A randomised controlled trial of Pre-Operative Oncotype DX testing in early-stage breast cancer (PRE-DX study) - Study protocol

\ua9 2024 Northgraves et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background The Oncotype DX\uae Breast Recurrence Score assay can guide recommendations made to patients with oestrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) breast cancer regarding post-surgery adjuvant therapy. Standard practice is to order the test in the post-operative setting on a specimen from the excised invasive carcinoma. However, it has been shown to be technically possible to perform the test on the diagnostic core biopsy. By testing the diagnostic core biopsy in the pre-operative setting, the wait for excised invasive carcinoma Recurrence Score results could be reduced allowing patients to be more accurately counselled regarding their treatment pathway sooner with any adjuvant treatment recommendations expedited. This would allow for more efficient streaming of follow up appointments. The aim of this study is to compare the impact on the patient treatment pathway of performing the Oncotype DX\uae test on the diagnostic core biopsy pre-operatively (intervention) as opposed to the excised invasive carcinoma (control). Methods and analysis This parallel group randomised controlled trial aims to recruit 330 newly diagnosed patients with grade 2 or grade 3, ER+, HER2-, invasive intermediate risk early-stage breast cancer. Participants will be randomised 2:1 to the preoperative testing of the diagnostic core biopsy compared to the post-operative testing of the excision specimen. The primary endpoint is number of clinical touchpoints between treating team and patient from initial approach until offer and prescription of the first adjuvant treatment. Secondary endpoints include time from diagnosis to offer and prescription of the first adjuvant treatment, patient-reported anxiety scores and health cost impact analysis collected at baseline, following the post-operative clinic and following the offer of adjuvant treatment, and number of alterations in treatment sequence from original planned surgical treatment to neoadjuvant therapy

A feasibility cluster randomised controlled trial of a paramedic-administered breathlessness management intervention for acute-on-chronic breathlessness (BREATHE)

Chronic breathlessness, persistent and disabling despite optimal treatment of underlying causes, is a prevalent and frightening symptom and is associated with many emergency presentations and admission to hospital. Breathlessness management techniques used by paramedics may reduce the need for conveyance to hospital. The Breathlessness RElief AT HomE study (BREATHE) aims to explore the feasibility of conducting a definitive cluster randomised controlled trial (cRCT) for people with acute-on-chronic breathlessness who have called an ambulance, to evaluate the effectiveness and cost-effectiveness of a paramedic-administered non-pharmacological breathlessness intervention. The trial is a mixed-methods feasibility cRCT. Eight paramedics will be randomised 1:1 to deliver either the BREATHE intervention in addition to usual care or usual care alone at call-outs for acute-on-chronic breathlessness. Sixty participants will be recruited to provide access to routine data relating to the index call-out with optional follow-up questionnaires at 14 days, 1 month and 6 months. An in-depth interview will be conducted with a subgroup. Feasibility outcomes relating to recruitment, data quality (especially candidate primary outcomes), and intervention acceptability and fidelity will be collected as well as providing data to estimate a sample size for a definitive trial. Yorkshire and The Humber-Sheffield Research Ethics Committee approved the trial protocol (19/YH/0314). The study results will inform progression to, or not, and design of a main trial according to predetermined stop-go criteria. Findings will be disseminated to relevant stakeholders and submitted for publication in a peer-reviewed journal

Sodium bicarbonate and high-intensity-cycling capacity: variability in responses

Purpose: The aim of this study was to determine whether gastrointestinal (GI) distress affects the ergogenicity of sodium bicarbonate and whether the degree of alkalaemia or other metabolic responses are different between individuals who improve exercise capacity and those who do not. Methods: Twenty-one males completed two cycling capacity tests at 110% of maximum power output. Participants were supplemented with 0.3 g∙kg-1BM of either placebo (maltodextrin) or sodium bicarbonate (SB). Blood pH, bicarbonate, base excess and lactate were determined at baseline, pre-exercise, immediately post-exercise and 5 minutes post-exercise. Results: SB supplementation did not significantly increase total work done (TWD) (P = 0.16, 46.8 ± 9.1 vs. 45.6 ± 8.4 kJ, d = 0.14), although magnitude based inferences suggested a 63% likelihood of a positive effect. When data were analysed without four participants who experienced GI discomfort, TWD (P = 0.01) was significantly improved with SB. Immediately post-exercise blood lactate was higher in SB for the individuals who improved but not for those who didn’t. There were also differences in the pre to post-exercise change in blood pH, bicarbonate and base excess between individuals who improved and individuals who did not. Conclusions: SB improved high intensity cycling capacity, but only with the exclusion of participants experiencing GI discomfort. Differences in blood responses suggest that sodium bicarbonate may not be beneficial to all individuals. Magnitude based inferences suggested that the exercise effects are unlikely to be negative; therefore individuals should determine whether they respond well to sodium bicarbonate supplementation prior to competition

