informal caregivers (n = 536) reported a low-to-moderate burden associated with PwD characteristics (instrumental activities of daily living, challenging behaviors) and caregiver characteristics (gender) as well as the relationship between the caregivers and PwDs. Women felt more burdened but also showed higher levels of personal development. No differences were observed among the different DCN governance types. CONCLUSIONS: DCNs might contribute toward moderate to low caregiver burden. Indicators of positive caregiving aspects can be used by DCNs to advance support structures for informal caregivers drawing upon interventions already established for other community settings. Particular interest should be paid to female and spousal caregivers who might be in in need of greater and/or different kinds of support.

[Regional Dementia Care Networks in Germany--results from the DemNet-D-Study regarding the quality of life of their users]. / Regionale Demenznetzwerke in Deutschland. Ergebnisse der DemNet-D-Studie zur Lebensqualität der Nutzer(innen).

BACKGROUND: Regional dementia care networks become more and more important in the care for community-dwelling persons with dementia (PwD). However, the quality of life of PwD, served by dementia care networks, has not been investigated yet. It also remains unclear if there are differences between urban and rural dementia care networks. This study therefore aims at investigating the quality of life of PwD using this care model, also regarding possible regional differences. METHODS: Within the DemNet-D-Study, PwD and their primary caregivers were interviewed using typical outcome parameters (quality of life: QoL-AD, depression: GDS, challenging behaviour: CMAI, capacities of daily living: IADL, caregiver burden: BIZA-D). In addition to these parameters, regional differences were analysed using multi-level-analysis. RESULTS: In total, 560 PwD (79.7 years; 57.0 % female) and their caregivers participated in the study. Both self- and proxy-rated quality of life is on a moderate level. The analysis shows a sufficient explanation of the quality of life. (self: p<0.001, R2=0.493; proxy: p<0.001, R2=0.406). Higher quality of life was found for PwD living together with their care givers and for those PwD with higher capacities of daily living. Regional (urban vs. rural) differences could not be found. CONCLUSION: The quality of life of community-dwelling PwD using regional dementia care networks is comparable to those in other studies of outpatient dementia care. Further investigation should be carried out regarding different types of dementia care networks.

Informative simultaneous confidence intervals for the fallback procedure.

The fallback procedure is an extension of the hierarchical test procedure relaxing the predefined hierarchical order. It can be applied for example in dose-finding studies. If interest is in extending the fallback procedure to simultaneous confidence intervals, one finds proposals in the literature, which have, however, the drawback that noninformative rejections may arise. A noninformative rejection means that the confidence interval of a rejected null hypothesis contains all parameters of the alternative and thus gives no useful information about the true value of the effect parameter. We present a modification of the fallback procedure with corresponding simultaneous confidence intervals that is informative in every case where a hypothesis is rejected. The main idea consists of splitting the level between the null hypotheses and a nested family of informative hypotheses constituting the alternative. The splitting weights depend continuously on the parameter. The new method is represented by a simple graph and can be easily implemented by an explicit algorithm. We give an example and compare our approach with an existing extension of the fallback procedure to simultaneous confidence intervals by simulations in the context of a dose-finding clinical trial. As a result, we see that the problem of noninformative rejections can be completely removed by the informative fallback procedure, while the involved power loss can be controlled by careful planning.

A new class of powerful and informative simultaneous confidence intervals.

Step-down tests uniformly improve single-step tests with regard to power and the average number of rejected hypotheses. However, when extended to simultaneous confidence intervals (SCIs), the resulting SCIs often provide no additional information to the sheer hypothesis test. We speak, in this case, of a non-informative rejection. Non-informative rejections are particularly problematic in clinical trials with multiple treatments, where an informative rejection is required to obtain useful estimates of the treatment effects. The extension of single-step tests to confidence intervals does not have this deficiency. As a consequence, step-down tests, when extended to SCIs, do not uniformly improve single-step tests with regard to informative rejections. To overcome this deficiency, we suggest the construction of a new class of simultaneous confidence intervals that uniformly improve the Bonferroni and Holm SCIs with regard to informative rejections. This can be achieved using a dual family of weighted Bonferroni tests, with the weights depending continuously on the parameter values. We provide a simple algorithm for these computations and show that the resulting lower confidence bounds have an attractive shrinkage property. The method is extended to union-intersection tests, such as the Dunnett procedure, and is investigated in a comparative simulation study. We further illustrate the utility of the method with an example from a real clinical trial in which two experimental treatments are compared with an active comparator with respect to non-inferiority and superiority.

Rapid geographical clustering of wound botulism in Germany after subcutaneous and intramuscular injection of heroin.

BACKGROUND: Wound infections due to Clostridium botulinum in Germany are rare and occur predominantly in heroin injectors, especially after subcutaneous or intramuscular injection of heroin ("skin popping"), which is contaminated with spores of C. botulinum. We report a rapid geographical clustering of cases in Germany in a region between Cologne, Bonn, and Aachen with wound botulism and consecutive systemic C. botulinum intoxication in intravenous drug users (IDUs) within 6 weeks in October and November 2005. PATIENTS: A group of 12 IDUs with wound botulism after "skin popping." RESULTS: Clinical data were available in 11 (92%) of 12 patients; in 7 (58%) of the 12 cases, there was cranial nerve involvement including mydriasis, diplopia, dysarthria, and dysphagia, followed by progressing symmetric and flaccid paralysis of proximal muscles of the neck, arms, trunk, and respiratory muscles. Mechanical respiratory support was necessary. Five of the IDUs were treated with antitoxin, but mechanical respiratory support could not be avoided. The mean ventilation duration was 27.4 days (range 6-77 days). In 4 patients (33%), mechanical ventilation could be avoided; two were treated with antitoxin. CONCLUSIONS: This report describes rapid geographical clustering of wound botulism with severe respiratory complications in IDUs after "skin popping," which has not previously been reported either in Germany or any other European country. Based on these observations and those in other European countries, we conclude that there is a trend towards "skin popping," suggesting a change in injection practices in IDUs. Secondly, we conclude that the total number of cases with wound botulism is likely to increase because "skin popping" is the main risk factor.

2-Deoxy-2-[18F]fluoro-D-glucose positron emission tomography in target volume definition for radiotherapy of patients with non-small-cell lung cancer.

PURPOSE: To discuss the potential contribution of 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography (FDG-PET) in radiotherapy planning for non-small-cell lung cancer (NSCLC) considering new concepts on target volume definition. PROCEDURES: Recent investigations on the topic are reviewed with regard to current concepts of target volume definition for NSCLC. RESULTS: As intrathoracic recurrence is the leading cause of death after primary radiotherapy of NSCLC, there is a need for improving local control by escalating treatment intensity to gross disease. The value of elective nodal irradiation (ENI), resembling prophylactic irradiation of macroscopically unaffected parts of the mediastinum, is being considered. CONCLUSION: As FDG-PET has been shown to enhance the diagnostic accuracy of computed tomography (CT), and to have a potentially high impact on the identification of malignant tissue, it should be implicated in prospective clinical trials on dose escalation and three-dimensional conformal radiotherapy, especially in those including a reduction of target volumes.