Efficacy and Safety Evaluating Study to Compare Uritos® (Imidafenacin) and Urotol® (Tolterodine) for Treatment of Overactive Bladder.

International, Multicenter, Open-label, Randomized, Comparative Clinical Study of Efficiency and Safety of Medicinal Product Uritos® (Imidafenacin, Film-coated Tablets; 0,1 mg, Kyorin Pharmaceutical Co. Ltd, Japan) and Urotol® (Tolterodine, Film-coated Tablets 2 mg, Zentiva k.s., Czech Republic) for Treatment of Overactive Bladder

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03575702

Enrollment

300

Registered

2018-07-02

Start date

2016-07-18

Completion date

2017-09-01

Last updated

2019-05-21

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Overactive Bladder

Keywords

overactive bladder, urinary incontinence, frequent urination, urge incontinence, urgency episodes

Brief summary

Objective of this study was confirmation on non-inferiority and validation of similar safety profile of new anti-muscarinic medicinal product Uritos® (Imidafenacin) in comparison with other product from m-cholinergic antagonists group Urotol® (Tolterodine).

Detailed description

To assess clinical efficiency and safety of Uritos® (Imidafenacin) in comparison to Urotol® (Tolterodine) according to its influence on urination frequency and number of urinary incontinence episodes a total of 327 patients underwent screening and 300 patients were randomized (150 patients in the Uritos® group and 150 patients in the Urotol® group). Screening period was not exceeding 2 weeks (14 days). Therapy was performed during 12 weeks (84 days). Every patient received only one treatment (Uritos® or Urotol®) during the treatment period. Patients were returning to the trial site to assessment visits on Weeks 2, 4, 8 and 12 with permissible variation ± 3 days. Observation period after the end of treatment - 30 ± 5 days (could be performed through telephone connection without need for physician appointment by patient). Maximum observation period: 136 days. Efficacy and safety parameters were assessed as per primary and secondary endpoints. The results of this study could potentially provide new optimum approaches to OAB treatment.

Interventions

DRUGUritos®

film-coated tablets 0.1 mg

DRUGUrotol®

film coated tablets, 2 mg

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 65 Years

Healthy volunteers

Inclusion criteria

1. Signed dated informed consent. 2. Confirmed overactive bladder (OAB). The OAB diagnosis was made based on characteristic symptoms of the patient: 1. urinary incontinence - 5 or more episodes a week; 2. frequent urination - 8 or more times a day; 3. imperative urination urge - 1 or more episodes a day. 3. The duration of the presence of OAB symptoms is 3 months or more (the assessment is based on patient's history and medical records). 4. Overactive bladder Awareness Tool Questionnaire (OAB Awareness Tool) score 8 and more at the screening visit and randomization visit. 5. Negative result of the urine pregnancy test at the screening and the randomization visit before receiving the first dose of the study drug in women of childbearing potential. 6. Female patients of childbearing potential and male patients and their female partners should use at least two birth control methods, one of those is barrier, during the entire study period and for at least 35 days following administration of the last dose of the study product. Acceptable methods of contraception: * oral, transdermal, implantation or injection hormone therapy; * effective intrauterine devices; * double barrier contraceptive methods. 7. Willingness and ability to follow the study visits schedule, treatment plan, laboratory tests and other study procedures.

