SPIRIT EXTENSION: Efficacy and Safety Extension Study of Relugolix in Women With Endometriosis-Associated Pain
- Conditions
- Endometriosis
- Interventions
- Registration Number
- NCT03654274
- Lead Sponsor
- Myovant Sciences GmbH
- Brief Summary
The purpose of this study is to evaluate the long-term efficacy and safety of relugolix 40 milligram (mg) once daily co-administered with low-dose estradiol (E2) and norethindrone acetate (NETA) for up to 104 weeks on endometriosis-associated pain in participants who previously completed a 24-week treatment period in one of the parent studies (MVT-601-3101 or MVT-601-3102).
- Detailed Description
This study is an international phase 3 open-label, single-arm, long-term efficacy and safety extension study that will enroll eligible participants who have completed their participation in one of the phase 3 randomized, double-blind, placebo-controlled parent studies, MVT-601-3101 (SPIRIT 1 - NCT03204318) or MVT-601-3102 (SPIRIT 2 - NCT03204331). All participants will receive relugolix 40 mg orally once daily co-administered with low-dose E2 (1.0 mg) and NETA (0.5 mg) for 80 weeks.
Approximately 800 women with endometriosis-associated pain will be enrolled, after having completed a 24-week treatment period in one of the parent studies. The objectives of the study are to evaluate long-term efficacy and safety through up to 104 weeks of treatment (including treatment during the parent study) of relugolix co-administered with low-dose E2/NETA.
Baseline procedures for this extension study will be performed on the same day as the Week 24 Visit of the parent study. This visit, referred to as the "Week 24/Baseline Visit, will be defined as the date of completion of the last Week 24 procedure in the parent study. Participants will have received their last dose of study drug in the parent study on the day prior to the Week 24/Baseline Visit and will receive their first dose of study drug for this extension study in the clinic after the participant is determined to be eligible for this extension study and has provided informed consent to participate. The administration of the first dose of study drug for MVT-601-3103 will define enrollment into this study. Study participants will then take the open-label study treatment orally, once daily for 80 weeks.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- Female
- Target Recruitment
- 802
- Completed 24 weeks of study drug treatment and study participation in either parent study, MVT-601-3101 or MVT-601-3102.
- Is not expected to undergo gynecological surgery or other surgical procedures for treatment of endometriosis (including ablation, shaving, or excision) during the study, including during the Follow-Up Period, and the participant does not desire such treatment during this time frame.
- Has agreed to continue to use only study-specified analgesic medications during the study and is not known to be intolerant to these.
Key
-
Has had a surgical procedure for treatment for endometriosis at any time during the parent study (MVT-601-3101 or MVT-601-3102).
-
Has any chronic pain or frequently recurring pain condition, other than endometriosis, that is treated with opioids or requires analgesics for ≥ 7 days per month.
-
Has a Z-score < -2.0 or has a ≥ 7% decrease in bone mineral density from the parent study Baseline at lumbar spine, total hip, or femoral neck based on the parent study Week 24 DXA assessment of bone mineral density.
-
Has any contraindication to treatment with low-dose E2 and NETA, including:
- Known, suspected, or history of breast cancer;
- Known or suspected estrogen-dependent neoplasia;
- Active deep vein thrombosis or pulmonary embolism, or history of these conditions prior to the Week 24/Baseline visit;
- History of or active arterial thromboembolic disease, including stroke and myocardial infarction;
- Known anaphylactic reaction or angioedema or hypersensitivity to E2 or NETA;
- Known protein C, protein S, or antithrombin deficiency, or other known thrombophilia disorders, including Factor V Leiden;
- Migraine with aura;
- History of porphyria.
-
Had any of the following clinical laboratory abnormalities at the parent study Week 20 visit or, if available, any subsequent visit in one of the parent studies (MVT-601-3101 or MVT-601-3102):
- Alanine aminotransferase or aspartate aminotransferase > 2.0 times the upper limit of normal (ULN); or
- Bilirubin (total bilirubin) > 1.5 x ULN (or > 2.0 x ULN if secondary to Gilbert syndrome or pattern consistent with Gilbert syndrome).
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Relugolix plus E2/NETA Estradiol/norethindrone acetate Relugolix co-administered with E2/NETA for 80 weeks. Relugolix plus E2/NETA Relugolix Relugolix co-administered with E2/NETA for 80 weeks.
