Benign Prostatic Hyperplasia
Conditions
Brief summary
The purpose of this trial is to evaluate the effect of tadalafil 5 milligrams (mg) daily for 8 weeks compared to placebo on prostatic blood perfusion in men with signs and symptoms of Benign Prostatic Hyperplasia (BPH), measured by resistive index (RI) in the prostate transition zone.
Interventions
DRUGTadalafil
Administered orally, once daily for 8 weeks
DRUGPlacebo
Administered orally, once daily for 8 weeks
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
MALE
Age
45 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Present with benign prostatic hyperplasia * Provide signed informed consent at the screening * Agree not to use other treatment for Benign Prostatic Hyperplasia, Erectile Dysfunction or Overactive Bladder (including herbal treatments) during the study
Exclusion criteria
* Have prostatic cancer or are being treated for cancer. * Any condition that may negatively influence the transrectal ultrasound. * Are being treated for heart disease with any drug that is called a nitrate (for example, nitroglycerin). * Any evidence of moderate to severe cardiac disease * Have had any of the following in the past 90 days: chest pain (called unstable angina or angina) that requires treatment, heart attack also known as myocardial infarction, heart bypass surgery (called coronary artery bypass graft surgery), had a procedure to open up blood vessels in the heart know as angioplasty or stent placement (percutaneous coronary intervention), positive cardiac stress test without effective cardiac intervention. * Have very high or very low blood pressure. * Have uncontrolled diabetes. * Have certain problems with your kidneys, liver, or nervous system.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to 8-Week Endpoint in Arterial Resistive Index (RI) in the Prostate Transition Zone | Baseline, Week 8 | Arterial RI was a measure of vascular resistance using Doppler ultrasound. RI was the ratio of (peak systolic velocity - end diastolic velocity)/peak systolic velocity, and increased as resistance to blood flow increased. The least squares (LS) mean was estimated from a mixed-effects model with repeated measures (MMRM) that included fixed effects for treatment, region, visit, and treatment-by-visit interaction, baseline as a covariate, a random effect of participant within treatment, and an unstructured covariance matrix. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to 4-Week Endpoint in Arterial Resistive Index (RI) in the Prostate Transition Zone | Baseline, Week 4 | Arterial RI was a measure of vascular resistance using Doppler ultrasound. RI was the ratio of (peak systolic velocity - end diastolic velocity)/peak systolic velocity, and increased as resistance to flow increased. The least squares (LS) mean was estimated from a mixed-effects model with repeated measures (MMRM) that included fixed effects for treatment, region, visit, and treatment-by-visit interaction, baseline as a covariate, a random effect of participant within treatment, and an unstructured covariance matrix. |
| Change From Baseline to 4 and 8 Weeks in Arterial Resistive Index (RI) in the Prostate Peripheral Zone and Bladder Neck | Baseline, Week 4 and Week 8 | Arterial RI was a measure of vascular resistance using Doppler ultrasound. RI was the ratio of (peak systolic velocity - end diastolic velocity)/peak systolic velocity, and increased as resistance to flow increased. The least squares (LS) mean was estimated from a mixed-effects model with repeated measures (MMRM) that included fixed effects for treatment, region, visit, and treatment-by-visit interaction, baseline as a covariate, a random effect of participant within treatment, and an unstructured covariance matrix. |
| Change From Baseline to 4 and 8 Weeks in Color Pixel Intensity (CPI) in the Prostate Transition Zone, Peripheral Zone, and Bladder Neck | Baseline, Week 4 and Week 8 | CPI quantified blood flow in a pre-specified region of interest by using color Doppler imaging. CPI was the mean color pixel intensity in the region of interest and scores could range from 0 to 160. An increase in CPI reflected an increase in blood flow. The least squares (LS) mean was estimated from a mixed-effects model with repeated measures (MMRM) that included fixed effects for treatment, region, visit, and treatment-by-visit interaction, baseline as a covariate, a random effect of participant within treatment, and an unstructured covariance matrix. |
