A real-life multicentre clinical practice study to evaluate the efficacy and safety of intravesical chondroitin sulphate for the treatment of interstitial cystitis
J. Curtis Nickel, Queen’s University, CIHR Canada Research Chair in Urologic Pain and Inflammation, Department of Urology, Kingston General Hospital, Kingston, Ontario, Canada K7L 2V7. e-mail: firstname.lastname@example.org
To report a multicentre, community based open-label study designed to assess the efficacy and safety of intravesical sodium chondroitin sulphate in the treatment of patients with the clinical diagnosis of interstitial cystitis (IC). Chondroitin sulphate is a naturally occurring glycosaminoglycan (GAG) in the bladder mucus layer and changes in this GAG have been implicated in the pathogenesis of IC, and small single-centre studies have suggested that intravesical chondroitin sulphate may have efficacy in IC.
PATIENTS AND METHODS
Patients with IC were treated with sodium chondroitin sulphate (Uracyst®, Stellar Pharmaceuticals Inc., London ON, Canada) solution 2.0% via urinary catheter weekly for 6 weeks and then monthly for 16 weeks for a total of 10 treatments. The primary efficacy endpoint was the percentage of responders to treatment as indicated by a marked or moderate improvement on a seven-point patient Global Response Assessment (GRA) scale at week 10 (4 weeks after the initial six treatments) compared with baseline. A major secondary efficacy endpoint (durability) was the percentage of responders on the GRA scale after 10 treatments. Additional secondary efficacy objectives were differences from baseline in Patient Symptom/Problem Index scores over the course of the treatment compared with baseline.
In all, 47% of the 53 enrolled patients with long standing moderately severe IC (mean [sd, range] diagnosis of IC 3.0 [3.4, 0.1–16] years; duration of symptoms 9.2 [9.2, 1–39] years; baseline symptom score 14.2 [3.2]) were responders at week 10. At 24 weeks, 60% were responders. There was a statistically and clinically significant decrease in the mean (sd) symptom and bother scores from baseline at 10 weeks and 24 weeks, at 9.0 (4.3) and 8.1 (5.0), respectively (P < 0.001). There were no significant safety issues during the study.
This multicentre community based real-life clinical practice study suggests that intravesical chondroitin sulphate may have an important role in the treatment of IC and validates the rationale for a randomized placebo-controlled trial.
the National Institutes Of Health
Interstitial Cystitis Data Base
potassium sensitivity test
Patient Global Response Assessment.
It is now recognized that interstitial cystitis (IC) is a heterogeneous condition with multiple causes that could include bladder, pelvic floor, neurological, genetic and/or systemic factors. The patients present as multiple phenotypes such as primary bladder pain, primary pelvic floor dysfunction, primary pelvic and related pain, or a combination of these phenotypes along with systemic associated conditions such as irritable bowel disease and fibromyalgia. This explains the elusiveness of effective, predictable therapies for IC . IC/painful bladder syndrome, also recently named bladder pain syndrome, describes the phenotype of IC in which bladder pain is the predominant symptom . These patients complain of suprapubic or bladder pain with bladder filling, relief with emptying but also bothersome urinary frequency and urgency. It has been hypothesized that a defective or abnormal (for whatever reason) glycosaminoglycan (GAG) layer, a mucus layer important for the integrity of the bladder mucosa, plays a role, perhaps by allowing urinary solutes, such as potassium, to diffuse into the subepithelial tissues inducing an inflammatory reaction and eventually stimulating a peripheral neuropathy. Over the long-term, central sensitization occurs . The GAG layer consists of GAGs such as chondroitin, heparin, dermatin and hyaluraonate . Multiple therapies targeting this GAG layer have been evaluated and used in the treatment of IC/painful bladder syndrome including the oral administration of the exogenous GAG pentosanpolysulphate  and the intravesical administration of pentosanpolysulphate , heparin , and hyaluronate .
