Strategies to address recruitment to a randomised trial of surgical and non-surgical treatment for cancer: results from a complex recruitment intervention within the Mesothelioma and Radical Surgery 2 (MARS 2) study.

OBJECTIVES: Recruiting to randomised trials is often challenging particularly when the intervention arms are markedly different. The Mesothelioma and Radical Surgery 2 randomised controlled trial (RCT) compared standard chemotherapy with or without (extended) pleurectomy decortication surgery for malignant pleural mesothelioma. Anticipating recruitment difficulties, a QuinteT Recruitment Intervention was embedded in the main trial phase to unearth and address barriers. The trial achieved recruitment to target with a 4-month COVID-19 pandemic-related extension. This paper presents the key recruitment challenges, and the strategies delivered to optimise recruitment and informed consent. DESIGN: A multifaceted, flexible, mixed-method approach to investigate recruitment obstacles drawing on data from staff/patient interviews, audio recorded study recruitment consultations and screening logs. Key findings were translated into strategies targeting identified issues. Data collection, analysis, feedback and strategy implementation continued cyclically throughout the recruitment period. SETTING: Secondary thoracic cancer care. RESULTS: Respiratory physicians, oncologists, surgeons and nursing specialists supported the trial, but recruitment challenges were evident. The study had to fit within a framework of a thoracic cancer service considered overstretched where patients encountered multiple healthcare professionals and treatment views, all of which challenged recruitment. Clinician treatment biases, shaped in part by the wider clinical and research context alongside experience, adversely impacted several aspects of the recruitment process by restricting referrals for study consideration, impacting eligibility decisions, affecting the neutrality in which the study and treatment was presented and shaping patient treatment expectations and preferences. Individual and group recruiter feedback and training raised awareness of key equipoise issues, offered support and shared good practice to safeguard informed consent and optimise recruitment. CONCLUSIONS: With bespoke support to overcome identified issues, recruitment to a challenging RCT of surgery versus no surgery in a thoracic cancer setting with a complex recruitment pathway and multiple health professional involvement is possible. TRIAL REGISTRATION NUMBER: ISRCTN ISRCTN44351742, Clinical Trials.gov NCT02040272.

Effectiveness and cost-effectiveness of radiofrequency denervation versus placebo for chronic and moderate to severe low back pain: study protocol for the RADICAL randomised controlled trial.

INTRODUCTION: Low back pain (LBP) is the leading global cause of disability. Patients with moderate to severe LBP who respond positively to a diagnostic medial nerve branch block can be offered radiofrequency denervation (RFD). However, high-quality evidence on the effectiveness of RFD is lacking. METHODS AND ANALYSIS: RADICAL (RADIofrequenCy denervAtion for Low back pain) is a double-blind, parallel-group, superiority randomised controlled trial. A total of 250 adults listed for RFD will be recruited from approximately 20 National Health Service (NHS) pain and spinal clinics. Recruitment processes will be optimised through qualitative research during a 12-month internal pilot phase. Participants will be randomised in theatre using a 1:1 allocation ratio to RFD or placebo. RFD technique will follow best practice guidelines developed for the trial. Placebo RFD will follow the same protocol, but the electrode tip temperature will not be raised. Participants who do not experience a clinically meaningful improvement in pain 3 months after randomisation will be offered the alternative intervention to the one provided at the outset without disclosing the original allocation. The primary clinical outcome will be pain severity, measured using a pain Numeric Rating Scale, at 3 months after randomisation. Secondary outcomes will be assessed up to 2 years after randomisation and include disability, health-related quality of life, psychological distress, time to pain recovery, satisfaction, adverse events, work outcomes and healthcare utilisation. The primary statistical analyses will be by intention to treat and will follow a prespecified analysis plan. The primary economic evaluation will take an NHS and social services perspective and estimate the discounted cost per quality-adjusted life-year and incremental net benefit of RFD over the 2-year follow-up period. ETHICS AND DISSEMINATION: Ethics approval was obtained from the London-Fulham Research Ethics Committee (21/LO/0471). Results will be disseminated in open-access publications and plain language summaries. TRIAL REGISTRATION NUMBER: ISRCTN16473239.

Extended pleurectomy decortication and chemotherapy versus chemotherapy alone for pleural mesothelioma (MARS 2): a phase 3 randomised controlled trial.

BACKGROUND: Extended pleurectomy decortication for complete macroscopic resection for pleural mesothelioma has never been evaluated in a randomised trial. The aim of this study was to compare outcomes after extended pleurectomy decortication plus chemotherapy versus chemotherapy alone. METHODS: MARS 2 was a phase 3, national, multicentre, open-label, parallel two-group, pragmatic, superiority randomised controlled trial conducted in the UK. The trial took place across 26 hospitals (21 recruiting only, one surgical only, and four recruiting and surgical). Following two cycles of chemotherapy, eligible participants with pleural mesothelioma were randomly assigned (1:1) to surgery and chemotherapy or chemotherapy alone using a secure web-based system. Individuals aged 16 years or older with resectable pleural mesothelioma and adequate organ and lung function were eligible for inclusion. Participants in the chemotherapy only group received two to four further cycles of chemotherapy, and participants in the surgery and chemotherapy group received pleurectomy decortication or extended pleurectomy decortication, followed by two to four further cycles of chemotherapy. It was not possible to mask allocation because the intervention was a major surgical procedure. The primary outcome was overall survival, defined as time from randomisation to death from any cause. Analyses were done on the intention-to-treat population for all outcomes, unless specified. This study is registered with ClinicalTrials.gov, NCT02040272, and is closed to new participants. FINDINGS: Between June 19, 2015, and Jan 21, 2021, of 1030 assessed for eligibility, 335 participants were randomly assigned (169 to surgery and chemotherapy, and 166 to chemotherapy alone). 291 (87%) participants were men and 44 (13%) women, and 288 (86%) were diagnosed with epithelioid mesothelioma. At a median follow-up of 22·4 months (IQR 11·3-30·8), median survival was shorter in the surgery and chemotherapy group (19·3 months [IQR 10·0-33·7]) than in the chemotherapy alone group (24·8 months [IQR 12·6-37·4]), and the difference in restricted mean survival time at 2 years was -1·9 months (95% CI -3·4 to -0·3, p=0·019). There were 318 serious adverse events (grade ≥3) in the surgery group and 169 in the chemotherapy group (incidence rate ratio 3·6 [95% CI 2·3 to 5·5], p<0·0001), with increased incidence of cardiac (30 vs 12; 3·01 [1·13 to 8·02]) and respiratory (84 vs 34; 2·62 [1·58 to 4·33]) disorders, infection (124 vs 53; 2·13 [1·36 to 3·33]), and additional surgical or medical procedures (15 vs eight; 2·41 [1·04 to 5·57]) in the surgery group. INTERPRETATION: Extended pleurectomy decortication was associated with worse survival to 2 years, and more serious adverse events for individuals with resectable pleural mesothelioma, compared with chemotherapy alone. FUNDING: National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (15/188/31), Cancer Research UK Feasibility Studies Project Grant (A15895).