Hyaluronic acid for IC/PBS

[Rufus]

Beyond the Abstract - Results of Endovesical Hyaluronic Acid/Chondroitin Sulfate in the Treatment of Interstitial Cystitis/Painful Bladder Syndrome

Tuesday, 24 June 2008

BERKELEY, CA (UroToday.com) - Hyaluronic acid (HA) is a natural proteoglycan that is hypothesized to replenish a defective glycosaminoglycan layer in interstitial cystitis/painful bladder syndrome (IC/PBS) (1) patients upon intravesical application. Initially, Morales (2) treated 25 patients and reported a 56% (week four) and 71% (week seven) response rate. Beyond week 24 effectiveness decreased but there was no significant toxicity. More recently, Nordling (3) reported a 3-year follow-up in a 3-month prospective, nonrandomized study evaluating the effect of intravesical hyaluronic acid on interstitial cystitis symptoms.

We based on the assumption that a more viscous compound than existent HA formulation, such as the one used, would be more effective in helping to restore a defective glycosaminoglycan layer. Besides, a solution consisting in a combination of HA and chondroitin sulphate, which had already been used as a single agent in IC/PBS patients (4), could produce additional benefits in patients than the use of its single components. Hyaluronic acid, also called sodium hyaluronate, was obtained in vials containing 40 ml of a clear, sterile, nonpyrogenic preparation of a high molecular weight fraction of sodium hyaluronate 1.6 % p/v associated with chondroitin sulfate 2.0 % p/v. Twenty-seven women 20 to 65 years old (mean 46.68, SD 13.63), with symptoms characteristic of Interstitial Cystitis/Painful Bladder Syndrome according to the criteria established by the National Institute of Health Consensus Conference (5) entered the trial, being recruited in two Centers.

After bladder catheterization with a sterile Nelaton catheter 10 or 12 Ch, the bladder was emptied, and the patients received endovesical administration of hyaluronic acid and chondroitin sulfate in normal saline, 40 ml, weekly for 12 weeks and then be-weekly for 6 months, if there was initial response; a single dose of oral antibiotic was administered before catheterization. The solution was maintained for 1 hour before voiding. The primary endpoint of our trial was to evaluate the efficacy of a therapeutic regimen consisting in weekly intravesical instillations of sodium hyaluronate 1.6 p/v with chondroitin sulfate 2.0 % 1.6 p/v, for a period of 12 weeks, in female patients with a diagnosis of IC/PBS. To this aim, assessment of urgency and pain by means of VAS (10 cm), reduction of number of voiding by means of voiding diary, and O’Leary-Sant IC Symptom and Problem Index (6), and PUF questionnaire (7) were used.

Outcomes were evaluated at baseline and 3 and 6 months after initiation of therapy.

Results were evaluated by comparing pre and post-treatment values of the following tests: 3-days voiding diary, O’Leary-Sant Symptom score, PUF questionnaire; VAS for urgency and pain.

The baseline values were compared to 12-week assessment and 6 months assessment. The statistical analysis was performed using the T-test for independent variables. We considered statistically significant p< 0.05.

Results

A total of 23 female patients completed the study. More than 91% of patients reported having symptoms for more than 1 year.

Mean follow-up was 5 months, range 3 to 8 months. No patient had intolerance and/or side effects related to treatment.

There were 69% who presented with moderate/severe pain and 69% with moderate/severe urgency, defined as a score of 5 or greater on the 0 to 10 VAS scale. Most patients were on concomitant oral therapies to relieve their bothersome symptoms.

The data from the analysis of the questionnaires at baseline and after 12 weeks treatment are reported in Table 1 and 2. Both Interstitial Cystitis Symptom and Problem Index and Pelvic Pain and Urgency/Frequency Symptom Scale (PUF) showed a mean significant improvement after 12 weeks of treatment.

The average number of voidings and mean voiding volumes revealed significant improvement after the 12 weeks’ treatment period, with a significant reduction and increase, respectively (Fig. 1-2); mean voiding volume increased significantly, from 143 ml to 191, which apparently was not reflected in a corresponding reduction of number of daily voids (from 15,5 to 14).

The analysis of the VAS showed the improvement reported in Table 2.

Two patients had to stop weekly intravesical treatment due to urinary tract infections observed after catheterization, and two additional patients had to stop maintenance be-weekly home self-administration of the product after completing 12 weeks intravesical treatment, due to bacterial urinary tract infections.

Conclusion

In our preliminary experience, the administration of intravesical hyaluronic acid plus chondroitin sulphate appears to be a safe and efficacious method of treatment in IC/PBS. In responsive patients, the effect appeared to persist during maintenance treatment and follow-up visits, consisting in an improvement of both urgency-frequency related symptoms and bladder/pelvic pain. No significant side effects were recorded, and concomitant oral therapies could be continued.

In order to confirm these initial encouraging results, further controlled, randomized studies are necessary with a greater number of patients and a longer follow-up.

References

1. Hanno P.(2002): Interstitial Cystitis and Related Disorders. In: Walsh P, ed. Campbell's Urology. 8th ed. Philadelphia: Elsevier; pp. 631.
2. Morales A et al. (1996) Intravesical hyaluronic acid in the treatment of refractory interstitial cystitis. J Urol 156: 45-48.
3. Nordling J, et al. (2001) Cystistat for the treatment of interstitial cystitis: a 3-year follow-up study. Urology 57 (6 Suppl 1): 123.
4. Palylyk-Colwell E. (2006) Chondroitin sulphate for interstitial cystitis. Issues Emerg health technol 86: 1-4.
5. Gillenwater JY and Wein AJ. (1988) Summary of the National Institute of Arthritis, Digestive and Kidney Diseases Workshop on Interstitial Cystitis, National Institutes of Health, Bethesda, Maryland, August 28-29, 1987. J Urol 140: 203.
6. Bernie JE, et al. (2001) The intravesical potassium sensitivity test and urodynamics: implications in a large cohort of patients with lower urinary tract symptoms. J Urol. Jul 166(1): 158-161.
7. O’Leary MP et al. (1997) The Interstitial Cystitis Symptom Index and Problem Index. Urology 49 (suppl 5A): 58-63.

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In contrast, we have this report from the recent ESSIC Meeting

CISTIC Study Report. Prospective Double-Blind Randomized Controlled Multi- Center Study Investigating the Efficacy of Hyaluronan in BPS/IC

It is unfortunately rare to learn details of large, negative studies sponsored by pharmaceutical companies, but in a superb and thoughtful presentation, results of the 5 year CISTIC study on intravesical hyaluronan, which involved 130 BPS/IC patients in 20 European and North American centers, were reported by Dr. Claus Riedl of Baden, Austria. Patients were treated with weekly instillations of hyaluronan or placebo in a 3:1 randomization for 8 weeks. Patient Global Assessment at week 9 was the primary endpoint. The projected size of the study was calculated with an estimate of efficacy of about 60% for treatment versus 30% for placebo. The 60% threshold was obtained. However, the placebo response in 30 patients was an astounding 80%. These patients received the alkalinized vehicle used in the active group. The way the study was powered, there appeared to be no statistical difference in terms of the primary end point between the hyaluronan and the control group. Controls used a significantly higher rate of concomitant medications and had a higher rate of bladder specific adverse events. Their disease duration was shorter than in the active treatment group. The presentation emphasized the difficulty designing studies in this population.

[Rufus]

Everybody is different.
Perhaps HA will work for some and not others.

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The point here is that the first study reporting positive findings had no placebo arm, no randomisation etc, so its value is extremely limited.