A Study to Evaluate the Efficacy, Safety and Tolerability of Mirabegron and Solifenacin Succinate Alone and in Combination for the Treatment of Overactive Bladder
- Conditions
- Urologic DiseasesUrinary Bladder DiseasesSigns and SymptomsUrinary Bladder, OveractiveUrological Manifestations
- Interventions
- Registration Number
- NCT01340027
- Lead Sponsor
- Astellas Pharma Europe B.V.
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 1307
-
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 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- FACTORIAL
- Arm && Interventions
Group Intervention Description Placebo Placebo Participants received matching placebo tablets orally once a day for 12 weeks Solifenacin 2.5 mg Solifenacin succinate Participants received solifenacin 2.5 mg tablets orally once a day for 12 weeks Solifenacin 10 mg Solifenacin succinate Participants received solifenacin 10 mg tablets orally once a day for 12 weeks Mirabegron 25 mg Mirabegron Participants received mirabegron 25 mg tablets orally once a day for 12 weeks Mirabegron 50 mg Mirabegron Participants received mirabegron 50 mg tablets orally once a day for 12 weeks Solifenacin 5 mg Solifenacin succinate Participants received solifenacin 5 mg tablets orally once a day for 12 weeks Solifenacin 2.5 mg and Mirabegron 25 mg Mirabegron Participants received solifenacin 2.5 mg and mirabegron 25 mg tablets orally once a day for 12 weeks Solifenacin 2.5 mg and Mirabegron 50 mg Mirabegron Participants received solifenacin 2.5 mg and mirabegron 50 mg tablets orally once a day for 12 weeks Solifenacin 2.5 mg and Mirabegron 25 mg Solifenacin succinate Participants received solifenacin 2.5 mg and mirabegron 25 mg tablets orally once a day for 12 weeks Solifenacin 2.5 mg and Mirabegron 50 mg Solifenacin succinate Participants received solifenacin 2.5 mg and mirabegron 50 mg tablets orally once a day for 12 weeks Solifenacin 5 mg and Mirabegron 25 mg Mirabegron Participants received solifenacin 5 mg and mirabegron 25 mg tablets orally once a day for 12 weeks Solifenacin 5 mg and Mirabegron 25 mg Solifenacin succinate Participants received solifenacin 5 mg and mirabegron 25 mg tablets orally once a day for 12 weeks Solifenacin 5 mg and Mirabegron 50 mg Mirabegron Participants received solifenacin 5 mg and mirabegron 50 mg tablets orally once a day for 12 weeks Solifenacin 5 mg and Mirabegron 50 mg Solifenacin succinate Participants received solifenacin 5 mg and mirabegron 50 mg tablets orally once a day for 12 weeks Solifenacin 10 mg and Mirabegron 25 mg Mirabegron Participants received solifenacin 10 mg and mirabegron 25 mg tablets orally once a day for 12 weeks Solifenacin 10 mg and Mirabegron 25 mg Solifenacin succinate Participants received solifenacin 10 mg and mirabegron 25 mg tablets orally once a day for 12 weeks Solifenacin 10 mg and Mirabegron 50 mg Mirabegron Participants received solifenacin 10 mg and mirabegron 50 mg tablets orally once a day for 12 weeks Solifenacin 10 mg and Mirabegron 50 mg Solifenacin succinate Participants received solifenacin 10 mg and mirabegron 50 mg tablets orally once a day for 12 weeks
- Primary Outcome Measures
Name Time Method Change From Baseline to End of Treatment (EOT) in Mean Volume Voided Per Micturition Baseline and Week 12 The average volume voided per micturition was calculated from the volume of each micturition measured by the participant and recorded in a micturition diary for 3 days before the Baseline and Week 12 clinic visits.
- Secondary Outcome Measures
Name Time Method Change From Baseline to Each Visit in Mean Volume Voided Per Micturition Baseline and Weeks 2, 4, 8 and 12 The average volume voided per micturition was calculated from the volume of each micturition measured by the participant and recorded in a micturition diary for 3 days before the Baseline and each post-baseline clinic visit.
Change From Baseline to End of Treatment in Mean Number of Incontinence Episodes Per 24 Hours Baseline and Week 12 The average number of incontinence episodes (any involuntary leakage of urine) per day was derived from the number of incontinence episodes recorded by the participant in the micturition diary for 3-days before the Baseline and Week 12 clinic visits.
