Title: Urodynamics for Prostate Surgery Trial; Randomised Evaluation of Assessment Methods (UPSTREAM) for diagnosis and management of bladder outlet obstruction in men
Funder: Department of Health and Social Care

Abstract: 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) Cost-effectiveness analysis will take a societal perspective with NHS costs reported separately. Resource use will be measured from randomisation to 18 months. Health service resource use will be collected from medical records and self-completed questionnaires at baseline, 6, 12 and 18 months. Other items including travel costs and time off work/ usual activities will also be collected. The difference in costs and in effectiveness in terms of surgery rates, IPSS scores and quality-adjusted-life-years (QALYs) derived from the EQ-5D-5L questionnaire (at baseline, 6, 12 and 18 months) will be examined. Impact of differing surgery rates and harm of surgery will be assessed. Qualitative assessment; to assess acceptability, a purposeful sample of men and surgeons will be asked to participate in qualitative interviews to explore experiences of, and attitudes to, invasive urodynamic testing and its impact on surgery decision making. Interview transcripts will be analysed using iterative thematic analysis to explore issues of particular relevance and importance. Quality of urodynamic testing will be according to International Continence Society requirements. Qmax at 4 months post operation will be used as a quality measure for surgery. 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.

Lay abstract: Some men develop difficulty passing urine (voiding) as they age. This may be because an enlarged prostate gland (which sits round the base of the bladder) narrows the bladder outlet (urethra), or because the bladder becomes less able to contract. Prostate surgery is more likely to help symptoms in the first group, while the second group may have no improvement after surgery, while being exposed to risk of complications of surgery. Invasive urodynamics involves putting a tube (catheter) into the bladder via the penis, and another into the rectum, to measure bladder and abdominal pressures while the bladder is filled with a sterile fluid. Invasive urodynamics can measure bladder pressures during filling and voiding, and bladder outlet obstruction pressures. The procedure is considered safe, but some men find it uncomfortable or undignified, and a few develop urine infection afterwards. We think that it could be useful to select the men who should and should not have surgery. However, no studies have been conducted so far to tell us if this is true: UPSTREAM is designed to find out if the invasive tests are worthwhile. UPSTREAM is a randomised controlled trial in men who have bothersome difficulty passing urine and who are considering having surgery for the symptoms. The group studied will be men who continue to be bothered by difficulty passing urine, despite initial treatment such as drugs, where symptoms are thought to be due to bladder outlet obstruction. The men will be assigned at random to either invasive urodynamic tests as well as the standard tests (“Invasive urodynamics”) or to the routine standard tests (“Usual care” control arm) alone. Routine standard tests include asking men to complete a questionnaire (the International Prostate Symptom Score (IPSS)) and a bladder diary, carrying out flow rate testing, and checking the urine for infection. Some surgeons also use “discretionary tests” such as the PSA cancer-screening blood test. The following men will be invited to participate (inclusion criterion); • Men seeking further treatment for their bothersome lower urinary tract symptoms (LUTS) which may include surgery. Men will not be invited to participate (exclusion criteria) if they; • are unable to pass urine without a catheter (urinary retention) • have a relevant neurological disease, such as a stroke • are undergoing treatment for prostate or bladder cancer • have previously had prostate surgery • are not medically fit for surgery, or are unable to complete outcome assessments • do not consent to be assigned at random to one of the pathways We will compare the two methods of investigation by finding out whether the men had similar relief of their symptoms, by measuring the change in the prostate symptom score (IPSS) in the two groups at 18 months after randomisation. We will also look at the following secondary outcomes; • Whether the invasive tests changed the decision for surgery in some of the men (how many men had surgery in each of the two groups?). • The cost-effectiveness of the two management pathways. • Adverse effects of (a) the tests and (b) the treatments (e.g. urinary infection, urinary retention). • Urinary symptoms at 6, 12 & 18 months using the International Consultation on Incontinence Questionnaires (ICIQ) and the Male Lower Urinary Tract Symptoms questionnaire (ICIQ-MLUTS) • Quality of life using the IPSS-QoL question • Sexual function assessed using the ICIQ-MLUTS sex questionnaire • Satisfaction with urodynamic testing using the ICIQ-UDS-S questionnaire • The maximum urinary flow rate (Qmax) at 18 months. We worked out that 400 men would need to participate in each arm of the trial to detect a difference of one point on the IPSS, which is the main clinical measure of the symptoms. Allowing for men who do not want to participate, and who drop out once the trial starts, we would need to approach 3800 men during an 18 month recruitment period to reach the required number in each arm. The study will be supported by a Trial Steering Committee, a Patient Involvement Panel and a Data Monitoring Committee. The information will be important for men trying to decide on management of their symptoms, for the doctors advising them, and for the NHS in ensuring best use is made of resources for this common problem.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;7.3 MANAGEMENT AND DECISION MAKING
Health categories: RENAL AND UROGENITAL