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Current Medical Research and Opinion
ISSN: 0300-7995 (Print) 1473-4877 (Online) Journal homepage: https://www.tandfonline.com/loi/icmo20
Efficacy of pentosan polysulfate for the treatment
of interstitial cystitis/bladder pain syndrome:
results of a systematic review of randomized
controlled trials
Arndt van Ophoven, Kirsten Vonde, Winfried Koch, Günter Auerbach & Klaus
P. Maag
To cite this article: Arndt van Ophoven, Kirsten Vonde, Winfried Koch, Günter Auerbach & Klaus
P. Maag (2019) Efficacy of pentosan polysulfate for the treatment of interstitial cystitis/bladder pain
syndrome: results of a systematic review of randomized controlled trials, Current Medical Research
and Opinion, 35:9, 1495-1503, DOI: 10.1080/03007995.2019.1586401
To link to this article: https://doi.org/10.1080/03007995.2019.1586401
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Published by Informa UK Limited, trading as
Taylor & Francis Group.
Accepted author version posted online: 08
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Published online: 19 Mar 2019.
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CURRENT MEDICAL RESEARCH AND OPINION
2019, VOL. 35, NO. 9, 1495–1503
https://doi.org/10.1080/03007995.2019.1586401
Article RT-0021.R1/1586401
REVIEW
Efficacy of pentosan polysulfate for the treatment of interstitial cystitis/bladder
pain syndrome: results of a systematic review of randomized controlled trials
Arndt van Ophovena
€nter Auerbachd and Klaus P. Maage
, Kirsten Vondeb, Winfried Kochc, Gu
Marien Hospital Herne, University Hospital Ruhr-Universit€at Bochum, Herne, Germany; bGranzer Regulatory Consulting & Services, Munich,
Germany; cBiostatistical Data Services Koch, Schwetzingen, Germany; dbene-Arzneimittel GmbH, Munich, Germany (since 2017 Dr. Pfleger
Arzneimittel GmbH, Bamberg, Germany); ebene pharmaChem GmbH & Co.KG, Geretsried, Germany
a
ABSTRACT
ARTICLE HISTORY
Background: Among the numerous therapeutic approaches used in the treatment of interstitial cystitis/bladder pain syndrome (IC/BPS) few have been assessed with a sufficient level of evidence. The
safety and efficacy of pentosan polysulfate sodium (PPS) has been shown in several open-label and
comparative clinical trials with different populations including two meta-analyses. In the context of the
approval procedure of PPS for the treatment of IC/BPS by the European Medicines Agency we
updated the findings of the previous analyses by incorporating the results of the latest studies.
Method: Relevant studies based on a systematic review of PubMed/Medline and the Cochrane Library
in June 2018 were identified. For completeness control, clinical trial registries were also searched. Only
randomized, placebo-controlled clinical trials providing sufficient information to estimate at least one
relevant effect size measure to compare the efficacy of PPS versus placebo were included in
the analysis.
Results: Of the studies identified in the literature search, six randomized placebo-controlled studies
met the pre-defined eligibility criteria. Analyses showed no indication of heterogeneity or publication
bias. Treatment with PPS led to a statistically significant improvement in the patient’s overall response
assessment (p < .001), pain (p ¼ .009) and urgency (p ¼ .005).
Conclusions: Our meta-analyses confirmed the results of preceding meta-analyses showing that PPS is
efficacious compared to placebo in the treatment of bladder pain, urinary urgency and frequency of
micturition and thus an evident option for the treatment of IC/BPS symptoms.
Received 11 January 2019
Revised 19 February 2019
Accepted 21 February 2019
Introduction
Interstitial cystitis/bladder pain syndrome (IC/BPS) is a poorly
defined clinical condition characterized by the symptoms
pelvic pain, urinary urgency and urinary frequency. The
symptoms overlap with those of other common conditions
and are not associated with specific pathognomonic changes.
Currently, IC/BPS is diagnosed via a process of exclusion
using the clinical symptoms and occasionally cystoscopic findings since many patients have no cystoscopic findings. It’s a
severe and significantly debilitating disease which is often
preceded by a long history of suffering before proper diagnosis. Many patients with mild disease are often misdiagnosed
with conditions such as recurrent urinary tract infections
(UITs), overactive bladder or gynecologic chronic pelvic pain1.
