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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.

International audience; Concerns have been raised that regulatory programs to accelerate approval of cancer drugs in cancer may increase uncertainty about benefits and harms for survival and quality of life (QoL). We analyzed all pivotal clinical trials and all non-pivotal randomized controlled trials (RCTs) for all cancer drugs approved for the first time by the FDA between 2000 and 2020. We report regulatory and trial characteristics. Effects on overall survival (OS), progression-free survival and tumor response were summarized in meta-analyses. Effects on QoL were qualitatively summarized. Between 2000 and 2020, the FDA approved 145 novel cancer drugs for 156 indications based on 190 clinical trials. Half of indications (49%) were approved without RCT evidence; 82% had a single clinical trial only. OS was primary endpoint in 14% of trials and QoL data were available from 25%. The median OS benefit was 2.55 months (IQR, 1.33-4.28) with a mean hazard ratio for OS of 0.75 (95%CI, 0.72-0.79, I(2) = 42). Improvement for QoL was reported for 7 (4%) of 156 indications. Over time, priority review was used increasingly and the mean number of trials per indication decreased from 1.45 to 1.12. More trials reported results on QoL (19% in 2000-2005; 41% in 2016-2020). For 21 years, novel cancer drugs have typically been approved based on one single, often uncontrolled, clinical trial, measuring surrogate endpoints. This leaves cancer patients without solid evidence that novel drugs improve their survival or QoL and there is no indication towards improvement.

OBJECTIVES: To determine the prevalence and predictors of subclinical giant cell arteritis (GCA) in patients with newly diagnosed polymyalgia rheumatica (PMR). METHODS: PubMed, Embase, and Web of Science Core Collection were systematically searched (date of last search July 14, 2021) for any published information on any consecutively recruited cohort reporting the prevalence of GCA in steroid-naïve patients with PMR without cranial or ischemic symptoms. We combined prevalences across populations in a random-effect meta-analysis. Potential predictors of subclinical GCA were identified by mixed-effect logistic regression using individual patient data (IPD) from cohorts screened with PET/(CT). RESULTS: We included 13 cohorts with 566 patients from studies published between 1965 to 2020. Subclinical GCA was diagnosed by temporal artery biopsy in three studies, ultrasound in three studies, and PET/(CT) in seven studies. The pooled prevalence of subclinical GCA across all studies was 23% (95% CI 14%-36%, I2=84%) for any screening method and 29% in the studies using PET/(CT) (95% CI 13%-53%, I2=85%) (n=266 patients). For seven cohorts we obtained IPD for 243 patients screened with PET/(CT). Inflammatory back pain (OR 2.73, 1.32-5.64), absence of lower limb pain (OR 2.35, 1.05-5.26), female sex (OR 2.31, 1.17-4.58), temperature >37° (OR 1.83, 0.90-3.71), weight loss (OR 1.83, 0.96-3.51), thrombocyte count (OR 1.51, 1.05-2.18), and haemoglobin level (OR 0.80, 0.64-1.00) were most strongly associated with subclinical GCA in the univariable analysis but not C-reactive protein (OR 1.00, 1.00-1.01) or erythrocyte sedimentation rate (OR 1.01, 1.00-1.02). A prediction model calculated from these variables had an area under the curve of 0.66 (95% CI 0.55-0.75). CONCLUSION: More than a quarter of patients with PMR may have subclinical GCA. The prediction model from the most extensive IPD set has only modest diagnostic accuracy. Hence, a paradigm shift in the assessment of PMR patients in favour of implementing imaging studies should be discussed. ispartof: SEMINARS IN ARTHRITIS AND RHEUMATISM vol:55 ispartof: location:United States status: published

Objectives: To systematically assess the kind of placebos used in investigator-initiated randomized controlled trials (RCTs), from where they are obtained, and the hurdles that exist in obtaining them. Study Design and Setting: PubMed was searched for recently published noncommercial, placebo-controlled randomized drug trials. Corresponding authors were invited to participate in an online survey. Results: From 423 eligible articles, 109 (26%) corresponding authors (partially) participated. Twenty-one of 102 (21%) authors reported that the placebos used were not matching (correctly labeled in only one publication). The main sources in obtaining placebos were hospital pharmacies (32 of 107; 30%) and the manufacturer of the study drug (28 of 107; 26%). RCTs with a hypothesis in the interest of the manufacturer of the study drug were more likely to have obtained placebos from the drug manufacturer (18 of 49; 37% vs. 5 of 29; 17%). Median costs for placebos and packaging were US$ 58,286 (IQR US$ 2,428– US$ 160,770; n = 24), accounting for a median of 10.3% of the overall trial budget. Conclusion: Although using matching placebos is widely accepted as a basic practice in RCTs, there seems to be no standard source to acquire them. Obtaining placebos requires substantial resources, and using nonmatching placebos is common.

