Benign Prostatic Hyperplasia
Conditions
Brief summary
The main purpose of this study is to evaluate the safety and efficacy of the study drug known as tadalafil in participants with benign prostatic hyperplasia who are being treated with an alpha1 blocker. This study has two treatment periods. Participants will receive tadalafil or placebo in each treatment period.
Interventions
DRUGTadalafil
Administered orally
DRUGPlacebo
Administered orally
DRUGAlpha1 Blocker
Administered orally
Sponsors
Nippon Shinyaku Co., Ltd.
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
MALE
Age
45 Years to No maximum
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. * Have been treated with a stable dose of an alpha1 blocker (tamsulosin 0.2 mg once daily or silodosin 4 mg twice daily) for at least 8 weeks prior to screening, and continue the same alpha1 blocker at the same dose for the entire duration of the study. * Are Japanese men. * Have prostate volume ≥20 milliliters (mL) estimated by transabdominal or transrectal ultrasound at screening. * Have BPH-LUTS with a Total International Prostate Symptom Score (IPSS) of ≥12 at screening and baseline. * Have moderate LUTS with urinary peak flow rate (Qmax) ≥4 to ≤15 mL/second at baseline, while meeting both of the following criteria: * Prevoid total bladder volume ≥150 to ≤550 mL as assessed by ultrasound * Minimum voided volume ≥125 mL * Demonstrate ≥80% compliance with alpha1 blocker treatment\* during the screening period, documented at baseline * \*Tamsulosin: (Number of doses taken / Number of days to be treated) × 100 * Silodosin: (Number of doses taken / Number of days to be treated) × 50
Exclusion criteria
* Prostate-specific antigen (PSA) \>10.0 nanograms (ng)/mL at screening. * PSA ≥4.0 to ≤10.0 ng/mL at screening if prostate malignancy has not been ruled out to the satisfaction of a urologist. * Bladder post-void residual (PVR) ≥150 mL by ultrasound determination at screening. * History of any of the following pelvic conditions: * 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 days of screening. * History of urinary retention or lower urinary tract (bladder) stones within 6 months of screening. * History of urethral obstruction due to stricture, valves, sclerosis, or tumor at screening. * History of any of the following treatments within the indicated duration: * Antiandrogens within 11 months before screening * Dutasteride within 5 months before screening * Finasteride within 2 months before screening * Any erectile dysfunction treatment previously or currently * Any overactive bladder treatment within 4 weeks before screening * Have a diagnosis or history of prostate cancer at screening. * Current or history of malignancy at screening (except for treatment-free and relapse-free for ≥3 years at screening). * Clinical evidence or history of any of the following bladder conditions: * Underactive Bladder * Detrusor-sphincter dyssynergia (contraction of the detrusor without sphincter relaxation) * Interstitial cystitis * Clinical evidence of any of the following urinary tract conditions: * Active urogenital infection * Clinically significant microscopic hematuria as determined by a urologist * History of significant renal insufficiency meeting either of the following: * Receiving renal dialysis * Creatinine clearance (CLcr) \<30 mL/minute * Clinical evidence of severe hepatic impairment or Aspartate Transaminase (AST) or Alanine Transaminase (ALT) \>3 times the upper limit of normal range. * History of any of the following cardiac conditions: * Current or history of angina requiring treatment with nitrates or nitric oxide donors * Current or history of unstable angina * Positive cardiac stress test without documented evidence of subsequent, effective cardiac intervention (e.g., coronary angioplasty) * History of any of the following coronary conditions within 90 days of screening: * Myocardial infarction * Coronary artery bypass graft surgery * Percutaneous coronary intervention (for example, angioplasty or stent placement) * Any evidence or history of heart failure (New York Heart Association \[NYHA\] ≥ Class III). * Currently receiving alpha1 blocker therapy for the treatment of hypertension. * Current or history of any of the following symptoms: * Symptoms associated with orthostasis (e.g., recurrent episodes of dizziness, lightheadedness, loss of consciousness, syncope) * Causeless fall within 1 year of screening * Blood pressure-related findings of any of the following at screening: * Systolic blood pressure \>160 or \<90 millimeters of mercury (mm Hg) * Diastolic blood pressure \>100 or \<50 mm Hg * Malignant hypertension * Uncontrolled arrhythmia
