A Study of the Pharmacokinetics and Pharmacodynamics of Vibegron (MK-4618) in Women With Overactive Bladder (MK-4618-004)

Study Overview
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Brief Summary
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The study is designed to investigate the effects of the investigational drug vibegron (MK-4618) compared to placebo on maximum urinary bladder capacity in women with overactive bladder. The study will also evaluate the safety and tolerability of multiple oral doses of vibegron in women with overactive bladder. Overactive bladder is best described as urgency and frequency of urination, with or without involuntary urination and/or the need to awaken during the night to urinate. The primary efficacy hypothesis is that vibegron is superior to placebo with respect to change from baseline in maximum cystometric capacity at 2 hours postdose on Day 7 (i.e., steady state) in participants with overactive bladder. A true mean increase (vibegron/placebo) of 25% in bladder volume is expected. The primary safety hypothesis is that administration of multiple oral doses of vibegron is sufficiently well-tolerated in participants with overactive bladder, based on assessment of clinical and laboratory adverse experiences, to permit continued clinical investigation.

Detailed Description
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Participants will be randomized in each of 2 treatment periods to 1 of 4 possible treatments, which will be administered in double-dummy fashion, and participants will undergo urodynamic procedures prior to dosing on Day 1 and after 7 days of treatment.

Official Title
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A Placebo and Active-Comparator Controlled Multiple-Dose Study to Evaluate the Pharmacokinetics and Pharmacodynamics of MK-4618 in Patients With Overactive Bladder

Conditions
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Overactive Bladder, Overactive Urinary Bladder

Intervention / Treatment
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* Drug: Vibegron
* Drug: Tolterodine ER
* Other: Placebo (vibegron)
* Other: Placebo (tolterodine ER)
* Drug: Prophylactic Antibiotic


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Non-child bearing potential (status post menopausal or post hysterectomy,oophorectomy or tubal ligation). If of reproductive potential, must be non-pregnant (confirmed via blood test) and agree to use (and/or have their partner use) two acceptable methods of birth control beginning at least 2 weeks prior to administration of the first dose of study drug,throughout the study (including washout intervals between treatment periods/panels) and until at least 2 weeks after administration of the last dose of study drug in the last treatment period. Body mass index (BMI) of ≤40 kg/m^2 (ie, not morbidly obese) Clinical history of overactive bladder symptoms (OAB) for at least 3 months Capable of completing an accurate daily diary for reporting purposes Exclusion Criteria: Mentally or legally incapacitated, such as significant emotional problems (other than situational depression) or diagnosed with a significant psychiatric disorder during the past 5-10 years Other types of urinary incontinence (ie,stress or mixed) History (current or past)of interstitial cystitis, painful bladder syndrome, or chronic pelvic pain or Stage III or greater pelvic organ prolapse Other types of kidney/urinary bladder disease/obstruction or infection. Participants with with a history of uncomplicated kidney stones may be enrolled in the study at the discretion of the investigator Inability to control bowel movements History of narrow angle glaucoma, immunocompromise, stroke, chronic seizures, major neurological disorders and/or other serious and chronic organ-system health conditions (ie, heart disease) Urinary catheter, either permanent or intermittent placement Failure to meet medication profile requirements or directives required for study eligibility Condition for which there is a warning, contraindication, or precaution against the use of tolterodine ER or anticipates the use of prescription medications contraindicated with the use of tolterodine ER Daily alcohol or caffeine intake exceeds study requirements (for alcohol: defined as greater than 2 glasses of alcoholic beverages (1 glass is approximately equivalent to: beer [284 mL/10 ounces], wine [125 mL/4 ounces], or distilled spirits [25 mL/1 ounce]) per day; and for caffeine: defined as greater than 3 servings (1 serving is approximately equivalent to 120 mg of caffeine) of coffee,tea, cola, or other caffeinated beverages (ie, Red Bull) per day Inability to refrain from smoking throughout the study's duration Illicit drug use Recent surgery or recent participation in another clinical trial Severe, frequent allergies or history of life-threatening reactions or intolerability to prescription or non prescription medications or food Intended or unintended extended absence or exposure to significant change in time zone or sleep schedule (ie, transmeridian travel or shift work) that will interfere with accurate completion of scheduled daily diary entries