ImportanceThere is concern that post-acute SARS-CoV-2 infection health outcomes (“post-COVID syndrome”) in children could be a serious problem but at the same time there is concern about the validity of reported associations between infection and long-term outcomes.ObjectiveTo systematically assess the validity of reported post-acute SARS-CoV-2 infection health outcomes in children.Evidence ReviewA search on PubMed and Web of Science was conducted to identify studies published up to January 22, 2022, that reported on post-acute SARS-CoV-2 infection health outcomes in children (Findings21 studies including 81,896 children reported up to 97 symptoms with follow-up periods of 2-11.5 months. Fifteen studies had no control group. The reported proportion of children with post-COVID syndrome was between 0% and 66.5% in children with SARS-CoV-2 infection (n=16,986) and 2% to 53.3% in children without SARS-CoV-2 infection (n=64,910). Only 2 studies made a clear causal interpretation of an association of SARS-CoV-2 infection and the main outcome of “post-COVID syndrome” and provided recommendations regarding prevention measures. Two studies mentioned potential limitations in the conclusion of the main text but none of the 21 studies mentioned any limitations in the abstract nor made a clear statement for cautious interpretation. The validity of all 21 studies was seriously limited due to an overall critical risk of bias (critical risk for confounding bias [n=21]; serious or critical risk for selection bias [n=19]; serious risk for misclassification bias [n=3], for bias due to missing data [n=14] and for outcome measurement [n=12]; and critical risk for selective reporting bias [n=16]).Conclusions and RelevanceThe validity of reported post-acute SARS-CoV-2 infection health outcomes in children is critically limited. None of the studies provided evidence with reasonable certainty on whether SARS-CoV-2 infection has an impact on post-acute health outcomes, let alone to what extent. Children and their families urgently need much more reliable and methodologically robust evidence to address their concerns and improve care.KEY POINTSQuestionHow valid are the reported results on health outcomes in children after acute SARS-CoV-2 infection?FindingsWe identified 21 studies with only 6 using a controlled design. Reported post-acute health-outcomes were numerous and heterogeneous. The reported proportion of children with post-COVID syndrome was up to 66.5% in children with and 53.3% in children without SARS-CoV-2 infection. All studies had seriously limited validity due to critical and serious risk of bias in multiple domains.MeaningThe validity of reported post-acute SARS-CoV-2 infection health outcomes in children is critically limited and methodological robust evidence is urgently needed.

ObjectivesComprehensive 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.DesignRepeated cross sectional study.SettingSwiss, German and Canadian research ethics committees (RECs).ParticipantsRCT protocols approved by RECs in 2012 (n=257) and 2016 (n=292).Primary and secondary outcome measuresThe 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 reportedResultsThe 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.ConclusionsIn 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.

BACKGROUND Several available therapies for neuroendocrine tumours (NETs) have demonstrated efficacy in randomised controlled trials.��However, translation of these results into improved care faces several challenges, as a direct comparison of the most pertinent therapies is incomplete. OBJECTIVES To evaluate the safety and efficacy of therapies for��NETs, to guide clinical decision-making, and to provide estimates of relative efficiency of the different treatment options (including placebo) and rank the treatments according to their efficiency based on a network meta-analysis. SEARCH METHODS We identified studies through systematic searches of the following bibliographic databases:��the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library; MEDLINE (Ovid); and Embase from January 1947��to December 2020. In addition,��we checked trial registries��for ongoing or unpublished eligible trials and manually searched for abstracts from scientific and clinical meetings. SELECTION CRITERIA We evaluated randomised controlled trials (RCTs) comparing two or more therapies in people with NETs (primarily gastrointestinal and pancreatic). DATA COLLECTION AND ANALYSIS Two review authors independently selected studies and extracted data to a pre-designed data extraction form. Multi-arm studies were included in the network meta-analysis using the R-package netmeta. We separately analysed two different outcomes (disease control and progression-free survival) and two types of NET (gastrointestinal and pancreatic NET) in four network meta-analyses.��A frequentist approach was used to compare the efficacy of therapies. MAIN RESULTS We identified 55 studies in 90 records in the qualitative analysis, reporting 39 primary RCTs and 16 subgroup analyses. We included 22 RCTs, with 4299��participants, that reported disease control and/or progression-free survival in the network meta-analysis. Precision-of-treatment estimates and estimated heterogeneity were limited, although the risk of bias was predominantly low. The network meta-analysis of progression-free survival found nine therapies for pancreatic NETs: everolimus (hazard ratio [HR], 0.36 [95% CI, 0.28 to 0.46]), interferon plus somatostatin analogue (HR, 0.34 [95% CI, 0.14 to 0.80]), everolimus plus somatostatin analogue (HR, 0.38 [95% CI, 0.26 to 0.57]), bevacizumab plus somatostatin analogue (HR, 0.36 [95% CI, 0.15 to 0.89]), interferon (HR, 0.41 [95% CI, 0.18 to 0.94]), sunitinib (HR, 0.42 [95% CI, 0.26 to 0.67]), everolimus plus bevacizumab plus somatostatin analogue (HR, 0.48 [95% CI, 0.28 to 0.83]), surufatinib (HR, 0.49 [95% CI, 0.32 to 0.76]), and somatostatin analogue (HR, 0.51 [95% CI, 0.34 to 0.77]); and six therapies for gastrointestinal NETs: 177-Lu-DOTATATE plus somatostatin analogue (HR, 0.07 [95% CI, 0.02 to 0.26]), everolimus plus somatostatin analogue (HR, 0.12 [95%CI, 0.03 to 0.54]), bevacizumab plus somatostatin analogue (HR, 0.18 [95% CI, 0.04 to 0.94]), interferon plus somatostatin analogue (HR, 0.23 [95% CI, 0.06 to 0.93]), surufatinib (HR, 0.33 [95%CI, 0.12 to 0.88]), and somatostatin analogue (HR, 0.34 [95% CI, 0.16 to 0.76]), with higher efficacy than placebo. Besides everolimus for pancreatic NETs, the results suggested an overall superiority of combination therapies, including somatostatin analogues. The results indicate that NET therapies have a broad range of risk for adverse events and effects on quality of life, but these were reported inconsistently. Evidence from this network meta-analysis (and underlying RCTs) does not support any particular therapy (or combinations of therapies) with respect to patient-centred outcomes��(e.g. overall survival and quality of life). AUTHORS' CONCLUSIONS The findings from this study suggest that a range of efficient therapies with different safety profiles is available for people with NETs.

Objectives: We aimed to provide a systematic overview of freely available tools which may help plan or monitor costs for randomized clinical trials (RCTs). Study Design and Setting: We systematically searched MEDLINE, EMBASE, and EconLit and conducted internet searches via Google (last search, October 2018). We included all freely available tools and determined their specific purpose, which parts of clinical trial projects and which types of costs they covered, and if they were user-tested or validated in any form. Results: We identified 25 available tools. Most tools were downloadable on websites from institutions related to clinical research. Seven tools were developed to plan the budget for an entire RCT, 17 tools for calculating budgets of an individual trial center, and one tool for monitoring costs of ongoing RCTs. Eighteen tools considered fixed, variable, and indirect costs. Only two tools were clearly user-tested or validated. Conclusion: Several freely available tools aim to support investigators in planning costs of an entire trial or in planning the budget for a clinical trial site. How valid and useful they are remains to be shown for most of them. Future tools should be openly shared, user-tested, and validated.