Exclusion criteria

1. A history of hypersensitivity or suspected hypersensitivity to tolterodine or imidafenacin. 2. Structural abnormalities of the bladder, including bladder cancer, bladder stones, interstitial cystitis. 3. The volume of residual urine is 100 ml or more with bladder ultrasound. 4. Documented diagnosis of stress urinary incontinence. 5. Operative interventions on the bladder or urethra within the previous 6 months or indications for surgical treatment for OAB. 6. Exacerbation of gynecological diseases including endometriosis, uterine leiomyoma exceeding 3 cm in diameter. 7. Prostate cancer. 8. Prostate diseases with clinically significant urodynamics abnormality (benign prostatic hyperplasia, acute and chronic prostatitis, prostatic calculus). 9. Renal and urinary inflammatory disorders (pyelonephritis, bacterial cystitis, urethritis). 10. For male, the prostatic specific antigen (PSA) level above 4 ng/mL. 11. Severe liver impairment alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) level 3 and more times exceeding the upper limit of normal and/or total bilirubin level 1.5 times exceeding the upper limit of normal. 12. Moderate or severe renal impairment based on the medical records and/or glomerular filtration rate \< 50 mL/min determined by Cockroft-Gault formula and/or blood creatinine level \> 133 μmol/L at screening. 13. A positive test result for hepatitis B, hepatitis C and human immunodeficiency virus (HIV). 14. Patients suffering from a neoplastic condition without remission at least within 5 years from the start of administration of the study product. 15. Vascular dementia, dementia in Alzheimer's disease, dementia in other diseases, including organic amnestic syndrome. 16. Parkinson's disease or secondary parkinsonism. 17. Nonspecific ulcerative colitis, including severe ulcerative colitis. 18. Thyroid disorders with hyperthyroidism signs. 19. Chronic heart insufficiency Stage III-IV by New York Heart Association Chronic heart insufficiency classification (NYHA). 20. Hypotension: systolic blood pressure (SBP) \< 90 mm Hg and/or diastolic blood pressure (DBP) \< 60 mm Hg. 21. Uncontrolled medically induced hypertension. 22. Hemodynamically and/or clinically significant heart arrhythmias. 23. QTc prolongation up to 450 ms and more in men and 470 ms and more in women. 24. Open-angle glaucoma. 25. Myasthenia gravis. 26. Megacolon, paralytic ileus, pyloric part of the stomach/duodenal occlusion and any other conditions associated with clinically significant gastric/intestinal obstruction or depressed motility. 27. Necessity of intake and/or intake of prohibited products listed in the Section Acceptable and prohibited recent and concomitant therapy within 7 days before the start of therapy. 28. Drug abuse, chronic alcoholism, any psychotic disorders. 29. Participation in other studies within 3 months prior to the beginning of the current study and/or during participation in this study. 30. Pregnancy and/or breastfeeding. 31. Female patients of childbearing potential, having an unprotected sexual contact with a male person non-sterilized by vasectomy during at least 6 months, within 14 days before administration of the study product. 32. Inability to follow protocol procedures. 33. Any other acute or exacerbation and/or decompensation of chronic diseases at inclusion in the study. 34. Patient's behavior, any safety reasons, clinical and administrative reasons, which, according to Investigator's opinion, may potentially affect the study drug safety/efficiency assessment. 35. Other medical and psychiatric conditions or deviations of laboratory parameter which may increase patient risk associated with participation in the study or administration of the study product, or which can influence the interpretation of the study results and, according to Investigator's opinion, make a person ineligible for participation in this study. 36. Patients who are employees of the study site or patients who are employees of the Sponsor/Contract Research Organization (CRO), directly involved in this clinical trial.

Design outcomes

Primary

Measure	Time frame	Description
Change in the Mean Daily Number of Urination Episodes at Week 12	Baseline and Week 12	The mean daily number of urination episodes was calculated as the total number of episodes (on the basis of the data that patients entered into their diaries) per day (from 7 am to 7 am the next day) for the study period (between visits) divided by the number of days in the period.