- Primary Outcome Measures
Name Time Method Percentage Of Participants Who Meet The NMPP Responder Criteria At Week 52 Week 52 Assessed using an NRS score (11-point scale) for pain recorded daily in an electronic diary. A participant was defined as a responder if the NRS score for NMPP declined from baseline to Week 52 by at least 2.1 points without increased use of protocol-specified analgesics for pelvic pain at Week 52 relative to baseline. Participants rated their pelvic pain on a scale from 0 to 10, with 0 indicating no pain and 10 indicating pain as bad as you can imagine.
Percentage Of Participants Who Meet The Dysmenorrhea Responder Criteria At Week 104 Week 104 Assessed using an NRS score (11-point scale) for pain recorded daily in an electronic diary. A participant was defined as a responder if the NRS score for dysmenorrhea declined from baseline to Week 104 by at least 2.8 points without increased use of protocol-specified analgesics for pelvic pain at Week 104 relative to baseline. Participants rated their pelvic pain on a scale from 0 to 10, with 0 indicating no pain and 10 indicating pain as bad as you can imagine.
Percentage Of Participants Who Meet The NMPP Responder Criteria At Week 104 Week 104 Assessed using an NRS score (11-point scale) for pain recorded daily in an electronic diary. A participant was defined as a responder if the NRS score for NMPP declined from baseline to Week 104 by at least 2.1 points without increased use of protocol-specified analgesics for pelvic pain at Week 104 relative to baseline. Participants rated their pelvic pain on a scale from 0 to 10, with 0 indicating no pain and 10 indicating pain as bad as you can imagine.
Percentage Of Participants Who Meet The Dysmenorrhea Responder Criteria At Week 52 Week 52 Assessed using an NRS score (11-point scale) for pain recorded daily in an electronic diary. A participant was defined as a responder if the NRS score for dysmenorrhea declined from baseline to Week 52 by at least 2.8 points without increased use of protocol-specified analgesics for pelvic pain at Week 52 relative to baseline. Participants rated their pelvic pain on a scale from 0 to 10, with 0 indicating no pain and 10 indicating pain as bad as you can imagine.
- Secondary Outcome Measures
Name Time Method Change From The Pivotal Phase 3 Study Baseline In The Endometriosis Health Profile (EHP)-30 Pain Domain Scores At Week 52 Week 52 Assessed using the pain domain of the EHP-30 questionnaire. The EHP-30 questionnaire was completed on an electronic tablet (eTablet) device. Participants reported the frequency (never, rarely, sometimes, often, and always) with which they had difficulty with activities such as standing, sitting, walking, sleeping, and performing jobs around the house because of pain. The Pain Domain normalized scores ranged from 0 to 100, with higher scores denoting greater functional impact of pain. The least squares (LS) mean was presented by pivotal study treatment group and by visit.
Percentage Of Participants Who Are "Better" Or "Much Better" On The PGIC For Dyspareunia At Week 52 Week 52 The PGIC for dyspareunia is a 1-item questionnaire designed to assess participant's impression of change in the severity of their pain during sexual intercourse. The questionnaire used a 7-point response scale: much better, better, a little better, the same, a little worse, worse, or much worse.
Percentage Of Participants Who Have A Reduction Of At Least 20 Points In The EHP-30 Pain Domain Scores From The Pivotal Phase 3 Study Baseline At Week 104 Week 104 Assessed using the Pain Domain of the EHP-30 questionnaire. The EHP-30 questionnaire was completed on an electronic tablet (eTablet) device. Participants reported the frequency (never, rarely, sometimes, often, and always) with which they had difficulty with activities such as standing, sitting, walking, sleeping, and performing jobs around the house because of pain. The Pain Domain normalized scores ranged from 0 to 100, with higher scores denoting greater functional impact of pain.
Change From The Pivotal Phase 3 Study Baseline In The Mean Dysmenorrhea NRS Score At Week 104 Week 104 Assessed using an NRS score (11-point scale) for pain recorded daily in an electronic diary. Participants rated their pelvic pain on a scale from 0 to 10, with 0 indicating no pain and 10 indicating pain as bad as you can imagine. The LS mean was presented by pivotal study treatment group and by visit.