Management of adults with primary frozen shoulder in secondary care (UK FROST): a multicentre, pragmatic, three-arm, superiority randomised clinical trial

Manipulation under anaesthesia and arthroscopic capsular release are costly and invasive treatments for frozen shoulder, but their effectiveness remains uncertain. We compared these two surgical interventions with early structured physiotherapy plus steroid injection. In this multicentre, pragmatic, three-arm, superiority randomised trial, patients referred to secondary care for treatment of primary frozen shoulder were recruited from 35 hospital sites in the UK. Participants were adults (≥18 years) with unilateral frozen shoulder, characterised by restriction of passive external rotation (≥50%) in the affected shoulder. Participants were randomly assigned (2:2:1) to receive manipulation under anaesthesia, arthroscopic capsular release, or early structured physiotherapy. In manipulation under anaesthesia, the surgeon manipulated the affected shoulder to stretch and tear the tight capsule while the participant was under general anaesthesia, supplemented by a steroid injection. Arthroscopic capsular release, also done under general anaesthesia, involved surgically dividing the contracted anterior capsule in the rotator interval, followed by manipulation, with optional steroid injection. Both forms of surgery were followed by postprocedural physiotherapy. Early structured physiotherapy involved mobilisation techniques and a graduated home exercise programme supplemented by a steroid injection. Both early structured physiotherapy and postprocedural physiotherapy involved 12 sessions during up to 12 weeks. The primary outcome was the Oxford Shoulder Score (OSS; 0-48) at 12 months after randomisation, analysed by initial randomisation group. We sought a target difference of 5 OSS points between physiotherapy and either form of surgery, or 4 points between manipulation and capsular release. The trial registration is ISRCTN48804508. Between April 1, 2015, and Dec 31, 2017, we screened 914 patients, of whom 503 (55%) were randomly assigned. At 12 months, OSS data were available for 189 (94%) of 201 participants assigned to manipulation (mean estimate 38·3 points, 95% CI 36·9 to 39·7), 191 (94%) of 203 participants assigned to capsular release (40·3 points, 38·9 to 41·7), and 93 (94%) of 99 participants assigned to physiotherapy (37·2 points, 35·3 to 39·2). The mean group differences were 2·01 points (0·10 to 3·91) between the capsular release and manipulation groups, 3·06 points (0·71 to 5·41) between capsular release and physiotherapy, and 1·05 points (-1·28 to 3·39) between manipulation and physiotherapy. Eight serious adverse events were reported with capsular release and two with manipulation. At a willingness-to-pay threshold of £20 000 per quality-adjusted life-year, manipulation under anaesthesia had the highest probability of being cost-effective (0·8632, compared with 0·1366 for physiotherapy and 0·0002 for capsular release). All mean differences on the assessment of shoulder pain and function (OSS) at the primary endpoint of 12 months were less than the target differences. Therefore, none of the three interventions were clinically superior. Arthoscopic capsular release carried higher risks, and manipulation under anaesthesia was the most cost-effective. The National Institute for Health Research Health Technology Assessment programme. [Abstract copyright: Copyright © 2020 The Author(s). Publishedx by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.

