Roxadustat in the Treatment of Anemia in End Stage Renal Disease (ESRD) Patients on Stable Dialysis
- Conditions
- AnemiaEnd Stage Renal Disease (ESRD)
- Interventions
- Registration Number
- NCT02278341
- Lead Sponsor
- Astellas Pharma Europe B.V.
- Brief Summary
This study was conducted to explore a new therapy for anemia in participants with end stage renal disease (ESRD) on dialysis. Anemia is a reduced number of red blood cells or hemoglobin. Hemoglobin (which contains iron) is important for the transport of oxygen in your blood. The purpose of this study was to evaluate if roxadustat is effective and safe in the maintenance treatment of anemia in ESRD participants on stable dialysis. Roxadustat was compared to epoetin alfa and darbepoetin alfa, commercially available medicines for treatment of anemia.
- Detailed Description
This study consisted of three study periods as follows:
* Screening Period: up to 6 weeks
* Treatment Period: a minimum of 52 weeks up to a maximum of 104 weeks
* Follow-up Period: 4 weeks
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 838
Main Inclusion:
- Participant is on stable hemodialysis (HD), hemodiafiltration (HDF) or peritoneal dialysis (PD) treatment with the same mode of dialysis for ≥4 months prior to randomization.
- Participant is on IV or SC epoetin or IV or SC darbepoetin alfa treatment for ≥8 weeks prior to randomization with stable weekly doses (during 4 weeks prior to randomization).
- Mean of the participant's three most recent Hb values, as measured by central laboratory, during the Screening Period.
- Participant's alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are ≤3 x upper limit of normal (ULN), and total bilirubin (TBL) is ≤1.5 x ULN
Main Exclusion:
- Participant has received a red blood cell (RBC) transfusion within 8 weeks prior to randomization.
- Participant has a known hereditary hematologic disease such as thalassemia or sickle cell anemia, pure red cell aplasia, or other known causes for anemia other than Chronic Kidney Disease (CKD).
- Participant has had a myocardial infarction, acute coronary syndrome, stroke, seizure, or a thrombotic/thrombo-embolic event (e.g., deep vein thrombosis or pulmonary embolism) within 12 weeks prior to randomization.
- Participant has had uncontrolled hypertension, in the opinion of the investigator, within 2 weeks prior to randomization.
- Participant has a history of malignancy, except for the following: cancers determined to be cured or in remission for ≥5 years, curatively resected basal cell or squamous cell skin cancers, cervical cancer in situ, or resected colonic polyps.
- Participant has had any prior organ transplant (that has not been explanted), or participant is scheduled for organ transplantation.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Roxadustat Iron Participants received roxadustat three times a week (TIW) for at least 52 weeks up to a maximum of 104 weeks. Participants received initial dose of roxadustat in doses of 100 mg, 150 mg or 200 mg, according to the average weekly dose of epoetin or darbepoetin alfa prior to randomization. Participants' roxadustat dosage was adjusted every 4 weeks to maintain Hb level within the target range 10.0 to 12.0 g/dL. Dose adjustment steps were as follows: 20, 40, 50, 70, 100, 150, 200, 250, 300, and 400 mg. Oral iron treatment of 200 mg was allowed for supplementation to support erythropoiesis. Treatment with intravenous iron was allowed only if certain protocol criteria were met. ESA (Erythropoiesis Stimulating Agent) treatment Iron Participants received epoetin alfa once weekly, twice weekly or TIW and darbepoetin alfa once a week or once every other week. Participants were treated for at least 52 weeks up to a maximum of 104 weeks. Treatment dosage was adjusted according to the pre-specified rule of keeping the participant's Hb levels between 10.0 to 12.0 g/dL. Participants were not allowed to switch from the epoetin alfa to darbepoetin alfa or vice versa. ESA (Erythropoiesis Stimulating Agent) treatment Epoetin alfa Participants received epoetin alfa once weekly, twice weekly or TIW and darbepoetin alfa once a week or once every other week. Participants were treated for at least 52 weeks up to a maximum of 104 weeks. Treatment dosage was adjusted according to the pre-specified rule of keeping the participant's Hb