Secondary

Measure	Time frame	Description
Change in the Mean Daytime Number of Incontinence Episodes at Week 12	Baseline and Week 12	The mean daytime number of incontinence episodes was calculated as the total number of episodes from 7 am to 11 pm for the study period (between visits) divided by the number of days in the period.
Change in the Mean Nighttime Number of Incontinence Episodes at Week 12	Baseline and Week 12	The mean nighttime number of incontinence episodes was calculated as the total number of episodes from 11 pm to 7 am for the study period (between visits) divided by the number of days in the period.
Change in the Mean Number of Incontinence Episodes at Week 2, 4 and 8	Baseline and Week 2, 4 and 8	Separately for daily, daytime and nighttime measurements.
Change in the Mean Weekly Number of Incontinence Episodes at Week 12	Baseline and Week 12	The mean weekly number of incontinence episodes was calculated as the total number of episodes per day (from 7 am to 7 am the next day) for the study period (between visits) divided by the number of weeks in the period.
Change in the Mean Daily Number of Urination Episodes at Week 2, 4 and 8 Visit as Compared to the Treatment Initiation Visit	Baseline and Week 2, 4 and 8	The mean daily number of incontinence episodes was calculated as the total number of episodes (on the basis of the data that patients entered into their diaries) per day (from 7 am to 7 am the next day) for the study period (between visits) divided by the number of days in the period.
Changes in the Overactive Bladder Symptom Score According to Overactive Bladder (OAB) Awareness Tool Questionnaire at 2, 4, 8 and 12 Week	Baseline and Week 2, 4, 8 and 12	Overactive bladder (OAB) Awareness Tool Questionnaire (version OAB-V8, containing 8 questions) is a validated questionnaire. Patient is asked to answer 8 questions concerning typical symptoms of OAB giving answers with a scale with minimum - 0 score defined as no bothering at all and maximmum - 5 score defined as a very big deal to assess the severity of these symptoms. All answers are simply summed to make a combined final score. Male participants should add 2 points to their final score. The final scores range from 0 to 40 (for women) and 42 (for men). The score equal to 8 and more is interpreted as high probability of OAB presence, with the higher scores indicating more bothersome symptoms of OAB.
Change in the EQ-5D-based Quality of Life at Week 12	Baseline and Week 12	The Euro Quality of Life five Dimensions questionnaire ( EQ-5D, version EQ-5D-5L) is a validated questionnaire for the assessment of health-related quality of life. It consists of a questionnaire and a visual analogue scale (EQ-VAS). The self-assessment questionnaire is self-reported description of the subject's current health in 5 dimensions i.e., mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The subject is asked to assess their own current level of function in each dimension by 5-level scale from no problems to significant problem grades. The EQ-VAS is a self-rated health status using a VAS in mm from 0 (the worse health status) to 100 (the best health status). The EQ-VAS records the subject's perceptions of their own current overall health quantitatively in mm and can be used to monitor changes with time. The results of patients assessment by VAS are presented.
Change in the Mean Daily Number of Incontinence Episodes at Week 12	Baseline and Week 12	The mean daily number of incontinence episodes was calculated as the total number of episodes (on the basis of the data that patients entered into their diaries) per day (from 7 am to 7 am the next day) for the study period (between visits) divided by the number of days in the period.

Other

Measure	Time frame	Description
Changes in the Volume of Residual Urine	Baseline and Week 4, 8 and 12	Measured via the urine bladder ultrasound (US)
Number of Patients With Clinically Significant Changes in Laboratory Parameters	Week 8 and 12	Including blood chemistry, blood count and urinalysis
Number of Patients With Clinically Significant Changes in ECG Parameters	Week 12 of treatment	—
Number of Patients With Clinically Significant Vital Signs Changes	Week 12 of treatment	—
Number of Patients With Serious Adverse Events (SAEs)	Up to 35 days after the end of treatment	—
Number of Patients With Adverse Events (AEs)	Up to 35 days after the end of treatment	—

Countries

Russia

Participant flow

Recruitment details

Subjects enrollment was conducted in 11 clinical sites in Russia between July 2016 and April 2017. After the screening period 300 patients (150 in each group) were included in the study. 299 patients started study treatments.

Participants by arm

Arm	Count
Uritos® one tablet orally twice a day (after breakfast and dinner) for 12 weeks Uritos®: film-coated tablets 0.1 mg	148
Urotol® one tablet orally twice a day (after breakfast and dinner) for 12 weeks Urotol®: film coated tablets, 2 mg	148
Total	296

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Lost to Follow-up	1	2
Overall Study	Patient non compliance	4	0
Overall Study	Protocol Violation	0	1
Overall Study	Withdrawal by Subject	1	1

Baseline characteristics

Characteristic	Uritos®	Urotol®	Total
Age, Continuous	47.2 years STANDARD_DEVIATION 13.5	46.1 years STANDARD_DEVIATION 13.54	46.6 years STANDARD_DEVIATION 13.51
Body Mass Index (BMI)	25.7 kg/m^2 STANDARD_DEVIATION 5.48	25.8 kg/m^2 STANDARD_DEVIATION 5.33	25.8 kg/m^2 STANDARD_DEVIATION 5.39
Race/Ethnicity, Customized Asian	2 Participants	0 Participants	2 Participants
Race/Ethnicity, Customized Caucasian	146 Participants	148 Participants	294 Participants
Sex: Female, Male Female	124 Participants	121 Participants	245 Participants
Sex: Female, Male Male	24 Participants	27 Participants	51 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 149	0 / 150
other Total, other adverse events	70 / 149	72 / 150
serious Total, serious adverse events	0 / 149	0 / 150

Outcome results

Primary

Change in the Mean Daily Number of Urination Episodes at Week 12

The mean daily number of urination episodes was calculated as the total number of episodes (on the basis of the data that patients entered into their diaries) per day (from 7 am to 7 am the next day) for the study period (between visits) divided by the number of days in the period.

