Long-Term Safety Evaluation of Dupilumab in Patients With Asthma (LIBERTY ASTHMA TRAVERSE)

Phase 3

Completed

Conditions: Asthma

Interventions: Drug: Dupilumab

Registration Number: NCT02134028

Lead Sponsor: Sanofi

Brief Summary: Primary Objective:

To evaluate the long-term safety and tolerability of dupilumab in participants with asthma who participated in a previous dupilumab asthma study (DRI12544, PDY14192, EFC13579, EFC13691).

Secondary Objectives:

To evaluate the long-term efficacy of dupilumab in participants with asthma who participated in a previous dupilumab asthma clinical study.

To evaluate dupilumab in participants with asthma who participated in a previous dupilumab asthma clinical study, with regards to:

* Systemic exposure

* Anti-drug antibodies

* Biomarkers

Detailed Description: A screening period, up to 3 weeks, applied only for participants who came from DRI12544 study. The total study duration, per participant, was a maximum of 108 weeks (or 111 weeks considering a maximum screening period of 3 weeks for study DRI12544) for the participants enrolled prior to Amendment 04 approval and a maximum of 60 weeks for the participants enrolled after Amendment 04 approval.

Following amendment 04 (dated 31 Oct 2016) the open-label treatment duration was amended to 48 weeks (1 year); and the 16-week post-treatment period was shortened to 12 weeks.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 2282

