Search

Objectives: The aim of this study was to evaluate antibiotic prescribing of medium-to-high prescribing primary care physicians being followed up after the completion of a Swiss national intervention trial of antibiotic prescription audit and feedback in the first SARS-CoV-2 pandemic year., Methods: We used health insurer based claims data to calculate monthly antibiotic prescription rates per 100 consultations (primary endpoint) and applying interrupted time series (ITS) analysis methods, we estimated the immediate (step change) and sustained effects (slope) of the SARS-CoV-2 epidemic in 2020 on antibiotic prescribing compared to the pre-pandemic trial period from 2017-2019., Results: We analysed data of 2945 of 3426 physicians (86.0%) from the trial with over 4 million consultations annually, who were in 2020 still in practice. Consultations dropped by 43% during the first pandemic year compared with 2017. Median monthly antibiotic prescription rates per 100 consultations in 2017 were 8.44 (Interquartile range [IQ] 6.32-11.50) and 8.35 (6.34-11.74) in the intervention and control groups, respectively, and increased to 15.63 (10.69-23.81) and 16.31 (10.65-24.72) per 100 consultations in 2020. ITS-derived incidence rate ratios for overall antibiotic prescriptions were 2.32 (95% CI 2.07-2.59) for the immediate pandemic effect, and 0.96 (0.95-0.98) for the sustained effect (change in slope in 2020 compared with 2017-2019)., Discussion: The SARS-CoV-2 pandemic had a major impact on antibiotic prescription patterns in primary care in Switzerland. For future viral pandemics, intervention plans with timely activation steps to minimize unjustified antibiotic consumption in primary care should be prepared., (Copyright © 2023 European Society of Clinical Microbiology and Infectious Diseases. All rights reserved.)

Importance: The role of axillary lymph node dissection (ALND) to determine nodal burden to inform systemic therapy recommendations in patients with clinically node (cN)-positive breast cancer (BC) is currently unknown., Objective: To address the association of ALND with systemic therapy in cN-positive BC in the upfront surgery setting and after neoadjuvant chemotherapy (NACT)., Design, Setting, and Participants: This was a prospective, observational, cohort study conducted from August 2018 to June 2022. This was a preplanned study within the phase 3 randomized clinical OPBC-03/TAXIS trial. Included were patients with confirmed cN-positive BC from 44 private, public, and academic breast centers in 6 European countries. After NACT, residual nodal disease was mandatory, and a minimum follow-up of 2 months was required., Exposures: All patients underwent tailored axillary surgery (TAS) followed by ALND or axillary radiotherapy (ART) according to TAXIS randomization. TAS removed suspicious palpable and sentinel nodes, whereas imaging-guidance was optional. Systemic therapy recommendations were at the discretion of the local investigators., Results: A total of 500 patients (median [IQR] age, 57 [48-69] years; 487 female [97.4%]) were included in the study. In the upfront surgery setting, 296 of 335 patients (88.4%) had hormone receptor (HR)-positive and Erb-B2 receptor tyrosine kinase 2 (ERBB2; formerly HER2 or HER2/neu)-negative disease: 145 (49.0%) underwent ART, and 151 (51.0%) underwent ALND. The median (IQR) number of removed positive lymph nodes without ALND was 3 (1-4) nodes compared with 4 (2-9) nodes with ALND. There was no association of ALND with the proportion of patients undergoing adjuvant chemotherapy (81 of 145 [55.9%] vs 91 of 151 [60.3%]; adjusted odds ratio [aOR], 0.72; 95% CI, 0.19-2.67) and type of systemic therapy. Of 151 patients with NACT, 74 (51.0%) underwent ART, and 77 (49.0%) underwent ALND. The ratio of removed to positive nodes was a median (IQR) of 4 (3-7) nodes to 2 (1-3) nodes and 15 (12-19) nodes to 2 (1-5) nodes in the ART and ALND groups, respectively. There was no observed association of ALND with the proportion of patients undergoing postneoadjuvant systemic therapy (57 of 74 [77.0%] vs 55 of 77 [71.4%]; aOR, 0.86; 95% CI, 0.43-1.70), type of postneoadjuvant chemotherapy (eg, capecitabine: 10 of 74 [13.5%] vs 10 of 77 [13.0%]; trastuzumab emtansine-DM1: 9 of 74 [12.2%] vs 11 of 77 [14.3%]), or endocrine therapy (eg, aromatase inhibitors: 41 of 74 [55.4%] vs 36 of 77 [46.8%]; tamoxifen: 8 of 74 [10.8%] vs 6 of 77 [7.8%])., Conclusion: Results of this cohort study suggest that patients without ALND were significantly understaged. However, ALND did not inform systemic therapy recommendations.

The study adapted the Family Gene Toolkit and developed a customized web application for Swiss and Korean families harboring BRCA1 or BRCA2 pathogenic variants to support family communication of genetic testing results and promote cascade genetic testing among at-risk relatives. In the first step, narrative data from 68 women with BRCA1 / BRCA2 pathogenic variants and clinician feedback informed a culturally sensitive adaptation of the content consistent with current risk management guidelines. In the second step, the Information Technology team developed the functions and the interface of the web application that will host the intervention. In the third step, a new sample of 18 women from families harboring BRCA1 / BRCA2 pathogenic variants tested the acceptability and usability of the intervention using "think-aloud" interviews and a questionnaire. Participants expressed high levels of satisfaction with the intervention. They provided positive feedback for the information regarding active coping, strategies to enhance family communication, interactive elements, and illustrative stories. They reported that the information was useful and the web application was easy to navigate. Findings suggest that the Family Gene Toolkit is well-designed and can increase rates of cascade testing among at-risk relatives. Its efficacy will be tested in a subsequent randomized trial.

Purpose: The aim of this study was to evaluate clinical practice heterogeneity in use of neoadjuvant systemic therapy (NST) for patients with clinically node-positive breast cancer in Europe., Methods: The study was preplanned in the international multicenter phase-III OPBC-03/TAXIS trial (ClinicalTrials.gov Identifier: NCT03513614) to include the first 500 randomized patients with confirmed nodal disease at the time of surgery. The TAXIS study's pragmatic design allowed both the neoadjuvant and adjuvant setting according to the preferences of the local investigators who were encouraged to register eligible patients consecutively., Results: A total of 500 patients were included at 44 breast centers in six European countries from August 2018 to June 2022, 165 (33%) of whom underwent NST. Median age was 57 years (interquartile range [IQR], 48-69). Most patients were postmenopausal (68.4%) with grade 2 and 3 hormonal receptor-positive and human epidermal growth factor receptor 2-negative breast cancer with a median tumor size of 28 mm (IQR 20-40). The use of NST varied significantly across the countries (p < 0.001). Austria (55.2%) and Switzerland (35.8%) had the highest percentage of patients undergoing NST and Hungary (18.2%) the lowest. The administration of NST increased significantly over the years (OR 1.42; p < 0.001) and more than doubled from 20 to 46.7% between 2018 and 2022., Conclusion: Substantial heterogeneity in the use of NST with HR+/HER2-breast cancer exists in Europe. While stringent guidelines are available for its use in triple-negative and HER2+ breast cancer, there is a need for the development of and adherence to well-defined recommendations for HR+/HER2-breast cancer., (© 2023. The Author(s).)

