STUDY TITLE: Efficacy of silodosin versus tamsulosin in lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia- A randomized open label parallel group clinical study

AIM:  To study the efficacy of silodosin versus tamsulosin in lower urinary tract symptoms due to benign prostatic hyperplasia in a tertiary care teaching institution.

OBJECTIVES:  (A) PRIMARY OBJECTIVE:   To evaluate the efficacy ofsilodosin versus tamsulosin in lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia. (B) SECONDARY OBJECTIVE: To evaluate the drug study safety and compliance to administered therapy.

RATIONALE:  To evaluate the efficacy of silodosin versus tamsulosin for BPH occurring in our hospital setting which to the best of our knowledge has not been documented or studied before in our Institution. To the best of our knowledge there is a scarcity of such comparative study published/documented in the Indian literature too. Silodosin is more selective towards alpha receptors than other alpha blockers like tamsulosin and alfuzosin⁽²⁾ receptors than other alpha blockers like tamsulosin and alfuzosin⁽²⁾

BRIEF REVIEW OF LITERATURE:  Rossi et al⁽¹⁾conducted a study titled silodosin in the treatment of Benign Prostatic Hyperplasia. The study showed that Silodosin is extremely efficacious not only in subjectively improving the symptoms but also in objectively helping in relieving the obstruction as seen by measuring peak flow rates due to its selectivity on alpha 1a receptors. Manohar et al⁽²⁾ conducted a study   regarding Safety and efficacy of tamsulosin, alfuzosin or silodosin as monotherapy for LUTS in BPH – a double-blind randomized trial^. The study concluded that silodosin was the most efficacious alpha blocker amongst the three as it is more selective towards the alpha receptors.  Hui et al⁽³⁾ conducted a study titled silodosin is effective for treatment of LUTS in men with BPH: a systematic review. The study revealed that silodosin is very effective in the treatment of LUTS though the adverse effect of retrograde ejaculation is more with silodosin. It also concluded that more RCTs are required to establish this conclusion having greater adverse effect of retrograde ejaculation with silodosin as compared to tamsulosin. Jung et al⁽⁴⁾ conducted a study titled silodosin for the treatment of lower urinary tract symptoms in men with benign prostatic hyperplasiaThe study concluded that Silodosin may reduce urological symptoms in a significant number of men when compared with placebo and also improves the flow rates though in terms of efficacy it is similar to other alpha blockers

Cho et al ⁽⁵⁾ conducted a study  titled Silodosin for the treatment of clinical benign prostatic hyperplasia: safety, efficacy, and patient acceptability.  A study conducted by Hideki et al⁽⁶⁾titled Randomized Crossover Comparison of the Short-Term Efficacy and Safety of Single Half-Dose Silodosin and Tamsulosin Hydrochoride in Men With Lower Urinary Tract Symptoms Secondary to Benign Prostatic Hyperplasia⁽⁶⁾the authors concluded that giving a single half dose of silodosin had same efficacy as tamsulosin single full dose in Japanese men. Pande et al ⁽⁷⁾conducted a study titled Evaluation of silodosin in comparison to tamsulosin in benign prostatic hyperplasia: A randomized controlled trial  which concluded that silodosin was similar to tamsulosin in terms of safety and retrograde ejaculation occurred mainly with silodosin and postural hypotension mainly with tamsulosin.

SETTING: Outpatient and Inpatient Department of Surgery(Urology), UCMS & GTB Hospital.

STUDY DESIGN: Prospective interventional randomized open label parallel clinical study

TIME FRAME: November 2019 to April 2021

NUMBER OF PATIENTS: 100 (50 in each group)

CONSENT & ETHICS: Written informed consent (Bilingual) & and Institutional Ethical Clearance.

INCLUSION CRITERIA:  All patients aged 45-80years giving informed consent to participate in the study. Patients with LUTS/ IPSS>8due to BPH with no absolute indication for surgery.Patients with enlarged prostate gland less than 30gms on either clinical examination or by ultrasound. Patients with previously diagnosed BPH not on any medical therapy (patients on alpha blockers will be given 2-week drug washout prior to enrolment).

