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The Prostate 37:246–252 (1998)
Double-Blind, Placebo-Controlled Trial to Assess
the Efficacy and Tolerability of Mepartricin in the
Treatment of BPH
Louis Denis,1* Francesco Pagano,2 Atanasio Nonis,3 Chris Robertson,3
Paolo Romano,4 and Peter Boyle3
1
Oncology Centre Antwerp, Antwerp, Belgium
Department of Urology, University of Padua, Padua, Italy
3
Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy
4
Medical Department, Società Prodotti Antibiotici, Milan, Italy
2
BACKGROUND. Mepartricin, a semisynthetic polyene derivative with a favorable effect on
urethro-prostatic function, was clinically evaluated, adopting the diagnostic and research
criteria recommended by the First International Consultation on BPH.
METHODS. A multicenter, randomized, double-blind, parallel-group study compared mepartricin 40 mg/daily to placebo in the treatment of 196 patients with newly diagnosed BPH
and mild-to-moderate symptomatology. International Prostate Symptom Score (I-PSS), quality of life (QoL) index and maximum urinary flow-rate (Qmax) were determined every 4 weeks
for 6 months; postvoiding volume, prostate volume, and prostate-specific antigen (PSA) were
assessed after 3 and 6 months of therapy.
RESULTS. Mepartricin was shown to determine a statistically significant improvement over
placebo in I-PSS and QoL index from month 2 onwards, and a significant linear increase in
Qmax over the study period. At month 6, the improvement in the mepartricin and placebo
groups in I-PSS, QoL index, and Qmax was 6.3 (standard error (SE) 0.51) and 4.2 (SE 0.60)
points (P = 0.003), 0.99 (SE 0.14) and 0.62 (SE 0.12) points (P = 0.036), and 2.7 (SE 0.46) and 1.2
(SE 0.46) ml/sec (P = 0.051), respectively. No significant differences were noted in postvoiding
residual volume, prostate volume, or PSA. Mepartricin tolerability was good, showing no
adverse events on sexual function.
CONCLUSIONS. Mepartricin proved to be an effective treatment of benign prostatic hyperplasia, determining an improvement in symptoms, quality of life, and peak urinary flow.
Prostate 37:246–252, 1998. © 1998 Wiley-Liss, Inc.
KEY WORDS:
mepartricin; BPH; estrogen withdrawal therapy
INTRODUCTION
Benign prostatic hyperplasia (BPH) is one of the
most common diseases of the aging man. Early histological changes associated with the pathogenesis of
BPH have been reported in nearly 100% of men over
age 80 years [1], and the age-specific prevalence of
prostatic enlargement was reported to be around 88%
in men over age 80 years [2]. Clinical BPH associated
with bladder outlet obstruction was found in as many
as 50% of men over age 70 years [3].
Although the pathogenesis of BPH would generally
be recognized as an androgen-dependent process, estrogens have also been implicated as an etiological
© 1998 Wiley-Liss, Inc.
factor. The proportion of serum estrogens relative to
androgens increases in aging men [4], estrogen recepOn behalf of the Mepartricin Study Group: Jens Altwein, Munich,
Germany; Aldo Bono, Varese, Italy; Johan Braeckman, Brussels, Belgium; Fernando Calais Da Silva, Lisbon, Portugal; Armenio Pinto de
Carvalho, Lisbon, Portugal; Paolo Ferrari, Modena, Italy; Fernando
Jimenez Cruz and José Ruiz Cerda, Valencia, Spain; Tullio Lotti and
Domenico Prezioso, Naples, Italy; Mario Reis, Porto, Portugal; Luis
Resel Estevez, Madrid, Spain; and Jose Vicente Rodriguez, Barcelona, Spain.
*Correspondence to: Prof. Dr. Louis Denis, Oncology Centre Antwerp, Lange Gasthuisstraat 35-37, 2000 Antwerp, Belgium.
