*2.2. Efficacy Assessment*

In Table 2, the overall GRA showed that at 3 months post-injection, 19 (67.9%) participants in the Control group and 23 (67.6%) participants in the Mix group had a significant response, without a statistical difference between the two groups. At 6 months, the response rate in the Mix group was remarkably higher than the rate in the Control group (58.8% vs. 28.6%, χ2 = 5.7, *p* = 0.02 < 0.05).

In Table 3, at 3 months post-injection, the clinical characteristics in each group had significantly improved from baseline and there was no statistical difference between the two groups. At 6 months, patients' QoL, VAS, ICSI and ICPI in the Control group had statistically improved from baseline, except for urinary frequency, bladder voided volume and PUF. In the Mix group, patients' urinary frequency, bladder voided volume, QoL, VAS, PUF, ICSI and ICPI had significantly improved from baseline, with a statistical difference from the Control group.


**Table 2.** Global response assessment at 3 and 6 months.

The mean effective duration of the responders in the Mix group was apparently better than that in the Control group (27.5 (range 0–89) vs. 4.9 (range 0–11) months, *p* < 0.05). The rates of the responders in the Mix therapy group were significantly higher than those in the Control group after 6 months of treatment (Figure 1A). In the Mix group, more than half of the participants could see a significant improvement within 6 months and a marked improvement at 12 months of treatment (Figure 1B). Furthermore, with repeated intravesical instillations of Sapylin, the grea<sup>t</sup> effect continues to maintain during the treatment. With a median follow-up of 32.5 [24.0, 92.0] months, the effective duration of the best responder in theMixgroupwas89months,whichcontinuestolast(symptomfree).

**Figure 1.** (**A**) \* *p* < 0.05, the rates of the responders in the Mix therapy group are significantly higher than those in the Control group after 6 months of treatment. (**B**) In the Mix group, more than half of the participants see a significant improvement within 6 months and a marked improvement at 12 months of treatment. Furthermore, with repeated intravesical instillations of Sapylin, the effect is maintained during the treatment.


**Table 3.** Secondary outcome changes from baseline to 3 and 6 months after treatment.

## *2.3. Safety Assessment*

None of the patients experienced serious adverse events. In the Mix group, mild or moderate adverse events related to the BoNT/A injection and Sapylin instillations occurred in 19 (19/34, 55.9%) cases, including 2 cases of acute urinary retention, 10 cases of dysuria, 3 cases of mild hematuria, 3 cases of urinary tract infection and 1 case of mild fever. In the Control group, mild or moderate adverse events related to BoNT/A injection occurred in 13 cases (13/28, 46.4%), including 1 case of acute urinary retention, 8 cases of dysuria, 2 cases of mild hematuria and 2 cases of urinary tract infection. The difference in the adverse events between the two groups had no statistical significance (*p* > 0.05) and they were cured spontaneously without any interventions, or with appropriate treatment, such as antibiotics.
