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Objectives Randomised controlled trials conducted using cohorts and routinely collected data, including registries, electronic health records and administrative databases, are increasingly used in healthcare intervention research. A Consolidated Standards of Reporting Trials (CONSORT) statement extension for trials conducted using cohorts and routinely collected data (CONSORT-ROUTINE) has been developed with the goal of improving reporting quality. This article describes the processes and methods used to develop the extension and decisions made to arrive at the final checklist.Methods The development process involved five stages: (1) identification of the need for a reporting guideline and project launch; (2) conduct of a scoping review to identify possible modifications to CONSORT 2010 checklist items and possible new extension items; (3) a three-round modified Delphi study involving key stakeholders to gather feedback on the checklist; (4) a consensus meeting to finalise items to be included in the extension, followed by stakeholder piloting of the checklist; and (5) publication, dissemination and implementation of the final checklist.Results 27 items were initially developed and rated in Delphi round 1, 13 items were rated in round 2 and 11 items were rated in round 3. Response rates for the Delphi study were 92 of 125 (74%) invited participants in round 1, 77 of 92 (84%) round 1 completers in round 2 and 62 of 77 (81%) round 2 completers in round 3. Twenty-seven members of the project team representing a variety of stakeholder groups attended the in-person consensus meeting. The final checklist includes five new items and eight modified items. The extension Explanation & Elaboration document further clarifies aspects that are important to report.Conclusion Uptake of CONSORT-ROUTINE and accompanying Explanation & Elaboration document will improve conduct of trials, as well as the transparency and completeness of reporting of trials conducted using cohorts and routinely collected data.

Background The Nutri-Score, a front-of-pack nutrition label, has been adopted in 2017 in France but its impact on low-income populations is unknown, and they are more at risk of having unhealthy diets. The present study assessed the effects of the Nutri-Score on the nutritional quality of purchasing intentions among low-income individuals, compared with the current French labelling situation: references intakes (RIs) and no label, using a three-arm parallel-group randomised controlled trial.Methods Low-income active adults from the NutriNet-Santé cohort (household income below €1200/month) were asked to perform a shopping task in an experimental online supermarket after being randomised in one of the three conditions (Nutri-Score, RIs or no labelling). The main outcome was the overall nutritional quality of the virtual shopping cart, assessed with the French-modified Food Standards Agency Nutrient Profiling System (FSAm-NPS), and secondary outcomes were the nutrient content of the shopping carts. 524 subjects were randomised, and 336 included in the analyses.Results The Nutri-Score resulted in the highest overall nutritional quality of the shopping cart, as reflected by a FSAm-NPS score (1.86 (SD 3.59) points) significantly lower (reflecting higher nutritional quality) than the RIs (3.21 (SD 4.14) points, p≤0.05) but not significantly lower than no label (2.60 (SD 3.09) points, p=0.3). The Nutri-Score also resulted into significantly lower contents in calories and saturated fatty acids in the shopping cart, compared with the RIs only (p≤0.05).Conclusion The implementation of the front of pack nutrition label Nutri-Score, adopted in France and in different European countries, appears to have the potential to encourage purchasing intentions of foods from higher nutritional quality among low-income individuals, compared with the RIs label promoted by food manufacturers.Trial registration number: NCT02769455

