World J Urol DOI 10.1007/s00345-014-1247-z
Original Article
Immunostimulation in chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS): a one‑year prospective, double‑blind, placebo‑controlled study Florian M. E. Wagenlehner · Stefania Ballarini · Kurt G. Naber
Received: 1 November 2013 / Accepted: 20 January 2014 © Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose Inflammation/immunological dysfunction are discussed etiological causes of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). OM-89 is an orally immunostimulating agent. We performed a phase three multicentre, randomized, double-blind, placebo-controlled, long-term (12 months) study with OM-89 produced with a different lysis process in patients with moderate-to-severe CP/CPPS type III. Methods Patients were randomized to OM-89 or placebo. Primary efficacy variable was difference of responders at the end of treatment (month 9) in patients receiving OM-89 versus placebo. Results Two hundred and three patients were screened, 185 patients (47.8 ± 8.4 years) (90 % of CP/CPPS type IIIb) were enrolled in 30 centers and included in the safety set. Ninety-four were randomized to OM-89, 91 to placebo. One hundred and seventy-six patients were subjected to the full analysis (FAS), 150 to the per protocol set (PPS). Baseline NIH-CPSI score in FAS was 21.8 ± 3.8 (OM-89) and 23.0 ± 5.6 (placebo). At primary efficacy endpoint (month 9), in the OM-89 group, 67.0 % in FAS (PPS 72.7 %) and On behalf of the OM-89 UV-2005/01 Study investigators (see appendix). F. M. E. Wagenlehner (*) Clinic for Urology, Pediatric Urology and Andrology, Justus-Liebig-University Giessen, Rudolf‑Buchheim‑Str. 7, 35385 Giessen, Germany e-mail: [email protected] S. Ballarini Vifor Pharma/OM Pharma, Meyrin, Geneva, Switzerland K. G. Naber Technical University, Munich, Germany
in the placebo group, 64.3 % in FAS (PPS 64.4 %) were responders [FAS: OR 1.19, p = 0.59; PPS: p = 0.19]. Mean relative decrease in NIH-CPSI was 40.5 and 44.0 % in the FAS. Treatment-related adverse events were low: 8.5 % with OM-89 and 5.5 % with placebo. Because of small numbers, no conclusion could be drawn regarding the potential benefit of OM-89 in CP/CPPS IIIa. Conclusions This placebo-controlled study evaluating OM-89 in patients with CP/CPPS showed a significant and long-lasting (12 months) favorable response with OM-89, but also with placebo. OM-89 was safe and well tolerated. EudraCT 2007-004609-85. Keywords Chronic prostatitis/chronic pelvic pain syndrome · Immunostimulation · Placebo effect
Introduction Chronic prostatitis/chronic pelvic pain syndrome syndrome (CP/CPPS) is a frequent condition [1, 2], and current pathophysiological understanding recognizes an initial insult in the context of alterations in psychoimmunoneurendocrine factors [3]. One of these factors comprises immune dysfunction including alterations in cytokine function [4] and autoimmunity [5], modulating neural afferent function [3] and leading to chronification of pain recognition. Various therapies in CP/CPPS have been assessed in placebo-controlled studies with average follow-up of 12 weeks [6–12]. A new approach involves stimulation and control of patient’s innate and adaptive immune systems [13, 14]. OM-89, an extract of lysed pathogenic Escherichia coli bacteria, was primarily developed to stimulate immune responses in patients suffering from recurrent urinary tract infections (UTI) [15]. It has been shown, however, that a
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Screening period Visit 1
Treatment period
Visit 2
Visit 3
Visit 4 End of 1st treatment
Baseline
Period
Month 0
Study period Period without treatment
Month 1
Month 2
Month 3
Month 4
Treatment period
Follow-up period
Visit 5
Month 5
Month 6
Visit 6 End of treatment
Month 7
Month 8
Month 9
Month 10
Visit 7 Follow up
Month 11
Month 12
Treatment Duration [days]
14
90
90
10
20
10
20
10
20
90
One OM-89 or placebo capsule taken daily for 10 days during each month, followed by a 20-day break each month (30 capsules in total)
One OM-89 or placebo capsule daily (90 capsules in total)
Treatment
No Treatment
Fig. 1 Study design
prolonged oral administration of immunostimulating drugs may induce a state of immune exclusion and immunological tolerance [13, 14, 16], a concept successfully proven in patients with rheumatoid arthritis [17, 18]. These positive results in a chronic inflammatory disease such as rheumatoid arthritis were the rational to investigate OM-89 in CP/CPPS where immune dysfunction and autoimmunity might play a causative role [4, 5]. Additionally, it has been shown that influencing the inflammatory state in CP/CPPS results in improved symptomatic outcome [19, 20].