One of the best studied ‘naturally occurring’ GAGs in IC/painful bladder syndrome has been chondroitin sulphate  and studies have indicated a deficit of this proteoglycan in the bladder uroepithelium in IC . Two small single-centre Canadian open-label uncontrolled and poorly designed studies suggested that intravesical chondroitin sulphate instillations may ameliorate IC symptoms [11,12]. A large randomized placebo-controlled study is definitely required; however, before such an expensive and labour intensive trial can be justified or even properly statistically powered, a larger, multicentre evaluation of this treatment approach is necessary to confirm the results of these two small single-investigator studies. We report a multicentre, community based open-label study designed to assess the efficacy and safety of intravesical sodium chondroitin sulphate (Uracyst®, Stellar Pharmaceuticals Inc., London ON, Canada) in the treatment of patients with the clinical diagnosis of IC.
PATIENTS AND METHODS
The study population was enrolled from clinical practices based in Ontario, Canada. The IC diagnosis was based on the less restrictive National Institutes of Health (NIH) Interstitial Cystitis Data Base (ICDB) Definition of cases . Patients must have had the clinical signs and symptoms of IC (urinary/bladder pain/discomfort and urinary frequency/urgency) persisting for ≥24 weeks. Endoscopic evaluation was to be performed at the investigator’s discretion but was not a prerequisite for study inclusion. Besides the clinical ICDB-based diagnosis of IC, the inclusion criteria consisted of negative urine pregnancy test at baseline or assurance of previous surgery, condition or state rendering conception impossible, sterile bacterial urine culture no more than 30 days before first treatment, an average urinary frequency of at least 11 times per day, an average pain/discomfort score of ≥4 or greater on a 0–10 cm visual analogue scale. The following patients were excluded from participation in this trial: pregnant or lactating, currently receiving or having received investigational drugs ≤30 days before screening, currently receiving or having had prior intravesical therapy with Uracyst (chondroitin sulphate), cystistat (hyaluronate solution) and heparin, receiving therapy for <3 months with antidepressants, antihistaminics, hormonal agonists or antagonists; hence patient not stabilized on therapy (stable therapy defined as continuous treatment for ≥3 months), currently receiving or having received prior therapy with oral pentosanpolysulphate (Elmiron®) for ≤3 months before screening, IC symptoms relieved by antimicrobials, anticholinergics or antispasmodic, neurological disease affecting bladder function; any previous surgery or procedure having affected bladder function, current UTI (must be treated and have a negative culture before study entry), current diagnosis of chemical, tuberculous or radiation cystitis, history of bladder or lower ureteric calculi, history of cancer within the last 5 years other than adequately treated nonmelanoma skin cancers, active sexual transmitted disease, current vaginitis, or current therapy for endometriosis.
The trial received Research Ethics Board approval (Queen’s University and Research Review Board Inc.) Patients signed informed consent before enrolment and intervention.
POTASSIUM-SENSITIVITY TEST (PST)
All patients were requested to undergo PST evaluation. The PST has been previously described . Briefly, a control solution of sterile water (40 mL) was instilled in the participant’s bladder and held for 5 min. After 5 min, the participant is asked to rank their sense of urgency and pain on a scale from 0 to 5 (none, mild, moderate or severe). The water was drained and replaced with 40 mL of potassium solution (40 mEq KCl in 100 mL of water) and held for 5 min. After 5 min, the participant was asked to rank their sense of urgency and pain on the same scale as used with the first solution. The participants were also asked to contrast the differences between solutions 1 and 2 and to rank how strongly the solutions differ. If pain on administration was quick and intense, the solution was drained immediately and the result considered positive. Otherwise, a positive PST occurred if the participant’s urgency or pain grade for the potassium solution was at least 2 points above 0 and caused more symptoms than the control solution. If neither solution was associated with any symptoms of urgency or pain the test was considered to be negative. Participants with negative and positive results were entered into the trial.
Patients received 20 mL of sterile sodium chondroitin sulphate 2.0% (Uracyst) via urinary catheter weekly for 6 weeks and then monthly for an additional four treatments for a total of 10 treatments.
The primary efficacy outcome was the percentage of responders to treatment as indicated by improvement on a seven-point Patient Global Response Assessment (GRA) scale at week 10 (4 weeks after six treatments; before initiation of monthly treatments) compared with baseline. The patient evaluates the overall change in their condition as ‘markedly improved’, ‘moderately improved’, ‘slightly improved’, ‘no change’, ‘slightly worse’, ‘moderately worse’ or ‘markedly worse’. Responders were defined as patients who reported either that they were moderately or markedly improved. A major secondary efficacy endpoint (durability) was the percentage of responders on GRA at 24 weeks (end of study).