levels between 10.0 to 12.0 g/dL. Participants were not allowed to switch from the epoetin alfa to darbepoetin alfa or vice versa. Roxadustat Roxadustat Participants received roxadustat three times a week (TIW) for at least 52 weeks up to a maximum of 104 weeks. Participants received initial dose of roxadustat in doses of 100 mg, 150 mg or 200 mg, according to the average weekly dose of epoetin or darbepoetin alfa prior to randomization. Participants' roxadustat dosage was adjusted every 4 weeks to maintain Hb level within the target range 10.0 to 12.0 g/dL. Dose adjustment steps were as follows: 20, 40, 50, 70, 100, 150, 200, 250, 300, and 400 mg. Oral iron treatment of 200 mg was allowed for supplementation to support erythropoiesis. Treatment with intravenous iron was allowed only if certain protocol criteria were met. ESA (Erythropoiesis Stimulating Agent) treatment Darbepoetin alfa Participants received epoetin alfa once weekly, twice weekly or TIW and darbepoetin alfa once a week or once every other week. Participants were treated for at least 52 weeks up to a maximum of 104 weeks. Treatment dosage was adjusted according to the pre-specified rule of keeping the participant's Hb levels between 10.0 to 12.0 g/dL. Participants were not allowed to switch from the epoetin alfa to darbepoetin alfa or vice versa.
- Primary Outcome Measures
Name Time Method Change From Baseline (BL) to the Average Hemoglobin (Hb) in Weeks 28-36 Without Rescue Therapy [EU (EMA)] Baseline and weeks 28 to 36 Baseline Hb was defined as the mean of four central laboratory Hb values; four latest Hb values prior or on the same date as the first study drug intake. For participants who did not have an available Hb value during the week 28-36 period, imputation rules were applied. For analyses without rescue therapy, participants who used rescue therapy after the initiation of rescue therapy were set to missing for 6 weeks from the start date of rescue therapy. If no Hb value was available, an imputation technique was used, with the mean of all available values from Day 1 to minimum (End of Efficacy Emergent Period) carried forward.
Change From BL to the Average Hb in Weeks 28 to 52 Regardless of Rescue Therapy [US (FDA)] Baseline and weeks 28 to 52 Baseline Hb was defined as the mean of four central laboratory Hb values: four latest Hb values prior or on the same date as first study drug intake. Change from baseline to the average Hb are observed values. Missing hemoglobin data was imputed for each treatment relying on non-missing data from all participants within each treatment group using the Monte Carlo Markov Chain (MCMC) imputation model with treatment, baseline hemoglobin, randomization stratification factors and the available non missing hemoglobin for each scheduled week.
- Secondary Outcome Measures
Name Time Method Percentage of Participants With Hb Response During Weeks 28 to 36 Weeks 28 to 36 Hb response during weeks 28-36, was defined as mean Hb from 10-12 g/dL without receiving rescue therapy in the 6 weeks prior to, or during, the evaluation period. The percentages and 95% CI were unadjusted, the exact method of Clopper-Pearson was used for 95% CI. The Efficacy Emergent Period was defined as the evaluation period from the Analysis date of first dose intake up to end of treatment (EOT) Visit or last non-missing Hb assessment (for participants who died during the treatment period).
Change From BL in Low Density Lipoprotein Cholesterol (LDL-C) to the Average LDL-C of Weeks 12 to 28 Baseline and weeks 12 to 28 Baseline LDL was defined as the LDL value on Day 1. If this value was missing, the latest value prior to first study drug administration was used.
Change From BL in Mean Arterial Pressure (MAP) to the Average MAP Value of Weeks 20 to 28 Baseline and weeks 20 to 28 Baseline MAP was defined as the MAP value on day 1. If this value was missing, the latest value prior to first study drug administration was used. Mean Arterial Pressure (MAP) is derived as: MAP = (2/3)\*DBP + (1/3)\*SBP.
Percentage of Participants With a Hb Response During Weeks 28 and 36 Regardless of Use of Rescue Therapy Weeks 28 to 36 Hb response was defined as mean Hb during weeks 28 to 36 within the target range of 10.0 to 12.0 g/dL. The percentages and 95% CI are unadjusted, the exact method of Clopper-Pearson was used for 95% CI.