Received 9 July 1998; Accepted 21 July 1998
Mepartricin in the Treatment of BPH
tors (ER␣) have been found to be localized in prostatic
stroma [5], and estradiol levels and the estrogen/
testosterone ratio have been reported [6,7] to be correlated significantly to the development of BPH. Attempts to treat BPH, by reducing the estrogen serum
concentration by treatment with the aromatase inhibitor atamestane, failed to produce evidence in support
of the estrogenic influence, possibly due to the concomitant increase in testosterone and dihydrotestosterone levels in serum during treatment [8].
Mepartricin is a semisynthetic derivative of a polyene antibiotic, isolated from the culture broth of a
Streptomyces aureofaciens strain [9]. This compound
binds irreversibly to certain steroids and is minimally
systemically absorbed after oral administration. It has
been proposed that mepartricin may interfere with the
reabsorption of estrogens from the gut, leading to increased fecal estrogen excretion and decreased estrogen plasma concentration, due to the effect on enterohepatic circulation. The concentration of testosterone
in serum has been shown to be reduced only marginally if at all, following mepartricin administration [10–
13]. It is therefore reasonable to propose that mepartricin may provide a new antiestrogenic approach to
the treatment of BPH [14]. Controlled clinical trials
carried out in patients with BPH have shown that mepartricin, at the dose of 40 mg daily, can promptly
improve symptomatology and urinary flow, with a
good tolerability and with no impact on sexual function [15,16].
The present study was established to evaluate the
efficacy and safety of mepartricin in the treatment of
BPH, adopting the use of the International Prostate
standard Symptom Score (I-PSS) and quality of life
(QoL) index for the assessment of clinical response, as
well as the diagnostic and research criteria recommended by the First International Consultation on
BPH held in 1991 [17].
PATIENTS AND METHODS
Patients
This multicenter trial was conducted at 11 centers
located in Belgium (1), Germany (1), Italy (3), Portugal
(3), and Spain (3). The protocol was submitted to and
approved by the relevant Ethics Committees of participating centers, and patients gave informed consent
before being recruited into the study. Patients were
enrolled into the study if they were between age 55–80
years, with newly diagnosed BPH and with I-PSS
scores between 12–25, a quality of life index (QoL) 艌3,
postvoiding residual urine 艋100 ml, and peak urinary
flow-rate between 6–15 ml/sec (with voided urine volume 艌150 ml). Patients on whom surgical treatment
247
was performed or was indicated, with genitourinary
cancer or infections, with normal digital rectal examination (DRE), and with known hypersensitivity to
polyene, were excluded.
Study Protocol
The trial was designed as a randomized doubleblind, placebo-controlled, parallel group study. Randomization was balanced within each center. Patients
who fulfilled entry criteria before and after a 2-week
run-in period were randomized to receive either mepartricin 50,000 U three times daily (corresponding to
40 mg/daily), or placebo in a double-blind fashion for
a period of 6 months. During the active treatment
phase of the study, follow-up visits were performed
every month. At the time of the screening visit, patients underwent the following investigations: medical history, including I-PSS and QoL assessment; routine physical examination, including DRE; routine hematology (hemoglobin, erythrocyte sedimentation
rate (ESR), erythrocytes, and leukocyte count) and biochemistry (glucose, urea, creatinin, total bilirubin, alkaline phosphatase, serum glutamic oxalacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), gamma glutamyl transferase (GGT),
prostate-specific antigen (PSA)); urinalysis by dip
stick and urine culture; urinary flow determination;
and postvoiding residual and prostate size assessment
(by transabdominal or transrectal ultrasonography).
Physical examination, I-PSS score, QoL assessment,
and urinary flow determination were repeated every
month throughout the study period. Residual urine
volume, hematology, and biochemistry were repeated
after 3 months of treatment and at the end of the
study. Prostate size assessment was reevaluated at the
end of the 6-month treatment period.