For quite some time the term BPS has been used to
describe a broader spectrum of symptoms that meet a more
inclusive, symptom-based definition, without cystoscopic and
histologic features. The change in terminology was put forward by the European Society for the Study of IC/BPS
CONTACT Klaus P. Maag
[email protected]
KEYWORDS
Bladder pain syndrome;
interstitial cystitis; drug
therapy; glycosaminoglycans; pentosan polysulfate;
review; randomized
controlled trials;
meta-analysis
(ESSIC)2 and has been adopted by the European Association
of Urology (EAU) in their respective guidelines3. Nowadays
both terms are commonly used, predominantly IC/BPS. The
clinical characteristics shared by all conditions falling under
the IC/BPS description are rather non-specific and, in order
to differentiate diagnostically between these very heterogeneous forms of IC/BPS, a classification scheme was introduced by the ESSIC group and implemented in the 2015
EAU guideline. This reflects the diagnostic usage of biopsy
and cystoscopy with hydrodistension including their respective findings. On the other hand the American Urologic
Association guidelines for the diagnosis of IC do not require
cystoscopy for diagnosis and it may be diagnosed based on
symptoms only.
Pharmacological treatments for IC/BPS may be administered
either orally or intravesically. Within the US, two treatments are
authorized for use in IC/BPS, oral pentosan polysulfate sodium
(PPS) or intravesical dimethyl sulfoxide (DMSO).
PPS has become established as an efficacious treatment for
IC/BPS, which is characterized by either glomerulations or
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A. VAN OPHOVEN ET AL.
Hunner’s lesions. The very first randomized placebo-controlled
clinical trial investigating the efficacy of PPS in treating IC/BPS
was published in 1987. Subsequently several randomized, controlled clinical trials and two meta-analyses have been published which evaluate the efficacy of PPS in the treatment of
IC/BPS. Hwang et al. conducted a first meta-analysis covering
the period 1966–19944. Based on a literature search four
randomized, controlled trials (RCTs) including 398 patients
were identified showing benefit differences for pain, urgency
and frequency in favor of PPS. In 2007, Dimitrakov et al.5 published a systematic review of the pharmacologic management
of IC. They identified five placebo-controlled RCTs out of six
RCTs with a total of 633 patients, whereby a meta-analysis of
effects suggests a statistically significant benefit for the treatment with PPS over placebo.
While PPS capsules for the treatment of IC/BPS were
approved in 1993 in Canada, 1994 in Australia and 1996 in the
US, it was only in June 2017 that PPS capsules (Elmiron1)
gained a marketing authorisation by the European Commission
as the first drug treatment for IC/BPS characterized by either
glomerulations or Hunner’s lesions in adults with moderate to
severe pain, urgency and frequency of micturition.
In relation to the approval procedure by the European
Commission, the findings of the comprehensive analyses by
Hwang et al. and Dimitrakov et al.4,5 have been updated
using a more conservative intent-to-treat (ITT) approach
instead of the original “as reported” approach and extended
by incorporating the results of the latest study6.
There was upfront analysis planning but the statistical
analyses were also influenced by the submission process
with regulatory advice implemented at the time when
received. As a consequence no final and complete planning
document was generated and registered on PROSPERO a priori. Current methodological guidance for reporting items for
systematic reviews and meta-analyses7 has been applied in
order to compare and critically evaluate all data available
from randomized, placebo-controlled trials testing PPS for
the treatment of IC/BPS.
Evidence acquisition
Search strategy
Relevant studies based on a systematic review of PubMed/
Medline and the Cochrane Library in June 2018 were identified
using the free-text search control terms “interstitial cystitis” or
“bladder pain syndrome” and “clinical trial”. Simultaneously a
search for additional potentially unpublished studies on PPS
was conducted on ClinicalTrials.gov as provided by the US
National Library of Medicine and the European Union Clinical
Trials Register for the active drug “pentosan polysulfate”. After
a first review of abstracts, full text was studied in more detail
to extract the required information.
Eligibility criteria
Only randomized, placebo-controlled clinical trials providing
sufficient information to estimate at least one relevant effect
size measure to compare the efficacy of oral PPS versus placebo were included in the meta-analyses following the
reporting items for systematic reviews and meta-analyses7.
