Strengthening Mental Abilities with Relational Training (SMART) in Multiple Sclerosis (MS): Study Protocol for a Feasibility Randomised Controlled Trial

Background Multiple Sclerosis (MS) is a chronic condition of the central nervous system, affecting around 1 in every 600 people in the UK, with 130 new diagnoses every week. Cognitive difficulties are common amongst people with MS, with up to 70% experiencing deficits in higher-level brain functions – such as planning and problem-solving, attention, and memory. Cognitive deficits make it difficult for people with MS to complete everyday tasks and limit their abilities to work, socialise, and live independently. There is a clear need – and recognised research priority – for treatments that can improve cognitive functioning in people with MS. The absence of effective cognitive interventions exacerbates burdens on the services accessed by people with MS – requiring these services to manage sequelae of untreated cognitive deficits, including reduced quality of life, greater disability and dependence, and poorer adherence to disease-modifying treatments. Our planned research will fill the evidence gap through developing – and examining the feasibility of trialling – a novel online cognitive rehabilitation programme for people with MS (SMART). Methods The primary objective of this study aims to conduct a feasibility study to inform development of a definitive trial of SMART for improving cognitive functioning in people with MS. Secondary objectives include accessing the acceptability to participants of the intervention, delivery format, inclusion/exclusion criteria, baselines and outcome measures, randomisation protocol, and the study procedures. It will further assess the framework for a cost-effectiveness analysis alongside a definitive trial; participant recruitment and retention rates, sample-size needed for a fully powered trial, and signal of efficacy. Discussion As a feasibility trial, outcomes are unlikely to immediately effect changes to NHS practice. However, this is a necessary step towards developing a definitive trial – and will give us a signal of efficacy, a prerequisite for progression to a definitive trial. If found to be clinically- and cost-effective, the latter trial could create a step-change in MS cognitive rehabilitation – improving service-delivery and optimising support with limited additional resources. Trial Registration: Registration ID: ClnicalTrials.gov: NCT04975685 – registered on July 23rd, 2021 Protocol version: 2.0, 25 November 2021

Sterile tuberculous granuloma in a patient with XDR-TB treated with bedaquiline, pretomanid and linezolid

Drug-resistant tuberculosis (DR-TB) continues to pose a threat to the global eradication of TB. Regimens for extensively drug-resistant (XDR) TB are lengthy and poorly tolerated, often with unsuccessful outcomes. The TB Alliance Nix-TB trial investigated the safety and efficacy of a 26-week regimen of bedaquiline, pretomanid and linezolid (BPaL) in participants with XDR-TB, multidrug-resistant (MDR) TB treatment failure or intolerance. In this trial 9 out of 10 participants were cured. We describe a trial participant with XDR-TB who presented with new-onset seizures soon after BPaL treatment completion. Imaging showed a right temporal ring-enhancing lesion, and a sterile tuberculous granuloma was confirmed after a diagnostic, excisional biopsy. Learning points include management of a participant with a tuberculoma after BPaL completion, efficacy of new medications for central nervous system (CNS) TB and a review of their CNS penetration. This is the first case of pretomanid use in CNS TB.

Methodological approaches for conducting follow-up research with clinical trial participants: a scoping review and expert interviews

Background Evidence-based establishment and implementation of best principles, laws and ordinances that regulate clinical research depend on the consultation and involvement of trial participants. Yet, guidance on methodological approaches to obtain trial participants’ perspectives is currently missing. This scoping review therefore aimed at identifying, describing and evaluating research approaches to obtain trial participants’ feedback on their views and experiences. Methods We searched the electronic databases Medline and PsycInfo via Ovid and the Web of Science Core Collection. Clinical trials were included that involved adult participants that were conducted in selected high-income countries and that were published in peer-reviewed journals between 1985 and 2018. In addition, 29 expert interviews were conducted between March and May 2019. Results Out of 5994 identified records, 23 articles were included in this review. Twelve studies used a qualitative approach, 10 were quantitative and one study used a mixed-method design. More than 75% of all work was conducted in the USA and the UK. The scoping review and the expert interviews highlighted that recruitment of participants was generally done through direct contact by principal investigators and/or study nurses or through searches in de-identified patient databases. Authors used surveys, interviews or focus group discussions. The tools used were either based on existing validated ones or developed and verified de novo with the support of experts and/or patient representatives. Conclusions To our knowledge, this is the first methodological literature review of approaches to researching experiences of clinical trial participants where findings were triangulated with expert interviews. Covering a range of indications, trial phases and study settings, it demonstrates that clinical trial participant perspectives and experience is heavily under-researched. This casts doubt on the overall robustness of available insight into trial participants’ views and experiences. Our results demonstrate that the methodology for studying participant opinion, perception and experience should be adapted to the measure of interest and conform to the study population. Using valid patient experience data is the basis to evaluate existing legal and regulatory human subject research frameworks for their appropriateness from a patient perspective. Such an evaluation will be critical to empower research participants.

