Interstitial cystitis/bladder pain syndrome (IC/BPS) is chronic disease usually associated with bladder pain, urinary urgency and frequency, and is often associated with an inflammatory condition in the bladder, especially when the Hunner lesion is present. Intravesical drug instillation is one of the treatment modalities of IC/BPS, and intravesical treatment using 50% dimethyl sulfoxide (DMSO) has been approved in USA and Canada. However, the efficacy of DMSO treatment had previously been shown only in open-labelled clinical trials including one observer-blinded, placebo-controlled study [Ref. 1]. We therefore developed KRP-116D (50% DMSO) as a therapeutic drug for IC/BPS and conducted a Phase 3 clinical trial in Japan. The aim of this study is to compare the efficacy and safety of intravesical treatment of KRP-116D with placebo in Japanese subjects with IC/BPS, in whom the bladder-centric phenotype was identified.

This study was designed as a 12-week randomized, double-blind, placebo-controlled, parallel-group, multicenter study for Japanese IC/BPS patients at 24 sites in Japan. A total of 111 patients were enrolled, and 97 patients first underwent the placebo lead-in treatment at 2 weeks prior randomization, which consisted of 4% lidocaine intravesical instillation followed by intravesical placebo instillation. In this study, to select patients with the bladder-centric phenotype of IC/BPS, we confirmed that all patients had either Hunner legions by cystoscopic examination or glomerulations during bladder hydrodistension, which was performed at least 6 months before the enrolment. Eligibility required the fulfilment of all of inclusion criteria such as; 1) 9 or more on O’Leary & Sant IC symptom index (ICSI), 2) within a 30% reduction of ICSI from the pre-value after the placebo lead-in treatment, and 3) 4 or more on 11-point bladder pain numerical rating scale (pain NRS). Ninety-six eligible patients entered the double-blinded treatment phase, and were randomized at a 1:1 ratio into either KRP-116D or placebo group. 
The intravesical KRP-116D or placebo treatment was performed every 2 weeks for 6 times. In each patient, a catheter was introduced into the bladder transurethrally, 4% lidocaine (20ml) was intravesically infused for local anaesthesia and drained through the catheter 5-15 min later and, thereafter, the KRP-116D or placebo solution (50 ml) was infused and retained in the bladder for 15 min. Efficacy assessments (ICSI, IC problem index (ICPI), 2-days voiding dairy) were performed at baseline and at week 4, 8, and 12, and the patients’ global assessment (GRA) was also evaluated at week 12. The primary outcome was the change in the ICSI score from baseline to week 12, and safety was monitored by vital sign, clinical laboratory test, electrocardiogram, and ophthalmic examination. The initial sample-size of calculation estimated that 45 patients per group (90 total) would provide 80% power using type 1 error rate of 0.05, anticipating 8 patients per group loss to follow-up and non-adherence. Ethical approval and written informed consent was obtained.

A total of 49 received KRP-116D and 47 received placebo. During the placebo lead-in phase, all patients exhibited an immediate reduction of bladder pain sensation after lidocaine instillation; however, none of them showed the more than 30% reduction of ICSI 2 weeks later at the time of randomization. KRP-116D significantly decreased the ICSI score from baseline to week 12 compared with placebo (-5.2 for KRP-116D vs -3.4 for placebo; p=0.019) (Fig. 1), as well as the ICPI score at week 12 (-4.9 vs -2.4; p=0.001). Pain NRS was significantly decreased at week 4 (-1.97 vs -1.11; p=0.026) and at week 8 (-2.57 vs -1.55; p=0.011), but not significantly different at week 12 (-2.87 for -2.09; p=0.097) (Table 1). In voiding symptoms, KRP-116D significantly decreased the daily number of voiding at week 12 (-4.17 vs -1.38), and average voiding volume and maximal voiding volume were also significantly improved by KRP-116D compared with placebo (Table 1). The rate of drug-related adverse event in KRP-116D was greater than placebo (59.2% for DMSO, 27.7% for placebo), but most of the adverse event were bladder stimulating events after the instillation treatment. The rate of KRP-116D-derived odour was only 6.1%. No drug-related serious adverse events were observed.

The intravesical treatment of KRP-116D improves IC/BPS symptoms, bladder pain and voiding parameters. These therapeutic effects of KRP-116D were significantly superior to placebo. Some of previous studies reported that DMSO causes garlic-like smell and it makes difficult to conduct placebo-controlled, double-blind study. In present study, adverse events related to odour occurred in only the KRP-116D group; however, the incidence of these events was very low (6.1 %). Therefore, the blind condition was not affected by KRP-116D-derived odour, and we believe that blind trial characteristics are maintained in this study. In addition, cystoscopic identification of bladder pathology such as Hunner lesions and confirmation of a short-term symptom reduction after lidocaine-induced local anaesthesia in the placebo lead-in phase would be useful for the selection of patients with the bladder-centric phenotype of IC/BPS.

This is the first randomized, double-blind, placebo-controlled clinical study to confirm the efficacy of intravesical treatment of DMSO compared with placebo and its safety profile. Therefore, intravesical DMSO therapy would be an effective treatment for IC/BPS patients, especially those with the bladder-centric phenotype.

Rawls et al., Neurourology and Urodynamics. 2017; 36: 1677-1684.