Clinical results

This chapter compares the clinical outcomes of urodynamics plus CCA versus CCA only at 3 months, 6 months and the final follow-up time point, which was either 15 or 24 months post randomisation, as detailed in Chapter 2.

Flow of participants through the trial

The CONsolidated Standards of Reporting Trials (CONSORT) diagram shows the number of participants providing data at each stage of the trial (Figure 4). There were 1103 participants randomised into the trial. Following randomisation, four participants were considered post-randomisation exclusions: three from the group randomised to urodynamics plus CCA (referred to as the urodynamics arm) and one from the group randomised to CCA only (referred to as the CCA only arm). This chapter reports the results from the remaining 1099 women.

FIGURE 4 Consolidated Standards of Reporting Trials diagram. (Figure not reproduced here; see the original article.)

Response rates to questionnaires are based on the numbers of participants randomised after accounting for post-randomisation exclusions. Completion rates of the participant questionnaires from 6 months onwards are above 90% (response rates are reported in the CONSORT diagram; see Figure 4). Participant-reported primary outcome data could not be collected from 53 participants who declined further follow-up (n = 48) or died (n = 5) during the follow-up period.

Intervention details

Of the 1099 participants included in the analysis, 491/550 (89.3%) randomised to urodynamics and 522/549 (95.1%) randomised to CCA only received the allocated assessment (intervention). Of those randomised to CCA only, 8 participants (1.5%) underwent urodynamics, whereas 13 participants randomised to urodynamics (2.4%) received CCA only. The remaining 65 participants (46 in the urodynamics arm and 19 in the CCA only arm) did not receive either intervention.

In both arms, participants underwent a detailed clinical assessment as per NICE guidelines3 and standard clinical practice in each of the collaborating sites. This included a detailed history-taking, abdominal and pelvic examination and a 3-day bladder diary.

In their clinical assessment, many clinicians/hospitals adopted the FUTURE trial purposely designed bladder diaries, while some used their standard bladder diaries to avoid duplication and reduce participant burden. The results of the bladder diaries in both arms are presented later in the chapter.

Urodynamics

Uroflowmetry

Table 4 shows that the uroflowmetry performed as part of the urodynamics assessment (392 participants in the urodynamics arm and 5 participants in the CCA only arm) was mostly conducted by either a nurse (229/397; 57.7%) or a hospital specialist (154/397; 38.8%). The operator’s impression of the uroflowmetry voiding pattern for two-thirds of the procedures was normal (275/397; 69.3%).

The median voided volume was 121 ml for those randomised to urodynamics [interquartile range (IQR) 57–233 ml] and 101 ml (IQR 51–225 ml) for those randomised to CCA only, and the PVR were 10 ml (IQR 0–40 ml) and 2 ml (IQR 0.5–16.5 ml) respectively. PVR urine volume was > 100 ml in 12.3% of participants undergoing uroflowmetry as part of the urodynamics assessment (compared to 12.6% of women in the CCA only arm with PVR > 100 ml on bladder scan).

Filling and voiding cystometry

For the participants who received cystometry as part of the urodynamic assessment (489 participants in the urodynamics arm and 7 participants in the CCA only arm), the procedure was mainly performed by a nurse (304/496; 61.3%) or staff doctor/specialist (199/496; 40.1%).

Of those randomised to urodynamics, 68 (13.9%) had a filling rate < 50 ml/minute, 306 (62.6%) had a filling rate ≥ 50 and < 100 ml/minute, and 100 (20.4%) had a filling rate of 100 ml/minute or above.

Participants in the urodynamics arm reported their first desire to void at a median of 118 ml (IQR 71–185 ml) and a strong desire to void at a median of 232.7 ml (IQR 155–339 ml). In terms of the maximum cytometric capacity, the median volumes were 347 ml (IQR 253–432.6). The operator’s impression of the voiding pattern was normal in 71% of the cases (347/489).

Following urodynamics, 57.7% of the women were diagnosed with DO or detrusor overactivity incontinence (DOI) and 8.0% were diagnosed with urodynamic MUI. Thirteen per cent had USI, while 21% had neither DO/DOI nor USI on urodynamics. Hence, in women with clinical refractory OAB/MUI, urodynamics did not show evidence of DO in 34% of women.

