Study of Relugolix With Estradiol and Norethindrone Acetate in Women With Heavy Menstrual Bleeding Associated With Uterine Fibroids
- Conditions
- Uterine LeiomyomaUterine Fibroids
- Interventions
- Drug: Placebo for E2/NETA
- Registration Number
- NCT03751124
- Lead Sponsor
- Myovant Sciences GmbH
- Brief Summary
The objectives of this randomized withdrawal study are to evaluate the long-term efficacy and safety of the combination of relugolix, estradiol (E2) and norethindrone acetate (NETA), once daily, for up to 104 weeks in patients with uterine fibroids who have completed a total of 52 weeks of treatment, including a 24-week treatment period in a parent study (study MVT-601-3001 or MVT-601-3002) and a 28-week treatment period in the open-label extension study (MVT-601-3003), and who meet the definition of responder, defined as a patient who demonstrates a menstrual blood loss of \< 80 mL and at least a 50% reduction from parent study baseline menstrual blood loss volume on the alkaline hematin analysis of the feminine products returned at Week 48 in the extension study.
- Detailed Description
This randomized withdrawal study is an international phase 3 double-blind, placebo-controlled study that will enroll eligible patients with uterine fibroids who have completed the 24-week treatment period in a parent study (MVT-601-3001 or MVT-601-3002) and the 28-week treatment period of the open-label extension study (MVT-601-3003). When including treatment during the parent study and the extension study, patients completing this randomized withdrawal study will have received up to a total of 104 weeks of treatment with relugolix.
Approximately 360 women with heavy menstrual bleeding associated with uterine fibroids completing the extension study with a response to treatment will be eligible to participate in this study. A responder is defined as a patient who demonstrates a menstrual blood loss of \< 80 mL and at least a 50% reduction from parent study baseline menstrual blood loss volume on the alkaline hematin analysis of the feminine products returned at Week 48 in the extension study.
Screening procedures will be done on the same day as the Week 52 visit for the extension study. This visit will be referred to as the "Week 52/Baseline visit." When the Week 52/Baseline procedures in the extension study have been completed, the investigator will assess patient eligibility for participation in this study. The eligibility assessment will be based on data available at the Week 52/Baseline visit.
Patients will be asked to provide feminine products for alkaline hematin analysis at each visit until the analysis confirms the return of heavy menstrual bleeding. The patients will then be offered retreatment with open-label relugolix with E2/NETA with the onset of the next menses. They will resume collection of feminine products for alkaline hematin analysis until two consecutive analyses confirm resolution of heavy menstrual bleeding (menstrual blood loss of \< 80 mL). Safety will be assessed throughout the study by monitoring adverse events, vital signs, physical examinations, clinical laboratory tests, and assessments of bone mineral density.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- Female
- Target Recruitment
- 229
- Completed the open-label extension study (MVT-601-3003).
- Is a responder: Has a menstrual blood loss of < 80 mL AND at least a 50% reduction from the parent study Baseline based on the results of the alkaline hematin testing performed on the feminine products returned at the Week 48 visit of the extension study.
- Is not expected to undergo gynecological surgery or ablation procedures for uterine fibroids within the study period
- Has undergone myomectomy, ultrasound-guided laparoscopic radiofrequency ablation, or any other surgical procedure for fibroids, uterine artery embolization, magnetic resonance guided focused ultrasound for fibroids, or endometrial ablation for abnormal uterine bleeding at any time during the Parent study or extension study.
