Accepted Manuscript

Title: A Relevant Mid-Term (12 Months) Placebo Effect on Lower Urinary

Tract Symptoms and Maximum Flow Rate in Male LUTS/BPH a Meta-
Analysis

Author: Klaus Eredics, Stephan Madersbacher, Ingrid Schauer

PII: S0090-4295(17)30502-2
DOI: http://dx.doi.org/doi: 10.1016/j.urology.2017.05.011
Reference: URL 20452

To appear in: Urology

Received date: 19-1-2017

Accepted date: 3-5-2017

Please cite this article as: Klaus Eredics, Stephan Madersbacher, Ingrid Schauer, A Relevant
Mid-Term (12 Months) Placebo Effect on Lower Urinary Tract Symptoms and Maximum Flow
Rate in Male LUTS/BPH a Meta-Analysis, Urology (2017), http://dx.doi.org/doi:
10.1016/j.urology.2017.05.011.

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service
to our customers we are providing this early version of the manuscript. The manuscript will
undergo copyediting, typesetting, and review of the resulting proof before it is published in its
final form. Please note that during the production process errors may be discovered which could
affect the content, and all legal disclaimers that apply to the journal pertain.
 A relevant mid-term (12 months) placebo effect on lower urinary
tract symptoms and maximum flow rate in male LUTS/BPH a
meta-analysis

Klaus Eredics, Stephan Madersbacher, Ingrid Schauer

Department of Urology, Kaiser-Franz-Josef Hospital, Vienna, Austria

CORRESPONDENCE

Stephan Madersbacher, MD, FEBU

Professor and chairman

Department of Urology

Kaiser-Franz-Josef Hospital

Kundratstrasse 3

A-1100 Vienna, Austria

e-mail: stephan.madersbacher@wienkav.at

ABSTRACT

Objective: To assess the mid- to long-term placebo effect of medical and

instrumental management of male lower urinary tract symptoms (LUTS). This is -

generally - a long-term treatment strategy. Therefore, knowledge on the mid- to long-

term placebo effect is of considerable interest. The paucity of data on this topic

prompted us to investigate this issue in a meta-analysis.

Page 1 of 15
Methods: All randomized controlled trials (RCTs) with the indication BPH/LUTS

containing a placebo- or sham treatment arm and with a follow-up of 12 months were

eligible. The 12-months effect of placebo/sham treatment on the International

Prostate Symptom Score (IPSS; the quality of life question was not analysed

herein)/American Urological Association (AUA) score and on the maximum flow rate

(Qmax) was quantified.

Results: A total of 25 RCTs with 10.587 patients were eligible. Twenty-three studies

were placebo-controlled (plant extracts: n=4, 5-reductase inhibitors (5ARIs) n=9, -

blocker: n=5, 5ARI/-blocker combination therapy n=3; intraprostatic botulinum toxin

A-injection n=2) and two RCTs with transurethral microwave thermotherapy (TUMT)

had a sham treatment arm. At 12-months, the mean IPSS improved by a mean of 4.4

points under placebo/sham treatment with a range of 0.7 to 6.8 points: plant extracts

-3.6, 5ARI -3.4, -blocker -4.3, combination therapy -4.3; botulinum Toxin A -3.9,

TUMT -6.8. The mean Qmax improvement at 12 months under placebo/sham was

not relevant (+0.8ml/sec) yet there were remarkable differences between trials: plant

extracts -0.3ml/sec, 5ARI +0.8ml/sec, -blocker +1.1ml/sec, combination therapy

+1.4ml/sec, TUMT +1.0ml/sec.

Conclusions: This meta-analysis demonstrates the mid-term placebo effect on lower

urinary tract function, particularly concerning subjective improvement. The degree of

the placebo effect varies considerable between studies even at 12-months.

Key words: lower urinary tract symptoms, management, placebo response, durability,
medical therapy, minimal invasive therapy

Page 2 of 15
INTRODUCTION

Placebo is defined as a substance or procedure that is objectively without

specific activity for the condition being treated. Randomized, placebo controlled trials

(RCT) are considered the gold standard in clinical research to provide level I

evidence on clinical efficacy [1]. Clinicians often distinguish between the efficacy and

the effectiveness of an intervention. Efficacy trials determine whether an intervention

produces the expected result under ideal circumstances. Effectiveness trials measure

the degree of beneficial effect under real world clinical settings.

