Head-to-head trials of systemic psoriasis therapies: a systematic review of study design and maximum acceptable treatment differences.

There is increasing use of head-to-head clinical trials in dermatology when establishing the efficacy of a new treatment. Active comparator trials (ACTs) can be classified into three distinct study trial designs: non-inferiority, equivalence and superiority. A better understanding of the statistical parameters, such as acceptable treatment differences (also known as the margin or delta), is necessary to properly design and interpret findings of active comparator trials (ACTs) in the field of dermatology. Therefore, the objective of this study was to summarize the maximum acceptable treatment differences in clinical trials that examine the efficacy of an oral or biologic psoriasis therapy with an active comparator. We conducted a systematic search using MEDLINE, Scopus, EMBASE, Cochrane Central Register of Controlled Trials, LILACS, Web of Science and ClinicalTrials.gov from inception to 31 August 2017. All ACTs with adult participants that had a primary outcome of the Psoriasis Area and Severity Index score were included. Bibliographies of articles were further reviewed. Two investigators independently assessed for article inclusion and separately completed data extraction of predefined data points. When there was a disagreement, a third investigator was consulted. Of the 49 ACTs included, there were 13 superiority, eight non-inferiority and seven equivalence trials. Another 21 studies had inadequate information for classification. All of the non-inferiority trials reported the margin, one of the superiority and six of the equivalence trials stated the treatment difference explicitly. For superiority trials, acceptable treatment differences ranged from 14% to 20%. The non-inferiority studies reported lower bound margins ranging from -20% to -10%. The equivalence trials reported upper and lower bound margins ranging from ±12.5% to ±18%. The results demonstrate the need for harmonization in the conduct of dermatological clinical trials and in the approaches of reporting research parameters.

Nivolumab versus ipilimumab in the treatment of advanced melanoma: a critical appraisal: ORIGINAL ARTICLE: Wolchok JD, Chiarion-Sileni V, Gonzalez R et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med 2017; 377:1345-56.

AIM: To show whether either nivolumab in combination with ipilimumab or nivolumab monotherapy vs. ipilimumab monotherapy extends overall survival (OS) or progression-free survival (PFS) in adults with previously untreated, advanced melanoma. SETTING AND DESIGN: The trial was conducted at 137 sites in 21 countries. Randomization (n = 945; 1 : 1 : 1 ratio) was stratified according to metastasis stage, BRAF mutation status and programmed death ligand 1 status. STUDY EXPOSURE: Adults were randomized to one of the following: nivolumab plus ipilimumab every 3 weeks for four doses, followed by nivolumab every 2 weeks; nivolumab every 2 weeks plus placebo; or ipilimumab every 3 weeks for four doses plus placebo. Treatment was continued until progression, unacceptable toxicity or withdrawal. OUTCOMES: OS, PFS and objective response rate were determined. Patients were also assessed for adverse events. The primary end points of interest were OS and PFS, comparing either the nivolumab plus ipilimumab group or the nivolumab-only group with the patients treated with ipilimumab only. RESULTS: At 3 years, the OS rates were 58%, 52% and 34% for the nivolumab plus ipilimumab, the nivolumab monotherapy and the ipilimumab monotherapy groups, respectively. For the nivolumab plus ipilimumab group, the median OS was not reached at the time of analysis. For the nivolumab-only group, the median OS was 37·6 months, and the ipilimumab-only group had a median OS of 19·9 months. The hazard ratio for death was 0·55 [95% confidence interval (CI) 0·45-0·69; P < 0·001] comparing nivolumab plus ipilimumab with ipilimumab, and 0·65 (95% CI 0·53-0·80; P < 0·001) comparing nivolumab with ipilimumab. The PFS rates at 3 years were 39% for the nivolumab plus ipilimumab group, 32% for the nivolumab monotherapy group and 10% for the ipilimumab monotherapy group, with 95% CIs for the two nivolumab groups that did not overlap with that for ipilimumab alone. CONCLUSIONS: Among patients with advanced melanoma, significantly longer OS and PFS occurred with the combination of nivolumab plus ipilimumab or with nivolumab alone compared with ipilimumab alone. Furthermore, survival outcomes favoured the nivolumab-containing groups over the ipilimumab group in subgroup analyses.