- Has a weight that exceeds the weight limit of the dual-energy x-ray absorptiometry (DXA) scanner
- Has developed any contraindication to treatment with estradiol or norethindrone acetate
- Is currently pregnant or lactating, or intends to become pregnant during the study period
- Met a withdrawal criterion in the open-label extension (OLE) study.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Relugolix plus E2/NETA Relugolix Relugolix 40 mg co-administered with estradiol (1.0 mg) and norethindrone acetate (0.5 mg) for up to 52 weeks. Relugolix plus E2/NETA Estradiol/norethindrone acetate Relugolix 40 mg co-administered with estradiol (1.0 mg) and norethindrone acetate (0.5 mg) for up to 52 weeks. Placebo tablets and capsules Placebo for E2/NETA * Placebo for relugolix co-administered with placebo for E2/NETA for up to 52 weeks or until heavy menstrual bleeding returns. * Retreatment with open-label relugolix with E2/NETA will be offered if heavy menstrual bleeding returns. Placebo tablets and capsules Placebo for relugolix * Placebo for relugolix co-administered with placebo for E2/NETA for up to 52 weeks or until heavy menstrual bleeding returns. * Retreatment with open-label relugolix with E2/NETA will be offered if heavy menstrual bleeding returns.
- Primary Outcome Measures
Name Time Method Percentage Of Participants Who Maintained MBL Volume Of <80 Milliliters (mL) At Week 76 During The Randomized Treatment Period Week 52/Baseline up to Week 76 MBL volume is measured using the alkaline hematin method. The method involves pummeling used feminine products in a 5% sodium hydroxide solution, which leads to the conversion of hemoglobin to alkaline hematin. The volume of MBL is measured in mL and a blood loss of 80 mL or more per cycle is considered diagnostic of heavy menstrual bleeding. The sustained responder rate was calculated as the Kaplan-Meier estimate of the cumulative probability of MBL volume \< 80 mL through Week 76 using the Kaplan-Meier method.
- Secondary Outcome Measures
Name Time Method Time To MBL Volume ≥80 mL During The Randomized Treatment Period From Week 52/Baseline through Week 104 MBL volume is measured using the alkaline hematin method. The method involves pummeling used feminine products in a 5% sodium hydroxide solution, which leads to the conversion of hemoglobin to alkaline hematin. The volume of MBL is measured in mL and a blood loss of 80 mL or more per cycle is considered diagnostic of heavy menstrual bleeding.
Percentage Of Participants Who Maintained MBL Volume Of <80 mL At Week 104 During The Randomized Treatment Period Week 52/Baseline up to Week 104 MBL volume is measured using the alkaline hematin method. The method involves pummeling used feminine products in a 5% sodium hydroxide solution, which leads to the conversion of hemoglobin to alkaline hematin. The volume of MBL is measured in mL and a blood loss of 80 mL or more per cycle is considered diagnostic of heavy menstrual bleeding. The sustained responder rate was calculated as the Kaplan-Meier estimate of the cumulative probability of MBL volume \< 80 mL through Week 104 using the Kaplan-Meier method.
Percentage Of Participants Achieving Or Maintaining Amenorrhea At Week 76 During The Randomized Treatment Period Week 76 Assessed using participant daily diary and MBL volume measured using the alkaline hematin method. Participants were deemed to be amenorrhoeic if one of the following criteria was met: No feminine products returned due to reported amenorrhea, or No feminine products returned due to reported spotting or feminine product collection with a negligible observed MBL volume (\<5 mL) coupled with other data indicating infrequent non-cyclic bleeding/spotting. If no feminine product collection because participant failed to collect used products per protocol or due to "Other" reason, the amenorrhea status was set to missing. Missing responses for menstrual bleeding questions in the paper diary were treated as "No Bleeding" if paper diary entry/compliance rate was \>70%.
Change From Week 52/Baseline To Week 76 In MBL Volume During The Randomized Treatment Period Week 52/Baseline to Week 76 MBL volume is measured using the alkaline hematin method. The method involves pummeling used feminine products in a 5% sodium hydroxide solution, which leads to the conversion of hemoglobin to alkaline hematin. Participants with amenorrhea are assigned with an MBL value of 0 mL and participants with spotting are assigned with an MBL value of 4.99 mL. The volume of MBL is measured in mL and a blood loss of 80 mL or more per cycle is considered diagnostic of heavy menstrual bleeding.