The aims of this Oncoplastic Breast Consortium and European Breast Cancer Research Association of Surgical Trialists initiative were to identify uncertainties and controversies in axillary management of early breast cancer and to recommend appropriate strategies to address them. By use of Delphi methods, 15 questions were prioritized by more than 250 breast surgeons, patient advocates and radiation oncologists from 60 countries. Subsequently, a global virtual consensus panel considered available data, ongoing studies and resource utilization. It agreed that research should no longer be prioritized for standardization of axillary imaging, de-escalation of axillary surgery in node-positive cancer and risk evaluation of modern surgery and radiotherapy. Instead, expert consensus recommendations for clinical practice should be based on current evidence and updated once results from ongoing studies become available. Research on de-escalation of radiotherapy and identification of the most relevant endpoints in axillary management should encompass a meta-analysis to identify knowledge gaps, followed by a Delphi process to prioritize and a consensus conference to refine recommendations for specific trial designs. Finally, treatment of residual nodal disease after surgery was recommended to be assessed in a prospective register., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Importance: Antibiotics are commonly prescribed in primary care, increasing the risk of antimicrobial resistance in the population., Objective: To investigate the effect of quarterly audit and feedback on antibiotic prescribing among primary care physicians in Switzerland with medium to high antibiotic prescription rates., Design, Setting, and Participants: This pragmatic randomized clinical trial was conducted from January 1, 2018, to December 31, 2019, among 3426 registered primary care physicians and pediatricians in single or small practices in Switzerland who were among the top 75% prescribers of antibiotics. Intention-to-treat analysis was performed using analysis of covariance models and conducted from September 1, 2021, to January 31, 2022., Interventions: Primary care physicians were randomized in a 1:1 fashion to undergo quarterly antibiotic prescribing audit and feedback with peer benchmarking vs no intervention for 2 years, with 2017 used as the baseline year. Anonymized patient-level claims data from 3 health insurers serving roughly 50% of insurees in Switzerland were used for audit and feedback. The intervention group also received evidence-based guidelines for respiratory tract and urinary tract infection management and community antibiotic resistance information. Physicians in the intervention group were blinded regarding the nature of the trial, and physicians in the control group were not informed of the trial., Main Outcomes and Measures: The claims data used for audit and feedback were analyzed to assess outcomes. Primary outcome was the antibiotic prescribing rate per 100 consultations during the second year of the intervention. Secondary end points included overall antibiotic use in the first year and over 2 years, use of quinolones and oral cephalosporins, all-cause hospitalizations, and antibiotic use in 3 age groups., Results: A total of 3426 physicians were randomized to the intervention (n = 1713) and control groups (n = 1713) serving 629 825 and 622 344 patients, respectively, with a total of 4 790 525 consultations in the baseline year of 2017. In the entire cohort, a 4.2% (95% CI, 3.9%-4.6%) relative increase in the antibiotic prescribing rate was noted during the second year of the intervention compared with 2017. In the intervention group, the median annual antibiotic prescribing rate per 100 consultations was 8.2 (IQR, 6.1-11.4) in the second year of the intervention and was 8.4 (IQR, 6.0-11.8) in the control group. Relative to the overall increase, a -0.1% (95% CI, -1.2% to 1.0%) lower antibiotic prescribing rate per 100 consultations was found in the intervention group compared with the control group. No relevant reductions in specific antibiotic prescribing rates were noted between groups except for quinolones in the second year of the intervention (-0.9% [95% CI, -1.5% to -0.4%])., Conclusions and Relevance: This randomized clinical trial found that quarterly personalized antibiotic prescribing audit and feedback with peer benchmarking did not reduce antibiotic prescribing among primary care physicians in Switzerland with medium to high antibiotic prescription rates., Trial Registration: ClinicalTrials.gov Identifier: NCT03379194.

Objectives: Availability of randomized controlled trial (RCT) protocols is essential for the interpretation of trial results and research transparency., Study Design and Setting: In this study, we determined the availability of RCT protocols approved in Switzerland, Canada, Germany, and the United Kingdom in 2012. For these RCTs, we searched PubMed, Google Scholar, Scopus, and trial registries for publicly available protocols and corresponding full-text publications of results. We determined the proportion of RCTs with (1) publicly available protocols, (2) publications citing the protocol, and (3) registries providing a link to the protocol. A multivariable logistic regression model explored factors associated with protocol availability., Results: Three hundred twenty-six RCTs were included, of which 118 (36.2%) made their protocol publicly available; 56 (47.6% 56 of 118) provided as a peer-reviewed publication and 48 (40.7%, 48 of 118) provided as supplementary material. A total of 90.9% (100 of 110) of the protocols were cited in the main publication, and 55.9% (66 of 118) were linked in the clinical trial registry. Larger sample size (>500; odds ratio [OR] = 5.90, 95% confidence interval [CI], 2.75-13.31) and investigator sponsorship (OR = 1.99, 95% CI, 1.11-3.59) were associated with increased protocol availability. Most protocols were made available shortly before the publication of the main results., Conclusion: RCT protocols should be made available at an early stage of the trial., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: To assess the quality of reporting of RCT protocols approved by UK research ethics committees before and after the publication of the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guideline., Methods: We had access to RCT study protocols that received ethical approval in the UK in 2012 (n=103) and 2016 (n=108). From those, we assessed the adherence to the 33 SPIRIT items (i.e. a total of 64 components of the 33 SPIRIT items). We descriptively analysed the adherence to SPIRIT guidelines as proportion of adequately reported items (median and interquartile range [IQR]) and stratified the results by year of approval and sponsor., Results: The proportion of reported SPIRIT items increased from a median of 64.9% (IQR, 57.6-69.2%) in 2012 to a median of 72.5% (IQR, 65.3-78.3%) in 2016. Industry-sponsored RCTs reported more SPIRIT items in 2012 (median 67.4%; IQR, 64.1-69.4%) compared to non-industry-sponsored trials (median 59.8%; IQR, 46.5-67.7%). This gap between industry- and non-industry-sponsored trials increased in 2016 (industry-sponsored: median 75.6%; IQR, 71.2-79.0% vs non-industry-sponsored: median 65.3%; IQR, 51.6-76.3%)., Conclusions: The adherence to SPIRIT guidelines has improved in the UK from 2012 to 2016 but remains on a modest level, especially for non-industry-sponsored RCTs., (© 2022. The Author(s).)

Aim: Demand for nipple- and skin- sparing mastectomy (NSM/SSM) with immediate breast reconstruction (BR) has increased at the same time as indications for post-mastectomy radiation therapy (PMRT) have broadened. The aim of the Oncoplastic Breast Consortium initiative was to address relevant questions arising with this clinically challenging scenario., Methods: A large global panel of oncologic, oncoplastic and reconstructive breast surgeons, patient advocates and radiation oncologists developed recommendations for clinical practice in an iterative process based on the principles of Delphi methodology., Results: The panel agreed that surgical technique for NSM/SSM should not be formally modified when PMRT is planned with preference for autologous over implant-based BR due to lower risk of long-term complications and support for immediate and delayed-immediate reconstructive approaches. Nevertheless, it was strongly believed that PMRT is not an absolute contraindication for implant-based or other types of BR, but no specific recommendations regarding implant positioning, use of mesh or timing were made due to absence of high-quality evidence. The panel endorsed use of patient-reported outcomes in clinical practice. It was acknowledged that the shape and size of reconstructed breasts can hinder radiotherapy planning and attention to details of PMRT techniques is important in determining aesthetic outcomes after immediate BR., Conclusions: The panel endorsed the need for prospective, ideally randomised phase III studies and for surgical and radiation oncology teams to work together for determination of optimal sequencing and techniques for PMRT for each patient in the context of BR., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Comprehensive protocols are key for the planning and conduct of randomised clinical trials (RCTs). Evidence of low reporting quality of RCT protocols led to the publication of the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklist in 2013. We aimed to examine the quality of reporting of RCT protocols from three countries before and after the publication of the SPIRIT checklist., Design: Repeated cross sectional study., Setting: Swiss, German and Canadian research ethics committees (RECs)., Participants: RCT protocols approved by RECs in 2012 (n=257) and 2016 (n=292)., Primary and Secondary Outcome Measures: The primary outcomes were the proportion of reported SPIRIT items per protocol and the proportion of trial protocols reporting individual SPIRIT items. We compared these outcomes in protocols approved in 2012 and 2016, and built regression models to explore factors associated with adherence to SPIRIT. For each protocol, we also extracted information on general trial characteristics and assessed whether individual SPIRIT items were reported RESULTS: The median proportion of reported SPIRIT items among RCT protocols showed a non-significant increase from 72% (IQR, 63%-79%) in 2012 to 77% (IQR, 68%-82%) in 2016. However, in a preplanned subgroup analysis, we detected a significant improvement in investigator-sponsored protocols: the median proportion increased from 64% (IQR, 55%-72%) in 2012 to 76% (IQR, 64%-83%) in 2016, while for industry-sponsored protocols median adherence was 77% (IQR 72%-80%) for both years. The following trial characteristics were independently associated with lower adherence to SPIRIT: single-centre trial, no support from a clinical trials unit or contract research organisation, and investigator-sponsorship., Conclusions: In 2012, industry-sponsored RCT protocols were reported more comprehensively than investigator-sponsored protocols. After publication of the SPIRIT checklist, investigator-sponsored protocols improved to the level of industry-sponsored protocols, which did not improve., Competing Interests: Competing interests: BvN is currently employed by Roche Pharma AG, Grenzach-Wyhlen, Germany. BK is currently employed by iOMEDICO AG, Freiburg, Germany. All other authors declare no financial relationships with any organisation that might have an interest in the submitted work and no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: We previously found that 25% of 1,017 randomized clinical trials (RCTs) approved between 2000 and 2003 were discontinued prematurely, and 44% remained unpublished at a median of 12 years follow-up. We aimed to assess a decade later (1) whether rates of completion and publication have increased; (2) the extent to which nonpublished RCTs can be identified in trial registries; and (3) the association between reporting quality of protocols and premature discontinuation or nonpublication of RCTs., Methods and Findings: We included 326 RCT protocols approved in 2012 by research ethics committees in Switzerland, the United Kingdom, Germany, and Canada in this metaresearch study. Pilot, feasibility, and phase 1 studies were excluded. We extracted trial characteristics from each study protocol and systematically searched for corresponding trial registration (if not reported in the protocol) and full text publications until February 2022. For trial registrations, we searched the (i) World Health Organization: International Clinical Trial Registry Platform (ICTRP); (ii) US National Library of Medicine (ClinicalTrials.gov); (iii) European Union Drug Regulating Authorities Clinical Trials Database (EUCTR); (iv) ISRCTN registry; and (v) Google. For full text publications, we searched PubMed, Google Scholar, and Scopus. We recorded whether RCTs were registered, discontinued (including reason for discontinuation), and published. The reporting quality of RCT protocols was assessed with the 33-item SPIRIT checklist. We used multivariable logistic regression to examine the association between the independent variables protocol reporting quality, planned sample size, type of control (placebo versus other), reporting of any recruitment projection, single-center versus multicenter trials, and industry versus investigator sponsoring, with the 2 dependent variables: (1) publication of RCT results; and (2) trial discontinuation due to poor recruitment. Of the 326 included trials, 19 (6%) were unregistered. Ninety-eight trials (30%) were discontinued prematurely, most often due to poor recruitment (37%; 36/98). One in 5 trials (21%; 70/326) remained unpublished at 10 years follow-up, and 21% of unpublished trials (15/70) were unregistered. Twenty-three of 147 investigator-sponsored trials (16%) reported their results in a trial registry in contrast to 150 of 179 industry-sponsored trials (84%). The median proportion of reported SPIRIT items in included RCT protocols was 69% (interquartile range 61% to 77%). We found no variables associated with trial discontinuation; however, lower reporting quality of trial protocols was associated with nonpublication (odds ratio, 0.71 for each 10% increment in the proportion of SPIRIT items met; 95% confidence interval, 0.55 to 0.92; p = 0.009). Study limitations include that the moderate sample size may have limited the ability of our regression models to identify significant associations., Conclusions: We have observed that rates of premature trial discontinuation have not changed in the past decade. Nonpublication of RCTs has declined but remains common; 21% of unpublished trials could not be identified in registries. Only 16% of investigator-sponsored trials reported results in a trial registry. Higher reporting quality of RCT protocols was associated with publication of results. Further efforts from all stakeholders are needed to improve efficiency and transparency of clinical research., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: DG contributed to the ASPIRE project as part of his PhD thesis before his current employment with Idorsia Pharmaceuticals Ltd. (his current employer had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript). BvN contributed to the ASPIRE project as part of her PhD thesis before her current employment with Roche (her current employer had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript). All authors have declared that no competing interests exist.

