Silodosin for the treatment of lower urinary tract symptoms in men with benign prostatic hyperplasia

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To assess the effectiveness and adverse effects of silodosin compared to placebo or other medical treatments in men with LUTS suggestive of BPH.

Background

Description of the condition

Benign prostatic hyperplasia (BPH) is characterised by an unregulated proliferative process of connective tissue, smooth muscle and glandular epithelium within the prostate, and is one of the most common conditions in elderly men (Roehrborn 2008). The prevalence of BPH rises significantly with increased age. Autopsy studies have observed a histological prevalence of 40% and 70% in the sixth and eighth decades of life, respectively (Barry 1997; Egan 2016; Roehrborn 2008). BPH can lead to troublesome lower urinary tract symptoms (LUTS), including storage disturbances (such as daytime urinary urgency and nocturia) and/or voiding disturbances (such as urinary hesitancy, weak urinary stream, straining to void, and prolonged voiding) (AUA Practice Guidelines Committee 2003; Gratzke 2015; McVary 2011). LUTS secondary to BPH (LUTS/BPH) may negatively impact on public health and reduce quality of life because BPH can progress over time and cause serious consequences such as acute urinary retention, urinary tract infection, and upper urinary tract deterioration (Crawford 2006; Kozminski 2015; Martin 2014). In 2000, the direct treatment cost for LUTS/BPH in the USA was more than USD 1 billion. Based on the Hospital Episode Statistics data from the UK, LUTS/BPH is the fifth most expensive disease and costs GBP 1.16 billion each year (Cornu 2010).

Diagnosis

Initial assessment of LUTS/BPH includes patient history, review of current medications, physical exam including a digital rectal examination, urinalysis, prostate specific antigen, frequency/volume chart, and validated symptom questionnaires such as the International Prostate Symptom Score (IPSS) and Benign Prostatic Hyperplasia Impact Index (BII) (AUA Practice Guidelines Committee 2003; Gratzke 2015; Juliao 2012; McVary 2011). The IPSS questionnaire is composed of: three domains related to storage symptoms (frequency, urgency, and nocturia); four domains related to voiding symptoms (hesitancy, weak stream, intermittence, and incomplete emptying); and one quality of life domain (AUA Practice Guidelines Committee 2003; Barry 1992). Seven symptom domains use a six‐point scale ranging from 0 (none) to 5 (5 or more) (Barry 1992). The quality of life domain is assigned a score from 1 to 6 (ordinal and range from 0 to 6: 0 = delighted, 1 = pleased, 2 = mostly satisfied, 3 = mixed, 4 = mostly dissatisfied, 5 = unhappy, 6 = terrible) (AUA Practice Guidelines Committee 2003).

Simultaneous with the development of the IPSS, the BII was developed to assess the effect of LUTS/BPH on the patient's health. The BII questionnaire is composed of four items: physical discomfort (0 = none, 1 = only a little, 2 = some, 3 = a lot); worry item (0 = none, 1 = only a little, 2 = some, 3 = a lot); bother item (0 = not at all bothersome, 1 = bothers me a little, 2 = bothers me some, 3 = bothers me a lot); the interference with usual activities item (0 = none of the time, 1 = a little of the time, 2 = some of the time, 3 = most of the time, 4 = all of the time) (Barry 1995). In addition, measurement of the peak urinary flow (Qmax) and postvoid residual volume (PVR) are widely used noninvasive tests to evaluate joint functioning between bladder and prostate (Gratzke 2015; McVary 2011). Although diagnostic thresholds of Qmax and PVR have not been determined, low Qmax and large PVR have been associated with an increased risk of symptom deterioration (Crawford 2006; Kozminski 2015). Other optional tests include imaging of the urinary tract and prostate, urodynamic evaluation of bladder function, and cystoscopy to predict the response to medical therapy or determine the need for invasive therapy and therefore, the best approach (Gratzke 2015; McVary 2011).