To be included in the meta-analyses, studies had to: (a)
evaluate the therapeutic effect of oral PPS on treating interstitial cystitis; (b) be placebo-controlled clinical trials; (c)
involve patients with a clinical and cystoscopically verified
diagnosis of IC; and (d) provide sufficient information to estimate at least one relevant effect size measure to compare
the efficacy of PPS versus placebo.
Evidence synthesis
The search identified 268 manuscripts, 1 Cochrane review
and 22 records from clinical trial databases. Six manuscripts
were included in the meta-analysis (Figure 1, Table 1).
Data extraction
Assessment of the impact of the different symptoms of BPS
is very subjective and differs between patients. If patients
assess “global response” to treatment, the measured effect
size will reflect the significance of the single symptoms for
the individual patient. Accordingly, the main focus of the
meta-analysis was patient global response assessment (GRA),
which was assessed in most of the identified studies. A
responder definition of at least moderate or 50% improvement in patient GRA has become established in the medical
community as a clinically relevant and meaningful improvement in BPS8. Further correlations with increased patient satisfaction, improved sleep scores and improved sexual
functioning show the clinical relevance of the chosen
responder definition for an improvement in GRA. For studies
that did not evaluate any form of global improvement versus
baseline, data was imputed based on the closest information
provided in the respective publication. In addition, the effect
of PPS on pain and urgency was assessed. No imputations
for results on pain or urgency were conducted.
Effect size data for the meta-analyses of target variables was
extracted from the original publications as well as from the
meta-analyses identified in the literature search4,5. Reasonable
efforts were made to clarify any discrepancies, including contacting authors of the publications, as far as possible.
Methods of statistical analysis
As the individual studies mostly analyzed and compared success rate differences, this approach was also followed for the
meta-analyses. Success rate was defined as the proportion of
responders per group and differences in success rates (PPS placebo) were denoted as benefit differences as a greater
difference in rates indicated higher benefit with PPS. The
intent-to-treat (ITT) principle including all randomized
patients was used for the meta-analyses. Patients with missing data were considered as failure.
Heterogeneity was assessed using Q and I2 statistics.
Publication bias was tested using various statistical methods
(classic fail-safe N; Orwin’s fail-safe N; Begg and Mazumdar
rank correlation test; Egger’s regression test); the funnel plot
EFFICACY OF PENTOSAN POLYSULFATE FOR TREATMENT OF IC/BPS
178 records idenfied
from Pubmed / Medline
1 Cochrane Review
90 Trials idenfied
from Cochrane Lib.
1497
22 records idenfied from
ClinicalTrials.gov and the
European Union Clinical Trials
No addional trial idenfied
184 of records aer 84 duplicates removed
184 of records screened
6 studies included in meta
analysis
178 records excluded
75 reviews
18 studies in animals
18 no intervenon
13 comments / leers
12 open label trials
11 intravesical treatments
editorials/summaries (9), re
analyses (7), not IC/BPS (5), case
reports (4), others (6)
Figure 1. Evidence acquisition in a systematic review on pentosan polysulfate in the treatment of bladder pain syndrome characterized by either glomerulations
or Hunner’s lesions in adults with moderate to severe pain, urgency and frequency of micturition.
was used to assess the symmetry of the distribution of studies. To estimate the between-study variance, the method of
moments by DerSimonian and Laird9 was used in all
meta-analyses.
To assess the treatment effect on symptom scores, mean
changes from baseline and standard deviations were used. In
most studies these results were immediately available, in
other studies standard deviations were estimated from other
measures e.g. from p values. The standardized mean difference was used as the effect measure. This was calculated by
dividing the raw mean difference between groups by the
pooled standard deviation of the two treatment groups.
Comprehensive Meta-Analysis Software from Biostat2 and
JMP3 were used for conducting the meta-analyses.
Results
Of the studies identified in the literature search, and in
accordance with the search results of two previous metaanalyses4,5, six randomized placebo-controlled studies met
the pre-defined eligibility criteria and were included in the
meta-analyses conducted. The study characteristics are summarized in Table 1.