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
dupilumab treatment	Dupilumab	For participants coming from the DRI12544 study: dupilumab loading dose subcutaneous (SC) on Day 1, followed by 1\* Dose every 2 weeks added to current controller medications. For participants coming from other studies: dupilumab 1 \* Dose SC every 2 weeks added to current controller medications.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)	From the first IMP injection in LTS12551 to the last IMP injection plus 14 weeks (up to 108 weeks)	An Adverse Event (AE) was any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which did not necessarily had to have causal relationship with treatment. TEAEs were defined as AEs that developed, worsened, or became serious during the treatment emergent AE period (time from first dose of investigational medicinal product \[IMP\] in LTS12551 up to the last dose of dupilumab plus 14 weeks). A Serious AE (SAE) was any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Potentially Clinically Significant Vital Signs Abnormalities During the TEAE Period	From the first IMP injection in LTS12551 to the last IMP injection plus 14 weeks (up to 108 weeks)	Criteria for potentially clinically significant vital sign abnormalities: * Systolic blood pressure (SBP): Less than or equal to (≤) 95 Adults (≤90 Adolescents) millimeters of mercury (mmHg) and decrease from baseline (DFB) greater than or equal to (≥) 20 mmHg; ≥ 160 Adults (≥ 119 Adolescents) mmHg and increase from baseline (IFB) ≥ 20 mmHg. * Diastolic blood pressure (DBP): ≤ 45 Adults (≤54 Adolescents) mmHg and DFB ≥ 10 mmHg; ≥ 110 Adults (≥78 Adolescents) mmHg and IFB ≥ 10 mmHg. * Heart rate (HR): ≤ 50 beats per minute (bpm) and DFB ≥ 20 bpm; ≥ 120 bpm and IFB ≥ 20 bpm. * Respiratory rate: less than (\<) 12 breaths/min(b/m); greater than (\>) 20 b/m. * Weight (kg): ≥ 5 percent (%) DFB; ≥ 5% IFB. * Temperature: ≥ 38.0 degree Celsius (°C) rectal/ear/temporal; ≥ 37.5°C oral; ≥ 37.2°C axillary. TEAE period was defined as the time from first dose of IMP in LTS12551 up to the last dose of dupilumab plus 14 weeks.
Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) at Weeks 48 and 96	Baseline of parent study, Week 48 and Week 96 of this extension study	FEV1 was the volume of air exhaled from the lungs in the first second of a forced expiration as measured by spirometer. For this analysis, baseline was defined as respective parent study baseline.
Number of Participants With Potentially Clinically Significant Laboratory Abnormalities: Hematological Parameters (Red Blood Cells [RBCs], Platelets and Coagulation) During the TEAE Period	From the first IMP injection in LTS12551 to the last IMP injection plus 14 weeks (up to 108 weeks)	Criteria for potentially clinically significant abnormalities: * Hemoglobin (Hb): ≤ 115 grams per liter (g/L)(Male \[M\]), ≤ 95 g/L (Female\[ F\]) (\< 100 g/L Adolescents); ≥ 185 g/L (M), ≥ 165 g/L (F) (≥ 200 g/L Adolescents); DFB ≥ 20 g/L. * Hematocrit: ≤ 0.37 volume/volume (v/v) (M); ≤ 0.32 v/v (F) (\<0.32 v/v Adolescents); ≥ 0.55 v/v (M); 0.5 v/v (F) (\>0.47 v/v Adolescents). * RBCs: ≥ 6 Tera/L. * Platelets: \< 100 Giga(G)/L; ≥ 700 G/L. TEAE period was defined as the time from first dose of IMP in LTS12551 up to the last dose of dupilumab plus 14 weeks.
Number of Severe Exacerbation Events	From the first IMP injection in LTS12551 to the last IMP injection plus 2 weeks (up to 96 weeks)	Severe asthma exacerbation events were defined as a deterioration of asthma which required: use of systemic corticosteroids for ≥ 3 days, (participants from study EFC13691 (NCT02528214), and who were taking systemic corticosteroids: the use of systemic corticosteroids at least double the current dose and for ≥3 days.) or, hospitalization or emergency room visit because of asthma, required systemic corticosteroids.
Annualized Event Rate Per Participant-Years for Severe Exacerbation	From the first IMP injection in LTS12551 to the last IMP injection plus 2 weeks (up to 96 weeks)	The annualized event rate per participant-years was defined as the total number of events that occurred during the treatment period divided by the total number of participant-years during the treatment period.
Change From Baseline in Percent Predicted FEV1 at Weeks 48 and 96	Baseline of parent study, Week 48 and Week 96 of this extension study	FEV1 was the volume of air exhaled from the lungs in the first second of a forced expiration as measured by spirometer. For this analysis, baseline was defined as respective parent study baseline.
Change From Baseline in Forced Expiratory Flow (FEF) 25-75% at Weeks 48 and 96	Baseline of parent study, Week 48, and Week 96 of this extension study	FEF was the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. FEF 25-75% was defined as the mean FEF between 25% and 75% of the FVC, where FVC was defined as the volume of air that can forcibly be blown out after full inspiration in the upright position, measured in liters. For this analysis, baseline was defined as respective parent study baseline.