Treatment

Treatment decisions are based on symptoms and degree of bother (AUA Practice Guidelines Committee 2003; McVary 2011; Oelke 2013). Watchful waiting is the reasonable treatment strategy for patients with mild LUTS (IPSS: 0 to 7) or those who do not perceive their symptoms to be particularly bothersome (Netto 1999). Lifestyle interventions such as modifying fluid intake or toileting behaviour can be used as conservative treatments in patients with mild LUTS (Yap 2009). In patients with bothersome moderate (IPSS: 8 to 19) to severe LUTS (IPSS: 20 to 35), surgical and medical therapies are the treatment options, and the choice of treatment depends on a number of factors such as the severity of disease, risk of progression, patient preference, and morbidity (AUA Practice Guidelines Committee 2003; McVary 2011; Oelke 2013).

Recently, the dynamic component of BPH has been elucidated, with a focus on symptoms rather than prostate enlargement, which has led to a shift from surgery to medical treatment (Yoo 2012). Alpha‐adrenergic receptor blockers (ABs), which reduce smooth‐muscle tone in the prostate and bladder neck with/without 5‐alpha reductase inhibitors (5 ARIs), which reduce prostate volume by inducing epithelial atrophy are an established treatment in LUTS/BPH and have been widely used as first‐line therapy for decades (McConnell 2003; Milani 2005; Yoo 2012). In particular, ABs which can decrease smooth muscle tone in the prostate and bladder neck have been considered as fundamental pharmacotherapy for men with BPH (Cornu 2010; Milani 2005; Yoo 2012). Prior systematic reviews have shown that ABs can typically reduce the IPSS by 20% to 50% and increase the Qmax by 15% to 45% (MacDonald 2005; Wilt 2006). ABs are the most commonly prescribed category of drug, accounting for about 70% of all medications prescribed in 2008 (Cornu 2010). Adverse effects of ABs include postural hypotension, dizziness, headache, asthenia, syncope, peripheral edema, and retrograde ejaculation, which cause approximately 4% to 10% of patients to withdraw from AB treatment (Djavan 1999; Gacci 2014; MacDonald 2005; Schulman 2003; Wilt 2006).

Other medical therapies, such as anticholinergics and desmopressin, have been used with ABs, depending on the main symptoms of patients (Brasure 2016; Dahm 2016; Oelke 2013). Alternatively, phosphodiesterase type 5 inhibitor, tadalafil (5 mg once daily), has been licensed for the treatment of male LUTS in the last few years, and various plant extracts have been proposed for the treatment of male LUTS (Keehn 2016; Oelke 2012). In patients with LUTS/BPH refractory to conservative/medical treatment or in cases of absolute clinical indications (e.g. acute urinary retention, recurrent urinary tract infection, bladder stones or diverticula, hematuria, or renal insufficiency), surgical techniques should be considered (AUA Practice Guidelines Committee 2003; McVary 2011; Oelke 2013). Transurethral resection of the prostate (TURP) is regarded as the standard surgical procedure for the treatment of LUTS/BPH (Juliao 2012; McVary 2011; Oelke 2013). Recently, minimal invasive laser therapies such as holmium laser enucleation of the prostate and photoselective vaporisation were introduced as treatment alternatives to TURP (Nair 2016).

Description of the intervention

Silodosin is a new subtype selective AB that was approved in Japan in 2006, and more recently has received approval in the USA and Europe (Kawabe 2006; Yoshida 2007). An initial randomised, placebo‐controlled trial, which was conducted in Japan showed a greater reduction in IPSS after 12 weeks treatment compared to both tamsulosin – which is a well established AB for LUTS – and placebo. Furthermore, a clinical benefit in IPSS in the silodosin group over placebo was found from one week onwards (Kawabe 2006). There were no significant differences in the incidence of cardiovascular adverse events between the silodosin and tamsulosin groups. Abnormal ejaculation was more frequent in the silodosin group than in the tamsulosin group (22.3% versus 1.6%), but only five men (2.9%) discontinued treatment due to abnormal ejaculation (Kawabe 2006).

