Imperial Prostate-4 Comparative Healthcare Research Outcomes of Novel Surgery in Prostate Cancer (Ip4-Chronos): Early Feasibility, Safety and Functional Outcomes from a Pilot Rct

INTRODUCTION AND OBJECTIVE: Randomised comparative outcomes are unavailable for focal therapy in localised prostate cancer. IP4 CHRONOS is an RCT aimed to optimise recruitment of patients dependent upon clinician and patient equipoise. METHOD(S): Patients with clinically significant localised prostate cancer could opt for IP4-CHRONOS-A or IP4-CHRONOS-B. IP4- CHRONOS-A randomised patients 1:1 between focal therapy(HIFU or cryotherapy) versus radical therapy(radiation or prostatectomy). Using a multi-arm-multistage(MAMS)design, IP4-CHRONOS-B randomised between focal alone(FTA) and focal combined with neoadjuvant medication (12 weeks of finasteride [FTF] or bicalutamide [FTB]). We report the pilot phase outcomes on feasibility of randomisation, early safety outcomes relative to treatment and genito-urinary functional outcomes following over 12 months treatment in IP4-CHRONOS-B. IP4-CHRONOS had ethics committee approval and was registered(ISRCTN17796995). RESULT(S): Following COVID-19 adjustments, IP4-CHRONOSA did not meet its feasibility target. Having randomised 36 patients via10 sites with a recruitment rate (95% CI) of 18% (13-23) & randomisation rate of 97%(86-100). IP4-CHRONOS-B did meet its target, randomising 64 patients across 7 sites with a recruitment rate of 43% (35-52) &randomisation rate of 100%(94-100). The only patients to withdraw were randomised to the radical arm of IP4-CHRONOS-A(4 [22%]) All patients in IP4-CHRONOS-B were compliant with neoadjuvant treatment.Only 1 patient reported CTCAE V4.0 grade>=3 adverse event(AE) in IP4-CHRONOS-A following radical treatment, another patient in each arm reported a serious adverse event(SAE) following treatment. 1 &3 patients reported an AE &SAE following FTB. 2 and 3 patients reported an AE &SAE following FTA. No patients reported any AE or SAE event following FTF. Figure 1 demonstrates generally well preserved genito-urinary function following focal treatment+/-neoadjuvant treatment. CONCLUSION(S): IP4-CHRONOS evaluated patient and physician equipoise regarding focal therapy. Traditional randomisation was not feasible due to strong patient preferences, while a MAMS RCT investigating the role of neoadjuvant agents combined with focal therapy was.

Ethical considerations on placebo-controlled vaccine trials in pregnant women

Placebo use in clinical trials, whenever a proven effective treatment exists, is one of the most debated topics in contemporary research ethics. This article addresses the ethical framework for placebo use in clinical trials assessing vaccine efficacy in pregnant women. Vaccine trial participants are healthy at the outset and some must be infected during the study to demonstrate the product's efficacy, meaning that placebo-treated participants are under risk of serious and irreversible harm. If effective vaccines exist, such risk precludes placebo use. This interdiction should be extended to any clinical trial of vaccine efficacy in pregnant women, because a demonstration of clinical efficacy in nonpregnant individuals and comparable immunogenic responses in pregnant women are predictors of efficacy in pregnancy as well. Moreover, product effectiveness in real-world use scenarios can be ascertained by observational studies conducted after its inclusion in vaccination campaigns. © 2023, Conselho Federal de Medicina. All rights reserved.

TrialTree: A Novel Application for Interactive Trial Design

Background: Important lapses in the research enterprise, notably low-quality studies, amount to research waste. Close to 50% of this research waste comes from research on low-priority research questions, omitting important outcomes, not involving stakeholders in research design and poor methodology. With the COVID-19 pandemic, the urge to generate evidence to address important questions regarding optimal management strategies has further aggravated this problem. Most COVID-related trials are of low quality. This is in part due to deficiencies in designing high-quality trials at short notice. Consequently, results from these trials do not reliably inform clinical practice for the treatment or management of patients with COVID-19. Innovative approaches to trial design that incorporate existing tools are required to ensure that trials can be designed rapidly, efficiently, and consistently. Learning objectives: (1) To understand the key features of trial design. (2) To apply the use of existing trial resources in trial design. (3) To learn about how to match the research question with the appropriate design features. (4) To be able to use an electronic application to design a trial. Outline: In the first part, participants will review core concepts in trial design (equipoise, research question formulation, knowledge gaps, hypotheses etc.) and a collection of tools/frameworks meant to enhance trial design. These tools/frameworks include the PRagmatic Explanatory Continuum Indicator Summary-2 (PRECIS-2), Template for Intervention Description and Replication (TIDieR), Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT), Core Outcome Measures in Effectiveness Trials (COMET;https://comet-initiative.org/), TrialForge (Tools aimed at improving trial efficiency;https:// www.trialforge.org/), Support for statistical analyses plans (SAP), PROGRESS-Plus (a framework of sociodemographic factors-Place of residence, Race/ethnicity/ culture/language, Occupation, Gender/Sex, Religion, Education, Socioeconomic status, and Social capital-'Plus' refers to other personal, time-dependent or relationship-dependent factors, such as pregnancy, age, disability, and sexual orientation). The second part will be a hands-on session in trial design using the TrialTree application (https://trialtree.logicnets.net/ lmc/TT) and the production of a design report. TrialTree is organized into eight modules that cover the main design features. It includes tips, prompts, and feedback on trial design. Evaluation: (1) Completion of a post-workshop quiz. (2) Production of a complete design report in TrialTree. Materials required: (1) A laptop (access to the TrialTree application will be provided free of charge). (2) Pre-workshop readings will be provided. Goals of Session: The goal of this session is to build capacity in novice and experienced trialists on the use of an electronic application for interactive trial design.