NIH classification [24], eligibility criteria, and NIH-CPSI for symptom evaluation [25, 26]. The study was designed according to the treatment recommendation of OM-89, as evaluated in clinical studies [21, 22], and was divided in four periods (Fig. 1): • 3 months one capsule daily of OM-89/placebo (visits 2–4), • 3 months without treatment (visits 4–5), • 3 months one capsule daily of OM-89/placebo for the first 10 days of each month (visits 5–6), • 3 months follow-up without treatment (visits 6–7).
Methods Study design The objective of this pilot multicentre, randomized, doubleblind, parallel, placebo-controlled, phase III study was to evaluate the long-term efficacy and safety (12 months) of OM-89 (OM Pharma SA., Geneva, Switzerland) containing 6 mg E. coli lysate per capsule compared with placebo in men suffering from CP/CPPS type III, using the established regimen for prophylaxis of recurrent UTI [21, 22] (EudraCT number: 2007-004609-85; ethical approval leading ethic commission: Ethikkommission Justus-Liebig Universität, Giessen, Germany—ethical vote: 173/07). The lysate was produced using a modified lysis process as compared to the product investigated in previous studies in recurrent UTI [21, 22]. Consensus criteria for clinical studies in CP/CPPS were adopted in this trial [23]: NIH definition of CP/CPPS [24],
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Patients were eligible, if they met the following inclusion criteria: • males 30–60 years; • CP/CPPS type III: pain or discomfort in the pelvic region for at least 3 months in the previous 6 months; • NIH-CPSI ≥15; • signed written informed consent. Patients were excluded if any of the following criteria were met: any known prostate, bladder, urethral cancer, seizure disorder; concurrent inflammatory bowel disease; disorder affecting the bladder; liver disease, inability to comply with requirements of protocol; known allergy, previous intolerance, known hypersensitivity to trial drug; participation in another clinical trial 3 months before and during present trial. Prior 12-month presence of symptomatic genital herpes, prior 6-month treatment with finasteride or
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other androgen hormone inhibitors, prior 3-month prostate biopsy, UTI or chronic bacterial prostatitis, urethritis, sexually transmitted diseases, epididymitis, pelvic radiation, systemic chemotherapy, intravesical chemotherapy or BCG, prostatic interventions, treatment for orchialgia without pelvic symptoms, treatment with systemic corticosteroids, methotrexate, other immunostimulant medication or live vaccine. Prior 40-week treatment with antimicrobial agents (oral or parenteral), started, stopped, or changed dose level of any prostatitis-specific medications. Prior 2-week treatment with bioflavonoid agents, zinc, or iron supplements. Statistics All randomized patients who received at least one dose of study medication were included in safety set (SS). The full analysis set (FAS) consisted of patients with CP/CPPS who received at least one dose of randomized treatment and attended at least one post-baseline visit (intent-totreat). Primary efficacy analysis was performed only in the FAS population. The per protocol set (PPS) comprised all patients treated with study medication without major protocol violation and with assessable primary endpoint (NIHCPSI score at baseline and visit 6). The primary efficacy endpoint was percentage of responders (reduction in NIH-CPSI score ≥6) at the end of treatment phase (visit 6) compared with baseline. Secondary efficacy endpoints were: • percentage of patients with reduction in NIH-CPSI score ≥6 at the end of first treatment period (after 3 months) as well as follow-up period (after 12 months) compared with baseline; • change in NIH-CPSI total score and subscales scores (pain, urinary symptoms, quality-of-life impact) at each post-baseline visit compared with baseline; • patients presenting a difference of ≥4 points from baseline in NIH-CPSI at each post-baseline visit; • intake of specific other treatments during study period; • global assessments of efficacy by patients and investigators; • primary efficacy variable by subgroups (CP/CPPS type and patients with α-blockers intake prior 4 weeks before enrollment). Logistic regression analysis with treatment group and baseline NIH-CPSI score as covariates was used for responder analysis, and repeated measures ANCOVA analysis was performed to calculate changes in NIH-CPSI scores from baseline. The biometrical sample size calculation was performed by Nquery (Version 4.0) and based on the following assumptions:
