Take Home Message
The Hydeal Cyst trial evaluates if Hydeal Cyst intravesical instillations can mitigate lower urinary tract symptoms from non–muscle invasive bladder cancer chemotherapy/immunotherapy. This aims to reduce treatment discontinuation by restoring the bladder’s protective barrier, potentially improving overall therapeutic response.
Abstract
In non–muscle-invasive bladder cancer (NMIBC), patients undergo adjuvant local therapies such as chemotherapy (mitomycin C [MMC]) or immunotherapy (Bacillus Calmette-Guérin [BCG]) to reduce the risk of relapse and local/systemic progression. The main issue related to these topic therapies is their toxicity that is mainly local with rare systemic events. Hyaluronic acid is recommended in cases where it is necessary to restore and/or protect the layer of glycosaminoglycans damaged by local therapies. The Hydeal Cyst (HC) trial is a multicenter, randomized, controlled, open-label clinical investigation that aims to evaluate if HC intravesical instillations could mitigate lower urinary tract symptoms (LUTS) and improve oncological outcomes. Overall, 200 patients affected by NMIBC (naïve or recurrent) underwent transurethral resection (TURB/re-TURB when indicated) in the 4 wk before enrolment, and candidates to BCG or MMC intravesical induction therapy with an International Prostrate Symptom Score ≤10 will be randomized to HC intravesical instillations or control. The primary objective is to investigate if multiple HC intravesical instillations decrease the LUTS. Secondary objectives are recurrence-free survival, progression-free survival, safety, and quality of life. This study has potential to change the current LUTS treatment approaches, reducing the rate of early treatment discontinuation and thereby leading to a higher rate of therapeutic response.
1. Introduction
Bladder cancer is the 10th cancer diagnosed in men, with global incidence rates of 9.5/100.000 for men and 2.4 for women [1]. Overall, 75% of patients present a tumor confined to the mucosa (Ta, CIS stage) or to the submucosa (T1).
Treatment for non–muscle invasive bladder cancer (NMIBC) involves transurethral resection of bladder tumor (TURBT) [2], [3] followed by adjuvant local therapies such as chemotherapy (mitomycin C [MMC]) or immunotherapy (Bacillus Calmette-Guérin [BCG]) to control local disease. These therapies are indicated by current European Association of Urology Guidelines [4]. Significant gaps in NMIBC knowledge include difficulties in the subclassification of T1 stage, the need for new tumor markers, debates on surgical techniques, and the lack of prospective studies on prophylaxis and treatment of BCG-induced complications [4]. Intravesical BCG or MMC involves a weekly induction cycle, followed by a maintenance schedule up to 3 yr depending on the tumor risk group [5].
The main concern related to BCG and MMC is their local toxicity, with BCG exhibiting higher toxicity than MMC [6]. Toxicity is mainly local, and systemic events are rare [7]. Local side effects include noninfectious cystitis, hematuria, dysuria, increased voiding frequency, granulomatous prostatitis, and epididymis orchitis. Systemic effects are arthritis, persistent high fever, and allergic reactions [5]. Other local and systemic adverse events are attributed to inflammatory responses from mycobacterial infection [8]. Brausi et al. (2014) [9] reported that BCG instillations damage the bladder’s urothelial glycosaminoglycan (GAG) layer. Palou et al. [10] proposed an anesthetic anti-inflammatory solution to reduce urinary frequency and pain. Local toxicity from intravesical BCG or MMC often prevents treatment completion, reducing efficacy [11].
New treatments aim to limit adverse events; for example, alum irrigation resolves hemorrhagic cystitis in 60% of patients [12]. In vitro studies suggest that quinolone antibiotics may reduce BCG-induced infections [8]. Identifying agents to reduce local toxicity from intravesical chemotherapy/immunotherapy is crucial for improving patient quality of life (QoL). Improved tolerability reduces early treatment discontinuation and enhances therapeutic response.
GAG layer alteration compromises the urothelium’s barrier, causing urine penetration, irritation, and inflammation. Hyaluronic acid (HA) is used for interstitial cystitis and for preventing recurrent lower urinary tract infections [13] and recommended to restore and/or protect the layer of GAGs.
Hydeal Cyst (HC) has been used in various bladder mucosal disorders including interstitial cystitis, radiation-induced cystitis, and post-chemotherapy irritation to restore urothelial GAGs by reducing impaired inflammation and discomfort. The mechanism involves sustained release of HA and Hydeal‑D, promoting urothelial healing and symptom relief without significant systemic exposure. HC is composed of HA sodium salt and Hydeal-D (benzyl ester of HA) to restore the function of the physiological protective barrier of the bladder wall against toxic urinary irritants, thus reducing irritation and inflammation and encouraging a reduction in pain. HC, on account of its prolonged action, provides optimal adhesion to the bladder mucosa, helping to restore the protective barrier [14].