Overall, the patient population enrolled was comparable
across studies for the proportion of female patients and age
distribution, and is reflective of the general population suffering from BPS. In four studies, the majority of patients had
their diagnosis confirmed by cystoscopy10–13, while Sant
et al. and Nickel et al.6,14 enrolled a more heterogeneous
patient population, in whom the diagnosis was mainly based
on clinical symptoms.
The last two studies were conducted in the US at a time,
when PPS was commercially available for the treatment of
IC. Both studies faced severe recruitment problems, which
might have led to enrollment of patients who had previously
been treated with PPS.
Two dosing schemes (3 100 mg PPS per day and
2 200 mg PPS per day) were evaluated in the six studies,
which were considered comparable. Furthermore, the treatment periods of the studies covered 3–6 months and were
considered comparable, although longer treatment with PPS
is expected to lead to better effects.
All studies focused on patient-reported response to treatment. However, only three studies (Mulholland et al., Parsons
et al., Sant et al.)11–13 evaluated comparable primary endpoints (the proportion of patients with 50% [moderate]
global improvement from baseline). A fourth study by Nickel
et al.6 used a responder analysis based on a 30% improvement in the ICSI (Interstitial Cystitis Symptom Index); a
responder analysis based on a 50% improvement in the GRA
scale was evaluated as secondary endpoint.
The study reported by Parsons and Mulholland10 did not
evaluate any form of global assessment but separately evaluated patient-reported improvement for four distinct subjective symptoms (urgency, frequency, nocturia and pain). A
patient reaching a 50% improvement compared to baseline
was considered a responder for the specific symptom. The
mean response rates by treatment group across the individual response rates of pain, urgency and frequency were
imputed for this study as response rates for the primary
meta-analysis.
Holm-Bentzen et al.14 evaluated improvement of the
patients under therapy by assessing the mean total symptom
score values with regard to the symptoms pain, frequency,
nocturia, dysuria and urgency. A decrease in the total symptom score values was classified as at least four steps (with a
total of 1.00 or 0.25 for each step). A decrease of at least 1.00
in mean total symptom score was considered to be a clinically significant improvement. Only absolute improvement was
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A. VAN OPHOVEN ET AL.
Table 1. Relevant characteristics of studies included into the meta-analysis.
Holm-Bentzen
Parsons and
et al. 198714
Mulholland 198710
Study design
Mean age (years)
Female (%)
Treatment duration
(months)
Dose
Diagnosis based
on cystoscopy
Prior PPS treatment
Early termination
Drop-outs/treated patients
ITT patients (PPS/placebo)
Primary endpoint –
responder analysis
Mulholland
et al. 199011
Parsons et al.
199312
Sant et al.
200313
Nickel et al.
20156
Parallel-group
Parallel-group
Parallel-groupa
Parallel-group
Parallel-group
57
90
4
n.a.
90
4
43
91
3
43
97
3
Parallel-group
(factorial design)
45
89
6
2 200 mg
3 100 mg
3 100 mg
3 100 mg
3 100 mg
No
2 200 mg,
3 100 mg
Yes
Yes
Yes
Yes
No
No
n.a.
10/115
58/57
No
n.a.
13/75
38/37
No
n.a.
12/110
54/56
No
n.a.
18/148
74/74
Yes
121/136
25/121
59/62
Total symptom score
Pain, urgency,
frequency, nocturia
GRA
GRA
GRA
Yes
368/645
163/251
122/118
(IC subgroup 29/32)
ICSI
43
93
6
a
Cross-over design (partial), but first treatment period (parallel group) used only.
n.a., Not available; PPS, Pentosan polysulfate sodium; ITT, Intention to treat; IC, Interstitial cystitis (IC/BPS); GRA, Global response assessment; ICSI, Interstitial
Cystitis Symptom Index.
Figure 2. Global response assessment (Holm-Bentzen14, Parsons10, Mulholland11, Parsons12, Sant13, Nickel6).
evaluated; no relative comparison to baseline made. The
responder analysis based on an improvement of at least 1.00
in mean total symptom score was therefore imputed in the
primary meta-analysis in order to approach the responder
definition (at least moderate or 50% improvement) used in all
other studies as close as possible.