Change From Baseline to Each Visit in Mean Number of Micturitions Per 24 Hours Baseline and Weeks 2, 4, 8 and 12 The average number of micturitions (urinations) per 24 hours was derived from the number of urinations (excluding incontinence only episodes) per day recorded by the participant in the micturition diary for 3-days before the Baseline and each post-baseline clinic visit.
Percentage of Participants With Zero Incontinence Episodes Post-baseline Weeks 2, 4, 8 and 12 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 participant.
Percentage of Participants With 50% Reduction in Incontinence Episodes Baseline and Weeks 2, 4, 8 and 12 The percentage of participants with at least a 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 participant's micturition diary.
Change From Baseline to Each Visit in Mean Number of Nocturia Episodes Per 24-Hours Baseline and Weeks 2, 4, 8 and 12 Nocturia is defined as waking at night one or more times to void. The average number of times a participant urinated (excluding incontinence only episodes) during sleeping time per day was derived from the 3-day micturition diary.
Change From Baseline to Each Visit in Mean Number of Urgency Episodes (Grade 3 and/or 4) Per 24 Hours Baseline and Weeks 2, 4, 8 and 12 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 participant in the 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.
Percentage of Participants With Deterioration in PPBC Baseline and Week 12 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'. Deterioration was defined as at least a 1 point increase from Baseline in PPBC score.
Change From Baseline to End of Treatment in Symptom Bother Score as Assessed by the Overactive Bladder Questionnaire (OAB-q) Baseline and Week 12 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.
Percentage of Participants With a Symptom Bother Response Baseline and Week 12 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. Symptom bother response is defined as improvement (decrease) of at least 10 points from Baseline.
Change From Baseline to End of Treatment in Health-related Quality of Life (HRQL) Total Score Baseline and Week 12 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.
Change From Baseline to End of Treatment in European Quality of Life-5 Dimensions (EQ-5D) Visual Analog Scale (VAS) Baseline and Week 12 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 End of Treatment in Mean Number of Micturitions Per 24 Hours Baseline and Week 12 The average number of micturitions (urinations) per 24 hours was derived from the number of urinations (excluding incontinence only episodes) per day recorded by the participant in the micturition diary for 3-days before the Baseline and Week 12 clinic visits.
Percentage of Participants With a Micturition Response Baseline and Weeks 2, 4, 8 and 12 A responder is defined as a participant with at most 8 micturitions per 24 hours post-baseline and a negative change (i.e. an improvement) from Baseline.
Change From Baseline to Each Visit in Mean Number of Incontinence Episodes Per 24 Hours Baseline and Weeks 2, 4, 8 and 12 The average number of incontinence episodes (any involuntary leakage of urine) per day was derived from the number of incontinence episodes recorded by the participant in the micturition diary for 3-days before the Baseline and each post-baseline clinic visit.
Change From Baseline to Each Visit in Mean Number of Urgency Incontinence Episodes Per 24 Hours Baseline and Weeks 2, 4, 8 and 12 Urgency incontinence is the involuntary leakage of urine accompanied by or immediately preceded by urgency, and was derived from the number of incontinence episodes classified by the participant 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 postpone voiding a short while; 3 = Severe urgency, could not postpone voiding; 4 = Urge incontinence, leaked before arriving to the toilet.
Percentage of Participants With a Health-related Quality of Life Total Score Response Baseline and Week 12 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. HRQL response is defined as improvement (decrease) of at least 10 points from Baseline.
Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Mobility Score Baseline and Week 12 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 End of Treatment health status and reports the number of patients in that category.Change From Baseline to Each Visit in Mean Level of Urgency Baseline and Weeks 2, 4, 8 and 12 Average of participants' ratings on the degree of urgency associated with each micturition and/or incontinence episode recorded in the 3-day micturition diary according to 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.
Change From Baseline to Each Visit in Mean Number of Pads Used Per 24 Hours Baseline and Weeks 2, 4, 8 and 12 The average number of times a participant recorded a new pad used per day during the 3-day micturition diary period.
Change From Baseline to End of Treatment in Patient Perception of Bladder Condition (PPBC) Baseline and Week 12 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'. A negative change from Baseline score indicates improvement.
Percentage of Participants With Improvement in PPBC Baseline and Week 12 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 (decrease) from Baseline in PPBC score.
Change From Baseline to End of Treatment in Treatment Satisfaction on Visual Analog Scale (TS-VAS) Baseline and Week 12 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). A positive change from Baseline indicates improvement.