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 Shifts in data sharing policy have increased researchers’ access to individual participant data (IPD) from clinical studies. Simultaneously the number of IPD meta-analyses (IPDMAs) is increasing. However, rates of data retrieval have not improved. Our goal was to describe the challenges of retrieving IPD for an IPDMA and provide practical guidance on obtaining and managing datasets based on a review of the literature and practical examples and observations. Methods We systematically searched MEDLINE, Embase, and the Cochrane Library, until January 2019, to identify publications focused on strategies to obtain IPD. In addition, we searched pharmaceutical websites and contacted industry organizations for supplemental information pertaining to recent advances in industry policy and practice. Finally, we documented setbacks and solutions encountered while completing a comprehensive IPDMA and drew on previous experiences related to seeking and using IPD. Results Our scoping review identified 16 articles directly relevant for the conduct of IPDMAs. We present short descriptions of these articles alongside overviews of IPD sharing policies and procedures of pharmaceutical companies which display certification of Principles for Responsible Clinical Trial Data Sharing via Pharmaceutical Research and Manufacturers of America or European Federation of Pharmaceutical Industries and Associations websites. Advances in data sharing policy and practice affected the way in which data is requested, obtained, stored and analyzed. For our IPDMA it took 6.5 years to collect and analyze relevant IPD and navigate additional administrative barriers. Delays in obtaining data were largely due to challenges in communication with study sponsors, frequent changes in data sharing policies of study sponsors, and the requirement for a diverse skillset related to research, administrative, statistical and legal issues. Conclusions Knowledge of current data sharing practices and platforms as well as anticipation of necessary tasks and potential obstacles may reduce time and resources required for obtaining and managing data for an IPDMA. Sufficient project funding and timeline flexibility are pre-requisites for successful collection and analysis of IPD. IPDMA researchers must acknowledge the additional and unexpected responsibility they are placing on corresponding study authors or data sharing administrators and should offer assistance in readying data for sharing.

Background Randomised trial protocols may incorporate interim analyses, with the potential to stop the study for futility if early data show insufficient promise of a treatment benefit. Previously, we have shown that this approach will theoretically lead to mis-estimation of the treatment effect. We now wished to ascertain the importance of this phenomenon in practice. Methods We reviewed the methods and results in a set of trials that had stopped for futility, identified through an extensive literature search. We recorded clinical areas, interventions, study design, outcomes, trial setting, sponsorship, planned and actual treatment effects, sample sizes; power; and if there was a data safety monitoring board, or a published protocol. We identified: if interim analyses were pre-specified, and how many analyses actually occurred; what pre-specified criteria might define futility; if a futility analysis formed the basis for stopping; who made the decision to stop; and the conditional power of each study, i.e. the probability of statistically significant results if the study were to continue to its complete sample size. Results We identified 52 eligible trials, covering many clinical areas. Most trials had multiple centres, tested drugs, and 40% were industry sponsored. There were 75% where at least one interim analysis was planned a priori; a majority had only one interim analysis, typically with about half the target total sample size. A majority of trials did not pre-define a stopping rule, and a variety of reasons were given for stopping. Few studies calculated and reported low conditional power to justify the early stop. When conditional power could be calculated, it was typically low, especially under the current trend hypothesis. However, under the original design hypothesis, a few studies had relatively high conditional power. Data collection often continued after the interim analysis. Conclusions Although other factors will typically be involved, we conclude that, from the perspective of conditional power, stopping early for futility was probably reasonable in most cases, but documentation of the basis for stopping was often missing or vague. Interpretation of truncated trials would be enhanced by improved reporting of stopping protocols, and of their actual execution.

Objectives Well conducted randomised controlled trials (RCTs) generate the most trustworthy evidence when newly developed or already existing clinical interventions are evaluated. However, RCTs require substantial resources and the costs seem to be increasing over time. As a result, the number of independent investigator-initiated RCTs decreased and a considerable proportion of RCTs are prematurely discontinued due to recruitment delays. Especially in academic research, it is common that clinical studies are underfinanced or that the compensations paid by funders or industries do not cover the actual costs. Therefore, tools for investigators to plan their budgets accurately are essential for the successful conduct of an RCT. In this scoping review we aimed to give an overview of the publicly available budget planning tools. Method We systematically searched Medline, EMBASE (both via Ovid) and EconLit from inception until May 2018. Additionally, two reviewers conducted an internet search between June and October 2018. We included any tools or cost templates and categorised them if they were primarily intended to (i) plan a budget for an entire RCT, (ii) plan a budget for a separate centre participating in a RCT, or (iii) monitor costs during the conduct of an RCT. From all tools we assessed if they considered direct costs (fixed costs and variable costs) as well as indirect costs, and if they were user tested or validated in any form. Results We identified 25 tools which were included (i.e. two from the literature search and 23 from the internet search). Of those, 22 tools consisted of programmed Microsoft excel sheets. Seven tools were developed to plan the budget for an entire RCT, 17 tools helped to calculate budgets for a separate study centre participating in an RCT, and the purpose of one tool was to monitor ongoing costs of RCTs. Direct costs, consisting of fixed costs and variable costs were considered by 25 and 21 tools, respectively. Indirect costs were considered by 19 tools. Overall, 18 tools considered all three of these cost aspects. Of the seven tools which can be used to plan costs of an entire RCT, only two included all three relevant cost aspects. Overall, we identified a description of user testing or validation for two tools only. Conclusions A variety of freely accessible budget planning tools for RCTs exist. Most of the tools were developed internally by different institutions and were not published in a scientific journal. Often it remained unclear if they underwent any form of validation or if they can also be applied in a useful way by researchers who are not part of the institution which developed the tool. We did not find any evidence during this project that a single tool was broadly applied for planning RCT budgets. The fact that many different organisations put effort in developing a budgeting tool shows that the need for accurate planning of RCT budgets was recognised at many levels. Identifying or creating a user-friendly tool which can be used flexibly for different RCTs in different settings should therefore be a research priority.

