Methods and practical arrangements

Trial design

Female Urgency, Trial of Urodynamics as Routine Evaluations was a pragmatic, parallel-group, multicentre, superiority RCT designed to compare the clinical and cost-effectiveness of routine urodynamics plus CCA versus CCA only in the management of women with refractory OAB symptoms.

A qualitative component was embedded within the trial design to evaluate patients’ attitudes to, and experiences of, invasive urodynamics, and clinicians’ views on the influence of urodynamics on their decision-making for diagnosis and subsequent treatments.

Further details of the trial design have been described previously1 and are represented in Figure 1. All trial case report forms (CRFs) and participant-completed questionnaires are included in Project Documents: Trial Paperwork-CRFs and Project Documents: Trial Paperwork-Questionnaires.

FIGURE 1 Flow diagram. EQ-5D-5L, EuroQol-5 Dimensions, five-level version (Figure not reproduced here; see the original article.)

Study population

Women aged ≥ 18 years with refractory OAB or urgency-predominant MUI were included if they:

• had failed conservative management (as per NICE guidelines, e.g. PFMT/bladder retraining)
• had failed or have not tolerated pharmacological treatment (at least two different drugs) unless contraindicated
• were being considered for invasive treatment.

Women were excluded from trial entry if any of the following criteria were met: predominant SUI symptoms; previous urodynamics in the last 12 months; current pelvic malignancy or clinically significant pelvic mass; bladder pain syndrome; neurogenic bladder (e.g. Parkinson’s disease, spinal injuries, etc.); urogenital fistulae; previous treatment with BoNT-A or SNM for UI; previous pelvic radiotherapy; prolapse beyond introitus; pregnant or planning pregnancy; recurrent UTI where a significant pathology has not been excluded; and inability to give informed consent.

Consent to participate

Women with OAB or urgency-predominant MUI who fulfilled the inclusion criteria were identified at outpatient clinics or from urodynamic/outpatient waiting lists. Participant identification centres were also used to identify potential participants. Women were given/sent the patient information leaflet (PIL) (see www.fundingawards.nihr.ac.uk/award/15/150/05) and had the opportunity to discuss the study with the local clinical team, research nurse and, if appropriate, their general practitioner (GP), family and friends. Women could make the decision to participate during their initial consultation, during a subsequent hospital visit or at home. Written informed consent was obtained from all participants prior to trial entry (see www.fundingawards.nihr.ac.uk/award/15/150/05).

Health technologies being compared

Women were randomised to one of the following interventions:

1. Urodynamics plus CCA
2. CCA only.

Treatment allocation

Eligible and consenting women were randomised by the research nurses to one of the two treatment arms in a 1 : 1 allocation ratio using the randomisation application at the trial office at the Centre for Healthcare Randomised Trials (CHaRT). The randomisation application was available as a web-based application and used stratified random permuted blocks with (1) site and (2) diagnosis of OAB versus urgency-predominant MUI used as stratum.

Blinding

Baseline data were reported by participants before randomisation using self-completed questionnaires. Participants, clinical staff and the central trial team could not be blinded to the allocated procedure because of the nature of the interventions.

Intervention: Urodynamics plus comprehensive clinical assessment

This was a comprehensive invasive and non-invasive assessment of women with urinary symptoms and included:

• cystometry
• free uroflowmetry with/without pressure flow studies with/without bladder scan
• detailed medical history (assessment of urinary symptoms (storage, filling and incontinence symptoms and the most bothersome urinary symptoms), previous investigations and/or treatments (conservative, pharmacological and/or surgical) for UI and OAB and past medical or surgical history of relevance)
• clinical examination including assessment for SUI, pelvic organ prolapse and pelvic masses and other pelvic pathology
• bladder diary for 3 days to assess daytime frequency, nocturia, urgency and UUI episodes; a minimum of 24 hours completed diary was accepted as a valid diary. Diary completed at a previous clinic visit within the last 3 months was also accepted.

Standardisation of intervention

To be assured of good quality measurements and accurate urodynamic data recording, a guide for standardising urodynamics best practice (see www.fundingawards.nihr.ac.uk/award/15/150/05) was developed in conformity with the ICS Good Urodynamics Practices.69

Prior to performing the first randomised urodynamics test, collaborating units were required to undertake urodynamic machine calibration checks and submit two anonymous urodynamics traces with their reports for central reading and review by a panel of experts within the FUTURE trial team. Feedback was given to sites with any required improvement steps.