Change From BL in Hb to Each Postdosing Time Point Baseline and weeks 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, 16, 18,20, 22, 24, 26, 28, 30, 32, 34, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72,76, 80, 84, 88, 92, 96, 100, and 104 Baseline Hb was defined as the mean of four latest central laboratory Hb values prior or on the same date as first study drug intake (pre-dose).
Hb Level Averaged Over Weeks 28 to 36, 44 to 52, and 96 to 104 Without Use of Rescue Therapy Weeks 28 to 36, 44 to 52, and 96 to 104 Baseline Hb was defined as the mean of four latest central laboratory Hb values prior or on the same date as first study drug intake (pre-dose). Averaged Hb values over weeks 28-36, weeks 44-52 and weeks 96-104 are observed values.
Change From BL in Hb to the Average of Weeks 28 to 36, 44 to 52, and 96 to 104 Regardless of the Use of Rescue Therapy Baseline and weeks 28 to 36, 44 to 52, and 96 to 104 Change from baseline to the average Hb are observed values. Baseline Hb was defined as the mean of four latest central laboratory Hb values prior or on the same date as first study drug intake (pre-dose).
Percentage of Hb Values ≥ 10 g/dL in Weeks 28 to 36, 44 to 52, and 96 to 104 Without Use of Rescue Therapy Weeks 28-36, 44-52 and 96-104 Percentage for each participant was calculated as Number of Hb values \>= 10.0 g/dL / Total number of Hb values\*100 in weeks 28 to 36, 44 to 52 and 96 to 104 without use of rescue therapy within 6 weeks prior to and during the 8 week evaluation period.
Percentage of Hb Values Within 10.0 to 12.0 g/dL in Weeks 28 to 36, 44 to 52, and 96 to 104 Without Use of Rescue Therapy Weeks 28-36, 44-52 and 96-104 Percentage for each participant was calculated as Number of Hb values within 10.0-12.0 g/dL / Total number of Hb values\*100 in weeks 28 to 36, 44 to 52 and 96 to 104 without use of rescue therapy within 6 weeks prior to and during the 8 week evaluation period.
Number of Hospitalizations Baseline to End of Treatment (EOT) (Up to week 104) The number of hospitalizations per participant were calculated during the Efficacy Emergent Period. The Efficacy Emergent Period was defined as the evaluation period from the Analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period). It included all Non-Hemodialysis (HD) hospitalizations. The HD days were not counted as hospitalizations, even when performed overnight.
Mean Monthly Intravenous (IV) Iron Use Day 1 to week 36 Participants with no or missing medication records of IV Iron have their monthly IV Iron use set to 0 mg. For participants who took IV Iron, but without a dosing frequency, the average values were set to missing.
Time to First Hospitalization Baseline to EOT (Up to week 104) Time to first hospitalization in years was defined in years as: (First event date during the Efficacy Emergent Period - Analysis date of First dose intake +1)/365.25, and the 'First event date' was defined as 'Date of first Admission and 'Analysis Date of first dose intake. For participants without hospitalization, the time to censoring was calculated as: (Date of End of Efficacy Emergent Period - Analysis Date of first dose intake + 1) / 365.25. Date of End of Efficacy Emergent Period was defined as as the treatment period up to the EOT visit. For participants who have experienced more than one hospitalization, only their first event following study treatment was used. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula.
Time to First Use of Rescue Therapy Baseline to EOT (Up to week 104) Rescue therapy was defined as red blood cell (RBC) transfusion for both treatment groups and ESA for roxadustat participants. Only rescue medication that was started during the study treatment and up to end of efficacy emergent period was taken into account and considered as use of rescue medication. For participants who have experienced more than one use of rescue therapy, only their first event following study treatment was used. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula.
Time to First RBC Transfusion Baseline to EOT (Up to week 104) For participants who have experienced more than one RBC transfusion, only their first event following study treatment was used. For RBC transfusions, when the number of units was not given but the volume transfused was, the number of units were estimated by volume transfused/250 mL (for transfusion of packed cell units) or volume transfused/500 mL (for transfusion of full blood). Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula.