Table 1 Demographic and baseline characteristics—FAS (N = 176) Parameters
OM-89 (N = 91)
Placebo (N = 85)
Overall (N = 176)
Patient age (years)
47.8 ± 8.7 [range 29–62] 177.8 ± 6.2 84.0 ± 10.2
47.6 ± 8.1 [range 31–62] 178.7 ± 6.4 83.2 ± 12.0
47.7 ± 8.4 [range 29–62] 178.3 ± 6.3 83.6 ± 11.1
6 (6.6 %) 85 (93.4 %) 21.8 ± 3.8 10.1 ± 2.5 4.1 ± 2.6
7 (8.2 %) 78 (91.8 %) 23.0 ± 5.6a 10.7 ± 2.9a 4.4 ± 2.6a
13 (7.4 %) 163 (92.6 %) 22.4 ± 4.8b 10.4 ± 2.7b 4.2 ± 2.6b
7.6 ± 1.7
8.0 ± 2.0a
7.8 ± 1.9b
Height (cm) Weight (kg) Type of CP/CPPS IIIa IIIb NIH-CPSI Pain domain Micturition domain Quality-of-life domain
Baseline is considered as Visit 2 Plus–minus values are means ± SD NIH-CPS National Institutes of Health-Chronic Prostatitis Symptom Score, higher scores indicate more severe symptoms. Score ranges are as follows: total score 0–43, pain score 0–21, urinary score 0–10, and quality-of-life score 0–12 a
N = 84 (missing value = 1)
b
N = 175 (missing value = 1)
The percentage of responders regarding the primary variable was stipulated to 10 % in the placebo group, and the level of significance was α = 5 % (two-tailed), power 80 %. With 80 patients per treatment group, a treatment effect (OM-89 minus placebo) of 18.7 % or more regarding responder rates could be detected. With an estimated 25 % dropout rate, a total of 200 patients had to be randomized. Statistical analyses were performed with SAS® Version 9.2.
Results Patients and baseline characteristics (FAS) (Table 1) Two hundred and three patients were screened and 185 (91.1 %) randomized (centers see acknowledgement). The FAS and PPS consisted of 176 (95.1 %) and 150 (81.1 %) patients, respectively (Fig. 2). The main symptoms of pain and discomfort in randomized patients were as follows: perineal (74.0 %), lower abdominal (69.1 %), suprapubic (61.3 %), penile (49.7 %), testicular (49.7 %), rectal (38.7 %), lower back symptoms (27.1 %), ejaculatory discomfort (47.5 %), and voiding symptoms (44.8 %). Gastrointestinal, musculoskeletal/connective tissue, skin/subcutaneous disorders were reported
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Fig. 2 Disposition of patients
N=203 PATIENTS SCREENED N=18 Patients excluded • Inclusion/ exclusion criteria not met (11) • Withdrawal of consent (6) • Lost to follow up (1)
N=185 SAFETY SET (SS) N=94 OM-89
N=91 PLACEBO
N=3 Patients excluded •
N=6 Patients excluded • No post baseline visit (1)
No post baseline visit (3)
• Chronic bacterial prostatitis (5) N=176 FULL ANALYSIS SET (FAS) N=91 (OM-89) FULL ANALYSIS SET (FAS)
N=85 (PLACEBO) FULL ANALYSIS SET (FAS)
N=14 Patients excluded
N=12 Patients excluded
• Major protocol violation (8) • Visit 6 not performed (6)
• Major protocol violation (4) • Visit 6 not performed (8)
N=150 PER PROTOCOL SET (PPS) N=77 (OM-89) PER PROTOCOL SET (PPS)
N=73 (PLACEBO) PER PROTOCOL SET (PPS)
Table 2 Efficacy outcomes responder analyses (≥6 point decrease of NIH-CPSI) compared with baseline Parameter Visit 6
OM-89 6 point decrease in NIH-CPSI
FAS
91
61 (67.0 %)
Placebo
Treatment difference OR [95 % CI]
85
p = 0.59
57 (64.3 %)
OR 1.19 [0.63–2.23]
EOT
N (%)
PPS
77
56 (72.7 %)
73
50 (64.4 %)
p = 0.19
OR 1.61 [0.79–3.25]
Visit 7
6 point decrease in NIH-CPSI
FAS
81
61 (75.3 %)
73
48 (65.8 %)
p = 0.18
OR 1.62 [0.80–3.28]
Follow-up
N (%)
PPS
74
57 (77.0 %)
70
45 (64.3 %)
p = 0.09
OR 1.90 [0.91–3.95]
Visit 4
6 point decrease in NIH-CPSI
FAS
87
58 (66.7 %)
79
52 (65.8 %)
p = 0.93
OR 1.03 [0.54–1.98]
EOT 1st
N (%)
PPS
n.d.
n.d.
n.d.
n.d.
