Safety and Tolerability of TAR-302-5018 in Subjects With Idiopathic Overactive Bladder

Inclusion criteria

(Part 1):

• Symptoms of overactive bladder (OAB) (frequency/urgency) with urge urinary incontinence or mixed urinary incontinence with a predominant urge component for at least 6 months

• 8 or more voids per 24 hours as recorded in a diary
• At least 4 incontinence episodes associated with urgency recorded in a 3-day diary.

• At least 1 episode must occur per each 24 hour day
• Inadequate response or limiting side effects with anticholinergics for the treatment of OAB

Exclusion criteria

(Part 1):

• Age <18 years.
• OAB caused by neurological condition.
• Presence of significant renal dysfunction at screening (Glomerular Filtration Rate <30 mL/min).
• Presence of significant polyuria of any cause at screening (urine output >4,000 mL/day).
• History of pelvic radiation.
• History of either bladder cancer or bladder pathology that the investigator deems unfit for study inclusion.
• Active malignancies within 12 months with the exception of those with a negligible risk of metastasis or death treated with expected curative outcome.
• Subjects with any bladder or urethral anatomic feature that may prevent the safe placement, indwelling use, or removal of TAR 302 5018.
• In the opinion of the investigator, the subject has a history of significant stress urinary incontinence.
• Subjects with active bladder stones or history of bladder stones <6 months prior to study entry.
• History of recurrent symptomatic urinary tract infections (UTIs) (>4 per 1 year).
• Subjects with either urinary retention or gastric retention or uncontrolled narrow-angle glaucoma.
• A post-void residual volume (PVR) of 300 mL or greater
• Subjects with known hypersensitivity to trospium, chemically-related drugs, or component excipients.
• Subjects with known hypersensitivity to the device materials, including silicone and nitinol.
• Subjects actively taking oral trospium.
• The addition of a new or a change in dose to a current medication for the treatment of OAB (i.e. anticholinergics, beta-3 adrenergic agonists, antispasmodics, antidepressants, or hormones) within 30 days prior to signing the informed consent form (ICF). A stable dose must continue through the final study visit. If previously used and discontinued, these medications must have been stopped for >2 weeks prior to Day 0.
• Intravesical onabotulinum toxin use within the last 9 months prior to the Screening Visit.
• Intravesical anticholinergic medications within the last 30 days prior to the Screening Visit.
• History of non-medication based therapy (i.e. InterStim therapy) for the treatment of OAB. History of non-invasive neuromodulation (i.e. Percutaneous Tibial Nerve Stimulation (PTNS)) is allowed if discontinued at least 8 weeks prior to Study Day 0.
• Female subject who is pregnant (as verified by urine test at time of screening) or lactating or of childbearing potential and not using acceptable methods of contraception.
• Subject has a medical condition that may cause noncompliance with the study protocol.
• Subject refuses to provide written informed consent.
• Subject will be unable or unwilling to complete the questionnaires, diaries, or attend all protocol mandated study visits.
• Participation in another drug, device, or behavioral study within 60 days prior to the Screening Visit.
• History or presence of any significant cardiovascular, pulmonary, hepatic, renal, gastrointestinal, gynecological, endocrine, immunological, dermatological, neurological or psychiatric disease or disorder that, in the opinion of the investigator, contraindicates participation.
• History of any of the following within 3 months prior to Screening Visit:

• Major illness/major surgery (requiring hospitalization), including pelvic, lower back surgery or procedure unrelated to bladder cancer; most outpatient procedures are not exclusionary
• Renal or ureteral stone disease or instrumentation
• Childbirth
• Difficulty providing blood samples.
• Other unspecified reasons that, in the opinion of the investigator or TARIS, make the subject unsuitable for enrollment.

Inclusion criteria

(Part 2):

• Symptoms of idiopathic overactive bladder (iOAB) (frequency/urgency) with urge urinary incontinence or mixed urinary incontinence with a predominant urge component for at least 6 months.

• 8 or more voids per 24 hours as recorded in a diary
• At least 4 incontinence episodes associated with urgency recorded in a 3-day diary.

• At least 1 episode must occur per each 24 hour day
• In the opinion of the investigator, the subject has experienced an inadequate response to or limiting side effects with prior oral medications for the treatment of OAB.

Exclusion criteria

(Part 2):

• Age <18 years.
• Neurologic bladder condition.
• Subjects with Diabetes Mellitus (both Type 1 & Type 2) must demonstrate optimal glycemic control with HbA1c levels < 7.5 % and an absence of significant glucosuria defined as 3+ glucose via dipstick at screening.
• Presence of significant polyuria of any cause at screening (urine output >3,000 mL/day).
• Presence of nocturnal polyuria at time of study screening defined as >30% of total 24-hour urine collected from time of evening (P.M.) sleep and inclusive of the first morning (A.M.) void.
• History of pelvic irradiation.
• History of either bladder cancer or bladder pathology that the investigator deems unfit for study inclusion.
• Currently uses intermittent catheterization (IC) to empty the bladder within 30 days of Day 0.
• Subjects with any bladder or urethral anatomic feature (e.g., urethral stricture) that in the opinion of the investigator may prevent the safe placement, indwelling use, or removal of IP.
• Subjects with active bladder stones or history of bladder stones < 6 months prior to study entry.
• Gross hematuria within 30 days of Day 0.
• History of uncontrolled bleeding, bleeding diathesis, or underlying coagulopathy within 30 days of Day 0.
• In the opinion of the investigator, the subject has a history of predominance of significant stress urinary incontinence.
• History of > 2 symptomatic urinary tract infections in the 6-months prior to Day 0.
• Subjects with either urinary retention or gastric retention or uncontrolled narrow-angle glaucoma within 90 days of Day 0.
• A post-void residual volume (PVR) of 100-mL or greater.
• Subjects with known hypersensitivity to trospium, chemically-related drugs, or component excipients.
• Subjects with known hypersensitivity to the device materials, including silicone and nitinol.
• Anticholinergic or beta-3 agonist use for the treatment of urge urinary incontinence < 2 weeks prior to Day 0.
• History of intravesical onabotulinum toxin use within the last 9 months prior to the Screening Visit.
• Intravesical anticholinergic medications within the last 14 days prior to the Screening Visit.
• History of procedural-based neuromodulation therapy (e.g. InterStim therapy, Percutaneous Tibial Nerve Stimulation [PTNS]) for the treatment of OAB.
• Female subject who is pregnant (as verified by serum test at time of screening) or lactating.
• Subject has, in the opinion of the investigator, a medical condition that may cause noncompliance with the study protocol.
• Subject who is unable or unwilling to complete the questionnaires, diaries, or attend all protocol mandated study visits.
• Participation in another drug, device, or behavioral study within 60 days prior to the Screening Visit.
• History or presence of any significant cardiovascular, pulmonary, hepatic, renal, gastrointestinal, gynecological, endocrine, immunological, dermatological, neurological or psychiatric disease or disorder, or other unspecified reasons that, in the opinion of the investigator or TARIS, make the subject unsuitable for enrollment.
• History of any of the following within 3 months prior to Screening Visit:

i. Major illness/major surgery (requiring hospitalization), including pelvic, lower back surgery or procedure; most outpatient procedures are not exclusionary.

ii. Childbirth.

• History of prostatic biopsy or surgery (ablative or non-ablative) within 6 months prior to Day 0.
• History of significant pelvic organ prolapse (Grade >/= 3).
• Difficulty providing blood samples.
• Known history of drug or alcohol dependency within 12 months of screening.
• Other unspecified reasons that, in the opinion of the investigator or TARIS, make the subject unsuitable for enrollment.