Overactive Bladder, Overactive Urinary Bladder
Conditions
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.
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.
Interventions
DRUGVibegron
Tablet, 50 or 100 mg, once daily, for up to 10 days based on treatment assignments and treatment period.
DRUGTolterodine ER
Capsule, 4 mg, once daily, for up to 10 days based on treatment assignment and treatment period.
OTHERPlacebo (vibegron)
Inactive agent in tablet form, oral administration, once daily, up to 5 weeks, based on treatment assignment in each treatment period.
OTHERPlacebo (tolterodine ER)
Inactive agent in capsule form, oral administration, once daily, up to 5 weeks, based on treatment assignment in each treatment period.
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.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
40 Years to 75 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Vibegron 100 mg + Tolterodine 4 mg → Placebo 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. | 1 |
| Placebo → Vibegron 100 mg 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. | 1 |
| Placebo → Tolterodine 4 mg 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. | 1 |
| Placebo → Vibegron 50 mg 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. | 1 |
| Total | 4 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Washout Period | Study site went out of business | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Vibegron 100 mg + Tolterodine 4 mg → Placebo | Placebo → Vibegron 100 mg | Placebo → Tolterodine 4 mg | Placebo → Vibegron 50 mg | Total |
|---|---|---|---|---|---|
| Age, Continuous | 49 Years | 61 Years | 55 Years | 68 Years | 58.3 Years STANDARD_DEVIATION 8.14 |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 4 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 1 | 0 / 1 | 0 / 1 | 0 / 4 |
| serious Total, serious adverse events | 0 / 1 | 0 / 1 | 0 / 1 | 0 / 4 |
Outcome results
Primary
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.
Time frame: Baseline (pre-dose Day 1) and Day 7 (post-dose)
Population: Study was terminated by the Sponsor prior to completion. No planned efficacy summaries or analyses were completed.
Primary
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.
Time frame: Up to 6 weeks (up to 3 weeks in Period 1 and up to 3 weeks in Period 2)
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Vibegron 100 mg | Number of Participants Who Discontinued Use of Study Drug Due to an AE | 0 Participants |
| Vibegron 100 mg + Tolterodine ER 4 mg | Number of Participants Who Discontinued Use of Study Drug Due to an AE | 0 Participants |
| Vibegron 50 mg | Number of Participants Who Discontinued Use of Study Drug Due to an AE | 0 Participants |
| Placebo | Number of Participants Who Discontinued Use of Study Drug Due to an AE | 0 Participants |
Primary
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.
Time frame: Up to 6 weeks (up to 3 weeks in Period 1 and up to 3 weeks in Period 2)
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Vibegron 100 mg | Number of Participants Who Experienced an Adverse Event (AE) | 0 Participants |
| Vibegron 100 mg + Tolterodine ER 4 mg | Number of Participants Who Experienced an Adverse Event (AE) | 0 Participants |
| Vibegron 50 mg | Number of Participants Who Experienced an Adverse Event (AE) | 0 Participants |
| Placebo | Number of Participants Who Experienced an Adverse Event (AE) | 0 Participants |
Secondary
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.
Time frame: Baseline (pre-dose Day 1) and Day 7 (post-dose)
Population: Study was terminated by the Sponsor prior to completion. No planned efficacy summaries or analyses were completed.