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

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).

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.

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.