Accommodating ''History Effects'' in Long Duration, Multisite Clinical Trials to Ensure Relevant and Compelling Evidence

Over the course of a clinical trial, changes in the practice environment have the potential to reduce internal and external validity and impact change in patient outcomes. Such ''history effects''1 can take the form of changes in standard of care, clinical guidelines and recommendations, new drug/device availability in the marketplace, testing and screening procedures, and, as recently experienced, a global pandemic. Clinical trials conducted over many years are particularly susceptible to history effects. Such effects can impact foundational ability to continue a trial, including clinician equipoise and ability to implement trial interventions, necessitating awareness and action planning. For example, Curtis et al.2 acknowledged challenges with clinical guideline history effects and issued recommendations for addressing them such as consideration of participant wellbeing, stakeholder engagement, safety monitoring, review of guideline and policy changes, and development of rules for protocol changes. This session will explore how four multisite clinical trials conducted with VA Cooperative Studies Program sponsorship and coordination have weathered history effects during prolonged periods of enrollment. Topics to be covered include the implementation of pragmatic designs, monitoring of clinical guidelines, assessing control group treatment conditions, modifying protocols, adjusting quality assurance procedures, refining recruitment pathways, and training site investigators. The speakers, Study Chairs, will describe best practices and provide recommendations for navigating history effects in prolonged multisite clinical trials that can ensure outcomes remain relevant and compelling to inform public health at trial commencement. The CSP 2008/PTXRx study is a pragmatic, randomized, double-blind, placebo-controlled, multicenter clinical trial of Veteran patients with diabetic kidney disease (DKD) examining whether pentoxifylline (PTX), when added to usual care, can delay time to end-stage renal disease or death. Enrollment for the study began in 2019, and it is anticipated that 9 years of follow-up will be required to observe the required number of primary events. Given the long duration of the study, changes in clinical guidelines were anticipated and have occurred, including the approval of new DKD therapies and introduction of a new formula for estimated glomerular filtration rate (eGFR) calculation. In anticipation of these changes, the study design allows for whatever standard of care is extant at any time during the course of the study. PTXR's pragmatic trial design and protocol leverage the VA's research infrastructure and remote platforms allowing the study to be responsive to external changes and to safely continue during a global pandemic. The CSP 596/OPTION study is a randomized, double- blind, multicenter trial of Veteran patients with a first or second recurrent Clostridium difficile infection (CDI) comparing (1) fidaxomicin and (2) vancomycin, followed by a taper and pulse to (3) a standard vancomycin regimen. Since enrollment began in 2016, significant changes in CDI epidemiology and clinical management have impacted the study. The COVID-19 pandemic also resulted in an administrative hold on all trial activity followed by staggered reopening of sites due to variable COVID-19 activity and clinical priorities. Many clinical laboratories switched to algorithms that included free toxin assays in addition to polymerase chain reaction (PCR) tests out of concern for overdiagnosis based on PCR testing alone, reducing the number of potentially enrollable cases. There has been increased empirical vancomycin treatment for recurrent CDI without confirmation by stool testing, a requirement for enrollment, and a recruitment strategy for identifying potential cases. Finally, conflicting clinical guidelines for recurrent CDI has created potential equipoise when considering enrollment. Ongoing educational efforts have been made to clarify the protocol and emphasize the validity of the research question as well as protoco changes to allow safe enrollment and follow-up of participants in the face of the ongoing COVID-19 pandemic. The CSP 2005/VALOR is a phase III randomized, open label, multicenter clinical trial of Veteran patients with operable stage I non-small cell lung cancer that compares stereotactic radiotherapy and anatomic pulmonary resection with a primary outcome measure of overall survival. The study was activated in 2017 and recruitment to the trial has been affected by ongoing changes in public and clinician perceptions about stereotactic radiotherapy and surgery that have interfered with equipoise and willingness of participants to enroll. The study team perpetually addresses this challenge through group conversations with local site investigators, study coordinators, and other research personnel to preserve group equipoise across the study. Since the study's activation, new safety information about stereotactic radiotherapy has emerged necessitating protocol modifications while aiming to preserve internal and external validity. The includes modifying standard operating procedures for the study's centralized quality assurance program that has had to adapt its process to remain contemporary. STARPORT, funded by VA CSRD with CSP collaboration, is a randomized, open label, multicenter clinical trial of Veteran patients with oligorecurrent prostate cancer comparing the effects of standard systemic therapy (SST) alone or with PET-directed local therapy using surgery or radiation. Although enrollment was initiated in 2021, changes are already evident in clinical practice guidelines regarding the use of imaging in workup in this patient population. Shortly before the start of accrual, 18F-DCFPyL PSMA PET/CT received FDA-approval. Consequently, it is being rapidly adopted at the STARPORT VA medical centers and the use of conventional imaging using CT or bone scan prior to PET/CT imaging-part of the original eligibility criteria-quickly is falling out of favor. Furthermore, shortly after the start of enrollment, NCCN guidelines adopted the stance that conventional imaging was no longer required in the setting of PSMA PET/CT imaging, solidifying the transition away from conventional imaging. Thus, the protocol is being amended to remove the requirement for conventional imaging as part of workup for oligorecurrence. In addition, to be generalizable, the study is designed to integrate future PSMA radiotracers that are incorporated into practice as well as changes in SST regimens over the time of the study.