NIH-CPSI National Institutes of Health-Chronic Prostatitis Symptom Score, EOT end of treatment, EOT1st end of first treatment, OR odds ratio, CI confidence interval, n.d. not done
in 12.7, 2.2, and 1.1 %, respectively. There were no significant differences between the two groups at start of doubleblind treatment. During the study, 74.1 % of patients had concomitant medication with no difference between groups.
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Efficacy analysis Percentage of responders at the end of treatment phase in FAS (primary efficacy endpoint) was 67.0 % of patients in OM-89 group and 64.3 % in placebo group (p = 0.59; OR 1.19 [95 %
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CI 0.63–2.23]), with a mean relative decrease in NIH-CPSI total score of 40.5 and 44.0 %, respectively (Table 2). In the PPS, the percentage of responders was higher in OM-89 group (72.7 %) and similar in placebo group (64.4 %) compared with the FAS although the treatment group difference did not reach statistical significance (p = 0.19). As the hypothesis of equality between treatment groups was not rejected for the primary endpoint, all secondary efficacy statistical results were only presented in an exploratory way. Responder rates at other visits (visit 4 and visit 7) in the FAS and PPS ranged between 66.7–77.0 % in the OM-89 group and 64.3–65.8 % in the placebo group, without the difference being statistically significant between groups (lowest p value 0.09 at visit 7 in PPS) (Table 2). The repeated mixed model analysis performed on absolute change NIH-CPSI score from baseline to each visit point demonstrated a visit effect (p 5 ** p value, Fisher test (twosided) because at least one expected cell count ≤5
Visit Treatment efficacy at Visit 4 (EOT 1st) N Worsening No change Improvement Treatment efficacy at Visit 6 (EOT) N Worsening No change Improvement Treatment efficacy at Visit 7 (follow-up) N Worsening No change Improvement
OM-89; 16.7 % placebo) and consisted mainly in gastrointestinal disorders for subjects treated with OM-89 (6.6 %) and musculoskeletal and connective tissue disorders for subjects randomized to placebo (4.3 %). The proportion of patients with at least one treatment-related AE was 8.5 % (OM-89) and 5.5 % (placebo), respectively: most frequently diarrhea for OM-89 and nausea for placebo. The proportion of patients experiencing serious adverse events (SAE) was two patients with two events in OM-89 group versus 8 patients with 14 events in the placebo group. None SAE was related to study treatment. One death occurred during the study period in the placebo group (traffic accident).
Discussion Various controlled studies have been performed in the last decade to test different interventions for the treatment of CP/CPPS [6, 7]. The majority of interventions have been tested only for a limited time period of 12 weeks [6, 7]. In a meta-analysis, a statistically significant placebo effect was found for all outcomes and the efficacy of all treatments increased over time [7]. In this study, 67 % of the subjects randomised to OM-89 and 64 % of those randomized to placebo were responders with a mean relative decrease in NIHCPSI total score of 40.5 and 44.0 %, respectively (Table 2). Baseline characteristics were well comparable to other studies, defining a moderate disease activity [6, 7]. The placebo responder proportion was much higher than anticipated in the biometrical sample size calculation and experienced in other controlled studies [19, 20]. According to the logistic regression model adjusted on the baseline NIH-CPSI total score, patients treated with OM-89 were slightly more likely
OM-89 [n (%)]
Placebo [n (%)]
p value
Total [n (%)]
88 3 (3.4 %) 20 (22.7 %) 65 (73.9 %)
88 3 (3.4 %) 28 (31.8 %) 57 (64.8 %)
0.43 (NS)**
176 6 (3.4 %) 48 (27.3 %) 122 (69.3 %)
85 4 (4.7 %) 18 (21.2 %) 63 (74.1 %)
82 3 (3.7 %) 24 (29.3 %) 55 (67.1 %)
0.49 (NS)**
167 7 (4.2 %) 42 (25.1 %) 118 (70.7 %)
84 3 (3.6 %) 18 (21.4 %)
80 3 (3.8 %) 26 (32.5 %)
0.28 (NS)**
164 6 (3.7 %) 44 (26.8 %)
63 (75.0 %)
51 (63.8 %)
114 (69.5 %)
to be responders than those treated with placebo, but this was not statistically significant (p = 0.59). The sensitive analysis performed on the PPS demonstrated a better effect of OM-89 on the proportion of patients with a reduction in NIH-CPSI score ≥6 than on the FAS (72.7 vs 67.0 %), respectively. For placebo, the responder rate in the PPS (64.4 %) was similar to the FAS (64.3 %). However, the logistic regression model adjusted on the baseline NIH-CPSI total score did not detect any significant difference between treatment groups. The repeated mixed model analysis performed on the absolute mean change NIH-CPSI score from baseline demonstrated a significant visit effect (p