RCTs evaluating drug responses in the treatment of lower urinary tract

symptoms (LUTS) due to benign prostatic enlargement (BPE)/benign prostatic

obstruction (BPO) have consistently reported relevant placebo responses for both

subjective and objective outcomes [2]. Although a manifest placebo effect in medical

treatment of LUTS/BPH is well established and frequently reported, only a few

studies examined the sham response to endoscopic and injection based therapies.

As recently systematically reviewed by Welliver et al, also instrumental therapies are

prone to a relevant placebo response [3].

Any management of male LUTS is - generally - a long-term treatment strategy.

Therefore, the magnitude of placebo-effect on a long-term perspective is of

considerable interest. None of the systematic reviews available on the placebo

response in male LUTS have specifically addressed the mid-/long-term effect. We

therefore aimed to analyze this issue in a meta-analysis by reviewing all randomized

controlled trials (RCTs) with the indication BPH/LUTS containing a placebo- or sham

treatment arm and with a follow-up of 12 months.

Page 3 of 15
METHODS

A systematic review was done based on the literature search through the

PubMedR-MedlineR data base. The key words used to search were placebo or

randomized controlled or sham and prostatic hyperplasia or benign prostatic

hyperplasia or male lower urinary tract symptoms. The literature search aimed to

identify all placebo controlled RCTs for medical therapy for BPH/LUTS and further

trials including a sham procedure (i.e. intraprostatic injection or microwave therapy)

between 1990 and February 2016. Additionally, previous systematic reviews on the

placebo response and the most recent version of EUA/AUA/German S2e guidelines

on BPH/LUTS were reviewed for suitable articles.

PubMed MEDLINE database search delivered 1710 results. After reviewing

the titles and abstracts of these trials 1631 were excluded as they did not meet our

study inclusion criteria (i.e. not placebo/sham controlled). Full-text articles of 72

obtaining studies were reviewed, subsequently 47 were excluded (mainly because of

a follow-up of less than 12 months or no standard deviation mentioned), so that 25

studies were eligible for meta-analysis.

Meta-analysis was performed using REVIEW MANAGER Version 5.3. A

random-effect model was used. Results of the meta-analysis were assessed by

graphical presentations of mean dierences according to the outcome and 95%

condence intervals were represented on Forest plots, with p<0.05 considered

signicant. Heterogeneity between studies was assessed, using a chi-squared-test

and P < 0.100 was considered signicant. Furthermore, the I statistic was used, with

high clinical heterogeneity dened as I >50%.

The outcomes of interest were changes in urinary symptom score (SS) and in

peak urinary flow (Qmax) 12 months after placebo/sham treatment. The International

Prostate Symptom Score (IPSS) and the American Urological Association Symptom
4

Page 4 of 15
Score (AUASS) were seen as equivalent in this study. The quality of life question in

the IPSS was not analyzed.

RESULTS

Twenty five randomized controlled trials were suitable for this meta-analysis.

The respective placebo/sham control arms of these studies contained at total of

10.583 patients that were subsequently analyzed herein. An overview of the included

studies is given in tables 1 and 2. We subsequently report herein the placebo

responses grouped according to the respective active treatment arms.

Plant Extracts

Four trials (placebo patients: n= 644) were included, one used a pumpkin

seed-extract [4], two a saw-palmetto-extract [5, 6] and one a stinging nettle root

extract [7] (tables 1, 2). At 12-months of placebo treatment LUTS improved with a

decrease of 3.6 points in the AUA/IPSS (CI 2.2-5.1; p=<0, 001; I =93%) (Fig. 1).

Qmax was investigated in two studies. No improvement in Qmax was seen after

treatment with placebo with a decrease of -0.3ml per second (ml/s) after 12 months

(p=0.38; I =0% (Fig. 1).

5-reductase inhibitors

A total of 9 studies [8-18] (finasteride n=3351; dutasteride n=2339) were

eligible with a total of 5.690 patients randomized to placebo (tables 1, 2). The IPSS

improved by 3.4 points (CI 2.74.1; p=<0,001; I=93%) under placebo at 12 months

(Fig. 2). The Qmax improved by 0.8 ml/s (CI 0.531.08; p=<0.001; I=66%) within the

same time period (Fig. 2).