Change From BL in Short Form-36 (SF-36) Health Survey Physical Functioning (PF) Sub-score to the Average of Weeks 12 to 28 Baseline and weeks 12 to 28 Baseline SF-36 PF was defined as the SF-36 PF value on Day 1.The SF-36 is a Quality of Life (QoL) instrument designed to assess generic health concepts relevant across age, disease, and treatment groups. The SF-36 contains 36 items that measure eight scales: (1) physical functioning (PF); (2) role limitations due to physical health problems (RP); (3) bodily pain (BP); (4) social functioning (SF); (5) general health perceptions (GH); (6) role limitations due to emotional problems (RE); (7) vitality, energy or fatigue (VT); and (8) mental health(MH). Each scale is transformed into 0-100 score, with higher scores indicating better health status. The SF-36 PF consists of 11 questions focused on health and ability to do usual activities, with higher scores indicating better health status.
Change From BL in SF-36 Vitality (VT) Sub-score to the Average of Weeks 12 to 28 Baseline and weeks 12 to 28 Baseline VT Subscore was defined as the VT value on Day 1. The SF-36 is a QoL instrument designed to assess generic health concepts relevant across age, disease, and treatment groups. The SF-36 vitality has four questions with score range from 0-100 with higher scores indicating better vitality status.
Change From BL in Mean Arterial Pressure (MAP) to the Average of Weeks 20 to 28 Baseline and weeks 20 to 28 Baseline MAP was defined as the MAP value on Day 1. If this value was missing, the latest value prior to first study drug administration was used. Mean Arterial Pressure (MAP) is derived as: MAP = (2/3)\*DBP + (1/3)\*SBP.
Time to First Occurrence of an Increase in Blood Pressure Weeks 1 to 36 Increase in Blood Pressure was defined as either: SBP ≥ 170 mmHg and an increase from BL ≥ 20 mmHg, or as: DBP ≥ 100 mmHg and an increase from BL ≥ 15 mmHg. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula.
Number of Days of Hospitalization Per Year Baseline to EOT (Up to week 104) The number of days of hospitalizations per year was calculated as the sum of the durations of all non-HD hospitalizations in days (Date of discharge - Date of admission + 1)\] / (duration of efficacy emergent period in days / 365.25). In case of missing dates, the hospitalization duration was imputed by the average duration per stay derived from the participants with non-missing duration within the same treatment group.
Mean Monthly Number of RBC Packs Per Participant Baseline to EOT (Up to week 104) During efficacy emergent period, the mean monthly number of RBC packs was calculated as the sum of blood volume and units transfused between the first dose and up to the last dose in the period divided by duration of efficacy emergent period (in days) divided by 28 days. Participants without medication records of RBC have their number of RBC packs and volume set to 0.
Mean Monthly Volume of RBC Transfusion Per Participant Baseline to EOT (Up to week 104) During Efficacy Emergent Period, the mean monthly volume of blood transfused was calculated as the sum of blood volume and units transfused between the first dose and up to the last dose in the period divided by duration of efficacy emergent period (in days) divided by 28 days. The Efficacy Emergent Period was defined as the evaluation period from the Analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period).
Time to First Use of IV Iron Supplementation Baseline to EOT (Up to week 104) For participants who have received more than one IV iron, only their first event following study treatment was used. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula.
Mean Monthly Intravenous (IV) Iron Per Participant During Weeks 37-52 and Weeks 53-104 Weeks 37-52 and weeks 53-104 Participants with no or missing medication records of IV Iron had their monthly IV Iron use set to 0 mg.
Percentage of Participants With Oral Iron Use Only Baseline to EOT (Up to week 104) Percentage of participants with/without IV iron only was calculated based on total number of participants within the Efficacy Emergent Period. The Efficacy Emergent Period is defined as the evaluation period from the Analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period).
Change From BL to Each Post-dosing Study Visit in Total Cholesterol Baseline and weeks 8, 28, 52, 104 Baseline assessment was the assessment from Day 1 visit. If baseline value was missing, then the latest screening period value was used as the baseline regardless of fasting status.