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Preferring Combination Therapy Over Alpha Blocker Alone on the Treatment Preference Questionnaire (TPQ) | Week 20 | TPQ was used to investigate participant's preference between alpha1 blocker monotherapy and combination therapy with alpha1 blocker plus tadalafil. At the end of Treatment Period 2 (or discontinuation), participants were asked to choose a preferred treatment between the two treatments given in Treatment Period 1 and Treatment Period 2. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline on the IPSS Storage (Irritative) Subscore | Baseline,Week 8 | IPSS Storage (Irritative) subscore was the sum of Questions 2, 4 and 7 of the IPSS questionnaire. Scores ranged from 0 (no irritative symptoms) to 5 (frequent irritative symptoms), with total subscore of the 3 questions for irritative subscore ranging from 0 to 15. Higher numerical scores from the IPSS questionnaire represent greater severity of symptoms. |
| Change From Baseline on the IPSS Voiding (Obstructive) Subscore | Baseline, Week 8 | IPSS voiding (obstructive) subscore is the sum of Questions 1, 3, 5 and 6 of the IPSS questionnaire. Scores ranged from 0 (no obstructive symptoms) to 5 (frequent obstructive symptoms), with total subscore of the 4 questions of the obstructive score ranging from 0 to 20. Higher numerical scores from the IPSS questionnaire represent greater severity of symptoms. |
| Change From Baseline on the International Prostate Symptom Score (IPSS) Total Score | Baseline, Week 8 | IPSS Total Score is the sum of Questions 1 through 7 of the IPSS questionnaire. Each question was scored from 0 (none/no symptoms) to 5 (frequent symptoms) for an IPSS Total Score ranging from 0 to 35 points; higher numerical scores from the IPSS questionnaire represent greater severity of symptoms. |
| Percentage of Participants With Global Impression of Improvement (PGI-I) | Week 8 | The PGI I is a participant rated instrument that measures the improvement or worsening of the subject's symptoms based on a 7 point scale. A score of 1 indicates that the subject feels his symptoms are very much better. A score of 4 indicates that the subjects feels no change in his symptoms and a score of 7 indicates that the subject feels his symptoms are very much worse. The percentage of participants who reported a PGI-I score of 1 to 3 are presented in the table below. |
| Percentage of Participants With PGI-I (Drug Attributes Questionnaire) on 8 Symptoms for BPH-Lower Urinary Tract Symptoms Improvement | Week 8 | PGI-I (Drug Attributes Questionnaire \[DRAQ\]) on 8 Symptoms for BPH-Lower Urinary Tract Symptoms.The DRAQ includes the following urinary symptoms: 1. Difficulty to void; 2. Frequent nighttime voiding; 3. Feeling of incomplete emptying; 4. Frequent daytime voiding; 5. Urinary urgency; 6. Taking a long time to urinate; 7. Need abdominal pressure to void; 8. Dribbling, leakage, and/or accidents. Each urinary symptom in the DRAQ will be evaluated by a participant using the PGI-I (discrete variables with seven categories) at the end of each treatment period, compared with how the symptom was before the participant's began taking medication in this study. The percentage of participants who reported a PGI-I (Drug Attributes Questionnaire) score of 1 to 3 are presented in the table below. |
| Change From Baseline on the IPSS Quality of Life Score (IPSS QoL ) | Baseline, Week 8 | IPSS QoL assess participant 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 are Delighted (0), Pleased (1); Mostly satisfied (2); mixed about equally satisfied and dissatisfied (3); Mostly dissatisfied (4); Unhappy (5); Terrible (6), with a total ranging from 0 to 6 with higher numerical score representing worse Quality of Life from BPH symptom. |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Tadalafil/Placebo 5 milligrams (mg) tadalafil administered QD orally for 8 weeks in one of two treatment periods.
Placebo administered once daily orally for 8 weeks in one of two treatment periods.
0.2 mg tamulosin once daily or 4 mg silodosin twice daily.
Participants will remain on stable dose of alpha1 blocker through both treatment periods. | 85 |
| Placebo/Tadalafil Placebo administered once daily orally for 8 weeks in one of two treatment periods.