Page 5 of 15
Alpha1-adrenergic antagonists

A total of 6 placebo controlled trials [10, 11, 15, 19-21] were available with

alfuzosin (n=761), doxazosin (n=1038 and terazosin (n=1278) as active arms (tables

1, 2). The symptom score decreased by a mean of 4.3 points (CI 3.55.0; p=<0.001;

I=91%) and the Qmax increased by 1.1 ml/s at 12 months under placebo (CI 0.8

1.5; p=0.006; I=73%) (Fig. 3).

Combination Therapy (-blocker plus 5ARI)

Two studies compared the effects of placebo vs doxazosin, finasteride vs a

combination of doxazosin/finasteride [10, 15]; one study compared placebo vs

terazosin, finasteride and a combination of terazosin/finasteride [11] (tables 1, 2). The

AUA/IPSS decreased by 4.3 points in placebo-treated patients (CI 2.75.9; p<0.001;

I=91%) (Fig. 4). The Qmax increased by 1.4ml/sec under placebo (CI 1-01.7;

p=<0.001 I=0%) (Fig. 4).

Transurethral microwave thermotherapy (TUMT)

Four randomized, sham-controlled, prospective, double-blind studies

compared transurethral microwave thermotherapy (TUMT) with a sham treatment

[22-25] (patients n=172) (tables 1, 2). IPSS data were available in two trials with a

decrease of 6.8 points (CI 5.97.7; p=<0.001; I=47%) (Fig. 5). All four studies

evaluated Qmax following a sham procedure (patients n=214) with an increase of

1.0ml/sec (CI 0.61.4; p=<0-001; I=92%) (Fig. 5).

Intraprostatic Botulinum Toxin A

Two studies with a total of 109 patients were eligible for analysis [26, 27]

(tables 1, 2). In these two studies the IPSS decreased by 3.9 after intraprostatic
6

Page 6 of 15
injection of placebo (CI 2.55.3; p=<0,001; I=92%) (Fig. 5). The way the data on

Qmax were presented (lacking of standard deviation), however, hindered the

inclusion to this meta-analysis.

DISCUSSION

This meta-analysis proves a considerable mid-term (12 months) placebo

response following medical/instrumental management of male LUTS/BPH,

particularly regarding symptomatic improvement but also for the maximum flow rate

(at least in some trials).

The placebo response is a well-known phenomenon in the management of

LUTS in both sexes . Van Leeuwen et al reviewed the placebo response in RCTs for

pharmacological treatment of LUTS including urinary incontinence, overactive

bladder and BPE in a non-systematic review [2]. In male LUTS/BPE patients, the

authors observed a 9-34% decline in symptom score. Regarding Qmax, the change

under placebo was less pronounced with an increase of 2-9% [4]. The divergence

between subjective and objective measures suggests that patient-reported symptom

scores are more vulnerable to a placebo response, which complicates the detection

of the true drug effect [28]. Welliver et al systematically reviewed randomized

controlled trials involving endoscopic or intraprostatic injection BPH treatments that

included a sham treatment arm [3]. A total of 14 trials were analyzed. An average

decrease of the AUA-score from 22.3 to 16.7 (-27%) was seen 3 months after sham

endoscopic treatment with an increase of Qmax of 1.3ml/sec (+14%, p=0.001) [5].

Prostate injection based studies with a follow-up of 3 months revealed a similar

improve in symptoms following placebo treatment with a decrease from 21.3 to 15.7

(-26%, p<0.001) [5]. Qmax increased by 2.0ml/sec following intraprostatic placebo

injection [5].

Page 7 of 15
 As any management of male LUTS is conventionally a mid-/long-term

treatment strategy, the magnitude of placebo-effect on a mid/long-term perspective is

a highly relevant issue. According to our knowledge, this is the first meta-analysis

specifically analyzing the placebo-effect at 12 months in managing male LUTS. Given

the long history of men with BPH/LUTS frequently covering 1-2 life decades, the 12-

months duration of this meta-analysis has to be considered at best mid-term.

However, only very few placebo-controlled trials with a study duration of >12 months

are available. Given the availability of established medical treatment options it is very

unlikely that long-term placebo controlled trials will be performed in the future.

As previously pointed out by Van Leeuwen et al, clinical studies on BPH/LUTS

include a wide range of patients (e.g. regarding prostate volume) with variability of

patient selection [4]. This fact needs to be considered when interpreting this meta-

analysis. Yet the inclusion criteria for the two outcome parameters of this meta-

analysis (Qmax/AUA-score) were comparable, at least in the majority of trials (see

also tables 1, 2).

