Ten Years of Interventional Research in Systemic Sclerosis: A Systematic Mapping of Trial Registries.

OBJECTIVE: To provide a comprehensive overview of interventional clinical trials registered in international databases and planned and conducted within the last 10 years in patients with systemic sclerosis (SSc). METHODS: We searched the International Clinical Trials Registry Platform for all records on interventional clinical trials targeting patients with SSc performed since September 2007. Two reviewers selected studies according to the prespecified eligibility criteria. Information on start date, country of origin, funding sources, phase of development, study design, (planned) sample size, enrollment status, outcomes, disease complication, and treatments investigated were retrieved and summarized. RESULTS: Among the 198 eligible studies identified (122 randomized controlled trials [RCTs; 62%]), 87 (30%) were conducted in Europe, 165 (83%) in a single country, and 81 (41%) were industry-funded. The majority of trials investigated pharmacologic treatments (75%), mostly nonbiotherapies (57%). RCTs were mostly 2-arm (82%) placebo-controlled (71%) studies with a median number of patients enrolled or planned to be enrolled of 40 (interquartile range 25-77 [range 10-586]). Twenty-one RCTs (17%) planned to enroll or enrolled >100 patients. Time to assess the primary outcome was found to be adequate in 29% to 50% of RCTs retrieved. Patients age >65 years were excluded in 14% of studies. SSc complications more frequently investigated in overall studies were skin thickness (26%), Raynaud's phenomenon/digital ulcers (24%), and interstitial lung disease (14%). CONCLUSION: The SSc research landscape is dominated by small, short, and mainly placebo-controlled trials, especially investigating pharmacologic treatments. Some patients' needs continue to be neglected.

Harms Reporting in Randomized Controlled Trials of Interventions Aimed at Modifying Microbiota: A Systematic Review.

Background: Probiotics, prebiotics, and synbiotics are used increasingly, although the safety and potential harms of these interventions are poorly understood. Purpose: To examine how harms-related information is reported in publications of randomized controlled trials (RCTs) of probiotics, prebiotics, and synbiotics. Data Sources: Cochrane Central Register of Controlled Trials, PubMed, EMBASE, and Web of Science (without language restrictions) from 1 January 2015 to 20 March 2018. Study Selection: RCTs assessing the safety or efficacy of at least 1 intervention involving probiotics, prebiotics, or synbiotics alone or in combination with another intervention compared with any control (such as a placebo or an antibiotic) for any clinical condition. Data Extraction: 4 reviewers independently assessed study characteristics, the reporting of harms, and the presentation of safety results. Data Synthesis: Of 384 trials conducted in healthy volunteers (n = 136) or patients with any of several medical conditions (n = 248), 339 (88%) were published in specialty journals. Trials most often evaluated probiotics (n = 265 [69%]). Studies in persons with medical conditions enrolled outpatients (n = 195) and high-risk patients (n = 53). No harms-related data were reported for 106 trials (28%), safety results were not reported for 142 (37%), and the number of serious adverse events (SAEs) per study group was not given for 309 (80%). Of 242 studies mentioning harms-related results, 37% (n = 89) used only generic statements to describe AEs and 16% (n = 38) used inadequate metrics. Overall, 375 trials (98%) did not give a definition for AEs or SAEs, the number of participant withdrawals due to harms, or the number of AEs and SAEs per study group with denominators. Limitation: Journal publication processes may have affected the completeness of reporting; only English-language publications were examined. Conclusion: Harms reporting in published reports of RCTs assessing probiotics, prebiotics, and synbiotics often is lacking or inadequate. We cannot broadly conclude that these interventions are safe without reporting safety data. Primary Funding Source: No specific funding.

Randomized controlled trials of simulation-based interventions in Emergency Medicine: a methodological review.

The number of trials assessing Simulation-Based Medical Education (SBME) interventions has rapidly expanded. Many studies show that potential flaws in design, conduct and reporting of randomized controlled trials (RCTs) can bias their results. We conducted a methodological review of RCTs assessing a SBME in Emergency Medicine (EM) and examined their methodological characteristics. We searched MEDLINE via PubMed for RCT that assessed a simulation intervention in EM, published in 6 general and internal medicine and in the top 10 EM journals. The Cochrane Collaboration risk of Bias tool was used to assess risk of bias, intervention reporting was evaluated based on the "template for intervention description and replication" checklist, and methodological quality was evaluated by the Medical Education Research Study Quality Instrument. Reports selection and data extraction was done by 2 independents researchers. From 1394 RCTs screened, 68 trials assessed a SBME intervention. They represent one quarter of our sample. Cardiopulmonary resuscitation (CPR) is the most frequent topic (81%). Random sequence generation and allocation concealment were performed correctly in 66 and 49% of trials. Blinding of participants and assessors was performed correctly in 19 and 68%. Risk of attrition bias was low in three-quarters of the studies (n = 51). Risk of selective reporting bias was unclear in nearly all studies. The mean MERQSI score was of 13.4/18.4% of the reports provided a description allowing the intervention replication. Trials assessing simulation represent one quarter of RCTs in EM. Their quality remains unclear, and reproducing the interventions appears challenging due to reporting issues.