Background The extent to which response and survival benefits with immunotherapy-based regimens persist informs optimal first-line treatment options. We provide long-term follow-up in patients with advanced renal cell carcinoma (aRCC) receiving first-line nivolumab plus ipilimumab (NIVO+IPI) versus sunitinib (SUN) in the phase 3 CheckMate 214 trial. Survival, response, and safety outcomes with NIVO+IPI versus SUN were assessed after a minimum of 42 months of follow-up.Methods Patients with aRCC were enrolled from October 16, 2014, through February 23, 2016. Patients stratified by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk and region were randomized to nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) every 3 weeks for four doses, followed by nivolumab (3 mg/kg) every 2 weeks; or SUN (50 mg) once per day for 4 weeks (6-week cycle). Primary endpoints: overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) per independent radiology review committee in IMDC intermediate-risk/poor-risk patients. Secondary endpoints: OS, PFS, and ORR in the intention-to-treat (ITT) population and safety. Favorable-risk patient outcomes were exploratory.Results Among ITT patients, 550 were randomized to NIVO+IPI (425 intermediate/poor risk; 125 favorable risk) and 546 to SUN (422 intermediate/poor risk; 124 favorable risk). Among intermediate-risk/poor-risk patients, OS (HR, 0.66; 95% CI, 0.55–0.80) and PFS (HR, 0.75; 95% CI, 0.62–0.90) benefits were observed, and ORR was higher (42.1% vs 26.3%) with NIVO+IPI versus SUN. In ITT patients, both OS benefits (HR, 0.72; 95% CI, 0.61–0.86) and higher ORR (39.1% vs 32.6%) were observed with NIVO+IPI versus SUN. In favorable-risk patients, HR for death was 1.19 (95% CI, 0.77–1.85) and ORR was 28.8% with NIVO+IPI versus 54.0% with SUN. Duration of response was longer (HR, 0.46–0.54), and more patients achieved complete response (10.1%–12.8% vs 1.4%–5.6%) with NIVO+IPI versus SUN regardless of risk group. The incidence of treatment-related adverse events was consistent with previous reports.Conclusions NIVO+IPI led to improved efficacy outcomes versus SUN in both intermediate-risk/poor-risk and ITT patients that were maintained through 42 months’ minimum follow-up. A complete response rate >10% was achieved with NIVO+IPI regardless of risk category, with no new safety signals detected in either arm. These results support NIVO+IPI as a first-line treatment option with the potential for durable response.Trial registration number NCT02231749.

Background Anti-programmed cell death ligand 1 (PD-L1)/programmed cell death 1 antibodies have shown clinical activity in platinum-treated metastatic urothelial carcinoma, resulting in regulatory approval of several agents, including avelumab (anti-PD-L1). We report ≥2-year follow-up data for avelumab treatment and exploratory subgroup analyses in patients with urothelial carcinoma.Methods Patients with previously treated advanced/metastatic urothelial carcinoma, pooled from two cohorts of the phase Ib JAVELIN Solid Tumor trial, received avelumab 10 mg/kg every 2 weeks until disease progression, unacceptable toxicity or withdrawal. End points included best overall response and progression-free survival (PFS) per RECIST V.1.1, overall survival (OS) and safety. Post hoc analyses included objective response rates (ORRs) in subgroups defined by established high-risk/poor-prognosis characteristics and association between time to response and outcome.Results 249 patients received avelumab; efficacy was assessed in 242 postplatinum patients. Median follow-up was 31.9 months (range 24–43), and median treatment duration was 2.8 months (range 0.5–42.8). The confirmed ORR was 16.5% (95% CI 12.1% to 21.8%; complete response in 4.1% and partial response in 12.4%). Median duration of response was 20.5 months (95% CI 9.7 months to not estimable). Median PFS was 1.6 months (95% CI 1.4 to 2.7 months) and the 12-month PFS rate was 16.8% (95% CI 11.9% to 22.4%). Median OS was 7.0 months (95% CI 5.9 to 8.5 months) and the 24-month OS rate was 20.1% (95% CI 15.2% to 25.4%). In post hoc exploratory analyses, avelumab showed antitumor activity in high-risk subgroups, including elderly patients and those with renal insufficiency or upper tract disease; ORRs were numerically lower in patients with liver metastases or low albumin levels. Objective response achieved by 3 months versus later was associated with longer OS (median not reached (95% CI 18.9 months to not estimable) vs 7.1 months (95% CI 5.2 to 9.0 months)). Safety findings were consistent with previously reported 6-month analyses.Conclusions After ≥2 years of follow-up, avelumab showed prolonged efficacy and acceptable safety in patients with platinum-treated advanced/metastatic urothelial carcinoma, including high-risk subgroups. Survival appeared longer in patients who responded within 3 months. Long-term safety findings were consistent with earlier reports with avelumab treatment in this patient population.

