Platform trials to overcome major shortcomings of traditional clinical trials in non-alcoholic steatohepatitis? Pros and cons.

Non-alcoholic fatty liver disease is a condition that affects 25% of the population. Non-alcoholic steatohepatitis (NASH) is a progressive form of the disease that can lead to severe complications such as cirrhosis and hepatocellular carcinoma. Despite its high prevalence, no drugs are currently approved for the treatment of NASH. The drug development pipeline in NASH is very active, yet most assets do not progress to phase III trials and those that do reach phase III often fail to achieve the endpoints necessary for approval by regulatory agencies. Amongst other reasons, the methodological and operational features of traditional clinical trials in NASH might impede optimal drug development. In this regard, platform trials might be an attractive complement or alternative to conventional clinical trials. Platform trials use a master protocol which enables evaluation of multiple investigational medicinal products concurrently or sequentially with a single, shared control arm. Through Bayesian interim analyses, these trials allow for early exit of drugs from the trial based on success or futility, while providing participants better chances of receiving active compounds through adaptive randomisation. Overall, platform trials represent an alternative for patients, pharmaceutical companies, and clinicians in the quest to accelerate the approval of pharmacologic treatments for NASH.

Hypothyroidism correlates with favourable survival prognosis in patients with brain metastatic cancer.

BACKGROUND: Several preclinical and epidemiologic studies have indicated tumour-promoting effects of thyroid hormones (THs). However, very limited knowledge exists on the prognostic impact of thyroid function in metastatic cancer. METHODS: We compiled a discovery cohort of 1692 patients with newly diagnosed brain metastases (BMs) of solid cancers treated at the Medical University of Vienna and an independent validation cohort of 191 patients with newly diagnosed BMs treated at the University Hospital Zurich. RESULTS: Hypothyroidism before diagnosis of cancer was evident in 133 of 1692 (7.9%) patients of the discovery, and in 18 of 191 (9.4%) patients of the validation cohort. In the discovery cohort, hypothyroidism was statistically significantly associated with favourable survival prognosis from diagnosis of cancer (31 vs. 21 months; p = 0.0026) and with survival prognosis from diagnosis of BMs (12 vs. 7 months; p = 0.0079). In multivariate analysis including the diagnosis-specific graded prognostic assessment score, primary tumour type and sex, hypothyroidism was an independent factor associated with survival after diagnosis of BMs (hazard ratio: 0.76; 95% confidence interval [CI]: (0.63; 0.91; p = 0.0034). In the validation cohort, the association of hypothyroidism and favourable survival prognosis from diagnosis of cancer (55 vs. 11 months; p = 0.00058), as well as from diagnosis of BMs (40 vs. 10 months; p = 0.0036) was confirmed. CONCLUSION: Pre-existing hypothyroidism was strongly and independently associated with prognosis in patients with newly diagnosed BMs, supporting the evidence from preclinical data that THs may indeed have a tumour-promoting effect. Further investigation of the underlying pathobiological mechanism and potential therapeutic implications are required.

Flexible alpha allocation strategies for confirmatory adaptive enrichment clinical trials with a prespecified subgroup.

Adaptive enrichment designs have recently received considerable attention as they have the potential to make drug development process for personalized medicine more efficient. Several statistical approaches have been proposed so far in the literature and the operating characteristics of these approaches are extensively investigated using simulation studies. In this paper, we improve on existing adaptive enrichment designs by assigning unequal weights to the significance levels associated with the hypotheses of the overall population and a prespecified subgroup. More specifically, we focus on the standard combination test, a modified combination test, the marginal combination test, and the partial conditional error rate approach and explore the operating characteristics of these approaches by a simulation study. We show that these approaches can lead to power gains, compared to existing approaches, if the weights are chosen carefully.

Sample Size Reassessment and Hypothesis Testing in Adaptive Survival Trials.

Mid-study design modifications are becoming increasingly accepted in confirmatory clinical trials, so long as appropriate methods are applied such that error rates are controlled. It is therefore unfortunate that the important case of time-to-event endpoints is not easily handled by the standard theory. We analyze current methods that allow design modifications to be based on the full interim data, i.e., not only the observed event times but also secondary endpoint and safety data from patients who are yet to have an event. We show that the final test statistic may ignore a substantial subset of the observed event times. An alternative test incorporating all event times is found, where a conservative assumption must be made in order to guarantee type I error control. We examine the power of this approach using the example of a clinical trial comparing two cancer therapies.

The distillation of "VISCI": towards a better identification of suicidal inmates.