Original Article
Immunostimulation in chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS): a one‑year prospective, double‑blind, placebo‑controlled study Florian M. E. Wagenlehner · Stefania Ballarini · Kurt G. Naber
Received: 1 November 2013 / Accepted: 20 January 2014 © Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose Inflammation/immunological dysfunction are discussed etiological causes of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). OM-89 is an orally immunostimulating agent. We performed a phase three multicentre, randomized, double-blind, placebo-controlled, long-term (12 months) study with OM-89 produced with a different lysis process in patients with moderate-to-severe CP/CPPS type III. Methods Patients were randomized to OM-89 or placebo. Primary efficacy variable was difference of responders at the end of treatment (month 9) in patients receiving OM-89 versus placebo. Results Two hundred and three patients were screened, 185 patients (47.8 ± 8.4 years) (90 % of CP/CPPS type IIIb) were enrolled in 30 centers and included in the safety set. Ninety-four were randomized to OM-89, 91 to placebo. One hundred and seventy-six patients were subjected to the full analysis (FAS), 150 to the per protocol set (PPS). Baseline NIH-CPSI score in FAS was 21.8 ± 3.8 (OM-89) and 23.0 ± 5.6 (placebo). At primary efficacy endpoint (month 9), in the OM-89 group, 67.0 % in FAS (PPS 72.7 %) and On behalf of the OM-89 UV-2005/01 Study investigators (see appendix). F. M. E. Wagenlehner (*) Clinic for Urology, Pediatric Urology and Andrology, Justus-Liebig-University Giessen, Rudolf‑Buchheim‑Str. 7, 35385 Giessen, Germany e-mail: [email protected] S. Ballarini Vifor Pharma/OM Pharma, Meyrin, Geneva, Switzerland K. G. Naber Technical University, Munich, Germany
in the placebo group, 64.3 % in FAS (PPS 64.4 %) were responders [FAS: OR 1.19, p = 0.59; PPS: p = 0.19]. Mean relative decrease in NIH-CPSI was 40.5 and 44.0 % in the FAS. Treatment-related adverse events were low: 8.5 % with OM-89 and 5.5 % with placebo. Because of small numbers, no conclusion could be drawn regarding the potential benefit of OM-89 in CP/CPPS IIIa. Conclusions This placebo-controlled study evaluating OM-89 in patients with CP/CPPS showed a significant and long-lasting (12 months) favorable response with OM-89, but also with placebo. OM-89 was safe and well tolerated. EudraCT 2007-004609-85. Keywords Chronic prostatitis/chronic pelvic pain syndrome · Immunostimulation · Placebo effect
Introduction Chronic prostatitis/chronic pelvic pain syndrome syndrome (CP/CPPS) is a frequent condition [1, 2], and current pathophysiological understanding recognizes an initial insult in the context of alterations in psychoimmunoneurendocrine factors [3]. One of these factors comprises immune dysfunction including alterations in cytokine function [4] and autoimmunity [5], modulating neural afferent function [3] and leading to chronification of pain recognition. Various therapies in CP/CPPS have been assessed in placebo-controlled studies with average follow-up of 12 weeks [6–12]. A new approach involves stimulation and control of patient’s innate and adaptive immune systems [13, 14]. OM-89, an extract of lysed pathogenic Escherichia coli bacteria, was primarily developed to stimulate immune responses in patients suffering from recurrent urinary tract infections (UTI) [15]. It has been shown, however, that a
13
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Screening period Visit 1
Treatment period
Visit 2
Visit 3
Visit 4 End of 1st treatment
Baseline
Period
Month 0
Study period Period without treatment
Month 1
Month 2
Month 3
Month 4
Treatment period
Follow-up period
Visit 5
Month 5
Month 6
Visit 6 End of treatment
Month 7
Month 8
Month 9
Month 10
Visit 7 Follow up
Month 11
Month 12
Treatment Duration [days]
14
90
90
10
20
10
20
10
20
90
One OM-89 or placebo capsule taken daily for 10 days during each month, followed by a 20-day break each month (30 capsules in total)
One OM-89 or placebo capsule daily (90 capsules in total)
Treatment
No Treatment
Fig. 1 Study design
prolonged oral administration of immunostimulating drugs may induce a state of immune exclusion and immunological tolerance [13, 14, 16], a concept successfully proven in patients with rheumatoid arthritis [17, 18]. These positive results in a chronic inflammatory disease such as rheumatoid arthritis were the rational to investigate OM-89 in CP/CPPS where immune dysfunction and autoimmunity might play a causative role [4, 5]. Additionally, it has been shown that influencing the inflammatory state in CP/CPPS results in improved symptomatic outcome [19, 20].