Background We report the clinical activity and safety of bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of the transforming growth factor β (TGF-β)RII receptor (a TGF-β ‘trap’) fused to a human IgG1 monoclonal antibody blocking programmed death-ligand 1 (PD-L1), in patients with heavily pretreated squamous cell carcinoma of the head and neck (SCCHN).Methods In this phase I dose-expansion cohort, patients with advanced SCCHN not amenable to curative therapy that progressed/recurred after platinum therapy in the recurrent/metastatic setting, or

BackgroundBiometric monitoring devices (BMDs) are wearable or environmental trackers and devices with embedded sensors that can remotely collect high-frequency objective data on patients’ physiological, biological, behavioral, and environmental contexts (for example, fitness trackers with accelerometer). The real-world effectiveness of interventions using biometric monitoring devices depends on patients’ perceptions of these interventions. ObjectiveWe aimed to systematically review whether and how recent randomized controlled trials (RCTs) evaluating interventions using BMDs assessed patients’ perceptions toward the intervention. MethodsWe systematically searched PubMed (MEDLINE) from January 1, 2017, to December 31, 2018, for RCTs evaluating interventions using BMDs. Two independent investigators extracted the following information: (1) whether the RCT collected information on patient perceptions toward the intervention using BMDs and (2) if so, what precisely was collected, based on items from questionnaires used and/or themes and subthemes identified from qualitative assessments. The two investigators then synthesized their findings in a schema of patient perceptions of interventions using BMDs. ResultsA total of 58 RCTs including 10,071 participants were included in the review (the median number of randomized participants was 60, IQR 37-133). BMDs used in interventions were accelerometers/pedometers (n=35, 60%), electrochemical biosensors (eg, continuous glucose monitoring; n=18, 31%), or ecological momentary assessment devices (eg, carbon monoxide monitors for smoking cessation; n=5, 9%). Overall, 26 (45%) trials collected information on patient perceptions toward the intervention using BMDs and allowed the identification of 76 unique aspects of patient perceptions that could affect the uptake of these interventions (eg, relevance of the information provided, alarm burden, privacy and data handling, impact on health outcomes, independence, interference with daily life). Patient perceptions were unevenly collected in trials. For example, only 5% (n=3) of trials assessed how patients felt about privacy and data handling aspects of the intervention using BMDs. ConclusionsOur review showed that less than half of RCTs evaluating interventions using BMDs assessed patients’ perceptions toward interventions using BMDs. Trials that did assess perceptions often only assessed a fraction of them. This limits the extrapolation of the results of these RCTs to the real world. We thus provide a comprehensive schema of aspects of patient perceptions that may affect the uptake of interventions using BMDs and which should be considered in future trials. Trial RegistrationPROSPERO CRD42018115522; https://tinyurl.com/y5h8fjgx

Abstract Osimertinib is a third‐generation, irreversible, oral epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitor (TKI) that potently and selectively inhibits both EGFR‐TKI sensitizing and EGFR T790M and has demonstrated efficacy in non‐small cell lung cancer (NSCLC) central nervous system metastases. In this phase I study, we assessed the effects of normal renal function (NRF) and severe renal impairment (SRI) on the pharmacokinetics (PK) of osimertinib in patients with solid tumors. Part A: patients with NRF (creatinine clearance [CrCL] ≥90 mL/min), and SRI, (CrCL

Objective: We aimed to explore biological predictive factors of progression after surgery in nonmetastatic renal cell carcinoma (RCC) using the collected tumors in the French cohort of the randomized S-TRAC trial patients.Patients and Methods: We analyzed the tumors of the French cohort of STRAC that included 44 cases of clear cell RCC (ccRCC) that were collected from six centers. The main objective was to explore biological predictive factors of progression (defined as PFS) to sunitinib. Broad-spectrum analysis including immunohistochemistry, fluorescent in situ hybridization (FISH), comparative genomic hybridization (CGH) array, and transcriptomic analyses were performed on the tumors.Results:Analysis of vascular density showed type 1 vascular stroma corresponding to high vascular density was associated with progression (p < 0.034). Loss of poly bromo-1 expression showed a distinct profile: a highly histopathological aggressive tumor with a marked angiogenic profile (vascular endothelial growth factor overexpression and immature vascular stroma type 2), no PD1 or PDL1 expression, and wild-type (WT) status of the VHL gene. There were 27 chromosome regions gained in patients with progression (on chromosomes 7 and 16, and to a lesser extent 8, 12, 17, 17, 19, 20 corresponding to 605 associated genes) and 10 regions lost in these same patients on chromosomes 8 and 9, and to a lesser extent 2 and 21 corresponding to 25 associated genes.Conclusion:We found that an angiogenic phenotype defined by a high vascular density with a vascular type 2 stroma was a predictive factor of sunitinib resistance. Regardless of adjuvant treatment, chromosomal gains and losses and genomic alterations including PBRM1 loss were associated with worse outcomes.Clinical Trial Registration: ClinicalTrials.gov number, NCT00375674.

