| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10004446 |
| E.1.2 | Term | Benign prostatic hyperplasia |
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| 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 assess the efficacy of fixed dose combinations of tamsulosin OCAS 0.4 mg and solifenacin (6 mg and 9 mg) in comparison with tamsulosin OCAS 0.4 mg monotherapy in male subjects with LUTS associated with BPH with a substantial storage component. |
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| E.2.2 | Secondary objectives of the trial |
To assess the safety and tolerability of fixed dose combinations of tamsulosin OCAS 0.4 mg and solifenacin (6 mg and 9 mg) in male subjects with LUTS associated with BPH with a substantial storage component;
To assess the efficacy of fixed dose combinations of tamsulosin OCAS 0.4 mg and solifenacin (6 mg and 9 mg) in comparison with placebo in male subjects with LUTS associated with BPH with a substantial storage component.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
At study entry (Visit 1):
1. Male subjects aged ≥45 years.
2. Written informed consent has been obtained.
3.Subject is willing and able to complete the micturition diary and questionnaires correctly.
4. Voiding symptoms (including incomplete emptying of the bladder, intermittency, weak stream or hesitancy) and storage symptoms (including frequency and urgency), diagnosed as LUTS associated with BPH for ≥3 months.
5. Total I-PSS of ≥13.
6. Substantial amount of storage symptoms for ≥3 months (at the discretion of the investigator, expected to have a micturition frequency of ≥8 and at least 2 episodes of urgency with PPIUS grade 3 or 4 per day).
7. A maximum urinary flow rate of ≥4.0 mL/s and ≤12.0 mL/s, with a voided volume of ≥120 mL during free flow.
At randomization (Visit 2):
8. Total I-PSS of ≥13.
9. Maximum urinary flow rate of ≥4.0 mL/s and ≤12.0 mL/s, with a voided volume of ≥120 mL during free flow.
10. A micturition frequency of ≥8 and at least 2 episodes of urgency (PPIUS grade 3 or 4) per day on average during the 3 day micturition diary.
11. Subject continues to meet all inclusion criteria of Visit 1.
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| E.4 | Principal exclusion criteria |
At study entry (Visit 1):
1. Any significant PVR volume (>150 mL).
2. Prostate with estimated weight ≥75 g as assessed by transvesical or transrectal ultrasound.
3. Evidence of symptomatic urinary tract infection or known history or diagnosis of any of the following urinary conditions:
- Recurrent symptomatic urinary tract infection defined as 2 or more episodes of such infection occurring in preceding 12 months,
- Urological Pain Syndromes as classified by the EAU Guideline on Chronic Pelvic Pain, update 2008, such as interstitial cystitis including bladder pain syndrome, urethral pain syndrome, penile pain syndrome, prostate pain syndrome, scrotal pain syndrome, testicular pain syndrome, post vasectomy pain and epididymal pain syndrome,
- Chronic prostatitis comprising type A (inflammatory) and type B (noninflammatory),
- Evidence of current symptomatic or asymptomatic urolithiasis
- Previous or current malignant disease of pelvic and urogenital organs with exception of carcinoma of bladder if longer than 5 years recurrence-free,
- Previous pelvic radiation therapy,
- Previous surgery to bladder neck or prostate,
- Bladder neck stenosis,
- Urethral stricture.
4. Narrow angle glaucoma, myasthenia gravis, severe gastrointestinal condition (incl. toxic megacolon), hiatal hernia, gastroesophageal reflux or subject is at risk for these conditions; urinary or gastric retention or any other medical condition, which in the opinion of the investigator presents a contraindication for the use of anticholinergics.
5. Clinically significant significant cardiovascular or cerebrovascular diseases within 6 months prior to Visit 1, such as myocardial infarction, uncontrolled angina, significant ventricular arrhythmias, heart failure (NYHA class III/IV) and stroke.
6. Any other cardiovascular or cerebrovascular diseases such as a clinically relevant history of orthostatic hypotension which in the opinion of the investigator makes the subject unsuitable for participation in study.
7. Non-drug treatment for LUTS associated with BPH or OAB, including electrostimulation therapy at start of the study or start of a bladder training program during the 2 weeks prior to or during the study.
8. Use of prohibited concomitant medication
- Other pharmacological treatment used for LUTS/BPH, such as alpha-adrenoceptor (α-AR)-antagonists and plant extracts.
- 5α-reductase inhibitors (within 3 months prior to Visit 1),
- Other drugs which may influence the pharmacodynamic effects of solifenacin or tamsulosin, phosphodiesterase type 5 (PDE5) inhibitors, anticholinergics, or CYP 3A4 inhibitors or inducers that may influence the PK of solifenacin or tamsulosin.
9. Use of combined α/ß-AR-antagonists, α2-agonists, oral and systemic β-agonists, cholinergics and any drugs with cholinergic or anticholinergic side effects, or diuretics However, long term therapy (>1 month prior to randomization) with a stable dosage of these drugs is permitted.
10. Diabetic neuropathy.
11. Planned cataract surgery during Study 905-CL-055 or Study 905-CL-057 or within 30 days after completion of any of the studies.
12. Severe renal impairment (including hemodialysis) or moderate or severe hepatic impairment.
13. Known polyuria.
14. Known or suspected hypersensitivity to solifenacin, other anticholinergics, tamsulosin (including drug-induced angioedema), other α-AR-antagonists, lactose or any of the other excipients of study medication.
15. Any clinically significant condition, which in the opinion of the investigator makes the subject unsuitable for the trial.
16. Participation in any clinical trial within 30 days (or limit set by national law, whichever is longer) prior to randomization.
17. Employee of Astellas Group, of CROs involved, or of investigator site executing study.
At randomization (Visit 2):
18. Subject did not complete micturition diary or I-PSS questionnaire according to instructions.
19. Significant PVR volume (PVR >150 mL).
20. Total daily urine volume >3 L/day on any day during the 3 days of micturition diary.
21. Any clinically significant abnormal ECG, which in the opinion of the investigator makes the subject unsuitable for the trial.
22. Severe renal impairment, including hemodialysis (creatinine clearance <30 mL/min using the calculation included in Section 5.4.4 of this protocol or on http://nephron.com/cgi-bin/CGSI.cgi) or moderate or severe hepatic impairment ALAT, ASAT outside 2 times the normal range, gamma GT outside 3 times the normal range).
23. Any other clinically significant out of normal range result of urinalysis, biochemistry (including prostate specific antigen [PSA]) or hematology, which in the opinion of the investigator makes the subject unsuitable for the trial.
24. Subject fulfills any exclusion criteria of Visit 1.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary endpoint 1: change from baseline to endpoint in total I-PSS.
Primary endpoint 2: change from baseline to endpoint in Total Urgency Score (TUS, from micturition diary) |
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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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| 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) | Yes |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 19 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 130 |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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