Other secondary efficacy objectives were change in O’Leary-Sant Symptom/Problem Index scores  over the course of the treatment until the end of study (24 weeks) compared with baseline. Pain, urgency and frequency scores (0–10 cm visual analogue pain scale) were also measured over the course of the treatment period.
Based on the placebo response from recent trials examining intravesical therapies in similar patients [16,17], a positive pilot trial (defined as a response that would justify a prospective randomized double-blind placebo-controlled trial) was conservatively set at 35% responder rate. We planned for enrolment of 50 patients from eight clinical practices.
For statistical analyses t-test, Mann–Whitney rank-sum test, z-test and proportional analysis were used as appropriate.
In all, 53 women with IC/painful bladder syndrome were enrolled at five centres. Table 1 shows the baseline demographics and variables. The cohort of patients in this trial was chronic, moderately to severely symptomatic and comparable with those enrolled in recent intravesical therapy treatment trials [16,17]. In all, 48 patients (90.6%) had a positive PST.
Baseline demographics and IC-related variables
|Number of patients||53|
|Mean (sd, range):|| |
| Age, years||44.1 (15.2, 21–80)|
| Duration of diagnosis, years||3.0 (3.4, 0.1–16)|
| Duration of symptoms, years||9.2 (9.2, 1–39)|
|Concurrent conditions, n (%)|| |
| Irritable bowel syndrome||14 (26.4)|
| Chronic fibromyalgia|| 5 (9.4)|
| Depression||13 (24.5)|
| Migraine headaches||20 (37.7)|
| Allergic phenomenon*||39 (73.6)|
| Endometriosis||6 (11.3)|
| Vulvodynia/vulvovestibulitis||3 (5.7)|
The outcomes are shown in Table 2. For the primary outcome at 10 weeks (after six weekly treatments), the responder rate was 47.2%. The O’Leary-Sant Symptom Score decreased by a mean of 5 points, the Bother Score decreased by a mean of 4.3, while the pain and urgency scores decreased by 2.6 and 2.7, respectively (All P < 0.001 compared with baseline). The responder rate increased to 60.4% by the end of the study (24 weeks) with further improvements in the symptom and bother scores as well as pain and urgency.
Table 2. Outcomes at 10 and 24 weeks in 53 patients with IC/painful bladder syndrome treated with intravesical chondroitin sulphate
|Primary outcome (% GRA responders)||na||47.2||na||na||60.4||na||na|
|Mean (sd) score:|| || || || || || || |
| symptom||14.2 (3.2)||9.0 (4.3)||5.0||<0.001||8.1 (5.0)||6.2||<0.001|
| bother||12.6 (2.7)||8.2 (4.0)||4.3||<0.001||7.0 (4.5)||5.7||<0.001|
| pain||6.9 (1.8)||4.3 (2.3)||2.6||<0.001||3.3 (2.5)||3.6||<0.001|
| urgency||7.4 (1.6)||4.7 (2.3)||2.7||<0.001||3.5 (2.5)||3.9||<0.001|
| frequency||7.9 (1.4)||5.3 (2.1)||2.6||<0.001||4.1 (2.4)||3.8||<0.001|
In all, 28 patients (53%) reported 65 adverse events: upper respiratory 19, unrelated pain (headache, neck back or associated with trauma) 17, genital (vulvar burning, vaginitis) 10, UTI six, bladder symptoms (increased frequency, urgency or incontinence) six, gastrointestinal six and other (vertigo) one. Of these 65 reported adverse events 20 may have been related to treatment (genital eight, UTIs six and increased bladder symptoms six) and were all considered mild.
Patients with long term IC/painful bladder syndrome had a significant improvement in global symptoms (47.2% were responders) after six weekly intravesical treatments with chondroitin sulphate. A further percentage of patients improved with additional monthly treatment sessions (60.4% at 24 weeks). This primary observation was validated by a significant decrease in the symptom and bother scores (P < 0.001) at 10 and 24 weeks. No safety issues were identified.