During the course of the study collaborating units were required to submit copies of the urodynamics trace/report for all participants randomised to the urodynamics arm for archiving purposes. Random central checks of traces/reports were undertaken after 10 traces/reports were submitted per unit (5 for low-recruiting units) for quality assurance (QA). When required, one-to-one feedback was provided, and closer monitoring (random central checks after five traces/reports) undertaken (further details are described in Chapter 7).

Treatment pathway following intervention

The treatment pathway following the intervention was guided by the urodynamics diagnosis and was in line with NICE guidelines25 which recommended BoNT-A as the first line treatment for refractory OAB (see www.fundingawards.nihr.ac.uk/award/15/150/05). NICE CG171 recommended BoNT-A at 200 units; however, since its publication, further evidence confirmed the efficacy of BoNT-A treatment at the lower dose of 100 units with fewer adverse events (AEs).70 Subsequent NICE guidelines (NG123) also recommended initial treatment with 100 units.3

NICE CG171 further recommended SNM treatment for patients who were unable or unwilling to perform clean intermittent self-catheterisation (CISC) or following unsuccessful BoNT-A treatment pending a local MDT discussion.25

However, in view of the lack of robust evidence on the best sequence of treatments in women with refractory OAB, participants with DO on urodynamics within FUTURE, could be offered either BoNT-A (100 units) or the SNM test; the decision was discussed in the local MDT or as per local standard best practice. This approach varied between units depending on their local clinical practice and the availability of treatments. Participants with other diagnoses on urodynamics were offered the appropriate treatments.

Depending on the clinical outcome of initial treatment, participants with persistent or de novo UI symptoms were offered further urodynamic tests and/or further/repeat treatment as appropriate (see www.fundingawards.nihr.ac.uk/award/15/150/05).

Intervention: comprehensive clinical assessment only

This was a non-invasive comprehensive intervention which included a detailed medical history, clinical examination, bladder diary (as outlined above) and PVR urine volume using ultrasound bladder scanning with/without non-invasive free uroflowmetry.

Treatment pathway following intervention

The treatment pathway following the intervention was guided by the clinical diagnosis and non-invasive tests (see www.fundingawards.nihr.ac.uk/award/15/150/05). As discussed above, participants with clinically diagnosed refractory OAB or urgency-predominant MUI could be offered either BoNT-A or the SNM test. Participants with other clinical diagnoses (such as overflow incontinence or SUI predominant MUI) were offered other appropriate treatments such as CISC, SUI surgery or other medical/conservative treatments as per local standard best practice, including MDT discussions.

Depending on the clinical outcome of initial treatment, participants with persistent or de novo UI symptoms were offered urodynamics and treatment accordingly or repeat/further treatment according to the CCA (see www.fundingawards.nihr.ac.uk/award/15/150/05).

Data collection

Participant-reported outcomes were assessed by self-completed questionnaires at baseline, 3, 6 and 15 months post randomisation (Table 1). A self-completed 3-day bladder diary was also completed at baseline, 6 and 15 months post randomisation. Up to three reminders were sent to participants by post, e-mail, phone or text message, taking into account any preferences they had for mode of communication.

Intervention data were collected on CRFs. For both arms this included data from the detailed medical history and clinical examination, as well as a baseline clinical diagnosis of OAB or urgency-predominant MUI.

For the urodynamics plus CCA arm, data were also collected from the urodynamics test, including urodynamic diagnosis, voiding assessment on free uroflowmetry and pressure flow studies (if the latter were performed) and maximum urethral closure pressure on urethral pressure profile (if performed). For the CCA arm, data were collected on the PVR urine volume using ultrasound bladder scanning (and/or non-invasive free uroflowmetry if performed).

A case-note review was also conducted by the local research team at 6 and 15 months post randomisation to collect information on treatments received, any subsequent and relevant outpatient clinic visits, investigations and treatments and AEs.

Implications of coronavirus disease-19 on data collection

The primary aim of the FUTURE trial was to assess participant-reported improvement in symptoms following treatment for OAB. However, as routine NHS treatments were initially suspended due to the coronavirus disease-19 (COVID-19) pandemic, some participants received the 15-month post-randomisation questionnaires before receiving their treatment.

Therefore, participants whose treatment had been delayed by the pandemic received an additional questionnaire at 24 months post randomisation. The questionnaire contained the same suite of questions as the 15-month post-randomisation questionnaire and followed the same reminder system. A case-note review was also conducted for these participants at 24 months post randomisation.