How the intervention might work

The A1a adrenergic receptors are a class of G protein‐coupled receptors that consists of three homologous subtypes, including A1a, A1b, and A1d receptors. The A1a receptor subtype predominates in the human prostate, bladder neck, and urethra (Minneman 1994; Schilit 2009). On the other hand, A1b receptor subtypes are mainly expressed in the peripheral vasculature and are important in the regulation of blood pressure. A1d receptor is expressed in the detrusor muscle of the bladder and the sacral region of the spinal cord (Minneman 1994; Schilit 2009). In the initial vitro study, it was shown that silodosin had a high binding ratio (162:1) for A1a versus A1b receptor, which can be more specific to the lower urinary tract, and may therefore induce a therapeutic effect without cardiovascular side effects, such as dizziness, headache, and orthostatic hypotension related to vasodilation, compared with the other ABs which have either no specific selectivity for the different adrenergic receptor subtypes (alfuzosin, doxazosin, terazosin) or a limited selectivity for A1a receptor (tamsulosin) (Osman 2012; Schilit 2009; Yoshida 2007).

Why it is important to do this review

Until now, it is unclear whether the high affinity of silodosin to A1a adrenergic receptor actually translates into more clinical benefits and less adverse effects in clinical practice (Cui 2012; Novara 2013). While there are existing systematic reviews that compare silodosin to other agents used to treat males with LUTS/BPH, none so far has used the same rigorous methodology as Cochrane Reviews, which include the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach (Cui 2012; Fusco 2016; Novara 2013). In this era, with the availability of numerous ABs to treat LUTS/BPH, the findings of this Cochrane Review will be relevant to policymakers, healthcare providers and patients.

Objectives

To assess the effectiveness and adverse effects of silodosin compared to placebo or other medical treatments in men with LUTS suggestive of BPH.

Methods

Criteria for considering studies for this review

Types of studies

We will only include parallel randomised trials. We will include studies regardless of their publication status or language of publication.

Types of participants

Adult men (aged 45 years and over) with LUTS/BPH with a minimum IPSS score of 8. The age limitation is based on the observation that the prevalence of BPH increases in middle‐aged and older men (Barry 1997; Egan 2016), and is infrequent in younger men.

We will exclude trials of men with a known neurogenic bladder due to spinal cord injury, multiple sclerosis, or central nervous system disease, and men who have been treated with surgery for BPH already. We will include studies in which only a subset of participants are relevant to this review, if data are available separately for the relevant subset.

Types of interventions

We plan to investigate the following comparisons of experimental intervention versus comparator intervention. Concomitant interventions will have to be the same in the experimental and comparator groups to establish fair comparisons.

Experimental interventions

• Silodosin

• Silodosin + any 5 ARIs (if available)

Silodosin at 8 mg/day is the clinically recommended dosage in Japan, Europe, and the USA (Chapple 2011; Kawabe 2006; Marks 2009). A recent study reported that silodosin at 4 mg/day was also useful for Japanese patients with BPH, in order to improve treatment compliance (Seki 2015). We will include trials with a dosage of silodosin at 8 mg/day (4 mg twice daily or 8 mg once daily) and, if available, 4 mg/day.

Comparator interventions

• Placebo

• Other ABs

• Other ABs + any 5 ARIs (if available)

Comparisons

• Silodosin versus placebo

• Silodosin versus other ABs

• Silodosin + any 5 ARIs versus other ABs + any 5 ARIs (if available)

Types of outcome measures

We will not use the measurement of the outcomes assessed in this review as an eligibility criterion.

Primary outcomes

• Mean change in urologic symptom scores, assessed with a validated scale (such as IPSS)

• Mean change in quality of life, assessed with a validated scale (such as IPSS or BII scores)

• Treatment withdrawals for any reason

We will consider improvement of the IPSS and BII score of 3.0 and 0.5 points as a slight improvement; an improvement of 5.1 and 1.1 points as moderate, and 8.8 and 2.2 as marked improvement, respectively (Barry 1995). No threshold was established for the IPSS quality of life question. We will use a minimal detectable difference of one to assess efficacy and comparative effectiveness (Brasure 2016).

