Clinical trial NCT01340027: A Study to Evaluate the Efficacy, Safety and Tolerability of Mirabegron and Solifenacin Succinate Alone and in Combination for the Treatment of Overactive Bladder
Official title: A Randomized, Double-Blind, Factorial, Parallel-Group, Active and Placebo-Controlled, Multicenter Dose-Ranging Study to Evaluate the Efficacy, Safety and Tolerability of Six Dose Combinations of Solifenacin Succinate and Mirabegron Compared to Mirabegron and Solifenacin Succinate Monotherapies in the Treatment of Overactive Bladder.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Urologic Diseases
Urinary Bladder Diseases
Urological Manifestations
Signs and Symptoms
Urinary Bladder, Overactive
Keywords: Urinary incontinence
Overactive bladder (OAB)
Micturition
Frequency
YM178
Urgency incontinence
Urgency
Lead sponsor: Astellas Pharma Inc
Sponsor class: INDUSTRY
First posted: 2011-04-21
Enrollment: 1307
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to examine how well two medicines in combination (solifenacin succinate and mirabegron) work in the treatment of bladder problems over a 12-week period.


Eligibility criteria: Inclusion Criteria:

* Inclusion Criteria at Visit 1/Screening:

  * Subject has a Body Mass Index (BMI) of between 18 and 35 kg/m\^2 and a total body weight between 50 and 95 kg;
  * Subject is willing and able to complete the micturition diary and questionnaires correctly and is willing and able to measure his/her vital signs at home at stipulated time points, using the device provided by the study personnel, and to adequately record the readings;
  * Subject has symptoms of overactive bladder (OAB; urinary frequency, urgency and/or urgency incontinence) for at least 3 months.
* Inclusion Criteria at Visit 3/Baseline:

  * Subject has experienced frequency of micturition on average ≥ 8 times per 24-hour period during the 3-day micturition diary period (incontinence episode should not be counted as a micturition);
  * Subject must experience at least 1 episode of urgency (grade 3 or 4) per 24-hour period (with or without urgency incontinence) during the 3 day micturition diary period.

Exclusion Criteria:

* Exclusion Criteria at Visit 1/Screening:

  * Subject is breastfeeding, pregnant or intends to become pregnant during the study. The pregnancy test (Beta Human Chorionic Gonadotropin in serum) at Screening must be negative in women of childbearing potential;
  * Female subjects of childbearing potential and not using a highly effective method of birth control during the study and for 30 days after final study drug administration.
  * Male subjects (unless surgically sterile) with female spouses/partners who are of childbearing potential, and not using a barrier method of contraception during the study and for 30 days after final study drug administration. In addition, female spouses/partners of male subjects and who are of childbearing potential should also use a highly effective method of birth control during the study and for 30 days after final study drug administration. Highly effective methods of birth control are defined as those, alone or in combination, that result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly.
  * Subject has significant post-void residual (PVR) volume (\> 150 mL);
  * Subject has significant stress incontinence or mixed stress/urgency incontinence where stress is the predominant factor as determined by the Investigator (for female subjects confirmed by the cough provocation test);
  * Subject has a neurological cause for detrusor overactivity;
  * Subject has an indwelling catheter or practices intermittent self-catheterization;
  * Subject has diabetic neuropathy;
  * Subject has chronic inflammation such as interstitial cystitis, bladder stones, previous pelvic radiation therapy or previous or current malignant disease of the pelvic organs;
  * Subject has had previous lower urinary tract or pelvic floor surgery (except cystoscopy);
  * Subject has had intravesical treatment in the past 12 months with e.g., botulinum toxin, resiniferatoxin, capsaicin;
  * Subject has uncontrolled narrow angle glaucoma, urinary or gastric retention, severe ulcerative colitis or Crohn's Disease, toxic megacolon, myasthenia gravis or any other condition which makes the use of anticholinergics contraindicated;
  * Subject has clinically significant cardiovascular or cerebrovascular diseases within 6 months prior to Screening, such as myocardial infarction, uncontrolled angina, significant ventricular arrhythmias, heart failure and stroke;
  * Subject is receiving current non-drug treatment including electro-stimulation therapy (with the exception of a bladder training program or pelvic floor exercises which started more than 30 days prior to Screening);
  * Subject is using medications intended to treat OAB or prohibited medications.
  * Subject has known or suspected hypersensitivity to solifenacin succinate, mirabegron or any of their excipients;
  * Subject has any significant neurological disease or defect affecting bladder function (e.g., neurogenic bladder, systemic or central neurological disease such as multiple sclerosis \[MS\] and Parkinson's disease);
  * Subject has severe hypertension which is defined as a sitting average systolic blood pressure ≥ 180 mmHg and/or an average diastolic blood pressure ≥ 110 mmHg;
* Exclusion Criteria at Visit 2/Placebo Run-In:

