Search

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.

Rationale There are no randomized trials examining the best treatment for acute basilar artery occlusion in the 6–24-hour time window. Aims To assess the safety and efficacy of thrombectomy for stroke due to basilar artery occlusion in patients randomized within 6–24 h from symptom onset or time last seen well. Sample size For an estimated difference of 20% in proportions of the primary outcome between the two groups, 318 patients will be included for 5% significance and 90% power with a planned interim analysis after two-thirds of the sample size (212 patients) have achieved the 90 days follow-up. Methods and design A prospective, multi-center, randomized, controlled, open-label and blinded-endpoint trial. The randomization employs a 1:1 ratio of mechanical thrombectomy with the detachable Solitaire thrombectomy device and best medical therapy (BMT) vs. BMT alone. Study outcomes The primary outcome will be the proportion of patients achieving modified Rankin Scale (mRS) 0–3 at 90 days. Key secondary outcomes are: dramatic early favorable response, dichotomized mRS score (0–2 vs. 3–6 and 0–4 vs. 5–6) at 90 days, ordinal (shift) mRS analysis at 90 days, infarct volume at 24 h, vessel recanalization at 24 h in both treatment arms, and successful recanalization in the thrombectomy arm according to the modified thrombolysis in cerebral infarction (mTICI) classification defined as mTICI 2 b or 3. Safety variables are mortality at 90 days, symptomatic intracranial hemorrhage rates at 24 h, and procedure-related complications. Discussion Results from this trial will indicate whether mechanical thrombectomy is superior to medical management alone in achieving favorable outcomes in subjects with acute stroke caused by basilar artery occlusion presenting within 6–24 h from symptom onset. Trial registration: URL: http://www.clinicaltrials.gov . ClinicalTrials.gov Identifier: NCT02737189.

Increased interest in real-world evidence (RWE) for clinical and regulatory decision making and the need to evaluate long-term benefits and risks of pharmaceutical products raise the importance of understanding the use of external controls (ECs) for uncontrolled extensions of randomized controlled trials (RCTs). We searched clinicaltrials.gov from 2009 to 2019 for uncontrolled extensions and assessed the use of ECs in the trial protocol registry and PubMed. We present characteristics of identified uncontrolled extensions, their adoption of ECs, and a qualitative appraisal of published uncontrolled extensions with ECs according to good pharmacoepidemiologic practice. The number of uncontrolled extensions increased slightly across the study period, resulting in a total of 1,115 studies. Most originated from phase III RCTs (62.2%) and specified safety outcomes (61.9% among those with specified outcomes). Most uncontrolled extensions incorporated no control group with only 7 out of 1,115 (0.6%) employing ECs. For those studies with ECs, all involved treatments for rare conditions and assessment of effectiveness. Attempts to balance comparison groups varied from none mentioned to propensity score matching. We noted consistent deficiencies in outcome ascertainment methods and approaches to address attrition bias. The contrast of the large and growing number of uncontrolled extensions with the small number of studies that utilized ECs showed clear opportunities for enhancement in design, measurement, and analysis of uncontrolled extensions to allow causal inferences on long-term treatment effects. As extensions continue to expand within RWE regulatory frameworks, development of guidelines for use of EC with uncontrolled extensions is needed.

Objective\ud : To explore how potential harms are assessed in trials of behavioural, lifestyle and psychological therapy interventions.\ud \ud \ud \ud Study Design and Setting\ud : This study was a review of protocols from the National Institute of Health Research Health Technology Assessment and Public Health Research programmes. Protocols were included if the study was a randomised controlled trial and the intervention intended to change lifestyle or behaviour to improve health or improve psychological outcomes.\ud \ud \ud \ud Results\ud : 95 of 151 protocols planned to record adverse events (AEs). Definitions of AEs were often not given and varied widely. Serious AEs were mostly defined using standards originally devised for pharmacological trials. Twenty-two protocols listed expected AEs. Few protocols described assessment of causation between AEs and intervention. Examples of useful AE recording practice were identified.\ud \ud \ud \ud Conclusion\ud : Monitoring and recording AEs in behavioural intervention trials was variable and frequently based on reporting guidelines for pharmacological trials. This may mean potential harms are being missed. Future trials should consider: 1) Potential harms posed by the intervention 2) How to define serious AEs 3) What are expected AEs. Further research to achieve consensus on AE recording is required, including identification of core adverse outcomes in clinical areas or caused by interventions.\ud \ud \ud • Harms or unintended consequences are known to be possible from trials of behavioural, lifestyle and psychological therapy interventions, yet are not always appropriately or consistently evaluated in trials.\ud \ud \ud • Reliance on definitions for harms (typically termed adverse events) originally devised for pharmacological trials, may result in omission of important harms.\ud \ud \ud • The level of risk or likelihood of harm from an intervention should always be assessed in trials of these interventions.\ud \ud \ud • Better details on adverse event recording in protocols is needed to increase transparency and consistency and improve practice, but consensus is needed on the appropriate approach.\ud \ud \ud • Examples of useful AE recording practices identified from trials included in this review are discussed, for example: alternative definitions of what constitutes a serious adverse event or methods of deriving lists of expected adverse events.

Non-inferiority trials are used to test if a novel intervention is not worse than a standard treatment by more than a prespecified amount, the non-inferiority margin (ΔNI). The ΔNI indicates the amount of efficacy loss in the primary outcome that is acceptable in exchange for non-efficacy benefits in other outcomes. However, non-inferiority designs are sometimes used when non-efficacy benefits are absent. Without non-efficacy benefits, loss in efficacy cannot be easily justified. Further, non-efficacy benefits are scarcely defined or considered by trialists when determining the magnitude of and providing justification for the non-inferiority margin. This is problematic as the importance of a treatment’s non-efficacy benefits are critical to understanding the results of a non-inferiority study. Here we propose the routine reporting in non-inferiority trial protocols and publications of non-efficacy benefits of the novel intervention along with the reporting of non-inferiority margins and their justification. The justification should include the specific trade-off between the accepted loss in efficacy (ΔNI) and the non-efficacy benefits of the novel treatment and should describe whether patients and other relevant stakeholders were involved in the definition of the ΔNI.

Introduction The chronic neuropathic pain associated with postherpetic neuralgia (PHN) can last for several months or even many years, seriously affecting the affected person’s work, sleep, mood, and daily life activities. In generaly, current treatments for PHN are at best limited and unsatisfactory, and adverse reactions are common, especially in elderly patients. Electroacupuncture (EA) is widely used clinically to manage painful diseases, but there remains a lack of evidence to support the effectiveness of EA on PHN. This study is designed to assess the efficacy and safety of EA on PHN, and to provide evidence-based medical evidence for EA treatment of PHN. Methods This multicenter, prospective, randomized controlled trial will recruit 448 patients with PHN at seven clinical centers. Multicenter stratified variable block randomization will be used, and the eligible patients will be randomly allocated in a ratio of 1:1 to the EA group or sham EA group. The EA group will receive 4 weeks of EA treatment, given as 30-min treatment sessions, once daily, 5 times per week, for a total of 20 treatments; the sham EA group will receive sham EA treatment under the same conditions. Planned Outcomes The primary outcome measure is the 11-point Numeric Rating Scale pain score at week 4. The secondary outcome measures, including mechanical pain threshold, pain area of PHN, average number of pain episodes, the short-form McGill Pain Questionnaire 2, Zoster Brief Pain Inventory, the Depression, Anxiety, and Positive Outlook Scale, Patient Global Impression of Change, safety of EA, and use of concomitant medications, among others. The primary analysis of the outcomes will be the mixed-effect model with repeated measurement between groups on an intent-to-treat population. Trial Registration Clinicaltrials.gov identifier: NCT04560361. Registered 23 September 2020 (https://clinicaltrials.gov/ct2/show/NCT04560361?term=NCT04560361&draw=2&rank=1). Supplementary Information The online version contains supplementary material available at 10.1007/s40122-021-00283-8.

