Urodynamics for Prostate Surgery Trial; Randomised Evaluation of Assessment Methods (UPSTREAM) for diagnosis and management of bladder outlet obstruction in men

The UPSTREAM project consists of two phases, “UPSTREAM – Phase I” and “UPSTREAM – Phase II”. Below are details for each phase. “UPSTREAM – Phase I” DESIGN; A two-arm controlled trial randomising men with bothersome lower urinary tract symptoms (LUTS), for whom surgeons would consider offering surgery, between a care pathway based on urodynamic tests with invasive multichannel cystometry (“Invasive urodynamics” interventional arm) and a care pathway based on non-invasive tests, i.e. without multichannel cystometry (“Usual care” comparator arm). Diagnostic pathways and thresholds of testing were informed by our recent survey of 30 UK surgeons. The minimum dataset comprises International Prostate Symptom Score (IPSS), maximum urinary flow rate (Qmax) with post-void bladder scan, bladder diary and urinalysis. SETTING; Urology departments of 26 NHS Hospitals TARGET POPULATION; Men with bothersome LUTS and suspected bladder outlet obstruction for whom surgeons would potentially offer surgery. INCLUSION CRITERION; 1. Men seeking further treatment for their bothersome LUTS which may include surgery. EXCLUSION CRITERIA; 1. Unable to pass urine without a catheter (urinary retention) 2. Relevant neurological disease 3. Undergoing active treatment, or on active surveillance, for prostate or bladder cancer 4. Previous prostate surgery 5. Not medically fit for surgery, or unable to complete outcome assessments 6. Men who do not consent to be randomised HEALTH TECHNOLOGIES BEING ASSESSED; Invasive urodynamics, in which catheters are used to measure bladder and abdominal pressures during bladder filling and passing urine, as a test for recommending surgery to relieve outlet obstruction (e.g. transurethral resection of prostate; TURP). Invasive urodynamics is used to calculate voiding parameters (bladder outlet obstruction index, contractility) and assess urine storage (detrusor overactivity, bladder capacity). Hence, it can distinguish men with bladder outlet obstruction, who should benefit from surgery to relieve obstruction, from men with reduced bladder contractility, who are unlikely to benefit from surgery. Without invasive urodynamics, usual care relies on the presumption of outlet obstruction based on voiding symptoms and a reduced flow rate (Qmax). OUTCOME AND COST MEASURES; • Primary outcome: difference in LUTS between the two arms at 18 months, measured with the International Prostate Symptom Score (IPSS). Secondary outcomes; • Surgery rate (the relative proportion of men in each group having surgery up to 18 months after randomisation) • Cost-effectiveness • Adverse events of testing and treatment (e.g. infection, urinary retention) • Quality of life (QoL) and LUTS at 6, 12 and 18 months, using the IPSS QoL and the International Consultation on Incontinence Questionnaires on Male LUTS (ICIQ-MLUTS) and sexual function in LUTS (ICIQ-MLUTSsex). • Qualitative assessment • Maximum urinary flow rate (Qmax) at 18 months • Satisfaction with urodynamic testing (ICIQ-UDS-S) SAMPLE SIZE; calculated on the outcomes; non-inferiority of symptoms from baseline to 18 months after randomisation and reduction in surgery rates in the intervention arm. Audit data for 5670 men from the Bristol trial centre suggests 73%-83% have surgery. If an invasive urodynamics test was conducted on the same men we predict that surgery would only be done in 60%, based on the prevalence of impaired bladder contractility. Using the more conservative difference we expect the intervention to reduce surgery from 73% in usual care to 60% in the intervention arm. A two group continuity corrected chi square test with a 5% two-sided significance level will have 90% power to detect such a difference when the sample size in each group is 291. Symptom scores will improve for those men in both arms who undergo appropriate surgery. For the men in the usual care arm presumed to have outlet obstruction incorrectly (due to less comprehensive testing) who undergo surgery, published research shows the effect on symptoms is uncertain. Symptom scores of the non-operated groups should be similar. We therefore anticipate the overall IPSS at 18 months in both arms could be similar. Assuming a mean difference in IPSS in the intervention arm of not more than one below the mean IPSS in the usual care arm, 310 men per arm will give us 80% power to test non-inferiority using a one-sided t-test (common standard deviation of 5) at the 5% significance level. In 14 centres (original proposal), each doing 120-450 TURPs annually, approximately 3800 men will undergo TURP in an 18 month period. Around 50% will