Change From BL to Each Post-dosing Study Visit in LDL-C/High-density Lipoprotein Cholesterol (HDL-C) Ratio Baseline and weeks 8, 28, 52, 104 Baseline was defined as the value on Day 1. If baseline value was missing, the latest value prior to first study drug administration was used regardless of fasting.
Change From BL to Each Postdosing Study Visit in Non-HDL Cholesterol Baseline and weeks 8, 28, 52, 104 Baseline was defined as the value on Day 1. If baseline value was missing, the latest value prior to first study drug administration was used regardless of fasting.
Change From BL to Each Postdosing Study Visit in Apolipoproteins A1 (ApoA1) Baseline and weeks 8, 28, 52, 104 Baseline was defined as the value on Day 1. If baseline value was missing, the latest value prior to first study drug administration was used regardless of fasting.
Change From BL to Each Postdosing Study Visit in Apolipoproteins B (ApoB) Baseline and weeks 8, 28, 52, 104 Baseline was defined as the value on Day 1. If baseline value was missing, the latest value prior to first study drug administration was used regardless of fasting.
Change From BL to Each Postdosing Study Visit in ApoB/ApoA1 Ratio Baseline and weeks 8, 28, 52, 104 Baseline was defined as the value on Day 1. If baseline value was missing, the latest value prior to first study drug administration was used.
Number of Participants With Mean LDL Cholesterol < 100 mg/dL Over Weeks 12 to 28 Weeks 12 to 28 Missing category for Fasting Only includes non-fasting participants and the participants with missing values.
Number of Participants With CKD Who Achieved Antihypertensive Treatment Goal Weeks 12 to 28 Achieved antihypertensive treatment goal was defined as SBP \< 140 mmHg and DBP \< 90 mmHg over an evaluation period based on the average of available values in weeks 12-28 (pre-dialysis).
Change From BL to the Average of Weeks 12 to 28 in SF-36 Physical Component Score (PCS) Baseline and weeks 12 to 28 Baseline SF-36 PCS was defined as the SF-36 PCS value on Day 1. SF-36 contains 36-item that measures 8 scales with scores ranging from 0-100: physical functioning (PF); role limitations due to physical health problems (RP); bodily pain (BP); social functioning (SF); general health perceptions (GH); role limitations due to emotional problems (RE); vitality, energy or fatigue (VT); and mental health (MH). These scores are normed to the US population (norm-based scoring had very little impact on results when data was collected in Western European countries) to have a mean of 50 and standard deviation of 10. The PCS was calculated based on all 8 scales and ranges from 5.02-79.78. For each of these above scales, higher scores always indicating better health status.
Change From BL to the Average of Weeks 12 to 28 in Anemia Subscale (AnS) ("Additional Concerns") of Functional Assessment of Cancer Therapy-Anemia (FACT-An) Score Baseline and weeks 12 to 28 Baseline FACT-An AnS was defined as the FACT-An AnS value on Day 1. Together with the Functional Assessment of Cancer Therapy - General (FACT-G), the Anemia Subscale (AnS) is referred to as the FACT-An Total. The AnS scale contains 13 fatigue specific items (the Fatigue Score) plus 7 items related to anemia. The Anemia AnS score range is 0 to 80. For the above score, a higher score indicates better QoL.
Change From BL to the Average Value of Weeks 12 to 28 in Total FACT-An Score Baseline and weeks 12 to 28 Baseline FACT-An Total Score was defined on Day 1. Total Fact-An score is composed of FACT-G and Ans scales. FACT-G contains 27 items that cover four dimensions of well-being: physical (PWB) - 7 items, functional (FWB) - 7 items, social/family (SWB) - 7 items, and emotional (EWB) - 6 items. The AnS scale contains 13 fatigue specific items (the Fatigue Score) plus 7 items related to anemia. The total score is obtained by summation of the scores from PWB, SWB, EWB, FWB and AnS. The FACT-An Total Score scale range is 0-188. A higher score indicates better QoL.