Zinc inhibits replication of the SARS‐CoV virus. We aimed to evaluate the safety, feasibility, and biological effect of administering high‐dose intravenous zinc (HDIVZn) to patients with COVID‐19. We performed a Phase IIa double‐blind, randomized controlled trial to compare HDIVZn to placebo in hospitalized patients with COVID‐19. We administered trial treatment per day for a maximum of 7 days until either death or hospital discharge. We measured zinc concentration at baseline and during treatment and observed patients for any significant side effects. For eligible patients, we randomized and administered treatment to 33 adult participants to either HDIVZn (n = 15) or placebo (n = 18). We observed no serious adverse events throughout the study for a total of 94 HDIVZn administrations. However, three participants in the HDIVZn group reported infusion site irritation. Mean serum zinc on Day 1 in the placebo, and the HDIVZn group was 6.9 ± 1.1 and 7.7 ± 1.6 µmol/l, respectively, consistent with zinc deficiency. HDIVZn, but not placebo, increased serum zinc levels above the deficiency cutoff of 10.7 µmol/l (p

Aim: Surgical site infection (SSI) is a common complication following emergency laparotomy, occurring in around 25% of patients in UK practice. The adoption of single-use negative-pressure dressings (SUNPDs) has been proposed as a prophylactic method of reducing the rate of SSI. The primary aim of the randomized controlled trial (RCT) described herein is to determine if a SUNPD reduces SSI at 30 days after an emergency laparotomy. Method: The Single Use Negative pRessure dressing for Reduction In Surgical site infection following Emergency laparotomy (SUNRRISE) study is an international, multicentre, pragmatic, phase III RCT with internal feasibility phase. As stated, the primary aim is to determine if a SUNPD reduces SSI at 30 days postoperatively. Patients will be randomized in a 1:1 ratio to receive either a SUNPD or a dressing of the surgeon's preference. Outcome assessors will be blinded to treatment allocation. The primary outcome measure is SSI within 30 days of surgery as defined by the US Centers for Disease Control criteria. A total of 840 patients will be required to detect a relative reduction of 40% in SSI rates (from 25% to 15%) with 90% power accounting for a 20% attrition rate. Discussion: SUNRRISE is an international, multicentre RCT evaluating the prophylactic use of SUNPD in primary closed emergency laparotomy wounds for the reduction of SSI. Our hypothesis is that a SUNPD is superior to the surgeon's preference of dressing in reducing SSIs at 30 days. The findings may influence dressing choice following emergency abdominal surgery in the future.

Aims In patients undergoing percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI), the risk of ischaemic complications is highest in the early phase (during the first 30 days), while most bleeding events occur predominantly during the maintenance phase of treatment (after the first 30 days). Data on the de-escalation of dual antiplatelet therapy by switching from ticagrelor to clopidogrel in stabilised AMI patients are limited. The aim of this study is to investigate the efficacy and safety of switching from ticagrelor to clopidogrel in AMI patients with no adverse event during the first month after the index PCI with newer-generation DES. Methods and results TALOS-AMI is a multicentre, randomised, open-label study enrolling 2,590 AMI patients with no adverse events during the first month after the index PCI. One month after the index PCI, eligible patients are randomly assigned either to 1) aspirin 100 mg plus clopidogrel 75 mg daily, or to 2) aspirin 100 mg plus ticagrelor 90 mg twice daily, in a 1:1 ratio. The primary endpoint is a composite of cardiovascular death, MI, stroke, and bleeding type 2, 3 or 5 according to the Bleeding Academic Research Consortium (BARC) criteria from 1 to 12 months after the index PCI. Conclusions The TALOS-AMI trial is the first large-scale, multicentre, randomised study exploring the efficacy and safety of the de-escalation of antiplatelet therapy by switching from ticagrelor to clopidogrel in stabilised AMI patients undergoing PCI.

Aims Cardiogenic shock (CGS) occurs in 6-10% of patients with acute coronary syndromes (ACS). Mortality has fallen over time from 80% to approximately 50% consequent on acute revascularisation but has plateaued since the 1990s. Once established, patients with CGS develop adverse compensatory mechanisms that contribute to the downward spiral towards death, which becomes difficult to reverse. We aimed to test in a robust, prospective, randomised controlled trial whether early support with veno-arterial extracorporeal membrane oxygenation (VA-ECMO) provides clinical benefit by improving mortality and morbidity. Methods and results The EURO SHOCK trial will test the benefit or otherwise of mechanical cardiac support using VA-ECMO, initiated early after acute percutaneous coronary intervention (PCI) for CGS. The trial sets out to randomise 428 patients with CGS complicating ACS, following primary PCI (P-PCI), to either very early ECMO plus standard pharmacotherapy, or standard pharmacotherapy alone. It will be conducted in 39 European centres. The primary endpoint is 30-day all-cause mortality with key secondary endpoints: 1) 12-month all-cause mortality or admission for heart failure, 2) 12-month all-cause mortality, 3) 12-month admission for heart failure. Cost-effectiveness analysis (including quality of life measures) will be embedded. Mechanistic and hypothesis-generating substudies will be undertaken. Conclusions The EURO SHOCK trial will determine whether early initiation of VA-ECMO in patients presenting with ACS-CGS persisting after PCI improves mortality and morbidity.

The Supreme Court Regulation Number 5 of 2020 concerning Trial Protocols and Security in a Court Environment has created a lot of pros and cons from various perspectives. There are many regulations that allow it as a form of freedom of expression, some are related to human rights violations, fulfillment and protection. In this paper the author uses a qualitative research methodology with legal materials sourced from the Supreme Court Regulation Number 5 of 2020 concerning Trial Protocols and Security in a Court Environment and other laws and regulations, and theories by experts from the literature related to this research. The results of the study state that the importance of implementing regulations regarding freedom of expression through digital media in Indonesia, and the application of Law No.39 of 1999 concerning Human Rights and specifically regulating Information and Electronic Transactions through Law No.11 of 2008.Keywords: Restriction; The judge; Record

BACKGROUND AND AIMS: Digital interventions are effective for reducing alcohol consumption but evidence is limited regarding smartphone apps. Drink Less is a theory- and evidence-informed app to help people reduce their alcohol consumption that has been refined in terms of its content and design for usability across the sociodemographic spectrum. We aim to evaluate the effectiveness and cost-effectiveness of recommending Drink Less at reducing alcohol consumption compared with usual digital care.DESIGN: Two-arm individually randomised controlled trial.SETTING: Online trial in the United Kingdom (UK).PARTICIPANTS: Hazardous or harmful drinkers (Alcohol Use Disorders Identification Test [AUDIT] score ≥8) aged 18+ who want to drink less alcohol (n = 5562). Participants will be recruited from July 2020 to May 2022 using multiple strategies with a focus on remote digital methods.INTERVENTION AND COMPARATOR: Participants will be randomised to receive either an email recommending that they use Drink Less (intervention) or view the National Health Service (NHS) webpage on alcohol advice (comparator).MEASUREMENTS: The primary outcome is change in self-reported weekly alcohol consumption, assessed using the extended AUDIT-Consumption, between baseline and 6-month follow-up. Secondary outcomes include change in self-reported weekly alcohol consumption assessed at 1- and 3-month follow-ups, and the proportion of hazardous drinkers; alcohol-related problems and injury; health-related quality of life; and use of health services assessed at 6-month follow-up. Effectiveness will be examined with adjusted regression models, adjusting for baseline alcohol consumption and using an intention-to-treat approach. A mixed-methods process evaluation will assess engagement, acceptability and mechanism of action. Economic evaluations will be conducted using both a short- and longer-term time horizon.COMMENTS: This study will establish the effectiveness and cost-effectiveness of the Drink Less app at reducing alcohol consumption among hazardous and harmful adult drinkers and will be the first randomised controlled trial of an alcohol reduction app for the general population in the United Kingdom. This study will inform the decision on whether it is worth investing resources in large-scale implementation.

To assess, with all available trial information, whether the assessment of the PRECIS-2 nine domains could provide a clear distinction between medicine masked pragmatic randomized controlled trials (pRCTs) and open-label pRCTs. A search was conducted of participant-level pRCTs on medicines published on 25 influential medical journals in July 2018–December 2019. All pre-licensing (phases 1–3) and cluster pRCTs were excluded. All trials’ available reports were searched through the published article information, Google Scholar, and trial websites. Instead of providing a score to each PRECIS-2 domain, these were classified as E (explanatory), N (neutral), or P (pragmatic). Of 128 pRCTs, 18 (14%) were participant-level pRCTs on medicines. The full trial protocol was available for 14 trials; 12 had published the protocol and nine had additional reports published. All trials were prospectively registered, and none was funded by industry. Ten and eight were masked and open-label trials, respectively. Masked pRCTS had 34% of pragmatic and 60% of explanatory domains; open-label pRCTS had 45% pragmatic and 45% explanatory domains. Among the 10 masked trials, only one had a majority of five pragmatic domains; among the eight open-label trials, four had a majority of six or five pragmatic domains. “Follow-up” was considered explanatory in the 18 pRCTs; “primary analysis” was pragmatic in 17 pRCTs. The PRECIS-2 tool seems not to be sensitive enough to clearly discriminate between medicine masked pRCTs and open-label pRCTs. When conducting systematic reviews, it is suggested that the PRECIS-2 tool should not be used to support placing masked trials in the pragmatic side of the explanatory/pragmatic continuum.

