An Evaluation of Dupilumab in Patients With Moderate to Severe Uncontrolled Asthma
- Conditions
- Asthma
- Interventions
- Drug: placeboDrug: ICS/LABA therapyDrug: Salbutamol/albuterolDrug: Levosalbutamol/levalbuterol
- Registration Number
- NCT01854047
- Lead Sponsor
- Sanofi
- Brief Summary
Primary Objective:
To evaluate the efficacy of different doses and regimens of dupilumab in participants with moderate to severe uncontrolled asthma.
Secondary Objective:
To evaluate different doses and regimens of dupilumab in participants with moderate to severe uncontrolled asthma, with regard to:
* Safety and tolerability
* Dupilumab systemic exposure and anti-drug antibodies
- Detailed Description
Total duration per participant of approximately 43 weeks including a screening period (14-21 days), a randomized treatment period (24 weeks), and a post-treatment period (16 weeks).
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 776
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Dupilumab 200 mg q2w Dupilumab 2 subcutaneous injections of Dupilumab 200 mg (for a total of 400 mg) as a loading dose on Day 1 (Week 1), followed by a single 200 mg injection q2w from Week 2 to Week 22 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication. Dupilumab 300 mg q4w ICS/LABA therapy 2 subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1 (Week 1) followed by a Placebo alternating with single 300 mg injection of Dupilumab q2w from Week 2 to Week 22 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication. Dupilumab 200 mg q2w ICS/LABA therapy 2 subcutaneous injections of Dupilumab 200 mg (for a total of 400 mg) as a loading dose on Day 1 (Week 1), followed by a single 200 mg injection q2w from Week 2 to Week 22 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication. Dupilumab 200 mg q4w Levosalbutamol/levalbuterol 2 subcutaneous injections of Dupilumab 200 mg (for a total of 400 mg) as a loading dose on Day 1 (Week 1) followed by a Placebo alternating with single 200 mg injection of Dupilumab q2w from Week 2 to Week 22 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication. Dupilumab 300 mg q2w ICS/LABA therapy 2 subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1 (Week 1), followed by a single 300 mg injection q2w from Week 2 to Week 22 added to stable inhaled corticosteroid/ long-acting beta-agonist (ICS/LABA) therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication. Dupilumab 300 mg q4w Levosalbutamol/levalbuterol 2 subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1 (Week 1) followed by a Placebo alternating with single 300 mg injection of Dupilumab q2w from Week 2 to Week 22 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication. Dupilumab 200 mg q4w placebo 2 subcutaneous injections of Dupilumab 200 mg (for a total of 400 mg) as a loading dose on Day 1 (Week 1) followed by a Placebo alternating with single 200 mg injection of Dupilumab q2w from Week 2 to Week 22 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication. Dupilumab 200 mg q4w Salbutamol/albuterol 2 subcutaneous injections of Dupilumab 200 mg (for a total of 400 mg) as a loading dose on Day 1 (Week 1) followed by a Placebo alternating with single 200 mg injection of Dupilumab q2w from Week 2 to Week 22 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication. Dupilumab 200 mg q2w Levosalbutamol/levalbuterol 2 subcutaneous injections of Dupilumab 200 mg (for a total of 400 mg) as a loading dose on Day 1 (Week 1), followed by a single 200 mg injection q2w from Week 2 to Week 22 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication. Dupilumab 300 mg q4w Dupilumab 2 subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1 (Week 1) followed by a Placebo alternating with single 300 mg injection of Dupilumab q2w from Week 2 to Week 22 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication. Dupilumab 300 mg q4w placebo 2 subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1 (Week 1) followed by a Placebo alternating with single 300 mg injection of Dupilumab q2w from Week 2 to Week 22 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication. Dupilumab 200 mg q4w ICS/LABA therapy 2 subcutaneous injections of Dupilumab 200 mg (for a total of 400 mg) as a loading dose on Day 1 (Week 1) followed by a Placebo alternating with single 200 mg injection of Dupilumab q2w from Week 2 to Week 22 