Change From Baseline in Asthma Control Questionnaire 5-Question Version (ACQ-5) Mean Scores at Weeks 24 and 48	Baseline of parent study, Weeks 24, and 48 of this extension study	The ACQ-5 had 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 mean score was mean of the scores of all 5 questions and, therefore, ranged from 0 (totally controlled) to 6 (severely uncontrolled), higher scores indicated lower asthma control. For this analysis, baseline was defined as respective parent study baseline.
Percentage of Participants Achieving AQLQ Global Score Response (AQLQ Responders) at Weeks 24 and 48	At Weeks 24, and 48 of this extension study	AQLQ global response was defined as participants with change from baseline in AQLQ global score ≥ 0.5. The AQLQ was designed to measure the functional impairments that are most troublesome to adults as a result of their asthma. The AQLQ comprised of 32 items in 4 domains: symptoms (12 items), activity limitation (11 items), emotional function (5 items), environmental stimuli (4 items). Each item was scored on a 7-point likert scale (1=severely impaired, 7=not impaired). 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). Higher scores indicated better quality of life.
Change From Baseline in Forced Vital Capacity (FVC) at Weeks 48 and 96	Baseline of parent study, Week 48, and Week 96 of this extension study	FVC was a standard pulmonary function test used to quantify respiratory muscle weakness. FVC was the volume of air that can forcibly be blown out after full inspiration in the upright position, measured in liters. For this analysis, baseline was defined as respective parent study baseline.
Change From Baseline in Evening Asthma Symptom Scores at Weeks 48 and 96: Participants From Study DRI12544	Baseline of parent study, Week 48, and Week 96 of this extension study	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; higher scores indicated more severe symptoms. For this analysis, baseline was defined as parent DRI12544 study baseline.
Change From Baseline in EQ-5D-3L VAS Scores at Weeks 48 and 96: Participants From Study DRI12544	Baseline of parent study, Week 48 and Week 96 of this extension study	EQ-5D VAS was used to record a participant's rating for his/her current health-related quality of life state and captured on a vertical VAS (0-100), where 0=worst imaginable health state and 100=best imaginable health state, where higher states indicated better outcomes. For this analysis, baseline was defined as parent DRI12544 study baseline.
Percentage of Participants Achieving ACQ-5 Score Response (ACQ-5 Responders) at Weeks 24 and 48	At Weeks 24, and 48 of this extension study	ACQ-5 response was defined as change from baseline in ACQ-5 scores ≥ 0.5. The ACQ-5 had 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 mean 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 Scores at Weeks 24 and 48	Baseline of parent study, Weeks 24, and 48 of this extension study	The AQLQ was designed to measure the functional impairments that are most troublesome to adults as a result of their asthma. The AQLQ comprised of 32 items in 4 domains: symptoms (12 items), activity limitation (11 items), emotional function (5 items), and environmental stimuli (4 items). Each item was scored on a 7-point likert scale ranged from 1=severely impaired to 7=not impaired. The 32 items of the questionnaire were averaged to produce one overall quality of life score ranging from 1 (severely impaired) to 7 (not impaired); higher scores indicated better quality of life. For this analysis, baseline was defined as respective parent study baseline.
Percentage of Participants With Antidrug Antibodies (ADA) Response	From the first IMP injection in LTS12551 to the last IMP injection plus 2 weeks (up to 96 weeks)	ADA response were categorized as: treatment emergent and treatment boosted response. 1) Treatment emergent was defined as an ADA positive response in the assay post first dose in LTS12551, when baseline results were negative or missing. 2) Treatment boosted was defined as: an ADA positive response in the assay post first dose that was greater-than or equal to 4-fold over baseline titer levels, when baseline results were positive. The criteria for positive was defined as "30 to \> 10,000", where low titer (\< 1,000); moderate (1,000 ≤ titer ≤ 10,000) and high titer (\> 10,000).
Change From Baseline in Number of Nocturnal Awakenings at Weeks 48 and 96: Participants From Study DRI12544	Baseline of parent study, Week 48 and Week 96 of this extension study	The number of nocturnal awakening because of asthma symptoms were recorded every morning by the participants in an electronic diary. Mean number of awakenings in last 7 days prior to each visit was calculated and was used in computation of data reported. For this analysis, baseline was defined as parent DRI12544 study baseline.