Time frame: Baseline and Week 12

Population: The efficiency analysis was performed on the FAS (Full Analysis Set) population, which included all randomized patients who received at least one dose of the drug and had at least one efficiency evaluation after visit 2.

Arm	Measure	Group	Value (MEAN)	Dispersion
Uritos®	Change in the Mean Daily Number of Urination Episodes at Week 12	Baseline	12.5 urination episodes per day	Standard Deviation 3.5
Uritos®	Change in the Mean Daily Number of Urination Episodes at Week 12	Week 12 of treatment	9.0 urination episodes per day	Standard Deviation 3
Uritos®	Change in the Mean Daily Number of Urination Episodes at Week 12	Change	-3.6 urination episodes per day	Standard Deviation 3
Urotol®	Change in the Mean Daily Number of Urination Episodes at Week 12	Baseline	11.9 urination episodes per day	Standard Deviation 2.7
Urotol®	Change in the Mean Daily Number of Urination Episodes at Week 12	Week 12 of treatment	8.6 urination episodes per day	Standard Deviation 2.5
Urotol®	Change in the Mean Daily Number of Urination Episodes at Week 12	Change	-3.4 urination episodes per day	Standard Deviation 2.6

Comparison: The null hypothesis is that effect of Urotol according to the assessment of mean daily urination episodes exceeds effect of Uritos.~A sample containing of 222 patients (111 per study group) is considered sufficient to prove the alternative hypothesis at the significance level 0.025% and study power 80%. Given the expected drop out rate during the treatment period, the total number of patients to be randomized is 300 (150 in each group).p-value: =0.5595ANCOVA

Secondary

Change in the EQ-5D-based Quality of Life at Week 12

The Euro Quality of Life five Dimensions questionnaire ( EQ-5D, version EQ-5D-5L) is a validated questionnaire for the assessment of health-related quality of life. It consists of a questionnaire and a visual analogue scale (EQ-VAS). The self-assessment questionnaire is self-reported description of the subject's current health in 5 dimensions i.e., mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The subject is asked to assess their own current level of function in each dimension by 5-level scale from no problems to significant problem grades. The EQ-VAS is a self-rated health status using a VAS in mm from 0 (the worse health status) to 100 (the best health status). The EQ-VAS records the subject's perceptions of their own current overall health quantitatively in mm and can be used to monitor changes with time. The results of patients assessment by VAS are presented.

Time frame: Baseline and Week 12

Arm	Measure	Group	Value (MEAN)	Dispersion
Uritos®	Change in the EQ-5D-based Quality of Life at Week 12	Baseline	67.7 score on a scale, mm	Standard Deviation 13.9
Uritos®	Change in the EQ-5D-based Quality of Life at Week 12	Week 12 of treatment	81.7 score on a scale, mm	Standard Deviation 13.4
Uritos®	Change in the EQ-5D-based Quality of Life at Week 12	Change (week 12)	13.8 score on a scale, mm	Standard Deviation 15.5
Urotol®	Change in the EQ-5D-based Quality of Life at Week 12	Week 12 of treatment	79.5 score on a scale, mm	Standard Deviation 15.4
Urotol®	Change in the EQ-5D-based Quality of Life at Week 12	Baseline	66.8 score on a scale, mm	Standard Deviation 15
Urotol®	Change in the EQ-5D-based Quality of Life at Week 12	Change (week 12)	12.5 score on a scale, mm	Standard Deviation 14.7

p-value: =0.4839t-test, 1 sided

Secondary

Change in the Mean Daily Number of Incontinence Episodes at Week 12

The mean daily number of incontinence episodes was calculated as the total number of episodes (on the basis of the data that patients entered into their diaries) per day (from 7 am to 7 am the next day) for the study period (between visits) divided by the number of days in the period.