Objectives: To investigate the adherence of randomised controlled trial (RCT) protocols evaluating non-regulated interventions (including dietary interventions, surgical procedures, behavioural and lifestyle interventions, and exercise programmes) in comparison with regulated interventions to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 Statement., Methods: We conducted a repeated cross-sectional investigation in a random sample of RCT protocols approved in 2012 (n = 257) or 2016 (n = 292) by research ethics committees in Switzerland, Germany, or Canada. We investigated the proportion of accurately reported SPIRIT checklist items in protocols of trials with non-regulated as compared to regulated interventions., Results: Overall, 131 (24%) of trial protocols tested non-regulated interventions. In 2012, the median proportion of SPIRIT items reported in these protocols (59%, interquartile range [IQR], 53%-69%) was lower than in protocols with regulated interventions (median, 74%, IQR, 66%-80%). In 2016, the reporting quality of protocols with non-regulated interventions (median, 75%, IQR, 62%-83%) improved to the level of regulated intervention protocols, which had not changed on average., Conclusions: Reporting of RCT protocols evaluating non-regulated interventions improved between 2012 and 2016, although remained suboptimal. SPIRIT recommendations need to be further endorsed by researchers, ethics committees, funding agencies, and journals to optimize reporting of RCT protocols., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Importance: Clinical trial registries are important for gaining an overview of ongoing research efforts and for deterring and identifying publication bias and selective outcome reporting. The reliability of the information in trial registries is uncertain., Objective: To assess the reliability of information across registries for trials with multiple registrations., Evidence Review: For this systematic review, 360 protocols of randomized clinical trials (RCTs) approved by research ethics committees in Switzerland, the UK, Canada, and Germany in 2012 were evaluated. Clinical trial registries were searched from March to September 2019 for corresponding registrations of these RCTs. For RCTS that were recorded in more than 1 clinical trial registry, key trial characteristics that should be identical among all trial registries (ie, sponsor, funding source, primary outcome, target sample size, trial status, date of first patient enrollment, results available, and main publication indexed) were extracted in duplicate. Agreement between the different trial registries for these key characteristics was analyzed descriptively. Data analyses were conducted from May 1 to November 30, 2020. Representatives from clinical trial registries were interviewed to discuss the study findings between February 1 and March 31, 2021., Findings: The analysis included 197 RCTs registered in more than 1 trial registry (151 in 2 registries and 46 in 3 registries), with 188 trials in ClinicalTrials.gov, 185 in the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT), 20 in ISRCTN, and 47 in other registries. The agreement of key information across all registries was as follows: 178 of 197 RCTs (90%; 95% CI, 85%-94%) for sponsor, 18 of 20 (90%; 95% CI, 68%-99%) for funding source (funding was not reported on ClinicalTrials.gov), 154 of 197 (78%; 95% CI, 72%-84%) for primary outcome, 90 of 197 (46%; 95% CI, 39%-53%) for trial status, 122 of 194 (63%; 95% CI, 56%-70%) for target sample size, and 43 of 57 (75%; 95% CI, 62%-86%) for the date of first patient enrollment when the comparison time was increased to 30 days (date of first patient enrollment was not reported on EudraCT). For results availability in trial registries, agreement was 122 of 197 RCTs (62%; 95% CI, 55%-69%) for summary data reported in the registry and 91 of 197 (46%; 95% CI, 39%-53%) for whether a published article with the main results was indexed. Different legal requirements were stated as the main reason for inconsistencies by representatives of clinical trial registries., Conclusions and Relevance: In this systematic review, for a substantial proportion of registered RCTs, information about key trial characteristics was inconsistent across trial registries, raising concerns about the reliability of the information provided in these registries. Further harmonization across clinical trial registries may be necessary to increase their usefulness.