Time To Resumption Of Menses For Participants Who Were Amenorrhoeic At Week 52/Baseline During The Randomized Treatment Period Week 52/Baseline up to Week 104 Assessed using participant daily diary. Participants were deemed to be amenorrhoeic if one of the following criteria was met: No feminine products returned due to reported amenorrhea, or No feminine products returned due to reported spotting or feminine product collection with a negligible observed MBL volume (\<5 mL) coupled with other data indicating infrequent non-cyclic bleeding/spotting. If no feminine product collection because participant failed to collect used products per protocol or due to "Other" reason, the amenorrhea status was set to missing. Missing responses for menstrual bleeding questions in the paper diary were treated as "No Bleeding" if paper diary entry/compliance rate was \>70%.
Change From Week 52/Baseline To Week 104 In MBL Volume During The Randomized Treatment Period Week 52/Baseline to Week 104 MBL volume is measured using the alkaline hematin method. The method involves pummeling used feminine products in a 5% sodium hydroxide solution, which leads to the conversion of hemoglobin to alkaline hematin. Participants with amenorrhea are assigned with an MBL value of 0 mL and participants with spotting are assigned with an MBL value of 4.99 mL. The volume of MBL is measured in mL and a blood loss of 80 mL or more per cycle is considered diagnostic of heavy menstrual bleeding.
Percentage Change From Week 52/Baseline To Week 104 In MBL Volume During The Randomized Treatment Period Week 52/Baseline to Week 104 MBL volume is measured using the alkaline hematin method. The method involves pummeling used feminine products in a 5% sodium hydroxide solution, which leads to the conversion of hemoglobin to alkaline hematin. Participants with amenorrhea are assigned with an MBL value of 0 mL and participants with spotting are assigned with an MBL value of 4.99 mL. The volume of MBL is measured in mL and a blood loss of 80 mL or more per cycle is considered diagnostic of heavy menstrual bleeding.
Percentage Change From Week 52/Baseline To Week 76 In MBL Volume During The Randomized Treatment Period Week 52/Baseline to Week 76 MBL volume is measured using the alkaline hematin method. The method involves pummeling used feminine products in a 5% sodium hydroxide solution, which leads to the conversion of hemoglobin to alkaline hematin. Participants with amenorrhea are assigned with an MBL value of 0 mL and participants with spotting are assigned with an MBL value of 4.99 mL. The volume of MBL is measured in mL and a blood loss of 80 mL or more per cycle is considered diagnostic of heavy menstrual bleeding.
Percentage Of Participants Achieving Or Maintaining Amenorrhea At Week 104 During The Randomized Treatment Period Week 104 Assessed using participant daily diary and MBL volume measured using the alkaline hematin method. Participants were deemed to be amenorrhoeic if one of the following criteria was met: No feminine products returned due to reported amenorrhea or no feminine products returned due to reported spotting or feminine product collection with a negligible observed MBL volume (\<5 mL) coupled with other data indicating infrequent non-cyclic bleeding/spotting. If no feminine product collection because participant failed to collect used products per protocol or due to "Other" reason, the amenorrhea status was set to missing. Missing responses for menstrual bleeding questions in the paper diary were treated as "No Bleeding" if paper diary entry/compliance rate was \>70%.
Percentage Of Participants Who Responded (MBL Volume <80 mL) To Retreatment During The Retreatment Period From Initiation of Retreatment to Week 104 MBL volume is measured using the alkaline hematin method. The method involves pummeling used feminine products in a 5% sodium hydroxide solution, which leads to the conversion of hemoglobin to alkaline hematin. The volume of MBL is measured in mL and a blood loss of 80 mL or more per cycle is considered diagnostic of heavy menstrual bleeding.