Secondary outcomes

• Treatment withdrawals due to adverse events

• Incidence of acute urinary retention

• Incidence of surgical intervention for LUTS/BPH

• Incidence of cardiovascular adverse events (dizziness, headache, orthostatic hypotension, and syncope)

• Incidence of sexual adverse events (retrograde ejaculation, anejaculation, and decreased libido)

Method and timing of outcome measurement

• Up to 12 months (short‐term)

• More than 12 months (long‐term)

We will consider outcomes measured up to and including 12 months after randomisation as short‐term, and later than 12 months as long‐term.

Main outcomes for 'Summary of findings' table

We will present a 'Summary of findings' table, reporting the following outcomes listed according to priority.

1. Mean change in urologic symptom scores

2. Mean change in quality of life

3. Treatment withdrawals for any reason

4. Incidence of cardiovascular adverse events

5. Incidence of sexual adverse events

Search methods for identification of studies

We will perform a comprehensive search with no restrictions on the language of publication or publication status. We plan to rerun searches within three months prior to anticipated publication of the review.

Electronic searches

We will search the following sources from inception of each database.

• Cochrane Library (via Wiley; for the search strategy, see Appendix 1)

  • Cochrane Database of Systematic Reviews (CDSR)

  • Cochrane Central Register of Controlled Trials (CENTRAL)

  • Database of Abstracts of Reviews of Effects (DARE)

  • Health Technology Assessment Database (HTA)

• MEDLINE (via Pubmed; Appendix 2)

• Embase (via Ovid; Appendix 3)

• Scopus (Appendix 4)

• Google Scholar (Appendix 5)

• Web of Science (Appendix 6)

We will also search the following.

• ClinicalTrials.gov (clinicaltrials.gov)

• World Health Organization International Clinical Trials Registry Platform search portal (who.int/trialsearch)

If we detect additional relevant key words during any of the electronic or other searches, we will modify the electronic search strategies to incorporate these terms and document the changes.

Searching other resources

We will try to identify other potentially eligible trials or ancillary publications by searching the reference lists of retrieved included trials, reviews, meta‐analyses and health technology assessment reports. We will also contact study authors of included trials to identify any further studies that we may have missed. We will contact drug/device manufacturers for ongoing or unpublished trials. We will search for unpublished studies by handsearching the abstract proceedings of the annual meetings of the American Urological Association, European Association of Urology, and International Continence Society for the last three years (2014 to 2016).

Data collection and analysis

Selection of studies

We will use reference management software to identify and remove potential duplicate records (EndNote 2016). Two review authors (JHJ, JK) will independently scan the abstract, title, or both, of remaining records retrieved, to determine which studies should be assessed further through Covidence. Two review authors (JHJ, JK) will investigate all potentially‐relevant records as full text, map records to studies, and classify studies as included studies, excluded studies, studies awaiting classification, or ongoing studies, in accordance with the criteria for each provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a). We will resolve any discrepancies through consensus or recourse to a third review author (PD). If resolution of a disagreement is not possible, we will designate the study as 'awaiting classification' and we will contact study authors for clarification. We will document reasons for exclusion of studies that may have reasonably been expected to be included in the review in a 'Characteristics of excluded studies' table. We will present an adapted PRISMA flow diagram showing the process of study selection (Liberati 2009).

Data extraction and management

We will develop a dedicated data abstraction form that we will pilot test ahead of time.

For studies that fulfil the inclusion criteria, two review authors (JHJ, JK) will independently abstract the following information, which we will provide in the 'Characteristics of included studies' table.