OP08 A feasibility cluster randomised controlled trial of a paramedic-administered breathlessness management intervention for acute-on-chronic breathlessness (BREATHE): study findings

BackgroundOne-fifth of conveyances to the emergency department (ED) are due to acute-on-chronic breathlessness. Paramedic breathlessness management may ease distress quicker and/or reduce ED conveyances. We evaluated the feasibility of a full trial of a paramedic delivered intervention to reduce avoidable conveyances (recruitment, randomisation, consent, training and intervention acceptability, adherence, data quality, best primary outcome, sample size estimation). The intervention comprised evidence-based non-drug techniques and a self-management booklet.MethodsThis mixed-methods feasibility cluster randomised controlled trial (ISRCTN80330546) with embedded qualitative study about trial processes, training and intervention delivery, randomised paramedics to usual care or to intervention+usual care. Retrospective patient consent to use call-out data and prospective patient/carer consent for follow-up was sought. Potential primary outcomes were breathlessness intensity (numerical rating scale) and ED conveyance. Follow-up included an interview for patients/carers and questionnaires at 14 days, 1 and 6 months and paramedic focus groups and survey.ResultsRecruitment was during the COVID-19 pandemic, leading to high demands on paramedics and fewer call-outs by eligible patients. We enrolled 29 paramedics; 9 withdrew. Randomisation/trial procedures were acceptable. Paramedics recruited 13 patients; 8 were followed up. Data quality was good. The intervention did not extend call-out time, was delivered with fidelity and no contamination and was acceptable to patients, carers, and paramedics. There were no repeat call-outs &lt; 48 hours. Recruitment stop-go criteria were not met. We had insufficient data for sample size estimation.ConclusionsA full trial in the same circumstances is not feasible. However, valuable information was gained on recruitment, attrition, consent, training and intervention acceptability and adherence, and patient-reported data collection.</jats:sec

Mixed-methods feasibility cluster randomised controlled trial of a paramedic-administered breathlessness management intervention for acute-on-chronic breathlessness (BREATHE): study findings.

INTRODUCTION: One-fifth of emergency department presentations by ambulance are due to acute-on-chronic breathlessness. We explored the feasibility of an evaluation-phase, cluster randomised controlled trial (cRCT) of the effectiveness and cost-effectiveness of a paramedic-administered, non-pharmacological breathlessness intervention for people with acute-on-chronic breathlessness at ambulance call-out (BREATHE) regarding breathlessness intensity and conveyance to hospital. METHODS: This mixed-methods, feasibility cRCT (ISRCTN80330546) randomised paramedics to usual care or intervention plus usual care. Retrospective patient consent to use call-out data (primary end-point) and prospective patient/carer consent for follow-up was sought. Potential primary outcomes included breathlessness intensity (numerical rating scale) and conveyance. Follow-up included: interviews with patients/carers and questionnaires at 14 days, 1 and 6 months; paramedic focus groups and surveys. RESULTS: Recruitment was during COVID-19, with high demands on paramedics and fewer call-outs by eligible patients. We enrolled 29 paramedics; nine withdrew. Randomisation/trial procedures were acceptable. Paramedics recruited 13 patients, not meeting recruitment target (n=36); eight patients and three carers were followed-up. Data quality was good but insufficient for future sample size estimation. The intervention did not extend call-out time, was delivered with fidelity and was acceptable to patients, carers and paramedics. There were no repeat call-outs within 48 h. All trained paramedics strongly recommended BREATHE as a highly relevant, simple intervention. CONCLUSION: Patient recruitment to target was not feasible during the pandemic. Training and intervention were acceptable and delivered with fidelity. Results include valuable information on recruitment, consent, attrition and data collection that will inform the design and delivery of a definitive trial

United Kingdom Frozen Shoulder Trial (UK FROST), multi-centre, randomised, 12 month, parallel group, superiority study to compare the clinical and cost-effectiveness of Early Structured Physiotherapy versus manipulation under anaesthesia versus arthroscopic capsular release for patients referred to secondary care with a primary frozen shoulder: study protocol for a randomised controlled trial

