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Study to Test the Efficacy and Safety of the Beta-3 Agonist Mirabegron (YM178) in Patients With Symptoms of Overactive Bladder (ARIES)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Astellas Pharma Inc
ClinicalTrials.gov Identifier:
NCT00662909
First received: April 17, 2008
Last updated: July 1, 2013
Last verified: July 2013
  Purpose

The study is intended to test the efficacy, safety and tolerability of two doses of mirabegron against placebo to treat patients with symptoms of overactive bladder


Condition Intervention Phase
Urinary Bladder, Overactive
Drug: Mirabegron
Drug: Placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: A Phase III, Randomized, Double-Blind, Parallel Group, Placebo Controlled, Multicenter Study to Assess the Efficacy and Safety of Mirabegron in Subjects With Symptoms of Overactive Bladder

Resource links provided by NLM:


Further study details as provided by Astellas Pharma Inc:

Primary Outcome Measures:
  • Change From Baseline to End of Treatment (Final Visit) in Mean Number of Incontinence Episodes Per 24 Hours [ Time Frame: Baseline and Week 12 (Final Visit) ] [ Designated as safety issue: No ]
    The average number of incontinence episodes (any involuntary leakage of urine) per day was derived from the number of incontinence episodes recorded by the patient in a micturition diary for 3-days before the Baseline and Week 12 clinic visits. Least Squares (LS) Means were generated from an analysis of covariance (ANCOVA) model with treatment group, gender, and geographic region as fixed factors and baseline as a covariate.

  • Change From Baseline to End of Treatment (Final Visit) in Mean Number of Micturitions Per 24 Hours [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]
    The average number of micturitions (urinations) per 24 hours was derived from the number of times a patient urinates (excluding incontinence only episodes) per day recorded by the patient in a micturition diary for 3-days before the Baseline and Week 12 clinic visits. LS Means generated from an ANCOVA model with treatment group, gender, and geographic region as fixed factors and baseline as a covariate.


Secondary Outcome Measures:
  • Change From Baseline to Final Visit in Mean Volume Voided Per Micturition [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]
    The average volume voided per micturition was calculated from the volume of each micturition measured by the patient and recorded in a micturition diary for 3 days before the Baseline and Week 12 clinic visits. LS Means were generated from an ANCOVA model with treatment group, gender, and geographic region as fixed factors and baseline as a covariate.

  • Change From Baseline to Week 4 in Mean Number of Incontinence Episodes Per 24 Hours [ Time Frame: Baseline and Week 4 ] [ Designated as safety issue: No ]
    The average number of incontinence episodes (any involuntary leakage of urine) per 24 hours was derived from the number of incontinence episodes recorded by the patient in a micturition diary for 3-days before the Baseline and Week 4 clinic visits. LS Means were generated from an ANCOVA model with treatment group, gender, and geographic region as fixed factors and baseline as a covariate.

  • Change From Baseline to Week 4 in Mean Number of Micturitions Per 24 Hours [ Time Frame: Baseline and Week 4 ] [ Designated as safety issue: No ]
    The average number of micturitions (urinations) per 24 hours was calculated from the number of micturitions recorded by the patient in a micturition diary for 3-days before the Baseline and Week 4 clinic visits. LS Means generated from an ANCOVA model with treatment group, gender, and geographic region as fixed factors and baseline as a covariate.

  • Change From Baseline to Week 8 and Week 12 in Mean Number of Incontinence Episodes Per 24 Hours [ Time Frame: Baseline and Weeks 8 and 12 ] [ Designated as safety issue: No ]
    The average number of incontinence episodes (any involuntary leakage of urine) per 24 hours was derived from the number of incontinence episodes recorded by the patient in a micturition diary for 3-days before the Baseline, Week 8 and Week 12 clinic visits. LS Means were generated from an ANCOVA model with treatment group, gender, and geographic region as fixed factors and baseline as a covariate.

  • Change From Baseline to Week 8 and Week 12 in Mean Number of Micturitions Per 24 Hours [ Time Frame: Baseline and Weeks 8 and 12 ] [ Designated as safety issue: No ]
    The average number of micturitions (urinations) per 24 hours was calculated from the number of micturitions recorded by the patient in a micturition diary for 3-days before the Baseline, Week 8 and 12 clinic visits. LS Means generated from an ANCOVA model with treatment group, gender, and geographic region as fixed factors and baseline as a covariate.

