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

• Sponsor: Eli Lilly and Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01460342
• Collaborator: (none)
• Enrollment: 610
• Locations: 17
• Arms: 2
• Duration (Months): 10
• Patients Per Site: 35.9
• Patients Per Site Per Month: 3.6

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Benign Prostatic Hyperplasia	Drug: Tadalafil; Drug: Placebo	Phase 3

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 610 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: Dec 1, 2011
• Actual Primary Completion Date: Oct 1, 2012
• Actual Study Completion Date: Oct 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo 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; 2 tablets (identical to 2.5-mg tadalafil tablets) given orally once daily.
Experimental: Tadalafil 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; 5 mg (2 x 2.5-mg tablets), given once daily as oral tablet; Other Names: Cialis LY450190 ; Drug: Placebo; 2 tablets (identical to 2.5-mg tadalafil tablets) given orally once daily.

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Total Score of International Prostate Symptom Score (IPSS) at 12 Weeks [Baseline, 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.

Secondary Outcome Measures

1. Change From Baseline in Total Score of International Prostate Symptom Score (IPSS) [Baseline, 4 weeks, 8 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.

2. Change From Baseline in the International Prostate Symptom Score (IPSS) Storage (Irritative) Subscore [Baseline, 4 weeks, 8 weeks, 12 weeks]

   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.

3. Change From Baseline in the International Prostate Symptom Score (IPSS) Voiding (Obstructive) Subscore [Baseline, 4 weeks, 8 weeks, 12 weeks]

   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.

4. Change From Baseline in the International Prostate Symptom Score (IPSS) Quality of Life (QoL) Index [Baseline, 4 weeks, 8 weeks, 12 weeks]

   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.

5. Patient Global Impression of Improvement (PGI-I) Scale at 12 Weeks [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).

6. Clinician Global Impression of Improvement (CGI-I) Scale at 12 Weeks [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).

7. Change From Baseline in Modified International Prostate Symptom Score (mIPSS) Score at 2 Weeks [Baseline, 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 45 Years and Older
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Chiba		Japan	270-0034
2	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Ehime		Japan	790-0962
3	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Fukuoka		Japan	816-0943
4	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Hyogo		Japan	650-0012
5	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Kagoshima		Japan	891-0105
6	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Kanagawa		Japan	252-0143
7	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Kyoto		Japan	600-8813
8	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Osaka		Japan	553-0001
9	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Saitama		Japan	331-0823
10	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Tokyo		Japan	150-0002
11	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Yamanashi		Japan	407-0015
12	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Goyang-Si		Korea, Republic of	412-270
13	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Incheon		Korea, Republic of	400-711
14	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Jeon Ju-City		Korea, Republic of	561-712
15	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Kwang Ju		Korea, Republic of	501-757
16	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Pusan		Korea, Republic of	609 735
17	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Seoul		Korea, Republic of	137-040

Sponsors and Collaborators

• Eli Lilly and Company

Investigators

• Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST), Eli Lilly and Company

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Eli Lilly and Company
• ClinicalTrials.gov Identifier: NCT01460342
• Other Study ID Numbers: 14101; H6D-JE-LVJF
• First Posted: Oct 26, 2011
• Last Update Posted: Sep 25, 2013
• Last Verified: Jul 1, 2013

• Keywords provided by Eli Lilly and Company: Prostatic hyperplasia; Benign prostatic hyperplasia; Lower urinary tract
• Additional relevant MeSH terms: Prostatic Hyperplasia; Hyperplasia; Tadalafil

Study Results

Participant Flow

Pre-assignment Detail	The study consisted of 3 periods: a screening/wash-out period (pre-randomization, 1 day up to 4 weeks), a placebo lead-in period (pre-randomization, 4 weeks, participant-blinded), and a double-blind treatment period (post-randomization, 12 weeks).

