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

• Sponsor: Merck Sharp & Dohme Corp. (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01500382
• Collaborator: (none)
• Enrollment: 4
• Arms: 4
• Actual Duration (Months): 10.2

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Overactive Bladder; Overactive Urinary Bladder	Drug: Vibegron; Drug: Tolterodine ER; Other: Placebo (vibegron); Other: Placebo (tolterodine ER); Drug: Prophylactic Antibiotic	Phase 1

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 4 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Placebo and Active-Comparator Controlled Multiple-Dose Study to Evaluate the Pharmacokinetics and Pharmacodynamics of MK-4618 in Patients With Overactive Bladder
• Actual Study Start Date: Feb 27, 2012
• Actual Primary Completion Date: Jan 2, 2013
• Actual Study Completion Date: Jan 2, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Vibegron 100 mg + tolterodine ER 4 mg → placebo 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; Tablet, 50 or 100 mg, once daily, for up to 10 days based on treatment assignments and treatment period.; Other Names: MK-4618 ; Drug: Tolterodine ER; Capsule, 4 mg, once daily, for up to 10 days based on treatment assignment and treatment period.; Other Names: Detrol LA™ ; Other: Placebo (vibegron); Inactive agent in tablet form, oral administration, once daily, up to 5 weeks, based on treatment assignment in each treatment period.; Other: Placebo (tolterodine ER); Inactive agent in capsule form, oral administration, once daily, up to 5 weeks, based on treatment assignment in each treatment period.; Drug: Prophylactic Antibiotic; 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.; Other Names: Levaquin Biocef Ed A-Ceph Keflex Keftab Panixine DisperDose Zartan
Experimental: Placebo → vibegron 100 mg 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; Tablet, 50 or 100 mg, once daily, for up to 10 days based on treatment assignments and treatment period.; Other Names: MK-4618 ; Other: Placebo (vibegron); Inactive agent in tablet form, oral administration, once daily, up to 5 weeks, based on treatment assignment in each treatment period.; Other: Placebo (tolterodine ER); Inactive agent in capsule form, oral administration, once daily, up to 5 weeks, based on treatment assignment in each treatment period.; Drug: Prophylactic Antibiotic; 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.; Other Names: Levaquin Biocef Ed A-Ceph Keflex Keftab Panixine DisperDose Zartan
Active Comparator: Placebo → tolterodine ER 4 mg 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; Capsule, 4 mg, once daily, for up to 10 days based on treatment assignment and treatment period.; Other Names: Detrol LA™ ; Other: Placebo (vibegron); Inactive agent in tablet form, oral administration, once daily, up to 5 weeks, based on treatment assignment in each treatment period.; Other: Placebo (tolterodine ER); Inactive agent in capsule form, oral administration, once daily, up to 5 weeks, based on treatment assignment in each treatment period.; Drug: Prophylactic Antibiotic; 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.; Other Names: Levaquin Biocef Ed A-Ceph Keflex Keftab Panixine DisperDose Zartan
Experimental: Placebo → vibegron 50 mg 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; Tablet, 50 or 100 mg, once daily, for up to 10 days based on treatment assignments and treatment period.; Other Names: MK-4618 ; Other: Placebo (vibegron); Inactive agent in tablet form, oral administration, once daily, up to 5 weeks, based on treatment assignment in each treatment period.; Other: Placebo (tolterodine ER); Inactive agent in capsule form, oral administration, once daily, up to 5 weeks, based on treatment assignment in each treatment period.; Drug: Prophylactic Antibiotic; 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.; Other Names: Levaquin Biocef Ed A-Ceph Keflex Keftab Panixine DisperDose Zartan

Outcome Measures

Primary Outcome Measures

1. Fold-change From Baseline in Maximum Cystometric Capacity Post-dose on Day 7 [Baseline (pre-dose Day 1) and Day 7 (post-dose)]

   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.

2. Number of Participants Who Experienced an Adverse Event (AE) [Up to 6 weeks (up to 3 weeks in Period 1 and up to 3 weeks in Period 2)]

   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.

3. Number of Participants Who Discontinued Use of Study Drug Due to an AE [Up to 6 weeks (up to 3 weeks in Period 1 and up to 3 weeks in Period 2)]

   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.

Secondary Outcome Measures

1. Fold-change From Baseline in Volume of Urine at First Desire to Void Post-dose on Day 7 [Baseline (pre-dose Day 1) and Day 7 (post-dose)]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 75 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Merck Sharp & Dohme Corp.