Countries
Austria, Italy, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo: tablet administered orally, once daily for 8 weeks. | 50 |
| Tadalafil Tadalafil: 5-milligram (mg) tablet administered orally, once daily for 8 weeks. | 47 |
| Total | 97 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 4 |
| Overall Study | Death | 1 | 0 |
| Overall Study | Protocol Violation | 1 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 3 |
Baseline characteristics
| Characteristic | Placebo | Tadalafil | Total |
|---|---|---|---|
| Age Continuous | 60.3 years STANDARD_DEVIATION 8.18 | 60.0 years STANDARD_DEVIATION 7.53 | 60.2 years STANDARD_DEVIATION 7.83 |
| Baseline Lower Urinary Tract Symptoms (LUTS) Severity Moderate | 22 participants | 20 participants | 42 participants |
| Baseline Lower Urinary Tract Symptoms (LUTS) Severity Severe | 28 participants | 27 participants | 55 participants |
| Body Mass Index | 27.4 kilograms per meter-squared (kg/m^2) STANDARD_DEVIATION 3.19 | 26.4 kilograms per meter-squared (kg/m^2) STANDARD_DEVIATION 3.28 | 26.9 kilograms per meter-squared (kg/m^2) STANDARD_DEVIATION 3.25 |
| ED Duration <1 year | 4 participants | 1 participants | 5 participants |
| ED Duration ≥1 year | 28 participants | 28 participants | 56 participants |
| ED Severity Mild | 11 participants | 9 participants | 20 participants |
| ED Severity Moderate | 16 participants | 15 participants | 31 participants |
| ED Severity Severe | 6 participants | 5 participants | 11 participants |
| Erectile Dysfunction (ED) Etiology Mixed | 13 participants | 12 participants | 25 participants |
| Erectile Dysfunction (ED) Etiology Organic | 18 participants | 15 participants | 33 participants |
| Erectile Dysfunction (ED) Etiology Psychogenic | 0 participants | 0 participants | 0 participants |
| Erectile Dysfunction (ED) Etiology Unknown | 2 participants | 2 participants | 4 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 50 Participants | 45 Participants | 95 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Postvoid Residual Volume | 59.0 milliliters (mL) STANDARD_DEVIATION 59.11 | 47.8 milliliters (mL) STANDARD_DEVIATION 44.47 | 53.6 milliliters (mL) STANDARD_DEVIATION 52.56 |
| Prostate Specific Antigen | 1.9 nanograms per milliliter (ng/mL) STANDARD_DEVIATION 1.7 | 2.1 nanograms per milliliter (ng/mL) STANDARD_DEVIATION 1.93 | 2.0 nanograms per milliliter (ng/mL) STANDARD_DEVIATION 1.81 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants | 3 Participants | 11 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 | 41 Participants | 42 Participants | 83 Participants |
| Region of Enrollment Austria | 6 participants | 7 participants | 13 participants |
| Region of Enrollment Belgium | 4 participants | 5 participants | 9 participants |
| Region of Enrollment Italy | 15 participants | 14 participants | 29 participants |
| Region of Enrollment United States | 25 participants | 21 participants | 46 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 50 Participants | 47 Participants | 97 Participants |
| Sitting Diastolic Blood Pressure | 81.8 millimeters of mercury (mm Hg) STANDARD_DEVIATION 8.73 | 81.5 millimeters of mercury (mm Hg) STANDARD_DEVIATION 6.85 | 81.7 millimeters of mercury (mm Hg) STANDARD_DEVIATION 7.83 |
| Sitting Systolic Blood Pressure | 131.0 millimeters of mercury (mm Hg) STANDARD_DEVIATION 13.69 | 131.7 millimeters of mercury (mm Hg) STANDARD_DEVIATION 11.96 | 131.4 millimeters of mercury (mm Hg) STANDARD_DEVIATION 12.82 |
| Urinary Peak Flow Rate (Qmax) | 9.6 milliliters per second (mL/sec) STANDARD_DEVIATION 2.5 | 10.4 milliliters per second (mL/sec) STANDARD_DEVIATION 2.78 | 10.0 milliliters per second (mL/sec) STANDARD_DEVIATION 2.65 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 4 / 50 | 10 / 47 |
| serious Total, serious adverse events | 2 / 50 | 0 / 47 |
Outcome results
Primary
Change From Baseline to 8-Week Endpoint in Arterial Resistive Index (RI) in the Prostate Transition Zone
Arterial RI was a measure of vascular resistance using Doppler ultrasound. RI was the ratio of (peak systolic velocity - end diastolic velocity)/peak systolic velocity, and increased as resistance to blood flow increased. The least squares (LS) mean was estimated from a mixed-effects model with repeated measures (MMRM) that included fixed effects for treatment, region, visit, and treatment-by-visit interaction, baseline as a covariate, a random effect of participant within treatment, and an unstructured covariance matrix.