Supplemental Digital Content is Available in the Text., BACKGROUND The etiology of cellulite is unclear. Treatment of cellulite has targeted adipose tissue, dermis, and fibrous septae with varying degrees of success and durability of response. OBJECTIVE Results from clinical trials that target different anatomical aspects of cellulite can provide insights into the underlying pathophysiology of cellulite. MATERIALS AND METHODS A search of the PubMed database and ClinicalTrials.gov website was conducted to identify clinical trials that have investigated treatments for cellulite. RESULTS A lack of trial protocol standardization, objective means for quantification of improvement and reported cellulite severity, and short-term follow-up, as well as variation in assessment methods have made comparisons among efficacy studies challenging. However, the lack of durable efficacy and inconsistency seen in clinical results suggest that dermal or adipose tissue changes are not the primary etiologies of cellulite. Clinical studies targeting the collagen-rich fibrous septae in cellulite dimples through mechanical, surgical, or enzymatic approaches suggest that targeting fibrous septae is the strategy most likely to provide durable improvement of skin topography and the appearance of cellulite. CONCLUSION The etiology of cellulite has not been completely elucidated. However, there is compelling clinical evidence that fibrous septae play a central role in the pathophysiology of cellulite.

Objectives Interpreting a randomized trial requires access to more than the main results paper. We aimed to determine the (1) proportion of trials referring to the protocol in the trial report and their accessibility, (2) proportion of protocols accessible from trial registry entry and by trial registration number search, and (3) types of additional publications associated with trial reports. Study Design and Setting A previously gathered sample of randomized trials of nonpharmacological interventions published in 2009 was used. Trial reports and registry entries were searched for protocol mentions and obtained when possible. Related publications were identified using citation searching. Results Of 133 trials, 96 (72%) mentioned the protocol within the report, 61 (64%) contained details about protocol acquisition, with 48 (36%) protocols obtainable. Of the 129 registered trials, 32 (25%) had protocols obtainable from registry entry. Citation tracking identified 1,030 related publications, most common were secondary analyses and qualitative studies. Conclusion Trial protocols facilitate good trial conduct and interpretation. However, they are often not linked to the main report or registry and can be difficult to obtain. Many trials have related publications that are inconsistently linked. Trial registries and registration numbers could facilitate the threading of articles related to a trial, but currently do not.

The COVID‐19 pandemic has halted many ongoing CNS clinical trials, especially in Alzheimer’s disease. These long‐duration trials involve many stakeholders, especially the patients and their family members, who have demonstrated their commitment to developing new therapeutic interventions for this devastating disease. We certainly do not want to lose all the knowledge we have gained from these ongoing trials because of the pandemic. While some of these trials will need to restart, others can re‐start at different points along the trial protocol with substantial protocol amendments. However, there is an urgent need to combine useful information from the completers with those subjects undergoing complex protocols deviations and amendments after re‐start. We propose the concept of mechanistic modeling‐based virtual twin patients as a possible solution to harmonize the readouts from these complex and fragmented clinical datasets in a biologically relevant way.

Introduction and hypotheses valuation of surgical skills, both technical and nontechnical, is possible through observations and video analysis. Besides technical failures, adverse outcomes in surgery can also be related to hampered communication, moderate teamwork, lack of leadership, and loss of situational awareness. Even though some surgeons are convinced about nontechnical skills being an important part of their professionalisation, there is paucity of data about a possible relationship between nontechnical skills and surgical outcome. In robot-assisted surgery, the surgeon sits behind the console and is at a remote position from the surgical field and team, making communication more important than in open surgery and conventional laparoscopy. A lack of structured research makes it difficult to assess the value of the different analysis methods for nontechnical skills, particularly in robot-assisted surgery. Our hypothesis includes the following: (1) introduction of robot-assisted surgery leads to an initial decay in nontechnical skills behaviour during the learning curve of the team, (2) nontechnical skills behaviour is more explicitly expressed in experienced robot-assisted surgery teams than in experienced open surgery teams, and (3) introduction of robot-assisted surgery leads to the development of different forms of nontechnical skills behaviour compared with open surgery. Design This study is a prospective, observational, multicentre, nonrandomised, case-control study including bladder cancer patients undergoing either an open radical cystectomy or a robot-assisted radical cystectomy at the Catharina Hospital Eindhoven, the Netherlands, or at the Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital Amsterdam. All patients are eligible for inclusion; there are no exclusion criteria. The Catharina Hospital Eindhoven, the Netherlands, performs on average 35 radical cystectomies a year. The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital Amsterdam, performs on average 100 radical cystectomies a year. Protocol overview The choice of treatment is at the discretion of the patient and the surgeon. Patient results will be obtained prospectively. Pathology results as well as complications occurring within 90 d following surgery will be registered. Surgical complications will be registered according to the Clavien-Dindo system. Measurements Nontechnical skills will be observed using five different methods: (1) NOTSS: Nontechnical Skills for Surgeons; (2) Oxford NOTECHS II: a modified theatre team nontechnical skills scoring system; (3) OTAS: Observational Teamwork Assessment for Surgery; (4) Interpersonal and Cognitive Assessment for Robotic Surgery (ICARS): evaluation of nontechnical skills in robotic surgery; and (5) analysis of human factors. Technical skills in robot-assisted radical cystectomy will be analysed using two different methods: (1) GEARS: Global Evaluative Assessment of Robotic Skill and (2) GERT: Generic Error Rating Tool. Safety criteria and reporting Formal ethical approval has been provided by Medical research Ethics Committees United (MEC-U), The Netherlands (reference number W19.048). We hope to present the results of this study to the scientific community at conferences and in peer-reviewed journals. Statistical analysis Frequency statistics will be calculated for patient demographical data, and a Shapiro-Wilk test with p > 0.05 will be used to define normal distribution. Univariate analysis will be conducted to test for statistically significant differences in observation scores between open radical cystectomy and robot-assisted radical cystectomy cohorts across all variables, using independent sample t tests and Mann-Whitney U testing, as appropriate. A variable-selection strategy will be used to create multivariate models. Binary logistic regression will be conducted to calculate odds ratios and 95% confidence intervals for significant predictors on univariate analysis and clinically relevant covariates. Statistical significance is set at p, This study uses a structured approach to the analysis of nontechnical skills (NTS) using extracorporeal videos of both open radical cystectomy and robot-assisted radical cystectomy surgeries, in order to obtain detailed data on NTS during open and minimally invasive surgery.

Background Accidental awareness during general anaesthesia (AAGA) is a complex and rare outcome to investigate in surgical patient populations, particularly obstetric patients. We report the protocol of the Direct Reporting of Awareness in Maternity patients (DREAMY) study, illustrating how the research was designed to address practical and methodological challenges for investigating AAGA in an obstetric cohort. Methods This is the trial protocol of a prospective, multicentre cohort study of patients undergoing obstetric surgery under general anaesthesia. Accidental awareness during general anaesthesia will be detected using three repetitions of standardised direct questioning over 30 days, with responses indicating memories during general anaesthesia verified using structured interviews. Reports will be adjudicated, then classified, in accordance with pre-defined and pre-validated structures, including the Michigan Awareness Classification tool. Quantitative data will be collected on general anaesthesia conduct for all participants. This descriptive study is being conducted in England and aims to recruit a minimum of 2015 patients. Results The DREAMY study was prospectively registered (ClinicalTrials.gov Identifier: NCT03100396) and ethical approval granted. Participant recruitment began in May 2017 and one year follow up concluded in August 2019. Publication of the results is anticipated in 2020. Conclusions The DREAMY study will provide data on incidence, experience and implications of AAGA for obstetric patients, using a robust methodology that will reliably detect and translate subjective AAGA reports into objective outcomes. In addition, the study is expected to improve vigilance for AAGA in participating hospitals and encourage adoption of recommendations for support of patients experiencing AAGA.

Objectives We assessed the proportion of primary health care (PHC) randomized controlled trial (RCT) protocols published in peer-reviewed journals that published results in subsequent papers in peer-reviewed journals; and whether this proportion changed over time. Study Design and Setting We searched (last update June 2019) for RCTs published in peer-reviewed journals reporting primary outcome results for 620 protocols that were published up to 2014 and were retrieved in PubMed. We recorded the absolute number and the proportion of protocols with published results per year; and estimated whether the proportion changed over time. Results Of the 620 published protocols, 525 (85%) disseminated their results through a published RCT by June 2019. The number of published protocols was increasing over time especially after 2001. However, the proportion of protocols per year with published results in subsequent papers was decreasing over time after 2002. Specifically, the proportion ranged from 86% to 96% for protocols published until 2010 while for those published from 2011 onward ranged from 76% to 86%. Mean time from protocol to results publication was 39 months (95% CI 37, 41). Conclusion Almost one-sixth of PHC trial protocols published in peer-reviewed journals did not publish their results in subsequent papers.