Background: In hereditary breast and ovarian cancer (HBOC), family communication of genetic test results is essential for cascade genetic screening, that is, identifying and testing blood relatives of known mutation carriers to determine whether they also carry the pathogenic variant, and to propose preventive and clinical management options. However, up to 50% of blood relatives are unaware of relevant genetic information, suggesting that potential benefits of genetic testing are not communicated effectively within family networks. Technology can facilitate communication and genetic education within HBOC families., Objective: The aims of this study are to develop the K-CASCADE (Korean-Cancer Predisposition Cascade Genetic Testing) cohort in Korea by expanding an infrastructure developed by the CASCADE (Cancer Predisposition Cascade Genetic Testing) Consortium in Switzerland; develop a digital health intervention to support the communication of cancer predisposition for Swiss and Korean HBOC families, based on linguistic and cultural adaptation of the Family Gene Toolkit; evaluate its efficacy on primary (family communication of genetic results and cascade testing) and secondary (psychological distress, genetic literacy, active coping, and decision making) outcomes; and explore its translatability using the reach, effectiveness, adoption, implementation, and maintenance framework., Methods: The digital health intervention will be available in French, German, Italian, Korean, and English and can be accessed via the web, mobile phone, or tablet (ie, device-agnostic). K-CASCADE cohort of Korean HBOC mutation carriers and relatives will be based on the CASCADE infrastructure. Narrative data collected through individual interviews or mini focus groups from 20 to 24 HBOC family members per linguistic region and 6-10 health care providers involved in genetic services will identify the local cultures and context, and inform the content of the tailored messages. The efficacy of the digital health intervention against a comparison website will be assessed in a randomized trial with 104 HBOC mutation carriers (52 in each study arm). The translatability of the digital health intervention will be assessed using survey data collected from HBOC families and health care providers., Results: Funding was received in October 2019. It is projected that data collection will be completed by January 2023 and results will be published in fall 2023., Conclusions: This study addresses the continuum of translational research, from developing an international research infrastructure and adapting an existing digital health intervention to testing its efficacy in a randomized controlled trial and exploring its translatability using an established framework. Adapting existing interventions, rather than developing new ones, takes advantage of previous valid experiences without duplicating efforts. Culturally sensitive web-based interventions that enhance family communication and understanding of genetic cancer risk are timely. This collaboration creates a research infrastructure between Switzerland and Korea that can be scaled up to cover other hereditary cancer syndromes., Trial Registration: ClinicalTrials.gov NCT04214210; https://clinicaltrials.gov/ct2/show/NCT04214210 and CRiS KCT0005643; https://cris.nih.go.kr/cris/., International Registered Report Identifier (irrid): PRR1-10.2196/26264., (©Sue Kim, Monica Aceti, Vasiliki Baroutsou, Nicole Bürki, Maria Caiata-Zufferey, Marco Cattaneo, Pierre O Chappuis, Florina M Ciorba, Rossella Graffeo-Galbiati, Viola Heinzelmann-Schwarz, Joon Jeong, MiSook M Jung, Sung-Won Kim, Jisun Kim, Myong Cheol Lim, Chang Ming, Christian Monnerat, Hyung Seok Park, Sang Hyung Park, Carla A Pedrazzani, Manuela Rabaglio, Jai Min Ryu, Ramon Saccilotto, Simon Wieser, Ursina Zürrer-Härdi, Maria C Katapodi. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 11.06.2021.)

Introduction: Antibiotic consumption is highest in primary care, and antibiotic overuse furthers antimicrobial resistance. In our recently published pilot-RCT, we used monthly aggregated claims data to provide personalized antibiotic prescription feedback to general practitioners (GPs). The pilot-RCT has shown that personalized prescription feedback is a feasible and promising low-cost intervention to reduce antibiotic prescribing. Here, we describe the rationale and design of the follow-up RCT with 3426 GPs in Switzerland. We now have access to pseudonymized patient-level data from routinely collected health insurance data of the three largest health insurers in Switzerland., Methods and Analysis: 1713 GPs randomized to the intervention group received once evidence-based treatment guidelines at the beginning, including region-specific antibiotic resistance information from the community and personalized feedback of their antibiotic prescribing, followed by quarterly personalized prescription feedback for two years. The first and the last mailings were sent out in December 2017 and September 2019, respectively. The 1713 GPs randomized to the control group were not notified about the study and they received no guidelines and no prescription feedback. The personalized prescription feedbacks and the analyses of the primary and secondary outcomes are entirely based on pseudonymized patient-level data from routinely collected health insurance data. The primary outcome is prescribed antibiotics per 100 patient consultations during the second year of intervention. The secondary outcomes include antibiotic use during the entire two-year trial period, use of broad-spectrum antibiotics, hospitalization rates (all-cause and infection-related), and antibiotic use in different age groups. If the feedback intervention proves to be efficacious, the intervention could be continued systemwide., Ethics and Dissemination: The trial is publicly funded by the Swiss National Science Foundation (SNSF, grant number 407240&#95;167066). The trial was approved by the ethics committee "Ethikkommission Nordwest-und Zentralschweiz" (EKNZ Project-ID 2017-00888). Results will be disseminated in peer-reviewed journals and international conferences., Competing Interests: DG, KAM, GM, SA, RS, AZ, AW, JB, AK and HCB declare no conflict of interest. The Basel Institute for Clinical Epidemiology and Biostatistics, University Hospital Basel, Basel, Switzerland was supported in 2013 by Santésuisse, the umbrella association of Swiss social health insurers. DG, KAM, GM, SA, RS, AZ, AW, JB, AK and HCB declare no other financial relationships with any organization that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work., (© 2021 The Authors.)

Background: Clearly structured and comprehensive protocols are an essential component to ensure safety of participants, data validity, successful conduct, and credibility of results of randomized clinical trials (RCTs). Funding agencies, research ethics committees (RECs), regulatory agencies, medical journals, systematic reviewers, and other stakeholders rely on protocols to appraise the conduct and reporting of RCTs. In response to evidence of poor protocol quality, the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guideline was published in 2013 to improve the accuracy and completeness of clinical trial protocols. The impact of these recommendations on protocol completeness and associations between protocol completeness and successful RCT conduct and publication remain uncertain., Objectives and Methods: Aims of the Adherence to SPIrit REcommendations (ASPIRE) study are to investigate adherence to SPIRIT checklist items of RCT protocols approved by RECs in the UK, Switzerland, Germany, and Canada before (2012) and after (2016) the publication of the SPIRIT guidelines; determine protocol features associated with non-adherence to SPIRIT checklist items; and assess potential differences in adherence across countries. We assembled an international cohort of RCTs based on 450 protocols approved in 2012 and 402 protocols approved in 2016 by RECs in Switzerland, the UK, Germany, and Canada. We will extract data on RCT characteristics and adherence to SPIRIT for all included protocols. We will use multivariable regression models to investigate temporal changes in SPIRIT adherence, differences across countries, and associations between SPIRIT adherence of protocols with RCT registration, completion, and publication of results. We plan substudies to examine the registration, premature discontinuation, and non-publication of RCTs; the use of patient-reported outcomes in RCT protocols; SPIRIT adherence of RCT protocols with non-regulated interventions; the planning of RCT subgroup analyses; and the use of routinely collected data for RCTs., Discussion: The ASPIRE study and associated substudies will provide important information on the impact of measures to improve the reporting of RCT protocols and on multiple aspects of RCT design, trial registration, premature discontinuation, and non-publication of RCTs observing potential changes over time.

Background: The burden and timeline of posttransplant infections are not comprehensively documented in the current era of immunosuppression and prophylaxis., Methods: In this prospective study nested within the Swiss Transplant Cohort Study (STCS), all clinically relevant infections were identified by transplant-infectious diseases physicians in persons receiving solid organ transplant (SOT) between May 2008 and December 2014 with ≥12 months of follow-up., Results: Among 3541 SOT recipients, 2761 (1612 kidney, 577 liver, 286 lung, 213 heart, and 73 kidney-pancreas) had ≥12 months of follow-up; 1520 patients (55%) suffered 3520 infections during the first year posttransplantation. Burden and timelines of clinically relevant infections differed between transplantations. Bacteria were responsible for 2202 infections (63%) prevailing throughout the year, with a predominance of Enterobacteriaceae (54%) as urinary pathogens in heart, lung, and kidney transplant recipients, and as digestive tract pathogens in liver transplant recipients. Enterococcus spp (20%) occurred as urinary tract pathogens in kidney transplant recipients and as digestive tract pathogens in liver transplant recipients, and Pseudomonas aeruginosa (9%) in lung transplant recipients. Among 1039 viral infections, herpesviruses predominated (51%) in kidney, liver, and heart transplant recipients. Among 263 fungal infections, Candida spp (60%) prevailed as digestive tract pathogens in liver transplant recipients. Opportunistic pathogens, including Aspergillus fumigatus (1.4%) and cytomegalovirus (6%), were rare, scattering over 12 months across all SOT recipients., Conclusions: In the current era of immunosuppression and prophylaxis, SOT recipients experience a high burden of infections throughout the first year posttransplantation, with rare opportunistic pathogens and a predominance of bacteria., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background : Never before have clinical trials drawn as much public attention as those testing interventions for COVID-19. We aimed to describe the worldwide COVID-19 clinical research response and its evolution over the first 100 days of the pandemic. Methods: Descriptive analysis of planned, ongoing or completed trials by April 9, 2020 testing any intervention to treat or prevent COVID-19, systematically identified in trial registries, preprint servers, and literature databases. A survey was conducted of all trials to assess their recruitment status up to July 6, 2020. Results: Most of the 689 trials (overall target sample size 396,366) were small (median sample size 120; interquartile range [IQR] 60-300) but randomized (75.8%; n=522) and were often conducted in China (51.1%; n=352) or the USA (11%; n=76). 525 trials (76.2%) planned to include 155,571 hospitalized patients, and 25 (3.6%) planned to include 96,821 health-care workers. Treatments were evaluated in 607 trials (88.1%), frequently antivirals (n=144) or antimalarials (n=112); 78 trials (11.3%) focused on prevention, including 14 vaccine trials. No trial investigated social distancing. Interventions tested in 11 trials with >5,000 participants were also tested in 169 smaller trials (median sample size 273; IQR 90-700). Hydroxychloroquine alone was investigated in 110 trials. While 414 trials (60.0%) expected completion in 2020, only 35 trials (4.1%; 3,071 participants) were completed by July 6. Of 112 trials with detailed recruitment information, 55 had recruited <20% of the targeted sample; 27 between 20-50%; and 30 over 50% (median 14.8% [IQR 2.0-62.0%]). Conclusions: The size and speed of the COVID-19 clinical trials agenda is unprecedented. However, most trials were small investigating a small fraction of treatment options. The feasibility of this research agenda is questionable, and many trials may end in futility, wasting research resources. Much better coordination is needed to respond to global health threats., Competing Interests: No competing interests were disclosed., (Copyright: © 2020 Janiaud P et al.)