Percentage Of Participants Whose Menses Had Resumed During The Randomized Treatment Period Week 52/Baseline to Week 76 and Week 104 Participants who were previously amenorrhoeic were deemed to resume menses according to the following rules: MBL volume of collected feminine product was ≥5 mL; MBL volume of collected feminine product was \<5 mL; however, there were more than 5 days and more than 3 consecutive days of bleeding with feminine product use during the visit; no feminine products were returned because the participant failed to collect used products per protocol; however, there were more than 5 days and more than 3 consecutive days of bleeding with feminine product use during the visit; or no feminine products were returned due to other reasons that indicated menstruation had occurred; also, there were more than 5 days and more than 3 consecutive days of bleeding with feminine product use during the visit.
Change From Week 52/Baseline In Hemoglobin Concentration During The Randomized Treatment Period Week 52/Baseline to Week 104 Blood samples were collected from participants for hemoglobin measurements in accordance with the specified time points.
Percentage Of Participants With MBL Volume Of ≥80 mL At Week 76 And Week 104 During the Randomized Treatment Period From Week 52/Baseline to Week 76 and Week 104 MBL volume is measured using the alkaline hematin method. The method involves pummeling used feminine products in a 5% sodium hydroxide solution, which leads to the conversion of hemoglobin to alkaline hematin. The volume of MBL is measured in mL and a blood loss of 80 mL or more per cycle is considered diagnostic of heavy menstrual bleeding.
Percent Change From Week 52/Baseline In Hemoglobin Concentration During The Randomized Treatment Period Week 52/Baseline to Week 104 Blood samples were collected from participants for hemoglobin measurements in accordance with the specified time points.
Percentage Of Participants Who Had Hemoglobin Level ≤10.5 g/dL Over Time During The Randomized Treatment Period Week 52/Baseline to Week 104 Blood samples were collected from participants for hemoglobin measurements in accordance with the specified time points.
Percentage Of Participants Who Had Hemoglobin Level <11.6 g/dL Over Time During The Randomized Treatment Period Week 52/Baseline to Week 104 Blood samples were collected from participants for hemoglobin measurements in accordance with the specified time points.
Change From Week 52/Baseline In Short Form 36v2 (SF-36v2) Domain During The Randomized Treatment Period Week 52/Baseline to Week 104 The Short-Form Health Survey Standard (SF-36) is a validated, 36-item questionnaire, assessing general overall quality of life and was completed by participants on paper before other study procedures were performed, except for at the Week 52/Baseline visit, which was completed after eligibility for this study was confirmed and all Week 52 procedures for the long-term extension study were completed. Scores are calculated for each domain and 2 summary scores - a physical component summary score (Domains \[number of items\]: Physical Functioning \[10\], Role-Physical \[4\], Bodily Pain \[2\], General Health \[5\]), a mental component summary score (Domains \[number of items\]: Vitality \[4\], Social Functioning \[2\], Role-Emotional \[3\], and Mental Health \[5\]), and reported Health Transition \[1\]. Individual domain and component summary scores range from 0 to 100. Higher scores indicate higher health-related quality of life.
Change From Week 52/Baseline In SF-36v2 Summary Component Scores During The Randomized Treatment Period Week 52/Baseline to Week 104 The Short-Form Health Survey Standard (SF-36) is a validated, 36-item questionnaire, assessing general overall quality of life and was completed by participants on paper before other study procedures were performed, except for at the Week 52/Baseline visit, which was completed after eligibility for this study was confirmed and all Week 52 procedures for the long-term extension study were completed. Scores are calculated for each domain and 2 summary scores - a physical component summary (PCS) score (Domains \[number of items\]: Physical Functioning \[10\], Role-Physical \[4\], Bodily Pain \[2\], General Health \[5\]), a mental component summary (MCS) score (Domains \[number of items\]: Vitality \[4\], Social Functioning \[2\], Role-Emotional \[3\], and Mental Health \[5\]), and reported Health Transition \[1\]. Individual domain and component summary scores range from 0 to 100. Higher scores indicate higher health-related quality of life.