Statistical Analysis
Since no data were available on the clinical response to mepartricin as evaluated by use of the I-PSS,
it was not possible to accurately determine the sample
size of the study, a priori. Based on previous experience, however, a sample size of 100 patients in each
arm was considered to be sufficient to establish, with
accepted statistical power, a clinically relevant difference between the mepartricin and placebo groups.
For the efficacy assessment, the primary end points
were established as a change in I-PSS, QoL index, and
maximum urinary flow (Qmax), after 1, 2, 3, 4, 5, and 6
months of treatment in comparison with month 0 (end
of the run-in period). Postvoiding residual volume,
prostate volume, and PSA, as well as laboratory
workup, were considered as secondary outcome variables: changes after 3 and 6 months of treatment were
compared relative to baseline data (collected during
248
Denis et al.
TABLE I. Reasons for Discontinuation of Patients From the Study
Treatment group
Lost to follow-up
Loss of patient’s interest
Adverse events
Lack of efficacy
Unrelated medical problems
Unmet entry criteria
Total
Mepartricin
(N = 98)
Placebo
(N = 98)
End of run-in
(N = 201)
6
3
2
2
1
1
2
1
2
1
12 (12)
the screening visit, before the run-in period). All available data at each follow-up visit were included in the
analysis. An intent-to-treat analysis of the primary end
points was also carried out, using last value carried
forward for the few patients dropping out.
The statistical analysis specified in the protocol was
to use the nonparametric Mann-Whitney U test, to test
if the differences in the scores (I-PSS, QoL, and Qmax)
at each follow-up visit, relative to month 0, were the
same in the two groups. The Wilcoxon signed rank
test was used to test if there was a change in scores
from month 0 to month 6, within each treatment
group. Although I-PSS is an ordinal variable ranging
from 0–35, the histograms showed that it could be
reasonably summarized as if it were a quantitative
variable. Thus, a multivariate analysis of variance for
repeated measures [18] was performed, in which the
fixed effects were treatment, time, and their interaction in order to utilize the data at all time points. The
same analyses were carried out for Qmax data, even
though it was necessary to use a square root transformation for the analysis of variance. The QoL index
was analyzed through a repeated measures multilevel
logistic regression, after having dichotomized it into:
score 1 for ‘‘delighted,’’ ‘‘pleased,’’ or ‘‘mostly satisfied’’; and score 0, otherwise [19].
For the other variables (postvoiding residual, prostate volume, and PSA) in which a normal distribution
may be assumed (possibly after appropriate transformation), the analyses were carried out using paired
t-tests, two-sample t-tests, and repeated measures
analyses of variance.
Eventually, the safety evaluation was carried out by
computing the proportion and 95% confidence interval of adverse events in each study group.
RESULTS
In all, 201 patients were recruited into the study
from September 1993–October 1995: 196 patients were
5 (5)
1
5 (2.5)
randomized to receive either placebo (98) or mepartricin (98); 5 patients withdrew from the study at the
end of the run-in period because of adverse events
(2 patients), loss of interest (1 patient), failure to return
to follow-up (1 patient), or decrease of the I-PSS below
the inclusion criteria range (1 patient).
Seventeen patients (8.3%) discontinued the treatment, 12 in the mepartricin arm of the study and 5 in
the placebo group; this was mainly due to the failure
of patients to return to follow-up (6 and 2 patients in
the mepartricin and placebo groups, respectively), or
due to loss of interest by patients (Table I).
Patients’ demographic and baseline characteristics
are reported in Table II. Means and standard deviations relative to age and weight were similar in the
two treatment groups. Patients in the two groups were
also similar at baseline with respect to I-PSS and QoL
scores, peak urinary flow-rate, PSA, and prostate volume, as well as with respect to their smoking and
alcohol-drinking habits.
Only data from evaluable patients are reported,
since the intent-to-treat analysis gave identical conclusions.
In both groups, there was evidence of a statistically
significant decrease, with respect to baseline (P =
0.0001), in the I-PSS score after 6 months. Patients in
the mepartricin group showed a lower I-PSS score
with respect to placebo at all follow-up visits, with the
difference between the two groups being statistically
significant as early as after 2 months of treatment (Fig.