The aims of the Oncoplastic Breast Consortium initiative were to identify important knowledge gaps in the field of oncoplastic breast-conserving surgery and nipple-sparing or skin-sparing mastectomy with immediate breast reconstruction, and to recommend appropriate research strategies to address these gaps. A total of 212 surgeons and 26 patient advocates from 55 countries prioritised the 15 most important knowledge gaps from a list of 38 in two electronic Delphi rounds. An interdisciplinary panel of the Oncoplastic Breast Consortium consisting of 63 stakeholders from 20 countries obtained consensus during an in-person meeting to select seven of these 15 knowledge gaps as research priorities. Three key recommendations emerged from the meeting. First, the effect of oncoplastic breast-conserving surgery on quality of life and the optimal type and timing of reconstruction after nipple-sparing or skin-sparing mastectomy with planned radiotherapy should be addressed by prospective cohort studies at an international level. Second, the role of adjunctive mesh and the positioning of implants during implant-based breast reconstruction should ideally be investigated by randomised controlled trials of pragmatic design. Finally, the BREAST-Q questionnaire is a suitable tool to assess primary outcomes in these studies, but other metrics to measure patient-reported outcomes should be systematically evaluated and quality indicators of surgical morbidity should be further assessed., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: According to the Swiss Law on Research in Humans, the reuse of routinely collected genetic and non-genetic data and samples from patients for research purposes requires the consent of patients. Unfortunately, the so far established paper-based processes are intrinsically linked to the hospital admission process, labour intensive and not yielding the targeted return rates. Therefore, the overall goal of the presented SPHN project is to increase patient reach by providing hospitals with a patient-centric, user-friendly and admission-independent electronic general consent pathway. As part of the project, feasibility of different digital pathways was evaluated in a usability testing., Methods: Based on a nationwide harmonised template, a mobile centric progressive web application was developed by the Department of Clinical Research Basel. Usability of the application and according user journeys were evaluated at all partner hospitals. Two options of giving consent were explored using 1) patients' smartphones without any involvement of hospital personnel and 2) a hospital device (tablet) with explicit confirmation of patient identity by hospital personnel. Participant signatures were captured as a picture of a handwritten signature on paper taken with the camera of the smartphone or tablet. Usability issues and feedback of participants were documented directly after usability testing., Results: In total, 122 users agreed to participate in the usability testing using a tablet or smartphone. The general consent request workflow on the smartphone or tablet was regarded as user friendly and easy to navigate by 96% of all participants. However, capturing a picture of a handwritten signature resulted in usability issues in multiple cases, i.e. due to missing pen or paper., Conclusion: Usability testing of our prototype application showed a broad acceptance of participants regarding the use of mobile electronic devices to give general consent. Therefore, we believe that easy-to-use digital general consent processes provide effective means to increase the patient pool for health-related research. Further discussions with legislative bodies are required to find patient centric, feasible and legally acceptable solutions in the specific case of electronic general consent for the near future.

Clinical trials form the backbone of evidence-based medicine. They are indispensable tools that make it possible to compare medical interventions or test medical devices for their efficacy and safety. Each study design exactly defines which data is to be collected. Case report forms (CRFs) are used to document the collected data. Preparing CRFs is complicating, time consuming and requires extensive knowledge in the fields of medicine, data management and statistics. In addition, there are no global standards for CRF design, which means that each research institution produces CRF data definitions at its own discretion. This hampers the exchange of data definitions among different research groups and variants of CRFs might be created for a similar study design. To address these problems, we developed a concept for a freely accessible portal in the form of a web application in which definitions for CRFs, variables and tables can be created. The created data definitions can be exported from the portal to be transferred to common electronic data capture systems (EDC) that can then generate CRFs using the definition. The overall objective of the project is to develop a data dictionary system that is used during the entire workflow of a study and that enables sharing and re-use of metadata.

Purpose: Indications for nipple-sparing mastectomy (NSM) have broadened to include the risk reducing setting and locally advanced tumors, which resulted in a dramatic increase in the use of NSM. The Oncoplastic Breast Consortium consensus conference on NSM and immediate reconstruction was held to address a variety of questions in clinical practice and research based on published evidence and expert panel opinion., Methods: The panel consisted of 44 breast surgeons from 14 countries across four continents with a background in gynecology, general or reconstructive surgery and a practice dedicated to breast cancer, as well as a patient advocate. Panelists presented evidence summaries relating to each topic for debate during the in-person consensus conference. The iterative process in question development, voting, and wording of the recommendations followed the modified Delphi methodology., Results: Consensus recommendations were reached in 35, majority recommendations in 24, and no recommendations in the remaining 12 questions. The panel acknowledged the need for standardization of various aspects of NSM and immediate reconstruction. It endorsed several oncological contraindications to the preservation of the skin and nipple. Furthermore, it recommended inclusion of patients in prospective registries and routine assessment of patient-reported outcomes. Considerable heterogeneity in breast reconstruction practice became obvious during the conference., Conclusions: In case of conflicting or missing evidence to guide treatment, the consensus conference revealed substantial disagreement in expert panel opinion, which, among others, supports the need for a randomized trial to evaluate the safest and most efficacious reconstruction techniques.

Background: Clinical studies in children are necessary yet conducting multiple visits at study centers remains challenging. The success of "care-at-home" initiatives and remote clinical trials suggests their potential to facilitate conduct of pediatric studies. This pilot aimed to study the feasibility of remotely collecting valid (i.e. complete and correct) saliva samples and clinical data utilizing mobile technology., Methods: Single-center, prospective pilot study in children undergoing elective tonsillectomy at the University of Basel Children's Hospital. Data on pain scores and concomitant medication and saliva samples were collected by caregivers on two to four inpatient study days and on three consecutive study days at home. A tailored mobile application developed for this study supported data collection. The primary endpoint was the proportion of complete and correct caregiver-collected data (pain scale) and saliva samples in the at-home setting. Secondary endpoints included the proportion of complete and correct saliva samples in the inpatient setting, subjective feasibility for caregivers, and study cost., Results: A total number of 23 children were included in the study of which 17 children, median age 6.0 years (IQR 5.0, 7.4), completed the study. During the at-home phase, 71.9% [CI = 64.4, 78.6] of all caregiver-collected pain assessments and 53.9% [CI = 44.2, 63.4] of all saliva samples were complete and correct. Overall, 64.7% [CI = 58.7, 70.4] of all data collected by caregivers at home was complete and correct. The predominant reason for incorrectness of data was adherence to the timing of predefined patient actions. Participating caregivers reported high levels of satisfaction and willingness to participate in similar trials in the future. Study costs for a potential sample size of 100 patients were calculated to be 20% lower for the at-home than for a traditional in-patient study setting., Conclusions: Mobile device supported studies conducted at home may provide a cost-effective approach to facilitate conduct of clinical studies in children. Given findings in this pilot study, data collection at home may focus on electronic data capture rather than biological sampling.