Time frame: Baseline, Week 8
Population: Randomized participants who received at least 1 dose of study medication, had non-missing data (arterial RI in the prostate transition zone) at baseline, and a post-baseline visit.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to 8-Week Endpoint in Arterial Resistive Index (RI) in the Prostate Transition Zone | -0.01 ratio | Standard Error 0.006 |
| Tadalafil | Change From Baseline to 8-Week Endpoint in Arterial Resistive Index (RI) in the Prostate Transition Zone | 0.00 ratio | Standard Error 0.006 |
p-value: 0.121Mixed-Model Repeated Measures
Secondary
Change From Baseline to 4 and 8 Weeks in Arterial Resistive Index (RI) in the Prostate Peripheral Zone and Bladder Neck
Arterial RI was a measure of vascular resistance using Doppler ultrasound. RI was the ratio of (peak systolic velocity - end diastolic velocity)/peak systolic velocity, and increased as resistance to flow increased. The least squares (LS) mean was estimated from a mixed-effects model with repeated measures (MMRM) that included fixed effects for treatment, region, visit, and treatment-by-visit interaction, baseline as a covariate, a random effect of participant within treatment, and an unstructured covariance matrix.
Time frame: Baseline, Week 4 and Week 8
Population: Randomized participants who received at least 1 dose of study medication.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline to 4 and 8 Weeks in Arterial Resistive Index (RI) in the Prostate Peripheral Zone and Bladder Neck | Week 4 Change, Prostate Peripheral Zone (n=45, 43) | 0.00 ratio | Standard Error 0.006 |
| Placebo | Change From Baseline to 4 and 8 Weeks in Arterial Resistive Index (RI) in the Prostate Peripheral Zone and Bladder Neck | Week 8 Change, Prostate Peripheral Zone (n=43, 38) | -0.01 ratio | Standard Error 0.006 |
| Placebo | Change From Baseline to 4 and 8 Weeks in Arterial Resistive Index (RI) in the Prostate Peripheral Zone and Bladder Neck | Week 4 Change, Bladder Neck (n=30, 30) | -0.01 ratio | Standard Error 0.012 |
| Placebo | Change From Baseline to 4 and 8 Weeks in Arterial Resistive Index (RI) in the Prostate Peripheral Zone and Bladder Neck | Week 8 Change, Bladder Neck (n=32, 26) | 0.01 ratio | Standard Error 0.015 |
| Tadalafil | Change From Baseline to 4 and 8 Weeks in Arterial Resistive Index (RI) in the Prostate Peripheral Zone and Bladder Neck | Week 8 Change, Bladder Neck (n=32, 26) | 0.02 ratio | Standard Error 0.016 |
| Tadalafil | Change From Baseline to 4 and 8 Weeks in Arterial Resistive Index (RI) in the Prostate Peripheral Zone and Bladder Neck | Week 4 Change, Prostate Peripheral Zone (n=45, 43) | 0.01 ratio | Standard Error 0.007 |
| Tadalafil | Change From Baseline to 4 and 8 Weeks in Arterial Resistive Index (RI) in the Prostate Peripheral Zone and Bladder Neck | Week 4 Change, Bladder Neck (n=30, 30) | 0.01 ratio | Standard Error 0.012 |
| Tadalafil | Change From Baseline to 4 and 8 Weeks in Arterial Resistive Index (RI) in the Prostate Peripheral Zone and Bladder Neck | Week 8 Change, Prostate Peripheral Zone (n=43, 38) | 0.01 ratio | Standard Error 0.007 |
p-value: 0.208Mixed-Model Repeated Measures
p-value: 0.066Mixed-Model Repeated Measures
p-value: 0.195Mixed-Model Repeated Measures
p-value: 0.625Mixed-Model Repeated Measures
Secondary
Change From Baseline to 4 and 8 Weeks in Color Pixel Intensity (CPI) in the Prostate Transition Zone, Peripheral Zone, and Bladder Neck
CPI quantified blood flow in a pre-specified region of interest by using color Doppler imaging. CPI was the mean color pixel intensity in the region of interest and scores could range from 0 to 160. An increase in CPI reflected an increase in blood flow. The least squares (LS) mean was estimated from a mixed-effects model with repeated measures (MMRM) that included fixed effects for treatment, region, visit, and treatment-by-visit interaction, baseline as a covariate, a random effect of participant within treatment, and an unstructured covariance matrix.