Change From BL to the Average of Weeks 12 to 28 in Euroqol Questionnaire-5 Dimensions 5 Levels (EQ-5D 5L) Visual Analogue Scale (VAS) Score Baseline and weeks 12 to 28 Baseline assessment was defined as the value on Day 1. The EuroQol Questionnaire -5 Dimensions -5 Levels (EQ-5D-5L) is a self-reported questionnaire, used as a measure of respondents' Health Related Quality of Life (HRQoL) and utility values. The EQ-5D consists of the descriptive system and the visual analogue scale (VAS). The EQ-5D descriptive system comprises 5 dimensions of health: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, extreme problems. The VAS records the respondent's self rated health status on a graduated (0-100) scale, where the endpoints are labeled 'Best imaginable health state' and 'Worst imaginable health state' with higher scores for higher HRQoL.
Percentage of Participants With Improvements Measured by Patients' Global Impression of Change (PGIC) Baseline and weeks 8, 12, 28, 36, 52, 76, 104 The PGIC is a patient-rated instrument that measures change in participant's overall status on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse), when compared to the start of treatment. The percentage of participants presented includes very much improved, much improved and minimally improved.
Change From BL in Serum Hepcidin Baseline and weeks 4, 12, 20, 36, 52, 104, and End of Study (EOS - up to 108 weeks) Baseline assessment was assessment from Day 1 visit. If baseline value was missing, the value from screening visit was used. In case of missing data, no imputation rules were applied.
Change From BL in Serum Ferritin Baseline and weeks 4, 8, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 104, and EOS (up to 108 weeks) Baseline assessment was assessment from Day 1 visit. If baseline value was missing, the value from screening visit was used. In case of missing data, no imputation rules were applied.
Change From BL in Transferrin Saturation (TSAT) Baseline and weeks 4, 8, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 104 and EOS (up to 108 weeks) Baseline assessment was assessment from Day 1 visit. If baseline value was missing, the value from screening visit was used. In case of missing data, no imputation rules were applied.
Change From BL in Glycated Hemoglobin (HbA1c) Level to Weeks 12, 28, 36, 44, 52, 60, 84, 104 and EOS (up to Week 108) Baseline and weeks 12, 28, 36, 44, 52, 60, 84, 104 and EOS (up to 108 weeks) Percentage of change from baseline to each study visit were calculated for HbA1c. Baseline assessment was assessment from Day 1 visit. If baseline value was missing, the value from screening visit was used. In case of missing data, no imputation rules were applied.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Baseline up to EOS (Up to week 108) Safety was assessed by evaluation of the following variables: (TEAEs; frequency, severity, seriousness, and relationship to study drug), Vital signs (systolic and diastolic blood pressure, pulse, respiratory rate and weight), Clinical laboratory variables (hematology, biochemistry including liver enzymes and total bilirubin, and urinalysis), Physical examination, 12-lead electrocardiogram (ECG) and Vascular Access Thrombosis. All AEs collected during the Safety Emergent Period were counted as TEAE. The TEAE was defined as an adverse event (AE) if it was observed after starting administration of the roxadustat or ESA. Any clinically significant abnormalities were reported as an AEs. All reported deaths after the first study drug administration and up to 28 days after the Analysis Date of Last Dose and considering last dosing frequency.