After 12 months of placebo/sham treatment the AUA/IPSS improvement

ranged from 3.6 points in plant extract trials to 6.8 points following TUMT-sham

treatment. With all study data pooled together, the placebo effect for medical therapy

on symptom score at 12 months is 3.7 points and -0.87/ml/sec on Qmax. When

pooled together, sham procedures in TUMT and intraprostatic injection improved

symptom score at 12 months by 4.4 points. It has been suggested that an AUA/IPSS

improvement of more than 3 points is considered as clinical relevant [29]. Hence it is

safe to conclude that placebo treatment leads to clinically relevant improvement of

LUTS over 12 months. It is worth to note that in most trials the long-term placebo

effect exceeds the difference between placebo and the active treatment arm. In a

recent meta-analysis Wang et al have shown a true drug effect for -blockers in the
8

Page 8 of 15
range of 2.0 points of the AUA/IPSS, for 5ARI of 1.0 points and for combination

therapy of 2.4 points [28].

Given this proven and relevant long-term placebo effect on male LUTS two

issues are of interest: (i) what are the mechanisms leading to this prolonged placebo

response and (ii) what determines the extent of this placebo response given the

relevant variability within the long-term trials.

Van Leeuwen et al reviewed potential factors influencing the placebo response in

LUTS [2]. The authors identified (i) condition-specific factors such as dysfunction of

neurotransmitters/neuropeptides, natural history of the disease (ii) patient-specific

factors such as age, disease severity, behavioral modifications and (iii) trial specific

factors such as placebo-run in period and the regression to the mean phenomenon.

Regression to the mean is a statistical phenomenon that occurs when repeated

measurements are made on the same subject or unit of observation. The effect of

regression to the mean increases with larger measurement variability. To reduce the

variability two or more baseline measurements (e.g. placebo-run in period) can be

performed. The study selection criterion (i.e. a cut-off) is then applied to either the

mean of the multiple measurements, or the second (or later) measurement,

assuming that the regression to the mean effect has taken place between the first

and second (or later) measurements.

This method has not been performed in any of the included trials, which could explain

the heterogeneity within the examined trials.

As pointed out by Ernst and Resch it is incorrect to equate the response seen

in the placebo arm of a clinical trial with the placebo effect [30]. The authors stated

that any response seen in a placebo arm is a function of the natural history of the

disease that may resolve spontaneously and non-specific treatment effects including

patient and physician expectations [33]. The fact that this meta-analysis has shown a
9

Page 9 of 15
prolonged (12-months) placebo effect suggests that the natural history of the disease

is unlikely to be an important determinant [33].

One interesting aspect is the fact that placebo-response varies considerable

between trials, even over a prolonged period of time. When reviewing medical

therapy trials, the placebo effect on symptoms scores was lowest in the plant extract

studies (-3.6 points) and highest in the combination therapy trials (-4.3 points). The

amount of the placebo response is even higher following sham invasive treatment (-

6.8 points). There seems to be a correlation between the magnitude of the effect on

symptoms and Qmax of the active and the placebo/sham study arm. This observation

suggests that patient expectations and information (formulation of the informed

consent) might also play a dominant role in the extent of the long-term placebo effect.

In clinical practice, patients experience the full clinical effectiveness (placebo plus

verum). Yet one must be aware, that the placebo effect attributes considerable to the

overall drug effectiveness in the range of 40-60%.

In conclusion, this meta-analysis demonstrates the mid-term placebo effect on

lower urinary tract function, particularly concerning subjective improvement.

The degree of the placebo effect varies considerable between studies even at 12-

months.