  • Change From Baseline to Week 4, Week 8 and Week 12 in Mean Volume Voided Per Micturition [ Time Frame: Baseline and Weeks 4, 8 and 12 ] [ Designated as safety issue: No ]
    The average volume voided per micturition was calculated from the volume of each micturition measured by the patient and recorded in a micturition diary for 3 days before the Baseline and Week 4, 8 and 12 clinic visits. LS Means generated from an ANCOVA model with treatment group, gender, and geographic region as fixed factors and baseline as a covariate.

  • Change From Baseline to Week 4, Week 8, Week 12 and Final Visit in Mean Number of Urgency Incontinence Episodes Per 24 Hours [ Time Frame: Baseline and Weeks 4, 8 and 12 ] [ Designated as safety issue: No ]
    The involuntary leakage of urine accompanied by or immediately proceeded by urgency, derived from the number of incontinence episodes classified by the patient in a 3-day micturition diary as 3 or 4 on the Patient Perception of Intensity of Urgency Scale: 0 = No urgency; 1 = Mild urgency; 2 = Moderate urgency, could postpone voiding a short while; 3 = Severe urgency, could not postpone voiding; 4 = Urge incontinence, leaked before arriving to the toilet. LS Means are from an ANCOVA with treatment group, gender, and geographic region as fixed factors and baseline as a covariate.

  • Change From Baseline to Week 4, Week 8, Week 12 and Final Visit in Mean Number of Urgency Episodes (Grades 3 or 4) Per 24 Hours [ Time Frame: Baseline and Weeks 4, 8 and 12 ] [ Designated as safety issue: No ]
    The average number of urgency episodes (the sudden, compelling desire to pass urine, which is difficult to defer), derived from urgency episodes classified by the patient in a 3-day micturition diary as grade 3 or 4 on the Patient Perception of Intensity of Urgency Scale: 0: No urgency; 1: Mild urgency; 2: Moderate urgency, could delay voiding a short while; 3: Severe urgency, could not delay voiding; 4: Urge incontinence, leaked before arriving to the toilet. LS Means are from an ANCOVA with treatment group, gender, and geographic region as fixed factors and baseline as a covariate.

  • Change From Baseline to Week 4, Week 8, Week 12 and Final Visit in Mean Level of Urgency [ Time Frame: Baseline and Weeks 4, 8 and 12 ] [ Designated as safety issue: No ]
    Average of patients' ratings on the degree of urgency associated with each micturition and/or incontinence episode recorded in a 3-day micturition diary according to the following 5-point categorical scale (Patient Perception of Intensity of Urgency Scale): 0: No urgency; 1: Mild urgency; 2: Moderate urgency, could delay voiding a short while; 3: Severe urgency, could not delay voiding; 4: Urge incontinence, leaked before arriving to the toilet. LS Means are from an ANCOVA with treatment group, gender, and geographic region as fixed factors and baseline as a covariate.

  • Change From Baseline to Week 4, Week 8, Week 12 and Final Visit in Mean Number of Nocturia Episodes Per 24 Hours [ Time Frame: Baseline and Weeks 4, 8 and 12 ] [ Designated as safety issue: No ]

    Nocturia is defined as waking at night one or more times to void. The average number of times a patient urinated (excluding incontinence only episodes) during sleeping time per day was derived from the 3-day patient micturition diary.

    LS Means are from an ANCOVA with treatment group, gender, and geographic region as fixed factors and baseline as a covariate.


  • Change From Baseline to Week 4, Week 8, Week 12 and Final Visit in Mean Number of Pads Used Per 24 Hours [ Time Frame: Baseline and Weeks 4, 8 and 12 ] [ Designated as safety issue: No ]

    The average number of times a patient records a new pad used per day during the 3-day micturition diary period.

    LS Means are from an ANCOVA with treatment group, gender, and geographic region as fixed factors and baseline as a covariate.


  • Percentage of Participants With Zero Incontinence Episodes at Weeks 4, 8, 12 and the Final Visit [ Time Frame: Weeks 4, 8 and 12 ] [ Designated as safety issue: No ]
    The percentage of participants with no incontinence episodes for the 3 days prior to each clinic visit derived from the micturition diary recorded by the patient.

