Safety of Brodalumab in Plaque Psoriasis: Integrated Pooled Data from Five Clinical Trials.

Brodalumab is approved for treatment of moderate-to-severe plaque psoriasis. Here, we assess the safety profile of brodalumab using pooled safety data from 5 phase II/III trials of brodalumab 140 mg or 210 mg. In total, 4,464 patients received brodalumab, representing 8,891.6 patient-years of exposure. During the placebo-controlled 12-week induction period, rates of serious adverse events per 100 patient-years were 10.8 and 9.6 (brodalumab 140 mg and 210 mg, respectively) vs 4.3 and 6.5 (ustekinumab and placebo, respectively); infections were the most frequent serious adverse event. Rates of serious adverse events during the comparator-controlled 52-week period were 14.4, 10.2 and 8.3 per 100 patient-years for brodalumab 210 mg, brodalumab 140 mg, and ustekinumab, respectively. Brodalumab was not associated with increased risks of malignancy, major adverse cardiac events, suicidal ideation and behaviour, or fatal events. Overall, brodalumab demonstrated an acceptable safety profile in short- and long-term treatment.

Effect of grass sublingual tablet immunotherapy is similar in children and adults: A Bayesian approach to design pediatric sublingual immunotherapy trials.

BACKGROUND: Large sample sizes are needed for sublingual immunotherapy (SLIT) trials because of inherent data variability secondary to inconsistent allergen exposure. Obtaining large sample sizes for pediatric SLIT trials is challenging, but a Bayesian approach using prior adult data can reduce the necessary sample size. OBJECTIVE: We sought to describe how a Bayesian framework using prior information from adult trials can be used to improve pediatric SLIT clinical development. METHODS: Data were compiled by using a frequentist approach (conventional clinical trial approach independent of prior data) from trials conducted during the clinical development of timothy grass SLIT-tablets. RESULTS: The treatment effect of timothy grass SLIT-tablets was considered similar between pediatric (n = 795) and adult (n = 2299) data pools, with relative total combined symptom plus medication score improvement versus placebo of 21% (95% CI, 11.0% to 30.4%) and 20% (95% CI, 14.6% to 24.4%), respectively. Phleum pratense-specific IgG4 and IgE-blocking factor increased from baseline in both children and adults treated with timothy grass SLIT-tablets. Given the reasonable assumption in similarity of treatment response between adults and children, a Bayesian approach is described to demonstrate rigorous efficacy criteria for pediatric trials incorporating information from prior adult trials and thereby reduce the sample size. CONCLUSIONS: Data support the similarity of efficacy and immunologic changes between children and adults treated with SLIT for allergic rhinoconjunctivitis. Therefore it is appropriate to use data from adult trials to design feasible trials in children, which might reduce unsafe off-label use by promoting more quickly proper labeling of approved products.

Estimation of health-related utility (EQ-5D index) in subjects with seasonal allergic rhinoconjunctivitis to evaluate health gain associated with sublingual grass allergen immunotherapy.

BACKGROUND: Grass allergen immunotherapy (AIT) reduces symptom severity in seasonal allergic rhinoconjunctivitis (ARC) but its impact on general health-related utility has not been characterised for the purposes of economic evaluation. The aim of this study was to model the preferred measure of utility, EQ-5D index, from symptom severity and estimate incremental quality adjusted life years (QALYs) associated with SQ-standardised grass immunotherapy tablet (GRAZAX®, 75,000 SQ-T/2,800 BAU, ALK, Denmark). METHODS: Data were analysed from five consecutive pollen seasons in a randomised placebo controlled trial of GRAZAX®. Binomial and Gaussian mixed effects modelling related weekly EQ-5D index score to daily symptom and medication scores (DSS & DMS respectively). In turn, daily EQ-5D index was estimated from ARC symptoms and medication use. RESULTS: DSS and DMS were the principal predictors of 'perfect' health (EQ-5D = 1.000; binomial) and 'imperfect' health (EQ-5D < 1.000; Gaussian). Each unit increase in DSS and DMS reduced the odds of 'perfect' health (EQ-5D = 1.000) by 27% and 16% respectively, and reduced 'imperfect' health by 0.17 and 0.13, respectively. Gender remained the only other significant main fixed effect (Male odds ratio [OR] = 1.82). Incremental estimated EQ-5D index utility for GRAZAX® was observed from day -30 to day +70 of the pooled pollen season; mean daily utility for GRAZAX® = 0.938 units (95%CI 0.932-0.943) vs. 0.914 (0.907-0.921) for placebo, an incremental difference of 0.0238 (p < 0.001). This translates into an incremental 0.0324 Quality Adjusted Life Years over the five year study period. CONCLUSIONS: ARC symptoms and medication use are the main predictors of EQ-5D index. The incremental QALYs observed for GRAZAX® may not fully describe the health benefits of this treatment, suggesting that economic modelling may be conservative.