Time frame: Baseline, Week 4 and Week 8
Population: Randomized participants who received at least 1 dose of study medication.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline to 4 and 8 Weeks in Color Pixel Intensity (CPI) in the Prostate Transition Zone, Peripheral Zone, and Bladder Neck | Week 4 Change, Prostate Transition Zone (n=44, 43) | -2.21 units on a scale | Standard Error 2.377 |
| Placebo | Change From Baseline to 4 and 8 Weeks in Color Pixel Intensity (CPI) in the Prostate Transition Zone, Peripheral Zone, and Bladder Neck | Week 8 Change, Prostate Transition Zone (n=43, 38) | 2.02 units on a scale | Standard Error 1.974 |
| Placebo | Change From Baseline to 4 and 8 Weeks in Color Pixel Intensity (CPI) in the Prostate Transition Zone, Peripheral Zone, and Bladder Neck | Week 4 Change, Prostate Peripheral Zone (n=44, 43) | -1.48 units on a scale | Standard Error 2.059 |
| Placebo | Change From Baseline to 4 and 8 Weeks in Color Pixel Intensity (CPI) in the Prostate Transition Zone, Peripheral Zone, and Bladder Neck | Week 8 Change, Prostate Peripheral Zone (n=43, 38) | 3.11 units on a scale | Standard Error 1.868 |
| Placebo | Change From Baseline to 4 and 8 Weeks in Color Pixel Intensity (CPI) in the Prostate Transition Zone, Peripheral Zone, and Bladder Neck | Week 4 Change, Bladder Neck (n=42, 40) | 7.37 units on a scale | Standard Error 4.022 |
| Placebo | Change From Baseline to 4 and 8 Weeks in Color Pixel Intensity (CPI) in the Prostate Transition Zone, Peripheral Zone, and Bladder Neck | Week 8 Change, Bladder Neck (n=38, 36) | -0.13 units on a scale | Standard Error 3.622 |
| Tadalafil | Change From Baseline to 4 and 8 Weeks in Color Pixel Intensity (CPI) in the Prostate Transition Zone, Peripheral Zone, and Bladder Neck | Week 4 Change, Bladder Neck (n=42, 40) | 3.17 units on a scale | Standard Error 4.14 |
| Tadalafil | Change From Baseline to 4 and 8 Weeks in Color Pixel Intensity (CPI) in the Prostate Transition Zone, Peripheral Zone, and Bladder Neck | Week 4 Change, Prostate Transition Zone (n=44, 43) | 0.42 units on a scale | Standard Error 2.408 |
| Tadalafil | Change From Baseline to 4 and 8 Weeks in Color Pixel Intensity (CPI) in the Prostate Transition Zone, Peripheral Zone, and Bladder Neck | Week 8 Change, Prostate Peripheral Zone (n=43, 38) | 2.55 units on a scale | Standard Error 1.987 |
| Tadalafil | Change From Baseline to 4 and 8 Weeks in Color Pixel Intensity (CPI) in the Prostate Transition Zone, Peripheral Zone, and Bladder Neck | Week 8 Change, Prostate Transition Zone (n=43, 38) | 2.53 units on a scale | Standard Error 2.083 |
| Tadalafil | Change From Baseline to 4 and 8 Weeks in Color Pixel Intensity (CPI) in the Prostate Transition Zone, Peripheral Zone, and Bladder Neck | Week 8 Change, Bladder Neck (n=38, 36) | 7.81 units on a scale | Standard Error 3.738 |
| Tadalafil | Change From Baseline to 4 and 8 Weeks in Color Pixel Intensity (CPI) in the Prostate Transition Zone, Peripheral Zone, and Bladder Neck | Week 4 Change, Prostate Peripheral Zone (n=44, 43) | 1.99 units on a scale | Standard Error 2.091 |
p-value: 0.439Mixed-Model Repeated Measures
p-value: 0.86Mixed-Model Repeated Measures
p-value: 0.24Mixed-Model Repeated Measures
p-value: 0.839Mixed-Model Repeated Measures
p-value: 0.468Mixed-Model Repeated Measures
p-value: 0.131Mixed-Model Repeated Measures
Secondary
Change From Baseline to 4-Week Endpoint in Arterial Resistive Index (RI) in the Prostate Transition Zone
Arterial RI was a measure of vascular resistance using Doppler ultrasound. RI was the ratio of (peak systolic velocity - end diastolic velocity)/peak systolic velocity, and increased as resistance to flow increased. The least squares (LS) mean was estimated from a mixed-effects model with repeated measures (MMRM) that included fixed effects for treatment, region, visit, and treatment-by-visit interaction, baseline as a covariate, a random effect of participant within treatment, and an unstructured covariance matrix.
Time frame: Baseline, Week 4
Population: Randomized participants who received at least 1 dose of study medication, had non-missing data (arterial RI in the prostate transition zone) at baseline, and a post-baseline visit.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to 4-Week Endpoint in Arterial Resistive Index (RI) in the Prostate Transition Zone | 0.00 ratio | Standard Error 0.006 |
| Tadalafil | Change From Baseline to 4-Week Endpoint in Arterial Resistive Index (RI) in the Prostate Transition Zone | 0.01 ratio | Standard Error 0.006 |
p-value: 0.226Mixed-Model Repeated Measures