Background and aims Sustained psychosocial support via online social groups may help former tobacco users maintain abstinence. This study aims to examine the effectiveness of participating in a WhatsApp social group for long-term smoking cessation. Design Two-arm, open-labelled, pragmatic, individually randomized controlled trial. Setting All participants are service users of smoking cessation clinics, and all interventions are delivered via mobile phones. Participants Participants included 1008 adult quitters who self-report no tobacco use in the past 3-30 days. Interventions The intervention group (n = 504) will join a WhatsApp social group to receive standardized and theory-based reminders of smoking relapse prevention and participate in discussion with other WhatsApp group members using their own mobile phones. All social groups will be led by counselors or specialist nurse practitioners. The control group (n = 504) will receive similar reminders via short messages to their own mobile phones but will not interact with other participants. The intervention duration for both groups is 8 weeks. Both groups will receive a booklet at baseline about how to prevent smoking relapse. Measurements The primary outcome is biochemically validated tobacco abstinence at 12 months after consent. Comments The findings will provide evidence concerning the utility of operating online social group discussion for prevention of smoking relapse and sustaining long-term abstinence.

Introduction. Well-known research showed that the skin conductance response (SCR) of the Autonomic Nervous System (ANS) in the Concealed Information Test (CIT) is typically increased in participants who are financially and motivationally incentivized to beat the CIT (the paradoxical “motivational impairment” effect). This is not what happens with Reaction Time (RT)-based CITs, P 300 CITs based on the 3-stimulus protocol, nor on the P 300 -based complex trial protocol for detection of malingering. In the Concealed Information Test (CIT), there are at least two kinds of stimuli randomly presented regarding order to participants: The (1) probes are the items expected to be remembered; they are often from a crime scene in a forensic scenario—such as, a stolen diamond necklace. The (2) irrelevant stimuli are other comparably valuable items (a watch, a bracelet, a broach, etc.) which are from the same category as the probe (jewelry), but are not identical to it, so are unrecognized by the thief as the stolen item. The probe is recognized, and therefore elicits a larger physiological response in only the knowledgeable participant. To innocent suspects, the probe is just another irrelevant so elicits a smaller or no physiological response. Purpose. To determine how financial compensation affect P 300 in the Complex Trial Protocol (CTP) Version in Concealed Information Test (CIT) in malingering detection. Methods. P 300 measured P 300 peak to the subsequent negative peak {“peak to peak”) from Fz, Cz, and Pz, was recorded, filtered, artifacted, and averaged. Signals were passed through a Mitsar 19 channel (model 201) amplifier with a.16 Hz high pass filter setting, and low pass filters at 30 Hz. Output was conveyed to a 16-bit Mitsar Analog to Digital converter sampling at 500 Hz. For analyses and displays, single sweeps and averages were digitally filtered; the filter passed frequencies from 0 to 6 Hz using a Kaiser filtering algorithm. The present report study of motivated malingerers instructed how to beat the test, with uninstructed motivated (paid and unpaid) and unmotivated (“simple malingering”) subjects, using episodic and semantic memory probes. The Test of Memory Malingering (TOMM) validated behavioral differences among groups. Results. The present reports found the lack of financially motivated influence with both episodic and semantic memory stimuli. Also semantic memory-evoked P 300 s exceeded episodic memory evoked P 300 s. An effect of specific test-beating instructions was found to enhance the CIT effect for semantic information. Originality. The “Concealed Information Test (CIT) effect” (probe-minus-irrelevant P 300 differences) did not differ among incentive groups. Conclution. P300 amplitude is associated with the amount of focused attention to stimuli. This suggests that since a financial incentive should increase attention, the incentive manipulation should also produce larger P 300 s to familiar stimuli. However, once attention is enough to assure recognition of probes within a memory type category, the resulting P 300 s consequently generated in a more all-or-none manner are no longer influenced by motivation. Apparently, in the present study, attention to stimuli was adequate to assure recognition, whose consequent P 300 s, were no longer modifiable by motivation.

Background No treatment has convincingly been proven to be beneficial for microvascular obstruction (MVO) in patients with ST-elevation myocardial infarction (STEMI). Several studies have described the effects of Danhong Injection. However, evidence of a rigorously designed verification study is still lacking, and the intervention timing of Danhong Injection is uncertain. Methods The DIRECTION study is a multicenter, prospective, randomized, evaluator-blind study. A total of 336 patients with STEMI receiving percutaneous coronary intervention (PCI) will be randomly assigned to conventional treatment, the preoperative Danhong Injection, or the postoperative Danhong Injection. The primary outcome is rate of ST-segment resolution (STR) ≥ 70% at 90 min after PCI. The secondary outcomes are the degree of STR, Thrombolysis in Myocardial Infarction (TIMI) flow grade, TIMI myocardial perfusion grade, left ventricular ejection fraction, N-terminal prohormone brain natriuretic peptide, high-sensitivity C-reactive protein, and infarct size expressed as area under the curve for cardiac troponin I (cTnI) and for creatine kinase MB. The major adverse cardiovascular events and hospital readmission events will be recorded. Health quality will be assessed with the 12-item Short Form Health Survey. The safety outcomes include bleeding events, adverse events, and abnormal changes in routine blood tests. Psychological status and dietary patterns will be evaluated using Hamilton Depression Rating Scale and Food Frequency Questionnaire as the relevant indicators. Discussion This trial will evaluate the efficacy and safety of Danhong Injection, as well as its optimal timing of intervention to prevent MVO in patients with STEMI. Trial registration Chinese Clinical Trial Registry, ChiCTR1900021440. Registered on February 21, 2019.

Contains fulltext : 220541.pdf (Publisher’s version ) (Open Access) BACKGROUND: Hypoglycaemia is the most frequent complication of treatment with insulin or insulin secretagogues in people with diabetes. Severe hypoglycaemia, i.e. an event requiring external help because of cognitive dysfunction, is associated with a higher risk of adverse cardiovascular outcomes and all-cause mortality, but underlying mechanism(s) are poorly understood. There is also a gap in the understanding of the clinical, psychological and health economic impact of 'non-severe' hypoglycaemia and the glucose level below which hypoglycaemia causes harm. AIM: To increase understanding of hypoglycaemia by addressing the above issues over a 4-year period. METHODS: Hypo-RESOLVE is structured across eight work packages, each with a distinct focus. We will construct a large, sustainable database including hypoglycaemia data from >100 clinical trials to examine predictors of hypoglycaemia and establish glucose threshold(s) below which hypoglycaemia constitutes a risk for adverse biomedical and psychological outcomes, and increases healthcare costs. We will also investigate the mechanism(s) underlying the antecedents and consequences of hypoglycaemia, the significance of glucose sensor-detected hypoglycaemia, the impact of hypoglycaemia in families, and the costs of hypoglycaemia for healthcare systems. RESULTS: The outcomes of Hypo-RESOLVE will inform evidence-based definitions regarding the classification of hypoglycaemia in diabetes for use in daily clinical practice, future clinical trials and as a benchmark for comparing glucose-lowering interventions and strategies across trials. Stakeholders will be engaged to achieve broadly adopted agreement. CONCLUSION: Hypo-RESOLVE will advance our understanding and refine the classification of hypoglycaemia, with the ultimate aim being to alleviate the burden and consequences of hypoglycaemia in people with diabetes.

Background: Although supplemental oxygen can be lifesaving, liberal oxygen administration causing hyperoxaemia may be harmful. The targets for oxygenation in patients with acute hypoxaemic respiratory failure acutely admitted to the intensive care unit (ICU) are strongly debated, and consensus on which targets to recommend has not been reached. The Handling Oxygenation Targets in the ICU (HOT-ICU) trial is a multicentre, randomised, parallel-group trial of a lower oxygenation target (arterial partial pressure of oxygen [PaO2] = 8 kPa) versus a higher oxygenation target (PaO2 = 12 kPa) in adult ICU patients with acute hypoxaemic respiratory failure. In this study, we aim to evaluate the effects of these targets on long-term cognitive and pulmonary function in Danish patients, enrolled in the HOT-ICU trial and surviving to 1-year follow-up. We hypothesise that a lower oxygenation target throughout the ICU stay may result in cognitive impairment, whereas a higher oxygenation target may result in impaired pulmonary function. Methods: All patients enrolled in the HOT-ICU trial at Danish sites and surviving to 1 year after randomisation are eligible to participate. The last patient is expected to be included by November 2021. A Repeatable Battery for the Assessment of Neuropsychological Status and a body plethysmography, including diffusion capacity for carbon monoxide, both pre-planned secondary long-term outcomes of the HOT-ICU trial, will be obtained. Conclusion: This study will provide important information on the long-term effects of a lower versus a higher oxygenation target on cognitive and pulmonary function in adult ICU patients with acute hypoxaemic respiratory failure.