  • Percentage of Participants With ≥ 50% Reduction in Incontinence Episodes at Weeks 4, 8, 12 and the Final Visit [ Time Frame: Baseline and Weeks 4, 8 and 12 ] [ Designated as safety issue: No ]
    The percentage of participants with at least 50% decrease from baseline in mean number of incontinence episodes per 24 hours during the 3 days prior to each clinic visit derived from the patient micturition diary.

  • Change From Baseline to Week 4, Week 8, Week 12 and Final Visit in Symptom Bother Score [ Time Frame: Baseline and Weeks 4, 8 and 12 ] [ Designated as safety issue: No ]

    Overactive bladder symptoms were assessed using the symptom bother scale of the overactive bladder questionnaire. The symptom bother scale consists of 8 questions answered by the participant on a scale from 1-6. The total symptom bother score was calculated from the 8 answers and then transformed to range from 0 to 100, with 100 indicating worst severity. A negative change from Baseline in symptom bother score indicates improvements.

    LS Means are from an ANCOVA with treatment group, gender, and geographic region as fixed factors and baseline as a covariate.


  • Change From Baseline to Week 4, Week 8, Week 12 and Final Visit in Health-related Quality of Life (HRQL) Total Score [ Time Frame: Baseline and Weeks 4, 8 and 12 ] [ Designated as safety issue: No ]

    Health-related quality of life was assessed by the HRQL subscales (coping, concern, sleep and social interaction) of the overactive bladder questionnaire (OABq). The HRQL total score was calculated by adding the 4 HRQL subscale scores, and transforming to a scale from 0 to 100, with higher scores indicating better quality of life. A positive change from Baseline in HRQL score indicates improvements.

    LS Means are from an ANCOVA with treatment group, gender, and geographic region as fixed factors and baseline as a covariate.


  • Change From Baseline to Week 12 and Final Visit in Work Productivity and Activity Impairment (WPAI): Percent Work Time Missed [ Time Frame: Baseline and Week12 ] [ Designated as safety issue: No ]
    The Work Productivity and Activity Impairment: Specific Health Problem (WPAI:SHP) questionnaire was used to assess the degree and extent to which overactive bladder (OAB) symptoms interfered with work productivity in the last 7 days. Percent of work time missed is derived from the number of hours of work missed due to OAB symptoms as a percentage of total hours that should have been worked. A higher percentage indicates more hours missed. A negative change from baseline indicates improvement.

  • Change From Baseline to Week 12 and Final Visit in Work Productivity and Activity Impairment (WPAI): Percent Impairment While Working [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]
    The Work Productivity and Activity Impairment: Specific Health Problem (WPAI:SHP) questionnaire was used to assess the degree and extent to which overactive bladder (OAB) symptoms interfered with work productivity in the last 7 days. Percent impairment while working was derived from the patient's assessment of the degree to which OAB affected their productivity while working. A higher percentage indicates greater impairment and less productivity. A negative change from baseline indicates improvement.

  • Change From Baseline to Week 12 and Final Visit in Work Productivity and Activity Impairment (WPAI): Percent Overall Work Impairment [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]
    The Work Productivity and Activity Impairment: Specific Health Problem (WPAI:SHP) questionnaire was used to assess the degree and extent to which overactive bladder (OAB) symptoms interfered with work productivity in the last 7 days. Percent overall work impairment takes into account both hours missed due to OAB symptoms and the patient's assessment of the degree to which OAB affected their productivity while working. A higher percentage indicates greater impairment and less productivity. A negative change from baseline indicates improvement.

  • Change From Baseline to Week 12 and Final Visit in Work Productivity and Activity Impairment (WPAI): Percent Activity Impairment [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]
    The Work Productivity and Activity Impairment: Specific Health Problem (WPAI:SHP) questionnaire was used to assess the degree and extent to which overactive bladder (OAB) symptoms interfered with daily activities over the last 7 days. Percent activity impairment is derived from the patient's assessment of the degree to which OAB affected their regular daily activities. A higher percentage indicates greater impairment. A negative change from baseline indicates improvement.

  • Change From Baseline to Week 4, Week 8, Week 12 and Final Visit in the European Quality of Life-5 Dimensions (EQ-5D) Visual Analog Scale (VAS) [ Time Frame: Baseline and Weeks 4, 8 and 12 ] [ Designated as safety issue: No ]
    The EQ-5D is an international, standardized, generic instrument for describing and evaluating health status. Health status is assessed by patients evaluating their health on a vertical, visual analog scale from 0 to 100 where the endpoints are labeled 'Worst imaginable health state' (=0) and 'Best imaginable health state' (=100). On the EQ-5D VAS, a positive change from baseline indicates improvement.

