Are investigators’ access to trial data and rights to publish restricted and are potential trial participants informed about this? A comparison of trial protocols and informed consent materials

Objectives To determine to which degree industry partners in randomised clinical trials own the data and can constrain publication rights of academic investigators. Methods Cohort study of trial protocols, publication agreements and other documents obtained through Freedom of Information requests, for a sample of 42 trials with industry involvement approved by ethics committees in Denmark. The main outcome measures used were: proportion of trials where data was owned by the industry partner, where the investigators right to publish were constrained and if this was mentioned in informed consent documents, and where the industry partner could review data while the trial was ongoing and stop the trial early. Results The industry partner owned all data in 20 trials (48%) and in 16 trials (38%) it was unclear. Publication constraints were described for 30 trials (71%) and this was not communicated to trial participants in informed consent documents in any of the trials. In eight trials (19%) the industry partner could review data during the trial, for 20 trials (48%) it was unclear. The industry partner could stop the trial early without any specific reason in 23 trials (55%). Conclusions Publication constraints are common, and data is often owned by industry partners. This is rarely communicated to trial participants. Such constraints might contribute to problems with selective outcome reporting. Patients should be fully informed about these aspects of trial conduct.

A Feasibility Study of a One-to-One Mindfulness-Based Intervention for Improving Mood in Stroke Survivors

Objectives Mindfulness is an evidence-based treatment for depression but has never been rigorously tested with stroke survivors with depression. This feasibility study examined several issues relevant to a potential trial of a mindfulness-based intervention (MBI) for improving mood after stroke. Methods In 2017–2019 in New Zealand, we recruited 20 stroke survivors with low mood to undergo a 6-week, one-on-one MBI course delivered by an occupational therapist experienced in MBIs. Pre, post, and 4-week follow-up assessments were completed. Results Fifteen participants completed all six sessions and a 4-week “booster” or top-up session. The 1-hour session duration was considered appropriate by participants and all enjoyed the face-to-face individualized format. Mean Beck Depression Inventory-II scores improved by more than one standard deviation and this was maintained at follow-up. However, the baseline assessment package was too long for some participants due to the cognitive component. Three participants indicated feeling emotionally challenged by some of the practices. These effects were managed by the mindfulness facilitator by adjusting the practice, so participants maintained their sense of agency, well-being, and overall benefit from the program. Conclusions MBI training delivered individually over six weekly sessions was acceptable to stroke survivors with 14/15 participants reporting improved mood. Three participants reported feeling emotionally challenged by some of the practices and we recommend MBIs for stroke survivors be provided by practitioners experienced in mindfulness, working with stroke, and trauma-informed therapy. It is important now to conduct rigorous randomized controlled trials to test the effectiveness and efficacy of MBIs for stroke survivors.

A systematic review of risk communication in clinical trials: How does it influence decisions to participate and what are the best methods to improve understanding in a trial context?

Background Effective risk communication is challenging. Ensuring potential trial participants’ understand ‘risk’ information presented to them is a key aspect of the informed consent process within clinical trials, yet minimal research has looked specifically at how to communicate probabilities to support decisions about trial participation. This study reports a systematic review of the literature focusing on presentation of probabilistic information or understanding of risk by potential trial participants. Methods A search strategy for risk communication in clinical trials was designed and informed by systematic reviews of risk communication in treatment and screening contexts and supplemented with trial participation terms. Extracted data included study characteristics and the main interventions/findings of each study. Explanatory studies that investigated the methods for presenting probabilistic information within participant information leaflets for a clinical trial were included, as were interventions that focused on optimising understanding of probabilistic information within the context of a clinical trial. Results The search strategy identified a total of 4931 studies. Nineteen papers were selected for full text screening, and seven studies included. All reported results from risk communication studies that aimed to support potential trial participants’ decision making set within hypothetical trials. Five of these were randomised comparisons of risk communication interventions, and two were prospectively designed, non-randomised studies. Study interventions focused on probability presentation, risk framing and risk interpretation with a wide variety of interventions being evaluated and considerable heterogeneity in terms of outcomes assessed. Studies show conflicting findings when it comes to how best to present information, although numerical, particularly frequency formats and some visual aids appear to have promise. Conclusions The evidence base surrounding risk communication in clinical trials indicates that there is as yet no clear optimal method for improving participant understanding, or clear consensus on how it affects their willingness to participate. Further research into risk communication within trials is needed to help illuminate the mechanisms underlying risk perception and understanding and provide appropriate ways to present and communicate risk in a trial context so as to further promote informed choices about participation. A key focus for future research should be to investigate the potential for learning in the evidence on risk communication from treatment and screening decisions when applied to decisions about trial participation.