Background In the UK, approximately 8% of live births are preterm (before 37 weeks gestation), more than 90% of whom are born between 30 and 36 weeks, forming the largest proportion of a neonatal units’ workload. Neonatologists are cautious in initiating full milk feeds for preterm infants due to fears of necrotising enterocolitis (NEC). There is now evidence to dispute this fear. Small studies have shown that feeding preterm infants full milk feeds enterally from birth could result in a shorter length of hospital stay, which is important to parents, clinicians and NHS services without increasing the risk of NEC. This trial aims to investigate whether full milk feeds initiated in the first 24 h after birth reduces the length of hospital stay in comparison to introduction of gradual milk feeding with IV fluids or parenteral nutrition. Methods FEED1 is a multi-centre, open, parallel group, randomised, controlled superiority trial of full milk feeds initiated on the day of birth versus gradual milk feeds for infants born at 30+0 to 32+6 (inclusive) weeks gestation. Recruitment will take place in around 40 UK neonatal units. Mothers will be randomised 1:1 to full milk feeds, starting at 60 ml/kg day, or gradual feeds, as per usual local practice. Mother’s expressed breast milk will always be the first choice of milk, though will likely be supplemented with formula or donor breast milk in the first few days. Feeding data will be collected until full milk feeds are achieved (≥ 140 ml/kg/day for 3 consecutive days). The primary outcome is length of infant hospital stay. Additional data will be collected 6 weeks post-discharge. Follow-up at 2 years (corrected gestational age) is planned. The sample size is 2088 infants to detect a between group difference in length of stay of 2 days. Accounting for multiple births, this requires 1700 women to be recruited. Primary analysis will compare the length of hospital stay between groups, adjusting for minimisation variables and accounting for multiple births. Discussion This trial will provide high-quality evidence on feeding practices for preterm infants. Full milk feeds from day of birth could result in infants being discharged sooner. Trial registration ISRCTN ISRCTN89654042. Prospectively registered on 23 September 2019: ISRCTN is a primary registry of the WHO ICTRP network, and all items from the WHO Trial Registration dataset are included.

The gluten-free diet is the treatment of coeliac disease but is also widely consumed worldwide outside patient treatment. It seems clear that the vast majority of individuals avoiding gluten do not have undetected coeliac disease. Gluten containing food contains both gluten as well as other potential culprits for effects, most notably fermentable oligo-, di-, monosaccharides and polyols. Randomized, controlled and double-blinded studies generally to do not support “pure” gluten as the culprit. Other lines of evidence, most notably serological markers, still suggest gluten sensitivity as a possible factor. The research field is hampered by the lack of uniform challenge trial protocols and lack of “objective gold standard” for diagnosis.

Aims: This study will aim to assess if a composite intervention which involves a specific evidence-based intervention for management of insomnia and non-hormonal pharmacotherapy to manage vasomotor symptoms (VMS) of menopause can improve quality of life for patients experiencing troublesome VMS after cancer who are not eligible for standard systemic menopausal hormone therapy (MHT). Participants will be asked to nominate a partner or companion to support them during this process as an additional form of support. Background: The menopause transition and its symptoms represent a significant challenge for many patients after cancer treatment, particularly those for whom conventional MHT is contraindicated. These symptoms include hot flushes, night sweats, urogenital symptoms as well as mood and sleep disturbance. These symptoms can exacerbate the consequences of cancer and its treatment. Methods: We will recruit 205 women who meet inclusion criteria and enrol them on a composite intervention which consists of four parts: (1) use of non-hormonal pharmacotherapy for the management of troublesome vasomotor symptoms of menopause tailored to the timing of predominant symptoms, (2) digital cognitive behavioural therapy for insomnia through the web based Sleepio service, (3) access to information regarding self-management strategies for the common symptoms of menopause and their consequences and (4) identification of a partner or other support person who commits to providing support during the study period. Outcomes: The primary outcome will be cancer specific quality of life measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ C30). Secondary outcomes will include sleep quality, bother/interference of vasomotor symptoms and communication between couples about their cancer diagnosis and their menopause experience. Sleep will be measured using the Sleep Condition Indicator (SCI) tool, bother/interference of vasomotor symptoms will be measured by the Hot Flush Rating Scale (HFRS) and communication will be measured using the Couples’ Illness Communication Scale (CICS). These validated scales will be administered at baseline, four weeks, three months and six months. Registration: This study is registered on ClinicalTrials.gov with number NCT 04766229.

Background Adolescent mothers have lower rates of initiation, continuation, and exclusivity of breastfeeding, and even more so in the first pregnancy. Current interventions target adult women, and little evidence is available for breastfeeding promotion among adolescents. Methods This is a pilot study protocol with a parallel, single-blind, randomized, and controlled trial design, to evaluate the feasibility of the intervention “Lactation Counseling” in first-time adolescent mothers to maintain exclusive breastfeeding in the first 6 months of life. The control group will receive routine education in prenatal care and prenatal and childbirth classes, the experimental group will receive additionally the intervention “Lactation Counseling”, for 4 weeks, both conducted by trained nurses. Feasibility outcome includes recruitment and dropout rates, and, pilot outcomes will be the exclusive breastfeeding rate and the breastfeeding knowledge. Measurements will be taken at baseline, post-intervention, and 2, 4, and 6 months after childbirth. Discussion Exclusive breastfeeding rates could be increased in adolescent mothers through nursing counseling interventions that are previously structured and evaluated from their feasibility. This study will allow the evaluation of the feasibility of an intervention in low-income, Latin American population adolescents. Trial registration ClinicalTrials.gov NCT04655846, Registered 7 December 2020.

BackgroundEvasive personality disorder (EPD) and social phobia (SP) have substantial costs to the patients and their families, and great economic costs to the community. While psychotherapy can be an efficient treatment, a large percentage of patients drop-out during treatment. Little is known about what can be done in order to decrease dropout from psychotherapy in general, including how to increase a patient’s readiness for psychotherapy. MethodsWe describe a feasibility randomized controlled trial of 42 individuals with a clinical diagnosis of either SP or evasive personality disorder, who are to initiate psychotherapeutic treatment in Danish outpatient mental health services. They will be randomized in a 1:1 ratio to either assessment-as-usual and receive no further assessment, or to a Modified Collaborative Assessment (MCA) provided as a pre-treatment intervention before psychotherapy initiation. MCA will included a battery of psychological tests designed to thoroughly assess the patients’ psychopathology. The tests is administered in collaboration with the patient including a detailed oral and written feedback. We hypothesize that the patients randomized to MCA will reach higher levels of readiness for psychotherapy as assessed with the University of Rhode Island Change Assessment Scale (URICA) and have lower dropout-rates than assessment-as-usual. DiscussionThis protocol assess the feasibility, efficacy, acceptability, and safety of an intervention aimed at changing the readiness for participation in psychotherapy for patients with SP and EVP. Results from this feasibility study could guide the development of future large-scale trials of MCA and procedures for MCA treatment fidelity assessment.

Background Patients with wake-up ischemic stroke who have evidence of salvageable tissue on advanced imaging can benefit from intravenous thrombolysis. It is not known whether patients who do not fulfil such imaging criteria might benefit from treatment, but studies indicate that treatment based on non-contrast CT criteria may be safe. Tenecteplase has shown promising results in patients with acute ischemic stroke. The aim of the Tenecteplase in Wake-up Ischemic Stroke Trial (TWIST) is to compare the effect of thrombolytic treatment with tenecteplase and standard care versus standard care alone in patients with wake-up ischemic stroke selected by non-contrast CT. Methods/design TWIST is an international, investigator-initiated, multi-centre, prospective, randomized-controlled, open-label, blinded end-point trial of tenecteplase ( n = 300) versus standard care ( n = 300) in patients who wake up with an acute ischemic stroke and can be treated within 4.5 h upon awakening. Seventy-seven centres in 10 countries (Denmark, Estonia, Finland, Latvia, Lithuania, New Zealand, Norway, Sweden, Switzerland, and the United Kingdom) participate. The primary outcome is the modified Rankin Scale on the ordinal scale (0–6) at three months. Discussion TWIST aims to determine the effect and safety of thrombolytic treatment with tenecteplase in patients with wake-up ischemic stroke selected by non-contrast CT. Trial registration ClinicalTrials.gov NCT03181360. EudraCT Number 2014-000096-80.

The present protocol study was used to summarize the findings of other major COVID-19 vaccination trials and provide an outline of our multicenter, single-blind, randomized controlled trial: the SWITCH trial. In the SWITCH, we compare the immunogenicity and reactogenicity of heterologous versus homologous vaccination strategies of COVID-19 vaccines. We recruit Health Care Workers (HCWs) who received ad.26.Cov2.S as their prime (first vaccination). We randomize HCWs in four groups: no boost (second vaccination), ad.26.Cov2.S, mRNA1273, and BNT162b2). The full protocol of the SWITCH trial can be found in the supplementary material.