Background Adequate reporting is crucial in full-text publications but even more so in abstracts because they are the most frequently read part of a publication. In 2008, an extension for abstracts of the Consolidated Standards of Reporting Trials (CONSORT-A) statement was published, defining which items should be reported in abstracts of randomized controlled trials (RCTs). Therefore, we compared the adherence of RCT abstracts to CONSORT-A before and after the publication of CONSORT-A. Methods RCTs published in the five surgical journals with the highest impact factor were identified through PubMed for 2005–2007 and 2014–2016. Adherence to 15 CONSORT-A items and two additional items for abstracts of non-pharmacological trials was assessed in duplicate. We compared the overall adherence to CONSORT-A between the two time periods using an unpaired t test and explored adherence to specific items. Results A total of 192 and 164 surgical RCT abstracts were assessed (2005–2007 and 2014–2016, respectively). In the pre-CONSORT-A phase, the mean score of adequately reported items was 6.14 (95% confidence interval [CI] 5.90–6.38) and 8.11 in the post-CONSORT-A phase (95% CI 7.83–8.39; mean difference 1.97, 95% CI 1.60–2.34; p

Background The clinical efficacy and safety of combination therapy with acetylcholinesterase inhibitor (AChEI) and memantine compared to AChEI or memantine alone in patients with Alzheimerrs disease is inconclusive. Aims of the study We conducted a systematic review and meta-analysis of randomised controlled trials (RCTs) comparing the clinical efficacy and safety of combination therapy of AChEI and memantine to monotherapy with either substance in patients with moderate to severe Alzheimer's disease (Mini-Mental State Examination score is l20). Methods We systematically searched EMBASE, Medline and CENTRAL until February 2018 for eligible RCTs. We pooled the outcome data using inverse variance weighting models assuming random effects, and assessed the quality of evidence (QoE) according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE). Results We included nine RCTs (2604 patients). At short-term follow-up (closest to 6 months), combination therapy compared to AChEI monotherapy had a significantly greater effect on cognition than AChEI monotherapy (standardised mean difference [SMD] 0.20, 95% confidence interval [CI] 0.05 to 0.35, 7 RCTs, low QoE) and clinical global impression (SMD m0.15, 95% CI m0.28 to m0.01, 4 RCTs, moderate QoE), but not on activities of daily living (SMD 0.09, 95% CI m0.01 to 0.18, 5 RCTs, moderate QoE) or behavioural and psychological symptoms of dementia (mean difference m3.07, 95% CI m6.53 to 0.38, 6 RCT, low QoE). There was no significant difference in adverse events (relative risk ratio 1.05, 95% CI 0.98 to 1.12, 4 RCTs, low QoE). Evidence for long-term follow-up (g 9 months) or nursing home placement was sparse. Only two studies compared combination therapy with memantine monotherapy. Conclusions Combination therapy had statistically significant effects on cognition and clinical global impression. The clinical relevance of these effects is uncertain. The overall QoE was very low. With the current evidence, it remains unclear whether combination therapy adds any benefit. Large pragmatic RCTs with long-term follow-up and focus on functional outcomes, delay in nursing home placement and adverse events are needed. &nbsp.

Importance Multiple therapies are currently available for patients with neuroendocrine tumors (NETs), yet many therapies have not been compared head-to-head within randomized clinical trials (RCTs). Objective To assess the relative safety and efficacy of therapies for NETs. Data Sources PubMed, Embase, the Cochrane Central Register of Controlled Trials, trial registries, meeting abstracts, and reference lists from January 1, 1947, to March 2, 2018, were searched. Key search terms included neuroendocrine tumors, gastrointestinal neoplasms, therapy, and randomized controlled trial. Study Selection Randomized clinical trials comparing 2 or more therapies in patients with NETs (primarily gastrointestinal and pancreatic) were evaluated. Thirty RCTs met the selection criteria. Data Extraction and Synthesis Pairs of independent reviewers screened studies, extracted data, and assessed the risk of bias. A network meta-analysis with a frequentist approach was used to compare the efficacy of therapies; the Preferred Reporting Items for Systematic Reviews and Meta-analyses guideline was used. Main Outcomes and Measures Disease control, progression-free survival, overall survival, adverse events, and quality of life. Results The systematic review identified 30 relevant RCTs comprising 3895 patients (48.4% women) assigned to 22 different therapies for NETs. These therapies showed a broad range of risk for serious and nonserious adverse events. The network meta-analyses included 16 RCTs with predominantly a low risk of bias; nevertheless, precision-of-treatment estimates and estimated heterogeneity were limited. The network meta-analysis found 7 therapies for pancreatic NETs: everolimus (hazard ratio [HR], 0.35 [95% CI, 0.28-0.45]), everolimus plus somatostatin analogue (HR, 0.35 [95% CI, 0.25-0.51]), everolimus plus bevacizumab plus somatostatin analogue (HR, 0.44 [95% CI, 0.26-0.75]), interferon (HR, 0.37 [95% CI, 0.16-0.83]) interferon plus somatostatin analogue (HR, 0.31 [95% CI, 0.13-0.71]), somatostatin analogue (HR, 0.46 [95% CI, 0.33-0.66]) , and sunitinib (HR, 0.42 [95% CI, 0.26-0.67]) and 5 therapies for gastrointestinal NETs: bevacizumab plus somatostatin analogue (HR, 0.22 [95% CI, 0.05-0.99]), everolimus plus somatostatin analogue (HR, 0.31 [95% CI, 0.11-0.90]), interferon plus somatostatin analogue (HR, 0.27 [95% CI, 0.07-0.96]), Lu 177-dotatate plus somatostatin analogue (HR, 0.08 [95% CI, 0.03-0.26], and somatostatin analogues (HR, 0.40 [95% CI, 0.21-0.78]) with higher efficacy than placebo and suggests an overall superiority of combination therapies. Conclusions and Relevance The findings from this study suggest that a range of efficient therapies with different safety profiles is available for patients with NETs.