1). At the end of the 6-month treatment period, decreases in scores of 4.2 (SE 0.60) and 6.3 (SE 0.051) in
the placebo and mepartricin group, respectively (P =
0.0031), were observed. Analysis of the mean I-PSS
over time showed a different linear trend between
groups (P = 0.006), with the I-PSS mean score in the
mepartricin group decreasing earlier than in the placebo group. Although in neither of the two groups
was a plateau in the I-PSS response reached, it was
apparent that the decrease in I-PSS score tended to
Mepartricin in the Treatment of BPH
249
TABLE II. Patients’ Demographic and Baseline Characteristics*
Treatment group
Number randomized
Age (years)
Weight (kg)
International Prostate Symptoms Score
Quality of life index
Mean peak urinary flow (ml/sec)
Total voided (ml)
Residual volume (ml)
Prostate volume (g)
Serum prostate-specific antigen (␮g/l)
Mepartricin
Placebo
98
64.5 ± 6.1
73.6 ± 9.4
16.5 ± 3.9
3.0 ± 1.2
10.5 ± 3.0
236 ± 87.8
42.7 ± 32.2
41.6 ± 17.5
2.7 ± 2.5
98
66 ± 6.3
74.1 ± 11.0
16.6 ± 3.9
3.2 ± 1.2
10.6 ± 3.2
236 ± 83.2
48.9 ± 33.6
44.6 ± 21.7
3.18 ± 3.7
*Baseline values are means ± SD. Data were obtained at the screening visit, before the placebo
run-in period. I-PSS ranges were from 0–35, and QoL index ranges were from 0–7. Postvoiding
residue volume, prostate volume, and PSA were obtained from fewer patients than those randomized (see Table III).
Fig. 1. International Prostate Symptoms Score (left) and quality of life index (right) in patients with benign prostatic hyperplasia,
according to treatment group. Scorres are expressed as mean changes from baseline (month 0) and 95% confidence intervals. Time − 0.5
month corresponds to the screening visit before the start of the placebo run-in period.
level off towards the end of the study period (P (for
curvature) = 0.04).
The result of the analysis of the QoL assessment
was consistent with the improvement in urinary
symptoms. In both groups there was a significant decrease in the QoL index after 6 months, compared to
month 0 (P < 0.0001). As shown in Figure 1, at all
follow-up visits, the QoL index decreased more in the
mepartricin group than in the placebo group, with the
differences being statistically significant after 2
months and all subsequent visits. There was also clear
evidence of an improved quality of life in the mepartricin group over time, with a strong increase in QoL
relative to the slight increase in the placebo group (P =
0.002).
Fig. 2. Mean changes (±95% confidence interval) in peak urinary
flow (Qmax) from baseline (month 0) over the study period, according to treatment group. Time − 0.5 month corresponds to the
screening visit before the start of the placebo run-in period.
250
Denis et al.
TABLE III. Postvoiding Residue Volume (ml), Prostate Volume (g), and PSA (ng/ml) at Baseline and After 3 and
6 Months of Treatment*
Postvoiding residue (no. of patients)
Baseline
Month 3
Month 6
Prostate volume (no. of patients)
PSA (no. of patients)
Mepartricin
Placebo
Mepartricin
Placebo
Mepartricin
Placebo
42.7 ± 32.2 (93)
40.1 ± 47.5 (82)
37.1 ± 48.4 (74)
48.9 ± 33.6 (92)
42.2 ± 49.6 (75)
44.4 ± 59.7 (75)
41.6 ± 17.5 (55)
44.6 ± 22.1 (29)
41.5 ± 20.7 (39)
44.6 ± 21.7 (60)
40.3 ± 12.4 (23)
40.5 ± 17.3 (33)
2.70 ± 2.6 (75)
3.13 ± 3.0 (70)
3.13 ± 3.0 (61)
3.18 ± 3.8 (76)
3.19 ± 2.2 (66)
3.26 ± 4.5 (65)
*Values are expressed as means ± SD. There was no evidence of differences in the mean values of these parameters between the two
treatment groups.
