Low-intensity repetitive transcranial magnetic stimulation is safe and well tolerated by people living with MS - outcomes of the phase I randomised controlled trial (TAURUS).

Background: Low-intensity repetitive transcranial magnetic stimulation (rTMS), delivered as a daily intermittent theta burst stimulation (iTBS) for four consecutive weeks, increased the number of new oligodendrocytes in the adult mouse brain. Therefore, rTMS holds potential as a remyelinating intervention for people with multiple sclerosis (MS). Objective: Primarily to determine the safety and tolerability of our rTMS protocol in people with MS. Secondary objectives include feasibility, blinding and an exploration of changes in magnetic resonance imaging (MRI) metrics, patient-reported outcome measures (PROMs) and cognitive or motor performance. Methods: A randomised (2:1), placebo controlled, single blind, parallel group, phase 1 trial of 20 rTMS sessions (600 iTBS pulses per hemisphere; 25% maximum stimulator output), delivered over 4-5 weeks. Twenty participants were randomly assigned to 'sham' (n = 7) or active rTMS (n = 13), with the coil positioned at 90° or 0°, respectively. Results: Five adverse events (AEs) including one serious AE reported. None were related to treatment. Protocol compliance was high (85%) and blinding successful. Within participant MRI metrics, PROMs and cognitive or motor performance were unchanged over time. Conclusion: Twenty sessions of rTMS is safe and well tolerated in a small group of people with MS. The study protocol and procedures are feasible. Improvement of sham is warranted before further investigating safety and efficacy.

Site-specific factors associated with clinical trial recruitment efficiency in general practice settings: a comparative descriptive analysis.

BACKGROUND: Recruitment of participants is crucial to the success of randomised control trials (RCTs) but can be challenging and expensive. Current research on trial efficiency is often focused at the patient-level with an emphasis on effective recruitment strategies. Less is known about selection of study sites to optimise recruitment. We examine site-level factors that are associated with patient recruitment and cost efficiency using data from an RCT conducted across 25 general practices (GP) in Victoria, Australia. METHODS: Data on number of participants screened, excluded, eligible, recruited, and randomised from each study site were extracted from a clinical trial. Details regarding site characteristics, recruitment practices, and staff time commitment were collected using a three-part survey. The key outcomes assessed were recruitment efficiency (ratio of screened to randomised), average time, and cost for each participant recruited and randomised. To identify practice-level factors associated with efficient recruitment and lower cost, outcomes were dichotomised (25th percentile vs others) and each practice-level factor assessed against the outcomes to determine its association. RESULTS: Across 25 GP study sites, 1968 participants were screened of which 299 (15.2%) were recruited and randomised. The mean recruitment efficiency was 7.2, varying from 1.4 to 19.8 across sites. The strongest factor associated with efficiency was assigning clinical staff to identify potential participants (57.14% vs. 22.2%). The more efficient sites were smaller practices and were more likely to be rural locations and in areas of lower socioeconomic status. The average time used for recruitment was 3.7 h (SD2.4) per patient randomised. The mean cost per patient randomised was $277 (SD161), and this varied from $74 to $797 across sites. The sites identified with the 25% lowest recruitment cost (n = 7) were more experienced in research participation and had high levels of nurse and/or administrative support. CONCLUSION: Despite the small sample size, this study quantified the time and cost used to recruit patients and provides helpful indications of site-level characteristics that can help improve feasibility and efficiency of conducting RCT in GP settings. Characteristics indicative of high levels of support for research and rural practices, which often tends to be overlooked, were observed to be more efficient in recruiting.

Impact of quarterly professional-mode flash glucose monitoring in adults with type 2 diabetes in general practice (GP-OSMOTIC): Secondary psychological and self-care outcomes of a pragmatic, open-label, 12-month, randomised controlled trial.

