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Safety and Efficacy of the Use of Intravesical and Oral Pentosan Polysulfate Sodium for Interstitial Cystitis: A Randomized Double-Blind Clinical Trial

Thursday, 14 February 2008

BERKELEY, CA (UroToday.com) - Clinical Trial: In an effort to improve treatment results for BPS/IC, Davis and colleagues from Glendora, California and Pittsburgh in a study supported by Ortho-McNeil examined the safety and efficacy of a combination of intravesical and oral pentosan polysulfate sodium (PPS) in the treatment of interstitial cystititis.

This randomized, double blind, placebo controlled trial compared 20 patients treated with oral PPS at a dose of 200mg twice daily for 18 weeks with 20 patients who had the same regimen of oral PPS, and intravesical PPS (400mg in 30cc buffered saline) twice weekly during the first six weeks.

At week 18 the proportion of responders (who reported that their overall IC condition improved in comparison to baseline) was comparable in the two groups. The placebo group reported significant reduction in voiding frequency at weeks 6 and 18 compared to the treatment group. The change in the total score of O’Leary-Sant Interstitial Cystitis Symptoms/Problems Index from baseline at week 18 was -12 in the active group and -8 in the placebo group.

The study suggests a statistically significant improvement in patients treated with intravesical PPS. One cannot comment on any effect of the oral medication, as there was no oral placebo arm employed. In addition, all patients in both groups received alkalinized lidocaine prior to intravesical therapy (saline or PPS), which could account for the improvement noted in the placebo group. It is not clear why the oral dose of 200mg BID of PPS was chosen, as this is not the approved dose of medication per the drug label, and no dose response to more than 300mg daily for oral PPS in the treatment of IC has been shown, while side effects are dose dependent1.

This is an interesting paper suggesting that intravesical glycosaminoglycan therapy may be effective in some patients. No conclusions about combined oral and intravesical therapy can be derived from the data as a result of the study design.

Davis EL, El Khoudary SR, Talbott EO, Davis J, Regan LJ

Journal of Urology, 179(1):177-185, 2008
doi:10.1016/j.juro.2007.08.170

PubMed Abstract
PMID:18001798

UroToday.com Painful Bladder Syndrome Section

Written by Philip M. Hanno, MD, a Contributing Editor with UroToday.

Reader Comments

Re: Response to the Comments of Philip M
Written by This email address is being protected from spam bots, you need Javascript enabled to view it on 2008-02-24 20:37:19

We read with interest the comments of Dr. Phillip Hanno regarding our study entitled “Safety and Efficacy of the Use of Intravesical and Oral Pentosan Polysulfate Sodium for Interstitial Cystitis: A Randomized Double-Blind Clinical Trial”.

We do not agree with the author’s final statement that no conclusions about combined oral and intravesical therapy can be derived from the data as a result of the study design. It was clearly stated in our article that the main goal of our clinical trial was to assess whether or not intravesical instillation of pentosan polysulfate sodium (PPS) in combination with oral PPS would enhance the reduction of Interstitial Cystitis (IC) symptoms compared to oral PPS alone. This study design was the most appropriate design to asses our intended goal given the fact that PPS has been approved since 1996 in the USA for oral therapy and has been widely considered “standard of care” for the treatment of IC, therefore, a non-treated (true placebo) IC group was not to be considered.

This randomized clinical trial showed that the participants who received both intravesical and oral PPS (treatment group) reported greater reduction (greater reduction equates with improvement) in their total score of the O’Leary-Sant and its components (ICSI & ICPI) from baseline to each end point (week 6, week 12, and week 18) compared to those who received oral PPS and intravesical placebo (placebo group).

The changes in the total score of the O’Leary-Sant instrument and the ICSI score were significantly greater among the treatment group compared to the placebo group at week 12, (p=0.04, 0.03 respectively). The significant improvement can only be attributed to the addition of intravesical PPS to the oral PPS given the fact that both groups received oral PPS.

It is somewhat surprising that the author attributed the resolution of IC symptoms reported among the placebo group (using the patient global assessment) to the use of alkalinized lidocaine prior to intravesical therapy (saline or PPS) and not to the oral PPS which the placebo group received during the entire study period.

It was clearly written in our paper (material and method section and figure 2) as well as in Dr. Hanno’s comments that all subjects received alkalinized intravesical lidocaine before the trial drug/placebo instillation. Therefore, if alkalinized lidocaine would have contributed to IC symptom resolution; both groups should have experienced similar improvement, not only the placebo group.

The statistically high non-significant proportion of responders (improvement in overall
condition) among both the placebo group (90%) and treatment group (85.7%) should not surprise the author. This result was expected because of the way we defined the responders in our study as those who reported any level of improvement. As the placebo group received oral PPS during the entire period of the study it should be expected that they will report some improvement. Therefore, the distribution of the level of improvement that was achieved among the responders in each group and at each end point should be more important than focusing on this general result. Importantly, our study showed that the majority of the responders in the treatment group evaluated themselves as greatly improved (72.2%, 13 of 18), compared to only 33.3% (6 of 18) of the responders in the placebo group (p = 0.04).

We agree with Dr. Hanno that no dose response to more than 300 mg daily for oral PPS in the treatment of IC has been shown; however our decision to use 400 mg daily was based on our clinical standard of patient safety and compliance issues. It was evident in our clinical practice that the mid daily dose of the 300 mg daily was often reported forgotten; therefore treatment with PPS was compromised because of compliance issues. We have used PPS 200 mg BID in clinical practice for multiple years and it has proven it’s safety and effectiveness in this dose regimen. The study required a method to help assure that compliance would not be an issue; therefore the two times a day dosage was part of protocol. Our study showed that an increase of 100 mg per day was not related to significant adverse effects and all blood work were within normal ranges.

In conclusion, the results of our clinical trial showed significant evidence that the use of a combination of oral and intravesical PPS increases the effective response in the management of the devastating symptoms of IC in female patients rather than oral PPS alone.

Written by: Davis EL, El Khoudary SR, Talbott EO, Davis J, Regan LJ

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