Abstract Background This study aimed 1) to assess whether the contribution of chronic conditions to disability varies according to the educational attainment, 2) to disentangle the contributions of the prevalence and of the disabling impact of chronic conditions to educational disparities. Methods Data of the 2008–09 Disability Health Survey were examined (N = 23,348). The disability indicator was the Global Activity Limitation Indicator (GALI). The attribution method based on an additive hazard model was used to estimate educational differences in disabling impacts and in the contributions of diseases to disability. Counterfactual analyses were used to disentangle the contribution of differences in disease prevalence vs. disabling impact. Results In men, the main contributors to educational difference in disability prevalence were arthritis (contribution to disability prevalence: 5.7% (95% CI 5.4–6.0) for low-educated vs. 3.3% (3.0–3.9) for high-educated men), spine disorders (back/neck pain, deformity) (3.8% (3.6–4.0) vs. 1.9% (1.8–2.1)), chronic obstructive pulmonary diseases (2.4% (2.3–2.6) vs. 0.6% (0.5–0.7)) and ischemic heart /peripheral artery diseases (4.1% (3.9–4.3) vs. 2.4% (2.2–3.0)). In women, arthritis (9.5% (9.1–9.9) vs. 4.5%, (4.1–5.2)), spine disorders (4.5% (4.3–4.7) vs. 2.1% 1.9–2.3) and psychiatric diseases (3.1% (3.0–3.3) vs. 1.1% (1.0–1.3)) contributed most to education gap in disability. The educational differences were equally explained by differences in the disease prevalence and in their disabling impact. Conclusions Public health policies aiming to reduce existing socioeconomic disparities in disability should focus on musculoskeletal, pulmonary, psychiatric and ischemic heart diseases, reducing their prevalence as well as their disabling impact in lower socioeconomic groups.

Introduction Transparent and accurate reporting is essential for readers to adequately interpret the results of a study. Journals can play a vital role in improving the reporting of published randomised controlled trials (RCTs). We describe an RCT to evaluate our hypothesis that asking peer reviewers to check whether the most important and poorly reported CONsolidated Standards of Reporting Trials (CONSORT) items are adequately reported will result in higher adherence to CONSORT guidelines in published RCTs.Methods and analysis Manuscripts presenting the primary results of RCTs submitted to participating journals will be randomised to either the intervention group (peer reviewers will receive a reminder and short explanation of the 10 most important and poorly reported CONSORT items; they will be asked to check if these items are reported in the submitted manuscript) or a control group (usual journal practice). The primary outcome will be the mean proportion of the 10 items that are adequately reported in the published articles. Peer reviewers and manuscript authors will not be informed of the study hypothesis, design or intervention. Outcomes will be assessed in duplicate from published articles by two data extractors (at least one blinded to the intervention). We will enrol eligible manuscripts until a minimum of 83 articles per group (166 in total) are published.Ethics and dissemination This pragmatic RCT was approved by the Medical Sciences Interdivisional Research Ethics Committee of the University of Oxford (R62779/RE001). If this intervention is effective, it could be implemented by all medical journals without requiring large additional resources at journal level. Findings will be disseminated through presentations in relevant conferences and peer-reviewed publications. This trial is registered on the Open Science Framework (https://osf.io/c4hn8).