AIMS: To investigate the impact of quarterly professional-mode flash glucose monitoring on psychological outcomes in adults with type 2 diabetes in primary care. METHODS: The GP-OSMOTIC trial randomised 299 adults with type 2 diabetes in 25 general practices to quarterly use of professional-mode flash glucose monitoring (sensor worn for 14 days; data discussed at clinic visit) or usual care. At baseline and 12 months, participants completed validated measures: general emotional well-being (WHO-5), diabetes-specific quality of life (DIDP), satisfaction with glucose monitoring (GME-Q), self-care activities (SDSCA) and perceived involvement in clinical care (PICS). Linear mixed-effects models examined between-group differences at 12 months. RESULTS: At 12 months, there were no clinically important between-arm differences in any secondary psychological or self-care outcomes. Per protocol analyses showed no clinically significant between-group differences. CONCLUSIONS: The GP-OSMOTIC intervention had no significant impact, at 12 months, on general emotional well-being, diabetes-specific quality of life or satisfaction with glucose monitoring, suggesting no added psychological burden. Lack of positive impact on self-reported self-care activities or perceived involvement in clinical care may warrant closer attention to the fidelity of intervention delivery, the context (e.g. the nature of clinician-patient interactions) and/or the sensitivity of the measures, as these will help plan future studies.

Use of professional-mode flash glucose monitoring, at 3-month intervals, in adults with type 2 diabetes in general practice (GP-OSMOTIC): a pragmatic, open-label, 12-month, randomised controlled trial.

BACKGROUND: Continuous glucose monitoring, either real-time (personal) or retrospective (professional mode), can identify day-to-day glucose profiles to guide management decisions for people with type 2 diabetes. We aimed to examine the effects of professional-mode flash glucose monitoring, done at 3-month intervals, in adults with type 2 diabetes in general practice. METHODS: We did a pragmatic, two-arm, open label, 12-month, individually randomised controlled trial (GP-OSMOTIC) in 25 general practices in Victoria, Australia. Eligible participants were adults aged 18-80 years, with type 2 diabetes diagnosed for at least 1 year and HbA1c at least 5·5 mmol/mol (0·5%) above their target in the past month despite being prescribed at least two non-insulin glucose-lowering drugs, insulin, or both (with therapy stable for at least 4 months). We randomly assigned participants (1:1) to either use of a professional-mode flash glucose monitoring system or usual clinical care (control). All participants wore the flash glucose monitoring sensor at baseline, and electronic randomisation (using permuted block sizes of four and six, and stratified by clinic) was done after the sensor was attached. Masking of participants and treating clinicians to group allocation was not possible, but the study statistician was masked to allocation when analysing the data. At baseline, and 3, 6, 9, and 12 months, participants in the flash glucose monitoring group wore the professional-mode flash glucose monitoring sensor for 5-14 days before their general practice visit. The sensor recorded interstitial glucose concentrations every 15 min, but the glucose data were not available to the participant until their general practice visit, where the sensor output would be uploaded to a computer by the health professional and discussed. Control group participants wore the sensor at baseline and at 12 months for data analysis only, and had usual care visits every 3 months. The primary outcome was the between-group difference in mean HbA1c at 12 months. Secondary outcomes were the between-group differences in: mean percentage time in target glucose range (4-10 mmol/L), based on ambulatory glucose profile data at 12 months; mean diabetes-specific distress (assessed with the Problem Areas In Diabetes [PAID] scale) at 12 months; and mean HbA1c at 6 months. Analysis was done by intention to treat. This trial is registered at the Australian and New Zealand Clinical Trials Registry, ACTRN12616001372471. FINDINGS: Between Oct 4, 2016, and Nov 17, 2017, we randomly assigned 299 adults: 149 to flash glucose monitoring and 150 to usual care. At 6 months, HbA1c was lower in the flash glucose monitoring group than in the usual care group (difference -0·5%, 95% CI -0·8% to -0·3%; p=0·0001). However, at 12 months (primary outcome), there was no significant between-group difference in estimated mean HbA1c (8·2% [95% CI 8·0 to 8·4] for flash glucose monitoring vs 8·5% [8·3 to 8·7] for usual care; between-group difference -0·3%, 95% CI -0·5 to 0·01; [66 mmol/mol, 95% CI 64 to 68 vs 69 mmol/mol, 67 to 72; between-group difference -3·0, 95% CI -5·0 to 0·1]; p=0·059). Mean percentage time spent in target glucose range at 12 months was 7·9% (95% CI 2·3 to 13·5) higher in the flash glucose monitoring group than in the usual care group (p=0·0060). Diabetes-specific distress PAID scores were unchanged at 12 months (between-group difference -0·7, 95% CI -3·3 to 1·9; p=0·61). No episodes of severe hypoglycaemia or treatment-related deaths were reported. One participant died during the study from causes unrelated to the intervention (following complications post-myocardial infarction with multiple comorbidities). INTERPRETATION: Professional-mode flash glucose monitoring in adults with type 2 diabetes in general practice did not improve the primary outcome of HbA1c at 12 months or diabetes-specific distress compared with usual care, but did improve time in target glucose range at 12 months and HbA1c at 6 months. Our findings suggest that professional-mode flash glucose monitoring can be implemented in a pragmatic primary care environment. Although there was no change in HbA1c at 12 months, the improved time in target range might reflect the potential of the technology to support personalised clinical care by providing insights into glycaemic profiles for some people with type 2 diabetes. FUNDING: National Health and Medical Research Council of Australia, Sanofi Australia, and Abbott Diabetes Care.