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication. Dupilumab 300 mg q2w Salbutamol/albuterol 2 subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1 (Week 1), followed by a single 300 mg injection q2w from Week 2 to Week 22 added to stable inhaled corticosteroid/ long-acting beta-agonist (ICS/LABA) therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication. Dupilumab 300 mg q2w Levosalbutamol/levalbuterol 2 subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1 (Week 1), followed by a single 300 mg injection q2w from Week 2 to Week 22 added to stable inhaled corticosteroid/ long-acting beta-agonist (ICS/LABA) therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication. Dupilumab 200 mg q2w Salbutamol/albuterol 2 subcutaneous injections of Dupilumab 200 mg (for a total of 400 mg) as a loading dose on Day 1 (Week 1), followed by a single 200 mg injection q2w from Week 2 to Week 22 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication. Dupilumab 300 mg q4w Salbutamol/albuterol 2 subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1 (Week 1) followed by a Placebo alternating with single 300 mg injection of Dupilumab q2w from Week 2 to Week 22 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication. Placebo q2w placebo 2 subcutaneous injections of Placebo (for Dupilumab) as a loading dose on Day 1 (Week 1) followed by a single injection q2w from Week 2 to Week 22 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication. Placebo q2w ICS/LABA therapy 2 subcutaneous injections of Placebo (for Dupilumab) as a loading dose on Day 1 (Week 1) followed by a single injection q2w from Week 2 to Week 22 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication. Placebo q2w Salbutamol/albuterol 2 subcutaneous injections of Placebo (for Dupilumab) as a loading dose on Day 1 (Week 1) followed by a single injection q2w from Week 2 to Week 22 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication. Placebo q2w Levosalbutamol/levalbuterol 2 subcutaneous injections of Placebo (for Dupilumab) as a loading dose on Day 1 (Week 1) followed by a single injection q2w from Week 2 to Week 22 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication. Dupilumab 300 mg q2w Dupilumab 2 subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1 (Week 1), followed by a single 300 mg injection q2w from Week 2 to Week 22 added to stable inhaled corticosteroid/ long-acting beta-agonist (ICS/LABA) therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication. Dupilumab 200 mg q4w Dupilumab 2 subcutaneous injections of Dupilumab 200 mg (for a total of 400 mg) as a loading dose on Day 1 (Week 1) followed by a Placebo alternating with single 200 mg injection of Dupilumab q2w from Week 2 to Week 22 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication.
- Primary Outcome Measures
Name Time Method Absolute Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) at Week 12: High Eosinophils -Intent to Treat (HEos-ITT) Population Baseline, Week 12 FEV1 was the volume of air exhaled in the first second of a forced expiration as measured by spirometer.
Absolute Change From Baseline in FEV1 at Week 12: ITT Population Baseline, Week 12 FEV1 was the volume of air exhaled in the first second of a forced expiration as measured by spirometer.
- Secondary Outcome Measures
Name Time Method Annualized Event Rate of LOAC During The Treatment Period: ITT Population Baseline to Week 24 LOAC was defined as any of the following: \>=6 additional reliever puffs of salbutamol/albuterol or levosalbutamol/levalbuterol in a 24-hour period (compared to baseline) on 2 consecutive days; increase in ICS \>=4 times the dose at randomization; use of systemic corticosteroids for \>=3 days; hospitalization or emergency room visit because of asthma, requiring systemic corticosteroids. Annualized event rate was the total number of LOAC that occurred during the treatment period divided by the total number of participant-years treated.
Change From Baseline in Number of Inhalations Per Day of Salbutamol/Albuterol or Levosalbutamol/Levalbuterol at Week 12: HEos-ITT Population Baseline, Week 12 Participants might administered salbutamol/albuterol or levosalbutamol/levalbuterol as reliever medication as needed during the study. The number of salbutamol/albuterol or levosalbutamol/levalbuterol inhalations were recorded by the participants in their electronic diary.