  * Subject has evidence of a urinary tract infection (UTI) (urine culture containing \> 100,000 cfu/mL). The subject can be enrolled into the study after successful treatment of the UTI (confirmed by a laboratory result of negative urine culture). However, the subject must be re screened if the initial screening visit was \> 28 days;
  * Subject has a QT interval \> 450 ms or is at risk of QT prolongation (e.g., family history of long QT syndrome, hypokalaemia) or is on drug treatment known to be associated with QT prolongation;
  * Subject has clinically significant abnormalities on the 12 lead electrocardiogram (ECG);
  * Subject has serum creatinine \> 150 µmol/L, aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) \> 2x upper limit of normal (ULN), gamma-glutamyltransferase (γ-GT) \> 3x ULN, or total bilirubin \> 2x ULN, as assessed in Screening samples;
* Exclusion Criteria at Visit 3/Baseline:

  * Subject had an average total daily urine volume \> 3000 mL as recorded in the micturition diary period;
  * Subject has severe hypertension which is defined as a sitting average systolic blood pressure ≥ 180 mmHg and/or an average diastolic blood pressure ≥ 110 mmHg.

Primary outcomes:
measure: Change From Baseline to End of Treatment (EOT) in Mean Volume Voided Per Micturition
timeFrame: Baseline and Week 12
Secondary outcomes:
measure: Change From Baseline to End of Treatment in Mean Number of Micturitions Per 24 Hours
timeFrame: Baseline and Week 12
measure: Change From Baseline to End of Treatment in Mean Number of Incontinence Episodes Per 24 Hours
timeFrame: Baseline and Week 12
measure: Change From Baseline to Each Visit in Mean Volume Voided Per Micturition
timeFrame: Baseline and Weeks 2, 4, 8 and 12
measure: Change From Baseline to Each Visit in Mean Number of Micturitions Per 24 Hours
timeFrame: Baseline and Weeks 2, 4, 8 and 12
measure: Percentage of Participants With a Micturition Response
timeFrame: Baseline and Weeks 2, 4, 8 and 12
measure: Change From Baseline to Each Visit in Mean Number of Incontinence Episodes Per 24 Hours
timeFrame: Baseline and Weeks 2, 4, 8 and 12
measure: Percentage of Participants With Zero Incontinence Episodes Post-baseline
timeFrame: Weeks 2, 4, 8 and 12
measure: Percentage of Participants With 50% Reduction in Incontinence Episodes
timeFrame: Baseline and Weeks 2, 4, 8 and 12
measure: Change From Baseline to Each Visit in Mean Number of Urgency Incontinence Episodes Per 24 Hours
timeFrame: Baseline and Weeks 2, 4, 8 and 12
measure: Change From Baseline to Each Visit in Mean Number of Urgency Episodes (Grade 3 and/or 4) Per 24 Hours
timeFrame: Baseline and Weeks 2, 4, 8 and 12
measure: Change From Baseline to Each Visit in Mean Level of Urgency
timeFrame: Baseline and Weeks 2, 4, 8 and 12
measure: Change From Baseline to Each Visit in Mean Number of Pads Used Per 24 Hours
timeFrame: Baseline and Weeks 2, 4, 8 and 12
measure: Change From Baseline to Each Visit in Mean Number of Nocturia Episodes Per 24-Hours
timeFrame: Baseline and Weeks 2, 4, 8 and 12
measure: Change From Baseline to End of Treatment in Patient Perception of Bladder Condition (PPBC)
timeFrame: Baseline and Week 12
measure: Percentage of Participants With Improvement in PPBC
timeFrame: Baseline and Week 12
measure: Percentage of Participants With Major Improvement in PPBC
timeFrame: Baseline and Week 12
measure: Percentage of Participants With Deterioration in PPBC
timeFrame: Baseline and Week 12
measure: Change From Baseline to End of Treatment in Symptom Bother Score as Assessed by the Overactive Bladder Questionnaire (OAB-q)
timeFrame: Baseline and Week 12
measure: Percentage of Participants With a Symptom Bother Response
timeFrame: Baseline and Week 12
measure: Change From Baseline to End of Treatment in Health-related Quality of Life (HRQL) Total Score
timeFrame: Baseline and Week 12
measure: Percentage of Participants With a Health-related Quality of Life Total Score Response
timeFrame: Baseline and Week 12
measure: Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Mobility Score
timeFrame: Baseline and Week 12
measure: Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Self-care Score