GP-OSMOTIC trial protocol: an individually randomised controlled trial to determine the effect of retrospective continuous glucose monitoring (r-CGM) on HbA1c in adults with type 2 diabetes in general practice.

INTRODUCTION: Optimal glycaemia can reduce type 2 diabetes (T2D) complications. Observing retrospective continuous glucose monitoring (r-CGM) patterns may prompt therapeutic changes but evidence for r-CGM use in T2D is limited. We describe the protocol for a randomised controlled trial (RCT) examining intermittent r-CGM use (up to 14 days every three months) in T2D in general practice (GP). METHODS AND ANALYSIS: General Practice Optimising Structured MOnitoring To achieve Improved Clinical Outcomes is a two-arm RCT asking 'does intermittent r-CGM in adults with T2D in primary care improve HbA1c?' PRIMARY OUTCOME: Absolute difference in mean HbA1c at 12 months follow-up between intervention and control arms. SECONDARY OUTCOMES: (a) r-CGM per cent time in target (4-10 mmol/L) range, at baseline and 12 months; (b) diabetes-specific distress (Problem Areas in Diabetes). ELIGIBILITY: Aged 18-80 years, T2D for ≥1 year, a (past month) HbA1c>5.5 mmol/mol (0.5%) above their individualised target while prescribed at least two non-insulin hypoglycaemic therapies and/or insulin (therapy stable for the last four months). Our general glycaemic target is 53 mmol/mol (7%) (patients with a history of severe hypoglycaemia or a recorded diagnosis of hypoglycaemia unawareness will have a target of 64 mmol/mol (8%)).Our trial compares r-CGM use and usual care. The r-CGM report summarising daily glucose patterns will be reviewed by GP and patient and inform treatment decisions. Participants in both arms are provided with 1 hour education by a specialist diabetes nurse.The sample (n=150/arm) has 80% power to detect a mean HbA1c difference of 5.5 mmol/mol (0.5%) with an SD of 14.2 (1.3%) and alpha of 0.05 (allowing for 10% clinic and 20% patient attrition). ETHICS AND DISSEMINATION: University of Melbourne Human Ethics Sub-Committee (ID 1647151.1). Dissemination will be in peer-reviewed journals, conferences and a plain-language summary for participants. TRIAL REGISTRATION NUMBER: >ACTRN12616001372471; Pre-results.