Time to First LOAC Event: Kaplan-Meier Estimates at Week 12 and Week 24: ITT Population Baseline up to Week 24 The time to first LOAC event was defined as the time from the date of first dose to the date of the first LOAC event. For participants who had no LOAC event on or before last dose date + 14 days, it was censored at the date of last dose date + 14 days. The median time to first LOAC was not estimated because the number of LOAC was too low in the Dupilumab arms. Therefore, alternative Kaplan-Meier statistics, the probability of LOAC at Week 12 and 24, are presented as the descriptive measure statistics.
Change From Baseline in AQLQ Global Score at Week 12: ITT Population Baseline, Week 12 The AQLQ is a disease-specific, self-administered quality of life questionnaire designed to measure functional impairments that are most important to participants with asthma. The AQLQ comprises of 32 items in 4 domains: symptoms (12 items), activity limitation (11 items), emotional function (5 items), environmental stimuli (4 items). Each item is scored on a 7-point Likert scale (1=maximal impairment, 7=no impairment). The 32 items of the questionnaire are averaged to produce one overall quality of life score ranging from 1 (severely impaired) to 7 (not impaired at all). Higher scores indicate better quality of life.
Percent Change From Baseline in FEV1 at Week 12: HEos-ITT Population Baseline, Week 12 FEV1 was the volume of air exhaled in the first second of a forced expiration as measured by spirometer.
Time to First Severe Exacerbation: Kaplan-Meier Estimates at Week 12 and 24: HEos-ITT Population Baseline up to Week 24 The time to first severe exacerbation was defined as the time from the date of first dose to the date of the first severe exacerbation event. For participants who had no severe exacerbation on or before last dose date + 14 days, it was censored at the date of last dose date + 14 days. The median time to first severe exacerbation was not estimated because the number of severe exacerbations was too low in the Dupilumab arms. Therefore, alternative Kaplan-Meier statistics, the probability of severe exacerbation at Week 12 and 24, are presented as the descriptive measure statistics.
Time to First Severe Exacerbation: Kaplan-Meier Estimates at Week 12 and 24: ITT Population Baseline up to Week 24 The time to first severe exacerbation was defined as the time from the date of first dose to the date of the first severe exacerbation event. For participants who had no severe exacerbation on or before last dose date + 14 days, it was censored at the date of last dose date + 14 days. The median time to first severe exacerbation was not estimated because the number of severe exacerbations was too low in the Dupilumab arms. Therefore, alternative Kaplan-Meier statistics, the probability of severe exacerbation at Week 12 and 24, are presented as the descriptive measure statistics.
Annualized Event Rate of Loss of Asthma Control (LOAC) During The Treatment Period: HEos-ITT Population Baseline to Week 24 LOAC was defined as any of the following: \>=6 additional reliever puffs of salbutamol/albuterol or levosalbutamol/levalbuterol in a 24-hour period (compared to baseline) on 2 consecutive days; increase in inhaled corticosteroid (ICS) \>=4 times the dose at randomization; use of systemic corticosteroids for \>=3 days; hospitalization or emergency room visit because of asthma, requiring systemic corticosteroids. Annualized event rate was the total number of LOAC that occurred during the treatment period divided by the total number of participant-years treated.
Change From Baseline in Evening Asthma Symptom Score at Week 12: ITT Population Baseline, Week 12 Evening asthma symptom score was determined using PM symptom scoring system which evaluated participant's overall asthma symptoms experienced during the day. It ranged from 0 to 4 as: 0=very well, no asthma symptoms, 1=one episode of wheezing, cough, or breathlessness, 2=more than one episode of wheezing, cough, or breathlessness without interference of normal activities, 3=wheezing, cough, or breathlessness most of the day, which interfered to some extent with normal activities, 4=asthma very bad, unable to carry out daily activities as usual.
Annualized Event Rate of Severe Exacerbation During The Treatment Period: HEos-ITT Population Baseline to Week 24 A severe exacerbation was defined as a deterioration of asthma requiring: use of systemic corticosteroids for \>=3 days; or hospitalization or emergency room visit because of asthma, requiring systemic corticosteroids. Annualized event rate was the total number of exacerbations that occurred during the treatment period divided by the total number of participant-years treated.