Recruitment, clinical equipoise, patient acceptance and compliance in the UK-ANZ POSNOC trial

Background: POSNOC is a UK-ANZ multicentre, non-inferiority, randomised trial comparing systemic therapy alone with systemic therapy plus Axillary Treatment (Axillary radiotherapy or ALND) for women with <=2 macrometastases at SNB. The primary outcome is axillary recurrence within 5 years. This paper describes screening, recruitment and compliance data. Method(s): Sites were requested on a monthly basis to upload screening data and provide reasons for nonrecruitment of eligible patients into the trial. Sites entered in the online database whether the patients were compliant with their randomisation allocation. Result(s): The study opened in July 2014 and completed target recruitment of 1900 women (24% of those screened) in July 2021, at 95 sites in the UK and 20 sites in Australia and New Zealand. The reason for non-enrolment was unknown in 1300 women. Of the remaining 4774 women with known reasons, who were screened but not randomised, the most common reasons for non-recruitment were due to either patients (n=2219, 46.5%) or their clinicians (n=782, 16.4%) favouring axillary treatment, or patients (n=490, 10.3%) or their clinicians (n=170, 3.6%) not wishing to have axillary treatment. Over the course of the study, there was an increase in the proportion of patients wanting axillary treatment and declining the trial (Mean % patients declined 2015 - 17.9%, 2021 - 39.1%). Mean number of participants recruited per site per month was 0.24 (SD 0.18) overall, 0.25 (SD 0.19) in the UK, and 0.19(SD 0.15) in ANZ. The mean was < 0.3 in 79 sites and >0.9 in only one site. Recruitment rate remained consistent throughout the study (mean 25.3 per month) except for during the first 6 months of recruitment (5.7) and during the COVID pandemic Apr-Sep 2020 (7.5). Of 89 (4.8%) participants non-compliant with allocation, n=45 (50.6%) received systemic therapy alone and n=44 (49.4%) received systemic therapy plus axillary treatment. There was no fluctuation in the direction of non-compliance during the study duration. There was increasing uptake of axillary radiotherapy to treat the axilla instead of ALND over the course of the study in patients receiving axillary treatment (Number who had ART of all who had axilla treatment2014-2017 - 248/454 (54.6 %);2018-2021 - 315/449 (70.2%)). Conclusion(s): Recruitment and compliance with randomised allocation remained consistent over a seven-year period. POSNOC with in-built radiotherapy QA will provide definitive data on axillary management in patients undergoing mastectomy or BCS with <=2 macrometastases on SNB.

Uses of equipoise in discussions of the ethics of randomized controlled trials of COVID-19 therapies.

BACKGROUND: Early in the COVID-19 pandemic, the urgent need to discover effective therapies for COVID-19 prompted questions about the ethical problem of randomization along with its widely accepted solution: equipoise. In this scoping review, uses of equipoise in discussions of randomized controlled trials (RCT) of COVID-19 therapies are evaluated to answer three questions. First, how has equipoise been applied to COVID-19 research? Second, has equipoise been employed accurately? And third, do concerns about equipoise pose a barrier to the ethical conduct of COVID-19 RCTs? METHODS: Google Scholar and Pubmed were searched for articles containing substantial discussion about equipoise and COVID-19 RCTs. 347 article titles were screened, 91 full text articles were assessed, and 48 articles were included. Uses of equipoise were analyzed and abstracted into seven categories. RESULTS AND DISCUSSION: Approximately two-thirds of articles (33/48 articles) used equipoise in a way that is consistent with the concept. They invoked equipoise to support (1) RCTs of specific therapies, (2) RCTs in general, and (3) the early termination of RCTs after achieving the primary outcome. Approximately one-third of articles (15/48 articles) used equipoise in a manner that is inconsistent with the concept. These articles argued that physician preference, widespread use of unproven therapies, patient preference, or expectation of therapeutic benefit may undermine equipoise and render RCTs unethical. In each case, the purported ethical problem can be resolved by correcting the use of equipoise. CONCLUSIONS: Our findings highlight the continued relevance of equipoise as it supports the conduct of well-conceived RCTs and provides moral guidance to physicians and researchers as they search for effective therapies for COVID-19.

