A Study in the Treatment of Erectile Dysfunction and Benign Prostate Hyperplasia

Study Overview
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Brief Summary
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Study LVHR is a Phase 3 study which will examine the efficacy and safety of tadalafil 2.5 and 5 mg once daily versus placebo for the treatment of erectile dysfunction (ED) and signs and symptoms of benign prostatic hyperplasia (BPH) in men with both ED and signs and symptoms of BPH.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Parallel Design, Multinational Study to Evaluate the Efficacy and Safety of Tadalafil 2.5 and 5 mg Once Daily Dosing for 12 Weeks for the Treatment of Erectile Dysfunction and Signs and Symptoms of Benign Prostatic Hyperplasia in Men With Both Erectile Dysfunction and Benign Prostatic Hyperplasia

Conditions
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Erectile Dysfunction, 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: Have BPH Lower Urinary Tract Symptoms (LUTS) based on the disease diagnostic criteria at 1st screening. Have a history of ED based on the disease diagnostic criteria at 1st screening. Have LUTS with a Total International Prostate Symptom Score (IPSS) greater than or equal to 13 at 2nd screening. Have bladder outlet obstruction as defined by a Peak Urine Flow Rate (Qmax) of greater than or equal to 4 to less than or equal to 15 milliliter (mL)/second (sec) (from a prevoid total bladder volume as assessed by ultrasound of greater than or equal to 150 to less than or equal to 550 mL and a minimum voided volume of 125 mL) at 2nd screening. Make at least 4 sexual intercourse attempts during the 4-weeks after 2nd screening as recorded in the Sexual Encounter Profile (SEP) diary. Are sexually active with an adult female partner, and expect to remain sexually active with the same adult female partner for the duration of the study. Agree not to use any other approved or experimental BPH, overactive bladder (OAB), or ED treatments as indicated in the protocol at any time during the study. Have not taken treatments indicated in the protocol prior to the 2nd screening. Exclusion Criteria: Current treatment with nitrates. Prostate-specific antigen (PSA) greater than 10.0 nanogram (ng)/mL at 1st screening. PSA greater than or equal to 4.0 to less than or equal to 10.0 ng/mL at 1st screening if prostate malignancy has not been ruled out to the satisfaction of a urologist. Clinical evidence of prostate cancer. Bladder postvoid residual volume (PVR) greater than or equal to 300 mL by ultrasound determination at 1st screening. History or clinical evidence of certain pelvic, bladder, urinary tract, or urinary retention conditions described in the protocol. Lower urinary tract instrumentation (including prostate biopsy) within 30 days of 1st screening. Clinical evidence of severe hepatic impairment at 1st screening. Current neurologic disease or condition associated with neurogenic bladder (for example, Parkinson's disease or multiple sclerosis). History of significant renal insufficiency as defined by the protocol. History of ED caused by other primary sexual disorders including premature ejaculation or ED caused by untreated endocrine disease. Presence of penile deformity judged by the investigator to be clinically significant. History of certain cardiac or cardiovascular conditions described in the protocol. History of resuscitated cardiac arrest. Current treatment with certain medications described in the protocol. 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 1st screening. Glycosylated hemoglobin (HbA1c) greater than 9% at 1st screening. Prior treatment with phosphodiesterase type 5 (PDE5) inhibitors judged by the investigator to be ineffective. However, if the investigator judges that a subject's lack of response to as-needed PDE5 inhibitors is the result of inadequate coordination between dosing and sexual activity with a treatment, the subject may be enrolled.

