New compact micro-hole zone catheter enables women to achieve effective bladder emptying without flow-stops

Investigation design

This investigation was a multi-centre, randomised, open-label, controlled cross-over study conducted across 11 sites in Denmark, the UK and France between August and November 2023.

The investigation was carried out in accordance with the Declaration of Helsinki II (1964, as amended in Fortaleza, Brazil, October 2013) (World Medical Association, 2013), approved by local medical research ethics committees and competent authorities and registered at ClinicalTrials.gov (NCT05814211). All subjects gave oral and written informed consent before being enrolled in the study.

Population

The investigation included women aged ≥18 years who had been carrying out CISC (catheter sizes CH12 or CH14) for at least 1 month up to inclusion, emptied their bladder by CISC at least three times a day and had used a compact catheter for at least half the catheterisations performed during the 2 weeks before enrolment.

The subjects were required to indicate willingness and ability to adhere to the intervention procedures and not participate in any other clinical studies throughout the duration of this investigation.

Subjects were excluded from participation if they had conditions that could affect their safety or the integrity of results (such as signs of a UTI), were pregnant or breastfeeding, had excessive production of urinary mucus/sediments/debris that potentially contraindicated the use of a regular intermittent catheter or were hypersensitive to the ingredients in the catheters being tested.

Intervention and procedure

The duration of the investigation was approximately 4 weeks for each subject, and it involved one information clinic visit on site (visit V0), three clinic visits on site (visits V1–V3) and two 2-week test periods at home (T1 and T2) using an MHZC in one and a CEC in the other (Figure 1).

At V1, subjects were enrolled, randomised to using either the CEC or the MHZC during their first test period (T1), then introduced to the catheter. At V2, participants were introduced to the second catheter, which would be tested during the second test period, T2. The cross-over design of the study ensured that all completing subjects would test both catheters. All endpoint data were collected at V2 and V3, which took place immediately after T1 and T2. V3 concluded the subjects' participation in the investigation.

Data were collected using bladder-emptying performance testing of both a health professional-led catheterisation and a self-catheterisation, a perception questionnaire related to the preceding test period with questions on ‘handling’, ‘sensation’, ‘confidence and control’ and ‘satisfaction’, scored on a five-point Likert scale, and a subjective scoring using a 10 cm visual analogue scale for discomfort during self-catheterisation related to insertion, emptying, completion and withdrawal of the catheter, with 0 cm indicating no discomfort and 10 cm indicating the worst possible pain. After catheterisation, the post-void residual urine volume was measured with a bladder scanner (BladderScan i10, Verathon).

The primary and secondary endpoints of the investigation were bladder-emptying performance during health professional-led catheterisation and self-catheterisation, and included the number of flow-stops and RV1. Although these endpoints are closely related, the RV1 during health professional-led catheterisation was assigned as the primary endpoint. Flow-stops were defined as a period of 2 seconds with an average flow rate below 0.8 ml/s, and RV1 was calculated as the difference between the total volume catheterised minus the volume catheterised at first flow-stop.

Sample size calculations were based on three exploratory studies that investigated prototypes of the MHZC with women and men who carried out CISC as well as healthy volunteers (Landauro et al, 2023a; 2023b; Thiruchelvam et al, 2024). An adequate sample size for the primary endpoint of RV1 was estimated to be 72 subjects, assuming a standard 20% drop-out rate.

Data analysis

Statistical analyses were performed on the full analysis set, where subjects used at least one catheter and had at least one endpoint recorded. Primary and secondary endpoints were analysed in a generalised linear mixed model, with subjects included as random components, and the visits and catheters as fixed variables. RV1 was compared by the mean difference between catheters and presented with 95% CI and P values, while flow-stops were compared using relative risk (RR).