This randomized controlled study evaluates if HC instillations, administered 48 hr post-BCG/MMC during induction, mitigate local urinary symptoms, preserve treatment adherence, and reduce early disease recurrence. We hypothesize that HC alleviates local symptoms associated with intravesical MMC/BCG instillations during induction.
2. Methods
2.1. Study objective
The study is designed to evaluate if an intervention with multiple HC intravesical instillations decreases the lower urinary tract symptoms (LUTS). Secondary objectives are recurrence-free survival (RFS), progression-free survival (PFS), safety, and QoL.
2.2. Study design
This is a multicenter, open-label, controlled, randomized clinical investigation (NCT06245603).
In this clinical investigation, we will enroll 200 patients with NMIBC treated with TURBT, with or without a second resection, undergoing intravesical BCG or MMC therapy, using a stratified block randomization method with a 1:1 ratio in two arms:
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1.
In arm A (experimental arm), patients receive weekly HC intravesical instillations during the BCG or MMC therapy period for 6 or 8 wk, respectively, as for clinical practice. HC will be administered after 48 h from BCG/MMC instillation (6/8 instillations).
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2.
In arm B (control arm), patients receive only standard therapy (BCG or MMC for 6 or 8 wk).
Randomization will be stratified by the type of oncological therapy (BCG vs MMC).
In this clinical investigation, HC will be used out of clinical indication as a pre-market medical device due to the number of instillations.
The design is summarized in Fig. 1.
Fig. 1.
Overview of the design of the Hydeal Cyst study.
Study inclusion, treatment, and follow-up occur at each local hospital.
2.3. Study end points and measurements
The primary end point of the present study is to evaluate whether an intervention with HC intravesical instillations could mitigate LUTS and improve oncological outcomes in patients with NMIBC undergoing intravesical BCG or MMC therapy. LUTS will be evaluated by the International Prostate Symptom Score (IPSS) questionnaire (score 0–35) at baseline and follow-up visits. The secondary clinical end points are the RFS that will be determined as the time from the date of randomization to the date of clinical disease recurrence; the PFS will be determined as the time from the date of randomization to the date of clinical disease progression to MIBC or to an higher grade (eg, from low to high grade); toxicity will be recorded and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v.5; and QoL will be evaluated at randomization (T0), at wk 4 and 6/8 (T6 for BCG/T8 for MMC) of instillation treatment and during follow-up period (wk 2, 6, and 18 after instillation treatment end). QoL will be assessed through the Functional Assessment of Cancer Therapy-Bladder (FACT-Bl) questionnaire. Table 1 summarizes end points and timescale.
Table 1.
Primary and secondary endpoints, definitions, and outcome measurements
| Endpoint | Definition | Time points |
|---|---|---|
| Primary endpoint | ||
| Decreasing LUTS | IPSS (Q1–Q6) | BL and cycle 1, 4, 6/8, and during FU |
| Secondary endpoints | ||
| RFS | From randomization to recurrence | T0, recurrence |
| PFS | From randomization to progression | T0, progression |
| Toxicity | CTCAE v.5 | From cycle 1 to cycle 6/8, and during FU |
| QoL | FACT-Bl | BL and cycle 1, 4, 6/8 |
BL = baseline; IPSS = International Prostatic Symptoms Score; RFS = recurrence-free survival; PFS = progression-free survival; CTCAE = Common Terminology Criteria for Adverse Events; FACT-BI = Functional Assessment of Cancer Therapy-Bladder; FU, follow-up; LUTS = lower urinary tract symptoms; QoL = quality of life.
2.4. Inclusion and exclusion criteria
Recruitment targets 200 male/female patients ≥18 yr with histologically confirmed NMIBC (naïve/recurrent). TURBT/re-TURBT must be within 4 wk pre-enrolment. Eligible patients are BCG/MMC induction candidates with IPSS ≤10 and negative urine culture within 2 wk pre-T0. Sexually active premenopausal/nonsurgically sterile women must use adequate contraception. Exclusions: upper-tract urothelial carcinoma, bladder diverticula, urethral stenosis, difficult catheterization, altered bladder compliance, post-voiding residue >150 ml, urinary tract infections requiring antibiotics, known device hypersensitivity, and neurogenic bladder. Planned surgery/invasive procedures or pelvic radiotherapy within 24 wk prior to study start are not permitted.
2.5. Randomization
Eligible patients will be randomized by each site in a 1:1 ratio stratified by oncological therapy (BCG or MMC). The random assignment will be performed by REDCap platform, an online Research Electronic Data Capture system.