Mean peak urinary flow at month 0 was 11.0 (SE 0.42)
ml/sec and 11.1 (SE 0.31) ml/sec in the placebo and
mepartricin groups, respectively (Fig. 2). Compared to
placebo, a statistically significant increase in the peak
urinary flow of patients treated with mepartricin was
observed after 1, 3, and 5 months of treatment. At month
6, the difference in the increase in peak flow as compared to month 0 (2.7 (SE 0.46) ml/sec in the mepartricin
group and 1.2 (SE 0.46) ml/sec in the placebo group)
was close to statistical significance (P = 0.051). A significant increasing linear trend over time in Qmax was observed in the mepartricin group (P = 0.031), with a linear
increase in peak urinary flow of 0.14 (SE 0.02) ml/sec per
month compared to 0.09 (SE 0.02) ml/sec per month in
the placebo group.
There was no evidence of any difference between
groups with respect to prostate volume, postvoiding
residue, and PSA, or the change in the mean values of
these parameters, as shown in Table III. In both
groups, prostate volume was measured in about 2/3
of patients at baseline and in 1/3 of patients at month
3 and 6.
All patients randomized to receive either mepartricin or placebo were evaluated for safety and tolerability and all adverse events, whether or not believed to
be treatment-related, were reported (Table IV). Overall, 11 adverse events were observed during the study,
7 by patients in the mepartricin group (7.1%), and 4 by
patients in the placebo group (4.0%). Only 2 adverse
events of severe intensity were observed (carpal tunnel syndrome in the mepartricin group, and impotence in the placebo group): all others were mild or
moderate. In patients treated with mepartricin, the
most frequently reported adverse events were gastric
discomfort (2) and pruritus (2). In the placebo group,
the adverse events reported were related to decreased
libido (1), impairment of sexual potency (2), and erectile dysfunction (1). Two patients discontinued treatment because of an adverse event occurring after 1
month of treatment: one in the mepartricin group
(pruritus), and one in the placebo group (impairment
of sexual potency).
TABLE IV. Adverse Events in the Two
Treatment Groups
Treatment group
Mepartricin
Placebo
98
98
2
0
2
0
1
0
0
0
3
1
1
1
0
0
Number of patients
Digestive system
Abdominal discomfort
Skin
Pruritus
Urogenital system
Balanopostitis
Erectile dysfunction
Decreased libido
Musculo-skeletal system
Tendinitis
Carpal tunnel syndrome
No differences were noted between the two groups
with respect to hematological or biochemical parameters, nor were any abnormal values of these tests reported as adverse events.
DISCUSSION
Mepartricin is a semisynthetic polyenic compound,
which has been approved in Italy as well as in some
other European and non-European countries for the
treatment of BPH. Mepartricin, which is minimally
systemically absorbed after oral administration, is
considered to exercise its antiestrogenic effect by interfering with the enterohepatic circulation of estrogens. Experimental studies in rats and dogs [12,14]
have shown that mepartricin treatment results in a
decrease in the concentration of estrogens in blood,
with a concomitant increase in fecal estrogen excretion
and an associated reduction in both prostate estrogen
and estrogen receptor levels.
In the present study, carried out to evaluate the
efficacy of mepartricin through the use of a standard
symptoms score, mepartricin was shown to determine
Mepartricin in the Treatment of BPH
a statistically significant improvement in I-PSS, QoL
index, and Qmax over placebo, in patients with mild or
moderate symptoms of BPH (I-PSS between 12–24).