Surgery for women with endometrioma prior to in vitro fertilisation: proposal for a feasible multicentre randomised clinical trial in the UK

STUDY QUESTION Is it feasible to undertake a randomised controlled trial to establish whether surgical removal of endometrioma or not, improves live birth rates from IVF? SUMMARY ANSWER A randomised controlled trial (RCT) comparing surgery versus no surgery to endometrioma prior to IVF is only feasible in UK if an adaptive rather than traditional study design is used; this would minimise resource wastage and complete the trial in an acceptable time frame. WHAT IS KNOWN ALREADY There is wide variation in the management of endometriomas prior to IVF, with decisions about treatment being influenced by personal preferences. STUDY DESIGN, SIZE, AND DURATION This was a mixed-methods study consisting of an online survey of clinicians, a focus group and individual interviews with potential trial participants. PARTICIPANTS/MATERIALS, SETTING, METHODS Endometriosis and fertility experts across the UK were invited to participate in an online anonymised questionnaire. Potential future trial participants were recruited from a tertiary care fertility centre and invited to participate in either individual interviews or focus groups. MAIN RESULTS AND THE ROLE OF CHANCE Clinicians and potential trial participants confirmed the need for an RCT to inform the management of an endometrioma prior to IVF. There were 126 clinicians who completed the survey, and the majority (70%) were willing to recruit to a trial. Half of those who responded indicated that they see at least 10 eligible women each year. The main barriers to recruitment were waiting lists for surgery and access to public funding for IVF. One focus group (n = 7) and five interviews were conducted with potential trial participants (n = 3) and their partners (n = 2). The findings from these discussions highlighted that recruitment and retention in a potential RCT could be improved by coordination between IVF and surgical services such that an operation does not delay IVF or affect access to public funding. Live birth was considered the most important outcome with an improvement of at least 10% considered the minimum acceptable by both patients and clinicians. LIMITATIONS, REASONS FOR CAUTION This feasibility study captured views of clinicians across the UK, but as patients were from a single Scottish centre, their views may not be representative of other areas with limited public funding for IVF. WIDER IMPLICATIONS OF THE FINDINGS There is a need for an appropriately powered RCT to establish whether or not surgical treatment of endometrioma prior to IVF improves live birth rates. There are logistical issues to be considered due to limited number of participants, funding of IVF and waiting times. These could be overcome in a RCT by using an adaptive design which would include a prospectively planned opportunity for modification of specified aspects of the study design based on interim analysis of the data, coordination of IVF treatments and endometriosis surgeries and international collaboration. Similar principles could be used for other questions in fertility where a traditional approach for randomised trials is not feasible. STUDY FUNDING/COMPETING INTEREST(S) Funding was received from the NHS Grampian R&D pump priming fund (RG14437-12). S.B. is Editor-in-Chief of HROPEN, and A.W.H. is Deputy Editor of HROPEN. Neither was involved in the review of this manuscript. L.S. reports grants from CSO and NIHR to do endometriosis research, outside the submitted work. K.C. reports grants from NIHR/HTA and CSO during the conduct of the study. J.H.e., A.W.H., J.D., S.B.r., K.B., G.B., J.H.u. and K.G. report no conflict of interest.