Arm/Group Title	Placebo	Tadalafil
Arm/Group Description	Placebo: 2 tablets [identical to 2.5-milligram (mg) tadalafil tablets] given orally once daily for 4 weeks, during the placebo lead-in period and for 12 weeks, during the double-blind treatment period.	Tadalafil: 5 mg (two 2.5-mg tablets), given orally once daily for 12 weeks, during the double-blind treatment period. This followed a 4-week placebo lead-in period [2 tablets (identical to 2.5-mg tadalafil tablets) given orally once daily].
Period Title: Overall Study
STARTED	304	306
Received at Least 1 Dose of Study Drug	304	306
COMPLETED	293	292
NOT COMPLETED	11	14

Baseline Characteristics

Arm/Group Title	Placebo	Tadalafil	Total
Arm/Group Description	Placebo: 2 tablets [identical to 2.5-milligram (mg) tadalafil tablets] given orally once daily for 4 weeks, during the placebo lead-in period and for 12 weeks, during the double-blind treatment period.	Tadalafil: 5 mg (two 2.5-mg tablets), given orally once daily for 12 weeks, during the double-blind treatment period. This followed a 4-week placebo lead-in period [2 tablets (identical to 2.5-mg tadalafil tablets) given orally once daily].	Total of all reporting groups
Overall Participants	304	306	610
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60.9 (8.1)	60.8 (7.7)	60.9 (7.9)
Age, Customized (participants) [Number]
<65 years	201 66.1%	198 64.7%	399 65.4%
>=65 years	103 33.9%	108 35.3%	211 34.6%
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	304 100%	306 100%	610 100%
Race/Ethnicity, Customized (participants) [Number]
Asian	304 100%	306 100%	610 100%
Region of Enrollment (participants) [Number]
Japan	222 73%	227 74.2%	449 73.6%
Korea, Republic of	82 27%	79 25.8%	161 26.4%
Body Mass Index (BMI) (kilograms per square meter (kg/m^2)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilograms per square meter (kg/m^2)]	24.1 (2.9)	24.0 (3.0)	24.0 (3.0)
Current Tobacco Use (participants) [Number]
Yes	55 18.1%	57 18.6%	112 18.4%
No	249 81.9%	249 81.4%	498 81.6%
Alcohol Use (participants) [Number]
Yes	196 64.5%	206 67.3%	402 65.9%
No	108 35.5%	100 32.7%	208 34.1%
Benign Prostatic Hyperplasia (BPH) Severity (participants) [Number]
Mild (IPSS Total Score 0 to 7)	5 1.6%	6 2%	11 1.8%
Moderate (IPSS Total Score 8 to 19)	167 54.9%	166 54.2%	333 54.6%
Severe (IPSS Total Score >=20)	132 43.4%	134 43.8%	266 43.6%
Duration of BPH (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	4.0 (3.3)	4.1 (3.2)	4.0 (3.2)
Patient Global Impression of Severity (PGI-S) Scale (participants) [Number]
Normal	0 0%	0 0%	0 0%
Mild	67 22%	64 20.9%	131 21.5%
Moderate	187 61.5%	195 63.7%	382 62.6%
Severe	50 16.4%	47 15.4%	97 15.9%
Clinical Global Impression of Severity (CGI-S) Scale (participants) [Number]
Normal	0 0%	0 0%	0 0%
Mild	33 10.9%	41 13.4%	74 12.1%
Moderate	218 71.7%	211 69%	429 70.3%
Severe	53 17.4%	54 17.6%	107 17.5%
Previous Alpha-Blocker Therapy (participants) [Number]
Yes	43 14.1%	39 12.7%	82 13.4%
No	261 85.9%	267 87.3%	528 86.6%
Previous Benign Prostatic Hyperplasia - Lower Urinary Tract Symptoms (BPH-LUTS) Therapy (Number) [Number]
Yes	21 6.9%	22 7.2%	43 7%
No	283 93.1%	284 92.8%	567 93%
Postvoid Residual Volume (PVR) (milliliters (mL)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [milliliters (mL)]	32.7 (50.0)	26.9 (37.7)	29.8 (44.3)
Prostate Volume (mL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mL]	31.6 (9.5)	30.7 (8.5)	31.1 (9.0)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Total Score of International Prostate Symptom Score (IPSS) at 12 Weeks
Description	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.
Time Frame	Baseline, 12 weeks

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug and had non-missing data at baseline.