A Service Evaluation of Venous Thromboembolism Prophylaxis Dosing during the first COVID-19 wave in the Intensive Care Unit, Queen Alexandra Hospital Portsmouth

Introduction: In December 2019 the first case of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified. Its predominant features are respiratory symptoms;however, in severe disease, coagulopathy is commonplace. Published reports from the early pandemic and emerging evidence described an increased incidence of venous thromboembolism (VTE) in these patients. Objectives: Evaluation of changes in VTE prophylaxis in patients with COVID-19 and its impact on VTE rates. Method: We performed a service evaluation of all patients admitted to ICU at Queen Alexandra Hospital (QAH) Portsmouth with confirmed COVID-19. Patients admitted from 10/03/2020 to 12/05/2020 were included. Interrogation of the computerised clinical and radiology systems were used. Patients were investigated for VTE based on clinical suspicion and observed until discharge from ICU, death, or transfer. Wealso evaluated adverse bleeding risks. Standard thromboprophylaxis for QAH is Enoxaparin, as per tables 1 and 2. Covid enhanced prophylaxis is defined in table 3. Results: 69 patients were admitted to ICU at QAH between 10/03/2020 to 12/05/2020 with confirmed COVID-19. Of these patients 37 were investigated for VTE. 17 patients had a thromboembolic event. 15 patients had a PE, of which 2 also had embolic strokes. 2 patients had a DVT. 45 patients received standard thromboprophylaxis, 18 received COVID prophylaxis, 4 received treatment dose, and 1 patient received no thromboprophylaxis. Data was unavailable for 1 patient. Adverse events were only found in 1 patient receiving treatment dose and the patient not on thromboprophylaxis. After interim analysis, on the 11th April 2021, the ICU venous thromboprophylaxis policy was changed to enhanced prophylaxis for patients being treated for COVID-19. Conclusions: This evaluation was able to identify early the increased risk of VTE in COVID patients, and the utility of ddimers to help consider VTE. The interim analysis demonstrated 50% of patients investigated had confirmed VTE. Following this analysis, along with emerging evidence and recommendations by national bodies, the VTE prophylaxis guideline was changed on the 11 April 2020 to enhanced dosing. The overall rate of confirmed VTE in our cohort was 27%. However, of those who underwent CT imaging, positive findings were found in 46%. 85% of patients admitted after 10/4/2020 were investigated for VTE, which reflects increased recognition of the issue and team confidence in transferring COVID patients. Owing to the low initial imaging rate, the evaluation is likely to have underestimated thrombosis rates. Comparing VTE rates between those who received standard and enhanced VTE prophylaxis showed no significant effect (p-value 0.425), indicating that VTE prophylaxis is unlikely to confer substantial benefit, and the low adverse event rates in both groups signal no significant harm from enhanced prophylaxis. In conclusion, this study demonstrates VTE is a significant concern in patients being treated for COVID-19 in an ICU setting. Non-peer reviewed data from large trials, suggest that anticoagulation may be of benefit in hospitalised but not intensive care patients. We continue to be guided by current evidence and still implement enhanced thromboprophylaxis in our guideline despite the equipoise demonstrated.

HALT - Targeted Therapy with or without Dose-Intensified Radiotherapy in Oligo-Progressive Disease in Oncogene Addicted Lung Tumours

Introduction: Following initial response to TKI, advanced NSCLC patients with actionable mutations ultimately develop treatment resistance. In a proportion of patients (15-40%), initial, limited progression (≤5 lesions) is observed, termed oligoprogressive disease (OPD). SBRT offers hypofractionated, targeted radiotherapy treatment hypothesised to prolong clinical benefit from TKI prior to widespread disease development. With limited evidence to date, and poor clinical/biological selection criteria, the potential benefit offered by SBRT to ablate OPD sites prior to change in systemic therapy is an important question to address. Methods: HALT is a randomised, multi-centre, phase II/III international trial with seamless transition to phase III incorporated. Eligible patients (stage IV NSCLC, actionable mutation, TKI response prior to OPD) are randomised 2:1 to SBRT/continued TKI or continued TKI alone. Eligibility is confirmed by a virtual MDT (vMDT) comprising trial clinicians and radiologists (confirmation of OPD, SBRT suitability). Follow-up assessments are aligned with routine care at 3-monthly intervals until change in systemic therapy is clinically indicated, with imaging and toxicity assessment at each visit. Results: Recruitment commenced November 2017 with 25 centres (17 UK;8 non-UK) open to date. Following the COVID-19 pandemic, recruitment is recovering with 129 registered and 74 randomised patients. Over the last 4 years, little evidence has emerged to confirm any potential benefit of SBRT in this patient group and the impact on patient toxicity remains unknown. Therefore, with persisting questions around clinical equipoise, HALT remains highly relevant. With an 18-month extension and a recent amendment to the HALT inclusion criteria (≤5 OPD lesions, ≤7cm and OPD assessments by PET-avidity), the target of 110 randomised patients remains achievable. Conclusions: As the first randomised trial assessing SBRT benefit in this mutation-positive NSCLC patient population, HALT will provide valuable treatment efficacy and safety information, informing subsequent trial design and contribute to the development of international guidelines for the identification and clinical management of oligoprogression in mutation positive lung cancer. Keywords: Stereotactic body radiotherapy, NSCLC, Phase II