Objectives: To assess the quality of antibiotic prescribing of Swiss primary care physicians with high prescription rates., Methods: In January 2015, we mailed a structured questionnaire to 2900 primary care physicians in Switzerland. They were included in a nationwide pragmatic randomized controlled trial on routine antibiotic prescription monitoring and feedback based on health insurance claims data. We asked them to record the diagnosis and antibiotic treatment for 44 consecutive patients with the most common conditions associated with antibiotic prescribing in primary care. We evaluated if the disease-specific antibiotic prescribing and the proportion of non-recommended antibiotics used, in particular quinolones, were within 'acceptable ranges' using adapted European Surveillance of Antimicrobial Consumption (ESAC) quality indicators., Results: Two hundred and fifty physicians (8.6%) responded, providing 9961 patient records. Responders were similar to the entire physician population. Overall, antibiotics were prescribed to 32.1% of patients. For tonsillitis/pharyngitis, acute otitis media, acute rhinosinusitis and acute bronchitis the acceptable maximum of antibiotic prescriptions was exceeded by 24.4%, 49.6%, 27.4% and 11.5%, respectively. The proportion of non-recommended antibiotics was for all diagnoses above the recommended maximum of 20% (31.5%-88.7% across all conditions). Quinolones were prescribed to 37.2% of women with urinary tract infections, substantially exceeding the recommended maximum of 5%., Conclusions: Antibiotic prescribing quality of Swiss primary care physicians with high prescription rates is low according to the indicators used, with substantial overtreatment of tonsillitis/pharyngitis, acute rhinosinusitis, acute otitis media and acute bronchitis. Routine nationwide and continuous monitoring of antibiotic use and specific interventions are warranted to improve prescribing in primary care., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Nicotinic acid (niacin) is known to decrease LDL-cholesterol, and triglycerides, and increase HDL-cholesterol levels. The evidence of benefits with niacin monotherapy or add-on to statin-based therapy is controversial., Objectives: To assess the effectiveness of niacin therapy versus placebo, administered as monotherapy or add-on to statin-based therapy in people with or at risk of cardiovascular disease (CVD) in terms of mortality, CVD events, and side effects., Search Methods: Two reviewers independently and in duplicate screened records and potentially eligible full texts identified through electronic searches of CENTRAL, MEDLINE, Embase, Web of Science, two trial registries, and reference lists of relevant articles (latest search in August 2016)., Selection Criteria: We included all randomised controlled trials (RCTs) that either compared niacin monotherapy to placebo/usual care or niacin in combination with other component versus other component alone. We considered RCTs that administered niacin for at least six months, reported a clinical outcome, and included adults with or without established CVD., Data Collection and Analysis: Two reviewers used pre-piloted forms to independently and in duplicate extract trials characteristics, risk of bias items, and outcomes data. Disagreements were resolved by consensus or third party arbitration. We conducted random-effects meta-analyses, sensitivity analyses based on risk of bias and different assumptions for missing data, and used meta-regression analyses to investigate potential relationships between treatment effects and duration of treatment, proportion of participants with established coronary heart disease and proportion of participants receiving background statin therapy. We used GRADE to assess the quality of evidence., Main Results: We included 23 RCTs that were published between 1968 and 2015 and included 39,195 participants in total. The mean age ranged from 33 to 71 years. The median duration of treatment was 11.5 months, and the median dose of niacin was 2 g/day. The proportion of participants with prior myocardial infarction ranged from 0% (4 trials) to 100% (2 trials, median proportion 48%); the proportion of participants taking statin ranged from 0% (4 trials) to 100% (12 trials, median proportion 100%).Using available cases, niacin did not reduce overall mortality (risk ratio (RR) 1.05, 95% confidence interval (CI) 0.97 to 1.12; participants = 35,543; studies = 12; I 2 = 0%; high-quality evidence), cardiovascular mortality (RR 1.02, 95% CI 0.93 to 1.12; participants = 32,966; studies = 5; I 2 = 0%; moderate-quality evidence), non-cardiovascular mortality (RR 1.12, 95% CI 0.98 to 1.28; participants = 32,966; studies = 5; I 2 = 0%; high-quality evidence), the number of fatal or non-fatal myocardial infarctions (RR 0.93, 95% CI 0.87 to 1.00; participants = 34,829; studies = 9; I 2 = 0%; moderate-quality evidence), nor the number of fatal or non-fatal strokes (RR 0.95, 95% CI 0.74 to 1.22; participants = 33,661; studies = 7; I 2 = 42%; low-quality evidence). Participants randomised to niacin were more likely to discontinue treatment due to side effects than participants randomised to control group (RR 2.17, 95% CI 1.70 to 2.77; participants = 33,539; studies = 17; I 2 = 77%; moderate-quality evidence). The results were robust to sensitivity analyses using different assumptions for missing data., Authors' Conclusions: Moderate- to high-quality evidence suggests that niacin does not reduce mortality, cardiovascular mortality, non-cardiovascular mortality, the number of fatal or non-fatal myocardial infarctions, nor the number of fatal or non-fatal strokes but is associated with side effects. Benefits from niacin therapy in the prevention of cardiovascular disease events are unlikely.

Background: Based on observational studies, administration of surgical antimicrobial prophylaxis (SAP) for the prevention of surgical site infection (SSI) is recommended within 60 min before incision. However, the precise optimum timing is unknown. This trial compared early versus late administration of SAP before surgery., Methods: In this phase 3 randomised controlled superiority trial, we included general surgery adult inpatients (age ≥18 years) at two Swiss hospitals in Basel and Aarau. Patients were randomised centrally and stratified by hospital according to a pre-existing computer-generated list in a 1:1 ratio to receive SAP early in the anaesthesia room or late in the operating room. Patients and the outcome assessment team were blinded to group assignment. SAP consisted of single-shot, intravenous infusion of 1·5 g of cefuroxime, a commonly used cephalosporin with a short half-life, over 2-5 min (combined with 500 mg metronidazole in colorectal surgery). The primary endpoint was the occurrence of SSI within 30 days of surgery. The main analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT01790529., Findings: Between Feb 21, 2013, and Aug 3, 2015, 5580 patients were randomly assigned to receive SAP early (2798 patients) or late (2782 patients). 5175 patients (2589 in the early group and 2586 in the late group) were analysed. Median administration time was 42 min before incision in the early group (IQR 30-55) and 16 min before incision in the late group (IQR 10-25). Inpatient follow-up rate was 100% (5175 of 5175 patients); outpatient 30-day follow-up rate was 88·8% (4596 of 5175), with an overall SSI rate of 5·1% (234 of 4596). Early administration of SAP did not significantly reduce the risk of SSI compared with late administration (odds ratio 0·93, 95% CI 0·72-1·21, p=0·601)., Interpretation: Our findings do not support any narrowing of the 60-min window for the administration of a cephalosporin with a short half-life, thereby obviating the need for increasingly challenging SAP timing recommendations., Funding: Swiss National Science Foundation, Hospital of Aarau, University of Basel, Gottfried und Julia Bangerter-Rhyner Foundation, Hippocrate Foundation, and Nora van Meeuwen-Häfliger Foundation., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objectives: To determine the proportion of pediatric randomized controlled trials (RCTs) that are prematurely discontinued, examine the reasons for discontinuation, and compare the risk for recruitment failure in pediatric and adult RCTs., Study Design: A retrospective cohort study of RCTs approved by 1 of 6 Research Ethics Committees (RECs) in Switzerland, Germany, and Canada between 2000 and 2003. We recorded trial characteristics, trial discontinuation, and reasons for discontinuation from protocols, corresponding publications, REC files, and a survey of trialists., Results: We included 894 RCTs, of which 86 enrolled children and 808 enrolled adults. Forty percent of the pediatric RCTs and 29% of the adult RCTs were discontinued. Slow recruitment accounted for 56% of pediatric RCT discontinuations and 43% of adult RCT discontinuations. Multivariable logistic regression analyses suggested that pediatric RCT was not an independent risk factor for recruitment failure after adjustment for other potential risk factors (aOR, 1.22; 95% CI, 0.57-2.63). Independent risk factors were acute care setting (aOR, 4.00; 95% CI, 1.72-9.31), nonindustry sponsorship (aOR, 4.45; 95% CI, 2.59-7.65), and smaller planned sample size (aOR, 1.05; 95% CI 1.01-1.09, in decrements of 100 participants)., Conclusion: Forty percent of pediatric RCTs were discontinued prematurely, owing predominately to slow recruitment. Enrollment of children was not an independent risk factor for recruitment failure., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Importance: Feedback interventions using routinely collected health data might reduce antibiotic use nationwide without requiring the substantial resources and structural efforts of other antibiotic stewardship programs., Objective: To determine if quarterly antibiotic prescription feedback over 2 years reduces antibiotic use when implemented in a complex health care system., Design, Setting, and Participants: Pragmatic randomized trial using routinely collected claims data on 2900 primary care physicians with the highest antibiotic prescription rates in Switzerland., Interventions: Physicians were randomized to quarterly updated personalized antibiotic prescription feedback over 2 years (n = 1450) or usual care (n = 1450). Feedback was provided both by mail and online from October 2013 to October 2015 and was supported by an initial 1-time provision of evidence-based guidelines., Main Outcomes and Measures: The primary outcome was the prescribed defined daily doses (DDD) of any antibiotic to any patient per 100 consultations in the first year analyzed by intention-to-treat. We further analyzed prescriptions of specific antibiotics, age groups, and sex for the first and second year to investigate persistency of effects over time., Results: The 2900 physicians had 10 660 124 consultations over 2 years of follow-up, prescribed 1 175 780 packages of antibiotics with 10 290 182 DDD. Physicians receiving feedback prescribed the same amount of antibiotics to all patients in the first year (between-group difference, 0.81%; 95% CI, -2.56% to 4.30%; P = .64) and second year (between-group difference, -1.73%; 95% CI, -5.07% to 1.72%; P = .32) compared with the control group. Prescribing to children aged 6 to 18 years was -8.61% lower in the feedback than in the control group in the first year (95% CI, -14.87% to -1.90%; P = .01). This difference diminished in the second year (between-group difference, -4.10%; 95% CI, -10.78% to 3.07%; P = .25). Physicians receiving feedback prescribed fewer antibiotics to adults aged 19 to 65 years in the second year (between-group difference, -4.59%; 95% CI, -7.91% to -1.16%; P < .01). Prescribing to other patient groups or of specific antibiotic types was not significantly different between groups., Conclusions and Relevance: This nationwide antibiotic stewardship program with routine feedback on antibiotic prescribing was not associated with a change of antibiotic use. In older children, adolescents, and younger adults less antibiotics were prescribed, but not consistently over the entire intervention period., Trial Registration: clinicaltrials.gov Identifier: NCT01773824.