Where a participant completed a 24-month questionnaire in addition to a 15-month questionnaire, the participant-reported outcomes at the final time point were those from the 24-month questionnaire. Participants who received but did not complete a 24-month questionnaire had their 15-month questionnaire used as the final time point; for all other participants the final time point reported was their 15-month questionnaire. Statistical modelling of repeated measures on a participant used the 3-month, 6-month and final time points where the relevant outcomes were collected. All completed questionnaires were used to identify AEs, complications and treatments received by a participant.

Primary clinical outcome measure

The primary outcome measure was participant-reported success at the last follow-up time point (either 15 or 24 months post randomisation) as measured by the PGI-I.

The PGI-I is a validated single-item questionnaire designed to assess a participant’s impression of changes in their urinary symptoms. The PGI-I asks the participant to best describe their urinary symptoms, compared with how they were before the trial intervention, on a seven-point scale scored as: (1) ‘very much improved’, (2) ‘much improved’, (3) ‘improved’, (4) ‘same’, (5) ‘worse’, (6) ‘much worse’ or (7) ‘very much worse’. In FUTURE, ‘Success’ was defined as responses of ‘very much improved’ or ‘much improved’.

Secondary clinical outcome measures

Other outcome measures included:

• a less strict definition of success at the last follow-up time point where success was defined as responses of ‘very much improved’, ‘much improved’ or ‘improved’
• participant-reported success in the first 2 months following BoNT-A (for women who received BoNT-A only)
• proportion of women receiving invasive treatment at 6, 15 and 24 months post randomisation
• OAB symptoms measured by the ICIQ-OAB and the urgency perception scale (UPS)
• urgency and UUI episodes measured using the 3-day bladder diary
• other urinary symptoms measured using the three domains of the ICIQ-FLUTS (filling, voiding and incontinence) and the bladder diary
• general HRQoL status measured using the EuroQol-5 Dimensions, five-level version (EQ-5D-5L) and condition-specific ICIQ-LUTSQoL assessment tools
• AEs.

Economic outcome measures

Hospital resource use was gathered at study visits by reviewing medical records, while primary care and non-NHS costs were captured by patient questionnaires. The EQ-5D-5L, as described above, was used to calculate QALYs for the cost-effectiveness analysis. Further details are given in Chapter 5.

Safety reporting

In FUTURE, only AEs and serious adverse events (SAEs) related to the trial interventions were recorded. A SAE was defined as any AE that: resulted in death; was life threatening; resulted in persistent or significant disability or incapacity; required hospitalisation or prolongation of existing hospitalisation; or was otherwise considered medically significant by the investigator.

All AEs and SAEs meeting the criteria for recording within the trial were recorded from the time a participant consented to join the trial until the end of their follow-up period. Every follow-up visit and questionnaire asked about AEs/SAEs. In addition, open-ended and non-leading verbal questioning of the participant was used to enquire about AE/SAE occurrence.

Depending on severity, when an AE/SAE that met the criteria for recording within the FUTURE trial occurred, it was the responsibility of the local principal investigator (PI) (or delegate) to review appropriate documentation (e.g. hospital notes, laboratory and diagnostic reports) related to the event. The PI or delegate recorded all relevant information in the CRF (and on the SAE form if required).

Principal investigator or delegates were responsible for notifying the trial office of any SAEs that required to be recorded in line with the FUTURE trial protocol. If a SAE was recorded on a participant questionnaire, the trial office liaised with the relevant research site to obtain further information.

When a SAE form was uploaded onto the trial website, the Trial Manager was automatically notified. If, in the opinion of the local PI and/or the chief investigator, the event was confirmed as being serious, related and unexpected, the chief investigator or trial manager would notify the trial co-sponsors University of Aberdeen/NHS Grampian (NHSG) within 24 hours of receiving the signed SAE notification. The sponsor would then provide an assessment of the SAE. The sponsor could not downgrade an assessment from the PI or chief investigator. Any disparity would be resolved by further discussion between the parties.

The chief investigator or delegate would also report any related and unexpected SAEs to the Research Ethics Committee (REC) within 15 days of the chief investigator becoming aware of the event.

