Rapid Onset of Action with Alfuzosin 10 Mg Once Daily in Men with Benign Prostatic Hyperplasia: a Randomized, Placebo-Controlled Trial

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Rapid onset of action with alfuzosin 10 mg once daily in men with benign prostatic hyperplasia: a randomized, placebo-controlled trial

MI Resnick1 and CG Roehrborn2 1Department of Urology, Case Medical Center, Cleveland, OH, USA and 2Department of Urology, Middlesex Hospital, London, UK

This randomized, double-blind, placebo-controlled study was conducted to investigate whether alfuzosin 10 mg once daily improves the maximum flow rate (Qmax) and lower urinary tract symptoms (LUTS) of benign prostatic hyperplasia (BPH) after 1 week and 1 month of treatment. A total of 372 men aged X50 years with symptomatic BPH received alfuzosin or placebo for 28 days. Qmax increased significantly from baseline at day 8 with alfuzosin (Po0.001 versus placebo); this improvement was evident within 24 h after the first dose and was maintained at day 29. LUTS improved from baseline with alfuzosin at day 8 (P ¼ 0.07 versus placebo) and day 29 (P ¼ 0.003 versus placebo). Alfuzosin 10 mg once daily exhibits a rapid onset of action, with improvements in Qmax and LUTS maintained through 1 month of treatment. Prostate Cancer and Prostatic Diseases (2007) 10, 155–159; doi:10.1038/sj.pcan.4500925; published online 9 January 2007

Keywords: benign prostatic hyperplasia; alfuzosin; urinary flow rate; lower urinary tract symptoms; onset of action

Introduction point decrease in the total International Prostate Symptom Score (IPSS) versus baseline (Po0.01) within 5 Uroselective a1-adrenergic blockers, such as alfuzosin, 3 months of alfuzosin 2.5 mg t.i.d. treatment. Compar- are recommended as first-line treatment for the manage- able improvements were also observed within the first 28 ment of uncomplicated, moderate-to-severe, lower uri- days of therapy with alfuzosin 10 mg q.d. In a pooled nary tract symptoms (LUTS) associated with benign analysis of three randomized, double-blind, placebo- 1 prostatic hyperplasia (BPH). Blockade of a1-adrenocep- controlled trials in men with LUTS secondary to BPH tors is associated with decreased smooth muscle con- (N ¼ 473), treatment with alfuzosin 10 mg q.d. resulted traction in various organs.2 In the urogenital tract, in a change from baseline in the IPSS of 44 points 8 a1-blockers improve urinary flow by blocking the (Po0.001 versus placebo). The onset of action of stimulation of a1-adrenoceptors, thereby preventing alfuzosin 10 mg q.d. appeared to be rapid, with a the contraction of smooth muscle within the prostate, significant increase from baseline in Qmax (Po0.005) at urethra, bladder neck and detrusor muscle.3 the first clinic visit at 14 days.8 A more recent investiga- Alfuzosin has been available in Europe since 1988 in tion suggested that the onset of therapeutic action begins immediate-release (2.5 mg three times per day (t.i.d.)) within hours after the first dose of alfuzosin 10 mg q.d.9 and sustained-release (5 mg twice per day (b.i.d.)) Eight hours after the first dose of alfuzosin 10 mg q.d. formulations. More recently, a new extended release in men with BPH who were known to respond to one-daily formulation, alfuzosin 10 mg q.d., became a1-blockers (N ¼ 34), significant increases in Qmax were available in Europe and the United States to improve observed (mean increase of 3.2 ml/s compared with patient compliance and tolerability. Results from trials 1.1 ml/s for placebo; P ¼ 0.002).9 with immediate- and sustained-release alfuzosin consis- To better determine the onset of symptom relief with tently demonstrated a significant decrease in the severity alfuzosin 10 mg q.d. in men with symptomatic BPH, we of LUTS, an increase in the maximum flow rate (Qmax), a conducted a short-term, randomized, controlled clinical decrease in residual urine volume and a decrease in the trial. For this investigation, we used both objective bother associated with LUTS.4–7 In one of these trials, uroflowmetry measures as well as symptom scores men with symptomatic BPH (N ¼ 289) exhibited a five- derived from a validated, ‘acute’ version of the IPSS (Acute IPSS).10,11 The Acute IPSS poses the same questions as the standard IPSS, but patients are asked Correspondence: Dr MI Resnick, Department of Urology, Case to report their symptoms during the preceding 1 week Medical Center, University Hospitals, 11100 Euclid Avenue, rather than the preceding 1 month. We also examined Cleveland, OH 44106, USA. E-mail: [email protected] improvements in LUTS after 28 days of treatment using Received 19 September 2006; accepted 11 October 2006; published the same 7-day Acute IPSS to assess the maintenance of online 9 January 2007 the therapeutic response. Onset of action of alfuzosin 10 mg q.d. in BPH MI Resnick and CG Roehrborn