Time frame: Baseline and Week 12

Arm	Measure	Group	Value (MEAN)	Dispersion
Uritos®	Change in the Mean Daily Number of Incontinence Episodes at Week 12	Change	-2.1 incontinence episodes per day	Standard Deviation 2.2
Uritos®	Change in the Mean Daily Number of Incontinence Episodes at Week 12	Baseline	2.5 incontinence episodes per day	Standard Deviation 2.4
Uritos®	Change in the Mean Daily Number of Incontinence Episodes at Week 12	Week 12 of treatment	0.4 incontinence episodes per day	Standard Deviation 0.9
Urotol®	Change in the Mean Daily Number of Incontinence Episodes at Week 12	Week 12 of treatment	0.5 incontinence episodes per day	Standard Deviation 1.2
Urotol®	Change in the Mean Daily Number of Incontinence Episodes at Week 12	Change	-1.9 incontinence episodes per day	Standard Deviation 1.8
Urotol®	Change in the Mean Daily Number of Incontinence Episodes at Week 12	Baseline	2.4 incontinence episodes per day	Standard Deviation 2.3

p-value: =0.0008ANCOVA

Secondary

Change in the Mean Daily Number of Urination Episodes at Week 2, 4 and 8 Visit as Compared to the Treatment Initiation Visit

Time frame: Baseline and Week 2, 4 and 8

Arm	Measure	Group	Value (MEAN)	Dispersion
Uritos®	Change in the Mean Daily Number of Urination Episodes at Week 2, 4 and 8 Visit as Compared to the Treatment Initiation Visit	Change (week 2)	-1.9 urination episodes per day	Standard Deviation 2.6
Uritos®	Change in the Mean Daily Number of Urination Episodes at Week 2, 4 and 8 Visit as Compared to the Treatment Initiation Visit	Change (week 4)	-2.8 urination episodes per day	Standard Deviation 2.7
Uritos®	Change in the Mean Daily Number of Urination Episodes at Week 2, 4 and 8 Visit as Compared to the Treatment Initiation Visit	Week 2 of treatment	10.6 urination episodes per day	Standard Deviation 2.9
Uritos®	Change in the Mean Daily Number of Urination Episodes at Week 2, 4 and 8 Visit as Compared to the Treatment Initiation Visit	Week 8 of treatment	9.4 urination episodes per day	Standard Deviation 2.7
Uritos®	Change in the Mean Daily Number of Urination Episodes at Week 2, 4 and 8 Visit as Compared to the Treatment Initiation Visit	Week 4 of treatment	9.6 urination episodes per day	Standard Deviation 2.7
Uritos®	Change in the Mean Daily Number of Urination Episodes at Week 2, 4 and 8 Visit as Compared to the Treatment Initiation Visit	Change (week 8)	-3.2 urination episodes per day	Standard Deviation 2.9
Uritos®	Change in the Mean Daily Number of Urination Episodes at Week 2, 4 and 8 Visit as Compared to the Treatment Initiation Visit	Baseline	12.5 urination episodes per day	Standard Deviation 3.5
Urotol®	Change in the Mean Daily Number of Urination Episodes at Week 2, 4 and 8 Visit as Compared to the Treatment Initiation Visit	Change (week 8)	-3.1 urination episodes per day	Standard Deviation 2.5
Urotol®	Change in the Mean Daily Number of Urination Episodes at Week 2, 4 and 8 Visit as Compared to the Treatment Initiation Visit	Baseline	11.9 urination episodes per day	Standard Deviation 2.7
Urotol®	Change in the Mean Daily Number of Urination Episodes at Week 2, 4 and 8 Visit as Compared to the Treatment Initiation Visit	Week 2 of treatment	10.3 urination episodes per day	Standard Deviation 2.6
Urotol®	Change in the Mean Daily Number of Urination Episodes at Week 2, 4 and 8 Visit as Compared to the Treatment Initiation Visit	Change (week 2)	-1.6 urination episodes per day	Standard Deviation 2.1
Urotol®	Change in the Mean Daily Number of Urination Episodes at Week 2, 4 and 8 Visit as Compared to the Treatment Initiation Visit	Week 4 of treatment	9.4 urination episodes per day	Standard Deviation 2.6
Urotol®	Change in the Mean Daily Number of Urination Episodes at Week 2, 4 and 8 Visit as Compared to the Treatment Initiation Visit	Change (week 4)	-2.6 urination episodes per day	Standard Deviation 2.3
Urotol®	Change in the Mean Daily Number of Urination Episodes at Week 2, 4 and 8 Visit as Compared to the Treatment Initiation Visit	Week 8 of treatment	8.9 urination episodes per day	Standard Deviation 2.4

p-value: =0.1348ANCOVA

p-value: =0.3199ANCOVA

p-value: =0.9537ANCOVA

Secondary

Change in the Mean Daytime Number of Incontinence Episodes at Week 12

The mean daytime number of incontinence episodes was calculated as the total number of episodes from 7 am to 11 pm for the study period (between visits) divided by the number of days in the period.