Percentage of Participants With Major Improvement in PPBC Baseline and Week 12 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'. Major improvement was defined as at least a 2-point improvement (decrease) from Baseline in PPBC score.
Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Self-care Score Baseline and Week 12 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 End of Treatment health status and reports the number of patients in that category.Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Anxiety/Depression Score Baseline and Week 12 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 End of Treatment health status and reports the number of patients in that category.Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Usual Activities Score Baseline and Week 12 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 End of Treatment health status and reports the number of patients in that category.Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Pain/Discomfort Score Baseline and Week 12 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 End of Treatment health status and reports the number of participants in that category.Change From Baseline to End of Treatment in Work Productivity and Activity Impairment (WPAI) Baseline and Week 12 This 6-item assessment measures productivity losses during the past 7 days and includes measures on work time missed due to health, impairment while working due to health (the participant's assessment of the degree to which health affected their productivity while working), overall work impairment due to health (takes into account both hours missed due to health and the participant's assessment of the degree to which health affected their productivity while working) and activity impairment due to health (the degree in which health problems affected their ability to do regular daily activities). Scores for each measure are expressed from 0 to 100 with higher numbers indicating greater impairment and less productivity, i.e., worse outcomes. A negative change from baseline indicates improvement.
Trial Locations
- Locations (133)
FR33111
🇫🇷Paris Cedex 13, France
SK42109
🇸🇰Banska Bystrica, Slovakia
SK42106
🇸🇰Piestany, Slovakia
SK42102
🇸🇰Presov, Slovakia
UA38102
🇺🇦Donetsk, Ukraine
GB44103
🇬🇧Bristol, United Kingdom
GB44104
🇬🇧Nantwich, United Kingdom
ES34109
🇪🇸Madrid, Spain
ES34103
🇪🇸Madrid, Spain
SK42112
🇸🇰Bratislava, Slovakia
ES34101
🇪🇸Madrid, Spain
GB44108
🇬🇧Cambridge, United Kingdom
GB44106
🇬🇧Garston, United Kingdom
GB44107
🇬🇧Plymouth, United Kingdom
UA38104
🇺🇦Dnepropetrovsk, Ukraine
SE46101
🇸🇪Gothenburg, Sweden
SE46103
🇸🇪Karlshamn, Sweden
ES34105
🇪🇸Pamplona, Spain
SE46104
🇸🇪Malmo, Sweden
SE46102
🇸🇪Stockholm, Sweden
GB44101
🇬🇧Reading, United Kingdom
SK42105
🇸🇰Pieštany, Slovakia
GB44110
🇬🇧Northwood, United Kingdom
ES34104
🇪🇸San Juan de Alicante, Spain
ES34102
🇪🇸Madrid, Spain
ES34107
🇪🇸Sevilla, Spain
SE46105
🇸🇪Tanumshede, Sweden
GB44111
🇬🇧Glasgow, United Kingdom
GB44105
🇬🇧Sandbach, United Kingdom