Percent Change From Baseline in Oral Corticosteroid (OCS) Dose at Weeks 48, and 96: Participants From Study EFC13691	Baseline of parent study, Weeks 48 and 96 of this extension study	OCS was allowed as background controller medication for the participants from study EFC13691 only. For this analysis, baseline was defined as parent study EFC13691 baseline.
Serum Concentrations of Dupilumab Over Time Till Week 96	Baseline of parent study, Weeks 0, 4, 12, 24, 48, 72, and 96 of this extension study	For this analysis, baseline was defined as respective parent study baseline. Here, 'number analyzed'=number of participants with available data for each specified category.
Change From Baseline in Blood Eosinophils Cells Count at Weeks 48 and 96	Baseline of parent study, Week 48 and Week 96 of this extension study	For this analysis, baseline was defined as respective parent study baseline.
Change From Baseline in Morning Peak Expiratory Flow (PEF) at Weeks 48 and 96: Participants From Study DRI12544	Baseline of parent study, Week 48 and Week 96 of this extension study	The PEF was a participant's maximum speed of expiration, as measured with a peak flow meter. Peak flow testing for PEF was performed at morning and evening. Morning PEF was performed within 15 minutes after arising (between 5:30 AM and 10 AM) prior to taking any salbutamol/albuterol or levosalbutamol/levalbuterol. For this analysis, baseline was defined as parent study DRI12544 baseline.
Percentage of Participants Achieving a Reduction of 50% or Greater (≥ 50% ) in OCS Dose Over Time at Weeks 48 and 96: Participants From Study EFC13691	Weeks 48 and 96 of this extension study	OCS was allowed as background controller medication for the participants from study EFC13691 only. Percentage of participants who achieved a reduction of ≥ 50% in OCS dose were reported.
Change From Baseline in Evening Peak Expiratory Flow (PEF) at Weeks 48 and 96: Participants From Study DRI12544	Baseline of parent study, Week 48 and Week 96 of this extension study	The PEF was a participant's maximum speed of expiration, as measured with a peak flow meter. Peak flow testing for PEF was performed at morning and evening. Evening PEF was performed in the evening (between 5:30 PM and 10 PM) prior to taking any salbutamol/albuterol or levosalbutamol/levalbuterol. For this analysis, baseline was defined as parent DRI12544 study baseline.
Change From Baseline in European-Quality of Life-5 Dimension Instrument-3 Levels (EQ-5D-3L) Index Scores at Weeks 48 and 96: Participants From Study DRI12544	Baseline of parent study, Week 48 and Week 96 of this extension study	EQ-5D-3L: validated and reliable self-report health status questionnaire consisted of EQ-5D descriptive system and visual analogue scale (VAS). EQ-5D descriptive system comprises 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension measured on 3 levels: no problem, some problems, and severe problems. The 5 dimensional 3-level systems was converted into single index utility score, and the score was 0 - 100, where 100=best health state; and 0=worst health state; where higher scores indicated better outcome. For this analysis, baseline was defined as parent DRI12544 study baseline.
Change From Baseline in Morning Asthma Symptom Scores at Weeks 48 and 96: Participants From Study DRI12544	Baseline of parent study, Week 48 and Week 96 of this extension study	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 ranges from 0 to 4 as: 0=no asthma symptoms, slept through the night, 1=slept well, but some complaints in the morning. No nighttime 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; higher scores indicated more severe symptoms. For this analysis, baseline was defined as parent DRI12544 study baseline.
Change From Baseline in Number of Inhalations Per Day of Salbutamol/Albuterol or Levosalbutamol/Levalbuterol for Symptom Relief at Weeks 48 and 96: Participants From Study DRI12544	Baseline of parent study, Week 48, and Week 96 of this extension study	The number of salbutamol/albuterol or levosalbutamol/levalbuterol inhalations was recorded daily by the participants in an electronic diary/PEF meter. Mean number of inhalations in last 7 days prior to each visit was calculated and was used in computation of data reported. For this analysis, baseline was defined as parent DRI12544 study baseline.
Percentage of Participants With Background OCS Completely Tapered Off Over Time at Weeks 48 and 96: Participants From Study EFC13691	Weeks 48, and 96 of this extension study	OCS was allowed as background controller medication for the participants from study EFC13691 only. Number of participants who gradually discontinued or reduced therapeutic dose were reported in this outcome measure.