10

Page 10 of 15
References

1. Fassler M, Meissner K, Kleijnen J, Hrobjartsson A, Linde K: A systematic review found no

consistent difference in effect between more and less intensive placebo interventions. J
Clin Epidemiol 2015, 68(4):442-451.
2. van Leeuwen JH, Castro R, Busse M, Bemelmans BL: The placebo effect in the pharmacologic
treatment of patients with lower urinary tract symptoms. Eur Urol 2006, 50(3):440-452;
discussion 453.
3. Welliver C, Kottwitz M, Feustel P, McVary K: Clinically and Statistically Significant Changes
Seen in Sham Surgery Arms of Randomized, Controlled Benign Prostatic Hyperplasia
Surgery Trials. J Urol 2015, 194(6):1682-1687.
4. Bach: Placebokontrollierte Langzeittherapiestudie mit Krbissamenextrakt bei BPH-
bedingten Miktionsbeschwerden. Urologe 2000, 40:437-443.
5. Barry MJ, Meleth S, Lee JY, Kreder KJ, Avins AL, Nickel JC, Roehrborn CG, Crawford ED, Foster
HE, Jr., Kaplan SA et al: Effect of increasing doses of saw palmetto extract on lower urinary
tract symptoms: a randomized trial. JAMA 2011, 306(12):1344-1351.
6. Bent S, Kane C, Shinohara K, Neuhaus J, Hudes ES, Goldberg H, Avins AL: Saw palmetto for
benign prostatic hyperplasia. N Engl J Med 2006, 354(6):557-566.
7. Schneider: Brennnesseltrockenextrakt (Bazoton-uno) in der Langzeittherapie des
benignen Prostatasyndroms (BPS). Urologe 2004, 43:302-306.
8. Abrams P, Schafer W, Tammela TL, Barrett DM, Hedlund H, Rollema HJ, Matos-Ferreira A,
Nordling J, Bruskewitz R, Andersen JT et al: Improvement of pressure flow parameters with
finasteride is greater in men with large prostates. Finasteride Urodynamics Study Group. J
Urol 1999, 161(5):1513-1517.
9. Kaplan SA, Lee JY, Meehan AG, Kusek JW: Long-term treatment with finasteride improves
clinical progression of benign prostatic hyperplasia in men with an enlarged versus a
smaller prostate: data from the MTOPS trial. J Urol 2011, 185(4):1369-1373.
10. Kirby RS, Roehrborn C, Boyle P, Bartsch G, Jardin A, Cary MM, Sweeney M, Grossman EB:
Efficacy and tolerability of doxazosin and finasteride, alone or in combination, in treatment
of symptomatic benign prostatic hyperplasia: the Prospective European Doxazosin and
Combination Therapy (PREDICT) trial. Urology 2003, 61(1):119-126.
11. Lepor H, Williford WO, Barry MJ, Brawer MK, Dixon CM, Gormley G, Haakenson C, Machi M,
Narayan P, Padley RJ: The efficacy of terazosin, finasteride, or both in benign prostatic
hyperplasia. Veterans Affairs Cooperative Studies Benign Prostatic Hyperplasia Study
Group. N Engl J Med 1996, 335(8):533-539.
12. Lowe FC, McConnell JD, Hudson PB, Romas NA, Boake R, Lieber M, Elhilali M, Geller J,
Imperto-McGinely J, Andriole GL et al: Long-term 6-year experience with finasteride in
patients with benign prostatic hyperplasia. Urology 2003, 61(4):791-796.
13. Marberger MJ: Long-term effects of finasteride in patients with benign prostatic
hyperplasia: a double-blind, placebo-controlled, multicenter study. PROWESS Study Group.
Urology 1998, 51(5):677-686.
14. McConnell JD, Bruskewitz R, Walsh P, Andriole G, Lieber M, Holtgrewe HL, Albertsen P,
Roehrborn CG, Nickel JC, Wang DZ et al: The effect of finasteride on the risk of acute urinary
retention and the need for surgical treatment among men with benign prostatic
hyperplasia. Finasteride Long-Term Efficacy and Safety Study Group. N Engl J Med 1998,
338(9):557-563.
15. McConnell JD, Roehrborn CG, Bautista OM, Andriole GL, Jr., Dixon CM, Kusek JW, Lepor H,
McVary KT, Nyberg LM, Jr., Clarke HS et al: The long-term effect of doxazosin, finasteride,
and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl
J Med 2003, 349(25):2387-2398.
11