2.6. Data management
Data will be entered into electronic case report forms. The data system includes password protection and internal quality checks, to identify data that appear inconsistent, incomplete, or inaccurate. Clinical data will be entered directly from the source documents. Clinical monitoring will be overseen by an authorized clinical monitor provided by the sponsor. This monitoring activity will include assessing the following for each site: data entry errors, missing data, and responsiveness to data queries from the central study team. Site investigators and clinical research coordinators will be contacted as needed for retraining and technical assistance if systematic data integrity issues are discovered at their site. The clinical project manager will review and approve a monthly update report that will be shared with each clinical site, and which will be stored for record keeping.
2.7. Recruitment and timescale
Recruitment began in December 2024, targeting nine third-level Italian hospitals. The recruitment phase is expected to last 2 yr. Currently, 68 patients have been randomized, 35 in arm A and 33 in arm B, respectively.
3. Protocol overview
Before the treatment period start, patients are screened within 4 wk from TURBT or repeated TURBT (re-TURBT). Screening includes written informed consent, review of inclusion/exclusion criteria, demographic information including age, sex, medical history, TURBT (or re-TURB), cancer history (stage, date of diagnosis, previous treatments, surgery, or radiotherapy), medications related to the disease or symptoms. Worst T stage will be considered for re-TURB. Negative urine culture is required 2 wk pre-screening. Patients are randomized and complete IPSS and FACT-BI questionnaires. Risk classification (low risk, intermediate risk, and high risk) is based on tumor stage, grade (World Health Organization [WHO] 1973 and WHO 2022) and risk factors as age >70 yr, multiple papillary tumors, and diameter >3 cm [15].
3.1. Experimental arm: HC treatment
Patients randomized to the experimental arm will be treated with HC. In particular, BCG or MMC will be started within 1–2 wk from randomization (within 4–6 wk after TURB or re-TURB), as for clinical practice. BCG (6 wk) or MMC (8 wk) is administered weekly (±1 d) as induction cycles. Physical examination and symptom evaluation precede instillations. New/worsened clinically significant abnormalities are recorded as AEs on the eCRF. IPSS and QoL questionnaire (FACT-BI) are administered to the patient at cycles 1, 4, and 6/8 (BCG/MMC) of treatment. Experimental arm patients will receive a 50-ml single-use HC solution intravesically 48 h after MMC/BCG instillation. BCG patients receive 6 HC instillation and MMC patients receive 8 HC intravesical instillation, administrated by study health care staff (urological nurses). Permitted concomitant medications include antimicrobials, anesthetics, and analgesics (eg, phenazopyridine, propantheline bromide, nonsteroidal anti-Inflammatory drugs). Antibiotic prophylaxis is routine on instillation days for catheter-related infection prevention. De novo antimuscarinics, beta-3 agonists, or alpha blockers are not permitted.
Postoperative assessment will involve follow-up after 2 (±3 d), 6, and 18 wk (±1 wk) from last BCG or MMC instillation. Follow-up visits include physical examination, urine culture, IPSS, and QoL evaluation. Cystoscopy is performed at wk 6 and 18, per clinical practice.
3.2. Control arm: no treatment
Control arm patients receive BCG or MMC according to clinical practice, without HC instillations. BCG (6 wk) or MMC (8 wk) is administered weekly via intravesical instillation.
4. Statistical and ethical considerations
The study protocol was approved by Comitato Etico Territoriale – Area Nord Veneto (CET ANV 2024-07) and registered in EUDAMED (n. CIV-IT-24-07-048476).
Sample size calculation was based on prior data [16], considering a between-group mean difference of 1.5 points in the IPSS change from baseline to 15 d after last instillation treatment (BCG or MMC) as clinically relevant. Assuming a pooled standard deviation of the change scores of 3.0 points, 85 patients per group (170 total) are required to achieve 90% power with a two-sided 5% significance level. To account for a potential dropout rate of 17%, 100 patients per arm will be recruited (200 total patients). The sample size calculation was based on an independent sample t test. All randomized patients who received at least one intravesical treatment will be included in the primary analysis (intention-to-treat analysis). Baseline demographics, clinical characteristics, and eligibility adherence will be presented overall and by arm. Discrete variables are summarized by frequencies and percentages. Percentages will be calculated excluding missing values. Continuous variables will be summarized by the use of standard measures of central tendency and dispersion: mean, standard deviation, median, first and third quartiles, minimum, and maximum. Data will be stratified by arm and results will be compared. To evaluate the statistical significance of differences in frequency distribution (between groups), the chi-square or Fisher test will be used. To show the difference in the basal modifications of parametric values, over time, and between groups, Student’s t test paired and nonpaired data will be applied; for nonparametric values or small samples, Mann-Whitney U test will be applied. All results will be considered significant if inferior to 0.05 (p < 0.05). At the end of the study a statistical report will be produced. Analysis will be performed using the qualified SAS Analytics Pro software version 9.4 (SAS Institute Inc., SAS Campus Drive, Cary, North Carolina, USA).