Investigators

• Study Director: Medical Director, Merck Sharp & Dohme Corp.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Merck Sharp & Dohme Corp.
• ClinicalTrials.gov Identifier: NCT01500382
• Other Study ID Numbers: 4618-004
• First Posted: Dec 28, 2011
• Last Update Posted: Dec 24, 2018
• Last Verified: Dec 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Additional relevant MeSH terms: Urinary Bladder, Overactive; Anti-Bacterial Agents; Tolterodine Tartrate

Study Results

Participant Flow

Arm/Group Title	Vibegron 100 mg + Tolterodine 4 mg → Placebo	Placebo → Vibegron 100 mg	Placebo → Tolterodine 4 mg	Placebo → Vibegron 50 mg
Arm/Group Description	During Treatment Period 1, participants received 7 days of once-daily vibegron 100 mg and tolterodine extended-release (ER) 4 mg. Participants then completed a 2-week single-blind double-dummy placebo washout period prior to Treatment Period 2. During Treatment Period 2, participants received 7 days of once-daily placebo to match vibegron and placebo to match tolterodine ER.	During Treatment Period 1, participants received 7 days of once-daily placebo to match vibegron and placebo to match tolterodine ER. Participants then completed a 2-week single-blind double-dummy placebo washout period prior to Treatment Period 2. During Treatment Period 2, participants received 7 days of once daily vibegron 100 mg and placebo to match tolterodine ER.	During Treatment Period 1, participants received 7 days of once-daily placebo to match vibegron and placebo to match tolterodine ER. Participants then completed a 2-week single-blind double-dummy placebo washout period prior to Treatment Period 2. During Treatment Period 2, participants received 7 days of once-daily tolterodine 4 mg and placebo to match vibegron.	During Treatment Period 1, participants received 7 days of once-daily placebo to match vibegron and placebo to match tolterodine ER. Participants then completed a 2-week single-blind double-dummy placebo washout period prior to Treatment Period 2. During Treatment Period 2, participants received 7 days of once daily vibegron 50 mg and placebo to match tolterodine ER.
Period Title: Treatment Period 1
STARTED	1	1	1	1
COMPLETED	1	1	1	1
NOT COMPLETED	0	0	0	0
Period Title: Treatment Period 1
STARTED	1	1	1	1
COMPLETED	1	1	0	1
NOT COMPLETED	0	0	1	0
Period Title: Treatment Period 1
STARTED	1	1	0	1
COMPLETED	1	1	0	1
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	Vibegron 100 mg + Tolterodine 4 mg → Placebo	Placebo → Vibegron 100 mg	Placebo → Tolterodine 4 mg	Placebo → Vibegron 50 mg	Total
Arm/Group Description	During Treatment Period 1, participants received 7 days of once-daily vibegron 100 mg and tolterodine extended-release (ER) 4 mg. Participants then completed a 2-week single-blind double-dummy placebo washout period prior to Treatment Period 2. During Treatment Period 2, participants received 7 days of once-daily placebo to match vibegron and placebo to match tolterodine ER.	During Treatment Period 1, participants received 7 days of once-daily placebo to match vibegron and placebo to match tolterodine ER. Participants then completed a 2-week single-blind double-dummy placebo washout period prior to Treatment Period 2. During Treatment Period 2, participants received 7 days of once daily vibegron 100 mg and placebo to match tolterodine ER.	During Treatment Period 1, participants received 7 days of once-daily placebo to match vibegron and placebo to match tolterodine ER. Participants then completed a 2-week single-blind double-dummy placebo washout period prior to Treatment Period 2. During Treatment Period 2, participants received 7 days of once-daily tolterodine 4 mg and placebo to match vibegron.	During Treatment Period 1, participants received 7 days of once-daily placebo to match vibegron and placebo to match tolterodine ER. Participants then completed a 2-week single-blind double-dummy placebo washout period prior to Treatment Period 2. During Treatment Period 2, participants received 7 days of once daily vibegron 50 mg and placebo to match tolterodine ER.	Total of all reporting groups
Overall Participants	1	1	1	1	4
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	49 (NA)	61 (NA)	55 (NA)	68 (NA)	58.3 (8.14)
Sex: Female, Male (Count of Participants)
Female	1 100%	1 100%	1 100%	1 100%	4 100%
Male	0 0%	0 0%	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Fold-change From Baseline in Maximum Cystometric Capacity Post-dose on Day 7
Description	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.
Time Frame	Baseline (pre-dose Day 1) and Day 7 (post-dose)

Outcome Measure Data

Analysis Population Description

Study was terminated by the Sponsor prior to completion. No planned efficacy summaries or analyses were completed.

Arm/Group Title	Vibegron 100 mg	Vibegron 100 mg + Tolterodine ER 4 mg	Vibegron 50 mg	Placebo
Arm/Group Description	Participants received 7 days of once-daily vibegron 100 mg and placebo to match tolterodine ER 4 mg.	Participants received 7 days of once-daily vibegron 100 mg and tolterodine ER 4 mg.	Participants received 7 days of once-daily vibegron 50 mg and placebo to match tolterodine ER 4 mg.	Participants received 7 days of once-daily placebo to match vibegron 100 mg and placebo to match tolterodine ER 4 mg.
Measure Participants	0	0	0	0

2. Secondary Outcome

Title	Fold-change From Baseline in Volume of Urine at First Desire to Void Post-dose on Day 7
Description	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.
Time Frame	Baseline (pre-dose Day 1) and Day 7 (post-dose)

Outcome Measure Data

Analysis Population Description

Study was terminated by the Sponsor prior to completion. No planned efficacy summaries or analyses were completed.