Arm/Group Title	Placebo	Tadalafil
Arm/Group Description	Placebo: 2 tablets [identical to 2.5-milligram (mg) tadalafil tablets] given orally once daily for 4 weeks, during the placebo lead-in period and for 12 weeks, during the double-blind treatment period.	Tadalafil: 5 mg (two 2.5-mg tablets), given orally once daily for 12 weeks, during the double-blind treatment period. This followed a 4-week placebo lead-in period [2 tablets (identical to 2.5-mg tadalafil tablets) given orally once daily].
Measure Participants	301	305
Least Squares Mean (Standard Error) [units on a scale]	-4.5 (0.4)	-6.0 (0.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tadalafil
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.5
	Confidence Interval	(2-Sided) 95%; -2.4 to -0.6
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.5
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in Total Score of International Prostate Symptom Score (IPSS)
Description	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.
Time Frame	Baseline, 4 weeks, 8 weeks

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug and had non-missing data at baseline.

Arm/Group Title	Placebo	Tadalafil
Arm/Group Description	Placebo: 2 tablets [identical to 2.5-milligram (mg) tadalafil tablets] given orally once daily for 4 weeks, during the placebo lead-in period and for 12 weeks, during the double-blind treatment period.	Tadalafil: 5 mg (two 2.5-mg tablets), given orally once daily for 12 weeks, during the double-blind treatment period. This followed a 4-week placebo lead-in period [2 tablets (identical to 2.5-mg tadalafil tablets) given orally once daily].
Measure Participants	301	305
Change at Week 4	-2.8 (0.3)	-4.0 (0.4)
Change at Week 8	-4.0 (0.4)	-5.2 (0.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tadalafil
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	The p-value is for the change from baseline in the IPSS Total Score at Week 4.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.3
	Confidence Interval	(2-Sided) 95%; -2.0 to -0.5
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.4
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tadalafil
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments	The p-value is for the change from baseline in the IPSS Total Score at Week 8.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.2
	Confidence Interval	(2-Sided) 95%; -2.0 to -0.4
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.4
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline in the International Prostate Symptom Score (IPSS) Storage (Irritative) Subscore
Description	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.
Time Frame	Baseline, 4 weeks, 8 weeks, 12 weeks

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug and had non-missing data at baseline.

Arm/Group Title	Placebo	Tadalafil
Arm/Group Description	Placebo: 2 tablets [identical to 2.5-milligram (mg) tadalafil tablets] given orally once daily for 4 weeks, during the placebo lead-in period and for 12 weeks, during the double-blind treatment period.	Tadalafil: 5 mg (two 2.5-mg tablets), given orally once daily for 12 weeks, during the double-blind treatment period. This followed a 4-week placebo lead-in period [2 tablets (identical to 2.5-mg tadalafil tablets) given orally once daily].
Measure Participants	301	305
Change at 4 Weeks	-0.9 (0.1)	-1.2 (0.2)
Change at 8 Weeks	-1.3 (0.2)	-1.7 (0.2)
Change at 12 Weeks	-1.4 (0.2)	-2.0 (0.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tadalafil
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.090
	Comments	The p-value was for the change from baseline in the IPSS Storage (Irritative) Subscore at Week 4.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.3
	Confidence Interval	(2-Sided) 95%; -0.6 to 0.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.2
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tadalafil
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.011
	Comments	The p-value was for the change from baseline in the IPSS Storage (Irritative) Subscore at Week 8.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.4
	Confidence Interval	(2-Sided) 95%; -0.8 to -0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.2
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tadalafil
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments	The p-value was for the change from baseline in the IPSS Storage (Irritative) Subscore at Week 12.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.6
	Confidence Interval	(2-Sided) 95%; -0.9 to -0.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.2
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline in the International Prostate Symptom Score (IPSS) Voiding (Obstructive) Subscore
Description	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.
Time Frame	Baseline, 4 weeks, 8 weeks, 12 weeks

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug and had non-missing data at baseline.