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tadalafil 2.5 mg<br> | Drug: Tadalafil<br>* tablet once daily by mouth for 12 weeks.<br>* Other names: LY450190;|
| Experimental: Tadalafil 5 mg<br> | Drug: Tadalafil<br>* tablet once daily by mouth for 12 weeks.<br>* Other names: LY450190;|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Matching 2.5 or 5 mg placebo tablet once daily by mouth for 12 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Total International Prostate Symptom Score (IPSS) at Week 12 Endpoint (5 mg) | The total IPSS is obtained by combining the scores of the responses to component questions 1 through 7. Each question is scored from 0-5 for a total IPSS range of 0-35 points; higher numerical scores from the IPSS questionnaire represent greater severity of symptoms. Least squares (LS) mean of change from baseline to endpoint is from an analysis of covariance (ANCOVA). The model includes terms for treatment group, region, baseline covariate, baseline-by-treatment interaction and treatment-by-region interaction. | Baseline, 12 weeks | 
| Change From Baseline in International Index of Erectile Function - Erectile Function (IIEF-EF) Domain Score at Week 12 Endpoint (5 mg) | Self-reported erectile function over the past 4 weeks. Questions 1-5 were scored from 0-5, and Question 15 from 1 to 5. Erectile Function Domain scores range from 1 to 30; lower numerical scores represent greater severity of erectile dysfunction. Least squares (LS) mean of change from baseline to endpoint is from an analysis of covariance (ANCOVA). The model includes terms for treatment group, region, baseline covariate, baseline-by-treatment interaction and treatment-by-region interaction. | Baseline, 12 weeks | 
| Change From Baseline in Total International Prostate Symptom Score (IPSS) at Week 12 Endpoint (2.5 mg) | The total IPSS is obtained by combining the scores of the responses to component questions 1 through 7. Each question is scored from 0-5 for a total IPSS range of 0-35 points; higher numerical scores from the IPSS questionnaire represent greater severity of symptoms. Least squares (LS) mean of change from baseline to endpoint is from an analysis of covariance (ANCOVA). The model includes terms for treatment group, region, baseline covariate, baseline-by-treatment interaction and treatment-by-region interaction. | Baseline, 12 weeks | 
| Change From Baseline in International Index of Erectile Function - Erectile Function (IIEF-EF) Domain Score at Week 12 Endpoint (2.5 mg) | Self-reported erectile function over the past 4 weeks. Questions 1-5 were scored from 0-5, and Question 15 from 1 to 5. Erectile Function Domain scores range from 1 to 30; lower numerical scores represent greater severity of erectile dysfunction. Least squares (LS) mean of change from baseline to endpoint is from an analysis of covariance (ANCOVA). The model includes terms for treatment group, region, baseline covariate, baseline-by-treatment interaction and treatment-by-region interaction. | Baseline, 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Yes Responses to Sexual Encounter Profile (SEP) Diary Question 3 at Week 12 Endpoint (5 mg) | Assessed as the mean change from baseline in the percentage of Yes responses to the SEP diary Question 3, Did your erection last long enough for you to have successful intercourse? Data are presented as the mean percentage of Yes responses per the number of sexual attempts for a participant during a study period. Least squares (LS) mean of change from baseline to endpoint is from an analysis of covariance (ANCOVA). The model includes terms for treatment group, region, baseline covariate, baseline-by-treatment interaction and treatment-by-region interaction. | Baseline, 12 weeks | 
| Change From Baseline in Benign Prostatic Hyperplasia (BPH) Impact Index (BII) at Week 12 Endpoint (5 mg) | The BII is a 4-item, self-administered questionnaire evaluating impact of urinary problems on overall health and activity. Total scores range from 0 to 13; higher scores represent increased perceived impact of benign prostatic hyperplasia-lower urinary tract symptoms on overall health. Least squares (LS) mean of change from baseline to endpoint is from an analysis of covariance (ANCOVA). The model includes terms for treatment group, region, baseline covariate, baseline-by-treatment interaction and treatment-by-region interaction. | Baseline, 12 weeks | 