Percentage Of Participants Who Are "Better" Or "Much Better" On The Patient Global Impression Of Change (PGIC) For Dysmenorrhea At Week 52 Week 52 The PGIC for dysmenorrhea is a 1-item questionnaire designed to assess participant's impression of change in the severity of pain during their menstrual cycle. The questionnaire used a 7-point response scale: much better, better, a little better, the same, a little worse, worse, or much worse.
Percentage Of Participants Not Using Opioids For Endometriosis-associated Pain At Week 104 Week 104 Assessed based on usage of study-specified opioids for endometriosis-associated pain recorded daily in an electronic diary. Participants received protocol-specified opioids for treatment of endometriosis-associated pain as needed for pain but not prophylactically.
Change From The Pivotal Phase 3 Study Baseline In The Endometriosis Health Profile (EHP)-30 Pain Domain Scores At Week 104 Week 104 Assessed using the pain domain of the EHP-30 questionnaire. The EHP-30 questionnaire was completed on an electronic tablet (eTablet) device. Participants reported the frequency (never, rarely, sometimes, often, and always) with which they had difficulty with activities such as standing, sitting, walking, sleeping, and performing jobs around the house because of pain. The Pain Domain normalized scores ranged from 0 to 100, with higher scores denoting greater functional impact of pain. The least squares (LS) mean was presented by pivotal study treatment group and by visit.
Change From The Pivotal Phase 3 Study Baseline In The Mean Dysmenorrhea NRS Score At Week 52 Week 52 Assessed using an NRS score (11-point scale) for pain recorded daily in an electronic diary. Participants rated their pelvic pain on a scale from 0 to 10, with 0 indicating no pain and 10 indicating pain as bad as you can imagine. The LS mean was presented by pivotal study treatment group and by visit.
Percentage Of Participants Who Have A Reduction Of At Least 20 Points In The EHP-30 Pain Domain Scores From The Pivotal Phase 3 Study Baseline At Week 52 Week 52 Assessed using the Pain Domain of the EHP-30 questionnaire. The EHP-30 questionnaire was completed on an electronic tablet (eTablet) device. Participants reported the frequency (never, rarely, sometimes, often, and always) with which they had difficulty with activities such as standing, sitting, walking, sleeping, and performing jobs around the house because of pain. The Pain Domain normalized scores ranged from 0 to 100, with higher scores denoting greater functional impact of pain.
Change From The Pivotal Phase 3 Study Baseline In The Mean NMPP NRS Score At Week 52 Week 52 Assessed using an NRS score (11-point scale) for pain recorded daily in an electronic diary. Participants rated their pelvic pain on a scale from 0 to 10, with 0 indicating no pain and 10 indicating pain as bad as you can imagine. The LS mean was presented by pivotal study treatment group and by visit.
Change From The Pivotal Phase 3 Study Baseline In The Mean Overall Pelvic Pain NRS Score At Week 52 Week 52 Assessed using an NRS score (11-point scale) for overall pain recorded daily in an electronic diary. Participants rated their overall pelvic pain on a scale from 0 to 10, with 0 indicating no pain and 10 indicating pain as bad as you can imagine. The LS mean was presented by pivotal study treatment group and by visit.
Percentage Of Participants Not Using Analgesics For Endometriosis-associated Pain At Week 104 Week 104 Assessed based on usage of study-specified analgesics for endometriosis-associated pain recorded daily in an electronic diary. Participants received protocol-specified analgesics for treatment of endometriosis-associated pain as needed for pain but not prophylactically.
Change From The Pivotal Phase 3 Study Baseline In The Mean NMPP NRS Score At Week 104 Week 104 Assessed using an NRS score (11-point scale) for pain recorded daily in an electronic diary. Participants rated their pelvic pain on a scale from 0 to 10, with 0 indicating no pain and 10 indicating pain as bad as you can imagine. The LS mean was presented by pivotal study treatment group and by visit.
Change From The Pivotal Phase 3 Study Baseline In The Mean Overall Pelvic Pain NRS Score At Week 104 Week 104 Assessed using an NRS score (11-point scale) for overall pain recorded daily in an electronic diary. Participants rated their overall pelvic pain on a scale from 0 to 10, with 0 indicating no pain and 10 indicating pain as bad as you can imagine. The LS mean was presented by pivotal study treatment group and by visit.