Trial Locations
- Locations (143)
Site PL48002
🇵🇱Katowice, Poland
Site HR38509
🇭🇷Zagreb, Grad Zagreb, Croatia
Site HR38505
🇭🇷Karlovac, Croatia
Site GE99504
🇬🇪Tbilisi, Georgia
Site DE49054
🇩🇪Dusseldorf, Germany
Site IT39006
🇮🇹Milano, Italy
Site HU36026
🇭🇺Kaposvar, Hungary
Site HR38507
🇭🇷Osijek, Croatia
Site FR33055
🇫🇷Saint Ouen, France
Site CZ42008
🇨🇿Liberec, Czechia
Site DE49056
🇩🇪Dormagen, Nordrhein-Westfalen, Germany
Site HR38506
🇭🇷Rijeka, Croatia
Site HR38501
🇭🇷Zadar, Croatia
Site BE32019
🇧🇪Antwerpen, Belgium
Site BE32002
🇧🇪Antwerp, Belgium
Site BE32013
🇧🇪Liege, Belgium
Site BG35925
🇧🇬Blagoevgrad, Bulgaria
Site CZ42021
🇨🇿Praha 6, Czechia
Site BG35924
🇧🇬Sofia, Bulgaria
Site BE32012
🇧🇪Baudour, Belgium
Site BE32017
🇧🇪Bonheiden, Belgium
Site BE32003
🇧🇪Leuven, Belgium
Site BG35915
🇧🇬Pleven, Bulgaria
Site BG35918
🇧🇬Varna, Bulgaria
Site HU36027
🇭🇺Kistarcsa, Hungary
Site HU36006
🇭🇺Szombathely, Hungary
Site FR33010
🇫🇷La Tronche, France
Site HU36036
🇭🇺Esztergom, Hungary
Site DE49020
🇩🇪Frankfurt am Main, Germany
Site HU36031
🇭🇺Gyor, Hungary
Site BG35909
🇧🇬Plovdiv, Bulgaria
Site BG35919
🇧🇬Plovdiv, Bulgaria
Site BG35938
🇧🇬Shumen, Bulgaria
Site DE49075
🇩🇪Heilbronn, Germany
Site BE32004
🇧🇪Brussels, Flemish Brabant, Belgium
Site HR38508
🇭🇷Cakovec, Croatia
Site BE32001
🇧🇪Aalst, Belgium
Site FR33005
🇫🇷Amiens cedex 1, France
Site FR33056
🇫🇷Valenciennes, France
Site DE49067
🇩🇪Berlin, Germany
Site IT39005
🇮🇹Roma, Italy
Site CZ42015
🇨🇿Rakovnik, Czechia
Site BG35931
🇧🇬Haskovo, Bulgaria
Site BG35920
🇧🇬Rousse, Bulgaria
Site DE49008
🇩🇪Dresden, Germany
Site BG35903
🇧🇬Veliko Tarnovo, Bulgaria
Site BG35921
🇧🇬Sofia, Bulgaria
Site HR38504
🇭🇷Slavonski Brod, Croatia
Site FR33007
🇫🇷Saint Priez En Jarez, France
Site HU36033
🇭🇺Baja, Hungary
Site HU36003
🇭🇺Zalsaegerszeg, Hungary
Site DE49073
🇩🇪Cloppenburg, Germany
Site DE49071
🇩🇪Villingen-Schwenningen, Germany
Site DE49001
🇩🇪Kaiserslautern, Germany
Site HU36032
🇭🇺Pecs, Hungary
Site HU36035
🇭🇺Pecs, Hungary
Site PT35128
🇵🇹Gaeiras, Portugal
Site PT35117
🇵🇹Faro, Portugal
Site PT35122
🇵🇹Setubal, Portugal
Site GB44087
🇬🇧Brighton, EastSussex, United Kingdom
Site GB44011
🇬🇧Canterbury, Kent, United Kingdom
Site GE99508
🇬🇪Tbilisi, Georgia
Site GE99503
🇬🇪Tbilisi, Georgia
Site RO40018
🇷🇴Bucharest, Romania
Site RS38104
🇷🇸Belgrade, Serbia
Site SK42102
🇸🇰Koshice, Slovakia
Site GB44080
🇬🇧Stoke on Trent, Staffordshire, United Kingdom
Site DE49065
🇩🇪Hamburg, Germany
Site DE49002
🇩🇪Solingen, Germany
Site BG35916
🇧🇬Varna, Bulgaria
Site BG35937
🇧🇬Yambol, Bulgaria
Site BG35906
🇧🇬Sofia, Bulgaria
Site BG35907
🇧🇬Stara Zagora, Bulgaria