Aims We conducted a systematic review assessing the reporting quality of studies validating models based on machine learning (ML) for clinical diagnosis, with a specific focus on the reporting of information concerning the participants on which the diagnostic task was evaluated on.Method Medline Core Clinical Journals were searched for studies published between July 2015 and July 2018. Two reviewers independently screened the retrieved articles, a third reviewer resolved any discrepancies. An extraction list was developed from the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis guideline. Two reviewers independently extracted the data from the eligible articles. Third and fourth reviewers checked, verified the extracted data as well as resolved any discrepancies between the reviewers.Results The search results yielded 161 papers, of which 28 conformed to the eligibility criteria. Detail of data source was reported in 24 of the 28 papers. For all of the papers, the set of patients on which the ML-based diagnostic system was evaluated was partitioned from a larger dataset, and the method for deriving such set was always reported. Information on the diagnostic/non-diagnostic classification was reported well (23/28). The least reported items were the use of reporting guideline (0/28), distribution of disease severity (8/28 patient flow diagram (10/28) and distribution of alternative diagnosis (10/28). A large proportion of studies (23/28) had a delay between the conduct of the reference standard and ML tests, while one study did not and four studies were unclear. For 15 studies, it was unclear whether the evaluation group corresponded to the setting in which the ML test will be applied to.Conclusion All studies in this review failed to use reporting guidelines, and a large proportion of them lacked adequate detail on participants, making it difficult to replicate, assess and interpret study findings.PROSPERO registration number CRD42018099167.

Abstract Background Randomized controlled trials (RCTs) are often complex and expensive to perform. Less than one third achieve planned recruitment targets, follow-up can be labor-intensive, and many have limited real-world generalizability. Designs for RCTs conducted using cohorts and routinely collected health data, including registries, electronic health records, and administrative databases, have been proposed to address these challenges and are being rapidly adopted. These designs, however, are relatively recent innovations, and published RCT reports often do not describe important aspects of their methodology in a standardized way. Our objective is to extend the Consolidated Standards of Reporting Trials (CONSORT) statement with a consensus-driven reporting guideline for RCTs using cohorts and routinely collected health data. Methods The development of this CONSORT extension will consist of five phases. Phase 1 (completed) consisted of the project launch, including fundraising, the establishment of a research team, and development of a conceptual framework. In phase 2, a systematic review will be performed to identify publications (1) that describe methods or reporting considerations for RCTs conducted using cohorts and routinely collected health data or (2) that are protocols or report results from such RCTs. An initial “long list” of possible modifications to CONSORT checklist items and possible new items for the reporting guideline will be generated based on the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) and The REporting of studies Conducted using Observational Routinely-collected health Data (RECORD) statements. Additional possible modifications and new items will be identified based on the results of the systematic review. Phase 3 will consist of a three-round Delphi exercise with methods and content experts to evaluate the “long list” and generate a “short list” of key items. In phase 4, these items will serve as the basis for an in-person consensus meeting to finalize a core set of items to be included in the reporting guideline and checklist. Phase 5 will involve drafting the checklist and elaboration-explanation documents, and dissemination and implementation of the guideline. Discussion Development of this CONSORT extension will contribute to more transparent reporting of RCTs conducted using cohorts and routinely collected health data.

Abstract Background We aimed to determine the best study designs for assessing interventions to improve the peer review process according to experts’ opinions. Furthermore, for interventions previously evaluated, we determined whether the study designs actually used were rated as the best study designs. Methods Study design: A series of six vignette-based surveys exploring the best study designs for six different interventions (training peer reviewers, adding an expert to the peer review process, use of reporting guidelines checklists, blinding peer reviewers to the results (i.e., results-free peer review), giving incentives to peer reviewers, and post-publication peer review). Vignette construction: Vignettes were case scenarios of trials assessing interventions aimed at improving the quality of peer review. For each intervention, the vignette included the study type (e.g., randomized controlled trial [RCT]), setting (e.g., single biomedical journal), and type of manuscript assessed (e.g., actual manuscripts received by the journal); each of these three features varied between vignettes. Participants: Researchers with expertise in peer review or methodology of clinical trials. Outcome: Participants were proposed two vignettes describing two different study designs to assess the same intervention and had to indicate which study design they preferred on a scale, from − 5 (preference for study A) to 5 (preference for study B), 0 indicating no preference between the suggested designs (primary outcome). Secondary outcomes were trust in the results and feasibility of the designs. Results A total of 204 experts assessed 1044 paired comparisons. The preferred study type was RCTs with randomization of manuscripts for four interventions (adding an expert, use of reporting guidelines checklist, results-free peer review, post-publication peer review) and RCTs with randomization of peer reviewers for two interventions (training peer reviewers and using incentives). The preferred setting was mainly several biomedical journals from different publishers, and the preferred type of manuscript was actual manuscripts submitted to journals. However, the most feasible designs were often cluster RCTs and interrupted time series analysis set in a single biomedical journal, with the assessment of a fabricated manuscript. Three interventions were previously assessed: none used the design rated first in preference by experts. Conclusion The vignette-based survey allowed us to identify the best study designs for assessing different interventions to improve peer review according to experts’ opinion. There is gap between the preferred study designs and the designs actually used.