While Holm-Bentzen et al. and Nickel et al.6,14 did not
show a statistical difference between PPS and placebo, four
studies detected a benefit of PPS over placebo, of which the
studies by Parsons and Mulholland, Mulholland et al. and
Parsons et al.10–12 revealed a clearly statistically significant
difference. The Sant et al.13 study for the primary efficacy
analysis used a rather conservative analysis method (exact
conditional test version of the Mantel–Haenszel method to
control for clinical center clustering) resulting in a p value of
.064; this was in slight contrast to our testing result for this
study (p ¼ .042) which was based on the simple chi-square
test as for all individual studies included in this
meta-analysis.
The efficacy endpoints evaluated in the placebo-controlled studies were all based on a patient-reported outcome
of subjective symptoms. In such analyses, placebo effects are
often high. Furthermore, each of the studies enrolled a very
limited number of patients due to the rarity of the disease.
These two aspects made it difficult to consistently detect
statistically significant differences in the individual studies.
Accordingly, meta-analysis of these studies is appropriate to
assess and estimate the overall difference in efficacy
between PPS and placebo (see also Figure 2).
Results of meta-analysis
In order to evaluate the improvement in individual patients’
burden of disease, the primary meta-analysis evaluated the
percentage of patients that experienced a clinically relevant
improvement in GRA compared to baseline (Figure 2). A
12.4% difference in the responder rates between PPS-treated
patients and placebo-treated patients was estimated (95% CI:
6.4%–18.3%). The combined difference between the two
groups was highly statistically significant (p < .001). This primary meta-analysis showed no indication of heterogeneity in
standard measures (Q-value ¼ 4.019, p ¼ .547, I2 ¼ 0).
The meta-analysis of the primary endpoints from the
publications did not show any indication of heterogeneity
(Q-value ¼ 5.098, p ¼ .404, I2 ¼ 1.924%); the estimated benefit difference was 11.9% (95% CI: 5.8%–18.0%) and thus very
EFFICACY OF PENTOSAN POLYSULFATE FOR TREATMENT OF IC/BPS
1499
Figure 3. Improvement in pain (Holm-Bentzen14, Parsons10, Mulholland11, Parsons12, Nickel6).
Figure 4. Improvement in urgency (Parsons10, Mulholland11, Parsons12, Nickel6).
close to that of the GRA-based analysis presented in
Figure 2.
In addition, the efficacy of PPS on pain (Figure 3) and
urgency (Figure 4) was evaluated across all identified studies
as far as respective results were reported. An improvement
in pain and urgency was considered to be a 50% reduction
compared to baseline.
For an improvement in pain, the estimated combined
responder rate difference between PPS and placebo was
12.1% (95% CI: 3.0–21.1%; p ¼ .009). Moderate heterogeneity
was detected for the efficacy of PPS on pain observed across
the studies (Q ¼ 7.35, p ¼ .119, I2 ¼ 45.6%). The results for an
improvement in urgency showed a statistically significant difference of 9.9% (95% CI: 2.9–16.8%) in the responder rates in
favor of PPS (p ¼ .005). The meta-analysis revealed no indication of heterogeneity (Q ¼ 2.163, p ¼ .539, I2 ¼ 0%).
Efficacy of pentosan polysulfate in patients with
interstitial cystitis/bladder pain syndrome diagnosed
based on cystoscopic findings
Focusing on the four studies that limited enrolment to those
patients diagnosed based on cystoscopic examinations, the
respective outcome results were even clearer. This was not
unexpected given the more homogeneous patient population. This patient population represents the patient population for whom PPS is currently indicated in the EU.
The primary meta-analysis on these four studies showed a
benefit difference of 17.0% (95% CI: 9.3–24.7%) in favor of
PPS (Figure 5). The difference was highly statistically significant (p < .001) without any indication of heterogeneity
(Q ¼ 0.470, p ¼ .925, I2 ¼ 0).
A more appropriate assessment of the clinical relevance
of the PPS effect size is a pooled analysis of results per treatment group (PPS treatment versus no PPS treatment) as the
pooled results allow a comparison between the magnitudes
of treatment effects in each treatment group. Results of this
analysis revealed an approximate duplication of response
rates between PPS and placebo for GRA, pain and urgency
(Figure 6).
The duplication of the treatment effect was confirmed by
an adequate meta-analysis which resulted in a benefit ratio
of GRA of 2.085 (95% CI: 1.464–2.967) (Figure 7).