NIH classification [24], eligibility criteria, and NIH-CPSI for symptom evaluation [25, 26]. The study was designed according to the treatment recommendation of OM-89, as evaluated in clinical studies [21, 22], and was divided in four periods (Fig. 1): • 3 months one capsule daily of OM-89/placebo (visits 2–4), • 3 months without treatment (visits 4–5), • 3 months one capsule daily of OM-89/placebo for the first 10 days of each month (visits 5–6), • 3 months follow-up without treatment (visits 6–7).
Methods Study design The objective of this pilot multicentre, randomized, doubleblind, parallel, placebo-controlled, phase III study was to evaluate the long-term efficacy and safety (12 months) of OM-89 (OM Pharma SA., Geneva, Switzerland) containing 6 mg E. coli lysate per capsule compared with placebo in men suffering from CP/CPPS type III, using the established regimen for prophylaxis of recurrent UTI [21, 22] (EudraCT number: 2007-004609-85; ethical approval leading ethic commission: Ethikkommission Justus-Liebig Universität, Giessen, Germany—ethical vote: 173/07). The lysate was produced using a modified lysis process as compared to the product investigated in previous studies in recurrent UTI [21, 22]. Consensus criteria for clinical studies in CP/CPPS were adopted in this trial [23]: NIH definition of CP/CPPS [24],
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Patients were eligible, if they met the following inclusion criteria: • males 30–60 years; • CP/CPPS type III: pain or discomfort in the pelvic region for at least 3 months in the previous 6 months; • NIH-CPSI ≥15; • signed written informed consent. Patients were excluded if any of the following criteria were met: any known prostate, bladder, urethral cancer, seizure disorder; concurrent inflammatory bowel disease; disorder affecting the bladder; liver disease, inability to comply with requirements of protocol; known allergy, previous intolerance, known hypersensitivity to trial drug; participation in another clinical trial 3 months before and during present trial. Prior 12-month presence of symptomatic genital herpes, prior 6-month treatment with finasteride or
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other androgen hormone inhibitors, prior 3-month prostate biopsy, UTI or chronic bacterial prostatitis, urethritis, sexually transmitted diseases, epididymitis, pelvic radiation, systemic chemotherapy, intravesical chemotherapy or BCG, prostatic interventions, treatment for orchialgia without pelvic symptoms, treatment with systemic corticosteroids, methotrexate, other immunostimulant medication or live vaccine. Prior 40-week treatment with antimicrobial agents (oral or parenteral), started, stopped, or changed dose level of any prostatitis-specific medications. Prior 2-week treatment with bioflavonoid agents, zinc, or iron supplements. Statistics All randomized patients who received at least one dose of study medication were included in safety set (SS). The full analysis set (FAS) consisted of patients with CP/CPPS who received at least one dose of randomized treatment and attended at least one post-baseline visit (intent-totreat). Primary efficacy analysis was performed only in the FAS population. The per protocol set (PPS) comprised all patients treated with study medication without major protocol violation and with assessable primary endpoint (NIHCPSI score at baseline and visit 6). The primary efficacy endpoint was percentage of responders (reduction in NIH-CPSI score ≥6) at the end of treatment phase (visit 6) compared with baseline. Secondary efficacy endpoints were: • percentage of patients with reduction in NIH-CPSI score ≥6 at the end of first treatment period (after 3 months) as well as follow-up period (after 12 months) compared with baseline; • change in NIH-CPSI total score and subscales scores (pain, urinary symptoms, quality-of-life impact) at each post-baseline visit compared with baseline; • patients presenting a difference of ≥4 points from baseline in NIH-CPSI at each post-baseline visit; • intake of specific other treatments during study period; • global assessments of efficacy by patients and investigators; • primary efficacy variable by subgroups (CP/CPPS type and patients with α-blockers intake prior 4 weeks before enrollment). Logistic regression analysis with treatment group and baseline NIH-CPSI score as covariates was used for responder analysis, and repeated measures ANCOVA analysis was performed to calculate changes in NIH-CPSI scores from baseline. The biometrical sample size calculation was performed by Nquery (Version 4.0) and based on the following assumptions:
Table 1 Demographic and baseline characteristics—FAS (N = 176) Parameters
OM-89 (N = 91)
Placebo (N = 85)
Overall (N = 176)
Patient age (years)
47.8 ± 8.7 [range 29–62] 177.8 ± 6.2 84.0 ± 10.2
47.6 ± 8.1 [range 31–62] 178.7 ± 6.4 83.2 ± 12.0
47.7 ± 8.4 [range 29–62] 178.3 ± 6.3 83.6 ± 11.1
6 (6.6 %) 85 (93.4 %) 21.8 ± 3.8 10.1 ± 2.5 4.1 ± 2.6
7 (8.2 %) 78 (91.8 %) 23.0 ± 5.6a 10.7 ± 2.9a 4.4 ± 2.6a
13 (7.4 %) 163 (92.6 %) 22.4 ± 4.8b 10.4 ± 2.7b 4.2 ± 2.6b
7.6 ± 1.7
8.0 ± 2.0a
7.8 ± 1.9b
Height (cm) Weight (kg) Type of CP/CPPS IIIa IIIb NIH-CPSI Pain domain Micturition domain Quality-of-life domain
Baseline is considered as Visit 2 Plus–minus values are means ± SD NIH-CPS National Institutes of Health-Chronic Prostatitis Symptom Score, higher scores indicate more severe symptoms. Score ranges are as follows: total score 0–43, pain score 0–21, urinary score 0–10, and quality-of-life score 0–12 a
N = 84 (missing value = 1)
b
N = 175 (missing value = 1)
The percentage of responders regarding the primary variable was stipulated to 10 % in the placebo group, and the level of significance was α = 5 % (two-tailed), power 80 %. With 80 patients per treatment group, a treatment effect (OM-89 minus placebo) of 18.7 % or more regarding responder rates could be detected. With an estimated 25 % dropout rate, a total of 200 patients had to be randomized. Statistical analyses were performed with SAS® Version 9.2.
Results Patients and baseline characteristics (FAS) (Table 1) Two hundred and three patients were screened and 185 (91.1 %) randomized (centers see acknowledgement). The FAS and PPS consisted of 176 (95.1 %) and 150 (81.1 %) patients, respectively (Fig. 2). The main symptoms of pain and discomfort in randomized patients were as follows: perineal (74.0 %), lower abdominal (69.1 %), suprapubic (61.3 %), penile (49.7 %), testicular (49.7 %), rectal (38.7 %), lower back symptoms (27.1 %), ejaculatory discomfort (47.5 %), and voiding symptoms (44.8 %). Gastrointestinal, musculoskeletal/connective tissue, skin/subcutaneous disorders were reported
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Fig. 2 Disposition of patients
N=203 PATIENTS SCREENED N=18 Patients excluded • Inclusion/ exclusion criteria not met (11) • Withdrawal of consent (6) • Lost to follow up (1)
N=185 SAFETY SET (SS) N=94 OM-89
N=91 PLACEBO
N=3 Patients excluded •
N=6 Patients excluded • No post baseline visit (1)
No post baseline visit (3)
• Chronic bacterial prostatitis (5) N=176 FULL ANALYSIS SET (FAS) N=91 (OM-89) FULL ANALYSIS SET (FAS)
N=85 (PLACEBO) FULL ANALYSIS SET (FAS)
N=14 Patients excluded
N=12 Patients excluded
• Major protocol violation (8) • Visit 6 not performed (6)
• Major protocol violation (4) • Visit 6 not performed (8)
N=150 PER PROTOCOL SET (PPS) N=77 (OM-89) PER PROTOCOL SET (PPS)
N=73 (PLACEBO) PER PROTOCOL SET (PPS)
Table 2 Efficacy outcomes responder analyses (≥6 point decrease of NIH-CPSI) compared with baseline Parameter Visit 6
OM-89 6 point decrease in NIH-CPSI
FAS
91
61 (67.0 %)
Placebo
Treatment difference OR [95 % CI]
85
p = 0.59
57 (64.3 %)
OR 1.19 [0.63–2.23]
EOT
N (%)
PPS
77
56 (72.7 %)
73
50 (64.4 %)
p = 0.19
OR 1.61 [0.79–3.25]
Visit 7
6 point decrease in NIH-CPSI
FAS
81
61 (75.3 %)
73
48 (65.8 %)
p = 0.18
OR 1.62 [0.80–3.28]
Follow-up
N (%)
PPS
74
57 (77.0 %)
70
45 (64.3 %)
p = 0.09
OR 1.90 [0.91–3.95]
Visit 4
6 point decrease in NIH-CPSI
FAS
87
58 (66.7 %)
79
52 (65.8 %)
p = 0.93
OR 1.03 [0.54–1.98]
EOT 1st
N (%)
PPS
n.d.
n.d.
n.d.
n.d.
