A Pilot Open-Label Prospective Study of Safety and Preliminary Efficacy of Endoscopic Submucosal Injection of Hyaluronic Acid Into the Bladder Wall in Patients With Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) (HA-IC/BPSPilot)

Study design in detail This is a prospective, open-label, single-center, pilot phase I-II clinical trial. No randomization or blinding is applied. All enrolled participants receive the same intervention. The study aims to enroll 10-20 evaluable participants with refractory interstitial cystitis/bladder pain syndrome (IC/BPS).

Rationale for submucosal injection of non-cross-linked hyaluronic acid Hyaluronic acid (HA) is a natural component of the extracellular matrix. Intravesical HA instillations are a standard therapy for IC/BPS but require frequent administration (up to 3 times per week for ≥6 months) and provide only temporary relief in many patients. Submucosal injection is hypothesized to achieve a higher and more prolonged local concentration of HA in the lamina propria, enhancing glycosaminoglycan layer repair, reducing inflammation, and stimulating fibroblast activity and neocollagenesis. This technique is technically identical to endoscopic botulinum toxin injection, which has an established safety profile in the bladder.

Extrapolated safety evidence

The safety of submucosal non-cross-linked HA injection is supported by extensive experience in other mucosal sites:

Laryngoplasty (vocal cords): no serious adverse events (SAEs) in published case series; histological evidence of biocompatibility without chronic inflammation or necrosis.

Vulvovaginal atrophy and provoked vestibulodynia: randomized and retrospective studies show only transient edema and pain (10-25%), no SAEs.

Non-surgical rhinoplasty: serious complication rate <0.05% with proper technique.

Endoscopic treatment of vesicoureteral reflux (VUR): >20 years of experience with dextranomer/hyaluronic acid copolymer (Deflux®) in >2500 patients - obstruction requiring intervention occurs in <1% of ureters; long-term follow-up (≥10 years) shows no malignancy or delayed tissue damage.

Intervention details

Device: Flexible or rigid cystoscope.

Injection needle: 23-25 Gauge, length 4 mm (standard endoscopic injection needle).

Product: Non-cross-linked hyaluronic acid (marketing authorization No. РЗН 2024/22715, Russian Federation). Each milliliter contains 10 mg of sodium hyaluronate.

Injection protocol: 20 submucosal injections of 0.5 mL each, evenly distributed over the bladder wall (trigone avoided). Total volume injected = 10 mL.

Anesthesia: Intravenous general anesthesia.

Post-procedure care: No indwelling catheter. Single dose of perioperative antibiotic (cephalosporin) for infection prophylaxis.

Optional repeat procedure Participants who show a positive clinical response (e.g., ≥2-point reduction in VAS pain score at week 4) may be offered a second identical injection at the week-4 visit (V4). This decision is made jointly by the investigator and the participant.

Histological and endoscopic evaluation

At baseline (V1) and at week 4 (V4, before optional repeat injection), punch biopsies are taken from predetermined sites (e.g., posterior wall, lateral wall). Tissue samples are fixed in formalin and stained with hematoxylin and eosin (H&E) and, if feasible, with alcian blue or for mast cell markers (c-kit/tryptase).

Endoscopic images and videos are recorded at V1 and V4 to assess changes in glomerulations, Hunner's lesions, and overall mucosal appearance.

Statistical analysis plan

Primary analysis (safety): Descriptive statistics - frequency and percentage of participants with adverse events (AEs) grade ≥2 according to CTCAE v5.0, and frequency of SAEs.

Secondary analysis (efficacy): Continuous variables (VAS, ICSI, PUF, functional bladder capacity, voiding frequency) are compared between baseline and follow-up time points (week 4, month 3) using paired t-test (if normally distributed) or Wilcoxon signed-rank test (if non-normal). Categorical variables (PGI-I response) are reported as proportions with exact 95% confidence intervals.

Missing data: No imputation for missing values; analysis is per protocol.

Software: SPSS (version 26 or later) or R.

Significance level: α = 0.05 (two-sided), no adjustment for multiple comparisons (pilot, exploratory).

Data monitoring and quality control The study is conducted at a single tertiary care center (Sverdlovsk Regional Clinical Hospital No. 1, Yekaterinburg). An independent data safety monitoring board (DSMB) is not planned because this is a low-risk pilot study. However, all adverse events are reviewed weekly by the principal investigator. Serious adverse events are reported to the local ethics committee within 24 hours. Source data verification will be performed by the sponsor (the institution) according to its standard operating procedures.

Duration of participation Each participant is expected to be in the study for approximately 6 months (screening through month-6 follow-up). The optional repeat injection extends active treatment to 2 injections (day 0 and week 4).

Funding and sponsorship The study is investigator-initiated and funded by the Sverdlovsk Regional Clinical Hospital No. 1. No commercial funding is involved.