Springer Science and Business Media LLC

Addressing the global burden of multidrug-resistant tuberculosis (MDR-TB) requires identification of shorter, less toxic treatment regimens. Médecins Sans Frontières (MSF) is currently conducting a phase II/III randomised controlled clinical trial, to find more effective, shorter and tolerable treatments for people with MDR-TB. Recruitment to the trial in Uzbekistan has been slower than expected; we aimed to study patient and health worker experiences of the trial, examining potential factors perceived to impede and facilitate trial recruitment, as well as general perceptions of clinical research in this context. We conducted a qualitative study using maximum variation, purposive sampling of participants. We carried out in-depth interviews (IDIs) and focus group discussions (FGDs) guided by semi-structured topic guides. In December 2019 and January 2020, 26 interviews were conducted with patients, Ministry of Health (MoH) and MSF staff and trial health workers, to explore challenges and barriers to patient recruitment as well as perceptions of the trial and research in general. Preliminary findings from the interviews informed three subsequent focus group discussions held with patients, nurses and counsellors. Focus groups adopted a person-centred design, brainstorming potential solutions to problems and barriers. Interviews and FGDs were audio recorded, translated and transcribed verbatim. Thematic analysis, drawing on constant comparison, was used to analyse the data. Health system contexts may compete with new approaches especially when legislative health regulations or policy around treatment is ingrained in staff beliefs, perceptions and practice, which can undermine clinical trial recruitment. Trust plays a significant role in how patients engage with the trial. Decision-making processes are dynamic and associated with relationship to diagnosis, assimilation of information, previous knowledge or experience and influence of peers and close relations. This qualitative analysis highlights ways in which insights developed together with patients and healthcare workers might inform approaches towards improved recruitment into trials, with the overall objective of delivering evidence for better treatments.

Electroconvulsive therapy (ECT) is the most effective treatment for severe depression, but its use is impeded by its cognitive side effects. Novel treatments that can counteract these side effects may therefore improve current treatment strategies for depression. The present randomized trial investigates (1) whether short-term add-on treatment with erythropoietin (EPO) can reduce the cognitive side -effects of ECT and (2) whether such effects are long-lasting. Further, structural and functional magnetic resonance imaging (MRI) will be used to explore the neural underpinnings of such beneficial effects of EPO. Finally, the trial examines whether potential protective effects of EPO on cognition are accompanied by changes in markers of oxidative stress, inflammation, and neuroplasticity. The trial has a double-blind, randomized, placebo-controlled, parallel group design. Patients with unipolar or bipolar disorder with current moderate to severe depression referred to ECT (N = 52) are randomized to receive four high-dose infusions of EPO (40,000 IU/ml) or placebo (saline). The first EPO/saline infusion is administered within 24 h before the first ECT. The following three infusions are administered at weekly intervals immediately after ECT sessions 1, 4, and 7. Cognition assessments are conducted at baseline, after the final EPO/saline infusion (3 days after eight ECT sessions), and at a 3 months follow-up after ECT treatment completion. The neuronal substrates for potential cognitive benefits of EPO are investigated with structural and functional MRI after the final EPO/saline infusion. The primary outcome is change from baseline to after EPO treatment (3 days after eight ECT sessions) in a cognitive composite score spanning attention, psychomotor speed, and executive functions. With a sample size of N = 52 (n = 26 per group), we have ≥ 80% power to detect a clinically relevant between-group difference in the primary outcome measure at an alpha level of 5% (two-sided test). Behavioral, mood, and blood-biomarker data will be analyzed using repeated measures analysis of covariance. Functional MRI data will be preprocessed and analyzed using the FMRIB Software Library. If EPO is found to reduce the cognitive side effects of ECT, this could have important implications for future treatment strategies for depression and for the scientific understanding of the neurobiological etiology of cognitive dysfunction in patients treated with ECT. ClinicalTrials.gov, NCT03339596 . Registered on 10 November 2017.

Exercise for the prevention of low back pain recurrences is recommended, but under-researched. The effectiveness and cost-effectiveness of a walking program for preventing low back pain recurrence remains unknown. This a priori statistical analysis plan describes the methods of analysis for the WalkBack trial.