Background Previously, young males administered 200 mg/week of testosterone enanthate during 28 days of energy deficit (EDef) gained lean mass and lost less total mass than controls (Optimizing Performance for Soldiers I study, OPS I). Despite that benefit, physical performance deteriorated similarly in both groups. However, some experimental limitations may have precluded detection of performance benefits, as performance measures employed lacked military relevance, and the EDef employed did not elicit the magnitude of stress typically experienced by Soldiers conducting operations. Additionally, the testosterone administered required weekly injections, elicited supra-physiological concentrations, and marked suppression of endogenous testosterone upon cessation. Therefore, this follow-on study will address those limitations and examine testosterone's efficacy for preserving Solder performance during strenuous operations. Methods In OPS II, 32 males will participate in a randomized, placebo-controlled, double-blind trial. After baseline testing, participants will be administered either testosterone undecanoate (750 mg) or placebo before completing four consecutive, 5-day cycles simulating a multi-stressor, sustained military operation (SUSOPS). SUSOPS will consist of two low-stress days (1000 kcal/day exercise-induced EDef; 8 h/night sleep), followed by three high-stress days (3000 kcal/day and 4 h/night). A 23-day recovery period will follow SUSOPS. Military relevant physical performance is the primary outcome. Secondary outcomes include 4-comparment body composition, muscle and whole-body protein turnover, intramuscular mechanisms, biochemistries, and cognitive function/mood. Conclusions OPS II will determine if testosterone undecanoate safely enhances performance, while attenuating muscle and total mass loss, without impairing cognitive function, during and in recovery from SUSOPS. Trial Registration ClinicalTrials.gov Identifier: NCT04120363.

Objectives To determine the incidence of outcome switching in follow-up publications of randomized controlled trials. Outcome switching leads to bias where treatment benefits are more likely to be overestimated or based on chance. Study design and setting Meta-research study including all follow-up publications 2014-2018 in the New England Journal of Medicine, The Lancet, the Journal of the American Medical Association, and the British Medical Journal. Two independent reviewers compared the primary outcomes of follow-up publications with the original RCT publication and the trial protocol. Results Seventy-eight follow-up publications were identified. Thirty-one (40%) used different primary outcomes in the follow-up publication compared with the original RCT. In seventeen (55%) of these the outcome switch was neither pre-specified nor explained in the journal publication. The incidence of outcome switching in follow-up studies rose to 70% when preceded by outcome switching in the corresponding initial RCT (P Conclusion In this study, outcome switching occurred in 40% of follow-up publications of previously published RCTs. The majority is neither pre-specified nor explained.

Background Although disproportionately affected by cardiovascular disease, Black adults remain underrepresented in clinical trials. The National Institutes of Health recommends that studies define goals for recruitment of underrepresented populations. However, the extent to which cardiovascular trials incorporate evidence‐based recruitment strategies in their protocols is understudied. Methods and Results We systematically reviewed National Institutes of Health‐funded cardiovascular clinical trials registered in ClinicalTrials.gov between 2000 and 2019. Based on publicly available or requested protocols, we focused on enrollment of Black adults as well as the following recruitment strategies: community‐based, electronic medical record‐based, and provider‐based recruitment. A total of 100 clinical trials focused on cardiovascular disease were included in our analysis, of which 62% had published protocols, and 46% of trials had enrolled populations that were Conclusions Black adults are underrepresented in National Institutes of Health‐funded cardiovascular trials, and the majority of these trials did not specify a Black enrollment target, did not meet targets, and largely did not report specific plans to enroll Black adults in their studies. Future interventions should target trial design and planning phases before study initiation to address these enrollment disparities.

Background: The aim of this pilot clinical study is to evaluate the safety and efficacy of the Selution Sustained Limus Release (SLR)™ sirolimus-coated balloon (M.A. MedAlliance SA, Nyon, Switzerland) for improving the patency of failing arterio-venous fistulas (AVF) in hemodialysis patients. We also present herein a pre-clinical pharmacokinetic and safety evaluation of Selution™ to justify its first use in hemodialysis patients for endovascular access salvage. Methods and results: This is an investigator-initiated prospective single-center, non-blinded single-arm trial. Forty patients with clinically significant de novo or recurrent stenoses in a mature AVF circuit will be recruited. All stenotic lesions will be prepared with high pressure non-compliant conventional balloon angioplasty (CBA) prior to deployment of the Sustained-Release Selution™ sirolimus drug-eluting balloon. The primary efficacy endpoint is 6-month target lesion primary patency and the primary safety endpoint is freedom from localized or systemic serious adverse events through 30 days. Secondary endpoints of interest include technical and clinical success rates and circuit access patency at 3 and 6 months. Follow-up will occur for 2 years for those patients whose AVFs remain patent. Pharmacokinetic and histological animal safety studies performed with the Selution™ coating formulation showed prolonged arterial tissue retention of sirolimus with therapeutic levels up to 60 days and non-toxic and rapidly declining blood levels. Histological results in animal models demonstrated safety, freedom from intraluminal thrombus, reduction in restenosis by sirolimus elution compared to CBA, and no evidence of embolic phenomena indicative of adverse particulate effects. Discussion: Long release sirolimus coated balloons may serve as a promising novel alternative therapy to paclitaxel-based technology for treating conduit stenosis secondary to neointimal hyperplasia. Pre-clinical pharmacokinetic and histological animal data are encouraging and provide suggestion of safety and efficacy in this setting. This single-center trial will provide a first step toward demonstration of efficacy and safety of this device for treatment of stenotic fistulas.

Background Randomized trials are designed to evaluate the effects of health care interventions. The recruitment process in a randomized trial can be challenging. Poor recruitment can have a negative impact on the allocated budget and estimated completion date of the study and may result in an underpowered research that will not adequately answer the original research question. Aim We aim to perform a Study Within A Trial (SWAT) to evaluate the impact of same-day consent or delayed consent on recruitment and retention in the host trial. Methods This SWAT is designed as an observational study. However, the host trial is a randomized controlled trial evaluating the effectiveness of an intensive lifestyle modification program in patients with peripheral arterial disease. For this trial and SWAT, same-day consent is defined as the patient giving consent on the same day, after the investigator has fully explained the predesigned information leaflet for the host trial. Delayed consent is defined as the patient feeling they still need further time to consider their decision to participate or not. Swat registration The SWAT was registered on the Northern Ireland Network for Trials Methodology Research.

Aim India contributes towards a large part of the worldwide epidemic of diabetes and its associated complications. However, there are limited longitudinal studies available in India to understand the occurrence of diabetes complications over time. This pan‐India longitudinal study was initiated to assess the real‐world outcomes of diabetes across the country. Methods The LANDMARC study is the first prospective, multicentre, longitudinal, observational study investigating a large cohort of people with type 2 diabetes mellitus across India over a period of 3 years. The primary objective of this ongoing study is to determine the proportion of people developing macrovascular diabetes complications over the duration of the study (36 months ± 45 days) distributed over seven visits; the secondary objective is to evaluate microvascular diabetes complications, glycaemic control and time‐to‐treatment adaptation or intensification. Overall, 6300 participants (aged 25–60 years) diagnosed with type 2 diabetes for at least 2 years will be included from 450 centres across India. Data will be recorded for baseline demographics, comorbidities, glycaemic measurements, use of anti‐hyperglycaemic medications and any cardiovascular or other diabetes‐related events occurring during the observational study period. Conclusions The LANDMARC study is expected to reveal the trends in complications associated with diabetes, treatment strategies used by physicians, and correlation among treatment, control and complications of diabetes within the Indian context. The findings of this study will help to identify the disease burden, emergence of early‐onset complications and dose titration patterns, and eventually develop person‐centred care and facilitate public health agencies to invest appropriate resources in the management of diabetes. (Trial Registration No: CTRI/2017/05/008452).

Background Treatment with TAS-102 has significantly improved the progression-free survival (PFS) and overall survival (OS) of patients with metastatic colorectal cancer (mCRC). Reportedly, the combination of TAS-102 plus bevacizumab extends the median PFS. The present study aimed to confirm the efficacy and safety of TAS-102 plus bevacizumab (biweekly administration) as third-line chemotherapy for patients with mCRC. Methods/design This is a single-arm, open-label, prospective, nonrandomized, multicenter phase II trial conducted in Japan. With a threshold and expected PFS of 2.1 and 3.5 months, respectively, the simulation results showed a sample size of 42 with α = 0.05 (both sides) for 90% power, based on the One-Arm Binomial test using the SWOG statistical tool. If the estimated dropout is 7%-8%, the target sample size is estimated to be 45. The TAS-CC4 study regimen comprised 28-day cycles with biweekly oral administration of TAS-102 (35 mg/m2 twice daily on days 1-5 and 15-19 of every 28-day cycle) and bevacizumab (5.0 mg/kg on days 1 and 15). The primary end point is the PFS; secondary end points include response rate (RR), OS, grade ≥3 neutropenia, and genetic alterations (KRAS/BRAF mutations) in the circulating cell-free DNA. Discussion The present study can contribute to the determination of the effective dosing interval of TAS-102 and bevacizumab in patients with mCRC and is thought to lead to prophylaxis of neutropenia and prolongation of the treatment period.