156 Methods measured to detect postural hypotension. Patients were given a 7-day supply of study medication (alfuzosin or This was a multicentered, randomized, double-blinded, placebo). During the double-blind treatment period, placebo-controlled, parallel-group, clinical trial in men patients underwent evaluations on days 2, 8 and 29. with symptomatic BPH. Men aged X50 years with LUTS On days 2 and 8, patients returned to the study clinic suggestive of BPH, including a history (X6 months) of between 0700 and 0800 h with a full bladder for storage (e.g., increased daytime frequency, urgency and uroflowmetry, supine and standing BP and heart rate nocturia) and/or voiding symptoms (e.g., difficulty measurements, and recording of any adverse events. On initiating micturition, feeling of incomplete voiding, day 8, patients completed the Acute IPSS and bother impaired quality of stream and interruption of stream). question and were given the remaining 3-week supply of Inclusion criteria were an IPSS of X13 points (score study medication. On day 29, or at the final study visit range 0–35, with higher scores indicating more severe for patients discontinuing treatment, a full set of clinical LUTS) and an IPSS bother score of X3 points (score and laboratory evaluations were conducted. The primary range 0–6, with a higher score indicating greater bother). study objective was to investigate whether alfuzosin The Qmax was required to be between 5 and 12 ml/s, with 10 mg q.d. exerts any beneficial effect on urodynamic and a voided volume of X150 ml and post-void residual of symptomatic parameters of BPH at day 8. The primary p350 ml by abdominal ultrasonography. Prostate vo- end points were the change from baseline at day 8 in lume was evaluated in all patients within 12 months Qmax and the total Acute IPSS. The main secondary end before or at study entry. Exclusion criteria included point was the mean change from baseline at day 29 in the conditions that could affect urinary functioning, such as IPSS bother score. Other secondary end points were the Parkinson’s disease, multiple sclerosis, poorly controlled change from baseline at days 2 and 29 in Qmax and the diabetes, severe heart failure, stroke, recent myocardial change from baseline at day 29 in the total Acute IPSS infarction (within the last 5 months) or concomitant and the BPH Impact Index. lower urinary tract disease (including neurogenic blad- Safety was assessed based on clinical, laboratory and der dysfunction, urethral stenosis, isolated bladder neck cardiovascular measures, as well as monitoring of disease, bacterial prostatitis or acute urinary tract patient-reported adverse events (AEs). Treatment-emer- infection). Patients were excluded from enrollment if gent adverse events (TEAEs), defined as AEs occurring they had previous prostatic surgery or radiation therapy, between the start of treatment and 48 h (i.e., five half- an endoscopic procedure within 1 month of screening lives) after administration of the last dose of study (day À28), spontaneous urinary retention during the medication, were examined among patients who re- preceding 12 months, an ongoing episode of urinary ceived at least one dose of study medication (i.e., the retention requiring an indwelling catheter, postural safety population). hypotension, or syncope or were known non-responders Based on previous placebo-controlled clinical trials of 13–17 to previous a1-blocker therapy at an adequate dose for alfuzosin, and with power set at 80%, it was symptomatic BPH. Furthermore, patients reporting con- estimated that at least 171 patients per treatment group comitant use of medications that might alter voiding were required to detect a 2-point difference in Acute IPSS patterns, including a-blockers within the last month, between alfuzosin- and placebo-treated patients. The androgens within 3 months, antiandrogens, 5a-reductase primary analysis was conducted on the intent-to-treat inhibitors and/or luteinizing hormone-releasing hor- (ITT) population (defined as all patients who had been mone analogs were not eligible. Patients with evidence randomized, took at least one dose of study medication, of clinically relevant biochemical abnormalities or a and provided efficacy data that contributed to at least serum prostate-specific antigen level of 410 ng/ml were one efficacy analysis), with missing values imputed excluded. For patients with a serum prostate-specific using the last observation carried forward method. The antigen level of between 4 and 10 ng/ml, prostate cancer study also examined end point measures derived from had to be excluded to the satisfaction of the investigator the per-protocol population (defined as patients with no before patient enrollment. missing Qmax and Acute IPSS values who took medica- At screening (day À28), patient eligibility was deter- tion appropriately and showed no evidence of any mined and informed consent was signed. Patient fundamental protocol violations). history and demographic information was obtained, Analysis of covariance was used to evaluate day 8 uroflowmetry and transabdominal ultrasonography Acute IPSS and Qmax values, with baseline values for were conducted, and relevant records of transrectal each of these assessments as the covariates. The baseline ultrasonography were reviewed. The Acute IPSS and value for all variables was defined as the last observation IPSS bother question were also completed. Samples were before administration of study drug. All statistical tests collected for laboratory testing, including complete blood were two-sided, and to maintain an overall error rate of counts, blood chemistry and urinalysis, and a 12-lead 0.05 with analysis of the primary end points, the adjusted electrocardiogram (ECG) was performed. During the P-value was set at 0.025. The P-value for analysis of the run-in phase (day À28 to day 0) patients received one main secondary end point (IPSS bother score at day 29) tablet of placebo per day on an open-label basis. At the was set at 0.05. end of the run-in phase, eligible patients were randomly assigned (1:1) to alfuzosin or a matching placebo tablet, to be taken once daily after the evening meal, at approximately 0700 h or as late as possible. Baseline Results (day 1) evaluations included uroflowmetry, the Acute IPSS, the IPSS bother question and the BPH Impact A total of 372 men were randomized to treatment; 186 to Index.12 Supine and standing blood pressure (BP) were alfuzosin and 186 to placebo. Baseline demographic and