Change From The Pivotal Phase 3 Study Baseline In The Mean Dyspareunia NRS Scores At Week 52 Week 52 Assessed using an NRS score (11-point scale) for pain recorded daily in an electronic diary. Participants were to report whether they had vaginal sexual intercourse and rated their level of pelvic pain during intercourse on a scale from 0 to 10, with 0 indicating no pain and 10 indicating pain as bad as you can imagine. The LS mean was presented by pivotal study treatment group and by visit.
Change From The Pivotal Phase 3 Study Baseline In Severity Scores On The Patient Global Assessment (PGA) For Overall Pelvic Pain At Week 104 Week 104 The PGA for pelvic pain severity is a 1-item questionnaire designed to assess participant's impression of the severity of their pain. The questionnaire used a 5-point response scale; each response was given a numerical score: absent (0), mild (1), moderate (2), severe (3), or very severe (4). The LS mean was presented by pivotal study treatment group and by visit.
Change From The Pivotal Phase 3 Study Baseline In Function Impairment On The PGA For Function At Week 52 Week 52 The PGA for functional impairment is a 1-item questionnaire designed to assess participant's impression of how their pain affected their usual activities. The participants responded to the question: "How much were your daily activities limited by endometriosis over the last 4 weeks?" using a 5-point response scale; each response was given a numerical score: not at all (0), minimally (1), moderately (2), significantly (3), or very significantly (4). The LS mean was presented by pivotal study treatment group and by visit.
Change From The Pivotal Phase 3 Study Baseline In The Mean Dyspareunia Functional Impairment At Week 104 Week 104 Assessed using the participant-modified Biberoglu and Behrman 5-point scale for dyspareunia recorded daily in an electronic diary. Participants were to report their pain during intercourse daily using the following response options: Severe (avoids intercourse because of pain), Moderate (intercourse painful to the point of causing interruption), Mild (tolerated pain), No pain (no pain during intercourse), or No intercourse (no intercourse for other reasons). Participants gave a possible score of 0 (no pain) to 3 (severe). The LS mean was presented by pivotal study treatment group and by visit.
Percentage Of Participants With Improvement, No Change, Or Worsening From Baseline In PGA Score For Function At Week 104 Week 104 The PGA for functional impairment is a 1-item questionnaire designed to assess participant's impression of how their pain affected their usual activities. The participants responded to the question: "How much were your daily activities limited by endometriosis over the last 4 weeks?" using a 5-point response scale; each response was given a numerical score: not at all (0), minimally (1), moderately (2), significantly (3), or very significantly (4).
Change From The Pivotal Phase 3 Study Baseline In Each Of The Non-Pain EHP-30 Domains At Week 104 Week 104 Assessed using the following non-pain domains of the EHP-30 questionnaire: Control and Powerlessness (questions 12 through 17), Emotional Well-Being (questions 18 through 23), Social Support (questions 24 through 27), and Self-Image (questions 28 through 30). The score for each domain ranged from 0 to 100. Higher scores represent a greater impact of endometriosis. The LS mean was presented by pivotal study treatment group and by visit.
Change From Pivotal Phase 3 Study Baseline In NMPP Functional Impairment Score At Week 52 Week 52 Assessed using the participant-modified Biberoglu and Behrman 4-point scale for pelvic pain recorded daily in an electronic diary. Participants reported their pain daily in an electronic diary using the following response options: Severe (requires strong analgesics), Moderate (noticeable pelvic pain), Mild (occasional pelvic pain), or No pain (no pain during past 24 hours). Participants gave a possible score of 0 (no pain) to 3 (severe). The LS mean was presented by pivotal study treatment group and by visit.
Percent Change From The Pivotal Phase 3 Study Baseline In BMD At Lumbar Spine (L1-L4), Femoral Neck, And Total Hip At Week 52 Week 52 Assessed by dual-energy X-ray absorptiometry (DXA) scan at lumbar spine, total hip, and femoral neck (same leg for each participant) at each designated time point. All participants who completed treatment or terminated from the study early were required to return for a 6-month post-treatment follow-up (PTFU) and a 12-month PTFU DXA scan (except if participant was beyond 14 months from last day on treatment). Participants were also to have clinical laboratory evaluations (vitamin D, thyroid stimulating hormone, parathyroid hormone, creatinine, calcium, and phosphorous) at the 6-month and 12-month PTFU only if the PTFU DXA scans showed a bone loss of ≥3% at the lumbar spine and/or total hip compared with the parent study baseline.