It is acknowledged that IC is a difficult urological condition to manage, particularly from the point of view of an evidence- based approach . While oral pentosanpolysulphate has shown some efficacy , its overall benefits are modest at best [19,20]. Hydroxyzine is recommended , but has not proven its efficacy in randomized placebo-controlled trials  and while amitriptyline looks promising , we await the results of the recently completed NIH placebo-controlled trial  to determine its true efficacy. Many cases of IC are thought to be related to bladder pathology (hence the names painful bladder syndrome and bladder pain syndrome ) and it is reasonable to consider bladder focused therapies. Several intravesical therapies are available and have been evaluated in clinical trials. Dimethyl sulfoxide has been traditionally used for treating IC , but only one small, short single-centre trial has reported efficacy . BCG and resiniferatoxin both were promising therapies based on early clinical evidence [26,27], but large multicentre randomized placebo-controlled trials failed to confirm this efficacy [16,17]. Heparinoids such as pentosanopolysulphate , heparin sulphate , and hyaluronate  have been suggested as therapeutic options for intravesical therapy, but no large definitive placebo-controlled trials have been presented or published to confirm their efficacy .
There appears to be a deficit of several luminal and basal proteoglycans, particularly luminal chondroitin sulphate , associated with IC . Recent studies strongly suggested that abnormal differentiation in the urothelium of patients with IC, independent of inflammation, was associated with loss of two specific proteoglycans, biglycan and perlecan . While it is thought that there may be several aetiological avenues for patients to arrive with a diagnosis of IC, it is likely that the bladder is involved to some extent in patients who present with primary bladder pain and voiding symptoms (painful bladder syndrome or bladder pain syndrome). Re-establishment of normal urothelial surface structure and function in the long term would be the ultimate goal of therapy; however, until we can achieve that, it is attractive to attempt exogenous means to do the same thing in the short term.
Two small single-centre studies [11,12] have suggested that intravesical chondroitin sulphate may have benefit but these studies were poorly designed with questionable follow-up and outcome measures. Sorensen  provided his personal experience in treating 20 patients; four were not analysed (two lost to follow-up and two stopped the treatment because of side-effects). He reported that the 12 patients followed for ≥1 year had significant improvement but the outcome tool used was not disclosed. Steinhoff  reported his personal series of 18 patients with IC. In an unorthodox analysis, he determined that of the 13 patients he was able to follow, six had a good response, two had a fair response while five had a partial or no response. He further correlated his subjective response with improvement in the O’Leary-Sant IC symptom and problem index score change.
The rationale for the use of chondroitin sulphate as a treatment method for IC and the personal, somewhat anecdotal, experience of two urologists in private practice are not enough evidence to recommend that this approach be used as a standard therapy for IC. Based on these reports there is not enough real evidence to even decide whether the concept should be tested in an expensive and labour intensive randomized placebo-controlled clinical trial. The present multicentre prospective clinical trial that enrolled patients with a clinical diagnosis of IC/painful bladder syndrome and used a validated symptom assessment plan, strongly indicated that intravesical chondroitin sulphate may have a role in the treatment of IC/painful bladder syndrome and should be subjected to more rigorous clinical assessment. The obvious major limitation of the present study was that it was not a randomized placebo-controlled trial. While it therefore has the bias of all ‘unblinded’ open-label studies, the study was designed as a pilot study to confirm the suggestions from previous very small single-investigator studies and to provide data to inform the next step, a definitive randomized placebo-controlled trial. The strengths of the present study were that the number of patients enrolled was sufficient to achieve endpoint, no patients withdrew from the study, and the results probably mimic the efficacy that would be seen in real-life clinical practice.
In conclusion, the present ‘real-life’ clinical practice study provides further confirmation of the possible efficacy of intravesical chondroitin sulphate therapy for IC/painful bladder syndrome, validates the need and provides data for appropriate power analysis for a randomized placebo-controlled trial. Such a trial will be required to definitively confirm the efficacy of intravesical chondroitin sulphate in the management of IC/painful bladder syndrome.
CONFLICT OF INTEREST
None declared. Source of funding: the study was funded by an independent investigator initiated grant by Stellar Pharmaceuticals Inc. to J. C. Nickel and Queen’s University.