Time frame: Baseline and Week 12

Arm	Measure	Group	Value (MEAN)	Dispersion
Uritos®	Change in the Mean Daytime Number of Incontinence Episodes at Week 12	Baseline	2.0 daytime incontinence episodes per day	Standard Deviation 1.9
Uritos®	Change in the Mean Daytime Number of Incontinence Episodes at Week 12	Week 12 of treatment	0.4 daytime incontinence episodes per day	Standard Deviation 0.7
Uritos®	Change in the Mean Daytime Number of Incontinence Episodes at Week 12	Change	-1.7 daytime incontinence episodes per day	Standard Deviation 1.7
Urotol®	Change in the Mean Daytime Number of Incontinence Episodes at Week 12	Baseline	1.9 daytime incontinence episodes per day	Standard Deviation 1.8
Urotol®	Change in the Mean Daytime Number of Incontinence Episodes at Week 12	Week 12 of treatment	0.4 daytime incontinence episodes per day	Standard Deviation 0.9
Urotol®	Change in the Mean Daytime Number of Incontinence Episodes at Week 12	Change	-1.5 daytime incontinence episodes per day	Standard Deviation 1.4

p-value: =0.0099ANCOVA

Secondary

Change in the Mean Nighttime Number of Incontinence Episodes at Week 12

The mean nighttime number of incontinence episodes was calculated as the total number of episodes from 11 pm to 7 am for the study period (between visits) divided by the number of days in the period.

Time frame: Baseline and Week 12

Arm	Measure	Group	Value (MEAN)	Dispersion
Uritos®	Change in the Mean Nighttime Number of Incontinence Episodes at Week 12	Week 12 of treatment	0.1 nighttime incontinence episode per day	Standard Deviation 0.3
Uritos®	Change in the Mean Nighttime Number of Incontinence Episodes at Week 12	Change	-0.4 nighttime incontinence episode per day	Standard Deviation 0.8
Uritos®	Change in the Mean Nighttime Number of Incontinence Episodes at Week 12	Baseline	0.5 nighttime incontinence episode per day	Standard Deviation 0.8
Urotol®	Change in the Mean Nighttime Number of Incontinence Episodes at Week 12	Baseline	0.5 nighttime incontinence episode per day	Standard Deviation 0.8
Urotol®	Change in the Mean Nighttime Number of Incontinence Episodes at Week 12	Week 12 of treatment	0.1 nighttime incontinence episode per day	Standard Deviation 0.4
Urotol®	Change in the Mean Nighttime Number of Incontinence Episodes at Week 12	Change	-0.4 nighttime incontinence episode per day	Standard Deviation 0.6

p-value: <0.0001ANCOVA

Secondary

Change in the Mean Number of Incontinence Episodes at Week 2, 4 and 8

Separately for daily, daytime and nighttime measurements.