Change From Baseline in Asthma Control Questionnaire 5-item Version (ACQ-5) Score at Week 12: HEos-ITT Population Baseline, Week 12 The ACQ-5 has 5 questions, reflecting the top-scoring five asthma symptoms: woken at night by symptoms, wake in the mornings with symptoms, limitation of daily activities, shortness of breath and wheeze. Participants were asked to recall how their asthma had been during the previous week and to respond to each of the five symptom questions on a 7-point scale ranged from 0 (no impairment) to 6 (maximum impairment). ACQ-5 total score was mean of the scores of all 5 questions and, therefore, ranged from 0 (totally controlled) to 6 (severely uncontrolled). Higher score indicated lower asthma control.
Change From Baseline in Number of Inhalations Per Day of Salbutamol/Albuterol or Levosalbutamol/Levalbuterol at Week 12: ITT Population Baseline, Week 12 Participants might administered salbutamol/albuterol or levosalbutamol/levalbuterol as reliever medication as needed during the study. The number of salbutamol/albuterol or levosalbutamol/levalbuterol inhalations were recorded by the participants in their electronic diary.
Percent Change From Baseline in FEV1 at Week 12: ITT Population Baseline, Week 12 FEV1 was the volume of air exhaled in the first second of a forced expiration as measured by spirometer.
Annualized Event Rate of Severe Exacerbation During The Treatment Period: ITT Population Baseline to Week 24 A severe exacerbation was defined as a deterioration of asthma requiring: use of systemic corticosteroids for \>=3 days; or hospitalization or emergency room visit because of asthma, requiring systemic corticosteroids. Annualized event rate was the total number of exacerbations that occurred during the treatment period divided by the total number of participant-years treated.
Time to First LOAC Event: Kaplan-Meier Estimates at Week 12 and Week 24: HEos-ITT Population Baseline up to Week 24 The time to first LOAC event was defined as the time from the date of first dose to the date of the first LOAC event. For participants who had no LOAC event on or before last dose date + 14 days, it was censored at the date of last dose date + 14 days. The median time to first LOAC was not estimated because the number of LOAC was too low in the Dupilumab arms. Therefore, alternative Kaplan-Meier statistics, the probability of LOAC at Week 12 and 24, are presented as the descriptive measure statistics.
Change From Baseline in Morning Asthma Symptom Score at Week 12: HEos-ITT Population Baseline, Week 12 Morning asthma symptom score was determined using AM (ante meridiem) symptom scoring system which evaluated participant's overall asthma symptoms experienced during the night. It ranged from 0 to 4 as: 0 = No asthma symptoms, slept through the night, 1= Slept well, but some complaints in the morning, no night-time awakenings, 2= Woke up once because of asthma (including early awakening), 3= Woke up several times because of asthma (including early awakening), 4= Bad night, awake most of the night because of asthma.
Change From Baseline in Morning Asthma Symptom Score at Week 12: ITT Population Baseline, Week 12 Morning asthma symptom score was determined using AM symptom scoring system which evaluated participant's overall asthma symptoms experienced during the night. It ranged from 0 to 4 as: 0 = No asthma symptoms, slept through the night, 1= Slept well, but some complaints in the morning, no night-time awakenings, 2= Woke up once because of asthma (including early awakening), 3= Woke up several times because of asthma (including early awakening), 4= Bad night, awake most of the night because of asthma.
Change From Baseline in Evening Asthma Symptom Score at Week 12: HEos-ITT Population Baseline, Week 12 Evening asthma symptom score was determined using PM (post meridiem) symptom scoring system which evaluated participant's overall asthma symptoms experienced during the day. It ranged from 0 to 4 as: 0=very well, no asthma symptoms, 1=one episode of wheezing, cough, or breathlessness, 2=more than one episode of wheezing, cough, or breathlessness without interference of normal activities, 3=wheezing, cough, or breathlessness most of the day, which interfered to some extent with normal activities, 4=asthma very bad, unable to carry out daily activities as usual.