Comparative healthcare research outcomes of novel Surgery in prostate cancer (IP4-CHRONOS): Pilot RCT assessing feasibility of randomization for focal therapy in localized prostate cancer

Background: Randomised comparative data is lacking for focal therapy in localised prostate cancer. Imperial Prostate 4 CHRONOS (IP4-CHRONOS) is an RCT designed to reflect patient and physician equipoise to maximise acceptance to randomisation. Methods: Patients and physicians could opt for CHRONOS-A or CHRONOS-B. CHRONOS-A randomised between focal therapy (HIFU/cryotherapy) and radical therapy (radiation/prostatectomy). Using a multi-arm-multistage design, CHRONOS-B randomised between focal and focal combined with neoadjuvant medication (3 months of either finasteride or bicalutamide). We report the pilot phase outcomes on feasibility of randomisation. IP4-CHRONOS had ethics committee approval and was registered (ISRCTN17796995). Results: Due to impact of COVID-19, the target for CHRONOS-A was modified from 60 to 36;36 patients were randomised over 24 months from 7 sites (Nov/2019-Nov/2021). CHRONOS-B randomised 64 patients over 14 months across 6 sites (Dec/2019-Feb/2021). Median (IQR) age and PSA (ng/ml) for CHRONOS-A were 69 (65-72) years and 6 (5-7) and for 66 (60.5-70) years and 6 (4-7) for CHRONOS-B, respectively. 34/36 (94%) and 60/64 (94%) had ISUP Grade Group > / = 2, respectively. 4/18 (22%) randomised to radical in CHRONOS-A withdrew consent;1/22 (5%) randomised to focal withdrew. In CHRONOS-B, only 1/21 (5%) randomised to focal alone, and another randomised to focal with neoadjuvant bicalutamide withdrew. A qualitative recruitment intervention partially improved accrual to CHRONOS-A. Conclusions: IP4-CHRONOS evaluated patient and physician equipoise regarding focal therapy. Randomising between focal and radical therapy is not feasible due to strong patient preferences. A multi-arm, multi-stage RCT investigating the role of neoadjuvant agents combined with focal therapy is feasible.

EXPLORING ATTITUDES TO VIRTUAL GASTROENTEROLOGY CLINIC PROVISION IN THE SOUTH WEST: A REGIONAL STAFF SURVEY

Introduction The COVID-19 pandemic has forced healthcare professionals (HCPs) to rapidly alter their delivery of outpatient services. Perceived benefits include reducing unnecessary travel and waiting times. However, as one of the geographically largest training regions in the UK, we aimed to determine satisfaction levels amongst gastroenterology HCPs with the 'new normal'. Methods Satisfaction surveys were disseminated electronically across 13 acute trusts in the South West between June and August 2021. These consisted of multiple choice questions and Likert 5-scale ranking questions, ranging from 'strongly agree' to 'strongly disagree'. Virtual clinics were defined as telephone or video consultations. Results 64 HCPs from 7 trusts responded (52% consultants;23% registrars;19% nurse specialists;6% dieticians). 80% had performed phone consultations and 23% were providing video consultations. 94% of participants stated face-to-face (F2F) consultations remained their preferred mode of clinic, whilst video consultation was the least favoured for new patients. For follow-up patients, the most favoured combination was phone and F2F consultations, followed by solely F2F consultations. Less than a third of respondents strongly agreed that they would be comfortable using a computer for video consultation (32%), compared to over half when using phone instead (53%). 47% of HCPs stated virtual clinics were now the default clinic mode in their trust. The majority of respondents found it difficult to develop a rapport with remote consultations, with only 19% respondents stating this was not an issue. There was equipoise about whether time efficiency improved with virtual consultations, though 60% of respondents agreed or strongly agreed that virtually delivered clinics can reduce clinic non-attendance. Two thirds of respondents did not have a local process to identify patients who would not benefit from virtual clinics, whilst over three quarters did not have technical support to troubleshoot issues during virtual clinics (78%). Only five respondents (8%) thought it was straightforward to include an interpreter on a virtual consultation and 70.3% had difficulties including relatives on virtual calls. Conclusions Gastroenterology departments in the South West continue to adapt to delivery of virtual clinics, through a predominantly telephone format. There is consensus that followup patients do not routinely need to F2F appointments, but new patients should primarily be seen F2F. Departments should have clear protocols to identify patients that will not benefit from virtual consultations. Finally, robust strategies are required to accommodate patients whose first language is not English to ensure they are not disproportionately disadvantaged.

Patient and health practitioner views and experiences of a cancer trial before and during COVID-19: qualitative study.