Page 11 of 15
16. Nickel JC, Fradet Y, Boake RC, Pommerville PJ, Perreault JP, Afridi SK, Elhilali MM: Efficacy
and safety of finasteride therapy for benign prostatic hyperplasia: results of a 2-year
randomized controlled trial (the PROSPECT study). PROscar Safety Plus Efficacy Canadian
Two year Study. CMAJ 1996, 155(9):1251-1259.
17. Roehrborn CG, Boyle P, Nickel JC, Hoefner K, Andriole G: Efficacy and safety of a dual
inhibitor of 5-alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic
hyperplasia. Urology 2002, 60(3):434-441.
18. Tsukamoto T, Endo Y, Narita M: Efficacy and safety of dutasteride in Japanese men with
benign prostatic hyperplasia. Int J Urol 2009, 16(9):745-750.
19. Fawzy A, Braun K, Lewis GP, Gaffney M, Ice K, Dias N: Doxazosin in the treatment of benign
prostatic hyperplasia in normotensive patients: a multicenter study. J Urol 1995,
154(1):105-109.
20. Roehrborn CG: Alfuzosin 10 mg once daily prevents overall clinical progression of benign
prostatic hyperplasia but not acute urinary retention: results of a 2-year placebo-controlled
study. BJU Int 2006, 97(4):734-741.
21. Roehrborn CG, Oesterling JE, Auerbach S, Kaplan SA, Lloyd LK, Milam DE, Padley RJ: The
Hytrin Community Assessment Trial study: a one-year study of terazosin versus placebo in
the treatment of men with symptomatic benign prostatic hyperplasia. HYCAT Investigator
Group. Urology 1996, 47(2):159-168.
22. Bdesha AS, Bunce CJ, Kelleher JP, Snell ME, Vukusic J, Witherow RO: Transurethral
microwave treatment for benign prostatic hypertrophy: a randomised controlled clinical
trial. BMJ 1993, 306(6888):1293-1296.
23. Blute ML, Patterson DE, Segura JW, Tomera KM, Hellerstein DK: Transurethral microwave
thermotherapy v sham treatment: double-blind randomized study. J Endourol 1996,
10(6):565-573.
24. Larson TR, Blute ML, Bruskewitz RC, Mayer RD, Ugarte RR, Utz WJ: A high-efficiency
microwave thermoablation system for the treatment of benign prostatic hyperplasia:
results of a randomized, sham-controlled, prospective, double-blind, multicenter clinical
trial. Urology 1998, 51(5):731-742.
25. Nawrocki JD, Bell TJ, Lawrence WT, Ward JP: A randomized controlled trial of transurethral
microwave thermotherapy. Br J Urol 1997, 79(3):389-393.
26. Marberger M, Chartier-Kastler E, Egerdie B, Lee KS, Grosse J, Bugarin D, Zhou J, Patel A, Haag-
Molkenteller C: A randomized double-blind placebo-controlled phase 2 dose-ranging study
of onabotulinumtoxinA in men with benign prostatic hyperplasia. Eur Urol 2013, 63(3):496-
503.
27. Maria G, Brisinda G, Civello IM, Bentivoglio AR, Sganga G, Albanese A: Relief by botulinum
toxin of voiding dysfunction due to benign prostatic hyperplasia: results of a randomized,
placebo-controlled study. Urology 2003, 62(2):259-264; discussion 264-255.
28. Wang X, Li S, Meng Z, Liu T, Zhang X: Comparative effectiveness of oral drug therapies for
lower urinary tract symptoms due to benign prostatic hyperplasia: a systematic review and
network meta-analysis. PLoS One 2014, 9(9):e107593.
29. Barry MJ, Williford WO, Chang Y, Machi M, Jones KM, Walker-Corkery E, Lepor H: Benign
prostatic hyperplasia specific health status measures in clinical research: how much change
in the American Urological Association symptom index and the benign prostatic
hyperplasia impact index is perceptible to patients? J Urol 1995, 154(5):1770-1774.
30. Ernst E, Resch KL: Concept of true and perceived placebo effects. BMJ 1995, 311(7004):551-
553.

12

Page 12 of 15
Fig. 1: Placebo response regarding symptoms and Qmax in plant extract trials,
in 5-reductase inhibitor monotherapy trials, in -blocker monotherapy trials
and in combination (-blocker/5-reductase inhibitor) therapy trials
(descending order)

Fig. 2: Placebo response regarding symptoms (top) and Qmax (middle) in

TUMT trials and regarding symptoms (bottom) in intraprostatic injection trials

13

Page 13 of 15
 Table 1: Overview of studies included: symptom improvement following
placebo/sham treatment