Change From Baseline in ACQ-5 Score at Week 12: ITT Population Baseline, Week 12 The ACQ-5 has 5 questions, reflecting the top-scoring five asthma symptoms: woken at night by symptoms, wake in the mornings with symptoms, limitation of daily activities, shortness of breath and wheeze. Participants were asked to recall how their asthma had been during the previous week and to respond to each of the five symptom questions on a 7-point scale ranged from 0 (no impairment) to 6 (maximum impairment). ACQ-5 total score was mean of the scores of all 5 questions and, therefore, ranged from 0 (totally controlled) to 6 (severely uncontrolled). Higher score indicated lower asthma control.
Change From Baseline in Asthma Quality of Life Questionnaire (AQLQ) Global Score at Week 12: HEos-ITT Population Baseline, Week 12 The AQLQ is a disease-specific, self-administered quality of life questionnaire designed to measure functional impairments that are most important to participants with asthma. The AQLQ comprises of 32 items in 4 domains: symptoms (12 items), activity limitation (11 items), emotional function (5 items), environmental stimuli (4 items). Each item is scored on a 7-point Likert scale (1=maximal impairment, 7=no impairment). The 32 items of the questionnaire are averaged to produce one overall quality of life score ranging from 1 (severely impaired) to 7 (not impaired at all). Higher scores indicate better quality of life.
Trial Locations
- Locations (201)
Investigational Site Number 392024
🇯🇵Sakai-Shi, Japan
Investigational Site Number 392003
🇯🇵Toride-Shi, Japan
Investigational Site Number 392035
🇯🇵Yokohama-Shi, Japan
Investigational Site Number 392018
🇯🇵Tsukubo-Gun, Japan
Investigational Site Number 152011
🇨🇱Santiago, Chile
Investigational Site Number 152001
🇨🇱Santiago, Chile
Investigational Site Number 840041
🇺🇸Huntington Beach, California, United States
Investigational Site Number 392042
🇯🇵Isesaki-Shi, Japan
Investigational Site Number 840013
🇺🇸Mission Viejo, California, United States
Investigational Site Number 840014
🇺🇸Rolling Hills Estates, California, United States
Investigational Site Number 840032
🇺🇸Colorado Springs, Colorado, United States
Investigational Site Number 840036
🇺🇸San Jose, California, United States
Investigational Site Number 840043
🇺🇸Denver, Colorado, United States
Investigational Site Number 840040
🇺🇸Colorado Springs, Colorado, United States
Investigational Site Number 840006
🇺🇸Denver, Colorado, United States
Investigational Site Number 840024
🇺🇸Denver, Colorado, United States
Investigational Site Number 840048
🇺🇸Albany, Georgia, United States
Investigational Site Number 840027
🇺🇸Daytona Beach, Florida, United States
Investigational Site Number 840026
🇺🇸River Forest, Illinois, United States
Investigational Site Number 840053
🇺🇸Evansville, Indiana, United States
Investigational Site Number 840017
🇺🇸Louisville, Kentucky, United States
Investigational Site Number 840052
🇺🇸Wheaton, Maryland, United States
Investigational Site Number 840045
🇺🇸North Dartmouth, Massachusetts, United States
Investigational Site Number 840018
🇺🇸Minneapolis, Minnesota, United States
Investigational Site Number 840002
🇺🇸Saint Louis, Missouri, United States
Investigational Site Number 840003
🇺🇸Saint Louis, Missouri, United States
Investigational Site Number 840004
🇺🇸Papillion, Nebraska, United States
Investigational Site Number 840016