The Natural Sit-to-Stand-Walk of the Frail

Sit-to-stand-walk (STW) is a complex task that sequentially transitions an individual from sitting through standing to walking. In this study we evaluate the unrestricted, natural pattern of movement of the STW task from a hospital bed of 21 (5 Female, 16 Male) frail (MFS > 55) adults (68.0±11.2 years) with a total of 144 unique trials. Bed height (low, medium, high) and bed rail condition (no rails, Hill-Rom®, Stryker®), were varied, generating 9 potential trial types per participant. A new STW phase, Stand Preparation, is defined specifically for the frail that occurs just prior to the Flexion Momentum Phase, also named here as the Stand Initiation Phase. In conjunction with the newly defined Stand Preparation Phase, movements used by the frail to maintain or regain balance during STW task are newly defined as corrective behaviors (CBs). These include hand, foot, leg and torso CBs. In 144 unique STW trials, 678 hand and foot CBs were observed and recorded. The most frequent CB type was the hand CB (335), followed by the foot CB (316). A coding system for use in the kinematic analysis of the natural STW task was developed that identifies CBs through visual observation. In addition, a 3D biomechanical model was generated from collected marker position data and will be used in future biomechanical analyses with the visually observed CB data. The Stand Initiation Phase contained the most CBs. Significant factors included bed height and phase, as well as their interaction (all with p-values ≤ 0.006). This is the first study to establish a more accurate and complete STW of the frail elderly, as well as to define CBs employed during their natural STW. The dataset from this coding system, along with the newly established STW phases of the frail, are currently being used for further analyses to determine the exact timing and position of fall initiations during STW of the frail.

Statistical Analysis Plan for EXtending the time for Thrombolysis in Emergency Neurological Deficits (EXTEND) trial

Background EXtending the time for Thrombolysis in Emergency Neurological Deficits (EXTEND) is a randomized, multicenter, double-blinded, placebo-controlled phase 3 trial to test the hypothesis of extending the thrombolysis time window to 9 h from stroke onset and in wake-up stroke (WUS) patients. Objective To formulate the detailed statistical analysis plan for the EXTEND trial prior to database lock. This statistical analysis plan is based on the published and registered EXTEND trial protocol and is developed by the blinded steering committee and management team. Results The developed EXTEND statistical analysis plan is transparent, verifiable, and predetermined before the database lock. It is consistent with reporting standards for clinical trials and provides for clear and open reporting. Conclusions Publication of a statistical analysis plan serves to reduce potential trial analysis and reporting bias and outlines pre-specified analyses to quantify the benefits and harms of extending the thrombolysis time window to 9 h from stroke onset and in wake-up stroke patients. Trial registration: ClinicalTrials.gov number NCT00887328 registered 23/Apr/2009 and NCT01580839 (EXTEND International) registered 19/Apr/2012

Statistical analysis plan (SAP) for the Very Early Rehabilitation in Speech (VERSE) after stroke trial: an international 3-arm clinical trial to determine the effectiveness of early, intensive, prescribed, direct aphasia therapy

Background Limited evidence exists to support very early intensive aphasia rehabilitation after stroke. VERSE is a PROBE trial designed to determine whether two types of intensive aphasia therapy, beginning within 14 days of acute stroke, provide greater therapeutic and cost-effectiveness than usual care. Objective To publish the detailed statistical analysis plan for the VERSE trial prior to unblinding. This statistical analysis plan was based on the published and registered VERSE trial protocol and was developed by the blinded steering committee and management team, led by the trial statistician. This plan was developed using outcome measures and trial data collection forms. Results The VERSE statistical analysis plan is consistent with reporting standards for clinical trials and provides for clear and open reporting. Conclusions Publication of a statistical analysis plan serves to reduce potential trial reporting bias and outlines transparent pre-specified analyses. Australian New Zealand Clinical Trials Registry (ANZCTR) Registration number: ACTRN12613000776707; Universal Trial Number (UTN) is U1111-1145-4130.