The Japanese phase 3 trial registered as JapicCTI-173566 and migrated to jRCT2080223511 compared KRP-116D, a named finished 50% weight/weight aqueous dimethyl sulfoxide formulation, with placebo in 96 treated adults with bladder-centric interstitial cystitis/bladder pain syndrome. The primary Interstitial Cystitis Symptom Index difference favored KRP-116D by 1.8 points at 12 weeks. Several voiding outcomes also favored it, but the week-12 pain score did not differ significantly. Treatment-related events were more frequent with KRP-116D, follow-up was short, and the selected population was mostly Hunner type. The result cannot be transferred to neat DMSO, another concentration, another formulation, or a catalog material.[1][2]
Study at a glance
| Field | Study record |
|---|---|
| Research question | Did KRP-116D improve bladder-centric IC/BPS symptoms over 12 weeks compared with placebo in a selected Japanese population? |
| Design | Multicenter phase 3, randomized, double-blind, placebo-controlled parallel trial at 24 Japanese sites, after a placebo run-in and eligibility confirmation |
| Population | 109 consented, 97 entered run-in, 96 randomized and treated; 83/96 had Hunner-type disease |
| Intervention | Historical study identifier: KRP-116D, a finished 50% w/w aqueous DMSO solution, in the protocol-defined intravesical schedule |
| Comparator | Matching-appearance placebo under the same trial procedures |
| Duration | 12-week randomized treatment period |
| Primary outcome | Change from baseline to week 12 in the Interstitial Cystitis Symptom Index (ICSI) |
| Registration | JapicCTI-173566, migrated to jRCT2080223511; completed |
| Publication | Yoshimura et al., International Journal of Urology 2021; PMID 33580603; PMCID PMC8247858; DOI 10.1111/iju.14505 |
| Sponsor/funding | Kyorin Pharmaceutical sponsored, designed, monitored, collected data, and performed the statistical analysis with investigators; two authors were employees and other financial ties were disclosed |
| Results-posting state | Japanese registry record completed and migrated; its text contains a sign-formatting error in the active primary mean and a completion arithmetic inconsistency |
The paper identifies a 50 mL protocol exposure repeated every two weeks for 12 weeks. Those historical details distinguish the experiment; they are not preparation, catheterization, administration, or treatment guidance.
Selection, run-in, randomization, and masking
Adults had bladder-centric IC/BPS, an ICSI score at least 9, qualifying cystoscopic findings, and short-term pain relief after a protocol lidocaine procedure. This enriched the trial for a specific phenotype and for participants capable of responding to a bladder instillation procedure. Eighty-three of 96 treated participants were classified as Hunner type and only 13 as non-Hunner type, limiting transfer to broader IC/BPS populations.[1]
After a placebo run-in, eligible participants were allocated using a centralized website and a minimization method that balanced baseline ICSI strata. The investigational and placebo solutions were intended to look alike, and participants, investigators, and sponsor staff involved in assessment remained masked. DMSO odor could nevertheless have made assignment easier to guess, a practical masking limitation acknowledged by the investigators.
Participant flow: 109, 97, 96, and 93 answer different questions
One hundred nine people consented. Twelve were excluded before the placebo run-in, leaving 97. One more was excluded after run-in, so 96 were randomized, exposed, and entered the full analysis set: 49 KRP-116D and 47 placebo. Forty-eight active and 45 placebo participants completed the randomized treatment period, for 93 completers. One active and two placebo participants discontinued after randomization because of adverse events.[1]
The Japanese registry narrative states that four participants discontinued and 93 completed, which sums to 97 rather than the 96 randomized and treated. Its adverse-event summary also says no active participant withdrew because of an adverse event, whereas the paper reports one active and two placebo adverse-event withdrawals. The registry does not reconcile either conflict, so the documented stages and source-specific statements remain separate.[1][2]
Primary symptom-index result
At week 12, adjusted mean ICSI change was −5.2 points for KRP-116D (95% CI −6.2 to −4.2) and −3.4 for placebo (95% CI −4.5 to −2.4). The adjusted between-group difference was −1.8 points (95% CI −3.3 to −0.3; p=.0188), favoring KRP-116D because lower scores indicate fewer symptoms.[1]
The registry renders the active result as positive 5.2 while displaying an entirely negative confidence interval. The paper and direction of the endpoint show that the mean change is −5.2; this is a registry sign-formatting error, not a positive worsening score.[2]
Placebo participants improved by 3.4 points, so the observed active-group change cannot all be attributed to the formulation. The randomized effect estimate is the 1.8-point difference, not the 5.2-point within-group change. Its confidence interval is compatible with a small 0.3-point difference through a larger 3.3-point difference. Statistical significance does not by itself show that the average incremental change crossed a patient-important threshold.