To evaluate the primary objective, for every patient the IPSS score at wk 1 of treatment phase and 2 wk after the intravesical instillation treatment (BCG or MMC) end will be calculated. Differences before/after treatment will be calculated for every patient, and the mean differences between groups will be compared and evaluated using Student’s t test or Mann-Whitney U test (Shapiro-Wilk test will be used for test of normality). For every patient, time between randomization date and disease recurrence (RFS) or clinical disease progression (PFS) date will be calculated. For patients without recurrence or progression, date of last follow-up will be used. RFS and PFS will be estimated by the Kaplan-Meier method, and the corresponding 95% confidence interval will be derived based on the Greenwood formula. Toxicity during the treatment will be described according to the NCI-CTCAE v.5: grade and relationship with the study treatment will be described for each AE. The QoL scores will be analyzed as continuous variables using linear mixed-effects models to investigate patterns of change over time. The model will include experimental arm, time of assessment as a categorical variable, and the treatment-by-time interaction as fixed effects. An unstructured covariance matrix will be used to account for the correlation between repeated measurements within the same individual.
5. Summary
In NMIBC, following TURBT, patients typically receive adjuvant intravesical therapies to reduce the risk of recurrence and progression. These treatments commonly include intravesical chemotherapy, such as MMC, or immunotherapy with BCG. Despite their therapeutic benefits, intravesical instillations are frequently associated with treatment-related toxicity. Notably, BCG immunotherapy tends to exhibit a higher toxicity profile compared to chemotherapy. Nevertheless, adverse effects are predominantly localized, with systemic toxicity that is considered relatively uncommon. Local toxicity is biologically based mainly on the progressive removal of the GAG component lining the surface layer of the bladder. Toxicity caused by intravesical treatment could lead to discontinuation of therapy with a consequent increased risk of progression and relapse. All this can expose the patient to a higher rate of recurrence, thus greatly influencing the prognosis of the disease. To date, the management of these symptoms is based on empirical drugs such as nonsteroidal anti-inflammatory drugs or antibiotic treatment as judged by the clinician. At the same time, several studies over the years have tried to highlight the use of alternative treatments such as anti-inflammatory anesthetic solutions to reduce the frequency of nocturnal urination. Alternatively, solutions based on aluminum salts or prostaglandins have been tested to promote the formation of a protective layer and reduce urinary symptoms. In summary, the HC trial will contribute to ascertain the efficacy of an additional intravesical instillation alongside the therapeutic one, consisting of a muco-protective preparation based on HA and Hydeal-D (benzyl ester of HA) to manage local symptoms. In fact, treatment with HA sodium salt and Hydeal-D restores the bladder wall against toxic urinary irritants, reducing irritation, inflammation, and pain. HC, thanks to its prolonged action, provides optimal adhesion to the bladder mucosa, helping to restore the protective barrier. In terms of limitations, we also know that the hospital setting is consuming but allows for safety monitoring of HC in this specific setting and in a clinical trial. Due to these several consideration, HC represents a promising alternative to classic antibiotic and anti-inflammatory treatment to prevent discontinuation of therapy and consequently improve patient outcomes.
Author contributions: Gian Luca De Salvo had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: De Salvo, Amodeo, Porreca, Crestani, Magni, Callegarin
Acquisition of data: Callegarin, Buran
Analysis and interpretation of data: De Salvo, Magni
Drang of the manuscript: De Salvo, Callegarin, Amodeo, Claps
Critical revision of the manuscript for important intellectual content: Callegarin, Amodeo, Claps, Crestani, Antonelli, Busetto, Dal Moro, Zanovello, Pavan, Magni, Buran, Di Gianfrancesco, De Salvo, Porreca
Statistical analysis: Magni
Obtaining funding: Porreca, De Salvo
Administrative, technical, or material support: None
Supervision: De Salvo, Porreca
Other (specify): None
Financial disclosures: Gian Luca De Salvo certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.
Funding/Support and role of the sponsor: The authors declare that Fidia Farmaceutici S.p.A will provide the medical device for free for the randomized patients in the experimental arm and partially support the study, without any other involvement in the trial.
Ethics statement: The present article consists of a presentation of a study protocol for a clinical trial that is actually ongoing. The study protocol presented in this article was approved by the ethics committee Comitato Etico Territoriale – Area Nord Veneto, and by the “Ministero della Salute.” The authors certify that the study, the protocol of which is presented here, is being performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. The trial registration number is NCT06245603 and CIV-IT-24-07-048476.
Data sharing statement: Preparation of this paper did not involve analysis of data.
Associate Editor: M. Carmen Mir
Statistical Editor: Melissa Assel
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