| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Adult men and women with either:
•OAB Wet
• OAB Dry
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Symptoms and general pathology [C23] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10059617 |
| E.1.2 | Term | Overactive bladder |
| E.1.2 | System Organ Class | 100000004857 |
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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 |
Primary Efficacy Objective: To evaluate the efficacy of vibegron compared to placebo in patients with symptoms of OAB, specifically the frequency of micturitions and frequency of urge urinary incontinence episodes
Primary Safety Objective: To evaluate the safety and tolerability of treatment with vibegron |
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| E.2.2 | Secondary objectives of the trial |
Secondary Efficacy Objective: To evaluate the overall efficacy of vibegron compared to placebo in patients with symptoms of OAB
Exploratory Objective: To evaluate the effect of vibegron compared with placebo in patients with symptoms of OAB on patient-perceived outcomes
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Pharmacokinetic (PK) sub-study - protocol v2.1 dated 12Feb2018
PK sub-study objectives:
* To evaluate the pharmacokinetic profile of vibegron in patients with symptoms of OAB
* To assess relationships between exposure and efficacy/safety in patients with symptoms of OAB receiving vibegron
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| E.3 | Principal inclusion criteria |
1. Willing and able to provide written informed consent.
2. Males or females ≥ 18 years of age. Note: Up to 15% of patients can be male.
3. Has a history of OAB (as diagnosed by a physician) for at least 3 months prior to the Screening Visit. Note: OAB is defined as urgency, with or without urge urinary incontinence (UUI), usually associated with frequency and nocturia. Urodynamic evaluation is not required.
4. Meets either the OAB Wet or OAB Dry criteria described below, based on the Patient Voiding Diary returned both at the Run-in Visit and Baseline Visit (all Complete Diary Days must be used in determining eligibility). A minimum of 6 Complete Diary Days [not necessarily consecutive] are required for the diary returned at the Run-in Visit, and 4 Complete Diary Days are required for the diary returned at the Baseline Visit. Averages should not be rounded up to the whole number:
• OAB Wet criteria:
o An average of ≥ 8.0 micturitions per Diary Day; and
o An average of ≥ 1.0 UUI episodes per Diary Day; and
o If stress urinary incontinence is present, the total number of UUI episodes must be greater than the total number of stress urinary incontinence episodes from the previous visit diary.
• OAB Dry criteria:
o An average of ≥ 8.0 micturitions per Diary Day; and,
o An average of ≥ 3.0 urgency episodes per Diary Day; and
o An average of < 1.0 UUI episodes per Diary Day; and
o If stress urinary incontinence is present, the total number of UUI episodes must be greater than the total number of stress urinary incontinence episodes from the previous visit diary.
Note: Up to 25% of patients that meet OAB Dry criteria may be enrolled.
5. For females of reproductive potential: Agrees to remain abstinent or use (or have their male partner use) an acceptable method of birth control (as defined in Section 5.2.1) each time the patient has intercourse from the Screening Visit until completion of the Follow-up Visit.
6. For females of reproductive potential: Agrees not to donate ova (eggs) until at least 1 month after the last dose of Study Treatment.
7. Has demonstrated ≥ 80% compliance with self-administration of Study Treatment during the Run-in Period.
8. Is ambulatory and in good general physical and mental health as determined by the Investigator.
9. In the opinion of the Investigator, is able and willing to comply with the requirements of the protocol, including completing electronic versions of questionnaires, the Patient Voiding Diary, and the Urine Volume Diary (will require ability to collect, measure, and record voided volume by herself/himself using a graduated urine collection and measurement container [provided by the Sponsor, if needed]).
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| E.4 | Principal exclusion criteria |
Urology Medical History
1. Patient has a history of 24-hour urine volume greater than 3,000 mL in the past 6 months, or a Urine Volume Diary day measurement greater than 3,000 mL during the Run-in Period.
2. Has lower urinary tract pathology that could, in the opinion of the Investigator, be responsible for urgency, frequency, or incontinence; including, but not limited to, urolithiasis, interstitial cystitis, prostate cancer, gastrointestinal (GI) cancer, tuberculosis, stone disease, urothelial tumor, prostatitis, and clinically relevant benign prostatic hypertrophy (BPH) or bladder outlet obstruction, as judged by the Investigator. Note: Male patients with mild to moderate BPH without evidence of bladder obstruction as determined by the Investigator may be included as long as they have been taking a medication for the treatment of BPH for at a least 1-year prior to Screening, with no change in dose of herbal medications, alpha antagonist medications or other symptomatic treatments or medications within 3 months prior to Screening, and no change in dose of 5 alpha reductase inhibitors within 6 months of Screening.
3. Has a history of surgery to correct stress urinary incontinence, pelvic organ prolapse, or procedural treatments for BPH within 6 months of Screening.
4. Has current history or evidence of Stage 2 or greater pelvic organ prolapse (prolapse extends beyond the hymenal ring).