• Study design

• Study dates (if dates are not available then this will be reported as such)

• Study settings and country

• Participant inclusion and exclusion criteria (e.g. age, baseline IPSS)

• Participant details, baseline demographics (e.g. age, ethnic background, IPSS)

• The number of participants by study and by study arm

• Details of relevant experimental and comparator interventions such as such as frequency (e.g. once a day or twice a day) and treatment duration (in weeks or months)

• Definitions of relevant outcomes, and method (e.g. type of instrument such as IPSS) and timing of outcome measurement (e.g. in weeks or months) as well as any relevant subgroups (e.g. based on age)

• Study funding sources

• Declarations of interest by primary investigators

We will extract outcome data relevant to this Cochrane Review as needed for calculation of summary statistics and measures of variance. For dichotomous outcomes, we will attempt to obtain numbers of events and totals for population of a 2 x 2 table, as well as summary statistics with corresponding measures of variance. For continuous outcomes, we will attempt to obtain means and standard deviations or data necessary to calculate this information.

We will resolve any disagreements by discussion, or, if required, by consultation with a third review author (PD).

We will provide information (including trial identifier), about potentially relevant ongoing studies in the table 'Characteristics of ongoing studies'.

We will attempt to contact authors of included studies to obtain key missing data as needed.

Dealing with duplicate and companion publications

In the event of duplicate publications, companion documents or multiple reports of a primary study, we will maximise yield of information by mapping all publications to unique studies and collating all available data. We will use the most complete data‐set aggregated across all known publications. In case of doubt, we will give priority to the publication reporting the longest follow‐up associated with our primary or secondary outcomes.

Assessment of risk of bias in included studies

Two review authors (JHJ, JK) will assess the risk of bias of each included study independently. We will resolve disagreements by consensus, or by consultation with a third review author (PD).

We will assess risk of bias using Cochrane's 'Risk of bias' assessment tool (Higgins 2011b). We will assess the following domains.

• Random sequence generation (selection bias)

• Allocation concealment (selection bias)

• Blinding of participants and personnel (performance bias)

• Blinding of outcome assessment (detection bias)

• Incomplete outcome data (attrition bias)

• Selective reporting (reporting bias)

• Other sources of bias

We will judge risk of bias domains as 'low risk', 'high risk', or 'unclear risk' and will evaluate individual bias items as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b). We will present a 'Risk of bias' summary figure to illustrate these findings.

For performance bias (blinding of participants and personnel) and detection bias (blinding of outcome assessment), we will evaluate the risk of bias separately for each outcome, and we will group outcomes according to whether measured subjectively or objectively when reporting our findings in the 'Risk of bias' tables.

We define all outcomes as subjective outcomes indicating a potentially important role for blinding the outcome assessors either to determine the event itself (e.g. retention or not) or the reason (e.g. withdrawal due to adverse event of a certain type).

• Mean change in urologic symptom scores

• Mean change in quality of life

• Treatment withdrawals for any reason

• Treatment withdrawals due to adverse events

• Incidence of acute urinary retention

• Incidence of surgical intervention for LUTS/BPH

• Incidence of cardiovascular adverse events (dizziness, headache, orthostatic hypotension, and syncope)

• Incidence of sexual adverse events (retrograde ejaculation, anejaculation, and decreased libido)

We will also assess attrition bias (incomplete outcome data) on an outcome‐specific basis, and will present the judgement for each outcome separately when reporting our findings in the 'Risk of bias' tables.

We will further summarise the risk of bias across domains for each outcome in each included study, as well as across studies and domains for each outcome, in accordance with the approach for summary assessments of the risk of bias presented in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b).

Measures of treatment effect

We will express dichotomous data as risk ratios (RRs) with 95% confidence intervals (CIs). We will express continuous data as mean differences (MDs) with 95% CIs unless different studies use different measures to assess the same outcome, in which case we will express data as standardised mean differences with 95% CIs. We will express time‐to‐event data as hazard ratios (HRs) with 95% CIs.

Unit of analysis issues

The unit of analysis will be the individual participant. We will exclude cross‐over trials or cluster‐randomised trials.

Dealing with missing data

We will obtain missing data from study authors, if feasible, and will perform intention‐to‐treat analyses if data are available; we will otherwise perform available case analyses. We will investigate attrition rates, e.g. dropouts, losses to follow‐up and withdrawals, and will critically appraise issues of missing data. We will not impute missing data.