| Change From Baseline in Yes Responses to Sexual Encounter Profile (SEP) Diary Question 3 at Week 12 Endpoint (2.5 mg) | Assessed as the mean change from baseline in the percentage of Yes responses to the SEP diary Question 3, Did your erection last long enough for you to have successful intercourse? Data are presented as the mean percentage of yes responses per the number of sexual attempts for a participant during a study period. Least squares (LS) mean of change from baseline to endpoint is from an analysis of covariance (ANCOVA). The model includes terms for treatment group, region, baseline covariate, baseline-by-treatment interaction and treatment-by-region interaction. | Baseline, 12 weeks | 
| Change From Baseline in BPH Impact Index (BII) at Week 12 Endpoint (2.5 mg) | The BII is a 4-item, self-administered questionnaire evaluating impact of urinary problems on overall health and activity. Total scores range from 0 to 13; higher scores represent increased perceived impact of benign prostatic hyperplasia-lower urinary tract symptoms on overall health. Least squares (LS) mean of change from baseline to endpoint is from an analysis of covariance (ANCOVA). The model includes terms for treatment group, region, baseline covariate, baseline-by-treatment interaction and treatment-by-region interaction. | Baseline, 12 weeks | 
| Change From Baseline in Modified IPSS (mIPSS) at Week 2 Endpoint | The Modified IPSS is the total IPSS collected at 2 weeks post-baseline. The total IPSS is obtained by combining the scores of the responses to component questions 1 through 7. Each question is scored from 0-5 for a total IPSS range of 0-35 points; higher numerical scores from the IPSS questionnaire represent greater severity of symptoms. Least squares (LS) mean of change from baseline to endpoint is from ANCOVA. The model includes terms for treatment group, region, baseline covariate, baseline-by-treatment interaction and treatment-by-region interaction. | Baseline, 2 weeks | 
| Change From Baseline in International Prostate Symptom Score (IPSS) at Week 4 and Week 8 Endpoint | The total IPSS is obtained by combining the scores of the responses to component questions 1 through 7. Each question is scored from 0-5 for a total IPSS range of 0-35 points; higher numerical scores from the IPSS questionnaire represent greater severity of symptoms. Least squares (LS) mean of change from baseline to endpoint is from an analysis of covariance (ANCOVA). The model includes terms for treatment group, region, baseline covariate, baseline-by-treatment interaction and treatment-by-region interaction. | Baseline, 4 weeks, 8 weeks | 
| Change From Baseline in International Index of Erectile Function - Erectile Function (IIEF-EF) Domain at Week 4 and Week 8 Endpoint | Self-reported erectile function over the past 4 weeks. Questions 1-5 were scored from 0-5, and Question 15 from 1 to 5. Erectile Function Domain scores range from 1 to 30; lower numerical scores represent greater severity of erectile dysfunction. Least squares (LS) mean of change from baseline to endpoint is from an analysis of covariance (ANCOVA). The model includes terms for treatment group, region, baseline covariate, baseline-by-treatment interaction and treatment-by-region interaction. | Baseline, 4 weeks, 8 weeks | 
| Change From Baseline in Yes Responses to Sexual Encounter Profile (SEP) Diary Question 3 at Week 4 and Week 8 Endpoint | Assessed as the mean change from baseline in the percentage of Yes responses to the SEP diary Question 3, Did your erection last long enough for you to have successful intercourse? Data are presented as the mean percentage of yes responses per the number of sexual attempts for a participant during a study period. Least squares (LS) mean of change from baseline to endpoint is from an analysis of covariance (ANCOVA). The model includes terms for treatment group, region, baseline covariate, baseline-by-treatment interaction and treatment-by-region interaction. | Baseline, 4 weeks, 8 weeks | 
| Change From Baseline in BPH Impact Index (BII) at Week 4 and 8 Endpoint | The BII is a 4-item, self-administered questionnaire evaluating impact of urinary problems on overall health and activity. Total scores range from 0 to 13; higher scores represent increased perceived impact of benign prostatic hyperplasia-lower urinary tract symptoms on overall health. Least squares (LS) mean of change from baseline to endpoint is from an analysis of covariance (ANCOVA). The model includes terms for treatment group, region, baseline covariate, baseline-by-treatment interaction and treatment-by-region interaction. | Baseline, 4 weeks, 8 weeks | 
