RCT1: flexible ureterorenoscopy versus extracorporeal shockwave lithotripsy: baseline, trial results and clinical effectiveness

Parts of this chapter are reproduced with permission from Wiseman et al.1 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) licence, which permits others to distribute, remix, adapt and build upon this work, even for commercial use, provided the original work is properly cited. See: https://creativecommons.org/licenses/by/4.0/. The text below includes additions and formatting changes to the original text.

RCT1 for stones ≤ 10 mm: flexible ureterorenoscopy versus extracorporeal shockwave lithotripsy

Trial recruitment

RCT1 compares FURS with ESWL. In total 466 participants were recruited to RCT1 from 48 UK recruitment centres. The median number of participants per recruitment centre was 7 [interquartile interval (IQI) 3–11]. We randomised 232 and 234 respectively to the care pathways FURS and ESWL. Participants were recruited between 9 May 2016 and 31 March 2021. The final follow-up was completed in January 2023 (see Appendix 5, Table 37 and Figure 16).

Recruitment was on track, but it was paused due to the COVID-19 pandemic between 16 March 2020 and 1 July 2020. Only 20 centres had the capacity to re-open to recruitment after the recruitment pause. A further 13 participants (3% of the total 466 participants) were recruited after the recruitment pause.

Participant flow

Figure 2 shows the Consolidated Standards of Reporting Trials (CONSORT) diagram for RCT1. We screened 1964 potentially eligible patients for inclusion in the trial and 1498 were excluded. Reasons for exclusion are shown in Figure 2. A total of 286 patients were ineligible due to stone size or position, 197 were unsuitable (surgical reasons) for FURS or ESWL, 689/1498 (46%) of the patients excluded indicated a preference for treatment as a reason for declining to take part. There were 5 post-randomisation exclusions, 2 in the FURS arm and 3 in the ESWL arm, leaving 230 and 231 participants in each arm respectively.

FIGURE 2 Consort flowchart – RCT1. a, See Table 4. AUC, area under the curve. (Figure not reproduced here; see the original article.)

The majority [382, (83%)] of participants had their intervention and reached their 12-week post-intervention time point prior to the COVID-19 restrictions (Table 2). However, 30% of participants completed their follow-up to 12 months post randomisation after COVID restrictions started.

Baseline characteristics

The randomised groups were mostly well balanced at baseline (Table 3). The mean age of participants was 53 years. The majority of participants were male. Stone measures from detailed imaging, (including stone Hounsfield unit density, as a marker of ‘hardness’, and skin-to-stone distance) were assessed at baseline after randomisation and were similar in both treatment arms (see Appendix 5, Table 39). The level of pain participants experienced related to their stone on the day of completing the baseline questionnaire was relatively low (mean 2 on a scale 1–10) and while 50% of the participants reported having experienced pain in the previous week, they required pain medication on a mean 1.6 days out of 7.

The EQ-5D score was imbalanced between the treatment groups at baseline, the FURS group scored 0.047 lower. This imbalance did not manifest in other health status and QoL measures at baseline, the EuroQol Group’s 5 dimensions health status questionnaire – visual analogue scale (EQ-5D-VAS) scale and both the SF-12 scores were similar in both treatment groups.

Care pathway and treatment received

Table 4 describes the allocated pathway and actual treatment received. The majority received their allocated pathway, with 189 (82.2%) on the FURS pathway and 208 (90%) on the ESWL pathway receiving their allocated treatment. However, 21 (9.1%) participants allocated to the FURS arm received ESWL and 10 (4.3%) in ESWL received FURS. One participant in each arm required a PCNL approach. Nineteen (8.3%) and 12 (5.2%) participants did not receive any active treatment in the FURS and ESWL arms, respectively. Many of these (particularly in the FURS pathway) instead received conservative management as agreed between clinician and participant.

The waiting time to initial treatment (see Table 4) was twice as long in the FURS treatment arm compared to ESWL. Length of hospital stay for first intervention treatment was short.

Primary outcome

Figure 3 shows the plots of mean EQ-5D score and the change in EQ-5D score from baseline over time. A similar pattern was seen for the EQ-5D-VAS scores (see Appendix 6, Figure 18).

FIGURE 3 Health status plots over time – RCT1. Time points B and 0 are baseline and pre intervention. Areas (a) and (b) do not necessarily represent 1 week, from week 1 to 12 all are 1-week intervals. (Figure not reproduced here; see the original article.)