CZ42006
🇨🇿Plzen, Czechia
DK45104
🇩🇰Holstebro, Denmark
BY37101
🇧🇾Minsk, Belarus
BY37102
🇧🇾Minsk, Belarus
BE32102
🇧🇪Brussels, Belgium
BE32104
🇧🇪Edegem, Belgium
CZ42005
🇨🇿Bohumín, Czechia
CZ42003
🇨🇿Hradec Kralove, Czechia
CZ42011
🇨🇿Ostrava, Czechia
CZ42007
🇨🇿Prague 4, Czechia
CZ42001
🇨🇿Prague, Czechia
CZ42009
🇨🇿Prague, Czechia
CZ42010
🇨🇿Roudnice nad Labem, Czechia
CZ42012
🇨🇿Sternberk, Czechia
CZ42002
🇨🇿Uherske Hradiste, Czechia
FI35801
🇫🇮Oulu, Finland
FR33108
🇫🇷Dijon, France
FR33103
🇫🇷Orleans, France
FR33112
🇫🇷Paris cedex 20, France
FR33106
🇫🇷Toulouse, France
DE49109
🇩🇪Bad Ems, Germany
DE49103
🇩🇪Göttingen, Germany
DE49117
🇩🇪Hagenow, Germany
DE49105
🇩🇪Hettstedt, Germany
DE49110
🇩🇪Neustadt I. Sachsen, Germany
DE49108
🇩🇪Leipzig, Germany
DE49118
🇩🇪Reutlingen, Germany
DE49101
🇩🇪Rostock, Germany
DE49111
🇩🇪Sangerhausen, Germany
HU36108
🇭🇺Csongrád, Hungary
HU36106
🇭🇺Körmend, Hungary
HU36110
🇭🇺Miskolc, Hungary
HU36103
🇭🇺Szekszárd, Hungary
HU36107
🇭🇺Tatabánya, Hungary
NL31102
🇳🇱Sneek, Netherlands
NL31101
🇳🇱Winterswijk, Netherlands
NO47104
🇳🇴Elverum, Norway
PL48108
🇵🇱Lublin, Poland
PL48106
🇵🇱Piaseczno, Poland
PL48104
🇵🇱Pulawy, Poland
PL48105
🇵🇱Warsaw, Poland
PT35105
🇵🇹Coimbra, Portugal
PT35104
🇵🇹Lisbon, Portugal
PT35101
🇵🇹Porto, Portugal
PT35106
🇵🇹Tomar, Portugal
RO40102
🇷🇴Bucharest, Romania
RO40106
🇷🇴Brasov, Romania
RO40104
🇷🇴Bucharest, Romania
RO40108
🇷🇴Bucharest, Romania
RO40105
🇷🇴Craiova, Romania
RU70108
🇷🇺Moscow, Russian Federation
RU70110
🇷🇺Moscow, Russian Federation
RU70101
🇷🇺Saint Petersburg, Russian Federation
RU70106
🇷🇺St. Petersburg, Russian Federation
RU70113
🇷🇺Ufa, Russian Federation
DK45101
🇩🇰Aarhus N, Denmark
DK45102
🇩🇰Herlev, Denmark
IT39103
🇮🇹Avellino, Italy
IT39101
🇮🇹Catanzaro, Italy
IT39105
🇮🇹Florence, Italy
IT39102
🇮🇹Treviglio (BG), Italy
FR33104
🇫🇷Colmar Cedex, France
FR33110
🇫🇷Tours, France
BE32103
🇧🇪Gent, Belgium
FI35803
🇫🇮Helsinki, Finland
BY37103
🇧🇾Minsk, Belarus
BY37104
🇧🇾Vitebsk, Belarus
BE32101
🇧🇪Leuven, Belgium
FI35804
🇫🇮Kouvola, Finland
FI35802
🇫🇮Tampere, Finland
NL31104
🇳🇱Amsterdam, Netherlands
NL31106
🇳🇱Maastricht, Netherlands
PL48101
🇵🇱Warsaw, Poland
HU36101
🇭🇺Gyor, Hungary
NO47102
🇳🇴Hamar, Norway
PL48107
🇵🇱Krakow, Poland
PL48103
🇵🇱Lodz, Poland
PL48112
🇵🇱Wiecbork, Poland
HU36104
🇭🇺Sopron, Hungary
UA38109
🇺🇦Kiev, Ukraine
PL48111
🇵🇱Wroclaw, Poland
PT35102
🇵🇹Coimbra, Portugal
SK42108
🇸🇰Trencin, Slovakia
SK42103
🇸🇰Zilina, Slovakia
UA38107
🇺🇦Lviv, Ukraine
UA38101
🇺🇦Odessa, Ukraine
PT35107
🇵🇹Lisbon, Portugal
RO40103
🇷🇴Bucharest, Romania
RO40101
🇷🇴Craiova, Romania
RU70112
🇷🇺Kazan, Russian Federation
RU70102
🇷🇺Saint Petersburg, Russian Federation
SK42107
🇸🇰Kosice, Slovakia
PT35110
🇵🇹Porto, Portugal
RU70109
🇷🇺St. Petersburg, Russian Federation
SK42104
🇸🇰Nitra, Slovakia
UA38111
🇺🇦Donetsk, Ukraine
RO40107
🇷🇴Sibiu, Romania
RU70103
🇷🇺Saint Petersburg, Russian Federation
SK42113
🇸🇰Malacky, Slovakia
RU70107
🇷🇺Saint Petersburg, Russian Federation
SK42101
🇸🇰Trenčín, Slovakia
UA38103
🇺🇦Zaporizhzhya, Ukraine
UA38106
🇺🇦Kiev, Ukraine
DE49104
🇩🇪Wismar, Germany