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vibegron 100 mg + tolterodine ER 4 mg → placebo<br>During Treatment Period 1, participants will receive 7 days of once-daily vibegron 100 mg and tolterodine extended-release (ER) 4 mg. Participants will then complete a 2-week single-blind double-dummy placebo washout period prior to Treatment Period 2. During Treatment Period 2, participants will receive 7 days of once-daily placebo to match vibegron and placebo to match tolterodine ER. | Drug: Vibegron<br>* Tablet, 50 or 100 mg, once daily, for up to 10 days based on treatment assignments and treatment period.<br>* Other names: MK-4618;Drug: Tolterodine ER<br>* Capsule, 4 mg, once daily, for up to 10 days based on treatment assignment and treatment period.<br>* Other names: Detrol LA™;Other: Placebo (vibegron)<br>* Inactive agent in tablet form, oral administration, once daily, up to 5 weeks, based on treatment assignment in each treatment period.<br>Other: Placebo (tolterodine ER)<br>* Inactive agent in capsule form, oral administration, once daily, up to 5 weeks, based on treatment assignment in each treatment period.<br>Drug: Prophylactic Antibiotic<br>* A pre-procedural prophylactic antibiotic (ie, levofloxacin 250 mg, cephalexin) administered orally, 30 minutes prior to each scheduled urodynamic study intervention. It is up to the discretion of the Investigator, based on study protocol recommendations, as to which type of antibiotic may be administered.<br>* Other names: Zartan;|
| Experimental: Placebo → vibegron 100 mg<br>During Treatment Period 1, participants will receive 7 days of once-daily placebo to match vibegron and placebo to match tolterodine ER. Participants will then complete a 2-week single-blind double-dummy placebo washout period prior to Treatment Period 2. During Treatment Period 2, participants will receive 7 days of once-daily vibegron 100 mg and placebo to match tolterodine ER. | Drug: Vibegron<br>* Tablet, 50 or 100 mg, once daily, for up to 10 days based on treatment assignments and treatment period.<br>* Other names: MK-4618;Other: Placebo (vibegron)<br>* Inactive agent in tablet form, oral administration, once daily, up to 5 weeks, based on treatment assignment in each treatment period.<br>Other: Placebo (tolterodine ER)<br>* Inactive agent in capsule form, oral administration, once daily, up to 5 weeks, based on treatment assignment in each treatment period.<br>Drug: Prophylactic Antibiotic<br>* A pre-procedural prophylactic antibiotic (ie, levofloxacin 250 mg, cephalexin) administered orally, 30 minutes prior to each scheduled urodynamic study intervention. It is up to the discretion of the Investigator, based on study protocol recommendations, as to which type of antibiotic may be administered.<br>* Other names: Zartan;|
| Active Comparator: Placebo → tolterodine ER 4 mg<br>During Treatment Period 1, participants will receive 7 days of once-daily placebo to match vibegron and placebo to match tolterodine ER. Participants will then complete a 2-week single-blind double-dummy placebo washout period prior to Treatment Period 2. During Treatment Period 2, participants will receive 7 days of once-daily tolterodine 4 mg and placebo to match vibegron. | Drug: Tolterodine ER<br>* Capsule, 4 mg, once daily, for up to 10 days based on treatment assignment and treatment period.<br>* Other names: Detrol LA™;Other: Placebo (vibegron)<br>* Inactive agent in tablet form, oral administration, once daily, up to 5 weeks, based on treatment assignment in each treatment period.<br>Other: Placebo (tolterodine ER)<br>* Inactive agent in capsule form, oral administration, once daily, up to 5 weeks, based on treatment assignment in each treatment period.<br>Drug: Prophylactic Antibiotic<br>* A pre-procedural prophylactic antibiotic (ie, levofloxacin 250 mg, cephalexin) administered orally, 30 minutes prior to each scheduled urodynamic study intervention. It is up to the discretion of the Investigator, based on study protocol recommendations, as to which type of antibiotic may be administered.<br>* Other names: Zartan;|
| Experimental: Placebo → vibegron 50 mg<br>During Treatment Period 1, participants will receive 7 days of once-daily placebo to match vibegron and placebo to match tolterodine ER. Participants will then complete a 2-week single-blind double-dummy placebo washout period prior to Treatment Period 2. During Treatment Period 2, participants will receive 7 days of once-daily vibegron 50 mg and placebo to match tolterodine ER. | Drug: Vibegron<br>* Tablet, 50 or 100 mg, once daily, for up to 10 days based on treatment assignments and treatment period.<br>* Other names: MK-4618;Other: Placebo (vibegron)<br>* Inactive agent in tablet form, oral administration, once daily, up to 5 weeks, based on treatment assignment in each treatment period.<br>Other: Placebo (tolterodine ER)<br>* Inactive agent in capsule form, oral administration, once daily, up to 5 weeks, based on treatment assignment in each treatment period.<br>Drug: Prophylactic Antibiotic<br>* A pre-procedural prophylactic antibiotic (ie, levofloxacin 250 mg, cephalexin) administered orally, 30 minutes prior to each scheduled urodynamic study intervention. It is up to the discretion of the Investigator, based on study protocol recommendations, as to which type of antibiotic may be administered.<br>* Other names: Zartan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fold-change From Baseline in Maximum Cystometric Capacity Post-dose on Day 7 | Filling cystometry procedures were performed pre-dose on Day 1 and post-dose on Day 7 in each treatment period. Individual values in fold-change from baseline and post-dose on Day 7 will be natural log-transformed and evaluated with a linear mixed effects model having period and treatment as fixed effects and participant as a random effect. | Baseline (pre-dose Day 1) and Day 7 (post-dose) | 
| Number of Participants Who Experienced an Adverse Event (AE) | An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to this medicinal product. | Up to 6 weeks (up to 3 weeks in Period 1 and up to 3 weeks in Period 2) | 
| Number of Participants Who Discontinued Use of Study Drug Due to an AE | An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to this medicinal product. The number of participants who discontinued study drug due to an AE were reported. | Up to 6 weeks (up to 3 weeks in Period 1 and up to 3 weeks in Period 2) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fold-change From Baseline in Volume of Urine at First Desire to Void Post-dose on Day 7 | Filling cystometry procedures were performed pre-dose on Day 1 and post-dose on Day 7 in each treatment period. Individual values in fold-change from baseline and post-dose on Day 7 will be natural log-transformed and evaluated with a linear mixed effects model having period and treatment as fixed effects and participant as a random effect. | Baseline (pre-dose Day 1) and Day 7 (post-dose) |