The "Viennese Instrument for Suicidality in Correctional Institutions" (VISCI) presented here is based on the results of a large case-control study and on research on literature examining suicide prevention in general and in the prison population in particular. The aim of this study was to validate the properties of the VISCI to differentiate between suicides and nonsuicides. The sensitivity and specificity of the VISCI was tested in the files of 55 correctional suicides, and 110 controls. VISCI differentiated well between suicides and nonsuicides. The routine administration of the VISCI may help to direct the existing professional attention to inmates with the highest need.

IFN-gamma-enhanced allergen penetration across respiratory epithelium augments allergic inflammation.

BACKGROUND: Respiratory allergen contact is the critical event in the elicitation and boosting of allergen-specific immune responses, as well as in the induction of immediate and late inflammatory reactions. OBJECTIVE: We sought to investigate the influence of various factors of allergic inflammation on the integrity and barrier function of respiratory epithelium for allergens. METHODS: We cultured the human bronchial epithelial cell line 16HBE14o- in a transwell culture system as a surrogate of intact respiratory epithelium and used purified iodine 125-labeled recombinant major birch pollen allergen (rBet v 1) to study the extent, kinetics, and factors influencing transepithelial allergen penetration. RESULTS: Culture supernatants from activated allergen-specific T H 1 clones decreased transepithelial resistance. A screening of various factors (histamine, IFN-gamma, IL-1beta, IL-2, IL-3, IL-4, IL-5, IL-8, IL-12, and TNF-alpha) identified IFN-gamma as a potent factor capable of reducing epithelial barrier properties and enhancing transepithelial allergen penetration. Increased submucosal allergen concentrations caused by IFN-gamma-mediated reduction of epithelial barrier function provoked a more than 7-fold augmentation of histamine release from sensitized basophils. CONCLUSION: These results demonstrate that the T H 1 cell-derived cytokine IFN-gamma facilitates allergen penetration through the respiratory epithelium and thereby can aggravate allergic inflammation.

Fixation of femoral fractures in multiple-injury patients with combined chest and head injuries.

BACKGROUND: The purpose of the present paper was to study the effects of a femoral shaft fracture and its early stabilization on the morbidity, mortality, and outcome of multiple-injury patients with combined blunt head and chest trauma. The clinical course of patients was analysed using a prospectively gathered data base. METHODS: Out of 352 multitrauma patients, from September 1992 to June 2000, we identified 28 patients with combined blunt chest and head trauma (abbreviated injury scale >/= 2) and a femoral fracture as the study group. A total of 120 patients with combined chest and head trauma but without femoral fracture formed the control group. Parameters examined included injury severity, injury pattern, haemodynamics at admission, mortality, duration of ventilation, length of stay in intensive care unit, and outcome. RESULTS: There were no significant differences regarding the demographics and injury severity (injury severity score) between the two groups. No significant differences were found in terms of mortality, duration of ventilation\intensive care unit stay and outcome. Injury severity (P < 0.0001), age (P = 0.0153), and haemodynamics at admission (P = 0.0036) were shown to have a significant effect on mortality and outcome. Injury severity (P < 0.0001) and age (P = 0.017) had a significant effect on the duration of ventilation\intensive care unit stay. CONCLUSIONS: The present study suggests that a femoral shaft fracture and its early stabilization in a multitrauma patient with combined chest and head injury do not adversely affect mortality and outcome and supports aggressive surgical management for these patients.

Effects of a femoral shaft fracture on multiply injured patients with a head injury.

To study the effects of a femoral shaft fracture and its early stabilization on the morbidity, mortality, and outcome of patients with multiple injuries and a concomitant head injury, we analyzed the clinical course of patients using a prospectively gathered database. A series of 42 patients with multiple injuries, including head injuries and femoral fractures, formed the study group. A series of 133 patients with multiple injuries and head injuries but without femoral fractures formed the control group. The parameters examined included injury severity, injury pattern, hemodynamics at admission, mortality, duration of ventilation, length of intensive care unit (ICU) stay, and outcome. There were no significant differences regarding the demographics, injury severity score (ISS), injury pattern except the extremity Abbreviated Injury Scale (AIS) between the study and control groups. No significant differences were found in terms of mortality, duration of ventilation/ICU stay, and outcome. Injury severity (ISS), severity of the head injury (AIS), and hemodynamics at admission were shown to have a significant effect on the examined parameters. The present study suggests that a femoral fracture and its early stabilization in a multitrauma patient with a concomitant head injury do not adversely affect mortality and outcome and supports aggressive surgical management for these patients.