EXCLUSION CRITERIA: Patients with mental disorders or illness who cannot understand or comply with the study protocol. BPH withcomplications (like CRF, hydronephrosis,acute bacterial prostatitis, hematuria. Patients with LUTS and or bladder outlet obstruction due to causes other than BPH. Patients with known drug allergy/contraindications to tamsulosin/ silodosin. Patients taking nitrates for CYP3A4 inhibitors(ketoconazole,ritonavir) and CYP3A4 inducers(rifampicin).Patients with previous history of prostate surgery, diagnosed cancer prostate. Patients on 5 alpha reductase inhibitor therapy. Patients with severe cardiac, hepatic or renal insufficiency. Patients with active untreated UTI, urolithiasis, PVR >200mls, patients in whom cystoscopy or biopsy has been done from urinary tract in the past 2 weeksurethral stricture disease, neurogenic bladder, prostate or urethral surgery, any previous history of continuous intermittent catheterization, h/o postural hypotension, patients with uncontrolled severe hypertension. H/O treatment with verapamil, androgens, anti androgens, diuretics, cholinergics, anticholinergics, phytotherapy in the past 3 months, h/o alcohol abuse, malignancy. Patients with h/o any conditions exposing them to increased risk of adverse effects of silodosin including any cardiovascular, renal, neurological, hepatic or any other systemic illness or disorder. Any other condition deemed as high risk in the clinical judgement/opinion of the investigator. 

METHODS: All patients with symptomatic LUTS due to BPH will be screened at the first visit for inclusion in this study, as per protocol entry criteria. After administering a written bilingual informed consent and local institutional ethics committee clearance, eligible patients will be counseled for enrolment in this study. Screening visit will comprise a detailed history, postural blood pressure measurement, focused urological examination and baseline investigations, uroflowmetry, IPSS,and QOL scores as per protocol.Eligible patients shall be computerrandomizedthrough draw of lots to receive therapy with either tab tamsulosin 0.4mg (comparator arm) or silodosin 8mg OD HS (intervention arm). Patients will be followed up as per protocol with outcome parameters for 2 months.

OUTCOME: (A) Primary Outcome: Efficacy outcome parameters will be assessed by (i)change inInternational prostatic symptom score (IPSS) uroflowstudy (peak flow rate) and (iii) Quality of life(QOL) indexat end of 2 months therapy. (B) Secondary Outcome: Safety outcome parameters will be assessed by (i) monitoringof treatment emergent adverse effects (TEAE), adverse drug reactions, side effects and adverse events and serious adverse effects of the drugs being administered, as per proforma, along with (ii) assessment of derangement in any of biochemistry/laboratory reports and (iii) Drug compliance will be assessed by asking the patient to present be all empty strips at each visit upto 2 months.

DATA ANALYSIS: Since both the drugs are alpha blockers the expected sample size to detect outcome differences based primarily on the basis of change in IPSS (change in 3 or 4 points) or peak flow rate(1 ml/sec) is likely to be about 25 per group (50 patients) for 80% power according to one such similar published study⁽⁷⁾. However, based on this study with outcome parameters almost similar to the above referenced study⁽⁷⁾ we have chosen 50 patients for each group after (assuming a dropout rate of 20%) which should be adequate for >80% power. Statistical analysis in the study would be done quantitatively by student t test and qualitatively by the mean, median and mode of the data.

REFERENCES

1. Rossi M, Roumeguère T. Silodosin in the treatment of benign prostatic hyperplasia. Drug Des Devel Ther. 2010 27;4:291–7.

2. Manohar CMS, Nagabhushana M, Karthikeyan VS, Sanjay RP, Kamath AJ, Keshavamurthy R. Safety and efficacy of tamsulosin, alfuzosin or silodosin as monotherapy for LUTS in BPH - a double-blind randomized trial. Cent Eur J Urol. 2017  30;70(2):148–53.

3. Ding H, Du W, Hou Z-Z, Wang H-Z, Wang Z-P. Silodosin is effective for treatment of LUTS in men with BPH: a systematic review. Asian J Androl. 2013 ;15(1):121–8.

4. Jung JH, Kim J, MacDonald R, Reddy B, Kim MH, Dahm P. Silodosin for the treatment of lower urinary tract symptoms in men with benign prostatic hyperplasia. Cochrane Database Syst Rev. 2017 22;11:CD012615.

5. Cho HJ, Yoo TK. Silodosin for the treatment of clinical benign prostatic hyperplasia: safety, efficacy, and patient acceptability. Res Rep Urol. 2014;6:113–9.

6. Takeshita H, Moriyama S, Arai Y, Washino S, Saito K, Chiba K, et al. Randomized Crossover Comparison of the Short-Term Efficacy and Safety of Single Half-Dose Silodosin and Tamsulosin Hydrochoride in Men With Lower Urinary Tract Symptoms Secondary to BPH. Low Urin Tract Symptoms. 2016;8(1):38–43.

7. Pande S, Hazra A, Kundu AK. Evaluation of silodosin in comparison to tamsulosin in BPH: a randomized controlled trial. Indian J Pharmacol. 2014 ;46(6):601–7.

8. The American Urological Association Symptom Index for Benign Prostatic Hyperplasia | J.Urol [2019]. Available from: https://www.auajournals.org/article/S0022-5347(16)31615-9/abstract

9. Michael P O’Leary. Validity of the “Bother Score” in the Evaluation and Treatment of symptomatic BPH. Rev Urol 2008;7(1):1-10.