Background Decisions about antidepressant use in pregnancy are complex. We performed a pilot randomized controlled trial assessing the feasibility of a trial protocol for an online patient decision aid (PDA) for women deciding about antidepressant use in pregnancy. Methods 96 preconception and pregnant Canadian women recruited from specialist (n = 51) and non-specialist (n = 45) settings with Decisional Conflict Scale (DCS, range 0–100) score of ≥25 signifying moderate-to-high decisional conflict were randomly allocated to either the PDA or a control condition that guided participants to publicly available resources for advice around antidepressants and pregnancy. Follow-up data were collected at 4 weeks post-randomization. Results About 88.9% of eligible participants consented to participate. Women's views of the tool were positive; 88.7% of participants provided follow-up data. At follow-up, mean DCS score had decreased by 19.9 points in the PDA group vs. 13.3 in controls (adjusted mean difference, MD, 7.01, 95% CI −14.3 to 0.30). In the non-specialist setting, DCS scores decreased more for PDA users (25.5 points) than controls (10.5 points; adjusted MD −15.1, 95% CI −25.6 to −4.55); the MD was negligible in the specialist setting. Limitations The main limitation is the highly educated, high-income nature of our sample. Conclusions Evaluation of an online PDA for antidepressant use in pregnancy with national recruitment is feasible. Pilot results suggest that the tool is acceptable and reduces decisional conflict more than clinical care alone in a non-specialist setting. Evaluation of the PDA's impact on longer-term maternal and child clinical outcomes is a key next step.

Background Migraine is one of the most common neurological disorders in clinical practice and is a substantial cause of disability worldwide. Current approaches to therapy are primarily based on medication but are often limited by inadequate effectiveness and common side effects. Newer, more effective medications are expensive. Mindfulness-based stress reduction (MBSR), an 8-week classroom-based meditation intervention, is inexpensive, has no known side effects, and has demonstrated clinically meaningful effectiveness for several chronic-pain syndromes. In addition, MBSR has shown promising results for migraine therapy in a few small case studies and pilot studies. We present here the protocol for a two-arm randomized controlled pilot trial of MBSR for moderate-to-severe episodic migraine, which, if successful, will form the basis for a fully powered clinical trial. Methods/design This study, set in Northern California, is a two-arm parallel-comparison single-blinded randomized controlled pilot trial with the goal of recruiting approximately 60 participants with moderate-to-severe episodic migraine. The feasibility outcomes include ability and time required to recruit, adherence to the MBSR treatment, and ability to measure outcomes using 31-day headache diaries and patient-reported questionnaire data. The active treatment arm consists of an 8-week community-based MBSR class plus usual care, and the wait-list control group is usual care. Recruitment is underway and expected to be complete by the end of 2018. Discussion To our knowledge, this is the first pragmatic trial in the U.S. of MBSR for migraine using community-based classes, and if it proves viable, we plan to conduct a fully powered trial to determine the effectiveness of the intervention for reducing headache days for moderate-to-severe episodic migraineurs. Trial registration Clinicaltrials.gov, NCT02824250. Registered on 6 July 2016. Electronic supplementary material The online version of this article (10.1186/s13063-019-3355-y) contains supplementary material, which is available to authorized users.

Background: A head-to-head trial (NCT03078478) between insulin degludec and insulin glargine U300 with the primary objective of comparing the risk of hypoglycemia is being conducted. During trial conduct, safety concerns related to the glycemic data collection system led to a postinitiation protocol amendment, described here. Methods: This randomized (1:1), open-label, treat-to-target, multinational trial was initiated in March 2017 with a planned treatment period of 52 weeks (16 weeks titration + 36 weeks maintenance). Overall, ~1600 insulin-experienced patients at risk of developing hypoglycemia based on predefined risk factors were included. The protocol amendment implemented in February 2018 resulted in assuring patient safety and an extension of the total treatment period up to 88 weeks (16 weeks titration + variable maintenance 1 + 36 weeks maintenance 2). The original glycemic data collection system (MyGlucoHealth blood glucose meter + electronic diary) was discontinued because of safety concerns and replaced with an Abbott blood glucose meter and paper diary to collect self-measured blood glucose and hypoglycemic episodes. The primary endpoint of number of severe or blood-glucose confirmed symptomatic hypoglycemic episodes will be evaluated with the same analysis duration and statistical methods as the original protocol. Only relevant changes were implemented to maintain patient safety while permitting evaluation of the scientific objectives of the trial. Conclusions: These observations highlight the importance of safety surveillance during trial conduct despite the use of currently marketed glucose monitoring devices. The prompt protocol amendment and ensuing actions ensured that the scientific integrity of the trial was not compromised.

Objectives The aim of the article was to assess the appropriateness and rationales of subgroup analyses planned in protocols of randomized controlled trials and reported in subsequent corresponding trial publications. Study Design and Setting We searched PubMed to identify trial protocols published in journals during 2006–2017. From a total of 3,774 initially identified records, we included a random sample of 479 protocols and identified 280 trial publications corresponding to the included protocols. Results Subgroup analyses were specified in 19% of the protocols and reported in 21% of the trial publications. Of the 94 protocols with planned subgroup analyses, 32% mentioned testing for interaction, and only three considered statistical power. Subgroup analyses were not prespecified in 56% of the 59 trial publications with subgroup analyses. Subgroup analyses were stated as prespecified in nine trial publications, without support evidence from the corresponding protocols. Subgroup analyses were often reported insufficiently for assessing the consistency of subgroup effects across studies. Justifications for subgroup analyses were provided in only four trial protocols and seven trial publications. Conclusion Inappropriate specification and reporting of subgroup analyses remain problematic in protocols and reports of randomized controlled trials. Justifications or rationales for subgroup analyses were only rarely provided in trial protocols and reports.

Background Inadequate and poor quality outcome reporting in clinical trials is a well-documented problem that impedes the ability of researchers to evaluate, replicate, synthesize, and build upon study findings and impacts evidence-based decision-making by patients, clinicians, and policy-makers. To facilitate harmonized and transparent reporting of outcomes in trial protocols and published reports, the Instrument for reporting Planned Endpoints in Clinical Trials (InsPECT) is being developed. The final product will provide unique InsPECT extensions to the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) and CONSORT (Consolidated Standards of Reporting Trials) reporting guidelines. Methods The InsPECT SPIRIT and CONSORT extensions will be developed in accordance with the methodological framework created by the EQUATOR (Enhancing the Quality and Transparency of Health Research Quality) Network for reporting guideline development. Development will consist of (1) the creation of an initial list of candidate outcome reporting items synthesized from expert consultations and a scoping review of existing guidance for reporting outcomes in trial protocols and reports; (2) a three-round international Delphi study to identify additional candidate items and assess candidate item importance on a 9-point Likert scale, completed by stakeholders such as trial report and protocol authors, systematic review authors, biostatisticians and epidemiologists, reporting guideline developers, clinicians, journal editors, and research ethics board representatives; and (3) an in-person expert consensus meeting to finalize the set of essential outcome reporting items for trial protocols and reports, respectively. The consensus meeting discussions will be independently facilitated and informed by the empirical evidence identified in the primary literature and through the opinions (aggregate rankings and comments) collected via the Delphi study. An integrated knowledge translation approach will be used throughout InsPECT development to facilitate implementation and dissemination, in addition to standard post-development activities. Discussion InsPECT will provide evidence-informed and consensus-based standards focused on outcome reporting in clinical trials that can be applied across diverse disease areas, study populations, and outcomes. InsPECT will support the standardization of trial outcome reporting, which will maximize trial usability, reduce bias, foster trial replication, improve trial design and execution, and ultimately reduce research waste and help improve patient outcomes. Electronic supplementary material The online version of this article (10.1186/s13063-019-3248-0) contains supplementary material, which is available to authorized users.