Percent Change From The Pivotal Phase 3 Study Baseline In BMD At Lumbar Spine (L1-L4), Femoral Neck, And Total Hip At Week 104 Week 104 Assessed by dual-energy X-ray absorptiometry (DXA) scan at lumbar spine, total hip, and femoral neck (same leg for each participant) at each designated time point. All participants who completed treatment or terminated from the study early were required to return for a 6-month post-treatment follow-up (PTFU) and a 12-month PTFU DXA scan (except if participant was beyond 14 months from last day on treatment). Participants were also to have clinical laboratory evaluations (vitamin D, thyroid stimulating hormone, parathyroid hormone, creatinine, calcium, and phosphorous) at the 6-month and 12-month PTFU only if the PTFU DXA scans showed a bone loss of ≥3% at the lumbar spine and/or total hip compared with the parent study baseline.
Percentage Of Participants Who Are "Better" Or "Much Better" On The PGIC For NMPP At Week 52 Week 52 The PGIC for NMPP is a 1-item questionnaire designed to assess participant's impression of change in the severity of pain when they are not menstruating. The questionnaire used a 7-point response scale: much better, better, a little better, the same, a little worse, worse, or much worse.
Change From The Pivotal Phase 3 Study Baseline In The Mean Dyspareunia NRS Scores At Week 104 Week 104 Assessed using an NRS score (11-point scale) for pain recorded daily in an electronic diary. Participants were to report whether they had vaginal sexual intercourse and rated their level of pelvic pain during intercourse on a scale from 0 to 10, with 0 indicating no pain and 10 indicating pain as bad as you can imagine. The LS mean was presented by pivotal study treatment group and by visit.
Change From The Pivotal Phase 3 Study Baseline In Severity Scores On The Patient Global Assessment (PGA) For Overall Pelvic Pain At Week 52 Week 52 The PGA for pelvic pain severity is a 1-item questionnaire designed to assess participant's impression of the severity of their pain. The questionnaire used a 5-point response scale; each response was given a numerical score: absent (0), mild (1), moderate (2), severe (3), or very severe (4). The LS mean was presented by pivotal study treatment group and by visit.
Percentage Of Participants With Improvement, No Change, Or Worsening From Baseline In PGA Score For Overall Pelvic Pain At Week 52 Week 52 The PGA for pelvic pain severity is a 1-item questionnaire designed to assess participant's impression of the severity of their pain. The questionnaire used a 5-point response scale; each response was given a numerical score: absent (0), mild (1), moderate (2), severe (3), or very severe (4).
Percentage Of Participants With Improvement, No Change, Or Worsening From Baseline In PGA Score For Overall Pelvic Pain At Week 104 Week 104 The PGA for pelvic pain severity is a 1-item questionnaire designed to assess participant's impression of the severity of their pain. The questionnaire used a 5-point response scale; each response was given a numerical score: absent (0), mild (1), moderate (2), severe (3), or very severe (4).
Percentage Of Participants With Improvement, No Change, Or Worsening From Baseline In PGA Score For Function At Week 52 Week 52 The PGA for functional impairment is a 1-item questionnaire designed to assess participant's impression of how their pain affected their usual activities. The participants responded to the question: "How much were your daily activities limited by endometriosis over the last 4 weeks?" using a 5-point response scale; each response was given a numerical score: not at all (0), minimally (1), moderately (2), significantly (3), or very significantly (4).
Change From The Pivotal Phase 3 Study Baseline In Dysmenorrhea Functional Impairment Score At Week 104 Week 104 Assessed using the participant-modified Biberoglu and Behrman 5-point scale for dysmenorrhea recorded daily in an electronic diary. Participants were to report their pain as related to functional impairment daily in an electronic diary using the following response options: Severe (in bed all day, incapacitation), Moderate (in bed part of the day, some loss of work efficiency), Mild (some loss of work efficiency), No pain (no pain associated with menstruation during past 24 hours), or did not menstruate during the past 24 hours. Participants gave a possible score of 0 (no pain) to 4 (did not menstruate). The LS mean was presented by pivotal study treatment group and by visit.
