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 , and the age-specific prevalence of prostatic enlargement was reported to be around 88% in men over age 80 years . Clinical BPH associated with bladder outlet obstruction was found in as many as 50% of men over age 70 years . 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 , 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 , 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 . Mepartricin is a semisynthetic derivative of a polyene antibiotic, isolated from the culture broth of a Streptomyces aureofaciens strain . 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 . 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 . 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  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 . 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 , 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 . 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  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%) . 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. 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