WalkBack is a prospectively registered, pragmatic, randomised controlled trial. The aim is to investigate the effectiveness and cost-effectiveness of a 6-month progressive and individualised walking and education program (intervention) for the prevention of low back pain recurrences, compared to a no-treatment control group. The primary outcome is days to the first recurrence of an episode of activity-limiting low back pain. Key secondary outcomes include days to any recurrence of low back pain, days to a care-seeking recurrence of low back pain, disability level, health-related quality of life, costs associated with low back pain and adverse events. All participants will be followed for a minimum of 12 months. Analysis will follow the intention-to-treat principle. Cox regression is planned to assess the effects for the outcomes of time to activity-limiting, minimal and care-seeking recurrence. Hazard ratios and median survival times with 95% confidence intervals will be calculated. The effect of the intervention on continuous outcomes will be estimated with repeated-measure linear mixed models. An economic evaluation will be performed from the societal perspective for recurrence prevented (yes/no) and quality-adjusted life years. The proportion of adverse events between groups will be compared using Fisher’s exact test.

The WalkBack trial will provide evidence on the effectiveness and cost-effectiveness of a walking intervention to prevent low back pain recurrences. This statistical analysis plan provides transparency on the analysis of the trial.

WalkBack - Effectiveness and cost-effectiveness of a progressive individualised walking and education program for the prevention of a recurrence of low back pain. ACTRN12619001134112. Date Registered: 14/08/2019.

Breastfeeding offers many medical and neurodevelopmental advantages for birthing parents and infants; however, the majority of parents stop breastfeeding before it is recommended. Professional lactation support by the International Board Certified Lactation Consultants (IBCLCs) increases breastfeeding rates; however, many communities lack access to IBCLCs. Black and Latinx parents have lower breastfeeding rates, and limited access to professional lactation support may contribute to this disparity. Virtual “telelactation” consults that use two-way video have the potential to increase access to IBCLCs among disadvantaged populations. We present a protocol for the digital Tele-MILC trial, which uses mixed methods to evaluate the impact of telelactation services on breastfeeding outcomes. The objective of this pragmatic, parallel design randomized controlled trial is to assess the impact of telelactation on breastfeeding duration and exclusivity and explore how acceptability of and experiences with telelactation vary across Latinx, Black, and non-Black and non-Latinx parents to guide future improvement of these services. 2400 primiparous, pregnant individuals age > 18 who intend to breastfeed and live in the USA underserved by IBCLCs will be recruited. Recruitment will occur via Ovia, a pregnancy tracker mobile phone application (app) used by over one million pregnant individuals in the USA annually. Participants will be randomized to (1) on-demand telelactation video calls on personal devices or (2) ebook on infant care/usual care. Breastfeeding outcomes will be captured via surveys and interviews and compared across racial and ethnic groups. This study will track participants for 8 months (including 6 months postpartum). Primary outcomes include breastfeeding duration and breastfeeding exclusivity. We will quantify differences in these outcomes across racial and ethnic groups. Both intention-to-treat and as-treated (using instrumental variable methods) analyses will be performed. This study will also generate qualitative data on the experiences of different subgroups of parents with the telelactation intervention, including barriers to use, satisfaction, and strengths and limitations of this delivery model. This is the first randomized study evaluating the impact of telelactation on breastfeeding outcomes. It will inform the design and implementation of future digital trials among pregnant and postpartum people, including Black and Latinx populations which are historically underrepresented in clinical trials. ClinicalTrials.gov NCT04856163. Registered on April 23, 2021

An increasing number of children are suffering from brain damage-related visual processing dysfunctions (VPD). There is currently a lack of evidence-based intervention methods that can be used early in development. We developed a visual intervention protocol suitable from 1 year of age. The protocol is structured, comprehensive and individually adaptive, and is paired with quantitative outcome assessments. Our aim is to investigate the effectiveness of this first visual intervention program for young children with (a risk of) VPD. This is a single-blind, placebo-controlled trial that is embedded within standard clinical care. The study population consists of 100 children born very or extremely preterm (< 30 weeks) at 1 year of corrected age (CA), of whom 50% are expected to have VPD. First, children undergo a visual screening at 1 year CA. If they are classified as being at risk of VPD, they are referred to standard care, which involves an ophthalmic and visual function assessment and a (newly developed) visual intervention program. This program consists of a general protocol (standardized and similar for all children) and a supplement protocol (adapted to the specific needs of the child). Children are randomly allocated to an intervention group (starting upon inclusion at 1 year CA) or a control group (postponed: starting at 2 years CA). The control group will receive a placebo treatment. The effectiveness of early visual intervention will be examined with follow-up visual and neurocognitive assessments after 1 year (upon completion of the direct intervention) and after 2 years (upon completion of the postponed intervention). Through this randomized controlled trial we will establish the effectiveness of a new and early visual intervention program. Combining a general and supplement protocol enables both structured comparisons between participants and groups, and custom habilitation that is tailored to a child’s specific needs. The design ensures that all included children will benefit from participation by advancing the age at which they start receiving an intervention. We expect results to be applicable to the overall population of children with (a risk of) VPD early in life. Netherlands Trial Register: NTR6952 . Registered 19 January 2018.