Change From Pivotal Phase 3 Study Baseline In NMPP Functional Impairment Score At Week 104 Week 104 Assessed using the participant-modified Biberoglu and Behrman 4-point scale for pelvic pain recorded daily in an electronic diary. Participants reported their pain daily in an electronic diary using the following response options: Severe (requires strong analgesics), Moderate (noticeable pelvic pain), Mild (occasional pelvic pain), or No pain (no pain during past 24 hours). Participants gave a possible score of 0 (no pain) to 3 (severe). The LS mean was presented by pivotal study treatment group and by visit.
Change From The Pivotal Phase 3 Study Baseline In The Mean Dyspareunia Functional Impairment At Week 52 Week 52 Assessed using the participant-modified Biberoglu and Behrman 5-point scale for dyspareunia recorded daily in an electronic diary. Participants were to report their pain during intercourse daily using the following response options: Severe (avoids intercourse because of pain), Moderate (intercourse painful to the point of causing interruption), Mild (tolerated pain), No pain (no pain during intercourse), or No intercourse (no intercourse for other reasons). Participants gave a possible score of 0 (no pain) to 3 (severe). The LS mean was presented by pivotal study treatment group and by visit.
Change From The Pivotal Phase 3 Study Baseline In Function Impairment On The PGA For Function At Week 104 Week 104 The PGA for functional impairment is a 1-item questionnaire designed to assess participant's impression of how their pain affected their usual activities. The participants responded to the question: "How much were your daily activities limited by endometriosis over the last 4 weeks?" using a 5-point response scale; each response was given a numerical score: not at all (0), minimally (1), moderately (2), significantly (3), or very significantly (4). The LS mean was presented by pivotal study treatment group and by visit.
Change From The Pivotal Phase 3 Study Baseline In Each Of The Non-Pain EHP-30 Domains At Week 52 Week 52 Assessed using the following non-pain domains of the EHP-30 questionnaire: Control and Powerlessness (questions 12 through 17), Emotional Well-Being (questions 18 through 23), Social Support (questions 24 through 27), and Self-Image (questions 28 through 30). The score for each domain ranged from 0 to 100. Higher scores represent a greater impact of endometriosis. The LS mean was presented by pivotal study treatment group and by visit.
Change From The Pivotal Phase 3 Study Baseline In Dysmenorrhea Functional Impairment Score At Week 52 Week 52 Assessed using the participant-modified Biberoglu and Behrman 5-point scale for dysmenorrhea recorded daily in an electronic diary. Participants were to report their pain as related to functional impairment daily in an electronic diary using the following response options: Severe (in bed all day, incapacitation), Moderate (in bed part of the day, some loss of work efficiency), Mild (some loss of work efficiency), No pain (no pain associated with menstruation during past 24 hours), or did not menstruate during the past 24 hours. Participants gave a possible score of 0 (no pain) to 4 (did not menstruate). The LS mean was presented by pivotal study treatment group and by visit.
Change From Pivotal Phase 3 Study Baseline In Predose Serum Concentrations Of Estradiol At Week 52 Week 52 Blood samples were collected from participants for estradiol measurements at each specified timepoints. Estradiol concentrations were measured using an immuno-enzymatic assay based on a commercially available kit.
Change From Pivotal Phase 3 Study Baseline In Predose Serum Concentrations Of Estradiol At Week 104 Week 104 Blood samples were collected from participants for estradiol measurements at each specified timepoints. Estradiol concentrations were measured using an immuno-enzymatic assay based on a commercially available kit.
