E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Primary treatment of the signs and symptoms of benign prostatic hyperplasia in men (also referred to as BPH-LUTS [lower urinary tract symptoms]). BPH-LUTS include urinary frequency, urgency, intermittency, nocturia, straining, incomplete emptying, and weak urinary stream. |
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MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To test the hypothesis that tadalafil 5 mg once a day for 12 weeks is superior to placebo in improving the International Prostate Symptom Score (IPSS) in men with signs and symptoms of benign prostatic hyperplasia. |
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E.2.2 | Secondary objectives of the trial |
• To examine whether a dose-response relationship exists for placebo and tadalafil 2.5 mg, 5 mg, 10 mg, and 20 mg once a day for 12 weeks in the treatment of BPH-LUTS. • To test the hypothesis that tadalafil 5 mg once a day for 12 weeks is superior to placebo in the treatment of BPH-LUTS. • To examine the impact of tadalafil once a day on erectile function in men with both BPH-LUTS and ED, as assessed by the International Index of Erectile Function (IIEF) Erectile Function Domain. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
[1] Present with BPH-LUTS based on the disease diagnostic criteria at Visit 1. [2] Are men 45 years of age or older at Visit 1. [3] Provide signed ICD at Visit 1. [4] Agree not to use any other approved or experimental pharmacologic BPH or ED treatments, including alpha blockers, 5-alpha reductase inhibitors, PDE5 inhibitors, or herbal preparations at any time during the study. [5] Have not taken the following treatments within the indicated duration: [a] Finasteride therapy for at least 3 months prior to Visit 2. [b] Dutasteride therapy for at least 12 months prior to Visit 2. [c] All other BPH therapy (including herbal preparations) for at least 4 weeks prior to Visit 2. [d] ED therapy for at least 4 weeks prior to Visit 2. [6] Have LUTS with a total IPSS ≥13 at Visit 2. [7] Have bladder outlet obstruction as defined by a urinary peak flow rate (Qmax) of ≥4 to ≤15 mL/second (from a prevoid total bladder volume [assessed by ultrasound] of ≥150 to ≤550 mL and a minimum voided volume of 125 mL) at Visit 2. [8] Demonstrate compliance with study drug administration requirements during the placebo run-in period by administering ≥70% of prescribed doses, confirmed by documentation that the subject returned ≤30% of prescribed doses at Visit 3. |
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E.4 | Principal exclusion criteria |
[9] PSA >10.0 ng/mL at Visit 1. [10] PSA ≥4.0 to ≤10.0 ng/mL at Visit 1 without documentation of a histologic biopsy of the prostate negative for cancer within 12 months of Visit 1. [11] Bladder PVR ≥300 mL by ultrasound determination at Visit 1. [12] History of any of the following pelvic conditions: [a] Pelvic surgery or any other pelvic procedure, including radical prostatectomy, pelvic surgery for removal of malignancy, or bowel resection. [b] Pelvic radiotherapy. [c] Any pelvic surgical procedure on the urinary tract, including penile implant surgery. [d] Lower urinary tract malignancy or trauma. [13] Lower urinary tract instrumentation (including prostate biopsy) within 30 days of Visit 1. [14] History of urinary retention or lower urinary tract (bladder) stones within 6 months of Visit 1. [15] History of urethral obstruction due to stricture, valves, sclerosis, or tumor. [16] Clinical evidence of any of the following bladder conditions: [a] Mullerian duct cysts. [b] Bladder calculi. [c] Atonic or hypocontractile bladder. [d] Detrusor-sphincter dyssynergia (contraction of the detrusor without sphincter relaxation). [17] Clinical evidence of any of the following urinary tract conditions at Visit 1: [a] Urinary tract infection. [b] Urinary tract inflammation (including prostatitis). [c] Current antibiotic therapy for urinary tract infection. Urinary tract infection/inflammation is defined as a positive result for leukocyte esterase from a urine dipstick or >5 WBC per high powered field on urinalysis from a centrifuged, clean-catch, midstream urine specimen. [18] Intravesical obstruction (for example, intravesical median lobe of the prostate). [19] Clinical evidence of prostate cancer. [20] Current neurologic disease or condition associated with neurogenic bladder (eg, Parkinson’s disease, multiple sclerosis). [21] History of significant renal insufficiency, defined as receiving renal dialysis or having an estimated creatinine clearance <50 mL/min at Visit 1 as calculated by the central laboratory using the Cockroft-Gault formula: (140 - age [years]) × weight [kg] / (72 × serum creatinine [mg/dL]) [22] Clinical evidence of hepatic impairment at Visit 1. [23] History of any of the following cardiac conditions: [a] Angina requiring treatment with long-acting nitrates. [b] Angina requiring treatment with short-acting nitrates within 90 days of Visit 1. [c] Unstable angina as defined in Protocol Attachment LVHG.2 (Braunwald 1989) within 90 days of Visit 1. [d] Positive cardiac stress test without documented evidence of subsequent, effective cardiac intervention. [24] History of any of the following coronary conditions within 90 days of Visit 1: [a] Myocardial infarction. [b] Coronary artery bypass graft surgery. [c] Percutaneous coronary intervention (for example, angioplasty or stent placement). [25] Any evidence of heart disease (NYHA ≥Class III as defined in Protocol Attachment LVHG.3) within 6 months of Visit 1. [26] Systolic blood pressure >160 or <90 mm Hg or diastolic blood pressure >100 or <50 mm Hg at Visit 1 (if stress is suspected, retest under basal conditions), or malignant hypertension. [27] Scheduled or planned surgery (or any procedure requiring general anesthesia) during the course of the study. [28] History of significant central nervous system (CNS) injuries (including stroke or spinal cord injury) within 6 months of Visit 1. [29] History of drug, alcohol, or substance abuse within 6 months of Visit 1. [30] Any condition that would interfere with subject ability to provide informed consent or comply with study instructions, would place subject at increased risk, or might confound the interpretation of the study results. [31] Current treatment with nitrates (as outlined in Exclusion Criterion [23]), cancer chemotherapy, androgens, antiandrogens, estrogens, LHRH agonists/antagonists, or anabolic steroids. [32] Current systemic treatment with a potent cytochrome P450 3A4 (CYP3A4) inhibitor, such as ketoconazole or ritonavir. [33] Glycosylated hemoglobin (HbA1c) >9% at Visit 1. [34] Investigators, site personnel directly affiliated with this study, and their immediate families (defined as a spouse, parent, child, or sibling, whether biological or legally adopted). [35] Employed by Lilly or ICOS (that is, employees, temporary contract workers, or designees responsible for the conduct the study) and their immediate families. [36] Previously completed or withdrawn from this study or any other study investigating tadalafil. [37] Received treatment within the last 30 days with a drug or device that has not received regulatory approval for any indication at the time of Visit 1. [38] History of loss of vision in one eye because of nonarteritic anterior ischemic optic neuropathy (NAION), regardless of whether this episode was in connection or not with previous PDE5 inhibitor exposure. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the change in total IPSS change from baseline to Week 12. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 48 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 13 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 15 |