  • Change From Baseline to Week 12 and Final Visit in Patient Perception of Bladder Condition (PPBC) [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]
    The PPBC scale is a global assessment tool that asks patients to rate their impression of their current bladder condition on a 6-point scale from 1: 'Does not cause me any problems at all'; 2: 'Causes me some very minor problems'; 3: 'Causes me some minor problems'; 4: 'Causes me (some) moderate problems'; 5: 'Causes me severe problems' and 6: 'Causes me many severe problems'. LS means are from an ANCOVA model with treatment group, gender, and geographical regions as fixed factors and baseline as a covariate. A negative change from Baseline score indicates improvement.

  • Change From Baseline to Week 12 and Final Visit in Treatment Satisfaction on Visual Analog Scale (TS-VAS) [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]
    The TS-VAS is a visual analog scale (VAS) that asks patients to rate their satisfaction with treatment by placing a vertical mark on a 10 cm line where the endpoints are labeled 'No, not at all' on the left (=0) to 'Yes, completely satisfied' on the right (=10). LS means are from an ANCOVA model with treatment group, gender, and geographical regions as fixed factors and baseline as a covariate. A positive change from baseline indicates improvement.

  • Change From Baseline to Week 4, Week 8, Week 12 and Final Visit in Number of Non-study Related Visits to Physician [ Time Frame: Baseline and Weeks 4, 8 and 12 ] [ Designated as safety issue: No ]
    The number of times the patient visited a physician's office during the 4 weeks prior to each study visit (excluding study visits) because of the patient's bladder condition.

  • Percentage of Participants With Improvement in Patient Perception of Bladder Condition (PPBC) at Week 12 and Final Visit [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]
    The PPBC scale is a global assessment tool that asks patients to rate their impression of their current bladder condition on a 6-point scale from 1: 'Does not cause me any problems at all'; 2: 'Causes me some very minor problems'; 3: 'Causes me some minor problems'; 4: 'Causes me (some) moderate problems'; 5: 'Causes me severe problems' and 6: 'Causes me many severe problems'. Improvement was defined as at least a 1 point improvement from Baseline to post-baseline and a major improvement was defined as at least a 2 point improvement from Baseline to post-baseline in PPBC score.

  • Change From Baseline to Final Visit in European Quality of Life-5 Dimensions (EQ-5D) Mobility Score [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]

    The EQ-5D is an international, standardized, nondisease-specific (i.e., generic) instrument for describing and valuing health status. Participants were asked to indicate which of the following statements best describes their health state:

    I have no problems in walking about; I have some problems in walking about; I am confined to bed.

    In the table below, each row title lists Baseline health status first followed by Final Visit health status and reports the number of patients in that category. Missing data indicates patients with no data available for that Visit.


  • Change From Baseline to Final Visit in European Quality of Life-5 Dimensions (EQ-5D) Self-care Score [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]

    The EQ-5D is an international, standardized, nondisease-specific (i.e., generic) instrument for describing and valuing health status. Participants were asked to indicate which of the following statements best describes their health state:

    I have no problems with self-care; I have some problems washing or dressing myself; I am unable to wash or dress myself. In the table below, each row title lists Baseline health status first followed by Final Visit health status and reports the number of patients in that category. Missing data indicates patients with no data available for that Visit.


  • Change From Baseline to Final Visit in European Quality of Life-5 Dimensions (EQ-5D) Usual Activities Score [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]
    The EQ-5D is a standardized, nondisease-specific instrument for describing health status. Participants were asked which statement best describes their health state with regard to usual activities (work, study or leisure): I have no problems performing my usual activities; I have some problems performing my usual activities; I am unable to perform my usual activities. In the table below, each row title lists Baseline health status first followed by Final Visit health status and reports the number of patients in that category. Missing data indicates patients with no data available at that Visit.

