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

Study Overview
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Brief Summary
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This is a phase 3, randomized, double-blind, placebo-controlled, parallel-design, multinational study to evaluate the efficacy and safety of tadalafil once-a-day dosing for 12 weeks in Asian men with signs and symptoms of benign prostatic hyperplasia.

Detailed Description
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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.

Official Title
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A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel-Design, Study to Evaluate the Efficacy and Safety of Tadalafil Once-a-day Dosing for 12 Weeks in Asian Men With Signs and Symptoms of Benign Prostatic Hyperplasia

Conditions
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Benign Prostatic Hyperplasia

Intervention / Treatment
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* Drug: Tadalafil
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 45 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Following the 4-week placebo lead-in period, this arm will consist of a 12-week placebo treatment period involving 2 x 2.5-milligram (mg) tadalafil placebo tablets taken orally once daily. | Drug: Placebo<br>* 2 tablets (identical to 2.5-mg tadalafil tablets) given orally once daily.<br>|
| Experimental: Tadalafil<br>Following the 4-week placebo lead-in period, this arm will consist of a 12-week treatment period involving 2 x 2.5-mg tadalafil tablets taken orally once daily. | Drug: Tadalafil<br>* 5 mg (2 x 2.5-mg tablets), given once daily as oral tablet<br>* Other names: LY450190;Drug: Placebo<br>* 2 tablets (identical to 2.5-mg tadalafil tablets) given orally once daily.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Total Score of International Prostate Symptom Score (IPSS) at 12 Weeks | The IPSS Total Score was the sum of Questions 1 through 7 in the IPSS questionnaire. Each question was based on the participant's urination experiences and prostate symptoms during the last month. Scores ranged from 0 (none/no symptoms) to 5 (frequent symptoms) for an IPSS Total Score that ranged from 0 to 35; higher numerical scores represented a greater severity of symptoms. Least squares (LS) mean was based on the mixed-effect model repeated measures (MMRM) model analysis with participants as random effects, treatment, prior alpha-blocker use (yes/no), country (Japan/Korea), visit, and treatment-by-visit interaction as fixed effects, and baseline value and placebo lead-in total IPSS change as fixed covariates. | Baseline, 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Total Score of International Prostate Symptom Score (IPSS) | The IPSS Total Score was the sum of Questions 1 through 7 in the IPSS questionnaire. Each question was based on the participant's urination experiences and prostate symptoms during the last month. Scores ranged from 0 (none/no symptoms) to 5 (frequent symptoms) for an IPSS Total Score that ranged from 0 to 35; higher numerical scores represented a greater severity of symptoms. Least squares (LS) mean was based on the mixed-effect model repeated measures (MMRM) model analysis with participants as random effects, treatment, prior alpha-blocker use (yes/no), country (Japan/Korea), visit, and treatment-by-visit interaction as fixed effects, and baseline value and placebo lead-in total IPSS change as fixed covariates. | Baseline, 4 weeks, 8 weeks | 
| Change From Baseline in the International Prostate Symptom Score (IPSS) Storage (Irritative) Subscore | The IPSS Storage (Irritative) Subscore was the sum of Questions 2, 4, and 7 in the IPSS questionnaire. Each question was scored from 0 (no irritative symptoms) to 5 (frequent irritative symptoms) for an IPSS Storage (Irritative) Subscore that ranged from 0 to 15; higher numerical scores represented a greater severity of symptoms. Least squares (LS) mean was based on the mixed-effect model repeated measures (MMRM) model analysis with participants as random effects, treatment, prior alpha-blocker use (yes/no), country (Japan/Korea), visit, and treatment-by-visit interaction as fixed effects, and baseline value and placebo lead-in total IPSS change as fixed covariates. | Baseline, 4 weeks, 8 weeks, 12 weeks | 
| Change From Baseline in the International Prostate Symptom Score (IPSS) Voiding (Obstructive) Subscore | The IPSS Voiding (Obstructive) Subscore was the sum of Questions 1, 3, 5, and 6 in the IPSS questionnaire. Each question was scored from 0 (no obstructive symptoms) to 5 (frequent obstructive symptoms) for an IPSS Voiding (Obstructive) Subscore that ranged from 0 to 20; higher numerical scores represented a greater severity of symptoms. Least squares (LS) mean was based on the mixed-effect model repeated measures (MMRM) model analysis with participants as random effects, treatment, prior alpha-blocker use (yes/no), country (Japan/Korea), visit, and treatment-by-visit interaction as fixed effects, and baseline value and placebo lead-in total IPSS change as fixed covariates. | Baseline, 4 weeks, 8 weeks, 12 weeks | 
| Change From Baseline in the International Prostate Symptom Score (IPSS) Quality of Life (QoL) Index | The IPSS QoL Index assessed the participant's response to the following question, If you were to spend the rest of your life with your urinary condition just the way it is now, how would you feel about that?. Response options were 0 (Delighted), 1 (Pleased), 2 (Mostly satisfied), 3 (Mixed, about equally satisfied and dissatisfied), 4 (Mostly dissatisfied), 5 (Unhappy), and 6 (Terrible), for a QoL Index Score that ranged from 0 to 6. Least squares (LS) mean was based on the mixed-effect model repeated measures (MMRM) model analysis with participants as random effects, treatment, prior alpha-blocker use (yes/no), country (Japan/Korea), visit, and treatment-by-visit interaction as fixed effects, and baseline value and placebo lead-in total IPSS change as fixed covariates. | Baseline, 4 weeks, 8 weeks, 12 weeks | 
| Patient Global Impression of Improvement (PGI-I) Scale at 12 Weeks | The PGI-I scale measured the participant's perception of improvement at the time of assessment compared with the start of treatment. Scores were 1 (Very much better), 2 (Much improved), 3 (Minimally improved), 4 (No change), 5 (Minimally worse), 6 (Much worse), and 7 (Very much worse). | 12 Weeks | 
| Clinician Global Impression of Improvement (CGI-I) Scale at 12 Weeks | The CGI-I measured the clinician's perception of participant improvement at the time of assessment compared with the start of treatment. Scores were 1 (Very much better), 2 (Much improved), 3 (Minimally improved), 4 (No change), 5 (Minimally worse), 6 (Much worse), and 7 (Very much worse). | 12 Weeks | 
| Change From Baseline in Modified International Prostate Symptom Score (mIPSS) Score at 2 Weeks | The mIPSS Total Score was the sum of Questions 1 through 7 in the mIPSS questionnaire, which was a modified version of the IPSS questionnaire. Questions about the participant's urination experiences and prostate symptoms in the IPSS questionnaire were modified to obtain responses based on time since the last visit rather than during the last month. Each question was scored from 0 (none/no symptoms) to 5 (frequent symptoms) for an mIPSS Total Score that ranged from 0 to 35; higher numerical scores represented a greater severity of symptoms. Least squares (LS) mean was based on the analysis of covariance (ANCOVA) model with treatment, prior alpha-blocker use (yes/no), and country (Japan/Korea) as fixed effects, and baseline value and placebo lead-in total IPSS change as fixed covariates. | Baseline, 2 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prostatic hyperplasia, Benign prostatic hyperplasia, Lower urinary tract