Heterogeneity and phylogenetic relationships of community-associated methicillin-sensitive/resistant Staphylococcus aureus isolates in healthy dogs, cats and their owners.

AIMS: To investigate the distribution of staphylococcal enterotoxin genes (se) and the molecular features of community-associated methicillin-sensitive/resistant Staphylococcus aureus (CA-MSSA/MRSA) isolates in the nostrils of healthy pets and their owners. METHODS AND RESULTS: A total of 114 Staph. aureus isolates were identified from 1563 nasal swab samples, and CA-MRSA accounted for 20·2% (n = 23) of the total identified isolates. CA-MRSA isolates (91·3%, 21/23) harboured higher percentage of se than did CA-MSSA isolates (58·2%, 53/91) (P < 0·01), and the two highest se profiles of CA-MRSA were seb-sek-seq (42·9%, 9/21) and seb-sek-seq-sep (28·6%, 6/21). Of the MSSAs, 42·8% (39/91) were resistant to at least one antimicrobial drug and 8·8% (8/91) were multidrug resistant (MDR). We identified nine staphylocoagulase (SC) types (I-VIII and X) and three multilocus sequence types (ST59-MRSA-IV/V, ST-239-MRSA-V and ST241-MRSA-V). SC VII (23·4%, 22/94), a staphylococcal food poisoning isolate found mainly in Japan, and ST-59-MRSA-IV/V (85%, 17/20), a widespread CA-MRSA clone found mainly in Taiwan, both were the most predominant types. Phylogenetic analysis together with se and molecular characteristics obtained using pulsed-field gel electrophoresis showed that high levels of antimicrobial resistance and the se-carrying clone ST59-MRSA-IV/V-SC VII were all clustered in genogroup 5. CONCLUSIONS: The CA-MRSA clone of se-carrying-MDR-ST-59-IV/V-SC VII was identified predominantly in this study, and this clone might play a significant role in staphylococcal food poisoning in community settings. SIGNIFICANCE AND IMPACT OF THE STUDY: To our knowledge, this is the first study focussing on enterotoxin-carrying CA-MRSA/MSSA in pets and their owners, and the results support the future warnings in animal-human bond caused by CA-staphylococci in the commonwealth and the need to take cautions worldwide.

Molecular detection and prevalence of enterovirus within environmental water in Taiwan.

AIMS: To investigate the presence of enterovirus RNA in various samples of environmental water collected in Taiwan during 2004-2005, and to characterize the genotypes and distribution of the viruses identified in Taiwan. METHODS AND RESULTS: Total 131 environmental samples were screened using the reverse transcription polymerase chain reaction (RT-PCR) for the highly conserved 5'-nontranslated regions (5'-NTR). Among these enterovirus RNA-positive samples, 32, 15 and 6 of the samples were recovered from surface water, ground water and sewage water respectively. However, the total positive detection rate increased to 40.5% with the application of seminested PCR. Sequencing revealed that the majority of isolates belonged to the following genotypes: coxsackie A2 (35.8%), coxsackie A6 (13.2%) and enterovirus (EV)71 (11.3%); echovirus 11, porcine EV9 and coxsackie A16 isolates were also observed. CONCLUSIONS: This study confirms that the major epidemic genotypes of enterovirus are prevalent in the surface and ground water of Taiwan. SIGNIFICANCE AND IMPACT OF THE STUDY: This study is helpful in understanding the significance and epidemiology of the virus within and beyond the study area. Moreover, it was possible to predict the enterovirus genotype and evaluate possible correlations between water contamination and viral sequences found among clinical samples.