Arm/Group Title	Placebo	Tadalafil
Arm/Group Description	Placebo: 2 tablets [identical to 2.5-milligram (mg) tadalafil tablets] given orally once daily for 4 weeks, during the placebo lead-in period and for 12 weeks, during the double-blind treatment period.	Tadalafil: 5 mg (two 2.5-mg tablets), given orally once daily for 12 weeks, during the double-blind treatment period. This followed a 4-week placebo lead-in period [2 tablets (identical to 2.5-mg tadalafil tablets) given orally once daily].
Measure Participants	301	305
Change at Week 4	-1.8 (0.2)	-2.8 (0.2)
Change at Week 8	-2.6 (0.3)	-3.4 (0.3)
Change at Week 12	-3.1 (0.3)	-4.0 (0.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tadalafil
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	The p-value was for the change from baseline in the IPSS Voiding (Obstructive) Subscore at Week 4.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.0
	Confidence Interval	(2-Sided) 95%; -1.5 to -0.4
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.3
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tadalafil
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.007
	Comments	The p-value was for the change from baseline in the IPSS Voiding (Obstructive) Subscore at Week 8.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.8
	Confidence Interval	(2-Sided) 95%; -1.3 to -0.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.3
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tadalafil
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments	The p-value was for the change from baseline in the IPSS Voiding (Obstructive) Subscore at Week 12.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.9
	Confidence Interval	(2-Sided) 95%; -1.5 to -0.3
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.3
	Estimation Comments

5. Secondary Outcome

Title	Change From Baseline in the International Prostate Symptom Score (IPSS) Quality of Life (QoL) Index
Description	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.
Time Frame	Baseline, 4 weeks, 8 weeks, 12 weeks

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug and had non-missing data at baseline.

Arm/Group Title	Placebo	Tadalafil
Arm/Group Description	Placebo: 2 tablets [identical to 2.5-milligram (mg) tadalafil tablets] given orally once daily for 4 weeks, during the placebo lead-in period and for 12 weeks, during the double-blind treatment period.	Tadalafil: 5 mg (two 2.5-mg tablets), given orally once daily for 12 weeks, during the double-blind treatment period. This followed a 4-week placebo lead-in period [2 tablets (identical to 2.5-mg tadalafil tablets) given orally once daily].
Measure Participants	301	305
Change at Week 4	-0.5 (0.1)	-0.6 (0.1)
Change at Week 8	-0.7 (0.1)	-0.8 (0.1)
Change at Week 12	-0.9 (0.1)	-1.1 (0.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tadalafil
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.277
	Comments	The p-value was for the change from baseline in the IPSS QoL Index Score at Week 4.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.2 to 0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.1
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tadalafil
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.170
	Comments	The p-value was for the change from baseline in the IPSS QoL Index Score at Week 8.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.3 to 0.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.1
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tadalafil
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.038
	Comments	The p-value was for the change from baseline in the IPSS QoL Index Score at Week 12.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 95%; -0.4 to -0.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.1
	Estimation Comments

6. Secondary Outcome

Title	Patient Global Impression of Improvement (PGI-I) Scale at 12 Weeks
Description	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).
Time Frame	12 Weeks

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug.

Arm/Group Title	Placebo	Tadalafil
Arm/Group Description	Placebo: 2 tablets [identical to 2.5-milligram (mg) tadalafil tablets] given orally once daily for 4 weeks, during the placebo lead-in period and for 12 weeks, during the double-blind treatment period.	Tadalafil: 5 mg (two 2.5-mg tablets), given orally once daily for 12 weeks, during the double-blind treatment period. This followed a 4-week placebo lead-in period [2 tablets (identical to 2.5-mg tadalafil tablets) given orally once daily].
Measure Participants	304	306
Very Much Better	9 3%	18 5.9%
Much Better	55 18.1%	79 25.8%
A Little Better	138 45.4%	148 48.4%
No Change	90 29.6%	55 18%
A Little Worse	7 2.3%	2 0.7%
Much Worse	0 0%	0 0%
Very Much Worse	2 0.7%	0 0%
Missing	3 1%	4 1.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tadalafil
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	The p-value was from the Cochran-Mantel-Haenszel test adjusted for baseline severity of benign prostatic hyperplasia lower urinary tract symptoms (BPH-LUTS) and previous alpha-blocker therapy.
	Method	Cochran-Mantel-Haenszel
	Comments

7. Secondary Outcome

Title	Clinician Global Impression of Improvement (CGI-I) Scale at 12 Weeks
Description	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).
Time Frame	12 Weeks

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug.