Methods and Reporting Studies Assessing Fecal Microbiota Transplantation: A Systematic Review.

BACKGROUND: Fecal microbiota transplantation (FMT) could be a novel treatment option for several chronic diseases associated with altered gut microbiota. PURPOSE: To examine the conduct and reporting of studies assessing FMT. DATA SOURCES: Cochrane Central Register of Controlled Trials, PubMed, EMBASE, and Web of Science from inception to 31 January 2017. STUDY SELECTION: Two reviewers independently examined titles and abstracts to identify all English-language reports of human clinical studies assessing the safety or efficacy of FMT. DATA EXTRACTION: Three reviewers independently assessed study types and characteristics and the reporting of important methodological components of the FMT intervention. DATA SYNTHESIS: Most (84%) of the 85 published reports found addressed the use of FMTs for Clostridium difficile infection or inflammatory bowel disease, and most (87%) were non-randomized controlled trials. Important methodological components that were not reported in published studies included the following: eligibility criteria for donors (47%), materials used for collecting stools and the period of collection (96%), methods used for conservation of stools (76%), the amount and type of stools used (for example, fresh or frozen), and duration of stool conservation (67%). Many (58%) did not report an analysis of microbiota composition. LIMITATIONS: Lack of universal consensus regarding the most important methodological components of FMT and inability to assess the actual conduct of studies and whether the publication process affected the completeness of reporting. CONCLUSION: Key components of FMT interventions, which are necessary to replicate and understand study findings about efficacy and safety, are poorly reported. PRIMARY FUNDING SOURCE: No specific funding.

Reporting of results from network meta-analyses: methodological systematic review.

OBJECTIVE: To examine how the results of network meta-analyses are reported. DESIGN: Methodological systematic review of published reports of network meta-analyses. DATA SOURCES: Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Medline, and Embase, searched from inception to 12 July 2012. STUDY SELECTION: All network meta-analyses comparing the clinical efficacy of three or more interventions in randomised controlled trials were included, excluding meta-analyses with an open loop network of three interventions. DATA EXTRACTION AND SYNTHESIS: The reporting of the network and results was assessed. A composite outcome included the description of the network (number of interventions, direct comparisons, and randomised controlled trials and patients for each comparison) and the reporting of effect sizes derived from direct evidence, indirect evidence, and the network meta-analysis. RESULTS: 121 network meta-analyses (55 published in general journals; 48 funded by at least one private source) were included. The network and its geometry (network graph) were not reported in 100 (83%) articles. The effect sizes derived from direct evidence, indirect evidence, and the network meta-analysis were not reported in 48 (40%), 108 (89%), and 43 (36%) articles, respectively. In 52 reports that ranked interventions, 43 did not report the uncertainty in ranking. Overall, 119 (98%) reports of network meta-analyses did not give a description of the network or effect sizes from direct evidence, indirect evidence, and the network meta-analysis. This finding did not differ by journal type or funding source. CONCLUSIONS: The results of network meta-analyses are heterogeneously reported. Development of reporting guidelines to assist authors in writing and readers in critically appraising reports of network meta-analyses is timely.

Analysis of the systematic reviews process in reports of network meta-analyses: methodological systematic review.

OBJECTIVE: To examine whether network meta-analyses, increasingly used to assess comparative effectiveness of healthcare interventions, follow the key methodological recommendations for reporting and conduct of systematic reviews. DESIGN: Methodological systematic review of reports of network meta-analyses. DATA SOURCES: Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Medline, and Embase, searched from inception to 12 July 2012. REVIEW METHODS: All network meta-analyses comparing clinical efficacy of three or more interventions based on randomised controlled trials, excluding meta-analyses with an open loop network of three interventions. We assessed the reporting of general characteristics and key methodological components of the systematic review process using two composite outcomes. For some components, if reporting was adequate, we assessed their conduct quality. RESULTS: Of 121 network meta-analyses covering a wide range of medical areas, 100 (83%) assessed pharmacological interventions and 11 (9%) non-pharmacological interventions; 56 (46%) were published in journals with a high impact factor. The electronic search strategy for each database was not reported in 88 (73%) network meta-analyses; for 36 (30%), the primary outcome was not clearly identified. Overall, 61 (50%) network meta-analyses did not report any information regarding the assessment of risk of bias of individual studies, and 103 (85%) did not report any methods to assess the likelihood of publication bias. Overall, 87 (72%) network meta-analyses did not report the literature search, searched only one database, did not search other sources, or did not report an assessment of risk of bias of individual studies. These methodological components did not differ by publication in a general or specialty journal or by public or private funding. CONCLUSIONS: Essential methodological components of the systematic review process-conducting a literature search and assessing risk of bias of individual studies-are frequently lacking in reports of network meta-analyses, even when published in journals with high impact factors.