Despite evidence of a quite large beneficial effect of endovascular treatment (EVT) for ischemic stroke caused by anterior circulation large vessel occlusion, many patients do not recover even after complete recanalization. To some extent, this may be attributable to incomplete microvascular reperfusion, which can possibly be improved by antiplatelet agents and heparin. It is unknown whether periprocedural antithrombotic medication in patients treated with EVT improves functional outcome. The aim of this study is to assess the effect of acetylsalicylic acid (ASA) and unfractionated heparin (UFH), alone, or in combination, given to patients with an ischemic stroke caused by an intracranial large vessel occlusion in the anterior circulation during EVT. MR CLEAN-MED is a multicenter phase III trial with a prospective, 2 × 3 factorial randomized, open label, blinded end-point (PROBE) design, which aims to enroll 1500 patients. The trial is designed to evaluate the effect of intravenous ASA (300 mg), UFH (low or moderate dose), both or neither as adjunctive therapy to EVT. We enroll adult patients with a clinical diagnosis of stroke (NIHSS ≥ 2) and with a confirmed intracranial large vessel occlusion in the anterior circulation on CTA or MRA, when EVT within 6 h from symptom onset is indicated and possible. The primary outcome is the score on the modified Rankin Scale (mRS) at 90 days. Treatment effect on the mRS will be estimated with ordinal logistic regression analysis, with adjustment for main prognostic variables. Secondary outcomes include stroke severity measured with the NIHSS at 24 h and at 5–7 days, follow-up infarct volume, symptomatic intracranial hemorrhage (sICH), and mortality. Clinical equipoise exists whether antithrombotic medication should be administered during EVT for a large vessel occlusion, as ASA and/or UFH may improve functional outcome, but might also lead to an increased risk of sICH. When one or both of the study treatments show the anticipated effect on outcome, we will be able to improve outcome of patients treated with EVT by 5%. This amounts to more than 50 patients annually in the Netherlands, more than 1800 in Europe, and more than 1300 in the USA. ISRCT, ISRCTN76741621 . Dec 6, 2017.

Novel therapies often fail to reach the bedside due to low trial recruitment rates. Prior to conducting one of the first chimeric antigen receptor (CAR) T cell therapy trials in Canada, we used the Theoretical Domains Framework, a novel tool for identifying barriers and enablers to behavior change, to identify physician-related barriers and enablers to screening and recruiting patients for an early phase immunotherapy trial. We conducted interviews with hematologists across Canada and used a directed content analysis to identify relevant domains reflecting the key factors that may affect screening and recruitment. In total, we interviewed 15 hematologists. Physicians expressed “cautious hope”; while expressing safety, feasibility, and screening criteria concerns, 14 out of 15 hematologists intended to screen for the trial (domains: knowledge, goals, beliefs about consequences, intentions). Physicians underscored the “challenging contexts,” identifying resources, workload, forgetting, and patient wait times to receive CAR T cells as key practical barriers to screening (domains: environmental context and resources, memory, attention and decision-making, behavioral regulation). They also highlighted “variability in roles and procedures” that may lead to missed trial candidates (domain: social and professional role). Left unaddressed, these barriers may undermine trial recruitment. This study is among the first to use the Theoretical Domains Framework from the physician perspective to identify recruitment challenges to early phase trials and demonstrates the value of this approach for identifying barriers to screening and recruitment that may not otherwise have been elicited. This approach can optimize trial procedures and may serve to inform future promising early phase cancer therapy trials. ClinicalTrials.gov Identifier: NCT03765177 . Registered on December 5, 2018.