5 mg tadalafil administered once daily (QD) orally for 8 weeks in one of two treatment periods.
0.2 mg tamulosin once daily or 4 mg silodosin twice daily.
Participants will remain on stable dose of alpha1 blocker through both treatment periods. | 86 |
| Total | 171 |
Baseline characteristics
| Characteristic | Tadalafil/Placebo | Placebo/Tadalafil | Total |
|---|---|---|---|
| Age, Continuous | 61.4 years STANDARD_DEVIATION 6.2 | 62.0 years STANDARD_DEVIATION 5.8 | 61.7 years STANDARD_DEVIATION 6 |
| Current Smoking Habit No | 71 participants | 66 participants | 137 participants |
| Current Smoking Habit Yes | 14 participants | 20 participants | 34 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 85 Participants | 86 Participants | 171 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 85 Participants | 86 Participants | 171 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Japan | 85 Participants | 86 Participants | 171 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 85 Participants | 86 Participants | 171 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 47 / 167 | 39 / 161 |
| serious Total, serious adverse events | 0 / 167 | 0 / 161 |
Outcome results
Primary
Percentage of Participants Preferring Combination Therapy Over Alpha Blocker Alone on the Treatment Preference Questionnaire (TPQ)
TPQ was used to investigate participant's preference between alpha1 blocker monotherapy and combination therapy with alpha1 blocker plus tadalafil. At the end of Treatment Period 2 (or discontinuation), participants were asked to choose a preferred treatment between the two treatments given in Treatment Period 1 and Treatment Period 2.
Time frame: Week 20
Population: All randomized participants who received at least one dose of study drug and completed the TPQ.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tadalafil/Placebo | Percentage of Participants Preferring Combination Therapy Over Alpha Blocker Alone on the Treatment Preference Questionnaire (TPQ) | Prefer therapy tadalafil + a1 blocker | 44.0 percentage of participants |
| Tadalafil/Placebo | Percentage of Participants Preferring Combination Therapy Over Alpha Blocker Alone on the Treatment Preference Questionnaire (TPQ) | Prefer therapy placebo + a1 blocker | 56.0 percentage of participants |
| Placebo/Tadalafil | Percentage of Participants Preferring Combination Therapy Over Alpha Blocker Alone on the Treatment Preference Questionnaire (TPQ) | Prefer therapy tadalafil + a1 blocker | 68.3 percentage of participants |
| Placebo/Tadalafil | Percentage of Participants Preferring Combination Therapy Over Alpha Blocker Alone on the Treatment Preference Questionnaire (TPQ) | Prefer therapy placebo + a1 blocker | 31.7 percentage of participants |
p-value: 0.0937Normal approximation (Z-test)
Secondary
Change From Baseline on the International Prostate Symptom Score (IPSS) Total Score
IPSS Total Score is the sum of Questions 1 through 7 of the IPSS questionnaire. Each question was scored from 0 (none/no symptoms) to 5 (frequent symptoms) for an IPSS Total Score ranging from 0 to 35 points; higher numerical scores from the IPSS questionnaire represent greater severity of symptoms.
Time frame: Baseline, Week 8
Population: All randomized participants who received at least one dose of study drug and had a baseline and post baseline IPSS measurement.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tadalafil/Placebo | Change From Baseline on the International Prostate Symptom Score (IPSS) Total Score | -2.5 units on a scale | Standard Deviation 5.1 |
| Placebo/Tadalafil | Change From Baseline on the International Prostate Symptom Score (IPSS) Total Score | -1.8 units on a scale | Standard Deviation 4.2 |
p-value: 0.148595% CI: [-1.69, 0.26]Mixed Models Analysis
Secondary
Change From Baseline on the IPSS Quality of Life Score (IPSS QoL )
IPSS QoL assess participant 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 are Delighted (0), Pleased (1); Mostly satisfied (2); mixed about equally satisfied and dissatisfied (3); Mostly dissatisfied (4); Unhappy (5); Terrible (6), with a total ranging from 0 to 6 with higher numerical score representing worse Quality of Life from BPH symptom.