Prostate Cancer and Prostatic Diseases Onset of action of alfuzosin 10 mg q.d. in BPH MI Resnick and CG Roehrborn disease characteristics were similar between the two For both the ITT and per-protocol populations, 157 treatment groups (Table 1). Ten (5.4%) patients in the comparable mean changes from baseline at day 29 in alfuzosin group and seven (3.8%) patients in the placebo the IPSS bother score, a measure of BPH-related quality group discontinued the treatment, prematurely. Good of life (QoL), were seen with alfuzosin (À0.7) and Clinical Practice violations at one site resulted in nine placebo (À0.6) (P ¼ 0.125). At day 29, a significantly patients (five alfuzosin patients and four placebo greater reduction from baseline in the BPH Impact Index patients) being excluded from the efficacy analyses. was observed in the ITT population with alfuzosin (À0.9) Patients in the ITT population who received treatment than with placebo (À0.5) (P ¼ 0.02). with alfuzosin had a significantly greater mean improve- Overall, the number of patients who experienced ment in Qmax from baseline at day 8 (1.92 ml/s) than TEAEs was similar between the two treatment groups patients in the placebo group (0.39 ml/s) (Po0.001; (alfuzosin, 46/185 (24.9%); placebo, 43/185 (23.2%)), Figure 1). An increase in Qmax was evident within 24 h with most TEAEs of mild or moderate severity. The of the first dose of alfuzosin (1.58 versus 0.71 ml/s in most frequently reported TEAE was dizziness (5.6%) in the placebo group; Po0.021) and persisted on day 29 the alfuzosin group and orthostatic hypotension (1.6%) (1.76 versus 0.36 ml/s for the placebo group; Po0.001; in the placebo group (Table 2). The incidence rates of Figure 1). The results were comparable for the per- vasodilatory and sexual function AEs were low and protocol population (Po0.001). comparable in the two treatment groups (Table 2). No At day 8, patients in the ITT population who received clinically significant changes in BP were observed treatment with alfuzosin had a mean change in the total after the first dose of alfuzosin or during the remainder Acute IPSS of À3.4 points compared with À2.7 points in of the study. No clinically meaningful trends were the placebo group (P ¼ 0.071; Figure 2). At day 29, the observed in clinical laboratory tests, vital signs, the difference between the two groups was statistically physical examination, the digital rectal examination, or significant (alfuzosin, À4.5 points; placebo, À3.1 points; ECG results. One patient from the alfuzosin group P ¼ 0.003). In the per-protocol population, however, reported a serious AE (non-insulin-dependent diabetes symptom improvement from baseline at day 8 with mellitus) that was judged by the investigator as alfuzosin (mean change from baseline in Acute IPSS of unrelated to study treatment. No patient discontinued À3.6 points) was significantly greater than with placebo the study because of a serious AE. Non-serious AEs led (mean change from baseline in Acute IPSS of À2.6 points) (P ¼ 0.043).