Abstract Background Patients with diabetes require knowledge and skills to self-manage their disease, a challenging aspect of treatment that is difficult to address in humanitarian settings. Due to the lack of literature and experience regarding diabetes self-management, education and support (DSMES) in refugee populations, Medecins Sans Frontieres (MSF) undertook a DSMES survey in a cohort of diabetes patients seen in their primary health care program in Lebanon. Methods Structured interviews were conducted with diabetes patients in three primary care clinics between January and February 2015. Scores (0–10) were calculated to measure diabetes core knowledge in each patient (the DSMES score). Awareness of long-term complications and educational preferences were also assessed. Analyses were conducted using Stata software, version 14.1 (StataCorp). Simple and multiple linear regression models were used to determine associations between various patient factors and the DSMES Score. Results A total of 292 patients were surveyed. Of these, 92% had type 2 diabetes and most (70%) had been diagnosed prior to the Syrian conflict. The mean DSMES score was 6/10. Having secondary education, previous diabetes education, a ‘diabetes confidant’, and insulin use were each associated with a higher DSMES Score. Lower scores were significantly more likely to be seen in participants with increasing age and in patients who were diagnosed during the Syrian conflict. Long-term complications of diabetes most commonly known by patients were vision related complications (68% of patients), foot ulcers (39%), and kidney failure (38%). When asked about the previous Ramadan, 56% of patients stated that they undertook a full fast, including patients with type 1 diabetes. Individual and group lessons were preferred by more patients than written, SMS, telephone or internet-based educational delivery models. Conclusions DSMES should be patient and context appropriate. The variety and complexities of humanitarian settings provide particular challenges to its appropriate provision. Understanding patient baseline DSMES levels and needs provides a useful basis for humanitarian organizations seeking to provide diabetes care.

Abstract Background Inadequate planning, selective reporting, and incomplete reporting of outcomes in randomized controlled trials (RCTs) contribute to the problem of waste of research. We aimed to describe such a waste and to examine to what extent this waste could be avoided. Methods This research-on-research study was based on RCTs included in Cochrane reviews with a summary of findings (SoF) table. We considered the outcomes reported in the SoF tables as surrogates for important outcomes for patients and other decision makers. We used a three-step approach. (1) First, in each review, we identified, for each important outcome, RCTs that were excluded from the corresponding meta-analysis. (2) Then, for these RCTs, we systematically searched for registrations and protocols to distinguish between inadequate planning (an important outcome was not reported in registries or protocols), selective reporting (an important outcome was reported in registries or protocols but not in publications), and incomplete reporting (an important outcome was incompletely reported in publications). (3) Finally, we assessed, with the consensus of five experts, the feasibility and cost of measuring the important outcomes that were not planned. We considered inadequately planned or selectively or incompletely reported important outcomes as avoidable waste if the outcome could have been easily measured at no additional cost based on expert evaluation. Results Of the 2711 RCTs included in the main comparison of 290 reviews, 2115 (78%) were excluded from at least one meta-analysis of important outcomes. Every trial contributed to 55%, on average, of the meta-analyses of important outcomes. Of the 310 RCTs published in 2010 or later, 156 were registered. Inadequate planning affected 79% of these RCTs, whereas incomplete and selective reporting affected 41% and 15%, respectively. For 63% of RCTs, we found at least one missing important outcome for which the waste was avoidable and for 30%, the waste was avoidable for all important outcomes. Conclusions Most of the RCTs included in our sample did not contribute to all the important outcomes in meta-analyses, mostly because of inadequate planning or incomplete reporting. A large part of this waste of research seemed to be avoidable.