Assessment of heterogeneity

In the event of excessive heterogeneity unexplained by subgroup analyses, we will not report outcome results as the pooled effect estimate in a meta‐analysis, but will provide a narrative description of the results of each study.

We will identify heterogeneity (inconsistency) through visual inspection of the forest plots to assess the amount of overlap of CIs, and the I² statistic, which quantifies inconsistency across studies to assess the impact of heterogeneity in the meta‐analysis (Higgins 2002; Higgins 2003); we will interpret the I² statistic as follows (Deeks 2011).

• 0% to 40%: may not be important

• 30% to 60%: may indicate moderate heterogeneity

• 50% to 90%: may indicate substantial heterogeneity

• 75% to 100%: considerable heterogeneity

When we find heterogeneity, we will attempt to determine possible reasons for it by examining individual study and subgroup characteristics.

Assessment of reporting biases

We will attempt to obtain study protocols to assess for selective outcome reporting.

If we include 10 studies or more investigating a particular outcome, we will use funnel plots to assess small study effects. Several explanations can be offered for the asymmetry of a funnel plot, including true heterogeneity of effect with respect to trial size, poor methodological design (and hence bias of small trials), and publication bias. We will therefore interpret results carefully.

Data synthesis

Unless there is good evidence for homogeneous effects across studies, we will summarise data using a random‐effects model. We will interpret random‐effects meta‐analyses with due consideration of the whole distribution of effects. In addition, we will perform statistical analyses according to the statistical guidelines contained in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a). For dichotomous outcomes, we will use the Mantel‐Haenszel method; for continuous outcomes, we will use the inverse variance method; and for time‐to‐event outcomes, we will use the generic inverse variance method. We will use Review Manager 5 software to perform analyses (RevMan 2014).

Subgroup analysis and investigation of heterogeneity

We expect the following characteristics to introduce clinical heterogeneity, and plan to carry out subgroup analyses with investigation of interactions.

• Severity of baseline symptoms based on IPSS (0 to 7 = mildly symptomatic; 8 to 19 = moderately symptomatic; 20 to 35 = severely symptomatic)

• Patient age (less than 65 years versus ≥ 65 years)

These subgroup analyses are based on the following observations.

• The relationship between changes in IPSS scores and patient global ratings of improvement is influenced by the baseline scores (Barry 1995)

• Tolerability of other ABs (as the main comparator) may differ by patient age but that this may be less the case for silodosin, which would represent a potential benefit of this agent (Kozminski 2015; Lepor 2007; Schilit 2009)

We will use the test for subgroup differences in Review Manager 5 to compare subgroup analyses if there are sufficient studies (RevMan 2014).

Sensitivity analysis

We plan to perform sensitivity analyses in order to explore the influence of the following factors (when applicable) on effect sizes.

• Restricting the analysis by taking into account risk of bias, by excluding studies at 'high risk' or 'unclear risk' of bias

'Summary of findings' table

We will present the overall quality of the evidence for each outcome according to the GRADE approach, which takes into account five criteria not only related to internal validity (risk of bias, inconsistency, imprecision, publication bias), but also to external validity, such as directness of results (Guyatt 2008). For each comparison, two review authors (JHJ, JK) will independently rate the quality of evidence for each outcome as 'high', 'moderate', 'low', or 'very low' using GRADEpro GDT. We will resolve any discrepancies by consensus, or, if needed, by arbitration by a third review author (PD). For each comparison, we will present a summary of the evidence for the main outcomes in a 'Summary of findings' table, which provides key information about the best estimate of the magnitude of the effect in relative terms and absolute differences for each relevant comparison of alternative management strategies; numbers of participants and studies addressing each important outcome; and the rating of the overall confidence in effect estimates for each outcome (Guyatt 2011; Schünemann 2011). If meta‐analysis is not possible, we will present results in a narrative 'Summary of findings' table.