timeFrame: Baseline and Week 12
measure: Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Usual Activities Score
timeFrame: Baseline and Week 12
measure: Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Pain/Discomfort Score
timeFrame: Baseline and Week 12
measure: Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Anxiety/Depression Score
timeFrame: Baseline and Week 12
measure: Change From Baseline to End of Treatment in European Quality of Life-5 Dimensions (EQ-5D) Visual Analog Scale (VAS)
timeFrame: Baseline and Week 12
measure: Change From Baseline to End of Treatment in Work Productivity and Activity Impairment (WPAI)
timeFrame: Baseline and Week 12
measure: Change From Baseline to End of Treatment in Treatment Satisfaction on Visual Analog Scale (TS-VAS)
timeFrame: Baseline and Week 12
Other outcomes:
Locations:
city: Minsk
country: Belarus
facility: BY37101
city: Minsk
country: Belarus
facility: BY37102
city: Minsk
country: Belarus
facility: BY37103
city: Vitebsk
country: Belarus
facility: BY37104
city: Brussels
country: Belgium
facility: BE32102
city: Edegem
country: Belgium
facility: BE32104
city: Gent
country: Belgium
facility: BE32103
city: Leuven
country: Belgium
facility: BE32101
city: Bohumín
country: Czechia
facility: CZ42005
city: Hradec Kralove
country: Czechia
facility: CZ42003
city: Ostrava
country: Czechia
facility: CZ42011
city: Plzen
country: Czechia
facility: CZ42006
city: Prague 4
country: Czechia
facility: CZ42007
city: Prague
country: Czechia
facility: CZ42001
city: Prague
country: Czechia
facility: CZ42009
city: Roudnice nad Labem
country: Czechia
facility: CZ42010
city: Sternberk
country: Czechia
facility: CZ42012
city: Uherske Hradiste
country: Czechia
facility: CZ42002
city: Aarhus N
country: Denmark
facility: DK45101
city: Herlev
country: Denmark
facility: DK45102
city: Holstebro
country: Denmark
facility: DK45104
city: Helsinki
country: Finland
facility: FI35803
city: Kouvola
country: Finland
facility: FI35804
city: Oulu
country: Finland
facility: FI35801
city: Tampere
country: Finland
facility: FI35802
city: Colmar Cedex
country: France
facility: FR33104
city: Dijon
country: France
facility: FR33108
city: Orleans
country: France
facility: FR33103
city: Paris Cedex 13
country: France
facility: FR33111
city: Paris cedex 20
country: France
facility: FR33112
city: Toulouse
country: France
facility: FR33106
city: Tours
country: France
facility: FR33110
city: Bad Ems
country: Germany
facility: DE49109
city: Göttingen
country: Germany
facility: DE49103
city: Hagenow
country: Germany
facility: DE49117
city: Hettstedt
country: Germany
facility: DE49105
city: Leipzig
country: Germany
facility: DE49108
city: Neustadt I. Sachsen
country: Germany
facility: DE49110
city: Reutlingen
country: Germany
facility: DE49118
city: Rostock
country: Germany
facility: DE49101
city: Sangerhausen
country: Germany
facility: DE49111
city: Wismar
country: Germany
facility: DE49104
city: Csongrád
country: Hungary
facility: HU36108
city: Gyor
country: Hungary
facility: HU36101
city: Körmend
country: Hungary
facility: HU36106
city: Miskolc
country: Hungary
facility: HU36110
city: Sopron
country: Hungary
facility: HU36104
city: Szekszárd
country: Hungary
facility: HU36103
city: Tatabánya
country: Hungary
facility: HU36107
city: Avellino
country: Italy
facility: IT39103
city: Catanzaro
country: Italy
facility: IT39101
city: Florence
country: Italy
facility: IT39105
city: Treviglio (BG)
country: Italy
facility: IT39102
city: Amsterdam
country: Netherlands
facility: NL31104
city: Maastricht
country: Netherlands
facility: NL31106
city: Sneek
country: Netherlands
facility: NL31102
city: Winterswijk
country: Netherlands
facility: NL31101
city: Elverum
country: Norway
facility: NO47104
city: Hamar
country: Norway
facility: NO47102
city: Krakow
country: Poland
facility: PL48107
city: Lodz
country: Poland
facility: PL48103
city: Lublin
country: Poland
facility: PL48108
city: Piaseczno
country: Poland
facility: PL48106
city: Pulawy
country: Poland
facility: PL48104
city: Warsaw
country: Poland
facility: PL48101
city: Warsaw
country: Poland