The purpose of the current study is to analyze a series of phase I cancer clinical trials, examine and compare trial protocols based on patients’ eligibility criteria. We evaluated all dose escalation phase I trial protocols with accessible or published results performed at Institute for Drug Development, Cancer Therapy and Research Center (San Antonio) between 1991 and 2016. Study protocols were categorized as non-restrictive (NRP) or restrictive (RP) based on several eligibility parameters. Fisher’s Exact and Chi-square tests were used to compare characteristics of NRP and RP. Of 284 protocols screened, 231 dose escalation phase I trial protocols (with accessible results) of solid tumors were included in this review. There were 145 NRP (involving 3190 patients) and 86 RP (involving 1892 patients). The median number of exclusion criteria for NRP and RP were 14 and 23, respectively. The most common reasons that made trial protocol to be restrictive were ECOG ≤ 1, strict requirements for renal or hepatic function (≤ 2.5 times upper limit of normal) and exclusion of subjects with brain metastases. The median accrual time for NRP was significantly shorter as compared to RP (17 vs 26 months). The median number of dose levels explored in NRP and RP were 9 and 6, respectively. RP had a higher screen failure as well as premature closure rate. The rates of DLTs, SAEs, toxicity-related death and response were not different between the two groups. Our study findings are in support of devising well thought and justified phase I study eligibility criteria.

Background The SCOPE trials (SCOPE 1, NeoSCOPE and SCOPE 2) have been the backbone of oesophageal RT trials in the UK. Many changes in oesophageal RT techniques have taken place in this time. The SCOPE trials have, in addition to adopting these new techniques, been influential in aiding centres with their implementation. We discuss the progress made through the SCOPE trials and include details of a questionnaire sent to participating centres. to establish the role that trial participation played in RT changes in their centre. Methods Questionnaires were sent to 47 centres, 27 were returned. Results 100% of centres stated their departmental protocol for TVD was based on the relevant SCOPE trial protocol. 4DCT use has increased from 42 to 71%. Type B planning algorithms, mandated in the NeoSCOPE trial, were used in 79.9% pre NeoSCOPE and now in 83.3%. 12.5% of centres were using a stomach filling protocol pre NeoSCOPE, now risen to 50%. CBCT was mandated for IGRT in the NeoSCOPE trial. 66.7% used this routinely pre NeoSCOPE/SCOPE 2 which has risen to 87.5% in the survey. Conclusion The results of the questionnaires show how participation in national oesophageal RT trials has led to the adoption of newer RT techniques in UK centres, leading to better patient care. Electronic supplementary material The online version of this article (10.1186/s13014-019-1225-0) contains supplementary material, which is available to authorized users.

Background There is an increasing need to organize the care around the patient and not the disease, while considering the complex realities of multiple physical and psychosocial conditions, and polypharmacy. Integrated patient-centered care delivery platforms have been developed for both patients and clinicians. These platforms could provide a promising way to achieve a collaborative environment that improves the provision of integrated care for patients via enhanced information and communication technology solutions for semiautomated clinical decision support. Objective The Collaborative Care and Cure Cloud project (C3-Cloud) has developed 2 collaborative computer platforms for patients and members of the multidisciplinary team (MDT) and deployed these in 3 different European settings. The objective of this study is to pilot test the platforms and evaluate their impact on patients with 2 or more chronic conditions (diabetes mellitus type 2, heart failure, kidney failure, depression), their informal caregivers, health care professionals, and, to some extent, health care systems. Methods This paper describes the protocol for conducting an evaluation of user experience, acceptability, and usefulness of the platforms. For this, 2 “testing and evaluation” phases have been defined, involving multiple qualitative methods (focus groups and surveys) and advanced impact modeling (predictive modeling and cost-benefit analysis). Patients and health care professionals were identified and recruited from 3 partnering regions in Spain, Sweden, and the United Kingdom via electronic health record screening. Results The technology trial in this 4-year funded project (2016-2020) concluded in April 2020. The pilot technology trial for evaluation phases 3 and 4 was launched in November 2019 and carried out until April 2020. Data collection for these phases is completed with promising results on platform acceptance and socioeconomic impact. We believe that the phased, iterative approach taken is useful as it involves relevant stakeholders at crucial stages in the platform development and allows for a sound user acceptance assessment of the final product. Conclusions Patients with multiple chronic conditions often experience shortcomings in the care they receive. It is hoped that personalized care plan platforms for patients and collaboration platforms for members of MDTs can help tackle the specific challenges of clinical guideline reconciliation for patients with multimorbidity and improve the management of polypharmacy. The initial evaluative phases have indicated promising results of platform usability. Results of phases 3 and 4 were methodologically useful, yet limited due to the COVID-19 pandemic. Trial Registration ClinicalTrials.gov NCT03834207; https://clinicaltrials.gov/ct2/show/NCT03834207 International Registered Report Identifier (IRRID) RR1-10.2196/21994

BackgroundSepsis contributes significantly to morbidity and mortality globally. In Australia, 20,000 develop sepsis every year, resulting in 5,000 deaths, and more than AUD$846 million in expenditure. Prompt, appropriate antibiotic therapy is effective in improving outcomes in sepsis. Conventional culture-based methods to identify appropriate therapy have limited yield and take days to complete. Recently, nanopore technology has enabled rapid sequencing with real-time analysis of pathogen DNA. We set out to demonstrate the feasibility and diagnostic accuracy of pathogen sequencing direct from clinical samples, and estimate the impact of this approach on time to effective therapy when integrated with personalised software-guided antimicrobial dosing in children and adults on ICU with sepsis.MethodsThe DIRECT study is a pilot prospective, non-randomized multicentre trial of an integrated diagnostic and therapeutic algorithm combining rapid direct pathogen sequencing and software-guided, personalised antibiotic dosing in children and adults with sepsis on ICU.Participants and interventionsDIRECT will collect microbiological and pharmacokinetic samples from approximately 200 children and adults with sepsis admitted to one of four ICUs in Brisbane. In Phase 1, we will evaluate Oxford Nanopore Technologies MinION sequencing direct from blood in 50 blood culture-proven sepsis patients recruited from consecutive patients with suspected sepsis. In Phase 2, a further 50 consecutive patients with suspected sepsis will be recruited in whom MinION sequencing will be combined with Bayesian software-guided (ID-ODS) personalised antimicrobial dosing.Outcome measuresThe primary outcome is time to effective antimicrobial therapy, defined as trough drug concentrations above the MIC of the pathogen. Secondary outcomes are diagnostic accuracy of MinION sequencing from whole blood, time to pathogen identification and susceptibility testing using sequencing direct from whole blood and from positive blood culture broth.DiscussionRapid pathogen sequencing coupled with antimicrobial dosing software has great potential to overcome the limitations of conventional diagnostics which often result in prolonged inappropriate antimicrobial therapy. Reduced time to optimal antimicrobial therapy may reduce sepsis mortality and ICU length of stay. This pilot study will yield key feasibility data to inform further, urgently needed sepsis studies. Phase 2 of the trial protocol is registered with the ANZCTR (ACTRN12620001122943).Trial registrationRegistered with the Australia New Zealand Clinical Trials Registry Number ACTRN12620001122943

Background: Children hospitalised with severe acute malnutrition (SAM) are frequently complicated (>50%) by diarrhoea (≥3 watery stools/day) which is accompanied by poor outcomes. Rehydration guidelines for SAM are exceptionally conservative and controversial, based upon expert opinion. The guidelines only permit use of intravenous fluids for cases with advanced shock and exclusive use of low sodium intravenous and oral rehydration solutions (ORS) for fear of fluid and/or sodium overload. Children managed in accordance to these guidelines have a very high mortality. The proposed GASTROSAM trial is the first step in reappraising current recommendations. We hypothesize that liberal rehydration strategies for both intravenous and oral rehydration in SAM children with diarrhoea may reduce adverse outcomes. Methods An open Phase II trial, with a partial factorial design, enrolling Ugandan and Kenyan children aged 6 months to 12 years with SAM hospitalised with gastroenteritis (>3 loose stools/day) and signs of moderate and severe dehydration. In Stratum A (severe dehydration) children will be randomised (1:1:2) to WHO plan C (100mls/kg Ringers Lactate (RL) with intravenous rehydration given over 3-6 hours according to age including boluses for shock), slow rehydration (100 mls/kg RL over 8 hours (no boluses)) or WHO SAM rehydration regime (ORS only (boluses for shock (standard of care)). Stratum B incorporates all children with moderate dehydration and severe dehydration post-intravenous rehydration and compares (1:1 ratio) standard WHO ORS given for non-SAM (experimental) versus WHO SAM-recommended low-sodium ReSoMal. The primary outcome for intravenous rehydration is urine output (mls/kg/hour at 8 hours post-randomisation), and for oral rehydration a change in sodium levels at 24 hours post-randomisation. This trial will also generate feasibility, safety and preliminary data on survival to 28 days. Discussion. If current rehydration strategies for non-malnourished children are safe in SAM this could prompt future evaluation in Phase III trials.