Categorical Change From Week 52/Baseline In PGA For Uterine Fibroid-related Function During The Randomized Treatment Period Week 52/Baseline to Week 104 The PGA for function is a 1-item questionnaire designed to assess participant's impression of the impact on their function related to uterine fibroids affected their usual activities and was completed on paper. The PGA for function was evaluated using a 5-point Likert scale (1 = No limitation at all; 5 = Extreme limitation) with higher numbers representing worse results. Endpoint values represent the worsening of function (deterioration), improvement of function (improvement), or no change by category at each time point. For example, a 4-category deterioration represents a change from 1 (No limitation at all) to 5 (Extreme limitation) and a 4-category improvement represents a change from 5 (Extreme limitation) to 1 (No limitation at all).
Categorical Change From Week 52/Baseline In PGA For Uterine Fibroid-related Symptoms During The Randomized Treatment Period Week 52/Baseline to Week 104 The PGA for symptoms is a 1-item questionnaire designed to assess participant's impression of the severity of their symptoms related to uterine fibroids and was completed on paper. The PGA for symptoms was evaluated using a 5-point Likert scale (1 = Not severe; 5 = Extremely severe) with higher numbers representing worse results. Endpoint values represent the worsening of symptoms (deterioration), improvement of symptoms (improvement), or no change by category at each time point. For example, a 4-category deterioration represents a change from 1 (Not severe) to 5 (Extremely severe) and a 4-category improvement represents a change from 5 (Extremely severe) to 1 (Not severe).
Change From Week 52/Baseline In The Work Productivity Activity Impairment - Percent Work Time Missed Due to Uterine Fibroids (WPAI-UF) Scores During The Randomized Treatment Period Week 52/Baseline up to Week 104 The WPAI-UF is a validated instrument used to measure self-reported absenteeism, presenteeism, and daily activity impairment attributed to uterine fibroids. The WPAI-UF was to be completed on a paper questionnaire and participants were to answer these questions.
Percent work time missed due to uterine fibroids was calculated from hours missed due to uterine fibroids divided by the sum of hours missed due to uterine fibroids plus hours actually worked. This value was then multiplied by 100 to get a percentage. The WPAI-UF outcomes are expressed as impairment percentages, with higher numbers indicating greater impairment and less productivity due to uterine fibroids, that is, worse outcomes.Change From Week 52/Baseline In The Work Productivity Activity Impairment - Percent Impairment While Working Due to Uterine Fibroids (WPAI-UF) Scores During The Randomized Treatment Period Week 52/Baseline up to Week 104 The WPAI-UF is a validated instrument used to measure self-reported absenteeism, presenteeism, and daily activity impairment attributed to uterine fibroids. The WPAI-UF was to be completed on a paper questionnaire and participants were to answer these questions.
Percent impairment while working due to uterine fibroid symptoms was calculated by taking the reported value from 1 (no effect) to 10 (completely prevented work) and dividing by 10. This value was then multiplied by 100 to get a percentage. The WPAI-UF outcomes are expressed as impairment percentages, with higher numbers indicating greater impairment and less productivity due to uterine fibroids, that is, worse outcomes.New: Change From Week 52/Baseline In The UFS-QoL Symptom Severity Score During The Randomized Treatment Period Week 52/Baseline to Week 104 Assessed using the UFS-QOL, which is a validated instrument used to evaluate symptom severity and quality of life in participants with uterine fibroids. The UFS-QoL was completed on a paper questionnaire and participants were to answer these questions. Items are scored on a 5-point scale, ranging from "not at all" to "a very great deal." A summed score was created for questions 1 through 8 and transformed to a normalized score with a range of possible values from 0 to 100, where a higher score was indicative of greater symptom severity and a lower score of lower symptom severity (negative score = improvement).