5. Patient is currently using a pessary for the treatment of pelvic organ prolapse.
6. Has a known history of elevated post-void residual volume defined as greater than 150 mL.
7. Has undergone bladder training or electrostimulation within 28 days prior to Screening or plans to initiate either during the study.
8. Has an active or recurrent (> 3 episodes per year) urinary tract infection by clinical symptoms or laboratory criteria (≥ 5 white blood cells [WBC] or a positive urine culture, defined as ≥ 105 colony forming units [CFU]/mL in 1 specimen). Patients diagnosed with a urinary tract infection (UTI) at the Screening Visit may be treated and re-screened once the infection has resolved.
9. Has a requirement for an indwelling catheter or intermittent catheterization.
10. Has received an intradetrusor injection of botulinum toxin within 9 months prior to Screening.
Please refer to protocol for other exclusion criteria (Other Medical History, Laboratory/Procedure History, Medical History and Other) |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Efficacy Endpoints:
* Change from baseline (CFB) at Week 12 in average number of micturitions per 24 hours in all OAB patients
* CFB at Week 12 in average number of urge urinary incontinence (UUI) episodes per 24 hours in OAB Wet patients
Primary Safety Endpoints:
* Incidence of adverse events
* Clinical laboratory assessments
* Vital signs and physical examinations
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Secondary Efficacy Endpoints:
* CFB at Week 12 in average number of urgency episodes (need to urinate immediately) over 24 hours in all OAB patients
* Percent of OAB Wet patients with at least a 75% reduction from baseline in UUI episodes per 24 hours at Week 12
* Percent of OAB Wet patients with a 100% reduction from baseline in UUI episodes per 24 hours at Week 12
* Percent of all OAB patients with at least 50% reduction from baseline in urgency episodes (need to urinate immediately) per 24 hours at Week 12
* CFB at Week 12 in average number of total incontinence episodes over 24 hours in OAB Wet patients
* CFB at Week 12 in Coping Score from the Overactive Bladder Questionnaire Long Form (OAB-q LF, 1-week recall) in all OAB patients
* CFB at Week 12 in average volume voided per micturition in all OAB patients
Additional secondary efficacy endpoints are described in the protocol
Exploratory Endpoints:
* Percent of OAB Wet patients with a 100% reduction from baseline in UUI episodes per 24 hours at Weeks 2, 4, and 8
* Percent of all OAB patients with at least a 50% reduction from baseline in urgency episodes (need to urinate immediately) per 24 hours at Weeks 2, 4, and 8
* Percent of all OAB patients with average number of micturitions < 8 per 24 hours at Weeks 2, 4, and 8
* Percent of OAB Wet patients with at least a 50% reduction from baseline in total incontinence episodes per 24 hours at Weeks 2, 4, and 8
* CFB at Weeks 2, 4, and 8 in average daily number of micturitions in all OAB patients
* CFB at Weeks 2, 4, and 8 in average daily number of UUI episodes in OAB Wet patients
* CFB at Weeks 2, 4, and 8 in average number of urgency episodes (need to urinate immediately) over 24 hours in all OAB patients
* CFB at Weeks 2, 4, and 8 in average number of total incontinence episodes over 24 hours in OAB Wet patients
* CFB in percent of dry Diary Days (zero total incontinence episodes) at Week 12 in OAB Wet patients
* CFB at Week 12 in total score of the Work Productivity and Activity Impairment Questionnaire-Urinary Symptoms (WPAI-US) in all OAB patients
* CFB at Week 12 in scores of the European Quality of Life-5 Dimension (EQ-5D) in all OAB patients
* CFB at Week 12 in overall symptom frequency based on Patient Global Impression of Symptom Frequency (PGI-Frequency) in all OAB patients
* CFB at Week 12 in overall urgency-related leakage over bladder symptoms based on Patient Global Impression of Urgency-Related Leakage (PGI-Leakage) in all OAB Wet patients
* Overall change of bladder symptoms based on Patient Global Impression of Change (PGI-Change) in all OAB patients at Week 12
* CFB at Week 12 in Concern Score from the OAB-q LF (1-week recall) in all OAB patients
* CFB at Week 12 in Sleep Score from the OAB-q LF (1-week recall) in all OAB patients
* CFB at Week 12 in Social Interaction Score from the OAB-q LF (1- week recall) in all OAB patients
* CFB at Weeks 2, 4, 8, and 12 in average number of nighttime voids for all patients
* CFB at Weeks 2, 4, 8, and 12 in number of Nighttime UUI for all OAB Wet patients with at least 1 Nighttime UUI at baseline
* For all OAB patients with ≥ 1 nighttime voids associated with urgency (NVU) at baseline, CFB at Weeks 2, 4, 8, and 12 in the average number of NVU per 24 hours
* Examination of the correlation between diary endpoints and PGI questions |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
| 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) | 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.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 92 |
| 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 |
| Canada |
| Hungary |
| Latvia |
| Lithuania |
| Poland |
| United States |
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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 | 20 |
| 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 | 20 |
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