Frozen shoulder (also known as adhesive capsulitis) occurs when the capsule, or the soft tissue envelope around the ball and socket shoulder joint, becomes scarred and contracted, making the shoulder tight, painful and stiff. It affects around 1 in 12 men and 1 in 10 women of working age. Although this condition can settle with time (typically taking 1 to 3 years), for some people it causes severe symptoms and needs referral to hospital. Our aim is to evaluate the clinical and cost-effectiveness of two invasive and costly surgical interventions that are commonly used in secondary care in the National Health Service (NHS) compared with a non-surgical comparator of Early Structured Physiotherapy.We will conduct a randomised controlled trial (RCT) of 500 adult patients with a clinical diagnosis of frozen shoulder, and who have radiographs that exclude other pathology. Early Structured Physiotherapy with an intra-articular steroid injection will be compared with manipulation under anaesthesia with a steroid injection or arthroscopic (keyhole) capsular release followed by manipulation. Both surgical interventions will be followed with a programme of post-procedural physiotherapy. These treatments will be undertaken in NHS hospitals across the United Kingdom. The primary outcome and endpoint will be the Oxford Shoulder Score (a patient self-reported assessment of shoulder function) at 12 months. This will also be measured at baseline, 3 and 6 months after randomisation; and on the day that treatment starts and 6 months later. Secondary outcomes include the Disabilities of Arm Shoulder and Hand (QuickDASH) score, the EQ-5D-5 L score, pain, extent of recovery and complications. We will explore the acceptability of the different treatments to patients and health care professionals using qualitative methods.The three treatments being compared are the most frequently used in secondary care in the NHS, but there is uncertainty about which one works best and at what cost. UK FROST is a rigorously designed and adequately powered study to inform clinical decisions for the treatment of this common condition in adults.International Standard Randomised Controlled Trial Register, ID: ISRCTN48804508 . Registered on 25 July 2014

Surgery versus cast immobilisation for adults with a bicortical fracture of the scaphoid waist (SWIFFT): a pragmatic, multicentre, open-label, randomised superiority trial

Background Scaphoid fractures account for 90% of carpal fractures and occur predominantly in young men. The use of immediate surgical fixation to manage this type of fracture has increased, despite insufficient evidence of improved outcomes over non-surgical management. The SWIFFT trial compared the clinical effectiveness of surgical fixation with cast immobilisation and early fixation of fractures that fail to unite in adults with scaphoid waist fractures displaced by 2 mm or less. Methods This pragmatic, parallel-group, multicentre, open-label, two-arm, randomised superiority trial included adults (aged 16 years or older) who presented to orthopaedic departments of 31 hospitals in England and Wales with a clear bicortical fracture of the scaphoid waist on radiographs. An independent remote randomisation service used a computer-generated allocation sequence with randomly varying block sizes to randomly assign participants (1:1) to receive either early surgical fixation (surgery group) or below-elbow cast immobilisation followed by immediate fixation if non-union of the fracture was confirmed (cast immobilisation group). Randomisation was stratified by whether or not there was displacement of either a step or a gap of 1–2 mm inclusive on any radiographic view. The primary outcome was the total patient-rated wrist evaluation (PRWE) score at 52 weeks after randomisation, and it was analysed on an available case intention-to-treat basis. This trial is registered with the ISRCTN registry, ISRCTN67901257, and is no longer recruiting, but long-term follow-up is ongoing. Findings Between July 23, 2013, and July 26, 2016, 439 (42%) of 1047 assessed patients (mean age 33 years; 363 [83%] men) were randomly assigned to the surgery group (n=219) or to the cast immobilisation group (n=220). Of these, 408 (93%) participants were included in the primary analysis (203 participants in the surgery group and 205 participants in the cast immobilisation group). 16 participants in the surgery group and 15 participants in the cast immobilisation group were excluded because of either withdrawal, no response, or no follow-up data at 6, 12, 26, or 52 weeks. There was no significant difference in mean PRWE scores at 52 weeks between the surgery group (adjusted mean 11·9 [95% CI 9·2–14·5]) and the cast immobilisation group (14·0 [11·3 to 16·6]; adjusted mean difference −2·1 [95% CI −5·8 to 1·6], p=0·27). More participants in the surgery group (31 [14%] of 219 participants) had a potentially serious complication from surgery than in the cast immobilisation group (three [1%] of 220 participants), but fewer participants in the surgery group (five [2%]) had cast-related complications than in the cast immobilisation group (40 [18%]). The number of participants who had a medical complication was similar between the two groups (four [2%] in the surgery group and five [2%] in the cast immobilisation group). Interpretation Adult patients with scaphoid waist fractures displaced by 2 mm or less should have initial cast immobilisation, and any suspected non-unions should be confirmed and immediately fixed with surgery. This treatment strategy will help to avoid the risks of surgery and mostly limit the use of surgery to fixing fractures that fail to unite.</p