When adjusted for the baseline clinical diagnosis:

• In the group of participants with a baseline diagnosis of OAB, their diagnosis following urodynamics was DO/DOI in 62.3% of cases, MUI in 6.2%, no evidence of USI or DO in 21.9% and USI in 8.3% of cases. Hence, in women with clinical refractory OAB, urodynamics did not show evidence of DO in 30% of women.
• In the group of participants with a baseline diagnosis of urgency-predominant MUI, their diagnosis following urodynamics was DO/DOI in 48.6% of cases, MUI in 10.9%, no evidence of USI or DO in 18.3% and USI in 21.7% of cases. Hence, in women with clinical refractory MUI, urodynamics did not show evidence of DO in 40% of women.

It is notable that USI was diagnosed following urodynamics in 8.3% and 21.7% of women with a baseline diagnosis of OAB and urgency-predominant MUI respectively. This diagnosis would lead to a change in their management plan according to the national and international clinical guidelines and the FUTURE trial treatment pathways.

Comprehensive clinical assessment

Uroflowmetry

For the participants who received uroflowmetry as part of the CCA (3 participants in the urodynamics arm and 257 participants in the CCA only arm), the procedure was primarily conducted by either a nurse (175/260; 67.3%) or a hospital specialist (78/260; 30.0%) and the operator’s impression of the voiding pattern was normal in approximately three-quarters of the cases (198/260; 76.2%) (see Table 4).

The median voided volume was 176 ml for those randomised to CCA only (IQR 103–282 ml) and 170 ml (IQR 162–188 ml) for those randomised to urodynamics, and the PVRs were 20 ml (IQR 0–55 ml) and 0 ml (IQR 0–20 ml), respectively. PVR urine volume was > 100 ml in 15.4% of participants in the CCA only arm.

Bladder scan

Three hundred and fifty-two women (3 women in the urodynamics arm and 349 women in the CCA only arm) underwent a bladder scan as part of their intervention. The median voided volume was 150 ml for those randomised to CCA only (IQR 75–220 ml) and 188 ml for the women randomised to urodynamics, and the PVRs were 10 ml (IQR 0–49 ml) and 0 ml, respectively. PVR urine volume was > 100 ml in 12.6% of those undergoing a bladder scan (see Table 4).

Following CCA, 63% were diagnosed with OAB/UUI; 33% had urgency-predominant MUI; 1% SUI and 3% other diagnoses.

Primary outcome: participant-reported success rates

The primary outcome was the proportion of participants who reported success at their final follow-up time point (15 or 24 months post randomisation). Success was a participant response of either ‘very much improved’ or ‘much improved’ to the question ‘How would you describe your urinary/bladder problems (urgency and/or incontinence) now compared to when you joined the study?’ on the PGI-I assessment tool [i.e. comparing their symptoms in the last 2 weeks (at time of completing the questionnaire) to their symptoms on the day they were randomised]. All other responses to this question (‘improved’, ‘same’, ‘worse’, ‘much worse’ and ‘very much worse’) were considered as unsuccessful.

At the final follow-up time point, 117 participants (23.6%) in the urodynamics arm and 114 participants (22.7%) in the CCA only arm reported success as ‘very much improved’ or ‘much improved’ (Table 5). The adjusted OR was 1.12 (95% CI 0.73 to 1.74; p = 0.601); that is, no significant difference between the groups. The per protocol success rates [113 (24.9%) vs. 111 (23.0%)] and effect sizes [1.22 (95% CI 0.78 to 1.91); p = 0.390] were similar to the ITT estimates. These results confirm that in women with refractory OAB/urgency-predominant MUI, the participant-reported success rates following treatment in participants who underwent urodynamics and CCA were not superior to those who underwent CCA only.

The success rates and effect sizes at 3 and 6 months favour CCA only, but this can be explained by the additional investigation delaying treatment for those randomised to urodynamics.

Sensitivity analysis

Figure 5 shows the sensitivity analysis of the participant-reported success on the PGI-I for the ITT population. The forest plot shows the observed effect as being consistent with the effect sizes obtained under multiple imputation and when all missing primary outcome data are assumed to be unsuccessful and then when all missing primary outcome data are assumed to be success. The only instances where the observed effect is not consistent with the imputation effects are in the extreme cases when all missing primary outcome data are assumed to be a success for those undergoing urodynamics but unsuccessful for those undergoing CCA only and vice versa.

FIGURE 5 Sensitivity analysis forest plot (ITT population). (Figure not reproduced here; see the original article.)