Workforce gender, company size and corporate financial support are predictors of availability of healthy meals in Danish worksite canteens.

OBJECTIVE: Environmental strategies at worksites may help consumers change dietary behaviour towards a more healthy diet. The present study aimed to evaluate the availability of healthy meal options at Danish worksite canteens and to identify predictors of worksite canteens providing healthy meals. DESIGN: A self-administered questionnaire was randomly mailed to 1967 worksite canteen managers. Besides information and characteristics about the canteen and the worksite, the canteen managers specified the menus available. Two different health groups (Healthy and Less Healthy) were defined in three different meal categories (Sandwiches, Hot meals and Salads) as well as a combined category (Combined) combining all the three meal categories. The characteristics of the worksites were compared with regard to the different health groups. SETTING: Randomly selected Danish worksite canteens. SUBJECTS: 553 Danish worksite canteen managers replied, resulting in a response rate of 29 %. RESULTS: Only 12 % of the canteens applied to the Healthy group combining all the three meal categories. In particular, worksites with more than 75 % female employees served healthy menus on a frequent basis. The size of the worksite was positively correlated with more healthy meal options. Furthermore, the present study suggests a positive relationship between corporate financial support and the availability of healthy meal options. CONCLUSIONS: Among the selected variables studied, workforce gender, company size and corporate financial support were significant predictors of the availability of healthy meal options in worksite canteens. More research is needed on the role that variance in organisation environment plays for the potential of worksite intervention, to make a difference in terms of healthy eating.

Prevalence and trends in overweight and obesity among children and adolescents in Denmark.

AIM: To study the current prevalence and trends in overweight and obesity among children and adolescents in Denmark from 1995 to 2000-2002. METHODS: Cross-sectional national dietary surveys were conducted in 1995 and 2000-2002. The analysis was based on two random population samples from the Danish civil registration system. Body mass index (BMI) was calculated from self-reported height and weight for 1,026 and 1,152 children and adolescents (4-18 years), who participated in 1995 and 2000-2002, respectively. The prevalence of overweight and obesity was defined according to the international age and gender-specific child BMI cut-off points. In the statistical analysis, overweight and obesity were included in the prevalence of overweight. RESULTS: Mean BMI increased significantly between 1995 and 2000-2002 for all combinations of age groups (4-6, 7-10, 11-14 and 15-18 years) and genders. Prevalence of overweight increased between survey years for boys and girls for all age groups (4-6, 7-10, 11-14 and 15-18 years), although formal statistical significance was not reached (p>0.05). When all children and adolescents (4-18 years) were analysed, the prevalence of overweight rose significantly from 10.9% (95% confidence interval (CI) 9.0-12.8) to 14.4% (95% CI 12.5-16.3) between 1995 and 2000- 2002 (p=0.01), whereas the increase in the prevalence of obesity did not reach significance (1995, 2.3% (95% CI 1.3-3.3) vs. 2000-2002, 2.4% (95% CI 1.6-3.3); p=0.74). CONCLUSIONS: The present study revealed a significant increase from 1995 to 2000-2002 in mean BMI for boys and girls for all age groups and a significant increase in the prevalence of overweight when all Danish children and adolescents (4-18 years) were analysed.

Antimicrobial drug resistance of Salmonella isolates from meat and humans, Denmark.

We compared 8,144 Salmonella isolates collected from meat imported to or produced in Denmark, as well as from Danish patients. Isolates from imported meat showed a higher rate of antimicrobial drug resistance, including multidrug resistance, than did isolates from domestic meat. Isolates from humans showed resistance rates lower than those found in imported meat but higher than in domestic meat. These findings indicate that programs for controlling resistant Salmonella spp. are a global issue.

Estimating the number of undetected multi-resistant Salmonella Typhimurium DT104 infected pig herds in Denmark.