Background: Antimicrobial resistance has become a serious worldwide public health problem and is associated with antibiotic overuses. Whether personalized prescription feedback to high antibiotic prescribers using routinely collected data can lower antibiotic use in the long run is unknown., Methods: We describe the design and rationale of a nationwide pragmatic randomized controlled trial enrolling 2900 primary care physicians in Switzerland with high antibiotic prescription rates based on national reimbursement claims data. About 1450 physicians receive quarterly postal and online antibiotic prescription feedback over 24 months allowing a comparison of the individual prescription rates with peers. Initially, they also receive evidence based treatment guidelines. The 1450 physicians in the control group receive no information. The primary outcome is the amount of antibiotics prescribed over a one year-period, measured as defined daily doses per 100 consultations. Other outcomes include the amount of antibiotics prescribed to specific age groups (<6, 6 to 18, 19 to 65, >65 years), to male and female patients, in addition to prescriptions of specific antibiotic groups. Further analyses address disease-specific quality indicators for outpatient antibiotic prescriptions, the acceptance of the intervention, and the impact on costs., Discussion: This trial investigates whether continuous personalized prescription feedback on a health system level using routinely collected health data reduces antibiotic overuse. The feasibility and applicability of a web-based interface for communication with primary care physicians is further assessed., Trial Registration: ClinTrials.gov NCT01773824 (Date registered: August 24, 2012).

Background: Little is known about publication agreements between industry and academic investigators in trial protocols and the consistency of these agreements with corresponding statements in publications. We aimed to investigate (i) the existence and types of publication agreements in trial protocols, (ii) the completeness and consistency of the reporting of these agreements in subsequent publications, and (iii) the frequency of co-authorship by industry employees., Methods and Findings: We used a retrospective cohort of randomized clinical trials (RCTs) based on archived protocols approved by six research ethics committees between 13 January 2000 and 25 November 2003. Only RCTs with industry involvement were eligible. We investigated the documentation of publication agreements in RCT protocols and statements in corresponding journal publications. Of 647 eligible RCT protocols, 456 (70.5%) mentioned an agreement regarding publication of results. Of these 456, 393 (86.2%) documented an industry partner's right to disapprove or at least review proposed manuscripts; 39 (8.6%) agreements were without constraints of publication. The remaining 24 (5.3%) protocols referred to separate agreement documents not accessible to us. Of those 432 protocols with an accessible publication agreement, 268 (62.0%) trials were published. Most agreements documented in the protocol were not reported in the subsequent publication (197/268 [73.5%]). Of 71 agreements reported in publications, 52 (73.2%) were concordant with those documented in the protocol. In 14 of 37 (37.8%) publications in which statements suggested unrestricted publication rights, at least one co-author was an industry employee. In 25 protocol-publication pairs, author statements in publications suggested no constraints, but 18 corresponding protocols documented restricting agreements., Conclusions: Publication agreements constraining academic authors' independence are common. Journal articles seldom report on publication agreements, and, if they do, statements can be discrepant with the trial protocol.

Objectives: To investigate the frequency of interim analyses, stopping rules, and data safety and monitoring boards (DSMBs) in protocols of randomized controlled trials (RCTs); to examine these features across different reasons for trial discontinuation; and to identify discrepancies in reporting between protocols and publications., Study Design and Setting: We used data from a cohort of RCT protocols approved between 2000 and 2003 by six research ethics committees in Switzerland, Germany, and Canada., Results: Of 894 RCT protocols, 289 prespecified interim analyses (32.3%), 153 stopping rules (17.1%), and 257 DSMBs (28.7%). Overall, 249 of 894 RCTs (27.9%) were prematurely discontinued; mostly due to reasons such as poor recruitment, administrative reasons, or unexpected harm. Forty-six of 249 RCTs (18.4%) were discontinued due to early benefit or futility; of those, 37 (80.4%) were stopped outside a formal interim analysis or stopping rule. Of 515 published RCTs, there were discrepancies between protocols and publications for interim analyses (21.1%), stopping rules (14.4%), and DSMBs (19.6%)., Conclusion: Two-thirds of RCT protocols did not consider interim analyses, stopping rules, or DSMBs. Most RCTs discontinued for early benefit or futility were stopped without a prespecified mechanism. When assessing trial manuscripts, journals should require access to the protocol., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: Randomized clinical trials that enroll patients in critical or emergency care (acute care) setting are challenging because of narrow time windows for recruitment and the inability of many patients to provide informed consent. To assess the extent that recruitment challenges lead to randomized clinical trial discontinuation, we compared the discontinuation of acute care and nonacute care randomized clinical trials., Design: Retrospective cohort of 894 randomized clinical trials approved by six institutional review boards in Switzerland, Germany, and Canada between 2000 and 2003., Setting: Randomized clinical trials involving patients in an acute or nonacute care setting., Subjects and Interventions: We recorded trial characteristics, self-reported trial discontinuation, and self-reported reasons for discontinuation from protocols, corresponding publications, institutional review board files, and a survey of investigators., Measurements and Main Results: Of 894 randomized clinical trials, 64 (7%) were acute care randomized clinical trials (29 critical care and 35 emergency care). Compared with the 830 nonacute care randomized clinical trials, acute care randomized clinical trials were more frequently discontinued (28 of 64, 44% vs 221 of 830, 27%; p = 0.004). Slow recruitment was the most frequent reason for discontinuation, both in acute care (13 of 64, 20%) and in nonacute care randomized clinical trials (7 of 64, 11%). Logistic regression analyses suggested the acute care setting as an independent risk factor for randomized clinical trial discontinuation specifically as a result of slow recruitment (odds ratio, 4.00; 95% CI, 1.72-9.31) after adjusting for other established risk factors, including nonindustry sponsorship and small sample size., Conclusions: Acute care randomized clinical trials are more vulnerable to premature discontinuation than nonacute care randomized clinical trials and have an approximately four-fold higher risk of discontinuation due to slow recruitment. These results highlight the need for strategies to reliably prevent and resolve slow patient recruitment in randomized clinical trials conducted in the critical and emergency care setting.