Secondary outcomes

Less strict definition of participant-reported success

A ‘less strict definition of success’ which included participant response of ‘improved’, ‘much improved’ and ‘very much improved’ was analysed as a secondary outcome. Inclusion of ‘improved’ had the effect of increasing the number of women reporting success in both the urodynamic arm [217 women (43.8%)] and the CCA only arm [209 women (41.6%)]. However, the effect size at the last follow-up time point was similar, at 1.14 (95% CI 0.79 to 1.65); p = 0.469 (see Table 5). This further confirms the robustness of results of the primary outcome.

Participant-reported success for those receiving botulinum toxin injection A

The most commonly utilised treatment in the FUTURE trial was BoNT-A, with 620 women receiving this treatment.

Restricting the PGI-I assessment to only those women receiving BoNT-A, the participant-reported success rate using the primary definition of success (‘very much improved’ and ‘much improved’) at the 3-month time point favoured the CCA only arm. However, at the final follow-up questionnaire time point, there were no significant differences: 36.7% versus 31.0% [OR: 1.40 (95% CI 0.87 to 2.23); p = 0.164] in the urodynamics arm and the CCA only arm, respectively (Table 6). Using the less strict definition of success (inclusion of ‘improved’), once again significantly more women in the CCA only arm reported a successful outcome at 3-month follow-up. However, at the final time point, the participant-reported success rate favoured the urodynamics arm: 61.4% versus 51.8% [OR 1.63 (95% CI 1.09 to 2.45); p = 0.018] in the urodynamics arm and the CCA only arm, respectively (see Table 6).

In participants receiving BoNT-A treatment, the fixed time points for assessment may have had an impact on the study results primarily due to the temporal effect of BoNT-A, where treatment tends to start waning 4 to 6 months post treatment. Hence, these fixed assessment time points may miss the peak effect of BoNT-A treatment. Therefore, in the final follow-up questionnaire, the group of women who received BoNT-A were asked an extra question to describe their PGI-I outcome ‘2 months following treatment’. The women’s responses to this question can therefore be the best representative of the participant-reported success rates for the subgroup who received BoNT-A treatment.

Using the primary definition of success on the PGI-I (‘very much improved’ and ‘much improved’), the participant-reported success rate was 63.8% versus 60.0% [OR: 1.17 (95% CI 0.73 to 1.89); p = 0.518] in the urodynamics arm and the CCA only arm, respectively (see Table 6). Using the less strict definition of success (inclusion of ‘improved’) the participant-reported success rate was 83.3% versus 76.4% [OR: 1.47 (95% CI 0.82 to 2.63); p = 0.195] in the urodynamics arm and the CCA only arm, respectively (see Table 6). The results indicate no evidence of significant differences in participant-reported success rates following BoNT-A treatment between the two groups. These results provide further reassurance in the primary outcome analyses.

Pre-planned subgroup analyses of the primary outcome

The participant-reported success rates within the subgroups (baseline clinical diagnosis of OAB vs. urgency-predominant MUI) are shown at 3 and 6 months and the final follow-up time point in Table 7. At 3-month follow-up, women in the CCA only arm had significantly higher participant-reported success rates in both subgroups (see Table 7). However, at the final time point the difference in both subgroups was not significant. This is best explained by the time to receiving treatment, which is shorter in the CCA arm as they did not have to wait to undergo urodynamics. The mean time to receiving the first dose of BoNT-A was 234.3 days in the urodynamics arm compared to 188.4 days in the CCA arm; that is, women in the CCA only arm have the opportunity to start to feel improvement in their symptoms earlier.

The urodynamic effects plotted in Figure 6 further show the subgroup effects at the final follow-up time point. The ORs of 1.14 (99% CI 0.33 to 3.90; p = 0.788) and 1.07 (99% CI 0.39 to 2.95; p = 0.861) for the original and less strict definitions of success, respectively, show that there is no evidence of a significant difference in the impact of urodynamics between participants with baseline clinical diagnosis of OAB compared to urgency-predominant MUI.

FIGURE 6 Subgroup analysis according to baseline diagnosis of OAB vs. urgency-predominant MUI at the final time point (ITT population). (Figure not reproduced here; see the original article.)