The PO and treatment comparison effect sizes are presented in Table 5. There were 164/230 (71.3%) on the FURS pathway with sufficient measures within the required time epochs and 188/231 (81.4%) in the ESWL treatment arm. All models show that participants on the FURS pathway may have slightly better outcome up to 12 weeks post intervention compared to ESWL. However, this is not significant in any of the models except for Sensitivity 1, which adjusts for waiting time. For context, the target difference the trial was designed to detect was a 0.3 SD difference, around 0.07 on the AUC score. The per-protocol (treatment as received) analyses are presented in Appendix 7, Table 41, and results are similar to the ITT analyses. The suite of multiple imputation approaches is described in Appendix 2, Description of different scenarios for multiple imputation and is presented in Appendix 7, Figure 20. The results were similar to the ITT analyses.

Secondary outcomes

Definitions and derivations of the secondary outcomes both for clinical outcomes and the patient-reported outcomes (pain, health status and QoL) are given in Appendix 2, Tables 33–35. Briefly to reiterate: stone clearance was further defined as complete clearance of the target stone from the urinary tract (defined as no further action or observation required for that stone); acceptable clearance, where observation was required but no intervention planned; and unacceptable clearance, where further intervention would be required.

Stone clearance and additional treatments by 12 weeks post intervention

At 12 weeks post intervention, more participants had complete stone clearance (as defined in Appendix 2, Table 33) in the FURS care pathway than for ESWL (71.7% vs. 36.4%) and the overall effect shows FURS to be superior to the ESWL odds ratio (OR): 4.26 (2.74–6.61). The number of participants who required additional treatment (defined in Appendix 2, Table 34) was lower in FURS group at 12 weeks compared to ESWL [RR: 0.34 (0.18–0.61) p < 0.001].

Stone clearance and additional treatments by 12 months post randomisation

The picture for the 12-month post-randomisation time point was complicated by some participants having long waiting times to initial treatment. The majority of participants in both groups reached the 12-month post-randomisation time point after their 12-week post-intervention time point, as intended in the original design. However, some did not have their intervention (or nominated treatment date in the case of conservative management) until after they had been in the trial for 12 months (12 months post randomisation). Others reached the 12-month post-randomisation time point somewhere between intervention and the 12-week post-intervention period. While this happened in both arms, the biggest impact was for the FURS care pathway (Table 6). Despite this, we also found that the FURS treatment arm was superior for both stone clearance and the additional treatment measure (also defined in Appendix 2, Tables 33 and 34) which (in the 12-month analysis) also includes those with more treatment still planned.

Complications

These were defined as episodes related to an intervention. The number of treatment-related complications was 48 in 44 participants in the FURS arm and 30 in 26 participants in the ESWL arm. There were 7/231 (3%) and 5/230 (2%) in each arm respectively that were graded Clavien 3 or above (Table 7).

Patient-reported health status, quality of life and pain

The participant-reported weekly pain and health statuses (EQ-5D score) are summarised in detail in Appendix 7, Tables 43–54. Appendix 7 also summarises the pre-intervention (see Table 42); and 12-month post-randomisation (see Table 55) pain, health status (EQ-5D score) and QoL (SF-12) measures.

All measures of pain (Table 8) show post-intervention patterns consistent with EQ-5D-5L plots (see Figure 3) where health status in the first couple of weeks post intervention was lower for FURS compared to ESWL then improved to a steady higher level later. Pain was higher in these first weeks for those allocated to FURS but then decreases.

The secondary outcomes of health status, measured by EQ-5D score, rather than AUC, EQ-5D-VAS are reported in Table 8 modelled over all 12 weeks. EQ-5D scores and VAS have similar health status patterns, with initial detriment of FURS followed by improvement after 2 weeks. Table 8 also reports the QoL – SF-12 scores (physical and mental domains) but modelled only on the available time points pre intervention and 12 weeks post intervention.

We explored the potential impact of two subgroup factors, reported at baseline determined a-priori: BMI and stone density as measured by the Hounsfield unit on the PO (AUC of the EQ-5D score) and two secondary outcomes: AUC from baseline and stone clearance to 12 weeks post intervention (definitions are in Appendix 2, Subgroup analyses and technical factors definitions).

The figures for the AUC outcomes (see Appendix 7, Figure 21: Subgroups ‒ main PO, Figures 22–24: Subgroups ‒ sensitivity 1, sensitivity 2, and AUC from baseline to 12 weeks) suggest that these subgroups were not statistically different with respect to treatment arm and their 99% CIs all include the original overall effect. This was also the case for the clinical outcome stone clearance at 12 weeks (see Figure 25, Subgroups ‒ stone clearance at 12 weeks).

Technical factors

We report the results for the main outcomes and covariates in the PO models (main, sensitivity 1 and sensitivity 2), the secondary AUC model (AUC from baseline to 12 weeks post intervention) and also for stone clearance at 12 weeks for the technical factors in Appendix 8 (see Tables 71–75). These were not a comparison between treatment arms (since they were within a specified treatment) but summaries of each of the outcomes and covariates for each technical factor across the two RCTs. They were restricted to technical factors for the first intervention.