Importance: Convalescent plasma is a proposed treatment for COVID-19. Objective: To assess clinical outcomes with convalescent plasma treatment vs placebo or standard of care in peer-reviewed and preprint publications or press releases of randomized clinical trials (RCTs). Data Sources: PubMed, the Cochrane COVID-19 trial registry, and the Living Overview of Evidence platform were searched until January 29, 2021. Study Selection: The RCTs selected compared any type of convalescent plasma vs placebo or standard of care for patients with confirmed or suspected COVID-19 in any treatment setting. Data Extraction and Synthesis: Two reviewers independently extracted data on relevant clinical outcomes, trial characteristics, and patient characteristics and used the Cochrane Risk of Bias Assessment Tool. The primary analysis included peer-reviewed publications of RCTs only, whereas the secondary analysis included all publicly available RCT data (peer-reviewed publications, preprints, and press releases). Inverse variance-weighted meta-analyses were conducted to summarize the treatment effects. The certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation. Main Outcomes and Measures: All-cause mortality, length of hospital stay, clinical improvement, clinical deterioration, mechanical ventilation use, and serious adverse events. Results: A total of 1060 patients from 4 peer-reviewed RCTs and 10 722 patients from 6 other publicly available RCTs were included. The summary risk ratio (RR) for all-cause mortality with convalescent plasma in the 4 peer-reviewed RCTs was 0.93 (95% CI, 0.63 to 1.38), the absolute risk difference was -1.21% (95% CI, -5.29% to 2.88%), and there was low certainty of the evidence due to imprecision. Across all 10 RCTs, the summary RR was 1.02 (95% CI, 0.92 to 1.12) and there was moderate certainty of the evidence due to inclusion of unpublished data. Among the peer-reviewed RCTs, the summary hazard ratio was 1.17 (95% CI, 0.07 to 20.34) for length of hospital stay, the summary RR was 0.76 (95% CI, 0.20 to 2.87) for mechanical ventilation use (the absolute risk difference for mechanical ventilation use was -2.56% [95% CI, -13.16% to 8.05%]), and there was low certainty of the evidence due to imprecision for both outcomes. Limited data on clinical improvement, clinical deterioration, and serious adverse events showed no significant differences. Conclusions and Relevance: Treatment with convalescent plasma compared with placebo or standard of care was not significantly associated with a decrease in all-cause mortality or with any benefit for other clinical outcomes. The certainty of the evidence was low to moderate for all-cause mortality and low for other outcomes.

BACKGROUND To ensure ethical oversight, researchers wanting to conduct “research” involving human beings are typically required to obtain prior approval from an independent ethics committee. However, it can sometimes be unclear if a project needs to be submitted for ethics approval. Swiss researchers can contact research ethics committees via a “jurisdictional inquiry” for clarification whether a project needs to be submitted for ethics approval. AIMS OF THE STUDY (1) To examine the characteristics of Swiss jurisdictional inquiries, and (2) to identify possible uncertainties regarding the correct interpretation of existing legislation in Switzerland. METHODS All jurisdictional inquiries submitted to Swiss research ethics committees between July and December 2017 were reviewed using qualitative content analysis. We then conducted an online survey between June 2018 and July 2018 with all researchers who had submitted a jurisdictional inquiry including a descriptive quantitative analysis. RESULTS The review included 271 jurisdictional inquiries. Analysis identified three groups of jurisdictional inquiries: 80.4% (218/271) sought clarification whether the project had to be submitted for ethical approval; 18.5% (50/271) requested a “declaration of no objection”; and 1.1% (3/271) asked for a clarification about which of the two ordinances was applicable to the project. Analysis identified eight distinct legal issues that appeared to be the main cause for a number of jurisdictional inquiries, with the two most frequently identified issues being whether the project will produce generalisable knowledge, and whether the project uses fully anonymised data. Overall, research ethics committees decided that 78.6% (213/271) of the jurisdictional inquiries were outside their jurisdiction and did not require ethical approval, and that 15.6% required submission for ethical approval. The online survey achieved a 56.8% response rate. The majority of respondents (94/166; 56.6%) reported that all the questions they were asked during the submission of the jurisdictional inquiry were easy to understand. Respondents reported that 88% (147/166) of all projects were started or planned to start. The vast majority (154/166; 93%) of respondents also agreed with the decisions made by the research ethics committee. CONCLUSIONS Jurisdictional inquiries are an important means for researchers to clarify whether their project requires ethical oversight. However, this mixed-methods study has identified some difficulties in the interpretation of legal terms, which often reflect persistent structural issues that many other countries also face. More detailed guidance may be helpful to reduce the researchers’ uncertainties and ethics committees’ workloads in relation to jurisdictional inquiries.

