A phase I pharmacokinetics study of lapatinib and tamoxifen in metastatic breast cancer (EORTC 10053 Lapatam study)

ObjectiveThis phase I study assessed the pharmacokinetic (PK), tolerability, safety and preliminary clinical activity of tamoxifen (T) and lapatinib (L) in patients with metastatic breast cancer (MBC).MethodsPatients (pts) with hormone receptor positive MBC, irrespective of HER-2 status, were randomly assigned to T → T + L group, tamoxifen in cycle 1 for 28 days then adding lapatinib on day 1 of cycle 2; or L → T + L group, lapatinib in cycle 1 for 14 days, then adding tamoxifen on day 1 of cycle 2 to evaluate the potential drug–drug PK interaction at steady-state. The dose of tamoxifen was 20 mg/day and lapatinib 1500 mg/day.ResultsTwenty-five pts were enrolled of which 23 started treatment, five (22%) of them were HER-2 positive. Median age was 59 years and 96% had PS ≤1. Eleven (91.7%) pts in the T → T + L group and 10 (76.9%) in L → T + L group received at least 2 cycles of treatment. The most frequently reported drug-related adverse events (>25% of patients) were diarrhoea (62%), anaemia (56%), rash (52%), fatigue (52%), dermatology other (34%) and leukopenia (28%). Grade 3–4 drug-related toxicities were infrequent (<10%). No cardiotoxicity was observed. T plasma concentrations did not appeared to be affected by the presence of lapatinib. L steady-state plasma concentrations were 20% lower after 28 days of co-administration with T. Eight (36.4%) patients experienced stable disease and median progression free survival was 2.7 months.ConclusionsThe combination of L and T was safe and clinically active. T affected L plasma concentrations, which remained within the therapeutic index.     

Development of a transmission-blocking malaria vaccine: Progress,challenges, and the path forward

New interventions are needed to reduce morbidity and mortality associated with malaria, as well as to accelerate elimination and eventual eradication. Interventions that can break the cycle of parasite transmission, and prevent its reintroduction, will be of particular importance in achieving the eradication goal. In this regard, vaccines that interrupt malaria transmission (VIMT) have been highlighted as an important intervention, including transmission-blocking vaccines that prevent human-to-mosquito transmission by targeting the sexual, sporogonic, or mosquito stages of the parasite (SSM-VIMT). While the significant potential of this vaccine approach has been appreciated for decades, the development and licensure pathways for vaccines that target transmission and the incidence of infection, as opposed to prevention of clinical malaria disease, remain ill-defined. This article describes the progress made in critical areas since 2010, highlights key challenges that remain, and outlines important next steps to maximize the potential for SSM-VIMTs to contribute to the broader malaria elimination and eradication objectives.     

Summary of knowledge gaps related to quality and efficacy of current influenza vaccines

Influenza viruses are a public health threat, as they are pathogenic, highly transmissible and prone to genetic changes. For decades vaccination strategies have been based on trivalent inactivated vaccines, which are regulated by specific guidelines. The progress in scientific knowledge and the lessons learned from the A(H1N1)2009 pandemic have highlighted further the need to improve current guidelines, including the immunogenicity criteria set by the CHMP in 1997, and to promote the discussion on the shortcomings encountered, e.g. the evaluation of vaccine efficacy in the paediatric and elderly populations, the measurement of the naivety of a population, the impact of prior immunity on subsequent vaccinations, and the technical issues with the serological assays for detection of immunity and immunogenicity.     

Inverse probability weighting for covariate adjustment in randomized studies

Covariate adjustment in randomized clinical trials has the potential benefit of precision gain. It also has the potential pitfall of reduced objectivity as it opens the possibility of selecting a ‘favorable’ model that yields strong treatment benefit estimate. Although there is a large volume of statistical literature targeting on the first aspect, realistic solutions to enforce objective inference and improve precision are rare. As a typical randomized trial needs to accommodate many implementation issues beyond statistical considerations, maintaining the objectivity is at least as important as precision gain if not more, particularly from the perspective of the regulatory agencies. In this article, we propose a two‐stage estimation procedure based on inverse probability weighting to achieve better precision without compromising objectivity. The procedure is designed in a way such that the covariate adjustment is performed before seeing the outcome, effectively reducing the possibility of selecting a ‘favorable’ model that yields a strong intervention effect. Both theoretical and numerical properties of the estimation procedure are presented. Application of the proposed method to a real data example is presented. Copyright © 2013 John Wiley & Sons, Ltd.     