BACKGROUND: Understanding patient and health practitioner perspectives on clinical trials can inform opportunities to enhance trial conduct and design, and therefore patient experience. Patients with haematological cancers have faced additional risk and uncertainty during the pandemic but it is unclear how they and practitioners have experienced cancer trials during this period. In the context of a haemato-oncology trial (PETReA), we compared patient and practitioner views and experiences of PETReA before and during COVID-19. METHODS: Qualitative study embedded within PETReA. Semi-structured interviews (N=41) with patients and practitioners from 16 NHS sites before (n=17) and during the first wave of COVID-19 (n=24). Analysis drew on the framework approach. RESULTS: Practitioners acknowledged the need for the trial to continue during the pandemic but their treatment preferences altered, becoming more pronounced for patients who had a favourable response to induction treatment, while staying unchanged for patients with a less favourable response. Practitioners commented that COVID-19 meant the evidence base for the trial arms was lacking or mixed, but that it likely increased the risks of maintenance treatment for patients with a favourable response to induction treatment. While only one participant interviewed withdrew from PETReA during the pandemic, others said they would consider withdrawing if information that they were at increased risk of severe illness from COVID-19 became available. During COVID-19, patients described less frequent contact with the trial team, which left some feeling less clear about their trial pathway. However, several described having in-depth, collaborative discussions with practitioners about the risks and benefits of randomisation in the context of COVID-19. Patients valued these discussions and were reassured by the emphasis practitioners placed on patients being free to withdraw if circumstances changed, and this helped patients feel comfortable about continuing in PETReA. CONCLUSIONS: The findings point to ways trial communication can support patients to feel comfortable about continuing in a trial during uncertain times, including adopting a more in-depth, collaborative exploration of the risks and benefits of trial arms with patients and emphasising voluntariness. The results are relevant to trialists recruiting patients who are clinically extremely vulnerable or are at increased risk of poor COVID-19 outcomes despite being vaccinated.

COMPARATIVE UTILITY OF ULTRASOUND IN KNOWN VS QUERY NEW INFLAMMATORY ARTHRITIS - A RETROSPECTIVE CASE-NOTE AUDIT

Background/Aims Ultrasound (US) imaging has become established in clinical Rheumatology practice to aid diagnosis and monitoring of inflammatory arthritis (IA). We firstly wanted to explore the utility of US in the assessment for active synovitis in subjects with known IA, but clinically uncertain disease control. Secondly we set out to compare this with the diagnostic contribution of US in patients presenting with new inflammatory joint symptoms and uncertain clinical synovitis. Methods Two contemporaneous samples of subjects were selected from consecutive, pre-Covid, Rheumatology Consultant-delivered Ultrasound Clinic lists in our department: (i) subjects with known IA where clinical disease activity was uncertain, and (ii) subjects without know IA who had symptoms with inconclusive signs of suspected IA. Both grey scale and power Doppler US imaging was used to determine a sonographic conclusion of active IA being present, absent or equivocal. Treatment changes/ decisions were ascertained from the next available clinic letter to explore diagnostic consequences following US. Results (i) In the sample of subjects with known IA (n=30, mean age 53.9 years, 63% female, RA 76.7%, all on DMARDs [20% biologics]), 43.3%(n=13) had US evidence of active IA, and 50% of inactive IA (and the remainder reported as equivocal). At clinic review (n=30) only 6 of 13 subjects with active US IA had their DMARD treatment escalated (all within same DMARD) and 5 out of 15 subjects with inactive US IA their DMARD de-escalated. (ii) In the sample of subjects with suspected IA (n=30, mean age 51.5 years, 73% female): 16.7% (n=5) had US evidence of IA and 77.7% not (and remainder reported as equivocal). At the next clinic review seven patients were commenced on DMARDs: three patients with IA on US, and 4 without. Conclusion In our department, Rheumatology clinicians appear to be referring for diagnostic US in known IA from a situation approaching clinical equipoise which would suggest optimum referral practice. If we assume that this clinical equipoise also applies to the assessment and referral practice of new patients with arthralgia but uncertain clinical synovitis, our diagnostic sensitivity of US is approximately 16.7%, meaning: six patients with suspected IA need referral for US to identify one with sonographic IA. Irrespective of this, we observed that the sonographic diagnosis in known or suspected IA is commonly not followed by a concordant treatment decision, suggesting that the US diagnosis forms only part of the diagnostic 'jigsaw' decision process.

NeuroSAFE PROOF. Update on a multi-centre, pragmatic, RCT for men undergoing robot-assisted radical prostatectomy: Trial in progress