Site DE49070
🇩🇪Muenchen, Germany
Site HU36046
🇭🇺Szekesfehervar, Hungary
Site HU36004
🇭🇺Szeged, Hungary
Site HU36034
🇭🇺Salgotarjan, Hungary
Site IT39028
🇮🇹Prato, Frazione Di Galciana, Italy
Site IT39014
🇮🇹Mestre, Venezia, Italy
Site IT39039
🇮🇹Cremona, Lombardia, Italy
Site PL48005
🇵🇱Warszawa, Poland
Site IT39010
🇮🇹Brescia, Italy
Site IT39008
🇮🇹Lecco, Italy
Site IT39037
🇮🇹Modena, Italy
Site IT39022
🇮🇹Padova, Italy
Site IT39036
🇮🇹Pavia, Italy
Site IT39035
🇮🇹Torino, Italy
Site IT39032
🇮🇹Trieste, Italy
Site PT35127
🇵🇹Aveiro, Portugal
Site PL48001
🇵🇱Krakow, Poland
Site PL48013
🇵🇱Szczecin, Poland
Site PL48014
🇵🇱Zamosc, Poland
Site RO40015
🇷🇴Bucharest, Romania
Site PL48006
🇵🇱Wroclaw, Poland
Site PT35121
🇵🇹Almada, Portugal
Site PT35139
🇵🇹Cascais, Portugal
Site PT35114
🇵🇹Leiria, Portugal
Site PT35102
🇵🇹Porto, Portugal
Site RO40019
🇷🇴Bucharest, Romania
Site RO40004
🇷🇴Oradea, Romania
Site RO40003
🇷🇴Bucuresti, Romania
Site RU70008
🇷🇺Kaluga, Russian Federation
Site RU70005
🇷🇺Moscow, Russian Federation
Site RU70051
🇷🇺Moscow, Russian Federation
Site RU70003
🇷🇺Nizhny Novgorod, Russian Federation
Site RU70004
🇷🇺Omsk, Russian Federation
Site RU70072
🇷🇺Saint Petersburg, Russian Federation
Site RU70002
🇷🇺Saint Petersburg, Russian Federation
Site RU70014
🇷🇺Rostov-on-Don, Russian Federation
Site RU70011
🇷🇺Saint-Petersburg, Russian Federation
Site RU70006
🇷🇺Smolensk, Russian Federation
Site RU70050
🇷🇺Saint-Petersburg, Russian Federation
Site RU70030
🇷🇺Sankt-Peterburg, Russian Federation
Site RS38105
🇷🇸Belgrade, Serbia
Site RU70001
🇷🇺Yaroslavl, Russian Federation
Site RU70037
🇷🇺Volgograd, Russian Federation
Site RS38102
🇷🇸Belgrade, Serbia
Site RS38120
🇷🇸Belgrade, Serbia
Site RS38117
🇷🇸Krusevac, Serbia
Site RS38101
🇷🇸Nis, Serbia
Site RS38116
🇷🇸Zrenjanin, Serbia
Site SK42119
🇸🇰Levice, Slovakia
Site SK42120
🇸🇰Lučenec, Slovakia
Site SK42116
🇸🇰Senica, Slovakia
Site SK42113
🇸🇰Puchov, Slovakia
Site ES34041
🇪🇸Santiago de Compostela, A Coruna, Spain
Site GB44081
🇬🇧Leicester, United Kingdom
Site ES34009
🇪🇸El Ejido, Almeria, Spain
Site ES34010
🇪🇸Alcorcon, Madrid, Spain
Site ES34030
🇪🇸Majadahonda, Madrid, Spain
Site ES34011
🇪🇸Galdakao, Vizcaya, Spain
Site ES34008
🇪🇸Barcelona, Spain
Site ES34006
🇪🇸Barcelona, Spain
Site ES34002
🇪🇸Badalona-Barcelona, Spain
Site ES34037
🇪🇸Madrid, Spain
Site ES34017
🇪🇸Jaen, Spain
Site ES34052
🇪🇸Valencia, Spain
Site GB44079
🇬🇧Liverpool, United Kingdom
Site GB44010
🇬🇧Hull, United Kingdom
Site GB44008
🇬🇧Cambridge, United Kingdom
Site GB44001
🇬🇧Swansea, United Kingdom
Site PL48009
🇵🇱Wroclaw, Poland
Site BE32011
🇧🇪Roeselare, Belgium