A post-hoc responder analysis was conducted to further evaluate bladder-emptying performance, testing the proportion of catheterisations achieving the desired treatment outcomes. Responses to treatment were defined as complete bladder drainage at first flow-stop and catheterisations without flow-stops. These outcomes were defined based on research on the male MHZC version, which identified an RV1 value of <10 ml as indicative of successful treatment (Landauro et al, 2023a). The number of successful treatment responses was analysed using a generalised linear mixed model, with individual subjects as a random component, and compared using odds ratios (OR). The responder analyses were performed on the health professional-led catheterisations and self-catheterisation pooled together to ensure statistical power (Snapinn and Jiang, 2007).

Descriptive statistics were used to present the ordinal scale questionnaire responses and the visual analogue scale scores of discomfort, and post-hoc statistical analyses were performed on the perception questionnaire data to generate comparative data by applying a generalised linear mixed model with subject included as a random component. Comparative analysis of the perception questions was presented using OR. All statistical analyses were performed with SAS v9.4/Enterprise Guide v7.1.

Baseline characteristics

In this investigation, 82 female CISC users were recruited and enrolled at 11 sites; four sites were in Denmark, four were in the UK and three were in France. One subject dropped out when it was discovered that she was pregnant after randomisation at V1 but before any product exposure, which meant that 81 subjects were included in the trial population; two discontinued the intervention without any endpoints recorded, leaving 79 subjects in the full analysis set (Figure 2).

Table 1 shows the baseline demographic characteristics of the study population. The average age of the subjects was 54.1 years (range 24-78 years) with 72% having neurogenic lower urinary tract dysfunction and 65% having normal urethral sensation. The most commonly used catheters at baseline were female SpeediCath compact catheters (Coloplast) – the Compact Eve (67%), Compact Female (15%) or Compact Female Plus (7%).

Bladder-emptying performance

Figure 3 shows the frequency distribution of bladder-emptying performance results for the health professional-led catheterisation and self-catheterisation.

A few unexpectedly high RV1 values were observed for both catheters, with 16 of 289 total catheterisations (eight for each catheter), resulting in an RV1>100 ml (Figure 3).

Table 2 presents the results regarding bladder-emptying performance of the MHZC and the CEC during both health professional-led and self-catheterisations. The mean RV1 differences between the catheters were −7.35 ml (P=0.480) in the health professional-led catheterisations and 7.89 ml (P=0.414) in the self-catheterisations. The risk of a flow-stop occurring was significantly lower when catheterising with the MHZC. The RR analyses showed a 2.74 times lower risk (P=0.024) during health professional-led catheterisations and a 2.52 times lower risk (P=0.036) during self-catheterisations. Furthermore, the responder analyses demonstrated that there was a significantly higher likelihood of both zero flow-stops and an RV1<10 ml with the MHZC.

Specifically, the OR for zero flow-stops was 0.49 (P=0.016) and the OR for RV <10 ml was 0.20 (P<0.001). Successful response to treatment in terms of achieving RV1 <10 ml was observed in 83% (95% CI [0.76–0.89]) of total catheterisations with the MHZC and 71% (95% CI [0.63–0.78]) with the CEC. When applying zero flow-stops as the criterion for a successful treatment response, 87% (95% CI [0.80–0.92] of total MHZC catheterisations achieved a successful treatment compared to 57% (95% CI [0.48–0.65] of total CEC catheterisations. The mean post-void residual urine volume in the bladder was 4.8 ml (SD 16.4) for the MHZC and 12.0 ml (SD 40.4) for the CEC after the health professional-led catheterisations. After self-catheterisations, the mean post-void residual volume was 7.7 ml (SD 13.9) with the MHZC and 9.3 ml (SD 20.5) using the CEC.

Perception and discomfort

The women answered the perception questions for the MHZC and the CEC using five-point Likert scales. They had a more positive perception of the MHZC than the CEC across all six handling-related questions (P<0.05), on six out of seven confidence-related questions (P<0.05), on all four sensation-related questions (P<0.001) and on all three satisfaction-related questions (P<0.001). Feeling confident that the catheter emptied the bladder completely was more likely after using the MHZC (P<0.001) and more women also agreed that it was fast to empty their bladder completely using the MHZC (P=0.017).

