A Crossover, Double-blinded, Two-period, Double Dummy Study to Evaluate the Effects of Extended Release Torsemide in Patients With Chronic Congestive Heart Failure and Symptoms of Overactive Bladder

This study has been designed to evaluate the efficacy of 24mg/48mg dose of Investigational Product [Extended Release Torsemide (ERT) of Sarfez Pharmaceuticals Inc.] to 20mg/40mg dose of generic Immediate Release Torsemide (IRT) in reducing the symptoms of overactive bladder (OAB) in Chronic Heart Failure (CHF) patients.

Study Rationale: Majority of chronic heart failure (CHF) patients are aged ≥50 and have symptoms of overactive bladder such as micturition frequency and urgency with or without urgency incontinence on stable dose of loop diuretics. Studies have shown that at normal physiological filling rate, intravesicular pressure does not rise until bladder capacity is reached. However, when the filling rate is higher than the normal physiological rate, the intravesicular pressure rises before bladder capacity is reached. Since loop diuretic increase filling rate, they are likely to raise intravesicular pressure much before it reaches capacity, and hence increase urgency. Therefore, there is a need for loop diuretic with a more gradual filling rate to alleviate loop diuretic induced exacerbation of symptoms OAB such as urgency and frequency. The proposed study follows upon successful clinical trial where in healthy volunteers, extended release torsemide of Sarfez Pharmaceutical Inc. decreased peak urine volume by >30% and induced gradual diuresis, indicating a gradual bladder filling. Therefore, this study is designed to determine if extended release torsemide of Sarfez Pharmaceutical Inc. can improve the bladder symptoms in heart failure patients as compared to a generic immediate release torsemide.

Patients who meet all inclusion and exclusion criteria, after obtaining written informed consent, will be screened using a four-question bladder condition assessment tool (score 0-5) and, only patients who score ≥4 score on each of the questions (total score ≥16) and meeting all other eligibility criteria will be enrolled in the study. The trial period will be divided into two periods as described above and shown in study flow schema (Figure 1). The total duration of the study would be 56 days excluding the day of enrollment in the study. Patients will visit the Clinical Research Unit/hospital at following schedules.

Visit 1: (Screening and Enrollment) start of study: After confirmation of eligibility and screening, patients will be randomized, HRQL tool and BS tool will be administered, (Baseline) and medications will be dispensed. Blood will be collected for NT-pro-BNP test and basic metabolic panel and body weight will also be measured. 6MWT will be performed. The other assessments will be done as mentioned in the study assessment schedule. Pregnancy test will be done to rule out pregnancy.

Period 1: All the enrolled patients who were on stable daily dose of furosemide will be randomized to either ERT or generic IRT. Patients who were on stable daily dose of furosemide 40 mg will be randomized to either ERT 24 mg or generic IRT 20 mg. Similarly, patients who were on stable daily dose of furosemide 80 mg will be randomized to either ERT 48 mg (two 24 mg tablets) or generic IRT 40 mg (two 20mg tablets). All pre-screening treatments will be recorded, and other concomitant medications will be continued (except non-steroidal anti-inflammatory agents but aspirin (<100 mg per day) will be permitted, cyclooxygenase-2 inhibitors such as Celecoxib, and allopurinol). On the same day HRQL tool and BS tool will be administered (Baseline assessments). Trained study coordinator will do a virtual visit on the last day of week 1, 2, and week 3 to provide and collect daily diary and to administer BS tool in week 2 and week 3. Upon diary collection, the study coordinator will check the diary for completion, and, if the diary is not properly completed, the study coordinator re-educates or re-instructs the patient with proper diary data filling procedures. Any retrospective modification or notation in the diary is strictly prohibited.