Undertaking the same subgroup analysis in participants who received BoNT-A treatment, the participant-reported success rates were not significantly different between the groups. In participants with a clinical diagnosis of OAB at baseline, the participant-reported success rates were 61/98 (62.2%) in the urodynamics arm versus 66/109 (60.6%) in the CCA only arm [OR 1.07 (99% CI 0.50 to 2.28); p = 0.816], while in participants with a baseline diagnosis of urgency-predominant MUI, the participant-reported success rates were 27/40 (67.5%) in the urodynamics arm and 33/56 (58.9%) in the CCA only arm [OR 1.44 (99% CI 0.45 to 4.56); p = 0.416].

The difference between the OAB and urgency-predominant MUI groups was non-significant [OR 0.74 (99% CI 0.19 to 2.96); p = 0.581], indicating that among participants who underwent BoNT-A treatment, urodynamics appears to be more effective in the urgency-predominant MUI group compared to OAB. However, the difference was not significant.

Urinary symptoms

The International Consultation on Incontinence Questionnaire female lower urinary tract symptoms

The ICIQ-FLUTS scores in the filling, voiding and incontinence domains improved from baseline to the final follow-up time point in both groups. The ICIQ-FLUTS voiding domain score increased by a small amount across the time points in both groups; therefore, there was no evidence of an improvement in voiding in both groups and no significant differences between groups [mean difference 0.2 (95% CI −0.1 to 0.6); p = 0.142]. For the ICIQ-FLUTS incontinence domain, the scores improved at the final time point compared to baseline, indicating improvement in both groups. However, there was no evidence of significant differences between the groups [mean difference −0.2 (95% CI −0.8 to 0.4); p = 0.512]. There was a difference for the ICIQ-FLUTS filling domain score: at the final follow-up point, the effect size was significant, with a small difference favouring urodynamics [mean difference −0.44 (95% CI −0.86 to −0.03); p = 0.036] (Table 8). This may indicate better filling-phase symptoms (such as urgency) in the urodynamics arm, but the level of certainty and the clinical significance are debated, especially since similar results were not shown when analysing the urgency perception symptom questionnaire.

International Consultation on Incontinence Questionnaire overactive bladder

ICIQ-OAB scores showed that across the trial, women in both groups reported a slight improvement in symptoms. At 3 and 6 months post randomisation, participants in the urodynamic arm reported poorer outcomes than those in the CCA only arm, although the difference was only small and there was no evidence of a significant difference. At the final follow-up time point, participants in the urodynamic arm reported a slightly better outcome than those in the CCA only arm, although the wide CI indicates the difference was not significant [mean difference −0.4 (95% CI −0.9 to 0.0); p = 0.063] (see Table 8).

Urgency perception

At baseline over two-thirds of participants in each group perceived their urgency as severe. This percentage decreased over time and at the final follow-up time point, 42.3% and 42.9% of participants reported severe urgency in the urodynamics and CCA only arm, respectively, while 25.6% and 22.6% reported no/mild urgency, respectively (Table 9).

At the 3-month time point, significantly more participants in the urodynamics group reported urgency compared to those in the CCA only group [OR 1.62 (95% CI 1.13 to 2.33); p = 0.009]. However, by the final follow-up time point, the effect was not significant [OR 0.87 (95% CI 0.63 to 1.21); p = 0.423] (see Table 9).

Table 9 further describes the change in urgency from baseline. At both 3 and 6 months post randomisation, participants in the CCA only arm were more likely to report ‘cure’ (defined as urgency at baseline but no urgency at follow-up) or ‘improvement’ (defined as reduced urgency from baseline but not to the extent of reporting no urgency) in their urgency symptoms compared to the urodynamics arm. However, the OR was only significant at the 6-month follow-up time point for the ‘improved’ group [OR 0.64 (95% CI 0.43 to 0.94); p = 0.022]. At the final follow-up time point, the OR suggests participants in the urodynamics arm were more likely to be in both the ‘cured’ and ‘improved’ categories. However, the uncertainty around the OR made the difference not significant [‘cured’: OR 2.04 (95% CI 0.86 to 4.80); p = 0.104; ‘improved’: OR 1.12 (95% CI 0.78 to 1.62); p = 0.532].

Three-day bladder diary

The numbers of participants completing the bladder diaries at 6 and 15 months were slightly higher for those randomised to CCA only [172 (31.3%) and 182 (33.1%) compared to 184 (33.5%) and 198 (36.1%), respectively]. The reporting of urgency and incontinence episodes was very similar between the two groups.