Trial Locations
- Locations (136)
Park Ridge
🇺🇸Park Ridge, Illinois, United States
Corpus Christi
🇺🇸Corpus Christi, Texas, United States
Dallas
🇺🇸Dallas, Texas, United States
Columbus
🇺🇸Columbus, Ohio, United States
Seattle
🇺🇸Seattle, Washington, United States
Scottsdale
🇺🇸Scottsdale, Arizona, United States
Tucson
🇺🇸Tucson, Arizona, United States
Tuscon
🇺🇸Tucson, Arizona, United States
Columbia
🇺🇸Columbia, South Carolina, United States
Fort Myers
🇺🇸Fort Myers, Florida, United States
St. Louis
🇺🇸Saint Louis, Missouri, United States
Gent
🇧🇪Gent, Oost-vlaanderen, Belgium
Porto Alegre
🇧🇷Porto Alegre, Sao Paulo, Brazil
Sao Paulo
🇧🇷Sao Paulo, Brazil
Stara Zagora
🇧🇬Stara Zagora, Bulgaria
București
🇷🇴București, Romania
Zaporizhzhya
🇺🇦Zaporizhzhya, Ukraine
Las Vegas
🇺🇸Las Vegas, Nevada, United States
San Diego
🇺🇸San Diego, California, United States
Miami
🇺🇸Miami, Florida, United States
San Antonio
🇺🇸San Antonio, Texas, United States
Brussels
🇧🇪Brussels, Belgium
Cordoba
🇦🇷Cordoba, Argentina
Wollongong
🇦🇺Wollongong, NS, Australia
Kyiv
🇺🇦Kyiv, Ukraine
Tbilisi
🇬🇪Tbilisi, Georgia
Łódź
🇵🇱Łódź, Lodzkie, Poland
Pécs
🇭🇺Pécs, Baranya, Hungary
Nyíregyháza
🇭🇺Nyíregyháza, Szabolcs-szatmar-bereg, Hungary
Coimbra
🇵🇹Coimbra, Portugal
Lublin
🇵🇱Lublin, Lubelskie, Poland
Catanzaro
🇮🇹Catanzaro, Italy
Szeged
🇭🇺Szeged, Csongrad, Hungary
Pavia
🇮🇹Pavia, Italy
Washington
🇺🇸Washington, District of Columbia, United States
Porto
🇵🇹Porto, Portugal
Nedlands
🇦🇺Nedlands, Western Australia, Australia
São Paulo
🇧🇷São Paulo, Sao Paulo, Brazil
Durban
🇿🇦Durban, Kwazulu-natal, South Africa
Norfolk
🇺🇸Norfolk, Virginia, United States
Shawnee
🇺🇸Shawnee Mission, Kansas, United States
Greenwood Village
🇺🇸Greenwood Village, Colorado, United States
Passo Fundo
🇧🇷Passo Fundo, Rio Grande Do Sul, Brazil
Salt Lake City
🇺🇸Salt Lake City, Utah, United States
Roma
🇮🇹Roma, Italy
Tampa
🇺🇸Tampa, Florida, United States
Omaha
🇺🇸Omaha, Nebraska, United States
Andalusia
🇺🇸Andalusia, Alabama, United States
Canoga Park
🇺🇸Canoga Park, California, United States
Los Angeles
🇺🇸Los Angeles, California, United States
Aventura
🇺🇸Aventura, Florida, United States
Hialeah
🇺🇸Hialeah, Florida, United States
Margate
🇺🇸Margate, Florida, United States
Norcross
🇺🇸Norcross, Georgia, United States
Atlanta
🇺🇸Atlanta, Georgia, United States
Augusta
🇺🇸Augusta, Georgia, United States
Idaho Falls
🇺🇸Idaho Falls, Idaho, United States
Oakbrook
🇺🇸Oakbrook Terrace, Illinois, United States
Towson
🇺🇸Towson, Maryland, United States
Marrero
🇺🇸Marrero, Louisiana, United States
Jefferson City
🇺🇸Jefferson City, Missouri, United States
Saginaw
🇺🇸Saginaw, Michigan, United States
Durham
🇺🇸Durham, North Carolina, United States
New Bern
🇺🇸New Bern, North Carolina, United States
Akron
🇺🇸Akron, Ohio, United States
Hershey
🇺🇸Hershey, Pennsylvania, United States
Englewood