Mepartricin induced a prompt effect. A statistically
significant improvement in I-PSS over placebo was observed following 2 months of treatment, and this effect
was maintained at each follow-up visit throughout the
study. At the end of the 6-month study period, the
mean improvement in I-PSS for patients receiving mepartricin was 39.4% (SE 3.2%) as compared to 25.1%
(SE 3.4%) for those receiving placebo, with the difference between the two groups being 14.3% (SE 4.7%).
In the study of the Veterans Affairs Cooperative Study
Group, which compared terazosin, finasteride, and the
combination of the two, and in which patients were
comparable with regard to intensity of symptoms,
Qmax, and prostate volume to those enrolled in the
present study [20], the reduction in the American Urological Association (AUA) symptom score observed
after 12 months of treatment with terazosin was 37.6%,
with the difference compared to placebo of 21.2%. The
peak effect of terazosin treatment occurred after 3
months of therapy, whereas in this study, symptom
improvement after mepartricin treatment was shown
to plateau after 6 months of therapy.
In the Veterans Affairs study, finasteride failed to
produce a symptomatic improvement greater than
that of placebo, presumably because it elicits clinical
efficacy only in patients with a prostate volume
greater than 50 ml [21]. Furthermore, finasteride was
shown in other studies to require up to 8 months before producing stable improvement in symptomatology [22,23].
A statistically significant improvement in peak urinary flow (Qmax) with mepartricin was not observed at
all follow-up visits, whereas a statistically significant
improvement in symptom score over placebo occurred. At the end of the study period, however, a
significant linear trend in the increase of peak urinary
flow was observed in the mepartricin group. A larger
sample size may be necessary to further investigate
the effect of mepartricin on peak urinary flow.
Due to difficulties in attributing a clinical meaning
to some of the parameters generally used to evaluate
the outcome of BPH treatment, QoL assessments are
increasingly being perceived as an important end
point in therapeutic evaluation. At the end of the treatment period, the improvement in QoL assessment paralleled the improvement in I-PSS: this was observed to
be 29.5% (SE 5.4%) following mepartricin treatment,
and 14.0% (SE 4.7%) in the placebo-treated group,
with a difference between the two groups of 15.5% (SE
7.2%).
Prostate volume was recorded in a small percentage of the recruited patients and was not influenced
251
by mepartricin treatment. Estrogens have been reported [24] to cause overgrowth of the fibromuscular
component of the prostatic stroma, as well as epithelial atrophy. In addition, an estrogen sensitizing effect
on urethral smooth muscle cells to alpha-adrenergic
stimulation has been described [25,26]. Should the ‘‘estrogen-withdrawal’’ role of mepartricin be confirmed
in men, there will be the need to further investigate its
effect on the glandular and stromal histology of the
prostate, as well as on the tone of the smooth musculature of the lower urinary tract.
Mepartricin was well-tolerated, with the more frequent adverse events being gastric discomfort and
pruritus. No adverse events related to sexual function
were reported in the mepartricin-treated group. Not
being orally absorbed, mepartricin is expected to have
good systemic tolerability. In both groups, few adverse events were reported, and a larger group of patients is now required to investigate more extensively
the tolerability profile of mepartricin. In an open-label
clinical investigation in which 1,640 patients received
mepartricin at a dose of 40 mg daily for 30–60 days,
gastrointestinal adverse events (abdominal pain, dyspepsia, nausea, meteroism, diarrhea, and constipation) were the most frequently reported (7.5%) [27].
Problems concerning sexual function, such as erectile
impairment and decrease of libido, occur quite frequently in patients with BPH [28,29]. In the present
study, a relatively high percentage of sexually related
adverse events was observed in the group treated with
placebo, although well within the range reported in
other placebo-controlled clinical trials [21,23].
CONCLUSIONS
Mepartricin was proven clinically effective in the
treatment of BPH, improving patients symptomatology, Qmax, and perceived health status as compared to
placebo. This, together with good tolerability and lack
of sexual impairment, makes mepartricin an interesting therapeutic option in treating BPH. However,
more research is needed to further investigate its
mechanism of action in men and the clinical outcome
following long-term treatment.
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