🇺🇸Rochester, New York, United States
Investigational Site Number 840020
🇺🇸Cincinnati, Ohio, United States
Investigational Site Number 840015
🇺🇸Cincinnati, Ohio, United States
Investigational Site Number 840001
🇺🇸Oklahoma City, Oklahoma, United States
Investigational Site Number 840031
🇺🇸Lake Oswego, Oregon, United States
Investigational Site Number 840009
🇺🇸Upland, Pennsylvania, United States
Investigational Site Number 840005
🇺🇸El Paso, Texas, United States
Investigational Site Number 840008
🇺🇸San Antonio, Texas, United States
Investigational Site Number 840054
🇺🇸Everett, Washington, United States
Investigational Site Number 840035
🇺🇸Richmond, Virginia, United States
Investigational Site Number 840033
🇺🇸Tacoma, Washington, United States
Investigational Site Number 032008
🇦🇷Caba, Argentina
Investigational Site Number 032004
🇦🇷Buenos Aires, Argentina
Investigational Site Number 032003
🇦🇷Buenos Aires, Argentina
Investigational Site Number 032002
🇦🇷La Plata, Argentina
Investigational Site Number 032001
🇦🇷Caba, Argentina
Investigational Site Number 032005
🇦🇷Rosario, Argentina
Investigational Site Number 032006
🇦🇷Rosario, Argentina
Investigational Site Number 032007
🇦🇷Rosario, Argentina
Investigational Site Number 032012
🇦🇷Santa Fe, Argentina
Investigational Site Number 036004
🇦🇺Adelaide, Australia
Investigational Site Number 032009
🇦🇷Tucumán, Argentina
Investigational Site Number 036002
🇦🇺Brisbane, Australia
Investigational Site Number 036001
🇦🇺Clayton, Australia
Investigational Site Number 036005
🇦🇺Campbelltown, Australia
Investigational Site Number 392020
🇯🇵Naka-Gun, Japan
Investigational Site Number 036008
🇦🇺Frankston, Australia
Investigational Site Number 036003
🇦🇺Nedlands, Australia
Investigational Site Number 036009
🇦🇺Prahran, Australia
Investigational Site Number 036006
🇦🇺Woolloongabba, Australia
Investigational Site Number 152007
🇨🇱Quillota, Chile
Investigational Site Number 152002
🇨🇱Santiago, Chile
Investigational Site Number 152014
🇨🇱Santiago, Chile
Investigational Site Number 152003
🇨🇱Santiago, Chile
Investigational Site Number 152005
🇨🇱Santiago, Chile
Investigational Site Number 152012
🇨🇱Santiago, Chile
Investigational Site Number 152013
🇨🇱Santiago, Chile
Investigational Site Number 152008
🇨🇱Talca, Chile
Investigational Site Number 152006
🇨🇱Viña Del Mar, Chile
Investigational Site Number 250009
🇫🇷Brest Cedex, France
Investigational Site Number 250004
🇫🇷Grenoble Cedex 09, France
Investigational Site Number 250010
🇫🇷Lille, France
Investigational Site Number 250006
🇫🇷Lyon, France
Investigational Site Number 250001
🇫🇷Marseille, France
Investigational Site Number 250002
🇫🇷Montpellier, France
Investigational Site Number 250005
🇫🇷Nantes, France
Investigational Site Number 250007
🇫🇷Nimes, France
Investigational Site Number 250003
🇫🇷Pessac, France
Investigational Site Number 250008
🇫🇷Strasbourg, France
Investigational Site Number 250011
🇫🇷Vernon, France
Investigational Site Number 380010
🇮🇹Ancona, Italy
Investigational Site Number 380009
🇮🇹Catania, Italy
Investigational Site Number 380002
🇮🇹Firenze, Italy
Investigational Site Number 380007
🇮🇹Padova, Italy
Investigational Site Number 380001
🇮🇹Pisa, Italy
Investigational Site Number 380006
🇮🇹Verona, Italy
Investigational Site Number 392009
🇯🇵Asahi-Shi, Japan
Investigational Site Number 392012
🇯🇵Edogawa-Ku, Japan
Investigational Site Number 392007
🇯🇵Chuoh-Ku, Japan
Investigational Site Number 392037