At baseline, there was a higher percentage of participants in the urodynamics arm reporting a daytime frequency ˃ 7 per day, which was also observed in the 6-month diary [72/162 (44.4%) vs. 70/180 (38.9%)]; this is also shown in a comparison of the daytime frequencies, being higher for those who received urodynamics [7.1 (SD 2.5); (N = 162) vs. 6.6 (SD 2.4); (N = 180)] and adjusted mean difference (0.5; 95% CI 0.1 to 0.9; p = 0.023). This is the only significant difference between the groups.

The percentage of participants reporting a nocturnal frequency ˃ 2 per night is higher in the CCA only arm at both the 6-month [88/180 (48.9%) vs. 70/162 (43.2%)] and 15-month [94/193 (48.7%) vs. 79/177 (44.6%)] time points. This difference was, however, also seen in the baseline diary. The summary of the follow-up diaries is shown in Table 10.

Health-related quality-of-life measures

Neither of the disease-specific or general HRQoL assessment tools showed a significant difference between participants undergoing urodynamics plus CAA versus CCA only. The ICIQ-LUTSQoL score showed an improvement from baseline to final follow-up time point in both groups. The EQ-5D-5L had small fluctuations across time points, with no evidence of significant differences between groups (see Table 8).

Treatment received following randomisation

The treatment received following randomisation was guided by either the urodynamic diagnosis or the CCA only diagnosis (see www.fundingawards.nihr.ac.uk/award/15/150/05). Adherence to the treatment pathways was monitored during the QA process, which recorded two deviations (see Chapter 7 for further details).

Table 11 shows the range of treatments received by participants following their assessment either from urodynamics or from CCA only. A slightly higher number of participants in the CCA only arm received treatment compared to those in the urodynamics arm [469 (85.4%) vs. 456 (82.9%)]. One hundred and seventy-four participants did not receive treatment from randomisation to the end of the follow-up period (94 participants in the urodynamics arm and 80 participants in the CCA arm).

The treatment received by the greatest number of women was BoNT-A in both groups (n = 620), with more participants in the CCA only arm receiving BoNT-A compared to those in the urodynamics arm [343 (71.6%) vs. 277 (59.3%)]. There were only 21 participants who received surgery for SUI and this was more likely amongst those randomised to urodynamics compared to CCA only [16 (3.4%) vs. 5 (1.0%)]. Nineteen women received SNM [11 (2.4%) vs. 8 (1.7%)] and 48 participants received percutaneous tibial nerve stimulation (PTNS) [19 (4.1%) vs. 29 (6.1%)] in both groups respectively (see Table 11).

The small number of women receiving PTNS (48 women), surgery for SUI (21 women) or SNM (19 women) would make comparison of outcomes by treatments recorded clinically and statistically non-meaningful. At the final time point:

• The participant-reported success rates (‘very much improved’ and ‘much improved’) in the urodynamics versus CCA only arms were 0% versus 11.5% for PTNS, 7.1% versus 20% for SUI and 20.0% versus 12.5% for SNM.
• Using the less strict definition of success (‘very much improved’, ‘much improved’ and ‘improved’) the success rates increased to 27.8% versus 30.8% for PTNS, 50.0% versus 40% for SUI and 30.0% versus 50.0% for SNM, respectively.

Safety data

Serious adverse events

There were nine SAEs reported during the follow-up period by nine participants. The nine SAEs included five deaths, all of which were not related to the trial participation. Four participants experienced expected SAEs. One participant experienced general-anaesthetic-related SAE (sudden desaturation and an upper respiratory tract infection) which required monitoring of oxygen levels and antibiotics. A second participant had possible pyelonephritis and a UTI which required hospitalisation, where a kidney, ureter and bladder X-ray was performed. Two participants were required to self-catheterise following intravesical BoNT-A, which was classified by the local PI as a SAE.

Adverse events

Two hundred and thirty-five participants experienced at least one AE during the follow-up period (113 participants in the urodynamics arm and 122 participants in the CCA arm). The rates of AE were low and similar between the two groups. The most frequently occurring AEs were UTIs (80 participants; 7.3%), requirement for prophylactic antibiotics (76 participants; 6.9%) and urinary retention requiring CISC (58 participants; 5.3%). As BoNT-A was the most common treatment received by the women, AEs following BoNT-A were amongst the most commonly reported. The AEs are shown in Table 12.