Change From Week 52/Baseline In The Work Productivity Activity Impairment - Percent Overall Work Impairment Due to Uterine Fibroids (WPAI-UF) Scores During The Randomized Treatment Period Week 52/Baseline up to Week 104 The WPAI-UF is a validated instrument used to measure self-reported absenteeism, presenteeism, and daily activity impairment attributed to uterine fibroids. The WPAI-UF was to be completed on a paper questionnaire and participants were to answer these questions.
Percent overall work impairment due to uterine fibroid symptoms was calculated from the work time missed due to uterine fibroids plus the value calculated from 1 minus the work time missed value multiplied by the value for impairment while working due to uterine fibroids. This value was then multiplied by 100 to get a percentage. The WPAI-UF outcomes are expressed as impairment percentages, with higher numbers indicating greater impairment and less productivity due to uterine fibroids, that is, worse outcomes.Change From Week 52/Baseline In The Work Productivity Activity Impairment - Percent Activity Impairment Due to Uterine Fibroids (WPAI-UF) Scores During The Randomized Treatment Period Week 52/Baseline up to Week 104 The WPAI-UF is a validated instrument used to measure self-reported absenteeism, presenteeism, and daily activity impairment attributed to uterine fibroids. The WPAI-UF was to be completed on a paper questionnaire and participants were to answer these questions.
Percent activity impairment due to uterine fibroid symptoms was calculated by taking the reported value from 1 (no effect) to 10 (completely prevented work) and dividing by 10. This value was then multiplied by 100 to get a percentage. The WPAI-UF outcomes are expressed as impairment percentages (0 to 100%), with higher numbers indicating greater impairment and less productivity due to uterine fibroids, that is, worse outcomes.Change From Week 52/Baseline In The UFS-QoL Bleeding And Pelvic Discomfort Score During The Randomized Treatment Period Week 52/Baseline to Week 104 Assessed using the UFS-QOL which is a validated instrument used to evaluate symptom severity and quality of life in participants with uterine fibroids. The UFS-QoL was completed on a paper questionnaire and participants were to answer the following questions: heavy bleeding during your menstrual period (Question 1), passing blood clots during your menstrual period (Question 2), and feeling tightness or pressure in your pelvic area (Question 5). Items are scored on a 5-point scale, ranging from "not at all" to "a very great deal." A summed score was created for questions 1, 2, and 5 and transformed to a normalized score with a range of possible values from 0 to 100, where a higher score was indicative of greater distress and a lower score of less distress (high scores = bad).
Original: Change From Week 52/Baseline In The UFS-QoL Symptom Severity Score During The Randomized Treatment Period Week 52/Baseline to Week 76 Assessed using the UFS-QOL, which is a validated instrument used to evaluate symptom severity and quality of life in participants with uterine fibroids. The UFS-QoL was completed on a paper questionnaire and participants were to answer these questions. Items are scored on a 5-point scale, ranging from "not at all" to "a very great deal." A summed score was created for questions 1 through 8 and transformed to a normalized score with a range of possible values from 0 to 100, where a higher score was indicative of greater symptom severity and a lower score of lower symptom severity (negative score = improvement).
Change From Week 52/Baseline In The UFS-QoL Score by Health-Related Quality Of Life Subscale And Total Scores During The Randomized Treatment Period Week 52/Baseline to Week 104 Assessed using the UFS-QOL which, is a validated instrument used to evaluate symptom severity and quality of life in participants with uterine fibroids. Items are scored on a 5-point scale, ranging from "none of the time" to "all of the time." The UFS-QoL was completed on a paper questionnaire and participants were to answer these questions. Questions 9 through 37 were used to calculate the total scores and the following subscales: concern, activities, revised activities, energy/mood, control, self-conscious, and sexual function. All raw scores are transformed to normalized scores with a range of possible values from 0 to 100. A positive score indicates improvement.
