| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Over active bladder (OAB) in men with Lower Urinary Tract Symptoms (LUTS) due to Benign Prostatic Hyperplasia (BPH) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Over active bladder in men who also have an enlarged prostate with voiding problems |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Male diseases of the urinary and reproductive systems [C12] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10046543 |
| E.1.2 | Term | Urinary incontinence |
| E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
|
| 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 study the efficacy of mirabegron versus placebo in men with OAB symptoms while taking tamsulosin hydrochloride for LUTS due to BPH. |
|
| E.2.2 | Secondary objectives of the trial |
To assess safety and tolerability of mirabegron versus placebo in men with OAB symptoms while
taking tamsulosin hydrochloride for LUTS due to BPH. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Institutional Review Board (IRB)/ Independent Ethics Committee (IEC)-approved written Informed Consent and privacy language as per national regulations (e.g., HIPAA Authorization for US sites) must be obtained from the subject or legally authorized representative prior to any study-related procedures (including withdrawal of prohibited medication, if applicable).
2. Men ≥40 years of age with history of OAB symptoms (urinary frequency and urgency with or without incontinence) while taking tamsulosin hydrochloride 0.4 mg daily for at least 2 months to treat LUTS due to BPH.
3. Subject has symptoms of OAB (frequency of ≥8 micturitions per day and urgency episodes of ≥2 per day) for ≥3 months prior to Screening.
4. Subject has an IPSS score ≥8.
5. Subject has Prostate-Specific Antigen (PSA) <4 ng/mL OR PSA ≥4 but <10 ng/mL with a prostate biopsy that is negative for cancer in the past two years.
6. Subject is willing and able to complete the 3-day diary (including urine volumes, vital sign measurements), and Quality of Life questionnaires.
7. Subject and their spouses/partners who are of childbearing potential must be using a highly effective method of birth control, which includes established use of oral, injected or implanted hormonal methods of contraception, placement of an IUD or IUS. Birth control must be practiced from Screening and continue throughout the study and for 30 days after the final study drug administration. In addition, sperm donation will not be allowed throughout the study and for 30 days after the final study drug administration.
8. Subject agrees not to participate in another interventional study while on treatment.
Inclusion Criteria assessed at Visit 2 (Baseline) based on the 3-day diary:
9. Subject continues to meet all inclusion criteria of Visit 1 (Screening).
10. Subject must experience an average of 8 or more micturitions per day over the 3-day diary period.
11. Subject must experience an average of 2 episodes of urgency per day (grade 3 or 4) over the 3-day diary period.
|
|
| E.4 | Principal exclusion criteria |
1. Subject has PVR >200 mL.
2. Subject has Qmax <5.0 mL/second with a minimum voided volume of 125 mL.
3. Subject has hematuria >3 rbc/hpf that has not been fully evaluated.
4. Subject has evidence of UTI.
5. Subject has neurogenic bladder (spinal cord injury, multiple sclerosis, Parkinson’s etc.).
6. Subject has diabetic neuropathy.
7. Previous open, robotic or minimally invasive prostate surgery (including transurethral
procedures). Planned (scheduled) pelvic or prostate surgery planned during the study
period.
8. Planned (scheduled) cataract surgery during the study period.
9. Subject with significant stress incontinence as determined by the Investigator.
10. Subject with clinically significant bladder outlet obstruction as determined by the
Investigator.
11. Subject has an indwelling catheter or practices intermittent self-catheterization.
12. Subject has experienced 3 or more episodes of recurrent urinary tract infection within the last 12 months.
13. Subject has a symptomatic urinary tract infection, prostatitis, chronic inflammation such as interstitial cystitis, bladder stones, previous pelvic radiation therapy, or previous or current malignant disease of the pelvic organs (i.e., within the confines of the pelvis including the bladder, prostate and rectum; organs of the lower gastrointestinal tract are not necessarily considered pelvic organs as the distal ascending colon, the full transverse colon and proximal portion of the descending colon are in the abdomen).
14. Subject has received intravesical injection in the past 12 months with botulinum toxin, resiniferatoxin, or capsaicin.
15. Subject has ever received electro-stimulation therapy for OAB (e.g. sacral nerve stimulation or Percutaneous Tibial Nerve Stimulation [PTNS]).
16. Subject began or has changed a bladder training program or pelvic floor exercises less than 30 days prior to Screening.
17. Subject has postural hypotension or syncope or postural orthostatic tachycardia.
18. Subject has moderate or severe hepatic impairment defined as Child-Pugh Class B or C.
19. Subject has severe renal impairment defined as estimated creatinine clearance less than 29 mL/min/1.73m2 as determined by central laboratory calculation of eGFR. A subject with End Stage Renal Disease (ESRD) or undergoing dialysis is also not a candidate for the study.