Additionally, there was no indication of heterogeneity for
this meta-analysis (Q ¼ 0.245, p ¼ .970, I2 ¼ 0). This confirms
that the benefit ratio is an appropriate measure to describe
the superiority of PPS over placebo.
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A. VAN OPHOVEN ET AL.
Figure 5. Global response assessment, cystoscopically diagnosed patients only (Parsons10, Mulholland11, Parsons12, Sant13).
Figure 6. Pooled responder rates per treatment arm, cystoscopically diagnosed patients only.
Publication bias
Six methods were applied to investigate publication bias;
three of them (including visual inspection of the funnel plot)
identified potential trends for publication bias. This finding is
best quantified by Duval and Tweedie’s Trim and Fill
approach (Figure 8) which identified one study as possibly
missing and this missing study was imputed to achieve
approximate symmetry. Based on this conservative imputation (red circle in Figure 8), the meta-analysis still showed a
clear superiority of PPS over placebo: 0.113 (0.056, 0.170)
(difference in GRA response rates with 95% CI).
Discussion
Four studies (Parsons and Mulholland; Mulholland et al.;
Parsons et al.; Sant et al.)10–13 and meta-analyses by Hwang
et al. and Dimitrakov et al.4,5 have demonstrated the efficacy
of PPS in the treatment of BPS. However, this clear and
homogeneous picture has been challenged in a more recent
publication by Nickel et al.6 in 2015 which has
raised questions.
Although the Nickel et al.6 study was a large study enrolling an appropriate number of patients and was planned
with good intent in accordance with best practices, it did
present several challenges. The relevant meta-analyses did
not show heterogeneity in standard measures used, but it
was rather obvious for us that the study deviated from the
remaining studies and a lot of effort was spent to explore
and explain this deviation. The authors themselves acknowledged considerable differences in the enrolled patient population compared to earlier studies. Patients were enrolled
with milder symptoms, without applying cut-off criteria for
pain or urgency, without determination of flare status, without an entry criterion based on cystoscopy findings, and
without the exclusion of conditions commonly associated
with BPS such as irritable bowel disease, depression or pelvic
floor dysfunction disease. In addition, the commercial availability of PPS for the treatment of IC/BPS some time before
the study was conducted may have impacted patient recruitment, leading to a very slow recruitment rate and ultimately
to early termination of the study. Furthermore, by potentially
including patients who were not PPS-naive, the study may
have inadvertently selected patients who were non-responders to previous PPS therapy or potential non-responders
based on disease phenotype. All these factors could have
severely biased the treatment and placebo responses; a
response was achieved in 51% of patients treated with placebo. If analysis is limited to only patients completing the
study, the placebo response rate is 76%. This high placebo
response rate was likely enhanced by the described multiple
factors of patient selection, including patients with milder IC
entering during a symptom flare, regression to the mean,
introduction (inadvertent or not) of conservative therapy,
EFFICACY OF PENTOSAN POLYSULFATE FOR TREATMENT OF IC/BPS
1501
Figure 7. Global response assessment, benefit ratio (Parsons10, Mulholland11, Parsons12, Sant13).
Figure 8. Exploration of publication bias – funnel plot of estimated benefit difference in GRA response rates corresponding to Figure 2.
¼ estimated benefit dif¼ estimated benefit difference in GRA response rates including the (red colored) imputed study.
ference in GRA response rates for all 6 studies;
Figure 9. Success rates under placebo - comparison of placebo response rates (Parsons10, Mulholland11, Parsons12, Sant13, van Ophoven16, Warren17).
which accentuated the benefits of placebo in another recent
trial, and failure of clinical sites to keep patients in the trial
which resulted in a high dropout rate.
The forest plot in Figure 9 illustrates the high placebo
response rate in the Nickel et al. study compared to the
placebo response rates of all other studies found in the literature. The response rate in the PPS group of the Nickel
study corresponds well with the overall picture of success
rates for PPS, but the particularly high response rate in the
placebo group is a point of concern. Overall, there are severe
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A. VAN OPHOVEN ET AL.
limitations to the Nickel study with regard to early termination, study design, enrolment criteria and high dropout rates.