🇯🇵Chiyoda-Ku, Japan
Investigational Site Number 392002
🇯🇵Chuo-Ku, Japan
Investigational Site Number 392017
🇯🇵Fukuoka-Shi, Japan
Investigational Site Number 392021
🇯🇵Fukuyama-Shi, Japan
Investigational Site Number 392004
🇯🇵Himeji-Shi, Japan
Investigational Site Number 392032
🇯🇵Hirakata-Shi, Japan
Investigational Site Number 392030
🇯🇵Habikino-Shi, Japan
Investigational Site Number 392013
🇯🇵Iizuka-Shi, Japan
Investigational Site Number 392023
🇯🇵Kanazawa-Shi, Japan
Investigational Site Number 392026
🇯🇵Itabashi-Ku, Japan
Investigational Site Number 392001
🇯🇵Kitakyushu-Shi, Japan
Investigational Site Number 392025
🇯🇵Kobe-Shi, Japan
Investigational Site Number 392022
🇯🇵Kiyose-Shi, Japan
Investigational Site Number 392040
🇯🇵Kodaira-Shi, Japan
Investigational Site Number 392044
🇯🇵Kokubunji-Shi, Japan
Investigational Site Number 392010
🇯🇵Kurashiki-Shi, Japan
Investigational Site Number 392036
🇯🇵Kyoto-Shi, Japan
Investigational Site Number 392041
🇯🇵Nagaoka-Shi, Japan
Investigational Site Number 392015
🇯🇵Nakano-Ku, Japan
Investigational Site Number 392005
🇯🇵Naruto-Shi, Japan
Investigational Site Number 392043
🇯🇵Ohta-Shi, Japan
Investigational Site Number 392019
🇯🇵Sagamihara-Shi, Japan
Investigational Site Number 392011
🇯🇵Sakaide-Shi, Japan
Investigational Site Number 392008
🇯🇵Sapporo-Shi, Japan
Investigational Site Number 392038
🇯🇵Setagaya-Ku, Japan
Investigational Site Number 392034
🇯🇵Sapporo-Shi, Japan
Investigational Site Number 392006
🇯🇵Tomakomai-Shi, Japan
Investigational Site Number 392028
🇯🇵Sumida-Ku, Japan
Investigational Site Number 392014
🇯🇵Yokohama-Shi, Japan
Investigational Site Number 392029
🇯🇵Tsu-Shi, Japan
Investigational Site Number 392045
🇯🇵Uruma-Shi, Japan
Investigational Site Number 410002
🇰🇷Bucheon, Korea, Republic of
Investigational Site Number 410003
🇰🇷Cheongju, Korea, Republic of
Investigational Site Number 410004
🇰🇷Seoul, Korea, Republic of
Investigational Site Number 410005
🇰🇷Seoul, Korea, Republic of
Investigational Site Number 484004
🇲🇽Mexico City, Mexico
Investigational Site Number 410001
🇰🇷Suwon, Korea, Republic of
Investigational Site Number 484001
🇲🇽Guadalajara, Mexico
Investigational Site Number 484006
🇲🇽Chihuahua, Mexico
Investigational Site Number 484005
🇲🇽Distrito Federal, Mexico
Investigational Site Number 554001
🇳🇿Dunedin, New Zealand
Investigational Site Number 484003
🇲🇽Monterrey, Mexico
Investigational Site Number 554002
🇳🇿Wellington, New Zealand
Investigational Site Number 616004
🇵🇱Gdansk, Poland
Investigational Site Number 616006
🇵🇱Bialystok, Poland
Investigational Site Number 616003
🇵🇱Gdansk, Poland
Investigational Site Number 616007
🇵🇱Krakow, Poland
Investigational Site Number 616001
🇵🇱Lodz, Poland
Investigational Site Number 616005
🇵🇱Lodz, Poland
Investigational Site Number 616008
🇵🇱Warszawa, Poland
Investigational Site Number 643002
🇷🇺Moscow, Russian Federation
Investigational Site Number 643003
🇷🇺Moscow, Russian Federation
Investigational Site Number 643007
🇷🇺Moscow, Russian Federation
Investigational Site Number 643001
🇷🇺Moscow, Russian Federation
Investigational Site Number 643012
🇷🇺Moscow, Russian Federation
Investigational Site Number 643010
🇷🇺Saint-Petersburg, Russian Federation
Investigational Site Number 643006
🇷🇺Novosibirsk, Russian Federation
Investigational Site Number 643011
🇷🇺Saint-Petersburg, Russian Federation
Investigational Site Number 643009
🇷🇺St-Petersburg, Russian Federation