Sample size calculation in cost‐effectiveness cluster randomized trials: optimal and maximin approaches

In this paper, the optimal sample sizes at the cluster and person levels for each of two treatment arms are obtained for cluster randomized trials where the cost‐effectiveness of treatments on a continuous scale is studied. The optimal sample sizes maximize the efficiency or power for a given budget or minimize the budget for a given efficiency or power. Optimal sample sizes require information on the intra‐cluster correlations (ICCs) for effects and costs, the correlations between costs and effects at individual and cluster levels, the ratio of the variance of effects translated into costs to the variance of the costs (the variance ratio), sampling and measuring costs, and the budget. When planning, a study information on the model parameters usually is not available. To overcome this local optimality problem, the current paper also presents maximin sample sizes. The maximin sample sizes turn out to be rather robust against misspecifying the correlation between costs and effects at the cluster and individual levels but may lose much efficiency when misspecifying the variance ratio. The robustness of the maximin sample sizes against misspecifying the ICCs depends on the variance ratio. The maximin sample sizes are robust under misspecification of the ICC for costs for realistic values of the variance ratio greater than one but not robust under misspecification of the ICC for effects. Finally, we show how to calculate optimal or maximin sample sizes that yield sufficient power for a test on the cost‐effectiveness of an intervention. Copyright © 2014 John Wiley & Sons, Ltd.     

Paper-based and web-based intervention modeling experiments identified the same predictors of general practitioners' antibiotic-prescribing behavior

ObjectivesTo evaluate the robustness of the intervention modeling experiment (IME) methodology as a way of developing and testing behavioral change interventions before a full-scale trial by replicating an earlier paper-based IME.Study Design and SettingWeb-based questionnaire and clinical scenario study. General practitioners across Scotland were invited to complete the questionnaire and scenarios, which were then used to identify predictors of antibiotic-prescribing behavior. These predictors were compared with the predictors identified in an earlier paper-based IME and used to develop a new intervention.ResultsTwo hundred seventy general practitioners completed the questionnaires and scenarios. The constructs that predicted simulated behavior and intention were attitude, perceived behavioral control, risk perception/anticipated consequences, and self-efficacy, which match the targets identified in the earlier paper-based IME. The choice of persuasive communication as an intervention in the earlier IME was also confirmed. Additionally, a new intervention, an action plan, was developed.ConclusionA web-based IME replicated the findings of an earlier paper-based IME, which provides confidence in the IME methodology. The interventions will now be evaluated in the next stage of the IME, a web-based randomized controlled trial.     

Network geometry shows evidence sequestration for medical vs. surgical practices: treatments for basal cell carcinoma

ObjectivesBasal cell carcinoma (BCC) is the most common cancer with 2 million treatments per year with little evidence-based guidelines for treatment. There are three classes of interventions (surgical, destructive, and topical) for BCC, and this study aimed to determine whether there are preferences or avoidances in comparisons of different types of treatments for BCC in randomized controlled trials (RCTs).Study Design and SettingPubMed, Cochrane Central Registry of Clinical Trials, and ClinicalTrials.Gov were used to identify eligible published and registered ongoing RCTs.ResultsFifty-five trials (42 published and 13 registered trials) were identified. Only one unpublished registered trial compared a topical vs. a surgical intervention, and only one trial compared a topical vs. a destructive intervention. Conversely, 44 of the 55 trials compared interventions within the same treatment class and 9 of 55 trials compared surgical vs. destructive interventions. In most trials, selection of same-class comparators was not necessitated by the type of BCC lesions (nonaggressive superficial or nodular vs. aggressive, infiltrative, morpheic BCCs, P = 0.155) or their location (face vs. nonfacial, P = 0.137).ConclusionThis is the first time that an evaluation of network geometry is applied to address issues of comparisons between different families of interventions that belong to different specialties and practices (medical vs. surgical). Previous evaluations of homophily have addressed different families of interventions, in which all interventions are medical (drugs) and performed in the same health-care settings. The noncommunicating bodies of evidence between medical and surgical interventions that we document highlight a problem of unnecessary sequestration of the evidence and the corresponding health-care practices.