Arm/Group Title	Placebo	Tadalafil
Arm/Group Description	Placebo: 2 tablets [identical to 2.5-milligram (mg) tadalafil tablets] given orally once daily for 4 weeks, during the placebo lead-in period and for 12 weeks, during the double-blind treatment period.	Tadalafil: 5 mg (two 2.5-mg tablets), given orally once daily for 12 weeks, during the double-blind treatment period. This followed a 4-week placebo lead-in period [2 tablets (identical to 2.5-mg tadalafil tablets) given orally once daily].
Measure Participants	304	306
Very Much Improved	10 3.3%	14 4.6%
Much Improved	74 24.3%	103 33.7%
Minimally Improved	115 37.8%	125 40.8%
No Change	93 30.6%	59 19.3%
Minimally Worse	8 2.6%	1 0.3%
Much Worse	0 0%	0 0%
Very Much Worse	1 0.3%	0 0%
Missing	3 1%	4 1.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tadalafil
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	The p-value was from the Cochran-Mantel-Haenszel test adjusted for baseline severity of benign prostatic hyperplasia lower urinary tract symptoms (BPH-LUTS) and previous alpha-blocker therapy.
	Method	Cochran-Mantel-Haenszel
	Comments

8. Secondary Outcome

Title	Change From Baseline in Modified International Prostate Symptom Score (mIPSS) Score at 2 Weeks
Description	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.
Time Frame	Baseline, 2 weeks

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug and had non-missing data at baseline.

Arm/Group Title	Placebo	Tadalafil
Arm/Group Description	Placebo: 2 tablets [identical to 2.5-milligram (mg) tadalafil tablets] given orally once daily for 4 weeks, during the placebo lead-in period and for 12 weeks, during the double-blind treatment period.	Tadalafil: 5 mg (two 2.5-mg tablets), given orally once daily for 12 weeks, during the double-blind treatment period. This followed a 4-week placebo lead-in period [2 tablets (identical to 2.5-mg tadalafil tablets) given orally once daily].
Measure Participants	301	305
Least Squares Mean (Standard Error) [units on a scale]	-2.1 (0.3)	-2.7 (0.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tadalafil
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.060
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.6
	Confidence Interval	(2-Sided) 95%; -1.2 to 0.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.3
	Estimation Comments