be eligible (n=1900) and we assume 40% will consent to randomisation. A feasibility phase of 3 months in 3 centres will ascertain whether full recruitment is achievable. We aim to recruit around 400 men per arm which allows for just over 20% attrition. Our previous experience suggests attrition will be nearer 10%, which would give 96% power to detect a difference in surgery rates and 84% power to detect equivalence in symptoms. TIMETABLE; The 54 months duration (i.e. 01 April 2014 to 30 September 2018) comprises 6 months setting up, 27 months recruitment, 18 months follow-up and 3 months data analysis, dissemination and publication. The trial will be supported by a Steering Committee, Data Monitoring Committee and Patient Involvement Panel. “UPSTREAM – Phase II (Further Follow Up Study)” DESIGN; Further follow up (five years post-randomisation) of the UPSTREAM randomised controlled trial (RCT). SETTING; Data collection is via patient reported outcome measures (PROMS; questionnaires) and data extraction via central NHS records (e.g. NHS Digital linked data). Thus, it is not necessary for men to return to their local Hospital, nor will they (or the coordinating research team) require contact with their Urology clinical care team. The central (coordinating) research team based at the Bristol Randomised Trials Collaboration (BRTC), as part of the Bristol Trials Centre (BTC), will be responsible for coordinating and delivering the study components. North Bristol NHS Trust will have oversight of data collection and responsibility for reporting through the NIHR. TARGET POPULATION; Existing participants of the UPSTREAM RCT (UPSTREAM - Phase I). INCLUSION / EXCLUSION CRITERION; Inclusion/exclusion criteria for this further follow up study (UPSTREAM - Phase II) differs between the ‘PROM’ (questionnaire) component and the ‘NHS Digital data extraction’ component. To summarise why; all men who enrolled in the UPSTREAM trial (Phase I) provided written informed consent, which included the essential statement “I agree that information relevant to the UPSTREAM study may be collected from my hospital and NHS records, including Office of National Statistics (ONS), NHS central registers and the Health and Social Care Information Centre, and that this data may be used to follow my ongoing health after the study”. Thus, additional (‘new’) consent is not required to request data via NHS Digital for the purpose of this study. The statement “I am willing to be contacted in the future for long-term follow-up”, however, was optional. These differences influence trial procedures, so the inclusion and exclusion criteria for each component are detailed in the trial Protocol (UPSTREAM – Phase II Protocol, v1.0, 21/10/2019). AIMS; The aim of this second phase of the UPSTREAM project (UPSTREAM - Phase II) is to undertake the longer term follow up of UPSTREAM participants at five years post-randomisation. We aim to identify: the symptom outcomes of treatment; definitive surgery rates in the two study arms; and the long-term impact of lower urinary tract symptoms (LUTS) and its therapy. The focus will continue to be on effectiveness and patient outcomes as per the original commissioning brief. OUTCOMES AND MEASURES; •LUTS will be measured with the widely-used patient reported outcome, the International Prostate Symptom Score (IPSS), at five years post-randomisation. •Measures from the International Consultation on Incontinence Questionnaires (ICIQ) will also be used, giving sensitive and comprehensive assessment of LUTS severity/ bother, sexual function and quality of life (QoL), i.e.: IPSS QoL, ICIQ Male LUTS (ICIQ-MLUTS), ICIQ sexual function in Male LUTS (ICIQ-MLUTS-sex). •The EQ-5D-5L will be used to provide the QoL weights used to calculate Quality Adjusted Life Years (QALYs). •Data for: Surgery rates (the relative proportion of men in each group having surgery up to five years post-randomisation); diagnostic testing after the main trial (where possible); and resource use will be obtained via a one-off bespoke data extraction of Health Episode Statistics (HES) and HES-Office of National Statistics (ONS) linked data, via NHS Digital. This will include individual level data about participants’ relevant: inpatient stays; outpatient attendances: including procedures; radiology and accident and emergency (A&E) episodes; and cause of death (where applicable). TIMETABLE; The start date for this second phase of UPSTREAM (UPSTREAM - Phase II) is 01 July 2019, and the study duration is expected to be 36 months, to 30th June 2022; this period represents months 64 – 99 (inclusive) of the overall UPSTREAM project. This phase of the project will be supported by a Steering Committee, Patient Involvement Panel and a Project Management Group.