Investigational Site Number 643008
🇷🇺Yaroslavl, Russian Federation
Investigational Site Number 710001
🇿🇦Cape Town, South Africa
Investigational Site Number 710002
🇿🇦Cape Town, South Africa
Investigational Site Number 724001
🇪🇸Barcelona, Spain
Investigational Site Number 724002
🇪🇸Barcelona, Spain
Investigational Site Number 724005
🇪🇸Barcelona, Spain
Investigational Site Number 724004
🇪🇸Cáceres, Spain
Investigational Site Number 724006
🇪🇸Pozuelo De Alarcón, Spain
Investigational Site Number 724003
🇪🇸Sabadell, Spain
Investigational Site Number 792002
🇹🇷Ankara, Turkey
Investigational Site Number 792008
🇹🇷Bursa, Turkey
Investigational Site Number 724007
🇪🇸Sant Boi De Llobregat, Spain
Investigational Site Number 792011
🇹🇷Amasya, Turkey
Investigational Site Number 792001
🇹🇷Istanbul, Turkey
Investigational Site Number 792007
🇹🇷Istanbul, Turkey
Investigational Site Number 792004
🇹🇷Istanbul, Turkey
Investigational Site Number 792003
🇹🇷Istanbul, Turkey
Investigational Site Number 792013
🇹🇷Kirikkale, Turkey
Investigational Site Number 792005
🇹🇷Izmir, Turkey
Investigational Site Number 804016
🇺🇦Donetsk, Ukraine
Investigational Site Number 804003
🇺🇦Kyiv, Ukraine
Investigational Site Number 804002
🇺🇦Poltava, Ukraine
Investigational Site Number 804012
🇺🇦Zaporozhye, Ukraine
Investigational Site Number 804001
🇺🇦Kharkiv, Ukraine
Investigational Site Number 792006
🇹🇷Mersin, Turkey
Investigational Site Number 804004
🇺🇦Kyiv, Ukraine
Investigational Site Number 804018
🇺🇦Kyiv, Ukraine
Investigational Site Number 804020
🇺🇦Kyiv, Ukraine
Investigational Site Number 804008
🇺🇦Kyiv, Ukraine
Investigational Site Number 804006
🇺🇦Odessa, Ukraine
Investigational Site Number 804019
🇺🇦Vinnytsya, Ukraine
Investigational Site Number 804015
🇺🇦Yalta, Ukraine
Investigational Site Number 840050
🇺🇸Fullerton, California, United States
Investigational Site Number 840019
🇺🇸Los Angeles, California, United States
Investigational Site Number 840022
🇺🇸Los Angeles, California, United States
Investigational Site Number 840029
🇺🇸Los Angeles, California, United States
Investigational Site Number 840044
🇺🇸Newport Beach, California, United States
Investigational Site Number 840051
🇺🇸Novi, Michigan, United States
Investigational Site Number 840037
🇺🇸Missoula, Montana, United States
Investigational Site Number 840011
🇺🇸Princeton, New Jersey, United States
Investigational Site Number 840034
🇺🇸Medford, Oregon, United States
Investigational Site Number 840042
🇺🇸Philadelphia, Pennsylvania, United States
Investigational Site Number 840010
🇺🇸Pittsburgh, Pennsylvania, United States
Investigational Site Number 840021
🇺🇸Spartanburg, South Carolina, United States
Investigational Site Number 840023
🇺🇸Dallas, Texas, United States
Investigational Site Number 840007
🇺🇸Riverside, California, United States
Investigational Site Number 840039
🇺🇸Miami, Florida, United States
Investigational Site Number 840030
🇺🇸Owensboro, Kentucky, United States
Investigational Site Number 840028
🇺🇸Baltimore, Maryland, United States
Investigational Site Number 840046
🇺🇸Novi, Michigan, United States
Investigational Site Number 032010
🇦🇷Caba, Argentina
Investigational Site Number 380004
🇮🇹Ferrara, Italy
Investigational Site Number 380008
🇮🇹Foggia, Italy
Investigational Site Number 380003
🇮🇹Modena, Italy
Investigational Site Number 380005
🇮🇹Torino, Italy
Investigational Site Number 840025
🇺🇸Cincinnati, Ohio, United States