Predose Concentration Of Estradiol At Week 56 Week 52/Baseline and Week 56 Blood samples were collected from participants for estradiol measurements and were analyzed using a standard clinical methodology. The change from Week 52/Baseline in estradiol concentration at Week 56 was presented in this outcome.
Participants With Adverse Events (AEs) As A Measure Of Safety And Tolerability Week 52/Baseline up to Week 104 Assessed by percentage of participants with AEs and serious AEs (SAEs). An AE was defined as any unfavorable or unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product, whether or not related to the medicinal product. An SAE is any untoward medical occurrence that, at any dose: results in death; is life-threatening; requires hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; or a congenital anomaly/birth defect. Events of heavy menstrual bleeding were only reported if the event met criteria as an SAE. A summary of serious and all other non-serious adverse events, regardless of causality, is located in the Reported Adverse Events module.
Percent Change From Week 52/Baseline In BMD At Lumbar Spine (L1-L4) Week 52/Baseline to Week 104 Assessed by dual-energy X-ray absorptiometry scan at the lumbar spine (L1-L4), total hip \[presented separately\], and femoral neck (same leg within each participant) \[presented separately\] at each designated timepoints. The least squares means and their 95% CI were based on analysis of covariance model with treatment, stratification factors, race as fixed factors, and age at Week 52/Baseline, Week 52/Baseline BMD value, and body mass index at Week 52/Baseline as covariates.
Percent Change From Week 52/Baseline In BMD At Femoral Neck And Total Hip Week 52/Baseline to Week 104 Assessed by dual-energy X-ray absorptiometry scan at the lumbar spine (L1-L4) \[presented separately\], total hip, and femoral neck (same leg within each participant) at each designated timepoints. The least squares means and their 95% CI were based on analysis of covariance model with treatment, stratification factors, race as fixed factors, and age at Week 52/Baseline, Week 52/Baseline BMD value, and body mass index at Week 52/Baseline as covariates.
Trial Locations
- Locations (94)
Houston
🇺🇸Houston, Texas, United States
Durham
🇺🇸Durham, North Carolina, United States
Nyíregyháza
🇭🇺Nyíregyháza, Hungary
Catanzaro
🇮🇹Catanzaro, Italy
SIENA
🇮🇹Siena, Italy
Debrecen
🇭🇺Debrecen, Hungary
São Paulo
🇧🇷São Paulo, Brazil
Kecskemét
🇭🇺Kecskemét, Bacs-kiskun, Hungary
Norfolk
🇺🇸Norfolk, Virginia, United States
Shawnee
🇺🇸Shawnee Mission, Kansas, United States
Birmingham
🇺🇸Birmingham, Alabama, United States
Olomouc
🇨🇿Olomouc, Czechia
České Budějovice
🇨🇿České Budějovice, Czechia
Tampa
🇺🇸Tampa, Florida, United States
La Mesa
🇺🇸La Mesa, California, United States
Lakewood
🇺🇸Lakewood, Colorado, United States
Aventura
🇺🇸Aventura, Florida, United States
Margate
🇺🇸Margate, Florida, United States
Oviedo
🇺🇸Oviedo, Florida, United States
West Palm Beach
🇺🇸West Palm Beach, Florida, United States
Weston
🇺🇸Weston, Florida, United States
Atlanta
🇺🇸Atlanta, Georgia, United States