OBJECTIVES The aims of this study were to (a) identify and assess the quality of reporting of published cost-effectiveness studies of bariatric surgery, (b) assess their transferability to Switzerland, and (c) adapt transferable cost-effectiveness results to Switzerland. METHODS A systematic literature search was performed in Medline, Embase and other databases. Two reviewers independently undertook screening, extraction, assessment of reporting quality utilising the Consolidated Health Economic Evaluation Reporting Standards, transferability, adaptation of cost data and recalculation of cost-effectiveness results. Cost data were adapted in three steps: correction for different levels of resource utilisation, for different prices of healthcare services and for change in costs over time. RESULTS Fifteen studies fulfilled criteria for adaptation of cost data to Switzerland. Four out of fifteen adapted studies with a long time-horizon for patients with a body mass index (BMI) >35kg/m2 indicated bariatric surgery to be a cost-saving (dominant) approach compared with conventional treatment. Other studies for patients with BMI >35kg/m2 showed cost-effective results, with incremental cost-effectiveness ratios (ICERs) below CHF 50,000 per quality adjusted life-year (QALY) gained. Two studies assessed cost-effectiveness for patients with BMI

Background Multiple surgical procedures in a single patient are relatively common and lead to dependent (clustered) data. This dependency needs to be accounted for in study design and data analysis. A systematic review was performed to assess how clustered data were handled in inguinal hernia trials. The impact of ignoring clustered data was estimated using simulations. Methods PubMed, Embase and the Cochrane Library were reviewed systematically for RCTs published between 2004 and 2013, including patients undergoing unilateral or bilateral inguinal hernia repair. Study characteristics determining the appropriateness of handling clustered data were extracted. Using simulations, various statistical methods accounting for clustered data were compared with an analysis ignoring clustering by assuming 100 hernias, with a varying percentage of patients having bilateral hernias. Results Of the 50 eligible trials including patients with bilateral hernias, 20 (40 per cent) did not provide information on how they dealt with clustered data and 18 (36 per cent) avoided clustering by assessing the outcome by patient and not by hernia. None of the remaining 12 trials (24 per cent) considered clustering in the design or analysis. In the simulations, ignoring clustering led to an increased type I error rate of up to 12 per cent and to a loss in power of up to 15 per cent, depending on whether the patient or the hernia was the randomization unit. Conclusion Clustering was rarely considered in inguinal hernia trials. The simulations underline the importance of considering clustering as part of the statistical analysis to avoid false-positive and false-negative results, and hence inappropriate study conclusions.

Reason for withdrawal from publication This protocol has been withdrawn from the Cochrane Library because there is an overlap with the published Cochrane Review on "Nutrition support in hospitalised adults at nutritional risk".

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.

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 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

AIMS OF THE STUDY To assess the cost-effectiveness of primarily surgical treatment (PST) versus primarily conservative treatment (PCT) in adults with intermediate severity, acute or subacute, lumbar radicular syndrome due to intervertebral disc herniation. METHODS A decision analytic model from healthcare system and societal perspectives was used to compare outcomes and costs of PST with those of PCT (physiotherapy, epidural injection and medication). Treatment pathways and quality of life were obtained from published clinical trials. Costs were derived from Swiss health insurance claims data. Swiss clinical experts provided information on use of medication and physiotherapy. The main outcome of interest was incremental cost per quality-adjusted-life-year (QALY) gained over a period of 2 years. Costs and QALYs gained were discounted from the second year, at a rate of 2% per year. RESULTS In the base-case analysis from a healthcare system perspective, over 2 years, PST compared with PCT led to 0.0634 additional QALYs per person, at an additional net cost of CHF 7198 per person. The corresponding incremental cost effectiveness ratio (ICER) amounted to CHF 113 396 per QALY gained. From a societal perspective the ICER was CHF 70 711 per QALY gained. ICERs were subject to substantial uncertainty because of limitations in available data. CONCLUSION A PST approach, when compared with PCT, may be cost effective from a societal perspective based on a willingness-to-pay threshold of CHF 100 000 per QALY gained. However, it is less likely to be cost effective from the perspective of the Swiss healthcare system. More research is needed to understand the long-term economic implications among this patient group.

The long-term effects of bariatric surgery have yet to be established, and a number of important studies have recently emerged. This systematic review aimed to assess the effects of bariatric surgery on all-cause mortality, cardiovascular events, and cancer compared to non-surgical treatment. We searched PubMed, EMBASE, and CENTRAL up to July 13, 2015, and included randomized controlled trials (RCTs) and non-randomized controlled studies comparing bariatric surgery versus non-surgical treatment and reporting data on the three defined outcomes at 1 year or longer. We analyzed RCTs and non-randomized controlled studies, respectively. Eleven RCTs, 4 non-randomized controlled trials, and 17 cohort studies were included. The randomized evidence suggested substantial uncertainty regarding the effects on all-cause mortality (0/382 vs. 1/287; 7 studies), cancer (OR 0.77, 95 % CI 0.22 to 2.71; 4 studies), and cardiovascular events (no data). The pooled adjusted estimates from non-randomized studies suggested that, compared to the control, the surgical group had lower risk of all-cause mortality (OR 0.55, 95 % CI 0.46 to 0.65; 10 studies), cancer (OR 0.74, 95 % CI 0.65 to 0.85; 2 studies), and cardiovascular events (MI: OR 0.71, 95 % CI 0.54 to 0.94; stroke: OR 0.66, 95 % CI 0.49 to 0.89; and their composite: OR 0.67, 95 % CI 0.54 to 0.83; 1 study). In conclusion, bariatric surgery could reduce all-cause mortality and probably reduce the risk of any type of cancer. The inference was, however, based on studies with limited methodological rigor. Uncertainty remains regarding the effects on cardiovascular events.

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 (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., In a document analysis of trial protocols and publications, Erik von Elm and colleagues investigate the potential impact of publication agreements between industry sponsors and academic investigators., Author Summary Why Was This Study Done? Many randomized trials are designed and sponsored by for-profit companies that contract academic investigators to recruit and manage patients. Clinical research under these circumstances is a business transaction that bears the potential for conflicts of interest, in particular with respect to trial publication. Besides evidence from a small sample, it was unclear how often trial protocols included publication agreements between industry and academic investigators, whether these agreements constrained the investigators’ publication rights, and how consistent such agreements stated in trial protocols were with those reported in corresponding publications. What Did the Researchers Do and Find? We investigated publication agreements in 647 randomized trial protocols approved in 2000–2003 by six research ethics committees in Switzerland, Canada, and Germany, and in 388 corresponding journal publications. Seventy percent of protocols mentioned an agreement on publication rights between industry and academic investigators; in 86% of those agreements, industry retained the right to disapprove or at least review manuscripts before publication. Seventy-four percent of agreements documented in protocols were not mentioned in corresponding journal articles. What Do These Findings Mean? Publication agreements constraining academic investigators’ independence are incompletely reported in publications; this may compromise the scientific evidence base established by randomized clinical trials. More transparency on publication constraints is warranted. Half of the included journal articles were published before 2008, leaving open the possibility that these findings do not reflect current reporting practice.