NIH-CPSI National Institutes of Health-Chronic Prostatitis Symptom Score, EOT end of treatment, EOT1st end of first treatment, OR odds ratio, CI confidence interval, n.d. not done
in 12.7, 2.2, and 1.1 %, respectively. There were no significant differences between the two groups at start of doubleblind treatment. During the study, 74.1 % of patients had concomitant medication with no difference between groups.
13
Efficacy analysis Percentage of responders at the end of treatment phase in FAS (primary efficacy endpoint) was 67.0 % of patients in OM-89 group and 64.3 % in placebo group (p = 0.59; OR 1.19 [95 %
World J Urol
CI 0.63–2.23]), with a mean relative decrease in NIH-CPSI total score of 40.5 and 44.0 %, respectively (Table 2). In the PPS, the percentage of responders was higher in OM-89 group (72.7 %) and similar in placebo group (64.4 %) compared with the FAS although the treatment group difference did not reach statistical significance (p = 0.19). As the hypothesis of equality between treatment groups was not rejected for the primary endpoint, all secondary efficacy statistical results were only presented in an exploratory way. Responder rates at other visits (visit 4 and visit 7) in the FAS and PPS ranged between 66.7–77.0 % in the OM-89 group and 64.3–65.8 % in the placebo group, without the difference being statistically significant between groups (lowest p value 0.09 at visit 7 in PPS) (Table 2). The repeated mixed model analysis performed on absolute change NIH-CPSI score from baseline to each visit point demonstrated a visit effect (p 5 ** p value, Fisher test (twosided) because at least one expected cell count ≤5
Visit Treatment efficacy at Visit 4 (EOT 1st) N Worsening No change Improvement Treatment efficacy at Visit 6 (EOT) N Worsening No change Improvement Treatment efficacy at Visit 7 (follow-up) N Worsening No change Improvement
OM-89; 16.7 % placebo) and consisted mainly in gastrointestinal disorders for subjects treated with OM-89 (6.6 %) and musculoskeletal and connective tissue disorders for subjects randomized to placebo (4.3 %). The proportion of patients with at least one treatment-related AE was 8.5 % (OM-89) and 5.5 % (placebo), respectively: most frequently diarrhea for OM-89 and nausea for placebo. The proportion of patients experiencing serious adverse events (SAE) was two patients with two events in OM-89 group versus 8 patients with 14 events in the placebo group. None SAE was related to study treatment. One death occurred during the study period in the placebo group (traffic accident).
Discussion Various controlled studies have been performed in the last decade to test different interventions for the treatment of CP/CPPS [6, 7]. The majority of interventions have been tested only for a limited time period of 12 weeks [6, 7]. In a meta-analysis, a statistically significant placebo effect was found for all outcomes and the efficacy of all treatments increased over time [7]. In this study, 67 % of the subjects randomised to OM-89 and 64 % of those randomized to placebo were responders with a mean relative decrease in NIHCPSI total score of 40.5 and 44.0 %, respectively (Table 2). Baseline characteristics were well comparable to other studies, defining a moderate disease activity [6, 7]. The placebo responder proportion was much higher than anticipated in the biometrical sample size calculation and experienced in other controlled studies [19, 20]. According to the logistic regression model adjusted on the baseline NIH-CPSI total score, patients treated with OM-89 were slightly more likely
OM-89 [n (%)]
Placebo [n (%)]
p value
Total [n (%)]
88 3 (3.4 %) 20 (22.7 %) 65 (73.9 %)
88 3 (3.4 %) 28 (31.8 %) 57 (64.8 %)
0.43 (NS)**
176 6 (3.4 %) 48 (27.3 %) 122 (69.3 %)
85 4 (4.7 %) 18 (21.2 %) 63 (74.1 %)
82 3 (3.7 %) 24 (29.3 %) 55 (67.1 %)
0.49 (NS)**
167 7 (4.2 %) 42 (25.1 %) 118 (70.7 %)
84 3 (3.6 %) 18 (21.4 %)
80 3 (3.8 %) 26 (32.5 %)
0.28 (NS)**
164 6 (3.7 %) 44 (26.8 %)
63 (75.0 %)
51 (63.8 %)
114 (69.5 %)
to be responders than those treated with placebo, but this was not statistically significant (p = 0.59). The sensitive analysis performed on the PPS demonstrated a better effect of OM-89 on the proportion of patients with a reduction in NIH-CPSI score ≥6 than on the FAS (72.7 vs 67.0 %), respectively. For placebo, the responder rate in the PPS (64.4 %) was similar to the FAS (64.3 %). However, the logistic regression model adjusted on the baseline NIH-CPSI total score did not detect any significant difference between treatment groups. The repeated mixed model analysis performed on the absolute mean change NIH-CPSI score from baseline demonstrated a significant visit effect (p