Time frame: Baseline, Week 8
Population: All randomized participants who received at least one dose of study drug and had a baseline and post baseline IPSS measurement.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tadalafil/Placebo | Change From Baseline on the IPSS Quality of Life Score (IPSS QoL ) | -0.4 units on a scale | Standard Deviation 1.1 |
| Placebo/Tadalafil | Change From Baseline on the IPSS Quality of Life Score (IPSS QoL ) | -0.4 units on a scale | Standard Deviation 0.9 |
Secondary
Change From Baseline on the IPSS Storage (Irritative) Subscore
IPSS Storage (Irritative) subscore was the sum of Questions 2, 4 and 7 of the IPSS questionnaire. Scores ranged from 0 (no irritative symptoms) to 5 (frequent irritative symptoms), with total subscore of the 3 questions for irritative subscore ranging from 0 to 15. Higher numerical scores from the IPSS questionnaire represent greater severity of symptoms.
Time frame: Baseline,Week 8
Population: All randomized participants who received at least one dose of study drug and had a baseline and post baseline IPSS measurement.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tadalafil/Placebo | Change From Baseline on the IPSS Storage (Irritative) Subscore | -0.6 units on a scale | Standard Deviation 2.1 |
| Placebo/Tadalafil | Change From Baseline on the IPSS Storage (Irritative) Subscore | -0.5 units on a scale | Standard Deviation 1.9 |
Secondary
Change From Baseline on the IPSS Voiding (Obstructive) Subscore
IPSS voiding (obstructive) subscore is the sum of Questions 1, 3, 5 and 6 of the IPSS questionnaire. Scores ranged from 0 (no obstructive symptoms) to 5 (frequent obstructive symptoms), with total subscore of the 4 questions of the obstructive score ranging from 0 to 20. Higher numerical scores from the IPSS questionnaire represent greater severity of symptoms.
Time frame: Baseline, Week 8
Population: All randomized participants who received at least one dose of study drug and had a baseline and post baseline IPSS measurement.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tadalafil/Placebo | Change From Baseline on the IPSS Voiding (Obstructive) Subscore | -2.0 units on a scale | Standard Deviation 3.6 |
| Placebo/Tadalafil | Change From Baseline on the IPSS Voiding (Obstructive) Subscore | -1.3 units on a scale | Standard Deviation 3 |
Secondary
Percentage of Participants With Global Impression of Improvement (PGI-I)
The PGI I is a participant rated instrument that measures the improvement or worsening of the subject's symptoms based on a 7 point scale. A score of 1 indicates that the subject feels his symptoms are very much better. A score of 4 indicates that the subjects feels no change in his symptoms and a score of 7 indicates that the subject feels his symptoms are very much worse. The percentage of participants who reported a PGI-I score of 1 to 3 are presented in the table below.
Time frame: Week 8
Population: All randomized participants who received at least one dose of study drug and had a baseline and post baseline PGI-I measurement.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tadalafil/Placebo | Percentage of Participants With Global Impression of Improvement (PGI-I) | 61.1 percentage of participants |
| Placebo/Tadalafil | Percentage of Participants With Global Impression of Improvement (PGI-I) | 53.4 percentage of participants |
Secondary
Percentage of Participants With PGI-I (Drug Attributes Questionnaire) on 8 Symptoms for BPH-Lower Urinary Tract Symptoms Improvement
PGI-I (Drug Attributes Questionnaire \[DRAQ\]) on 8 Symptoms for BPH-Lower Urinary Tract Symptoms.The DRAQ includes the following urinary symptoms: 1. Difficulty to void; 2. Frequent nighttime voiding; 3. Feeling of incomplete emptying; 4. Frequent daytime voiding; 5. Urinary urgency; 6. Taking a long time to urinate; 7. Need abdominal pressure to void; 8. Dribbling, leakage, and/or accidents. Each urinary symptom in the DRAQ will be evaluated by a participant using the PGI-I (discrete variables with seven categories) at the end of each treatment period, compared with how the symptom was before the participant's began taking medication in this study. The percentage of participants who reported a PGI-I (Drug Attributes Questionnaire) score of 1 to 3 are presented in the table below.