| Change From Baseline in International Prostate Symptom Score Voiding (Obstructive) Subscore at Week 12 Endpoint | IPSS obstructive subscore is the sum of Questions 1, 3, 5 and 6 of the IPSS questionnaire. The obstructive subscore ranges from 0 to 20 with a higher score representing greater obstruction. Least squares (LS) mean of change from baseline to endpoint is from an analysis of covariance (ANCOVA). The model includes terms for treatment group, region, baseline covariate, baseline-by-treatment interaction and treatment-by-region interaction. | Baseline, 12 weeks | 
| Change From Baseline in International Prostate Symptom Score Storage (Irritative) Subscore at Week 12 Endpoint | IPSS irritative subscore is the sum of Questions 2, 4 and 7 of the IPSS questionnaire. The irritative subscore ranges from 0 to 15 with a higher score representing more irritative symptoms. Least squares (LS) mean of change from baseline to endpoint is from an analysis of covariance (ANCOVA). The model includes terms for treatment group, region, baseline covariate, baseline-by-treatment interaction and treatment-by-region interaction. | Baseline, 12 weeks | 
| Change From Baseline in International Prostate Symptom Score Nocturia Question at Week 12 | The IPSS Nocturia question (Question 7) measures the number of times needed to get up at night to urinate. Scores range from 0 (none) to 5 (5 or more times). Least squares (LS) mean of change from baseline to endpoint is from an analysis of covariance (ANCOVA). The model includes terms for treatment group, region, baseline covariate, baseline-by-treatment interaction and treatment-by-region interaction. | Baseline, 12 weeks | 
| Change From Baseline in International Prostate Symptom Score Quality of Life (QoL) at Week 12 Endpoint | Assessment of quality of life (QoL) by urinary symptoms, with scores ranging from 0 (delighted) to 6 (terrible). Least squares (LS) mean of change from baseline to endpoint is from an analysis of covariance (ANCOVA). The model includes terms for treatment group, region, baseline covariate, baseline-by-treatment interaction and treatment-by-region interaction. | Baseline, 12 weeks | 
| Change From Baseline in International Index of Erectile Function - Overall Satisfaction Domain at Week 12 Endpoint | Self-reported overall satisfaction over the past 4 weeks. Calculated as the sum of IIEF Questions 13 and 14. Each question is scored from 1 through 5, with a possible total score of 2 through 10. Higher scores represent greater satisfaction. Least squares (LS) mean of change from baseline to endpoint is from an analysis of covariance (ANCOVA). The model includes terms for treatment group, region, baseline covariate, baseline-by-treatment interaction and treatment-by-region interaction. | Baseline, 12 weeks | 
| Change From Baseline in International Index of Erectile Function - Intercourse Satisfaction Domain at Week 12 Endpoint | Self-reported intercourse satisfaction over the past 4 weeks. Calculated as the sum of IIEF Questions 6, 7 and 8. Each question is scored from 0 through 5 with a possible total score of 0 through 15. Higher score represent greater satisfaction. Least squares (LS) mean of change from baseline to endpoint is from an analysis of covariance (ANCOVA). The model includes terms for treatment group, region, baseline covariate, baseline-by-treatment interaction and treatment-by-region interaction. | Baseline, 12 weeks | 
| Change From Baseline in International Index of Erectile Function Question 3 at Week 12 Endpoint | IIEF Question 3 asks how often a subject was able to penetrate his partner over the past 4 weeks. Scores range from 0 (did not attempt intercourse) to 5 (almost always or always). Least squares (LS) mean of change from baseline to endpoint is from an analysis of covariance (ANCOVA). The model includes terms for treatment group, region, baseline covariate, baseline-by-treatment interaction and treatment-by-region interaction. | Baseline, 12 weeks | 
| Change From Baseline in International Index of Erectile Function Question 4 at Week 12 Endpoint | IIEF Question 4 asks whether how often a subject was able to maintain an erection after penetration over the past 4 weeks. Scores range from 0 (did not attempt intercourse) to 5 (almost always or always). Least squares (LS) mean of change from baseline to endpoint is from an analysis of covariance (ANCOVA). The model includes terms for treatment group, region, baseline covariate, baseline-by-treatment interaction and treatment-by-region interaction. | Baseline, 12 weeks | 