🇺🇸Englewood, Ohio, United States
Memphis
🇺🇸Memphis, Tennessee, United States
Beaumont
🇺🇸Beaumont, Texas, United States
Chattanooga
🇺🇸Chattanooga, Tennessee, United States
Houston
🇺🇸Houston, Texas, United States
Irving
🇺🇸Irving, Texas, United States
Fort Worth
🇺🇸Fort Worth, Texas, United States
Webster
🇺🇸Webster, Texas, United States
Sugar Land
🇺🇸Sugar Land, Texas, United States
San Isidro
🇦🇷San Isidro, Buenos Aires, Argentina
Virginia Beach
🇺🇸Virginia Beach, Virginia, United States
Rosario
🇦🇷Rosario, Santa Fe, Argentina
Ciudad de Buenos Aires
🇦🇷Ciudad de Buenos Aires, Buenos Aires, Argentina
Leuven
🇧🇪Leuven, Flemish Brabant, Belgium
Taringa
🇦🇺Taringa, Queensland, Australia
Adelaide
🇦🇺Adelaide, South Australia, Australia
La Louvière
🇧🇪La Louvière, Hainaut, Belgium
São Bernardo do Campo
🇧🇷São Bernardo do Campo, Sao Paulo, Brazil
Sofia
🇧🇬Sofia, Sofiya, Bulgaria
Blagoevgrad
🇧🇬Blagoevgrad, Bulgaria
Pleven
🇧🇬Pleven, Bulgaria
Waterloo
🇨🇦Waterloo, Ontario, Canada
Red Deer
🇨🇦Red Deer, Alberta, Canada
Varna
🇧🇬Varna, Bulgaria
Victoriaville
🇨🇦Victoriaville, Quebec, Canada
Santiago
🇨🇱Santiago, Chile
Písek
🇨🇿Písek, Jihocesky Kraj, Czechia
Tábor
🇨🇿Tábor, Jihormoravsky Kraj, Czechia
Vodňany
🇨🇿Vodňany, Jihocesky, Czechia
Náchod
🇨🇿Náchod, Kralovehradecky, Czechia
Praha 2
🇨🇿Praha 2, Praha, Czechia
Oulu
🇫🇮Oulu, Finland
Olomouc
🇨🇿Olomouc, Czechia
Praha 10
🇨🇿Praha 10, Praha, Czechia
Praha 8 - Libeň
🇨🇿Praha 8 - Libeň, Czechia
České Budějovice
🇨🇿České Budějovice, Czechia
Kuopio
🇫🇮Kuopio, Eastern Finland, Finland
Helsinki
🇫🇮Helsinki, Southern Finland, Finland
Kecskemét
🇭🇺Kecskemét, Bacs-kiskun, Hungary
Debrecen
🇭🇺Debrecen, Hajdu-bihar, Hungary
Békéscsaba
🇭🇺Békéscsaba, Bekes, Hungary
Gyula
🇭🇺Gyula, Bekes, Hungary
Monserrato
🇮🇹Monserrato, Cagliari, Italy
Napoli
🇮🇹Napoli, Italy
Remuera
🇳🇿Remuera, Auckland, New Zealand
Christchurch
🇳🇿Christchurch, New Zealand
Palmerston North
🇳🇿Palmerston North, Manawatu-wanganui, New Zealand
Warszawa
🇵🇱Warszawa, Mazowieckie, Poland
Białystok
🇵🇱Białystok, Podlaskie, Poland
Katowice
🇵🇱Katowice, Slaskie, Poland
Skórzewo
🇵🇱Skórzewo, Wielkopolskie, Poland
Szczecin
🇵🇱Szczecin, Zachodniopomorskie, Poland
Almada
🇵🇹Almada, Lisboa, Portugal
Covilhã
🇵🇹Covilhã, Portugal
Brasov
🇷🇴Brasov, Romania
Bucuresti
🇷🇴Bucuresti, Romania
Port Elizabeth
🇿🇦Port Elizabeth, Eastern Cape, South Africa
Roodepoort
🇿🇦Roodepoort, Gauteng, South Africa
Cape Town
🇿🇦Cape Town, Western Cape, South Africa
Centurion
🇿🇦Centurion, Gauteng, South Africa
Valencia
🇪🇸Valencia, Spain
Kharkiv
🇺🇦Kharkiv, Ukraine
Ivano-Frankivsk
🇺🇦Ivano-Frankivsk, Ukraine
Chernivtsi
🇺🇦Chernivtsi, Ukraine
Kiev
🇺🇦Kiev, Ukraine
Sarasota
🇺🇸Sarasota, Florida, United States
Sydney
🇦🇺Sydney, New South Wales, Australia
Madrid
🇪🇸Madrid, Spain
Winston Salem
🇺🇸Winston-Salem, North Carolina, United States
Richmond
🇺🇸Richmond, Virginia, United States