Introduction & Objectives: Robot-assisted Radical Prostatectomy (RARP) is an effective cure for organ confined prostate cancer but is associated with considerable post-operative functional toxicity. The NeuroSAFE technique (intra-operative frozen section analysis of the neurovascular structure adjacent margin) may help improve functional outcomes by promoting optimal nerve-sparing (NS) RARP without compromising on oncological outcomes. NeuroSAFE technique has reported favourably in retrospective, single-centre studies but has never been evaluated prospectively by a randomised study. The NeuroSAFE PROOF Feasibility Study has succeeded in demonstrating feasibility and has been succeeded by the fully powered, definitive NeuroSAFE PROOF Randomized Controlled Trial (RCT) (NCT03317990). Materials & Methods: Potent men (IIEF-5>21) with localised prostate cancer at 4 regional uro-oncology centres in the UK (UCLH, Bristol, Sheffield and Glasgow) are eligible. Participants are randomised 1:1 to RARP with NS decision guided by standard of care (clinical information, DRE and pre-operative mpMRI surgical plan) vs. RARP with NS decision guided by standard of care information and the NeuroSAFE technique. The primary outcome is erectile function (EF) recovery assessed by IIEF-5 score at 12-months. Important secondary outcomes include detailed peri-operative outcomes, histological outcomes, post-operative complications, biochemical recurrence rates, urinary continence (assessed by ICIQ), health related quality of life (assessed by Rand-36 and EQ-5D-5L), and health economics. In order to demonstrate a difference of 15% in EF recovery rates between the arms, a total of 404 men will be randomised and treated. Patient follow-up will continue for 5 years after RARP. Results: At the time of writing, 160 men have been recruited and treated with RARP as per random allocation at 4 participating sites. The independent DMC has met twice to ensure the oncological safety of the trial and will continue to review the data at intervals. Covid-19 has led to significant challenges, including suspension of recruitment and difficulties performing follow-up. The trial team have developed new methods of recruitment, consent and follow-up to ensure conduct of the study remains in line with the highest standards of trial conduct, including electronic remote consent processes and remote collection of PROMs. Conclusions: The NeuroSAFE technique has been reported as a method to optimise outcomes for men undergoing RARP for over a decade, but, in the absence of Level 1 evidence, equipoise remains. Despite the Covid-19 pandemic recruitment continues to be favourable. We hope that our

Prostate pathway embedded comparative trial: The ip3-prospect study

Introduction & Objectives: The strength of evidence to support much of how we treat localized prostate cancer can be underwhelming. This is not due to a lack of trying. We have attempted many trials to assess interventions for localized prostate cancer which have unfortunately failed to accrue. There have been admirable exceptions, but many others have struggled. There are multiple reasons for this including a lack of equipoise to clinical questions posed amongst clinicians, or potential participants not wanting to sacrifice their health autonomy when joining trials. A further factor may be our reliance on the head-to-head Randomised Controlled Trial (RCT). We aimed to determine whether level-one evidence might be gathered using a novel trial design. Materials & Methods: IP3-PROSPECT (NCT04400656) is a cohort multiple RCT, designed to test multiple prostate cancer interventions from eligible men in one cohort. The design is based on the Zelen randomisation concept in which participants are randomised before consent in an effort to address accrual rates and to reduce potential bias of participants to control treatments. To address the ethical implications using of Zelen, the cmRCT design uses two points of consent. First, at point-of-consent 1, participants on invitation to the cohort, consent to being randomly invited in future to consider interventions for which they might be eligible. Later, at point-of-consent 2, participants are then randomly invited to consider interventions they are eligible for, and consent only to those they wish to. To include as broad a group of participants as possible our inclusion criteria are deliberately broad. These comprise those aged >/=18 years with a life expectancy of >/=5 years, who are referred for clinical suspicion of prostate cancer, or those in whom there is already a diagnosis of prostate cancer referred for specialist treatment. Acceptability and feasibility will be measured by a combination of quantitative and qualitative methods. The primary outcome is the rate of consent to inclusion to the IP3-PROSPECT cohort. Secondary outcomes include the completeness of data collection at sites and return rates of patient reported outcome measures using validated questionnaires. We will also interview patients and healthcare professionals to explore their thoughts on the implementation, practicality and efficiency of IP3-PROSPECT. Results: Enrolment to IP3-PROSPECT began in September 2020 and is recruiting to schedule despite the global COVID19 pandemic. 26 patients have been recruited at two centres, and four further sites are expected to open in the first half of 2021. Conclusions: The trial reports a good pace of recruitment and expects to complete in the third quarter of 2021. Interest amongst men referred for investigations of prostate cancer is high and we expect to demonstrate the feasibility of developing a cmRCT cohort of men referred for investigations of prostate cancer within the study period.

Many trials of hydroxychloroquine for SARS-CoV-2 were redundant and potentially unethical: an analysis of the NIH clinical trials registry.

OBJECTIVE: We sought to map the landscape of trials investigating hydroxychloroquine (HCQ) for SARS-CoV-2 in order to draw conclusions about how clinical trials have been conducted in the pandemic environment and offer potential regulatory recommendations. STUDY DESIGN AND SETTING: We identified and captured data related to registered studies using HCQ to treat SARS-CoV-2 registered with the publicly available National Institutes of Health (NIH) Clinical Trials Registry between February and November 2020. RESULTS: Between February and November 2020, 206 studies investigating HCQ in SARS-CoV-2 were registered with the NIH Clinical Trials Registry. As of November 2020, 135 studies were listed as ongoing, 22 have been completed, and 46 are either suspended or have been terminated. Reasons for suspension or termination included difficulties with patient recruitment (n = 9), emerging evidence showing a lack of benefit of HCQ (n = 7), and recommendations by regulatory boards to discontinue (n = 10). CONCLUSION: Many clinical trials of HCQ were launched in the first months of the pandemic, and a significant proportion of them remained active as of November 2020. The medical community appears to have responded very quickly to political interest in HCQ, while responding much more slowly to the evolving medical evidence of its lack of efficacy.