Time frame: Baseline and Week 2, 4 and 8

Arm	Measure	Group	Value (MEAN)	Dispersion
Uritos®	Change in the Mean Number of Incontinence Episodes at Week 2, 4 and 8	Baseline number of daily incontinence episodes	2.5 incontinence episodes per day	Standard Deviation 2.4
Uritos®	Change in the Mean Number of Incontinence Episodes at Week 2, 4 and 8	Change in daily incontinence episodes (week 4)	-1.8 incontinence episodes per day	Standard Deviation 2
Uritos®	Change in the Mean Number of Incontinence Episodes at Week 2, 4 and 8	Change in daily incontinence episodes (week 8)	-2.0 incontinence episodes per day	Standard Deviation 2
Uritos®	Change in the Mean Number of Incontinence Episodes at Week 2, 4 and 8	Change in daytime incontinence episodes (week 4)	-1.5 incontinence episodes per day	Standard Deviation 1.5
Uritos®	Change in the Mean Number of Incontinence Episodes at Week 2, 4 and 8	Change in daily incontinence episodes (week 2)	-1.5 incontinence episodes per day	Standard Deviation 1.8
Uritos®	Change in the Mean Number of Incontinence Episodes at Week 2, 4 and 8	Baseline number of daytime incontinence episodes	2.0 incontinence episodes per day	Standard Deviation 1.9
Uritos®	Change in the Mean Number of Incontinence Episodes at Week 2, 4 and 8	Change in daytime incontinence episodes (week 2)	-1.2 incontinence episodes per day	Standard Deviation 1.3
Uritos®	Change in the Mean Number of Incontinence Episodes at Week 2, 4 and 8	Change in daytime incontinence episodes (week 8)	-1.7 incontinence episodes per day	Standard Deviation 1.5
Uritos®	Change in the Mean Number of Incontinence Episodes at Week 2, 4 and 8	Baseline number of nightime incontinence episodes	0.5 incontinence episodes per day	Standard Deviation 0.8
Uritos®	Change in the Mean Number of Incontinence Episodes at Week 2, 4 and 8	Change in nighttime incontinence episodes (week 2)	-0.3 incontinence episodes per day	Standard Deviation 0.6
Uritos®	Change in the Mean Number of Incontinence Episodes at Week 2, 4 and 8	Change in nighttime incontinence episodes (week 4)	-0.3 incontinence episodes per day	Standard Deviation 0.8
Uritos®	Change in the Mean Number of Incontinence Episodes at Week 2, 4 and 8	Change in nighttime incontinence episodes (week 8)	-0.3 incontinence episodes per day	Standard Deviation 0.7
Urotol®	Change in the Mean Number of Incontinence Episodes at Week 2, 4 and 8	Change in nighttime incontinence episodes (week 4)	-0.4 incontinence episodes per day	Standard Deviation 0.6
Urotol®	Change in the Mean Number of Incontinence Episodes at Week 2, 4 and 8	Baseline number of daily incontinence episodes	2.4 incontinence episodes per day	Standard Deviation 2.3
Urotol®	Change in the Mean Number of Incontinence Episodes at Week 2, 4 and 8	Change in daytime incontinence episodes (week 2)	-1.0 incontinence episodes per day	Standard Deviation 1.1
Urotol®	Change in the Mean Number of Incontinence Episodes at Week 2, 4 and 8	Change in daily incontinence episodes (week 4)	-1.7 incontinence episodes per day	Standard Deviation 1.5
Urotol®	Change in the Mean Number of Incontinence Episodes at Week 2, 4 and 8	Change in nighttime incontinence episodes (week 2)	-0.3 incontinence episodes per day	Standard Deviation 0.5
Urotol®	Change in the Mean Number of Incontinence Episodes at Week 2, 4 and 8	Change in daytime incontinence episodes (week 8)	-1.4 incontinence episodes per day	Standard Deviation 1.3
Urotol®	Change in the Mean Number of Incontinence Episodes at Week 2, 4 and 8	Change in daytime incontinence episodes (week 4)	-1.3 incontinence episodes per day	Standard Deviation 1.3
Urotol®	Change in the Mean Number of Incontinence Episodes at Week 2, 4 and 8	Change in nighttime incontinence episodes (week 8)	-0.4 incontinence episodes per day	Standard Deviation 0.6
Urotol®	Change in the Mean Number of Incontinence Episodes at Week 2, 4 and 8	Change in daily incontinence episodes (week 2)	-1.3 incontinence episodes per day	Standard Deviation 1.3
Urotol®	Change in the Mean Number of Incontinence Episodes at Week 2, 4 and 8	Change in daily incontinence episodes (week 8)	-1.8 incontinence episodes per day	Standard Deviation 1.5
Urotol®	Change in the Mean Number of Incontinence Episodes at Week 2, 4 and 8	Baseline number of nightime incontinence episodes	0.5 incontinence episodes per day	Standard Deviation 0.8
Urotol®	Change in the Mean Number of Incontinence Episodes at Week 2, 4 and 8	Baseline number of daytime incontinence episodes	1.9 incontinence episodes per day	Standard Deviation 1.8

p-value: <0.0001ANCOVA

p-value: =0.0236ANCOVA

p-value: <0.0001ANCOVA

p-value: =0.0018ANCOVA

p-value: =0.3835ANCOVA

p-value: =0.0088ANCOVA

p-value: =0.0004ANCOVA

p-value: <0.0001ANCOVA

Secondary

Change in the Mean Weekly Number of Incontinence Episodes at Week 12

The mean weekly number of incontinence episodes was calculated as the total number of episodes per day (from 7 am to 7 am the next day) for the study period (between visits) divided by the number of weeks in the period.