Appendices

Appendix 1. Cochrane Library search strategy

1. "Prostatic Hyperplasia" [Mesh]

2. (hyperplasia NEAR/3 prostat*):ti,ab,kw

3. "hyperplasia of the prostate":ti,ab,kw

4. "prostatic hyperplasia":ab,ti

5. (hypertrophy NEAR/3 prostat*):ti,ab,kw

6. (adenoma* NEAR/3 prostat*):ti,ab,kw

7. "lower urinary tract symptom" [Mesh]

8. "lower urinary tract": ti,ab,kw

9. LUTS: ti,ab,kw

10. "prostatism": ti,ab,kw

11. "prostatism"[Mesh]

12. "Urinary Bladder Neck Obstruction" [Mesh]

13. "bladder outlet obstruction": ti,ab,kw

14. (prostat* NEAR/3 enlarg*): ti,ab,kw

15. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14

16. silodosin: ti,ab,kw

17. "KMD‐3213": ti,ab,kw

18. 16 or 17

Appendix 2. MEDLINE (via Pubmed) search strategy

1. "Prostatic Hyperplasia" [Mesh] or prostatic hyperplasia [TIAB]

2. "Lower Urinary Tract Symptoms" [Mesh] or lower urinary tract [TIAB] or LUST [TIAB]

3. hyperplasia of the prostate [TIAB]

4. "Prostatic hypertrophy" [TIAB]

5. "Prostatic adenoma" [TIAB]

6. "Prostatism" [Mesh] or Prostatism [TIAB]

7. "Urinary Bladder Neck Obstruction" [Mesh] or "Urinary Bladder Neck Obstruction" [TIAB]

8. bladder outlet obstruction [TIAB]

9. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8

10. silodosin [Supplementary Concept]

11. silodosin [TIAB]

12. KMD‐3213 [TIAB]

13. rapaflo [TIAB]

14. urief [TIAB]

15. urorec [TIAB]

16. 10 or 11 or 12 or 13 or 14 or 15

17. randomized controlled trial [PT]

18. controlled clinical trial [PT]

19. randomized [TIAB]

20. placebo [TIAB]

21. drug therapy [Sh]

22. randomly [TIAB]

23. trial [TIAB]

24. groups [TIAB]

25. 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24

26. 9 AND 16 AND 25

27. (animals [Mesh]) NOT (humans [Mesh] and animals [Mesh])

28. 26 NOT 27

Appendix 3. Embase (via Elsevier) search strategy

1. 'prostate hypertrophy'/exp

2. (hyper* NEAR/3 prostat*):ab,ti

3. (adenoma* NEAR/3 prostat*):ab,ti

4. 'BPH' or 'BPO' or 'BPE':ab,ti

5. 'lower urinary tract symptom'/exp

6. 'lower urinary tract' or 'LUTS':ab,ti

7. 'prostatism':ab,ti

8. 'prostatism'/exp

9. 'bladder obstruction'/exp

10. ('bladder* NEAR/3 obstruct*)' or 'BOO' :ab,ti

11. (prostat* NEAR/3 (enlarg* or obstruct*)):ab,ti

12. ((urinary or urethra* or urination or LUT*) NEAR/3 (symptom* or complain*)):ab,ti

13. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12

14. 'silodosin'/exp

15. silodosin or 'KMD‐3213' or kad3213 or rapaflo or silodyx or urief or urorec or Silofast or Thrupas:tw

16. '160970‐54‐7' or '160970‐64‐9' or '169107‐04‐4':rn

17. 14 or 15 or 16

18. random$ or factorial$ or crossover$ or cross over$ or 'cross‐over$' or placebo$ or (doubl$ adj blind$) or (singl$ adj blind$) or assign$ or allocat$ or volunteer$:tw

19. 'crossover procedure'/exp OR 'double blind procedure'/exp OR 'randomized controlled trial'/exp OR 'single blind procedure'/exp

20. 18 or 19

21. 13 AND 17 AND 20

22. ('animals'/exp) NOT ('humans'/exp and 'animals'/exp)