To gain a clear indication of the efficacy of PPS based on
all placebo-controlled, randomized clinical studies conducted
to date, the meta-analyses described above were conducted.
Based on the large number of patients (n ¼ 368) enrolled in
the Nickel study, the study results were assessed with relevant weight in these meta-analyses (as demonstrated by the
size of the square describing the results per study in
Figures 2–4).
The overall evaluation of all available data resulted in a
statistically significant benefit of PPS over placebo in terms
of patients reaching at least a moderate or 50% improvement in their GRA compared to baseline. Furthermore, statistically significantly more patients reached a 50%
improvement in pain and urgency compared to baseline.
These effects were even more pronounced when the metaanalysis focused on the more homogeneous patient population that was diagnosed based on cystoscopic findings,
which is not an unexpected finding.
The pooled response rate on GRA improvement following
PPS treatment indicated that 33.0% of patients experienced
a clinically relevant reduction in disease burden while the
same effect was only observed in 15.8% treated with placebo. The relative difference of 109% in responder rates
between PPS and placebo is clearly clinically relevant. This is
supported further by the effects on the symptoms pain and
urgency following PPS treatment. For GRA the percentage of
responders experiencing 50% improvement in pain and
urgency was approximately two-fold higher following PPS
compared to placebo.
As stated in more detail before, in 2008 the ESSIC classification was established accompanied with a change in terminology, reflecting the diagnostic value of biopsy and
cystoscopy. This classification became established as a defacto standard to differentiate diagnostically between distinct
forms of IC/BPS. Recognizing this, evidence regarding differences in the therapeutic benefit of PPS in relation to biopsy
results and cystoscopic findings would be valuable. However,
the available results of the early studies included do not provide further information in this regard. While most studies
were conducted long before the ESSIC criteria became established, this also applies in particular for the latest study.
Conclusion
Our current meta-analysis confirms the results of a preceding
meta-analysis and comprehensive review showing that PPS is
more efficacious than placebo in the treatment of pain,
urgency and frequency, and beneficial for symptoms of IC/
BPS. The response rates of the studies included correspond
well with the overall picture of success rates for PPS, but limitations like the particular high drop-out rate and response
rate in the placebo group in the latest studies are to
be considered.
In summary, treatment with PPS led to a statistically significant and clinically relevant improvement in patients’
overall response assessment (at least moderate or 50%
improvement from baseline) in addition to clinically relevant
improvements in the main symptoms of IC/BPS, i.e. pain and
urgency (50% improvement from baseline). Thus PPS is an
evident option for the treatment of IC/BPS symptoms as
stipulated in the clinical guidelines of the relevant professional associations3,15.
Notes
1.
2.
3.
Elmiron is a registered trade mark of bene-Arzneimittel GmbH,
Munich, Germany.
Comprehensive Meta-Analysis (CMA) software for meta-analysis Version
3, Biostat, Englewood, USA.
JMP (Version 11.2.1) is a registered trade mark of SAS Institute Inc., Cary,
NC, USA.
Transparency
Declaration of funding
All work performed was financially supported by bene-Arzneimittel
GmbH and bene pharmaChem GmbH & Co.KG.
Author contributions
Study concept and design: A.v.O., G.A., K.P.M., K.V., W.K.; data acquisition:
K.P.M., K.V., W.K.; analysis and interpretation of data: A.v.O., G.A., K.P.M.,
K.V., W.K.; manuscript: A.v.O., K.P.M., K.V.; revision: A.v.O., G.A., K.P.M.,
K.V., W.K.; supervision: A.v.O., K.P.M.
Declaration of financial/other relationships
A.v.O., K.V., W.K., G.A. and K.P.M. have disclosed that they are employees,
former employees or consultants of bene-Arzneimittel GmbH and bene
pharmaChem GmbH & Co. KG. Pfleger Arzneimittel GmbH markets
Elmiron in Germany; bene pharmaChem GmbH & Co. KG is the manufacturer of pentosan polysulfate. CMRO peer reviewers on this manuscript
have no relevant financial or other relationships to disclose.
Acknowledgements
No assistance in the preparation of this article is to be declared.
ORCID
Arndt van Ophoven
http://orcid.org/0000-0002-9982-4637
Klaus P. Maag
http://orcid.org/0000-0002-1014-5719
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