  • Change From Baseline to Final Visit in European Quality of Life-5 Dimensions (EQ-5D) Pain/Discomfort Score [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]

    The EQ-5D is an international, standardized, nondisease-specific (i.e., generic) instrument for describing and valuing health status. Participants were asked to indicate which of the following statements best describes their health state:

    I have no pain or discomfort; I have moderate pain or discomfort; I have extreme pain or discomfort. In the table below, each row title lists Baseline health status first followed by Final Visit health status and reports the number of patients in that category. Missing data indicates patients with no data available for that Visit.


  • Change From Baseline to Final Visit in European Quality of Life-5 Dimensions (EQ-5D) Anxiety/Depression Score [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]

    The EQ-5D is an international, standardized, nondisease-specific (i.e., generic) instrument for describing and valuing health status. Participants were asked to indicate which of the following statements best describes their health state:

    I am not anxious or depressed; I am moderately anxious or depressed; I am extremely anxious or depressed. In the table below, each row title lists Baseline health status first followed by Final Visit health status and reports the number of patients in that category. Missing data indicates patients with no data available for that Visit.



Enrollment: 2149
Study Start Date: April 2008
Study Completion Date: April 2009
Primary Completion Date: April 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Placebo
Participants received matching placebo tablets orally once a day for 12 weeks
Drug: Placebo
Oral
Experimental: Mirabegron 50 mg
Participants received mirabegron 50 mg tablets orally once a day for 12 weeks
Drug: Mirabegron
Oral
Other Names:
  • YM178
  • Myrebtriq
Experimental: Mirabegron 100 mg
Participants received mirabegron 100 m tablets, orally once a day for 12 weeks
Drug: Mirabegron
Oral
Other Names:
  • YM178
  • Myrebtriq

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patient is willing and able to complete the micturition diary and questionnaires correctly
  • Patient has symptoms of overactive bladder for ≥ 3 months
  • Patient must experience frequency of micturition on average ≥ 8 times per 24-hour period during the 3-day micturition diary period
  • Patient must experience at least 3 episodes of urgency (grade 3 or 4) with or without incontinence during the 3-day micturition diary period

Exclusion Criteria:

  • Patient is breastfeeding, pregnant, intends to become pregnant during the study, or of childbearing potential, sexually active and not practicing a highly reliable method of birth control
  • Patient has significant stress incontinence or mixed stress/urge incontinence where stress is the predominant factor
  • Patient has an indwelling catheter or practices intermittent self-catheterization
  • Patient has diabetic neuropathy
  • Patient has evidence of a symptomatic urinary tract infection, chronic inflammation such as interstitial cystitis, bladder stones, previous pelvic radiation therapy or previous or current malignant disease of the pelvic organs
  • Patient receives non-drug treatment including electro-stimulation therapy
  • Patient has severe hypertension
  • Patient has a known or suspected hypersensitivity to YM178, other beta-adrenoreceptor (ß-AR) agonists, or any of the other inactive ingredients
  • Patient has been treated with any investigational drug or device within 30 days
  • Patient had an average total daily urine volume > 3000 mL as recorded in the 3-day micturition diary period
  • Patient has serum creatinine of >150 μmol/L, or aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2x upper limit of normal range (ULN), or Gamma glutamyl transferase (γ-GT) > 3x ULN
  • Patient has a clinically significant abnormal electrocardiogram (ECG)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00662909

  Show 125 Study Locations
Sponsors and Collaborators
Astellas Pharma Inc
Investigators
Study Director: Use Central Contact Astellas Pharma Global Development
  More Information

Publications:
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Astellas Pharma Inc
ClinicalTrials.gov Identifier: NCT00662909     History of Changes
Other Study ID Numbers: 178-CL-047
Study First Received: April 17, 2008
Results First Received: July 11, 2012
Last Updated: July 1, 2013
Health Authority: United States: Food and Drug Administration
Canada: Health Canada

Keywords provided by Astellas Pharma Inc:
Overactive bladder (OAB)
Frequency
Micturition
Urgency
Urinary incontinence
Urinary urge incontinence
YM178

Additional relevant MeSH terms:
Urinary Bladder, Overactive
Lower Urinary Tract Symptoms
Signs and Symptoms
Urinary Bladder Diseases
Urologic Diseases
Urological Manifestations
Mirabegron
Cholinergic Agents
Cholinergic Antagonists
Molecular Mechanisms of Pharmacological Action
Muscarinic Antagonists
Neurotransmitter Agents
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses
Urological Agents

ClinicalTrials.gov processed this record on November 20, 2014