How to continue COVID-19 vaccine clinical trials? The ethics of vaccine research in a time of pandemic.

Between December 2020 and March 2021, the US Food and Drug Administration and the European Medicines Agency issued Emergency Use Authorizations and Conditional Marketing Authorizations for the distribution of the first COVID-19 vaccines. Although these vaccines were thoroughly assessed before their approval, regulators required companies to continue ongoing placebo-controlled clinical trials in order to gather further reliable scientific information on their safety and efficacy, as well as to start new studies to evaluate additional candidates. The aim of this paper is to present and discuss the ethical issues raised by the tension between the need to continue these types of clinical trials and the obligations related to the protection of the rights and well-being of research participants. Specifically, we question whether-how, and to what extent-fundamental principles governing research involving human beings can be applied to the current pandemic situation. We argue that continuing ongoing placebo-controlled clinical trials can be considered ethically justifiable only if all participants are adequately informed of any developments that may affect their willingness to remain enrolled, including the current situation of resource scarcity and the prioritization criteria established for vaccination. However, we also argue that currently approved vaccines, which are considered safe and effective enough to be administered to millions of people as part of the vaccination campaign, necessarily represent the "best proven intervention" currently available and, therefore, should be used as comparators in future studies instead of placebo.

Early COVID-19 therapy with azithromycin plus nitazoxanide, ivermectin or hydroxychloroquine in outpatient settings significantly improved COVID-19 outcomes compared to known outcomes in untreated patients.

In a prospective observational study (pre-AndroCoV Trial), the use of nitazoxanide, ivermectin and hydroxychloroquine demonstrated unexpected improvements in COVID-19 outcomes when compared to untreated patients. The apparent yet likely positive results raised ethical concerns on the employment of further full placebo controlled studies in early-stage COVID-19. The present analysis aimed to elucidate, through a comparative analysis with two control groups, whether full placebo-control randomized clinical trials (RCTs) on early-stage COVID-19 are still ethically acceptable. The Active group (AG) consisted of patients enrolled in the Pre-AndroCoV-Trial (n = 585). Control Group 1 (CG1) consisted of a retrospectively obtained group of untreated patients of the same population (n = 137), and Control Group 2 (CG2) resulted from a precise prediction of clinical outcomes based on a thorough and structured review of indexed articles and official statements. Patients were matched for sex, age, comorbidities and disease severity at baseline. Compared to CG1 and CG2, AG showed reduction of 31.5-36.5% in viral shedding (p < 0.0001), 70-85% in disease duration (p < 0.0001), and 100% in respiratory complications, hospitalization, mechanical ventilation, deaths and post-COVID manifestations (p < 0.0001 for all). For every 1000 confirmed cases for COVID-19, at least 70 hospitalizations, 50 mechanical ventilations and five deaths were prevented. Benefits from the combination of early COVID-19 detection and early pharmacological approaches were consistent and overwhelming when compared to untreated groups, which, together with the well-established safety profile of the drug combinations tested in the Pre-AndroCoV Trial, precluded our study from continuing employing full placebo in early COVID-19.

An international multicenter study of protocols for liver transplantation during a pandemic: A case for quadripartite equipoise.

BACKGROUND & AIMS: The outbreak of COVID-19 has vastly increased the operational burden on healthcare systems worldwide. For patients with end-stage liver failure, liver transplantation is the only option. However, the strain on intensive care facilities caused by the pandemic is a major concern. There is an urgent need for ethical frameworks to balance the need for liver transplantation against the availability of national resources. METHODS: We performed an international multicenter study of transplant centers to understand the evolution of policies for transplant prioritization in response to the pandemic in March 2020. To describe the ethical tension arising in this setting, we propose a novel ethical framework, the quadripartite equipoise (QE) score, that is applicable to liver transplantation in the context of limited national resources. RESULTS: Seventeen large- and medium-sized liver transplant centers from 12 countries across 4 continents participated. Ten centers opted to limit transplant activity in response to the pandemic, favoring a "sickest-first" approach. Conversely, some larger centers opted to continue routine transplant activity in order to balance waiting list mortality. To model these and other ethical tensions, we computed a QE score using 4 factors - recipient outcome, donor/graft safety, waiting list mortality and healthcare resources - for 7 countries. The fluctuation of the QE score over time accurately reflects the dynamic changes in the ethical tensions surrounding transplant activity in a pandemic. CONCLUSIONS: This four-dimensional model of quadripartite equipoise addresses the ethical tensions in the current pandemic. It serves as a universally applicable framework to guide regulation of transplant activity in response to the increasing burden on healthcare systems. LAY SUMMARY: There is an urgent need for ethical frameworks to balance the need for liver transplantation against the availability of national resources during the COVID-19 pandemic. We describe a four-dimensional model of quadripartite equipoise that models these ethical tensions and can guide the regulation of transplant activity in response to the increasing burden on healthcare systems.