Table 1 Baseline demographic and clinical characteristics Alfuzosin 10 mg q.d. Placebo (n ¼ 185) (n ¼ 185)

Age (years) 63.578.4 64.478.0 Weight (kg) 87.76714.1 88.02716.2 Prostate volume (mm3)a 41.2720.1 38.8720.2 7 7 Qmax (ml/s) 10.9 4.6 11.1 4.5 Residual urine volume 107.9781.1 93.2778.5 (ml) Figure 2 Total Acute IPSS at baseline and after 7 and 28 days of IPSS total 17.077.0 17.876.4 treatment with alfuzosin 10 mg q.d. and placebo (ITT population). IPSS bother score 3.671.2 3.871.1 *P ¼ 0.003 for mean change from baseline in total Acute IPSS versus BPH Impact Index 3.972.8 4.272.6 placebo.

Abbreviations: BPH, benign prostatic hyperplasia; IPSS, international prostate symptom score; q.d., once daily; Qmax, maximum urinary flow rate. All values represent mean7s.d. a Prostate volume was calculated as (4/3 Â 3.14 Â width/2 Â height/ Table 2 Treatment-emergent adverse eventsa 2 Â length/2)/1000. Adverse event Alfuzosin 10 mg q.d. Placebo (n ¼ 185) (n ¼ 185)

No. of patients (%)

Dizziness 11 (5.9) 0 Headache 5 (2.7) 2 (1.1) Upper respiratory 4 (2.2) 2 (1.10) tract infection Orthostatic 3 (1.6) 4 (2.2) hypotension Fatigue 2 (1.1) 1 (0.5) Insomnia 2 (1.1) 0 Erectile dysfunction 1 (0.5) 2 (1.1) Cough 0 2 (1.1) Dry mouth 0 2 (1.1) Figure 1 Maximum urinary flow rate (Qmax) at baseline and after Gastroesophageal 0 2 (1.1) 1, 7 and 28 days of treatment with alfuzosin 10 mg q.d. and placebo reflux disease (ITT population). *Pp0.02 for mean change from baseline in Qmax versus placebo. aAdverse events with 41.0% incidence in either group.

Prostate Cancer and Prostatic Diseases Onset of action of alfuzosin 10 mg q.d. in BPH MI Resnick and CG Roehrborn

158 to the discontinuation of treatment in three alfuzosin continue long-term treatment for BPH symptom man- patients (headache, palpitations, confusional state and agement. dizziness) and one placebo patient (urinary frequency).

Acknowledgements Discussion This study was sponsored by Sanofi-Aventis.