NCOG-27. STATUS AS A CLINICAL TRIAL PARTICIPANT AND OUTCOME IN IDH-WILDTYPE GLIOBLASTOMA

INTRODUCTION Standard of care for glioblastoma consists of surgery, followed by combined chemoradiation and adjuvant chemotherapy, as per the seminal EORTC study from 2005. Clinical trial patients, being a population selected for functional status, hepatic function, renal function, and lack of other malignancies, may have improved outcome over the general treated population. METHOD Single center retrospective analysis of status as a clinical trial patient in the upfront setting and other clinical factors/biomarkers, analyzed for correlation with outcomes (PFS/OS) in IDH-wildtype glioblastomas. RESULTS 82 patients with IDH-wildtype glioblastoma were identified between 2014 and 2020, treated with standard of care or with an upfront clinical study (43% women; median age 66 years, range 35-91 years of age). 22 patients (27%) were treated with upfront clinical study. Status as a patient treated in an upfront clinical study did not correlate with outcome (hazard ratio HR PFS 0.99, CI 0.57-1.7, p=0.97; HR OS 1.09, CI 0.56-2.1, p=0.81). Frontal lobe was most frequently involved (n=36, 44%), followed by parietal lobe (n=33, 40%). Age was not a strong predictor of survival (R2 0.01). No statistically significant correlation was observed between outcome and laterality or location. MGMT promoter methylation was associated with improved PFS (HR 0.56, CI 0.33-0.94, p=0.03) and OS (HR 0.40, CI 0.19-0.85, p=0.02), with mPFS 6 months vs 9 months and mOS 16 months vs 20 months (unmethylated vs methylated respectively). CONCLUSION In this retrospective cohort of IDH-wildtype glioblastomas, age, tumor laterality, and tumor location were not significant predictors of outcome. MGMT promoter methylation predicted for superior PFS/OS. Patient selection for clinical studies are influenced by entry criteria, however at least in this retrospective review, status as a clinical study patient in the upfront setting did not correlate with outcome compared to patients treated with upfront standard of care.

The use of electronic health records for recruitment in clinical trials: a mixed methods analysis of the Harmony Outcomes Electronic Health Record Ancillary Study

Background The electronic health record (EHR) contains a wealth of clinical data that may be used to streamline the identification of potential clinical trial participants. However, there is little empirical information on site-level facilitators of and barriers to optimal use of EHR systems with respect to trial recruitment. Methods We conducted qualitative focus groups and quantitative surveys as part of the EHR Ancillary Study, which is being conducted alongside the multicenter, global, Harmony Outcomes Trial comparing albiglutide to standard care for the prevention of cardiovascular events in type 2 diabetes. Subject matter experts used findings from focus groups to draft a 20-question survey examining the use of the EHR for participant identification, common site recruitment strategies, and variation in perceived barriers to optimal use of the EHR. The final survey was fielded with 446 site investigators actively enrolling participants in the main trial. Results Nearly two-thirds of respondents were study coordinators (63.2%), 23.1% were principal investigators, and 13.7% held other research roles. Approximately half of the respondents reported using the EHR to find potential trial participants. Of these, 79.4% reported using EHR searches in conjunction with other recruitment methods, including reviewing of upcoming clinic schedules (75.3%) and contacting past trial participants (71.2%). Important barriers to optimal use of the EHR included the lack of availability of certain research-focused EHR modules and limitations on the ability to contact patients cared for by other providers. Of survey respondents who did not use the EHR to find potential participants, one-quarter reported that the EHR was not accessible in their country; this finding varied from 2.6% of respondents in North America to 50% of respondents in the Asia Pacific. Conclusions While EHR screening was commonly used for recruitment in a cardiovascular outcomes trial, important technical, governance, and regulatory barriers persist. Multifaceted, scalable, and customizable strategies are needed to support the optimal use of the EHR for trial participant identification. Trial registration ClinicalTrials.gov NCT02465515. Registered on 8 June 2015