Background Streptococcus pneumoniae is responsible for approximately 1.6 million yearly deaths worldwide. An up-to-date evidence base on the effects of pneumococcal conjugate vaccines (PCVs) on infectious diseases and mortality in any population or setting regardless of age or health status is currently lacking.

Background Colchicine is an anti-inflammatory drug that is used for a wide range of inflammatory diseases. Cardiovascular disease also has an inflammatory component but the effects of colchicine on cardiovascular outcomes remain unclear. Previous safety analyses were restricted to specific patient populations. Objectives To evaluate potential cardiovascular benefits and harms of a continuous long-term treatment with colchicine in any population, and specifically in people with high cardiovascular risk. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, ClinicalTrials.gov, WHO International Clinical Trials Registry, citations of key papers, and study references in January 2015. We also contacted investigators to gain unpublished data. Selection criteria Randomised controlled trials (parallel-group or cluster design or first phases of cross-over studies) comparing colchicine over at least six months versus any control in any adult population. Data collection and analysis Primary outcomes were all-cause mortality, myocardial infarction, and adverse events. Secondary outcomes were cardiovascular mortality, stroke, heart failure, non-scheduled hospitalisations, and non-scheduled cardiovascular interventions. We conducted predefined subgroup analyses, in particular for participants with high cardiovascular risk. . Main results We included 39 randomised parallel-group trials with 4992 participants. Colchicine had no effect on all-cause mortality (RR 0.94, 95% CI 0.82 to 1.09; participants = 4174; studies = 30; I² = 27%; moderate quality of evidence). There is uncertainty surrounding the effect of colchicine in reducing cardiovascular mortality (RR 0.34, 95% CI 0.09 to 1.21, I² = 9%; participants = 1132; studies = 7; moderate quality of evidence). Colchicine reduced the risk for total myocardial infarction (RR 0.20, 95% CI 0.07 to 0.57; participants = 652; studies = 2; moderate quality of evidence). There was no effect on total adverse events (RR 1.52, 95% CI 0.93 to 2.46; participants = 1313; studies = 11; I² = 45%; very low quality of evidence) but gastrointestinal intolerance was increased (RR 1.83, 95% CI 1.03 to 3.26; participants = 1258; studies = 11; I² = 74%; low quality of evidence). Colchicine showed no effect on heart failure (RR 0.62, 95% CI 0.10 to 3.88; participants = 462; studies = 3; I² = 45%; low quality of evidence) and no effect on stroke (RR 0.38, 95% CI 0.09 to 1.70; participants = 874; studies = 3; I² = 45%; low quality of evidence). Reporting of serious adverse events was inconsistent; no event occurred over 824 patient-years (4 trials). Effects on other outcomes were very uncertain. Summary effects of RCTs specifically focusing on participants with high cardiovascular risk were similar (4 trials; 1230 participants). Authors' conclusions There is much uncertainty surrounding the benefits and harms of colchicine treatment. Colchicine may have substantial benefits in reducing myocardial infarction in selected high-risk populations but uncertainty about the size of the effect on survival and other cardiovascular outcomes is high, especially in the general population from which most of the studies in our review were drawn. Colchicine is associated with gastrointestinal side effects based on low-quality evidence. More evidence from large-scale randomised trials is needed.

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.

Colchicine is an old anti-inflammatory drug that has shown substantial cardiovascular benefits in recent trials. We systematically reviewed cardiovascular benefits and harms of colchicine in any population and specifically in patients with high cardiovascular risk. We evaluated randomised controlled trials comparing colchicine over at least 6 months versus any control in any adult population. Primary outcomes were all-cause mortality, myocardial infarction and adverse events. Cardiovascular mortality was a secondary outcome. We included 39 trials with 4992 patients. The quality of evidence for mortality outcomes and myocardial infarction was moderate but lower for adverse events. Colchicine had no effect on all-cause mortality (RR 0.94, 95% CI 0.82 to 1.09; I(2)=27%; 30 trials). Cardiovascular mortality was reduced in some but not all meta-analytical models (random-effects RR 0.34, 0.09 to 1.21, I(2)=9%; Peto's OR 0.24, 0.09 to 0.64, I(2)=15%; Mantel-Haenszel fixed-effect RR 0.20, 0.06 to 0.68, I(2)=0%; 7 trials). The risk for myocardial infarction was reduced (RR 0.20, 0.07 to 0.57; 2 trials). There was no effect on total adverse events (RR 1.52, 0.93 to 2.46, I(2)=45%; 11 trials) but gastrointestinal intolerance was increased (RR 1.83, 1.03 to 3.26, I(2)=74%; 11 trials). Reporting of serious adverse events was inconsistent; no event occurred over 824 patient-years (4 trials). Effects in high cardiovascular risk populations were similar (4 trials; 1230 patients). We found no evidence supporting colchicine doses above 1 mg/day. Colchicine may have substantial cardiovascular benefits; however, there is sufficient uncertainty about its benefit and harm to indicate the need for large-scale trials to further evaluate this inexpensive, promising treatment in cardiovascular disease.