Misrepresentation of randomized controlled trials in press releases and news coverage: a cohort study.

BACKGROUND: Previous studies indicate that in published reports, trial results can be distorted by the use of "spin" (specific reporting strategies, intentional or unintentional, emphasizing the beneficial effect of the experimental treatment). We aimed to (1) evaluate the presence of "spin" in press releases and associated media coverage; and (2) evaluate whether findings of randomized controlled trials (RCTs) based on press releases and media coverage are misinterpreted. METHODS AND FINDINGS: We systematically searched for all press releases indexed in the EurekAlert! database between December 2009 and March 2010. Of the 498 press releases retrieved and screened, we included press releases for all two-arm, parallel-group RCTs (n = 70). We obtained a copy of the scientific article to which the press release related and we systematically searched for related news items using Lexis Nexis. "Spin," defined as specific reporting strategies (intentional or unintentional) emphasizing the beneficial effect of the experimental treatment, was identified in 28 (40%) scientific article abstract conclusions and in 33 (47%) press releases. From bivariate and multivariable analysis assessing the journal type, funding source, sample size, type of treatment (drug or other), results of the primary outcomes (all nonstatistically significant versus other), author of the press release, and the presence of "spin" in the abstract conclusion, the only factor associated, with "spin" in the press release was "spin" in the article abstract conclusions (relative risk [RR] 5.6, [95% CI 2.8-11.1], p < 0.001). Findings of RCTs based on press releases were overestimated for 19 (27%) reports. News items were identified for 41 RCTs; 21 (51%) were reported with "spin," mainly the same type of "spin" as those identified in the press release and article abstract conclusion. Findings of RCTs based on the news item was overestimated for ten (24%) reports. CONCLUSION: "Spin" was identified in about half of press releases and media coverage. In multivariable analysis, the main factor associated with "spin" in press releases was the presence of "spin" in the article abstract conclusion.

Impact of single centre status on estimates of intervention effects in trials with continuous outcomes: meta-epidemiological study.

OBJECTIVE: To compare estimates of intervention effects between single centre and multicentre randomised controlled trials with continuous outcomes. DESIGN: Meta-epidemiological study. DATA SOURCES: 26 meta-analyses totalling 292 randomised controlled trials (177 single centre, 115 multicentre) with continuous outcomes published between January 2007 and January 2010 in the Cochrane database of systematic reviews. DATA EXTRACTION: Data were extracted on characteristics of trials, single or multicentre status, risk of bias using the risk of bias tool of the Cochrane Collaboration, and results. DATA SYNTHESIS: The intervention effects were estimated with standardised mean differences. For each meta-analysis, random effects meta-regression was used to estimate the difference in standardised mean differences between single centre and multicentre trials. Differences in standardised mean differences were then pooled across meta-analyses by a random-effects meta-analysis model. A combined difference in standardised mean differences of less than 0 indicated that single centre trials showed larger treatment effects, on average, than did multicentre trials. Because single centre trials may be more prone to publication bias and may have lower methodological quality than multicentre trials, sensitivity analyses were done with adjustment for sample size and domains of the risk of bias tool. RESULTS: Single centre trials showed larger intervention effects than did multicentre trials (combined difference in standardised mean differences -0.09, 95% confidence interval -0.17 to -0.01, P=0.04), with low heterogeneity across individual meta-analyses (I(2)=0%, between meta-analyses variance τ(2)=0.00). Adjustment for sample size slightly attenuated the difference (-0.08, -0.17 to 0.01). Adjustment for risk of bias yielded similar estimates with wider confidence intervals, some of them crossing 0 (-0.09, -0.17 to 0.00 for overall risk of bias). CONCLUSIONS: On average, single centre clinical trials with continuous outcomes showed slightly larger intervention effects than did multicentre trials. Further research is needed to investigate potential causes of these differences.