Sample size

A survey of the collaborating units showed that in clinical practice most women with refractory OAB are initiated on BoNT-A treatment (60–70%) compared to SNM (15–20%) or other/no treatments (10–25%). In addition, Rovner et al. and Chapple et al. both showed a success rate of around 60% in women with refractory OAB without the urodynamics diagnosis of DO.50,51 These two studies defined success differently: Chapple et al. assessed participant-reported success at 12 weeks following injection of 100 units BoNT-A and defined success as ‘greatly improved’ or ‘improved’;51 Rovner et al. used a dose of 300 units and defined success as no UUI episodes recorded in a 7-day diary recorded at 12 weeks post treatment.50

A consensus was also established amongst clinicians and their patient and public involvement groups (PPI) that for urodynamics to be worthwhile, it would need to demonstrate a minimum of 10% superiority over CCA only. For 90% power and a 5% level of significance, 986 participants (493/group) were needed using a chi-squared test with continuity correction,71,72 rising to 1096 (or 548/group) to allow for 10% attrition at 15 months post randomisation.

Statistical analysis

Analyses were conducted using Stata version 17 (StataCorp LP, College Station, TX, USA).73 Primary and secondary outcomes were compared using generalised linear models (GLMs), with adjustment for the minimisation covariates (site and diagnosis of OAB vs. urgency-predominant MUI).

The statistical analysis of the primary outcome was based on the intention-to-treat (ITT) principle, analysing women in the groups to which they were randomised. A per protocol analysis was also included as a secondary supporting analysis (see Report Supplementary Material 1).

The primary outcome was participant-reported success as measured by the PGI-I at the last follow-up time point. For the primary analysis, the PGI-I responses were dichotomised to ‘success’ defined as ‘very much improved’ or ‘much improved’. A repeated-measures mixed-effects logistic regression was used, including the 6-month measurement to increase the power to estimate the treatment effect at the last follow-up time point.

Secondary outcomes were analysed using the appropriate linear model. For example, the less strict definition of success was analysed using a repeated-measures mixed-effects logistic regression in the same way as the primary outcome was analysed. The proportion of women receiving invasive treatment was analysed using a logistic regression. Continuous outcomes such as ICIQ-FLUTS and EQ-5D-5L were analysed using a repeated-measures mixed-effects linear regression.

Economic evaluation

The economic analysis consisted of a within-trial analysis of individual participant-level cost and effect (QALY) and a patient lifetime analysis to inform cost-effectiveness in the longer term. See Chapter 5 for a detailed description of the methods used.

Qualitative research

Semistructured interviews were conducted with participants and clinicians and analysed according to the principles of thematic content analysis. See Chapter 6 for a detailed description of the methods used.

Urodynamic quality assurance

A QA process was developed to ensure good-quality measurements and accurate urodynamics data recording. See Chapter 7 for a detailed description of the methods used.

Management of the trial

The trial management team, based within CHaRT, provided day-to-day support for the recruiting sites led by a local PI. PIs, supported by dedicated research nurses, were responsible for all aspects of local organisation including recruitment of participants, delivery of the interventions and notification of any problems or unexpected developments during the trial period.

The trial was supervised by the project management group (PMG), which consisted of grant holders (clinicians, statisticians, health economists and qualitative researchers) and representatives from the Trial Office. The PMG met approximately every 2–3 months throughout the trial duration.

Oversight of the trial

Trial Steering Committee

A Trial Steering Committee (TSC) was established at the onset of the trial to oversee its conduct and progress. The TSC met seven times between October 2017 and February 2023 (approximately annually) and consisted of an independent chair, independent clinical and methodological experts, an independent patient representative and key members of the PMG. The independent members of the TSC are listed in the Acknowledgements.

Data-Monitoring Committee

An independent data monitoring committee (DMC) was established at the onset to oversee the safety of participants in the FUTURE trial. The committee met eight times between September 2017 and February 2023 at agreed intervals to monitor the trial data and make recommendations as to any required modifications to the protocol or the termination of all or part of the trial. It consisted of three independent experts, who are listed in the Acknowledgements.

Changes to the trial protocol

There were 10 protocol amendments during the lifetime of the project, most of which were minor clarifications. Amendments included a change to the randomisation algorithm from minimisation to stratified permuted blocks (prior to the first randomisation), an extension to the recruitment period due to a slower than expected recruitment rate and the COVID-19 pandemic, inclusion of an additional time point (24 months post randomisation) for those participants whose treatments have been delayed due to the pandemic, and conversion from written consent to verbal consent for the qualitative interviews. A summary of all changes can be found in the published protocol.1

All amendments were reviewed by the sponsor and funder before being submitted to and approved by the REC (where appropriate).