Phase 3 Study of Tadalafil Once-Daily in Asian Men With Benign Prostatic Hyperplasia (BPH)

Tadalafil is being investigated as a treatment for men with signs and symptoms of benign prostatic hyperplasia [BPH; also referred to as urinary disturbance or BPH-LUTS (BPH-lower urinary tract symptoms)] in Japan and overseas. Overseas studies and the Japanese dose-finding study LVIA (NCT00783094) identified tadalafil 5 mg once-daily as the recommended dose. The long-term safety and maintenance of effect was confirmed in the open-label extension of study LVIA. The risk-benefit profile was further studied in the Asian study LVHB (NCT00861757).

This study, LVJF, is to confirm the efficacy and safety of tadalafil 5 mg once-daily in Asian men with BPH-LUTS.

Inclusion criteria

• Present with benign prostatic hyperplasia (BPH; also referred to as BPH-LUTS), based on the disease diagnostic criteria, at study entry.
• Provide signed informed consent at study entry.
• Have BPH-LUTS with a Total International Prostate Symptom Score (IPSS) of ≥13 at beginning of placebo lead-in period.
• Have bladder outlet obstruction of intermediate severity as defined by a urinary peak flow rate (Qmax) of ≥4 to ≤15 milliliters per second (mL/sec) [from a prevoid total bladder volume (assessed by ultrasound) of ≥150 to ≤550 milliliters (mL) and a minimum voided volume of 125 mL] at beginning of placebo lead-in period.
• Have prostate volume ≥20 mL estimated by transabdominal or transrectal ultrasound at study entry.
• Agree not to use any other approved or experimental pharmacologic BPH, erectile dysfunction (ED) and/or overactive bladder (OAB) treatments, including alpha-blockers, 5-alpha reductase inhibitors (5-ARIs), phosphodiesterase type 5 (PDE5) inhibitors, or herbal preparations at any time during the study.
• Have not taken the following treatments within the indicated duration:

• Finasteride therapy for at least 3 months prior to beginning of placebo lead-in period.
• Dutasteride therapy for at least 6 months prior to beginning of placebo lead-in period.
• Anti-androgenic hormone therapy at least 12 months prior to beginning of placebo lead-in period.
• All other BPH therapy (including herbal preparations) for at least 4 weeks prior to beginning of placebo lead-in period.
• ED therapy for at least 4 weeks prior to beginning of placebo lead-in period.
• OAB therapy for at least 4 weeks prior to beginning of placebo lead-in period.
• Demonstrate compliance with study drug administration requirements during the placebo lead-in period by administering ≥70% of prescribed doses, confirmed by documentation that the participant returned ≤30% of prescribed doses at randomization.

Exclusion criteria

• Prostate-specific antigen (PSA) >10.0 nanograms per milliliter (ng/mL) at study entry.
• PSA ≥4.0 to ≤10.0 ng/mL at study entry, if prostate malignancy has not been ruled out to the satisfaction of an urologist.
• Bladder postvoid residual (PVR) ≥300 mL by ultrasound determination at study entry.
• History of any of the following pelvic conditions (checked at study entry):

• Pelvic surgery or any other pelvic procedure, including radical prostatectomy, pelvic surgery for removal of malignancy, or bowel resection.
• Pelvic radiotherapy.
• Any pelvic surgical procedure on the urinary tract, including minimally invasive BPH-LUTS therapies and penile implant surgery.
• Lower urinary tract malignancy or trauma.
• Lower urinary tract instrumentation (including prostate biopsy) within 30 day of study entry.
• History of urinary retention or lower urinary tract (bladder) stones within 6 months of study entry.
• History of urethral obstruction due to stricture, valves, sclerosis, or tumor.
• Current neurologic disease or condition associated with neurogenic bladder (for example, Parkinson's disease, multiple sclerosis) at study entry.
• Clinical evidence of prostate cancer.
• Clinical evidence of any of the following bladder conditions:

• Mullerian duct cysts.
• Atonic, decompensated, or hypocontractile bladder.
• Detrusor-sphincter dyssynergia (contraction of the detrusor without sphincter relaxation).
• Intravesical obstruction (for example, intravesical median lobe of the prostate).
• Interstitial cystitis.
• Clinical evidence of any of the following urinary tract conditions at study entry:

• Urinary tract infection.
• Urinary tract inflammation (including prostatitis). Urinary tract infection/inflammation is defined as a positive result for leukocyte esterase from a urine dipstick or >5 white blood cells (WBCs) per high-powered field on urinalysis from a centrifuged, clean-catch, midstream urine specimen.
• Current antibiotic therapy for urinary tract infection.
• Clinically significant microscopic hematuria as determined by an urologist.
• History of significant renal insufficiency, defined as receiving renal dialysis or having an estimated creatinine clearance <30 milliliters per minute (mL/min) at study entry, as calculated by the central laboratory using the Cockcroft-Gault formula.
• Clinical evidence of severe hepatic impairment [aspartate transaminase (AST) or alanine transaminase (ALT) >3-fold of the upper limit of normal range] at study entry.
• History of any of the following cardiac conditions (checked at study entry):

• Angina requiring treatment with long-acting nitrates.
• Angina requiring treatment with short-acting nitrates within 90 days of study entry.
• Unstable angina within 90 days of study entry.
• Positive cardiac stress test without documented evidence of subsequent, effective cardiac intervention.
• History of any of the following coronary conditions within 90 days of study entry:

• Myocardial infarction.
• Coronary artery bypass graft surgery.
• Percutaneous coronary intervention (for example, angioplasty or stent placement).
• Any evidence of heart disease [New York Heart Association (NYHA) ≥Class III] within 6 months of study entry.
• Systolic blood pressure >160 or <90 millimeters of mercury (mm Hg) or diastolic blood pressure >100 or <50 mm Hg at study entry (if stress is suspected, retest under basal conditions), or malignant hypertension.
• Glycosylated hemoglobin (HbA1c) >9% at study entry.
• Scheduled or planned surgery (or any procedure requiring general, spinal, or epidural anesthesia) during the course of the study.
• History of significant central nervous system injuries (including stroke or spinal cord injury) within 6 months of study entry.
• History of drug, alcohol, or substance abuse within 6 months of study entry.
• Current treatment with nitrates, androgens, antiandrogens, estrogens, luteinizing hormone-releasing hormone agonists/antagonists, or anabolic steroids at study entry.
• Current systemic treatment with any of the following:

• Potent cytochrome P450 3A4 (CYP3A4) inhibitors, such as ketoconazole or ritonavir.
• CYP3A4 inducers such as rifampicin.
• Known or suspected to be hypersensitive to tadalafil, or any study drug components.
• Any conditions that would interfere with a participant's ability to provide informed consent or comply with study instructions, would place participant at increased risk, or might confound the interpretation of the study results.
• Previously completed or withdrawn from this study or any other study investigating tadalafil.
• Received treatment within the last 30 days with a drug or device that has not received regulatory approval for any indications at the time of informed consent. Participants who have been screen failures in previous studies may be eligible.