facility: PL48105
city: Wiecbork
country: Poland
facility: PL48112
city: Wroclaw
country: Poland
facility: PL48111
city: Coimbra
country: Portugal
facility: PT35102
city: Coimbra
country: Portugal
facility: PT35105
city: Lisbon
country: Portugal
facility: PT35104
city: Lisbon
country: Portugal
facility: PT35107
city: Porto
country: Portugal
facility: PT35110
city: Porto
country: Portugal
facility: PT35101
city: Tomar
country: Portugal
facility: PT35106
city: Brasov
country: Romania
facility: RO40106
city: Bucharest
country: Romania
facility: RO40102
city: Bucharest
country: Romania
facility: RO40104
city: Bucharest
country: Romania
facility: RO40103
city: Bucharest
country: Romania
facility: RO40108
city: Craiova
country: Romania
facility: RO40101
city: Craiova
country: Romania
facility: RO40105
city: Sibiu
country: Romania
facility: RO40107
city: Kazan
country: Russian Federation
facility: RU70112
city: Moscow
country: Russian Federation
facility: RU70108
city: Moscow
country: Russian Federation
facility: RU70110
city: Saint Petersburg
country: Russian Federation
facility: RU70102
city: Saint Petersburg
country: Russian Federation
facility: RU70103
city: Saint Petersburg
country: Russian Federation
facility: RU70101
city: Saint Petersburg
country: Russian Federation
facility: RU70107
city: St. Petersburg
country: Russian Federation
facility: RU70106
city: St. Petersburg
country: Russian Federation
facility: RU70109
city: Ufa
country: Russian Federation
facility: RU70113
city: Banska Bystrica
country: Slovakia
facility: SK42109
city: Bratislava
country: Slovakia
facility: SK42112
city: Kosice
country: Slovakia
facility: SK42107
city: Malacky
country: Slovakia
facility: SK42113
city: Nitra
country: Slovakia
facility: SK42104
city: Piestany
country: Slovakia
facility: SK42106
city: Pieštany
country: Slovakia
facility: SK42105
city: Presov
country: Slovakia
facility: SK42102
city: Trencin
country: Slovakia
facility: SK42108
city: Trenčín
country: Slovakia
facility: SK42101
city: Zilina
country: Slovakia
facility: SK42103
city: Madrid
country: Spain
facility: ES34103
city: Madrid
country: Spain
facility: ES34101
city: Madrid
country: Spain
facility: ES34109
city: Madrid
country: Spain
facility: ES34102
city: Pamplona
country: Spain
facility: ES34105
city: San Juan de Alicante
country: Spain
facility: ES34104
city: Sevilla
country: Spain
facility: ES34107
city: Gothenburg
country: Sweden
facility: SE46101
city: Karlshamn
country: Sweden
facility: SE46103
city: Malmo
country: Sweden
facility: SE46104
city: Stockholm
country: Sweden
facility: SE46102
city: Tanumshede
country: Sweden
facility: SE46105
city: Dnepropetrovsk
country: Ukraine
facility: UA38104
city: Donetsk
country: Ukraine
facility: UA38102
city: Donetsk
country: Ukraine
facility: UA38111
city: Kiev
country: Ukraine
facility: UA38106
city: Kiev
country: Ukraine
facility: UA38109
city: Lviv
country: Ukraine
facility: UA38107
city: Odessa
country: Ukraine
facility: UA38101
city: Zaporizhzhya
country: Ukraine
facility: UA38103
city: Bristol
country: United Kingdom
facility: GB44103
city: Cambridge
country: United Kingdom
facility: GB44108
city: Garston
country: United Kingdom
facility: GB44106
city: Glasgow
country: United Kingdom
facility: GB44111
city: Nantwich
country: United Kingdom
facility: GB44104
city: Northwood
country: United Kingdom
facility: GB44110
city: Plymouth
country: United Kingdom
facility: GB44107
city: Reading
country: United Kingdom
facility: GB44101
city: Sandbach
country: United Kingdom
facility: GB44105
Study officials:
affiliation: Astellas Pharma Europe B.V.
name: Study Physician
role: STUDY_DIRECTOR
affiliation: Bristol Urological Institute
name: Principal Investigator
role: PRINCIPAL_INVESTIGATOR
References:
citation: Abrams P, Kelleher C, Staskin D, Rechberger T, Kay R, Martina R, Newgreen D, Paireddy A, van Maanen R, Ridder A. Combination treatment with mirabegron and solifenacin in patients with overactive bladder: efficacy and safety results from a randomised, double-blind, dose-ranging, phase 2 study (Symphony). Eur Urol. 2015 Mar;67(3):577-88. doi: 10.1016/j.eururo.2014.02.012. Epub 2014 Feb 19.