Objective: To investigate the prevalence of discontinuation and nonpublication of surgical versus medical randomized controlled trials (RCTs) and to explore risk factors for discontinuation and nonpublication of surgical RCTs., Background: Trial discontinuation has significant scientific, ethical, and economic implications. To date, the prevalence of discontinuation of surgical RCTs is unknown., Methods: All RCT protocols approved between 2000 and 2003 by 6 ethics committees in Canada, Germany, and Switzerland were screened. Baseline characteristics were collected and, if published, full reports retrieved. Risk factors for early discontinuation for slow recruitment and nonpublication were explored using multivariable logistic regression analyses., Results: In total, 863 RCT protocols involving adult patients were identified, 127 in surgery (15%) and 736 in medicine (85%). Surgical trials were discontinued for any reason more often than medical trials [43% vs 27%, risk difference 16% (95% confidence interval [CI]: 5%-26%); P = 0.001] and more often discontinued for slow recruitment [18% vs 11%, risk difference 8% (95% CI: 0.1%-16%); P = 0.020]. The percentage of trials not published as full journal article was similar in surgical and medical trials (44% vs 40%, risk difference 4% (95% CI: -5% to 14%); P = 0.373). Discontinuation of surgical trials was a strong risk factor for nonpublication (odds ratio = 4.18, 95% CI: 1.45-12.06; P = 0.008)., Conclusions: Discontinuation and nonpublication rates were substantial in surgical RCTs and trial discontinuation was strongly associated with nonpublication. These findings need to be taken into account when interpreting surgical literature. Surgical trialists should consider feasibility studies before embarking on full-scale trials.

Objective: To investigate the planning of subgroup analyses in protocols of randomised controlled trials and the agreement with corresponding full journal publications., Design: Cohort of protocols of randomised controlled trial and subsequent full journal publications., Setting: Six research ethics committees in Switzerland, Germany, and Canada., Data Sources: 894 protocols of randomised controlled trial involving patients approved by participating research ethics committees between 2000 and 2003 and 515 subsequent full journal publications., Results: Of 894 protocols of randomised controlled trials, 252 (28.2%) included one or more planned subgroup analyses. Of those, 17 (6.7%) provided a clear hypothesis for at least one subgroup analysis, 10 (4.0%) anticipated the direction of a subgroup effect, and 87 (34.5%) planned a statistical test for interaction. Industry sponsored trials more often planned subgroup analyses compared with investigator sponsored trials (195/551 (35.4%) v 57/343 (16.6%), P<0.001). Of 515 identified journal publications, 246 (47.8%) reported at least one subgroup analysis. In 81 (32.9%) of the 246 publications reporting subgroup analyses, authors stated that subgroup analyses were prespecified, but this was not supported by 28 (34.6%) corresponding protocols. In 86 publications, authors claimed a subgroup effect, but only 36 (41.9%) corresponding protocols reported a planned subgroup analysis., Conclusions: Subgroup analyses are insufficiently described in the protocols of randomised controlled trials submitted to research ethics committees, and investigators rarely specify the anticipated direction of subgroup effects. More than one third of statements in publications of randomised controlled trials about subgroup prespecification had no documentation in the corresponding protocols. Definitive judgments regarding credibility of claimed subgroup effects are not possible without access to protocols and analysis plans of randomised controlled trials., (© The DISCO study group 2014.)

Importance: The discontinuation of randomized clinical trials (RCTs) raises ethical concerns and often wastes scarce research resources. The epidemiology of discontinued RCTs, however, remains unclear., Objectives: To determine the prevalence, characteristics, and publication history of discontinued RCTs and to investigate factors associated with RCT discontinuation due to poor recruitment and with nonpublication., Design and Setting: Retrospective cohort of RCTs based on archived protocols approved by 6 research ethics committees in Switzerland, Germany, and Canada between 2000 and 2003. We recorded trial characteristics and planned recruitment from included protocols. Last follow-up of RCTs was April 27, 2013., Main Outcomes and Measures: Completion status, reported reasons for discontinuation, and publication status of RCTs as determined by correspondence with the research ethics committees, literature searches, and investigator surveys., Results: After a median follow-up of 11.6 years (range, 8.8-12.6 years), 253 of 1017 included RCTs were discontinued (24.9% [95% CI, 22.3%-27.6%]). Only 96 of 253 discontinuations (37.9% [95% CI, 32.0%-44.3%]) were reported to ethics committees. The most frequent reason for discontinuation was poor recruitment (101/1017; 9.9% [95% CI, 8.2%-12.0%]). In multivariable analysis, industry sponsorship vs investigator sponsorship (8.4% vs 26.5%; odds ratio [OR], 0.25 [95% CI, 0.15-0.43]; P < .001) and a larger planned sample size in increments of 100 (-0.7%; OR, 0.96 [95% CI, 0.92-1.00]; P = .04) were associated with lower rates of discontinuation due to poor recruitment. Discontinued trials were more likely to remain unpublished than completed trials (55.1% vs 33.6%; OR, 3.19 [95% CI, 2.29-4.43]; P < .001)., Conclusions and Relevance: In this sample of trials based on RCT protocols from 6 research ethics committees, discontinuation was common, with poor recruitment being the most frequently reported reason. Greater efforts are needed to ensure the reporting of trial discontinuation to research ethics committees and the publication of results of discontinued trials.

Background: Randomized controlled trials (RCTs) may be discontinued because of apparent harm, benefit, or futility. Other RCTs are discontinued early because of insufficient recruitment. Trial discontinuation has ethical implications, because participants consent on the premise of contributing to new medical knowledge, Research Ethics Committees (RECs) spend considerable effort reviewing study protocols, and limited resources for conducting research are wasted. Currently, little is known regarding the frequency and characteristics of discontinued RCTs., Methods/design: Our aims are, first, to determine the prevalence of RCT discontinuation for specific reasons; second, to determine whether the risk of RCT discontinuation for specific reasons differs between investigator- and industry-initiated RCTs; third, to identify risk factors for RCT discontinuation due to insufficient recruitment; fourth, to determine at what stage RCTs are discontinued; and fifth, to examine the publication history of discontinued RCTs.We are currently assembling a multicenter cohort of RCTs based on protocols approved between 2000 and 2002/3 by 6 RECs in Switzerland, Germany, and Canada. We are extracting data on RCT characteristics and planned recruitment for all included protocols. Completion and publication status is determined using information from correspondence between investigators and RECs, publications identified through literature searches, or by contacting the investigators. We will use multivariable regression models to identify risk factors for trial discontinuation due to insufficient recruitment. We aim to include over 1000 RCTs of which an anticipated 150 will have been discontinued due to insufficient recruitment., Discussion: Our study will provide insights into the prevalence and characteristics of RCTs that were discontinued. Effective recruitment strategies and the anticipation of problems are key issues in the planning and evaluation of trials by investigators, Clinical Trial Units, RECs and funding agencies. Identification and modification of barriers to successful study completion at an early stage could help to reduce the risk of trial discontinuation, save limited resources, and enable RCTs to better meet their ethical requirements.

This is the protocol for a review and there is no abstract. The objectives are as follows: To assess the clinical benefit and harm of fibrates versus placebo or usual care or fibrates plus other lipid-modifying drugs versus other lipid-modifying drugs alone for the primary prevention of CVD events and mortality.

Objective: Research has shown 1.5 minutes of surgical hand antisepsis with alcohol-based hand rub to be at least as effective under experimental conditions as the 3-minute reference disinfection recommended by European Norm 12791. The aim of the present study was to validate the effectiveness of 1.5 minutes of surgical hand antisepsis in a clinical setting by comparing the effectiveness of 1.5- and 3-minute applications of alcohol-based hand rub (45% vol/vol 2-propanol, 30% vol/vol 1-propanol, and 0.2% mecetronium ethylsulphate)., Design: Prospective crossover trial in which each surgeon served as his or her own control, with individual randomization to the 1.5- or the 3-minute group during the first part of the trial., Setting: Basel University Hospital, Switzerland., Participants: Thirty-two surgeons with different levels of postdoctoral training., Methods: We measured the bactericidal effectiveness of 1.5 minutes and 3 minutes of surgical hand antisepsis with alcohol-based hand rub by assessing the mean (+/-SD) log10 number of colony-forming units before the application of hand rub (baseline), after the application of hand rub (immediate effect), and after surgery (sustained effect) so as to follow European Norm 12791 as closely as possible., Results: The immediate mean (+/-SD) log10 reduction in colony-forming units (cfu) was 2.26 +/- 1.13 log10 cfu for the 1.5-minute group and 3.01 +/- 1.06 log10 cfu for the 3-minute group (P = .204). Similarly, there was no statistically significant difference between the 2 groups with respect to the sustained effect; the mean (+/-SD) log10 increase in bacterial density during surgery was 1.08 +/- 1.13 log10 cfu for the 1.5-minute group and 0.95 +/- 1.27 log10 cfu for the 3-minute group (P = .708). No adverse effects were recorded., Conclusion: In this clinical trial, surgical hand antisepsis with alcohol-based hand rub resulted in a similar bacterial reduction, regardless of whether it was applied for 3 or 1.5 minutes, which confirms experimental data generated with healthy volunteers.