Augusta
🇺🇸Augusta, Georgia, United States
Dacatur
🇺🇸Decatur, Georgia, United States
Covington
🇺🇸Covington, Louisiana, United States
Marrero
🇺🇸Marrero, Louisiana, United States
Las Vegas
🇺🇸Las Vegas, Nevada, United States
Webster
🇺🇸Webster, Texas, United States
Richmond
🇺🇸Richmond, Virginia, United States
Porto Alegre
🇧🇷Porto Alegre, Brazil
Gyula
🇭🇺Gyula, Hungary
Szentes
🇭🇺Szentes, Hungary
Bialystok
🇵🇱Białystok, Poland
Poznan
🇵🇱Poznan, Poland
Durban
🇿🇦Durban, South Africa
Roodepoort
🇿🇦Roodepoort, South Africa
Detroit
🇺🇸Detroit, Michigan, United States
Miami
🇺🇸Miami, Florida, United States
Canoga Park
🇺🇸Canoga Park, California, United States
Mesa
🇺🇸Mesa, Arizona, United States
Tucson
🇺🇸Tucson, Arizona, United States
Huntington Beach
🇺🇸Huntington Beach, California, United States
Los Angeles
🇺🇸Los Angeles, California, United States
Norwalk
🇺🇸Norwalk, California, United States
San Diego
🇺🇸San Diego, California, United States
Denver
🇺🇸Denver, Colorado, United States
Clearwater
🇺🇸Clearwater, Florida, United States
Deland
🇺🇸DeLand, Florida, United States
Jacksonville
🇺🇸Jacksonville, Florida, United States
Ft. Lauderdale
🇺🇸Fort Lauderdale, Florida, United States
Jupiter
🇺🇸Jupiter, Florida, United States
Fort Myers
🇺🇸Fort Myers, Florida, United States
Orlando
🇺🇸Orlando, Florida, United States
Sarasota
🇺🇸Sarasota, Florida, United States
United States, Florida
🇺🇸West Palm Beach, Florida, United States
College Park
🇺🇸College Park, Georgia, United States
Duluth
🇺🇸Duluth, Georgia, United States
Savannah
🇺🇸Savannah, Georgia, United States
Norcross
🇺🇸Norcross, Georgia, United States
Smyrna
🇺🇸Smyrna, Georgia, United States
Chicago
🇺🇸Chicago, Illinois, United States
Oak brook
🇺🇸Oak Brook, Illinois, United States
Baltimore
🇺🇸Baltimore, Maryland, United States
Metairie
🇺🇸Metairie, Louisiana, United States
Canton
🇺🇸Canton, Michigan, United States
Towson
🇺🇸Towson, Maryland, United States
Lawrenceville
🇺🇸Lawrenceville, New Jersey, United States
Williamsville
🇺🇸Williamsville, New York, United States
Raleigh
🇺🇸Raleigh, North Carolina, United States
Winston Salem
🇺🇸Winston-Salem, North Carolina, United States
Cincinnati
🇺🇸Cincinnati, Ohio, United States
Bluffton
🇺🇸Bluffton, South Carolina, United States
Charleston
🇺🇸Charleston, South Carolina, United States
Columbia
🇺🇸Columbia, South Carolina, United States
Chattanooga
🇺🇸Chattanooga, Tennessee, United States
Memphis
🇺🇸Memphis, Tennessee, United States
Longview
🇺🇸Longview, Texas, United States
Dallas
🇺🇸Dallas, Texas, United States
San Antonio
🇺🇸San Antonio, Texas, United States
São Bernardo do Campo
🇧🇷São Bernardo Do Campo, SAO Paulo, Brazil
Spokane
🇺🇸Spokane, Washington, United States
Sao Paulo
🇧🇷São Paulo, Sao Paulo, Brazil
Santiago
🇨🇱Santiago, Chile
Pisek
🇨🇿Písek, Czechia
Providencia
🇨🇱Providencia, Chile
Torino
🇮🇹Torino, Italy
Roma
🇮🇹Roma, Italy
Szczecin
🇵🇱Szczecin, Zachodniopomorskie, Poland
Katowice
🇵🇱Katowice, Poland
Centurion
🇿🇦Centurion, Gauteng, South Africa
Bloemfontein
🇿🇦Bloemfontein, Free State, South Africa
Cape Town
🇿🇦Cape Town, Western Cape, South Africa
San Ramon
🇨🇱San Ramón, Chile
Warszawa
🇵🇱Warszawa, Poland