In Denmark, the detection of multi-resistant Salmonella Typhimurium DT104 (MRDT104)-infected pig herds relies on the national Salmonella surveillance programme at the farm and slaughterhouse levels of production. With the surveillance sampling protocol and the diagnostic methods currently used, some herds might remain undetected. The number of undetected Danish pig herds infected with MRDT104 in the period 1 August 2001-31 July 2002 was estimated and compared with the number of culture-confirmed detected herds. A flow chart was constructed to illustrate where infected herds will go undetected in the surveillance system and Monte Carlo simulation was used to model the actual number of pig herds infected with MRDT1104. We estimated that 52 (90% CI [28, 178]) finisher herds were infected with MRDT104 compared to 23 (44%) detected. Among sow herds with production of weaners or growers, we estimated that 38 (90% CI [23, 74]) were infected with MRDT104 compared to 7 (18%) actually detected. Among breeder and multiplier herds, we estimated that five (90% CI [3, 8]) herds were infected with MRDT104 compared to three (60%) detected. In total, we estimated that 102 pig herds were infected with MRDT104 from 1 August 2001 till 31 July 2002 (90% CI [63, 228]). In comparison, 33 (32%) infected herds were detected in this period. The predicted proportion of undetected herds varied considerably with herd type. We infer that the proportion of detected MRDT104 infected herds depended on the intensity of the combined serological and bacteriological testing.

Principles, application areas and an example of risk assessment conducted at the Danish Institute for Food and Veterinary Research.

The Department for Epidemiology and Risk Analysis at the Danish Institute for Food and Veterinary Research (DFVF) is concerned with risk analyses in the areas of food safety, zoonoses, antimicrobial resistance and OIE (World Organisation for Animal Health) list A and B diseases. The DFVF is responsible for the risk assessment component of the risk analysis process and provides advice and support for the risk management and risk communication component, which is generally under the auspices of the Danish Veterinary and Food Administration (DVFA). The paper presents guidelines for the conduct of risk assessments at the DFVF. Important elements of these guidelines are the independence between risk assessment and risk management, the commitment to science-based, transparent and fully documented procedures and adherence to a protocol that regulates the cooperation between DFVF and DVFA. Typical steps of a quantitative risk assessment are the description of the risk scenario, information retrieval, mathematical modelling with stochastic simulation, final risk estimation with a sensitivity analysis and reporting. The procedure is exemplified using a Monte Carlo simulation model for the assessment of the risk of BSE transmission to calves by tallow-based calf milk replacer.

Risk factors associated with faecal shedding of verocytotoxin-producing Escherichia coli O157 in eight known-infected Danish dairy herds.

A risk-factor study was performed in eight dairy herds found to excrete verocytotoxin-producing Escherichia coli (VTEC) O157 in a former prevalence study. Associations between excretion of VTEC O157 and management factors such as housing and feeding were analysed in a generalised linear mixed model. The animals were stratified in three age groups and sampled four times during 1 year. The risk of excreting VTEC O157 was higher among weaned calves than non-weaned calves. Among the calves aged 1-4 months, the risk was reduced if the calf had suckled colostrum from the mother or if the calf had stayed >2 days with the mother after calving. Calves aged 5-24 months that had been moved within the last 2 weeks had a higher risk, but risk was reduced if fed barley silage. Cows fed grain or molasses had a higher risk of excreting VTEC O157.

Impact of integrated fish farming on antimicrobial resistance in a pond environment.

Integrated fish farming combines livestock production with fish farming. Animal manure is shed directly into a fish pond as fertilizer and supports the growth of photosynthetic organisms. The livestock, mainly chickens and pigs, is often fed feed containing growth promoters. In this study we investigated the impact of integrated fish farming on the levels of antimicrobial-resistant bacteria in a pond environment. One integrated broiler chicken-fish farm was studied for 2 months immediately after the start of a new fish production cycle. A significant increase over time in the resistance to six different antimicrobials was found for the indicator organism Acinetobacter spp. isolated from composite water-sediment samples. The initial resistance levels prior to the new production cycle were 1 to 5%. After 2 months the levels of resistance to oxytetracycline and sulfamethoxazole reached 100%, and the levels of resistance to ciprofloxacin were more than 80%. The long-term effects of resistance on integrated farming were studied on seven additional farms. The resistance levels were particularly high among Enterococcus spp. and were also high among Acinetobacter spp. isolated from water-sediment samples compared to the resistance levels at four control farms. In conclusion, integrated fish farming seems to favor antimicrobial-resistant bacteria in the pond environment. This could be attributed to the selective pressure of antimicrobials in the pond environment and/or to the introduction of antimicrobial-resistant bacteria from animal manure. Potential risks to human health were not addressed in this study and remain to be elucidated.