The Experience of Women in a Phase II Trial of Hypnosis and Progressive Muscle Relaxation for Body Image: Exploring Possible Mechanisms

Purpose: The purpose of this study was to explore potential mechanisms of two interventions, hypnosis and progressive muscle relaxation to nature sounds (PMR), to improve body image in a randomized phase II trial. Participant comments were explored in an unplanned qualitative analysis.Methods:This qualitative study employed thematic analysis, a hybrid approach of inductive and deductive coding. We analyzed participant feedback given at any point during the 6-week intervention. Results:In the parent study 87 women were randomized in a 2:1 fashion, 59 to hypnosis and 28 to PMR. Sixty-three of the 87 women participating (72%) were motivated to write comments elaborating on their study experience. Thematic analysis generated five themes, including: relaxation and stress management, mind-body connection, improved mood, sleep, and sexual health. Four of the themes were represented in both groups while sexual health was only represented in the hypnosis group. Conclusions: This analysis suggests that both hypnosis and PMR may improve body image through the ability to relax and manage stress, sleep better, improve mood and create a mind-body connection. Sexual health emerged as an important theme among participants in the hypnosis group, but not the PMR group. Hypnosis, due to the hypnotic suggestions for sexual health, may have a positive impact on sexual health specifically. Improving body image alone may not have profound effects on the broader concept of sexual health. More research is needed.

Effects of the Consumption of Low-Fat Cooked Ham with Reduced Salt Enriched with Antioxidants on the Improvement of Cardiovascular Health: A Randomized Clinical Trial

The aim of the study was to analyze how cardiovascular risk factors can be modified using nutritionally improved cooked ham enriched with a pool of antioxidants to influence relevant metabolic targets. Sixty-five untreated subjects (49.2% males, 50.8% females, mean age 40.92 ± 9.03 years) with total cholesterol level ≥180 mg/dL or LDL cholesterol ≥130 mg/dL participated in a 8-weeks randomized, double-blind controlled trial. Participant in the intervention group (51.5% males, 48.5% females, mean age 41.6 ± 9.8 years and mean BMI 25.1 ± 3.6 kg/m2) consumed cooked ham enriched with antioxidants (100 g/d) and controls (49.9% males, 53.1% females, mean age 40.2 ± 8.3 years and mean BMI 26.3 ± 3.2 kg/m2) received placebo. At 8 weeks, oxidized LDL decreased significantly between experimental and placebo groups (p < 0.036). Experimental group differences were also significant (p < 0.05). Similar findings in malondialdehyde, total cholesterol, high-sensitivity C-reactive protein, and interleukin 6 were observed in the intervention group. Significant between-group differences in these variables were also found, except for total cholesterol and interleukin 6. The effects on inflammation and oxidation support the direct action of these antioxidants on the etiopathogenic factors of atheromatous plaque. We also observed an improvement in the lipid profiles among the subjects.

Neural encoding of actual and imagined touch within human posterior parietal cortex

In the human posterior parietal cortex (PPC), single units encode high-dimensional information with partially mixed representations that enable small populations of neurons to encode many variables relevant to movement planning, execution, cognition, and perception. Here, we test whether a PPC neuronal population previously demonstrated to encode visual and motor information is similarly engaged in the somatosensory domain. We recorded neurons within the PPC of a human clinical trial participant during actual touch presentation and during a tactile imagery task. Neurons encoded actual touch at short latency with bilateral receptive fields, organized by body part, and covered all tested regions. The tactile imagery task evoked body part-specific responses that shared a neural substrate with actual touch. Our results are the first neuron-level evidence of touch encoding in human PPC and its cognitive engagement during a tactile imagery task, which may reflect semantic processing, attention, sensory anticipation, or imagined touch.