Feeling a pinching/stinging sensation during catheterisation was less likely when catheterising with the MHZC (P<0.001) and more subjects agreed that it was ‘gentle’ to insert the MHZC catheter (P=0.001), empty the bladder (P<0.001), and to withdraw the catheter (P=0.001). More subjects reported satisfaction with the MHZC (P<0.001) and wanting to use the MHZC in the future (P<0.001).

The perception questions and results are shown in Table 3.

The mean scores of discomfort on the 10 cm visual analogue scale for the MHZC was 0.3 cm (SD 0.8) at insertion, 0.2 cm (SD 0.7) during emptying, 0.3 cm (SD 0.7) by completion and 0.4 cm (SD 1.2) at withdrawal. For the CEC, the mean visual analogue scale-scored discomfort was 1.1 cm (SD 2.3) at insertion, 0.9 cm (SD 1.8) during emptying, 1.2 cm (SD 2.3) by completion, and 1.3 cm (SD 2.4) at withdrawal.

Adverse events

A total of 23 adverse events were observed during the investigation, none of which were serious. Three of these were related to the MHZC and four to the CEC. The seven adverse related to the devices concerned well-established risks of catheter use, including UTI, haematuria and dysuria.

Flow-stops and residual urine

Compact catheters are highly valued by CISC users for their convenience and discretion (Pinder et al, 2015), and provide a suitable bladder-emptying solution for the vast majority of women, consistently enabling successful catheterisation (Biering-Sørensen et al, 2007). With CECs, however, successful catheterisation often relies on repositioning the catheter to fully empty the bladder because of urine flow-stops (Glahn, 1988; Glahn et al, 1988; Tentor et al, 2022a).

The female compact MHZC was designed to combine discretion with the improved catheterisation experience of achieving an empty bladder without the need for repositioning; MHZCs have been recognised by the EAUN CISC guideline as being able to do this (Vahr Lauridsen et al, 2024).

When the flow of urine stops during catheterisation, CISC users are advised to slowly withdraw the catheter in small steps (Vahr Lauridsen et al, 2024). This repositioning can make the urine flow again if flow-stops have arisen because the catheter eyelets have become blocked by bladder mucosa being sucked into them by hydrodynamic pressure (Glahn, 1988). To ensure that the bladder is completely empty, repeated cycles of flow-stops and repositioning might be needed at each catheterisation. This can cause repeated damage to the bladder tissue; in-vivo experiments using animal models have demonstrated how mucosal suction can cause microtrauma to the bladder tissue during catheter repositioning (Tentor et al, 2022b). In addition, withdrawing the catheter prematurely, potentially because of misinterpreting a flow-stop as an empty bladder, risks leaving residual urine in the bladder (Kennelly et al, 2019).

UTIs are complex and multifactorial (Vasudeva and Madersbacher, 2014; Kennelly et al, 2019) and a burden on CISC users that needs addressing (Pannek, 2011; Nazari et al, 2020; Buchter et al, 2022). Since both residual urine in the bladder and bladder microtrauma are risk factors for UTIs (Kennelly et al, 2019), catheter repositioning with CECs creates a dilemma. The benefit of using the MHZC is that it helps to avoid the dilemma by having significantly fewer flow-stops and enabling significantly more successful catheterisations without flow-stops, as the results of this investigation show. These results are supported by the earlier investigations on the MHZC for men, which found that MHZCs performed significantly better than CECs, including fewer flow-stops and a lower RV1 (Landauro et al, 2023a; 2023b; Thiruchelvam et al, 2024).