BACKGROUND: To investigate prognosis and effects of first-line therapy in elderly primary central nervous system lymphoma (PCNSL) patients.PATIENTS AND METHODS: A systematic review of studies about first-line therapy in immunocompetent patients ≥60 years with PCNSL until 2014 and a meta-analysis of individual patient data from eligible studies and international collaborators were carried out.RESULTS: We identified 20 eligible studies; from 13 studies, we obtained individual data of 405 patients, which were pooled with data of 378 additional patients (N = 783). Median age and Karnofsky Performance Score (KPS) was 68 years (range: 60-90 years) and 60% (range: 10%-100%), respectively. Treatments varied greatly, 573 (73%) patients received high-dose methotrexate (HD-MTX)-based therapy. A total of 276 patients received whole-brain radiotherapy (median 36 Gy, range 28.5-70 Gy). KPS ≥ 70% was the strongest prognostic factor for mortality [hazard ratio (HR) 0.50, 95% confidence interval (CI) 0.41-0.62]. After a median follow-up of 40 months, HD-MTX-based therapy was associated with improved survival (HR 0.70, 95% CI 0.53-0.93). There was no difference between HD-MTX plus oral chemotherapy and more aggressive HD-MTX-based therapies (HR 1.39, 95% CI 0.90-2.15). Radiotherapy was associated with an improved survival, but correlated with an increased risk for neurological side-effects (odds ratio 5.23, 95% CI 2.33-11.74).CONCLUSIONS: Elderly PCNSL patients benefit from HD-MTX-based therapy, especially if combined with oral alkylating agents. More aggressive HD-MTX protocols do not seem to improve outcome. WBRT may improve outcome, but is associated with increased risk for neurological side-effects. Prospective trials for elderly PCNSL patients are warranted.

Copyright © 2015 Wolters Kluwer Health Inc. All rights reserved. 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.

Correction: Volume: 349 Article Number: g4921 DOI: 10.1136/bmj.g4921 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

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 [95CI 22.3 27.6]). Only 96 of 253 discontinuations (37.9 [95CI 32.0 44.3]) were reported to ethics committees. The most frequent reason for discontinuation was poor recruitment (101/1017; 9.9[95CI 8.2 12.0]). In multivariable analysis industry sponsorship vs investigator sponsorship (8.4 vs 26.5; odds ratio [OR] 0.25 [95CI 0.15 0.43]; P < .001) and a larger planned sample size in increments of 100 ( 0.7; OR 0.96 [95CI 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 [95CI 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. Copyright 2014 American Medical Association. All rights reserved.

BackgroundSystematic reviews of preclinical studies, in vivo animal experiments in particular, can influence clinical research and thus even clinical care. Dissemination bias, selective dissemination of positive or significant results, is one of the major threats to validity in systematic reviews also in the realm of animal studies. We conducted a systematic review to determine the number of published systematic reviews of animal studies until present, to investigate their methodological features especially with respect to assessment of dissemination bias, and to investigate the citation of preclinical systematic reviews on clinical research.MethodsEligible studies for this systematic review constitute systematic reviews that summarize in vivo animal experiments whose results could be interpreted as applicable to clinical care. We systematically searched Ovid Medline, Embase, ToxNet, and ScienceDirect from 1st January 2009 to 9th January 2013 for eligible systematic reviews without language restrictions. Furthermore we included articles from two previous systematic reviews by Peters et al. and Korevaar et al.ResultsThe literature search and screening process resulted in 512 included full text articles. We found an increasing number of published preclinical systematic reviews over time. The methodological quality of preclinical systematic reviews was low. The majority of preclinical systematic reviews did not assess methodological quality of the included studies (71%), nor did they assess heterogeneity (81%) or dissemination bias (87%). Statistics quantifying the importance of clinical research citing systematic reviews of animal studies showed that clinical studies referred to the preclinical research mainly to justify their study or a future study (76%).DiscussionPreclinical systematic reviews may have an influence on clinical research but their methodological quality frequently remains low. Therefore, systematic reviews of animal research should be critically appraised before translating them to a clinical context.

Objective To quantify the overall effects of bariatric surgery compared with non-surgical treatment for obesity. Design Systematic review and meta-analysis based on a random effects model. Data sources Searches of Medline, Embase, and the Cochrane Library from their inception to December 2012 regardless of language or publication status. Eligibility criteria Eligible studies were randomised controlled trials with ≥6 months of follow-up that included individuals with a body mass index ≥30, compared current bariatric surgery techniques with non-surgical treatment, and reported on body weight, cardiovascular risk factors, quality of life, or adverse events. Results The meta-analysis included 11 studies with 796 individuals (range of mean body mass index at baseline 30-52). Individuals allocated to bariatric surgery lost more body weight (mean difference −26 kg (95% confidence interval −31 to −21)) compared with non-surgical treatment, had a higher remission rate of type 2 diabetes (relative risk 22.1 (3.2 to 154.3) in a complete case analysis; 5.3 (1.8 to 15.8) in a conservative analysis assuming diabetes remission in all non-surgically treated individuals with missing data) and metabolic syndrome (relative risk 2.4 (1.6 to 3.6) in complete case analysis; 1.5 (0.9 to 2.3) in conservative analysis), greater improvements in quality of life and reductions in medicine use (no pooled data). Plasma triglyceride concentrations decreased more (mean difference −0.7 mmol/L (−1.0 to −0.4) and high density lipoprotein cholesterol concentrations increased more (mean difference 0.21 mmol/L (0.1 to 0.3)). Changes in blood pressure and total or low density lipoprotein cholesterol concentrations were not significantly different. There were no cardiovascular events or deaths reported after bariatric surgery. The most common adverse events after bariatric surgery were iron deficiency anaemia (15% of individuals undergoing malabsorptive bariatric surgery) and reoperations (8%). Conclusions Compared with non-surgical treatment of obesity, bariatric surgery leads to greater body weight loss and higher remission rates of type 2 diabetes and metabolic syndrome. However, results are limited to two years of follow-up and based on a small number of studies and individuals. Systematic review registration PROSPERO CRD42012003317 (www.crd.york.ac.uk/PROSPERO).