Time frame: Week 8
Population: All randomized participants who received at least one dose of study drug and had a baseline and post baseline PGI-I (DRAQ) measurement.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tadalafil/Placebo | Percentage of Participants With PGI-I (Drug Attributes Questionnaire) on 8 Symptoms for BPH-Lower Urinary Tract Symptoms Improvement | Difficulty to void - | 44.9 percentage of participants |
| Tadalafil/Placebo | Percentage of Participants With PGI-I (Drug Attributes Questionnaire) on 8 Symptoms for BPH-Lower Urinary Tract Symptoms Improvement | Frequent nighttime voiding | 48.5 percentage of participants |
| Tadalafil/Placebo | Percentage of Participants With PGI-I (Drug Attributes Questionnaire) on 8 Symptoms for BPH-Lower Urinary Tract Symptoms Improvement | Feeling of incomplete emptying | 48.5 percentage of participants |
| Tadalafil/Placebo | Percentage of Participants With PGI-I (Drug Attributes Questionnaire) on 8 Symptoms for BPH-Lower Urinary Tract Symptoms Improvement | Frequent daytime voiding | 42.5 percentage of participants |
| Tadalafil/Placebo | Percentage of Participants With PGI-I (Drug Attributes Questionnaire) on 8 Symptoms for BPH-Lower Urinary Tract Symptoms Improvement | Urinary urgency | 37.1 percentage of participants |
| Tadalafil/Placebo | Percentage of Participants With PGI-I (Drug Attributes Questionnaire) on 8 Symptoms for BPH-Lower Urinary Tract Symptoms Improvement | Taking a long time to urinate | 42.5 percentage of participants |
| Tadalafil/Placebo | Percentage of Participants With PGI-I (Drug Attributes Questionnaire) on 8 Symptoms for BPH-Lower Urinary Tract Symptoms Improvement | Need abdominal pressure to void | 33.5 percentage of participants |
| Tadalafil/Placebo | Percentage of Participants With PGI-I (Drug Attributes Questionnaire) on 8 Symptoms for BPH-Lower Urinary Tract Symptoms Improvement | Dribbling, leakage, and/or accidents | 26.9 percentage of participants |
| Placebo/Tadalafil | Percentage of Participants With PGI-I (Drug Attributes Questionnaire) on 8 Symptoms for BPH-Lower Urinary Tract Symptoms Improvement | Dribbling, leakage, and/or accidents | 27.3 percentage of participants |
| Placebo/Tadalafil | Percentage of Participants With PGI-I (Drug Attributes Questionnaire) on 8 Symptoms for BPH-Lower Urinary Tract Symptoms Improvement | Difficulty to void - | 37.9 percentage of participants |
| Placebo/Tadalafil | Percentage of Participants With PGI-I (Drug Attributes Questionnaire) on 8 Symptoms for BPH-Lower Urinary Tract Symptoms Improvement | Urinary urgency | 31.7 percentage of participants |
| Placebo/Tadalafil | Percentage of Participants With PGI-I (Drug Attributes Questionnaire) on 8 Symptoms for BPH-Lower Urinary Tract Symptoms Improvement | Frequent nighttime voiding | 42.9 percentage of participants |
| Placebo/Tadalafil | Percentage of Participants With PGI-I (Drug Attributes Questionnaire) on 8 Symptoms for BPH-Lower Urinary Tract Symptoms Improvement | Need abdominal pressure to void | 33.5 percentage of participants |
| Placebo/Tadalafil | Percentage of Participants With PGI-I (Drug Attributes Questionnaire) on 8 Symptoms for BPH-Lower Urinary Tract Symptoms Improvement | Feeling of incomplete emptying | 34.8 percentage of participants |
| Placebo/Tadalafil | Percentage of Participants With PGI-I (Drug Attributes Questionnaire) on 8 Symptoms for BPH-Lower Urinary Tract Symptoms Improvement | Taking a long time to urinate | 32.9 percentage of participants |
| Placebo/Tadalafil | Percentage of Participants With PGI-I (Drug Attributes Questionnaire) on 8 Symptoms for BPH-Lower Urinary Tract Symptoms Improvement | Frequent daytime voiding | 37.9 percentage of participants |