23. 21 NOT 22

Appendix 4. Scopus search strategy

1. TITLE‐ABS‐KEY (hyperplasia W/3 prostat*)

2. TITLE‐ABS‐KEY (hypertrophy W/3 prostat*)

3. TITLE‐ABS‐KEY (adenoma* W/3 prostat*)

4. TITLE‐ABS‐KEY (prostat* W/3 (enlarg* or obstruct*))

5. TITLE‐ABS‐KEY ((urinary OR urethra* OR urination OR lut*) W/3 (symptom* OR complain*))

6. TITLE‐ABS‐KEY (prostatism)

7. TITLE‐ABS‐KEY (bladder* W/3 obstruct*)

8. TITLE‐ABS‐KEY ("lower urinary tract")

9. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8

10. TITLE‐ABS‐KEY (silodosin or 'KMD‐3213' or rapaflo or silodyx or urief or urorec or Silofast or Thrupas)

11. CASREGNUMBER (160970‐54‐7 OR 160970‐64‐9 OR 169107‐04‐4)

12. 10 or 11

13. TITLE‐ABS‐KEY ("Double blind*" OR "Single Blind*" OR "Cross over stud*")

14. 9 AND 12 AND 13

Appendix 5. Google Scholar search strategy

allintitle: ("Prostatic Hyperplasia" OR "prostate hypertrophy" OR "hyperplasia of the prostate" OR "lower urinary tract" OR "LUTS" OR prostatism OR "bladder obstruction" OR "bladder outlet obstruction") AND (silodosin OR KMD‐3213 OR rapaflo OR Silodyx OR kad3213 OR urief OR urorec OR Silodal OR Rapilif OR Silofast OR Thrupas)

Appendix 6. Web of Science search strategy

1. TS = (hyper* NEAR/3 prostat*) OR (adenoma* NEAR/3 prostat*) OR "BPH" OR "BPO" OR "BPE" OR "lower urinary tract" OR "luts" OR prostatism OR ("bladder NEAR/3 obstruct*") OR "BOO" OR (prostat* NEAR/3 (enlarg* or obstruct*)) OR ((urinary or urethra* or urination or LUT*) NEAR/3 (symptom* or complain*))

2. TS = (silodosin OR KMD‐3213 OR rapaflo OR urief)

3. TS = "clinical trial*" OR "controlled trial*" OR "randomized controlled trial*" OR (single blind*) OR (double blind*)

4. 1 AND 2 AND 3

Appendix 7. ClinicalTrials.gov

Basic search = ("Prostatic Hyperplasia" OR "prostate hypertrophy" OR "hyperplasia of the prostate" OR "lower urinary tract" OR "LUTS" OR prostatism OR "bladder obstruction" OR "bladder outlet obstruction") AND (silodosin OR KMD‐3213 OR rapaflo OR urief OR Thrupas)

Appendix 8. World Health Organization International Clinical Trials Registry Platform Search Portal

In the title = ("Prostatic Hyperplasia" OR "prostate hypertrophy" OR "hyperplasia of the prostate" OR "lower urinary tract" OR "LUTS" OR prostatism OR "bladder obstruction" OR "bladder outlet obstruction") AND In the intervention= (silodosin OR KMD‐3213 OR rapaflo OR Silodyx OR urief OR urorec OR Silodal OR Thrupas)

Contributions of authors

JH Jung (JHJ): designed and wrote the protocol

J Kim (JK): wrote the protocol

MH Kim (MHK): designed the search strategy and wrote the protocol

R MacDonald (RM): designed and wrote the protocol

P Dahm (PD): conceived, designed and wrote the protocol

Sources of support

Internal sources

• No sources of support provided, Other.

External sources

• No sources of support provided, Other.

Declarations of interest

JH Jung: none known

J Kim: none known

MH Kim: none known

R MacDonald (RM): none known

P Dahm: none known

Notes

We have based parts of the Methods section of this protocol on a standard template developed by the Cochrane Metabolic and Endocrine Disorders Group, which has been modified and adapted for use by the Cochrane Urology Group.

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