| Change From Baseline in Yes Responses to Sexual Encounter Profile (SEP) Diary Question 2 at Week 12 Endpoint | Assessed as the mean change from baseline in the percentage of Yes responses to the SEP diary Question 2, Were you able to insert your penis into your partner's vagina? Data are presented as the mean percentage of yes responses per the number of sexual attempts for a participant during a study period. Least squares (LS) mean of change from baseline to endpoint is from an analysis of covariance (ANCOVA). The model includes terms for treatment group, region, baseline covariate, baseline-by-treatment interaction and treatment-by-region interaction. | Baseline, 12 weeks | 
| Change From Baseline in Yes Responses to Sexual Encounter Profile (SEP) Diary Question 4 at Week 12 Endpoint | Assessed as the mean change from baseline in the percentage of Yes responses to the SEP diary Question 4, Were you satisfied with the hardness of your erection? Data are presented as the mean percentage of yes responses per the number of sexual attempts for a participant during a study period. Least squares (LS) mean of change from baseline to endpoint is from an analysis of covariance (ANCOVA). The model includes terms for treatment group, region, baseline covariate, baseline-by-treatment interaction and treatment-by-region interaction. | Baseline, 12 weeks | 
| Change From Baseline in Yes Responses to Sexual Encounter Profile (SEP) Diary Question 5 | Assessed as the mean change from baseline in the percentage of Yes responses to the SEP diary Question 5, Were you satisfied overall with this sexual experience? Data are presented as the mean percentage of yes responses per the number of sexual attempts for a participant during a study period. Least squares (LS) mean of change from baseline to endpoint is from an analysis of covariance (ANCOVA). The model includes terms for treatment group, region, baseline covariate, baseline-by-treatment interaction and treatment-by-region interaction. | Baseline, 12 weeks | 
| Patient Global Impression of Improvement (PGI-I) at Week 12 Endpoint | A scale that measures the patient's perception of urinary symptoms at endpoint compared with the start of treatment. The score ranges from 1 (very much better) to 7 (very much worse). The data are presented as the number of participants in each of the seven categories: very much better (1); much better (2); a little better (3); no change (4); a little worse (5); much worse (6); very much worse (7). | 12 weeks | 
| Clinician Global Impression of Improvement (CGI-I) at Week 12 Endpoint | A scale that measures clinician's rating of the total change in the patient's urinary symptoms at endpoint compared with the start of treatment. Scores range from 1 (very much better) to 7 (very much worse).The data are presented as the number of participants in each of the seven categories: very much better (1); much better (2); a little better (3); no change (4); a little worse (5); much worse (6); very much worse (7). | 12 weeks | 
| Erectile Function General Assessment Questionnaire (EF-GAQ) | The EF-GAQ consisted of two questions: (1) Has the treatment you have been taking during this study improved your erections? and (2) If yes, has the treatment improved your ability to engage in sexual activity? Each question has a Yes/No response. | 12 weeks | 
| Change From Baseline in Uroflowmetry Parameters - Peak Urine Flow Rate (Qmax) at Week 12 Endpoint | Qmax is defined as the peak urine flow rate (measured in milliliters per second [mL/sec] using standard calibrated flowmeter). At each visit, a uroflowmetry assessment was considered valid and the data were included in the statistical analyses only if the prevoid total bladder volume (assessed by ultrasound) was >=150 to <=550 milliliters (mL) and the voided volume (Vcomp) was >= 125 mL. | Baseline, 12 weeks | 
| Change From Baseline in Uroflowmetry Parameters - Mean Urine Flow Rate (Qmean) at Week 12 Endpoint | Qmean is defined as the average urine flow rate (measured in milliliters per second [mL/second] using standard calibrated flowmeter). At each visit, a uroflowmetry assessment was considered valid and the data were included in the statistical analyses only if the prevoid total bladder volume (assessed by ultrasound) was >=150 to <=550 milliliters (mL) and the voided volume (Vcomp) was >= 125 mL. | Baseline, 12 weeks | 
| Change From Baseline in Uroflowmetry Parameters - Voided Volume (Vcomp) at Week 12 Endpoint | Vcomp is defined as the volume of urine voided (measures in mL using a standard calibrated flowmeter). At each visit, a uroflowmetry assessment was considered valid and the data were included in the statistical analyses only if the prevoid total bladder volume (assessed by ultrasound) was >=150 to <=550 milliliters (mL) and the voided volume (Vcomp) was >= 125 mL. | Baseline, 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Erectile Dysfunction, Benign Prostatic Hyperplasia