Although rapid, measurable effects on Qmax following alfuzosin administration are well established, the timing of symptomatic relief has not been as extensively studied.9 Measurement of early symptom relief in References controlled clinical trials has generally not employed a 1 AUA Practice Guidelines Committee. AUA guideline on validated symptom assessment instrument that evalu- management of benign prostatic hyperplasia (2003). Chapter 1: ates symptom severity during the preceding days rather diagnosis and treatment recommendations. JUrol2003; 170: than months. The current investigation addressed this 530–547. issue by using the validated Acute version of the 2 Chapple CR, Aubry ML, James S, Greengrass PM, Burnstock G, IPSS,10,11 allowing us to evaluate symptom relief after 1 Turner-Warwick RT et al. Characterisation of human prostatic week of alfuzosin therapy. Our data suggest that adrenoceptors using pharmacology receptor binding and rapid symptom relief occurs with alfuzosin 10 mg q.d. localisation. Br J Urol 1989; 63: 487–496. 3 Djavan B, Marberger M. A meta-analysis on the efficacy and treatment. After 7 days of alfuzosin treatment, Qmax significantly increased from baseline, with increases tolerability of alpha1-adrenoceptor antagonists in patients with lower urinary tract symptoms suggestive of benign prostatic observed within 24 h after administration of the first obstruction. Eur Urol 1999; 36: 1–13. alfuzosin dose and persisting through day 29. The total 4 Buzelin JM, Roth S, Geffriaud-Ricouard C, Delauche-Cavallier Acute IPSS also improved at day 8 and 29 with alfuzosin MC. Efficacy and safety of sustained-release alfuzosin 5 mg in treatment. These improvements in Qmax and LUTS with patients with benign prostatic hyperplasia. ALGEBI Study alfuzosin were associated with a significant improve- Group. Eur Urol 1997; 31: 190–198. ment in BPH-related quality of life, as assessed with the 5 The Italian Alfuzosin Co-Operative Group. Safety, efficacy and BPH Impact Index. impact on patients’ quality of life of a long-term treatment with In a pooled analysis of three randomized, placebo- the alpha(1)-blocker alfuzosin in symptomatic patients with controlled, clinical trials of alfuzosin (N ¼ 693), a sig- BPH. Eur Urol 2000; 37: 680–686. nificant increase from baseline in Q was seen 14 days 6 Lukacs B, Grange JC, Comet D. One-year follow-up of 2829 max patients with moderate to severe lower urinary tract symptoms following the first alfuzosin dose when compared 8 treated with alfuzosin in general practice according to IPSS and with placebo. In addition, data from a small trial a health-related quality-of-life questionnaire. BPM Group in (N ¼ 34) showed that Qmax significantly increased from General Practice. Urology 2000; 55: 540–546. baseline as soon as 8 h after administration of the first 7 Sanchez-Chapado M, Guil M, Alfaro V, Badiella L, Fernandez- alfuzosin dose.16 Our present findings, which are Hernando N. Safety and efficacy of sustained-release alfuzosin based on a larger patient sample, confirm this previous on lower urinary tract symptoms suggestive of benign prostatic report. Men in the present study exhibited a mean hyperplasia in 3095 Spanish patients evaluated during general practice. Eur Urol 2000; 37: 421–427. improvement from baseline in Qmax of 1.58 ml/s within 24 h after the first dose of alfuzosin versus only 0.71 ml/s 8 Roehrborn CG, Van Kerrebroeck P, Nordling J. Safety and efficacy of alfuzosin 10 mg once-daily in the treatment of lower with placebo. After 7 and 28 days of alfuzosin treatment, urinary tract symptoms and clinical benign prostatic hyperpla- the increases from baseline in Qmax were sustained. sia: a pooled analysis of three double-blind, placebo-controlled Sustained efficacy and symptom improvement with studies. BJU Int 2003; 92: 257–261. alfuzosin therapy for up to 3 years is well estab- 9 Marks LS, Roehrborn CG, Gittelman M, Kim D, Forrest J, lished.16–18 The profile of rapid and sustained efficacy Jacobs S. First dose efficacy of alfuzosin once daily in men with with alfuzosin therapy, paired with good tolerability symptomatic benign prostatic hyperplasia. Urology 2003; 62: and safety, has positive implications for patient 888–893. compliance. AEs observed in the present study were 10 Barry MJ, Fowler Jr FJ, O’Leary MP, Bruskewite RC, Holtgrewe similar to those reported previously with alfuzosin.8 The HL, Mebust WK et al. The American Urological Association overall incidence of TEAEs was similar with alfuzosin symptom index for benign prostatic hyperplasia. The Measure- ment Committee of the American Urological Association. J Urol and placebo. The low incidence of sexual side effects 1992; 148: 1549–1557; discussion 1564. with alfuzosin is in agreement with the results of 11 Barry M, Batista J, Donovan J et al. Measuring the symptoms and 8 previous clinical trials. health impact of benign prostatic hyperplasia and its treatments. In conclusion, improvements in Qmax, as assessed with In: Chatelain C, Denis L, Foo K, Khoury S, McConnell J (eds). uroflowmetry, are evident within 24 h of the first dose Benign Prostatic Hyperplasia. Health Publication: United King- of alfuzosin 10 mg q.d. Relief of BPH symptoms, as dom, 2001, pp 203–220. measured with the Acute IPSS scale, is observed after 7 12 Barry MJ, Fowler Jr FJ, O’Leary MP, Bruskewitz RC, Holtgrewe days of alfuzosin treatment. 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Prostate Cancer and Prostatic Diseases Onset of action of alfuzosin 10 mg q.d. in BPH MI Resnick and CG Roehrborn 159 prostatic hyperplasia. ALFORTI Study Group. Eur Urol 2000; 37: management of benign prostatic hyperplasia. Drugs 2002; 62: 306–313. 633–653. 14 Roehrborn CG. Efficacy and safety of once-daily alfuzosin in the 17 Roehrborn CG. Alfuzosin 10 mg once daily prevents overall treatment of lower urinary tract symptoms and clinical benign clinical progression of benign prostatic hyperplasia but not acute prostatic hyperplasia: a randomized, placebo-controlled trial. urinary retention: results of a 2-year placebo-controlled study. Urology 2001; 58: 953–959. BJU Int 2006; 97: 734–741. 15 Nordling J. Efficacy and safety of two doses (10 and 15 mg) of 18 Van Kerrebroeck P, Jardin A, van Cangh P, Laval KU. Long-term alfuzosin or tamsulosin (0.4 mg) once daily for treating sympto- safety and efficacy of a once-daily formulation of alfuzosin matic benign prostatic hyperplasia. BJU Int 2005; 95: 1006–1012. 10 mg in patients with symptomatic benign prostatic hyper- 16 McKeage K, Plosker GL. Alfuzosin: a review of the therapeutic plasia: open-label extension study. Eur Urol 2002; 41: 54–60; use of the prolonged-release formulation given once daily in the discussion 60-61.

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