Adverse Events

Arm/Group Title	Placebo		Tadalafil
Arm/Group Description	Placebo: 2 tablets [identical to 2.5-milligram (mg) tadalafil tablets] given orally once daily for 4 weeks, during the placebo lead-in period and for 12 weeks, during the double-blind treatment period.		Tadalafil: 5 mg (two 2.5-mg tablets), given orally once daily for 12 weeks, during the double-blind treatment period. This followed a 4-week placebo lead-in period [2 tablets (identical to 2.5-mg tadalafil tablets) given orally once daily].
All Cause Mortality
	Placebo		Tadalafil
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Tadalafil
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/304 (0.3%)		2/306 (0.7%)
Cardiac disorders
Cardio-respiratory arrest	1/304 (0.3%)	1	0/306 (0%)	0
Hepatobiliary disorders
Cholecystitis	0/304 (0%)	0	1/306 (0.3%)	1
Injury, poisoning and procedural complications
Spinal cord injury cervical	1/304 (0.3%)	1	0/306 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	0/304 (0%)	0	1/306 (0.3%)	1
Other (Not Including Serious) Adverse Events
	Placebo		Tadalafil
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	75/304 (24.7%)		87/306 (28.4%)
Blood and lymphatic system disorders
Anaemia	0/304 (0%)	0	2/306 (0.7%)	2
Cardiac disorders
Supraventricular extrasystoles	0/304 (0%)	0	1/306 (0.3%)	1
Ear and labyrinth disorders
Ear discomfort	1/304 (0.3%)	1	0/306 (0%)	0
Vertigo	1/304 (0.3%)	1	0/306 (0%)	0
Eye disorders
Asthenopia	0/304 (0%)	0	1/306 (0.3%)	1
Astigmatism	0/304 (0%)	0	1/306 (0.3%)	1
Erythema of eyelid	0/304 (0%)	0	1/306 (0.3%)	1
Eyelid oedema	0/304 (0%)	0	1/306 (0.3%)	1
Vision blurred	1/304 (0.3%)	1	0/306 (0%)	0
Vitreous detachment	0/304 (0%)	0	1/306 (0.3%)	1
Vitreous floaters	0/304 (0%)	0	1/306 (0.3%)	1
Gastrointestinal disorders
Abdominal discomfort	1/304 (0.3%)	1	2/306 (0.7%)	3
Abdominal distension	1/304 (0.3%)	1	0/306 (0%)	0
Abdominal pain lower	1/304 (0.3%)	1	0/306 (0%)	0
Constipation	1/304 (0.3%)	1	0/306 (0%)	0
Diarrhoea	1/304 (0.3%)	1	5/306 (1.6%)	5
Dry mouth	0/304 (0%)	0	1/306 (0.3%)	1
Dyspepsia	2/304 (0.7%)	2	12/306 (3.9%)	12
Frequent bowel movements	0/304 (0%)	0	1/306 (0.3%)	1
Gastric ulcer	2/304 (0.7%)	2	0/306 (0%)	0
Gastritis	0/304 (0%)	0	2/306 (0.7%)	2
Gastritis atrophic	1/304 (0.3%)	1	0/306 (0%)	0
Gastrointestinal motility disorder	1/304 (0.3%)	1	0/306 (0%)	0
Gastrooesophageal reflux disease	1/304 (0.3%)	1	0/306 (0%)	0
Gingivitis	0/304 (0%)	0	1/306 (0.3%)	1
Lip dry	1/304 (0.3%)	1	0/306 (0%)	0
Periodontal disease	2/304 (0.7%)	2	0/306 (0%)	0
Periodontitis	2/304 (0.7%)	2	0/306 (0%)	0
Stomatitis	1/304 (0.3%)	1	0/306 (0%)	0
Vomiting	0/304 (0%)	0	2/306 (0.7%)	2
General disorders
Granuloma	1/304 (0.3%)	1	0/306 (0%)	0
Malaise	0/304 (0%)	0	1/306 (0.3%)	1
Oedema peripheral	0/304 (0%)	0	1/306 (0.3%)	1
Therapeutic response unexpected	0/304 (0%)	0	1/306 (0.3%)	1
Hepatobiliary disorders
Drug-induced liver injury	0/304 (0%)	0	1/306 (0.3%)	1
Hepatic function abnormal	3/304 (1%)	3	1/306 (0.3%)	1
Infections and infestations
Bronchitis	1/304 (0.3%)	1	1/306 (0.3%)	1
Fungal skin infection	0/304 (0%)	0	1/306 (0.3%)	1
Gastroenteritis	1/304 (0.3%)	1	0/306 (0%)	0
Herpes simplex	1/304 (0.3%)	1	0/306 (0%)	0
Herpes zoster	2/304 (0.7%)	2	0/306 (0%)	0
Influenza	1/304 (0.3%)	1	1/306 (0.3%)	1
Nasopharyngitis	10/304 (3.3%)	11	13/306 (4.2%)	14
Otitis media	0/304 (0%)	0	1/306 (0.3%)	1
Pharyngitis	0/304 (0%)	0	3/306 (1%)	3