Arm/Group Title	Vibegron 100 mg	Vibegron 100 mg + Tolterodine ER 4 mg	Vibegron 50 mg	Placebo
Arm/Group Description	Participants received 7 days of once-daily vibegron 100 mg and placebo to match tolterodine ER 4 mg.	Participants received 7 days of once-daily vibegron 100 mg and tolterodine ER 4 mg.	Participants received 7 days of once-daily vibegron 50 mg and placebo to match tolterodine ER 4 mg.	Participants received 7 days of once-daily placebo to match vibegron 100 mg and placebo to match tolterodine ER 4 mg.
Measure Participants	0	0	0	0

3. Primary Outcome

Title	Number of Participants Who Experienced an Adverse Event (AE)
Description	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.
Time Frame	Up to 6 weeks (up to 3 weeks in Period 1 and up to 3 weeks in Period 2)

Outcome Measure Data

Analysis Population Description

The All Subjects as Treated (AST) population, which included all participants who received at least one dose of study drug, was used for the safety evaluation. AEs are reported/grouped by drug taken at the time and not by randomly assigned sequence.

Arm/Group Title	Vibegron 100 mg	Vibegron 100 mg + Tolterodine ER 4 mg	Vibegron 50 mg	Placebo
Arm/Group Description	Participants received 7 days of once-daily vibegron 100 mg and placebo to match tolterodine ER 4 mg.	Participants received 7 days of once-daily vibegron 100 mg and tolterodine ER 4 mg.	Participants received 7 days of once-daily vibegron 50 mg and placebo to match tolterodine ER 4 mg.	Participants received 7 days of once-daily placebo to match vibegron 100 mg and placebo to match tolterodine ER 4 mg.
Measure Participants	1	1	1	4
Number [Participants]	0 0%	0 0%	0 0%	0 0%

4. Primary Outcome

Title	Number of Participants Who Discontinued Use of Study Drug Due to an AE
Description	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.
Time Frame	Up to 6 weeks (up to 3 weeks in Period 1 and up to 3 weeks in Period 2)

Outcome Measure Data

Analysis Population Description

The AST population, which included all participants who received at least one dose of study drug, was used for the safety evaluation. AEs are reported/grouped by drug taken at the time and not by randomly assigned sequence.

Arm/Group Title	Vibegron 100 mg	Vibegron 100 mg + Tolterodine ER 4 mg	Vibegron 50 mg	Placebo
Arm/Group Description	Participants received 7 days of once-daily vibegron 100 mg and placebo to match tolterodine ER 4 mg.	Participants received 7 days of once-daily vibegron 100 mg and tolterodine ER 4 mg.	Participants received 7 days of once-daily vibegron 50 mg and placebo to match tolterodine ER 4 mg.	Participants received 7 days of once-daily placebo to match vibegron 100 mg and placebo to match tolterodine ER 4 mg.
Measure Participants	1	1	1	4
Number [Participants]	0 0%	0 0%	0 0%	0 0%

Adverse Events

Time Frame	Up to 6 weeks (up to 3 weeks in Period 1 and up to 3 weeks in Period 2)
Adverse Event Reporting Description	The AST population, which included all participants who received at least one dose of study drug, was used for the safety evaluation. AEs are reported/grouped by drug taken at the time and not by randomly assigned sequence.
Arm/Group Title	Vibegron 100 mg		Vibegron 100 mg + Tolterodine ER 4 mg		Vibegron 50 mg		Placebo
Arm/Group Description	Participants received 7 days of once-daily vibegron 100 mg and placebo to match tolterodine ER 4 mg.		Participants received 7 days of once-daily vibegron 100 mg and tolterodine ER 4 mg.		Participants received 7 days of once-daily vibegron 50 mg and placebo to match tolterodine ER 4 mg.		Participants received 7 days of once-daily placebo to match vibegron 100 mg and placebo to match tolterodine ER 4 mg.
All Cause Mortality
	Vibegron 100 mg		Vibegron 100 mg + Tolterodine ER 4 mg		Vibegron 50 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Vibegron 100 mg		Vibegron 100 mg + Tolterodine ER 4 mg		Vibegron 50 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/1 (0%)		0/1 (0%)		0/1 (0%)		0/4 (0%)
Other (Not Including Serious) Adverse Events
	Vibegron 100 mg		Vibegron 100 mg + Tolterodine ER 4 mg		Vibegron 50 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/1 (0%)		0/1 (0%)		0/1 (0%)		0/4 (0%)

Limitations/Caveats

This study was terminated early due to insufficient recruitment. Only four participants in total participated in the study with three completing and one discontinuation.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The SPONSOR must have the opportunity to review all proposed abstracts, manuscripts,or presentations regarding this study 60 days prior to submission for publication/presentation.