Feasibility of Comparative Health Research Outcome of Novel Surgery in prostate cancer (IP4-CHRONOS): statistical analysis plan for the randomised feasibility phase of the CHRONOS study

Abstract

Background Randomised controlled trials (RCTs) for surgical interventions have often proven difficult with calls for innovative approaches. The Imperial Prostate (IP4) Comparative Health Research Outcomes of Novel Surgery in prostate cancer (IP4-CHRONOS) study aims to deliver level 1 evidence on outcomes following focal therapy which involves treating just the tumour rather than whole-gland surgery or radiotherapy. Our aim is to test the feasibility of two parallel RCTs within an overarching strategy that fits with existing patient and physician equipoise and maximises the chances of success and potential benefit to patients and healthcare services. Methods and design IP4-CHRONOS is a randomised, unblinded multi-centre study, including two parallel randomised controlled trials targeting the same patient population: IP4-CHRONOS-A and IP4-CHRONOS-B. IP4-CHRONOS-A is a 1:1 RCT and the other is a multi-arm, multi-stage (MAMS) RCT starting with three arms and a 1:1:1 randomisation. The two linked RCTs are discussed with patients at the time of consent and the choice of A or B is dependent on physician and patient equipoise. The primary outcome is the feasibility of recruitment, acceptance of randomisation and compliance to allocated arm. Results This paper describes the statistical analysis plan (SAP) for the feasibility study within IP4-CHRONOS given its innovative approach. Version 1.0 of the SAP has been reviewed by the Trial Steering Committee (TSC), Chief Investigator (CI), Senior Statistician and Trial Statistician and signed off. The study is ongoing and recruiting. Recruitment is scheduled to finish later in 2021. The SAP documents approved methods and analyses that will be conducted. Since this is written in advance of the analysis, we avoid bias arising from prior knowledge of the study data and findings. Discussion Our feasibility analysis will demonstrate if IP4-CHRONOS is feasible in terms of recruitment, randomisation and compliance, and whether to continue both A and B or just one to the main stage. Trial registration ISRCTN ISRCTN17796995. Registered on 08 October 2019

Cryotherapy for partial gland ablation of prostate cancer: Oncologic and safety outcomes

“… 42 A randomized trial CHRONOS, now in early stages in England, is expected by 2027 to provide Level 1 evidence regarding PGA of prostate cancer. 43 …”

“…Moreover, a recent study from Oxford University raises the possibility that cancer genomics (“unappreciated molecular relationships between histologically benign and cancerous regions”) may disrupt the current focal‐therapy paradigm 42 . A randomized trial CHRONOS, now in early stages in England, is expected by 2027 to provide Level 1 evidence regarding PGA of prostate cancer 43 …”

“…42 A randomized trial CHRONOS, now in early stages in England, is expected by 2027 to provide Level 1 evidence regarding PGA of prostate cancer. 43 AUTHOR CONTRIBUTIONS Mamdouh Aker: Conceptualization (lead); data curation (lead); formal analysis (equal); investigation (equal); methodology (equal); project administration (equal); resources (equal); software (equal); supervision (equal); validation (equal); visualization (equal); writing -original draft (lead); writing -review and editing (lead). Wayne Brisbane: Conceptualization (lead); data curation (equal); formal analysis (equal); funding acquisition (equal); investigation (equal); methodology (equal); project administration (equal); resources (equal); software (equal); supervision (equal); validation (equal); visualization (equal); writing -original draft (equal); writing -review and editing (equal).…”

Focal therapy for prostate cancer: what is really needed to move from investigational to valid therapeutic alternative?—a narrative review

“…Hence, due to the numerous failures of ‘traditional’ RCTs in localised PCa, the Imperial Prostate (IP4) Comparative Health Research Outcomes of Novel Surgery in prostate cancer (IP4-CHRONOS) was established to deliver FT oncological outcomes by using an innovative RCT framework ( 48 ). It does so by running two separate parallel RCTs where on one side a ‘traditional’ head-to-head RCT comparing FT to radical treatment is assessed, and on the other, for those who express a strong preference for focal therapy, a surgical multi-arm, multi-stage (MAMS) RCT.…”