Time frame: Baseline and Week 12

Arm	Measure	Group	Value (MEAN)	Dispersion
Uritos®	Change in the Mean Weekly Number of Incontinence Episodes at Week 12	Baseline	17.2 incontinence episodes per week	Standard Deviation 16.8
Uritos®	Change in the Mean Weekly Number of Incontinence Episodes at Week 12	Week 12 of treatment	3.0 incontinence episodes per week	Standard Deviation 6.5
Uritos®	Change in the Mean Weekly Number of Incontinence Episodes at Week 12	Change	-14.5 incontinence episodes per week	Standard Deviation 15.3
Urotol®	Change in the Mean Weekly Number of Incontinence Episodes at Week 12	Baseline	16.9 incontinence episodes per week	Standard Deviation 15.7
Urotol®	Change in the Mean Weekly Number of Incontinence Episodes at Week 12	Week 12 of treatment	3.2 incontinence episodes per week	Standard Deviation 8.3
Urotol®	Change in the Mean Weekly Number of Incontinence Episodes at Week 12	Change	-13.6 incontinence episodes per week	Standard Deviation 12.4

p-value: 0.0008ANCOVA

Secondary

Changes in the Overactive Bladder Symptom Score According to Overactive Bladder (OAB) Awareness Tool Questionnaire at 2, 4, 8 and 12 Week

Overactive bladder (OAB) Awareness Tool Questionnaire (version OAB-V8, containing 8 questions) is a validated questionnaire. Patient is asked to answer 8 questions concerning typical symptoms of OAB giving answers with a scale with minimum - 0 score defined as no bothering at all and maximmum - 5 score defined as a very big deal to assess the severity of these symptoms. All answers are simply summed to make a combined final score. Male participants should add 2 points to their final score. The final scores range from 0 to 40 (for women) and 42 (for men). The score equal to 8 and more is interpreted as high probability of OAB presence, with the higher scores indicating more bothersome symptoms of OAB.

Time frame: Baseline and Week 2, 4, 8 and 12

Arm	Measure	Group	Value (MEAN)	Dispersion
Uritos®	Changes in the Overactive Bladder Symptom Score According to Overactive Bladder (OAB) Awareness Tool Questionnaire at 2, 4, 8 and 12 Week	Change (week 4)	-10.6 scores on a scale	Standard Deviation 7.7
Uritos®	Changes in the Overactive Bladder Symptom Score According to Overactive Bladder (OAB) Awareness Tool Questionnaire at 2, 4, 8 and 12 Week	Change (week 12)	-14.2 scores on a scale	Standard Deviation 8.5
Uritos®	Changes in the Overactive Bladder Symptom Score According to Overactive Bladder (OAB) Awareness Tool Questionnaire at 2, 4, 8 and 12 Week	Baseline	24.3 scores on a scale	Standard Deviation 7.5
Uritos®	Changes in the Overactive Bladder Symptom Score According to Overactive Bladder (OAB) Awareness Tool Questionnaire at 2, 4, 8 and 12 Week	Change (week 8)	-12.4 scores on a scale	Standard Deviation 8.5
Uritos®	Changes in the Overactive Bladder Symptom Score According to Overactive Bladder (OAB) Awareness Tool Questionnaire at 2, 4, 8 and 12 Week	Change (week 2)	-8.0 scores on a scale	Standard Deviation 8.2
Urotol®	Changes in the Overactive Bladder Symptom Score According to Overactive Bladder (OAB) Awareness Tool Questionnaire at 2, 4, 8 and 12 Week	Change (week 2)	-8.2 scores on a scale	Standard Deviation 6.6
Urotol®	Changes in the Overactive Bladder Symptom Score According to Overactive Bladder (OAB) Awareness Tool Questionnaire at 2, 4, 8 and 12 Week	Change (week 12)	-14.5 scores on a scale	Standard Deviation 8
Urotol®	Changes in the Overactive Bladder Symptom Score According to Overactive Bladder (OAB) Awareness Tool Questionnaire at 2, 4, 8 and 12 Week	Change (week 4)	-10.8 scores on a scale	Standard Deviation 6.9
Urotol®	Changes in the Overactive Bladder Symptom Score According to Overactive Bladder (OAB) Awareness Tool Questionnaire at 2, 4, 8 and 12 Week	Change (week 8)	-13.0 scores on a scale	Standard Deviation 8
Urotol®	Changes in the Overactive Bladder Symptom Score According to Overactive Bladder (OAB) Awareness Tool Questionnaire at 2, 4, 8 and 12 Week	Baseline	23.8 scores on a scale	Standard Deviation 7.1

p-value: =0.5321t-test, 1 sided

Other Pre-specified