Tonsillitis	0/304 (0%)	0	1/306 (0.3%)	1
Tracheitis	0/304 (0%)	0	1/306 (0.3%)	1
Upper respiratory tract infection	5/304 (1.6%)	5	2/306 (0.7%)	2
Urinary tract infection	1/304 (0.3%)	1	0/306 (0%)	0
Injury, poisoning and procedural complications
Arthropod sting	1/304 (0.3%)	1	0/306 (0%)	0
Hand fracture	1/304 (0.3%)	1	0/306 (0%)	0
Joint dislocation	0/304 (0%)	0	1/306 (0.3%)	1
Ligament sprain	2/304 (0.7%)	2	0/306 (0%)	0
Muscle strain	0/304 (0%)	0	1/306 (0.3%)	1
Upper limb fracture	0/304 (0%)	0	1/306 (0.3%)	1
Investigations
Alanine aminotransferase increased	4/304 (1.3%)	4	0/306 (0%)	0
Aspartate aminotransferase increased	6/304 (2%)	6	1/306 (0.3%)	1
Blood bilirubin increased	1/304 (0.3%)	1	0/306 (0%)	0
Blood chloride decreased	0/304 (0%)	0	1/306 (0.3%)	1
Blood creatine phosphokinase increased	7/304 (2.3%)	7	7/306 (2.3%)	7
Blood sodium decreased	0/304 (0%)	0	1/306 (0.3%)	1
Blood urine	1/304 (0.3%)	1	0/306 (0%)	0
Creatinine renal clearance decreased	1/304 (0.3%)	1	4/306 (1.3%)	4
Gamma-glutamyltransferase increased	3/304 (1%)	3	1/306 (0.3%)	1
Glucose urine present	0/304 (0%)	0	2/306 (0.7%)	2
White blood cell count decreased	2/304 (0.7%)	2	0/306 (0%)	0
Metabolism and nutrition disorders
Glucose tolerance impaired	0/304 (0%)	0	1/306 (0.3%)	1
Hyperuricaemia	0/304 (0%)	0	1/306 (0.3%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	1/304 (0.3%)	1	2/306 (0.7%)	2
Arthropathy	0/304 (0%)	0	1/306 (0.3%)	1
Back pain	3/304 (1%)	3	4/306 (1.3%)	4
Gouty arthritis	1/304 (0.3%)	1	0/306 (0%)	0
Limb discomfort	0/304 (0%)	0	1/306 (0.3%)	1
Musculoskeletal stiffness	1/304 (0.3%)	1	1/306 (0.3%)	1
Myalgia	1/304 (0.3%)	1	3/306 (1%)	3
Pain in extremity	1/304 (0.3%)	1	2/306 (0.7%)	2
Periarthritis	0/304 (0%)	0	1/306 (0.3%)	1
Scoliosis	1/304 (0.3%)	1	0/306 (0%)	0
Tenosynovitis	1/304 (0.3%)	1	0/306 (0%)	0
Nervous system disorders
Burning sensation	0/304 (0%)	0	1/306 (0.3%)	1
Carotid arteriosclerosis	0/304 (0%)	0	1/306 (0.3%)	1
Dizziness	0/304 (0%)	0	2/306 (0.7%)	2
Headache	6/304 (2%)	6	9/306 (2.9%)	9
Hypoaesthesia	0/304 (0%)	0	1/306 (0.3%)	1
Psychiatric disorders
Anxiety disorder	1/304 (0.3%)	1	0/306 (0%)	0
Renal and urinary disorders
Haematuria	1/304 (0.3%)	1	0/306 (0%)	0
Proteinuria	1/304 (0.3%)	1	0/306 (0%)	0
Renal impairment	1/304 (0.3%)	1	0/306 (0%)	0
Urinary retention	1/304 (0.3%)	1	0/306 (0%)	0
Reproductive system and breast disorders
Erection increased	0/304 (0%)	0	1/306 (0.3%)	1
Spontaneous penile erection	0/304 (0%)	0	1/306 (0.3%)	1
Respiratory, thoracic and mediastinal disorders
Cough	2/304 (0.7%)	2	0/306 (0%)	0
Epistaxis	1/304 (0.3%)	1	0/306 (0%)	0
Oropharyngeal discomfort	0/304 (0%)	0	1/306 (0.3%)	1
Rhinitis allergic	0/304 (0%)	0	1/306 (0.3%)	1
Rhinorrhoea	0/304 (0%)	0	1/306 (0.3%)	1
Upper respiratory tract inflammation	1/304 (0.3%)	1	0/306 (0%)	0
Skin and subcutaneous tissue disorders
Dermatitis	0/304 (0%)	0	1/306 (0.3%)	1
Dermatitis allergic	1/304 (0.3%)	1	0/306 (0%)	0
Eczema	2/304 (0.7%)	2	4/306 (1.3%)	4
Photosensitivity reaction	0/304 (0%)	0	1/306 (0.3%)	1
Pruritus	0/304 (0%)	0	1/306 (0.3%)	1
Urticaria	2/304 (0.7%)	2	0/306 (0%)	0
Surgical and medical procedures
Electrocauterisation	1/304 (0.3%)	1	0/306 (0%)	0
Rectal polypectomy	1/304 (0.3%)	1	0/306 (0%)	0
Tooth extraction	2/304 (0.7%)	2	0/306 (0%)	0
Vascular disorders
Hot flush	1/304 (0.3%)	1	2/306 (0.7%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.