Despite the significantly lower number of flow-stops with the MHZC, no difference in RV1 means was observed, possibly a result of the influence of a few flow-stops with both catheters that resulted in extreme RV1 values but did not display any apparent pattern or systematic relation to the subjects. Flow-stop identification in this investigation relied on the average urine flow rate and did not have the added feature of a pressure sensor that similar investigations involving the male version of the MHZC included (Landauro et al, 2023a; Thiruchelvam et al, 2024). This meant that flow-stops resulting from mucosal suction could not be distinguished from other flow-stops. Animal experiments have demonstrated how the mucosal suction flow-stops that commonly occur with CECs are negligible with MHZCs (Schrøder et al, 2024). The flow-stops resulting in extreme RV1 values presumably occurred early during catheterisation and therefore are likely to stem from other causes of low flow rate, such as a catheter handling issue or incomplete catheter insertion. The flow-stops with the CECs later in the catheterisation, when the bladder empties and the bladder wall comes increasingly closer to the catheter eyelets, are more likely to result from mucosal suction into the eyelets.

Achieving successful catheterisations

In this clinical investigation, responder analyses were introduced as an expansion of the data analyses because of the few extreme RV1 values, which presented a challenge to the predetermined statistical model.

The general distribution of RV1 values tends to be positively skewed since most are close to 0 ml, which can cause such extreme values so as to prevent meaningful interpretation of the mean values and evaluation of actual catheter performance.

Responder analyses assessed the proportion of patients who achieved the positive treatment response threshold, highlighting individual patient responses rather than average effects across the entire population (Snapinn and Jiang, 2007; Henschke et al, 2014). Successful treatment responses were identified as the desired outcome of catheterisation being achieved in individuals, ie complete and effective bladder emptying without repositioning, zero flow-stops and complete emptying of the bladder, which was defined as an RV1<10 ml.

Defining an empty bladder is not straightforward considering the continuous production of urine into the bladder (Huang Foen Chung and van Mastrigt, 2009) and that, even with normal bladder function, empty does not necessarily equal 0 ml of residual urine (Haylen, 2007). The <10 ml threshold was defined based on clinical investigations on the male MHZC model, in which 90% of catheterisations resulted in RV1<10 ml; this is a reasonable indicator of an empty bladder, certain to have no clinically significant volume of residual urine (Asimakopoulos et al, 2016). The results of the responder analyses indicated that a significantly higher proportion of CISC users would be enabled by the MHZC to empty their bladder fully without experiencing flow-stops and having to reposition the catheter.

Catheter perception

This investigation included a broad sample of women with a variety of underlying reasons for using CISC, including 28% with non-neurogenic lower urinary tract dysfunction. All had experience of compact catheter use and the majority reported normal urethral sensation, with only 11% reporting no urethral sensation, which helped to ensure the validity of discomfort evaluation and perception questionnaire responses.

Overall, 19 out of the 20 perception questions resulted in a significantly higher positive response rate for the MHZC than for the CEC, which showed that women could clearly perceive and appreciate the differences between the two catheterisation experiences.

Some important factors for improving quality of life for CISC users relate to increasing autonomy and self-confidence in the procedure and treatment success (Fumincelli et al, 2017). The benefit of this investigations, with the results showing fewer flow-stops and more successful catheterisations without flow-stops, was supported by the CISC users' own perception of the MHZC. Significantly more users felt confident that the MHZC emptied their bladder completely and they reported general satisfaction with the MHZC.

Pain also influences CISC users' overall satisfaction (Moghalu et al, 2021) and, with the MHZC, significantly fewer CISC users felt a pinching/stinging sensation during catheterisation. This was supported by the perception of catheter insertion, bladder emptying and withdrawal, where significantly more CISC users reported a milder sensation when using the MHZC than when using CECs. Additionally, reports of discomfort relating to catheter insertion, emptying, completion and withdrawal using visual analogue scale were low for MHZC, with means in a range of 0.2–0.4 cm. As the visual analogue scale is rated 0-10 cm, with 0 cm indicating no discomfort and 10 cm indicating the worst possible pain, visual analogue scale reports of 0–3 cm during CISC have been characterised as ‘no or minimal pain’ (Kessler et al, 2009), meaning that both catheters caused no or minimal discomfort in this investigation.

Overall, the perception and discomfort results supported the investigation's bladder-emptying performance results in illustrating the benefits to the women of using an MHZC by enabling effective bladder emptying without flow-stops and with minimal discomfort.