Secondary outcomes include both positive and null findings
The Interstitial Cystitis Problem Index difference was −2.5 points (95% CI −4.0 to −1.0; p=.0014). Compared with placebo, KRP-116D was associated with 2.11 fewer micturitions per 24 hours (95% CI −3.62 to −0.60), 24.8 mL greater mean voided volume (95% CI 8.0 to 41.6), and 34.8 mL greater maximum voided volume (95% CI 12.8 to 56.8). These outcomes describe average short-term symptom and diary changes, not remission or prevention of later disease.[1]
The week-12 numerical-rating-scale pain difference was −0.78 (95% CI −1.71 to 0.15; p=.0973), so it did not meet the conventional significance threshold. Pain differences reported at weeks 4 and 8 do not override the null week-12 comparison. Selecting only positive time points would distort the endpoint pattern.
For global response assessment, the paper reports 52.1% versus 30.4%, an absolute difference of 21.6 percentage points (95% CI 1.8 to 39.2; p=.0385). The table’s response counts sum to 48 active and 46 placebo observations, 25 responders plus 23 nonresponders, and 14 plus 32, rather than all 49 and 47 randomized. That missing week-12 assessment should stay visible.
Adverse events and serious events
Treatment-emergent adverse events affected 34/49 KRP-116D participants (69.4%) and 28/47 placebo participants (59.6%). Events judged related to study treatment affected 29/49 (59.2%) and 13/47 (27.7%). Events around administration were also more frequent with active treatment, 30/49 versus 15/47. These comparisons show a higher reported tolerability burden with KRP-116D even though reported reactions were mild or moderate.[1]
Serious adverse events occurred in 2/49 active participants and 1/47 placebo participant. The active events were a femur fracture and vertigo; the placebo event was cerebral infarction. Investigators judged none related to study treatment. One active and two placebo participants withdrew because of adverse events. No deaths or ocular toxicities were reported during the study, but 96 people followed for 12 weeks cannot characterize uncommon or delayed harm.
Sponsor role and conflicts
Kyorin Pharmaceutical sponsored the study and worked with investigators on its design and conduct. The sponsor monitored the trial, collected the data, and performed the statistical analysis. Two authors, T. Uno and A. Ohinata, were Kyorin employees. The paper lists consulting, honoraria, and clinical-investigation payments involving several investigators and companies.[1][2]
Sponsor involvement does not make the randomization or results unusable. It raises the importance of prespecified methods, transparent missing-data accounting, full null-result reporting, registry reconciliation, and independent replication.
Statistical significance, effect, uncertainty, and importance
- Statistical significance: the ICSI primary comparison and several voiding outcomes crossed .05; week-12 pain did not.
- Effect size: the primary incremental effect was −1.8 ICSI points, distinct from the −5.2 active within-group change.
- Uncertainty: the 95% CI ranged from −3.3 to −0.3, global response omitted two week-12 observations, and only 13 participants were non-Hunner type.
- Clinical importance: short-term score and diary differences do not establish sustained remission, less healthcare use, or better long-term function.
Important limitations
- Eligibility and run-in procedures selected a bladder-centric, lidocaine-responsive population.
- Eighty-three of 96 participants had Hunner-type disease, limiting inference for non-Hunner IC/BPS.
- The randomized period lasted only 12 weeks.
- Odor may have weakened masking.
- The sample was too small for uncommon or delayed harms.
- Observed week-12 ICSI and global-response denominators were smaller than the randomized set.
- Sponsor personnel performed several core trial and analysis functions.
What this study does not prove
jRCT2080223511 does not prove that KRP-116D eliminates IC/BPS, provides durable benefit after 12 weeks, improves every symptom domain, works in an unselected or mainly non-Hunner population, or has fully characterized safety. The week-12 pain result was null and belongs beside the positive symptom-index and voiding results.[1][2]
The trial tested a named 50% w/w aqueous finished formulation. It does not validate neat DMSO, a different concentration, another solvent system, topical or oral exposure, a compounded preparation, or a catalog material.
Frequently asked questions
Why are the numbers 109, 97, 96, and 93 all reported?
They mark consent, entry into placebo run-in, randomization/treatment, and completion. They are sequential flow stages, not conflicting estimates of one population.[1][2]
What was the primary effect estimate?
The adjusted week-12 difference in ICSI change was −1.8 points, with a 95% confidence interval from −3.3 to −0.3.[1]
Why not call the active effect a 5.2-point benefit?
Because −5.2 was the within-group change. Placebo changed by −3.4, so the randomized incremental estimate was −1.8.[1]
Did pain significantly improve at week 12 versus placebo?
No. The difference was −0.78 on the numerical rating scale, with a confidence interval crossing zero and p=.0973.[1]
How common were treatment-related events?
Investigators classified events as treatment related in 29/49 active participants and 13/47 placebo participants.[1]
Why are there two registry identifiers?
JapicCTI-173566 was the original Japanese registry identifier; the record migrated to the current jRCT identifier jRCT2080223511.[2]
Does the trial apply to any DMSO material?
No. It concerns the KRP-116D finished 50% aqueous formulation under one protocol, not neat DMSO or a different concentration, formulation, route, supplier, or lot.