Placebo/sham Minimum/Maximum
Number of treatment: symptom cutoff for trial entry
Reference Active treatment patients score: baseline/final
Bach 2000 [4] Plant extracts 238 17.7/12.2 (-5.5) 7/28
Barry 2011[5] Plant extracts 181 14.7/11.7 (-3.0) 8/24
Bent 2006[6] Plant extracts 113 15.0/14.30 (-0.70) 8/35
Schneider 2004[7] Plant extracts 112 18.5/13.9 (-4.7) 13/18,7
Abrams 1999[8] 5ARI 40 17.4/14.1 (-3.30) -/-
Kaplan 2011[9] 5ARI 288 16.8/12.6 (-4.20) 8/30
Kirby 2003[10] 5ARI 253 17.2/11.8 (-5.40) 12/30
Lepor 1996[11] 5ARI 305 15.8/13.2 (-2.60) 8/35
Lowe 2003[12] 5ARI 212 13.1/10.1 (-3.0) 12/35
McConell 1998[14] 5ARI 1516 15.0/13.4 (-1.60) 0/35
McConell 2003[15] 5ARI 737 16.8/11.9 (-4.90) 8/35
Roehrborn 12/35
2002[17] 5ARI 2158 17.1/14.7 (-2.40)
Tsukamoto 8/30
2009[18] 5ARI 181 16.0/12.3 (-3.70)
Kirby 2003 [10] ARB 253 17.2/11.8 (-6.9) 12/30
Lepor 1996 [11] ARB 305 15.8/13.2 (-2.60) 8/35
McConell 2003[15] ARB 737 16.8/11.9 (-4.90) 8/35
Roehrborn 13/35
1996[21] ARB 973 20.1/16.4 (-3.70)
Roehrborn 13/30
2006[20] ARB 761 19.2/14.5 (-4.70)
Combination 12/30
Kirby 2003[10] Therapy 253 17.2/11.8 (-5.40)
Combination 8/35
Lepor 1996[11] Therapy 305 15.8/13.2 (-2.60)
Combination 8/35
McConell 2003[15] Therapy 737 16.8/11.9 (-4.90)
Marberger Onabotulinumtoxin 12/30
2013[26] A 94 21.0/15.5 (-5.50)
Onabotulinumtoxin 8/35
Maria 2003[27] A 15 23.3/23.30 (-0.0)
Larson 1998[24] TUMT 42 21.3/14.3 (-7.0) 9/35
Blute 1996[23] TUMT 37 20.8/16.3 (-4.50) 8/35

14

Page 14 of 15
 Table 2. Overview of studies included: Qmax improvement following
placebo/sham treatment

Placebo/sham Minimum/Maximum
Number of treatment: Qmax: cutoff for trial entry
References Active treatment patients baseline/final (Qmax)
Barry 2011[5] Plant extracts 181 14.0/14.8 (0.80) 4/15
Bent 2006[6] Plant extracts 113 11.6/11.6 (0.0) 4/15
Abrams 1999[8] 5ARI 40 7.0/9.1 (2.10) -/-
Kaplan 2011[9] 5ARI 288 10.4/11.9 (1.50) 4/15
Kirby 2003 [10] 5ARI 253 10.8/12.1 (1.30) 5/15
Lepor 1996[11] 5ARI 305 10.4/11.4 (1.0) 4/15
Marberger
1998[13] 5ARI 1115 10.9/11.7 (0.80) 5/15
McConell
1998[14] 5ARI 1516 11.0/11.2 (0.20) -/15
Nickel 1996[16] 5ARI 303 10.9/11.2 (0.30) 5/15
Roehrborn
2002[17] 5ARI 2158 10.4/11.2 (0.80) -/15
Tsukamoto[18] 5ARI 181 11.2/11.9 (0.70) -/15
Fawzi 1995[19] ARB 48 9.9/10.6 (0.70) 5/15
Kirby 2003[10] ARB 253 10.8/12.1 (1.30) 5/15
Lepor 1996 [11] ARB 305 10.4/11.8 (1.40) 4/15
Roehrborn
1996[21] ARB 140 9.6/10.4 (0.80) 2.4/15
Roehrborn
2006[20] ARB 757 8.8/10.1 (1.30) 5/12
Combination
Kirby 2003[10] Therapy 253 10.8/12.1 (1.30) 5/15
Combination
Lepor 1996[11] Therapy 305 10.4/11.8 (1.40) 4/15
Larson 1998[24] TUMT 39 7.8/9.8 (2.0) -/12
Bdesha
1993[22] TUMT 18 10.8/9.8 (-1.0) -/15
Blute 1996[23] TUMT 37 7.4/9.4 (2.0) -/10
Nawrocki
1997[25] TUMT 120 9.44/9.49 (0.05) -/15

15

Page 15 of 15