20. Subject has severe uncontrolled hypertension, which is defined as a sitting systolic blood pressure ≥180 mmHg and/or diastolic blood pressure ≥110 mmHg.
21. Subjects has baseline resting pulse rate <60 BPM or >90 BPM.
22. Subject has evidence of QT prolongation on Screening (Visit 1) or Baseline (Visit 2) electrocardiogram (ECG) defined as QTcF >450 msec.
23. Subject has any clinically significant ECG abnormality, as determined by the Investigator.
24. Subject has AST or ALT >2x upper limit of normal (ULN), or y-GT >3x ULN and considered clinically significant by the Investigator.
25. Subject has a hypersensitivity to any components of mirabegron, tamsulosin hydrochloride, or any of the inactive ingredients.
26. Subject has a history of angioedema.
27. Subject has any clinically significant condition, which in the opinion of the Investigator makes the subject unsuitable for study participation.
28. Subject has been treated with an experimental device within 28 days or received an investigational agent within 28 days or 5 half-lives, whichever is longer, prior to Screening.
29. Subject has a concurrent malignancy or history of any malignancy (within the past 5 years), except non-metastatic basal or squamous cell carcinoma of the skin that has been treated successfully.
30. Subject has ongoing alcohol and/or drug abuse.
31. Subject is using prohibited medications defined in Appendix 1, Part A within 30 days prior to Screening (Visit 1) through Follow-Up Phone Call (Visit 6).
32. Subject has stopped, started or changed the dose of a restricted medication (defined in Appendix 1, Part B) within 30 days prior to Screening (Visit 1) through Follow-Up Phone Call (Visit 6).
33. Subject has participated in an interventional trial within 30 days prior to Screening (Visit 1).
34. Subject is involved in the conduct of the study as an employee of the Astellas group, third party associated with the study, or the study site team.
35. Subject has previously received mirabegron in the 6 months prior to Screening (Visit 1).
Exclusion Criteria assessed at Visit 2 (Baseline):
36. Subject was non-compliant during the 4-week tamsulosin hydrochloride run-in period, defined as taking less than 80% or greater than 120% of study medication.
37. Subject had an average total daily urine volume >3000mL as recorded in the 3-day diary. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from Baseline (Visit 2) to Week 12/ End of Treatment (Visit 5) in mean number of micturitions per day based on a 3-day diary. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
● Change from Baseline (Visit 2) to Week 4, Week 8, and Week 12/End of Treatment (Visit 5) in mean volume voided per micturition.
● Change from Baseline (Visit 2) to Week 4, Week 8, and Week 12/End of Treatment (Visit 5) in mean number of incontinence episodes per day (FAS-I).
● Change from Baseline (Visit 2) to Week 4, Week 8, and Week 12/End of Treatment (Visit 5) in mean number of urgency episodes (grade 3 and 4) per day.
● Change from Baseline (Visit 2) to Week 4, Week 8, and Week 12/End of Treatment (Visit 5) in IPSS total score and subscales (Voiding, Storage, and Quality of Life).
● Change from Baseline (Visit 2) to Week 4, Week 8, and Week 12/End of Treatment (Visit 5) in mean number of urgency incontinence episodes per day (FAS-I).
● Change from Baseline (Visit 2) to Week 4, Week 8, and Week 12/End of Treatment (Visit 5) in Symptom Bother Total Health Related Quality of Life and subscale
(coping, concern, sleep, social interaction, and symptom bother) scores as assessed by OAB-q questionnaire.
● Change from Baseline (Visit 2) to Week 4, Week 8, and Week 12/End of Treatment (Visit 5) as assessed by EQ-5D-5L questionnaire.
● Change from Baseline (Visit 2) to Week 4, Week 8, and Week 12/End of Treatment (Visit 5) in PPBC.
● Change from Baseline (Visit 2) to Week 4, Week 8, and Week 12/End of Treatment (Visit 5) in Total Urgency and Frequency Score (TUFS) using PPIUS (Grade 3 or 4).
● Change from Baseline (Visit 2) to Week 4, Week 8, and Week 12/End of Treatment (Visit 5) in mean number of nocturia episodes per day.
● Change from Baseline (Visit 2) to Week 4, Week 8, and Week 12/End of Treatment (Visit 5) in TS-VAS scores.
● Change from Baseline (Visit 2) to Week 4, Week 8, and Week 12/End of Treatment (Visit 5) in the number of protective garments (e.g. absorbent pads, incontinence
briefs, disposable underwear). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| 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) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| 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.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| 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 | No |
| 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 |
|
| 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
|
| The end of trial in all participating countries is defined as the Last Subject’s Last Visit. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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