Trial Locations

Locations (365): Investigational Site Number 840402
🇺🇸
Tucson, Arizona, United States
Investigational Site Number 840045
🇺🇸
Long Beach, California, United States
Investigational Site Number 840044
🇺🇸
Newport Beach, California, United States
Investigational Site Number 840041
🇺🇸
North Hollywood, California, United States
Investigational Site Number 840014
🇺🇸
Rolling Hills Estates, California, United States
Investigational Site Number 840121
🇺🇸
San Jose, California, United States
Investigational Site Number 840137
🇺🇸
Aventura, Florida, United States
Investigational Site Number 840055
🇺🇸
Sarasota, Florida, United States
Investigational Site Number 840032
🇺🇸
Fort Mitchell, Kentucky, United States
Investigational Site Number 840080
🇺🇸
Owings Mills, Maryland, United States
Investigational Site Number 840102
🇺🇸
Saint Louis, Missouri, United States
Investigational Site Number 840002
🇺🇸
Saint Louis, Missouri, United States
Investigational Site Number 840093
🇺🇸
Saint Louis, Missouri, United States
Investigational Site Number 840037
🇺🇸
Missoula, Montana, United States
Investigational Site Number 840004
🇺🇸
Papillion, Nebraska, United States
Investigational Site Number 840111
🇺🇸
Brick, New Jersey, United States
Investigational Site Number 840065
🇺🇸
New York, New York, United States
Investigational Site Number 840083
🇺🇸
Charlotte, North Carolina, United States
Investigational Site Number 840126
🇺🇸
Charlotte, North Carolina, United States
Investigational Site Number 840107
🇺🇸
Greensboro, North Carolina, United States
Investigational Site Number 840907
🇺🇸
High Point, North Carolina, United States
Investigational Site Number 840942
🇺🇸
Toledo, Ohio, United States
Investigational Site Number 840112
🇺🇸
Edmond, Oklahoma, United States
Investigational Site Number 840049
🇺🇸
Middleburg Heights, Ohio, United States
Investigational Site Number 840104
🇺🇸
Tulsa, Oklahoma, United States
Investigational Site Number 840046
🇺🇸
Bethlehem, Pennsylvania, United States
Investigational Site Number 840085
🇺🇸
Hershey, Pennsylvania, United States
Investigational Site Number 840021
🇺🇸
Spartanburg, South Carolina, United States
Investigational Site Number 840062
🇺🇸
Amarillo, Texas, United States
Investigational Site Number 840038
🇺🇸
Boerne, Texas, United States
Investigational Site Number 840124
🇺🇸
Cypress, Texas, United States
Investigational Site Number 840923
🇺🇸
El Paso, Texas, United States
Investigational Site Number 840922
🇺🇸
Fort Worth, Texas, United States
Investigational Site Number 840118
🇺🇸
Plano, Texas, United States
Investigational Site Number 840070
🇺🇸
McKinney, Texas, United States
Investigational Site Number 840027
🇺🇸
Fort Worth, Texas, United States
Investigational Site Number 840035
🇺🇸
Draper, Utah, United States
Investigational Site Number 840059
🇺🇸
Fairfax, Virginia, United States
Investigational Site Number 840951
🇺🇸
Bellingham, Washington, United States
Investigational Site Number 032096
🇦🇷
Bahia Blanca, Argentina
Investigational Site Number 032004
🇦🇷
Buenos Aires, Argentina
Investigational Site Number 032003
🇦🇷
Buenos Aires, Argentina
Investigational Site Number 032011
🇦🇷
Caba, Argentina
Investigational Site Number 032001
🇦🇷
Caba, Argentina
Investigational Site Number 032097
🇦🇷
Caba, Argentina
Investigational Site Number 032010
🇦🇷
Caba, Argentina
Investigational Site Number 032091
🇦🇷
Caba, Argentina
Investigational Site Number 032095
🇦🇷
Capital Federal, Argentina
Investigational Site Number 032002
🇦🇷
La Plata, Argentina
Investigational Site Number 032009
🇦🇷
San Miguel De Tucumán, Argentina
Investigational Site Number 036001
🇦🇺
Clayton, Australia
Investigational Site Number 036004
🇦🇺
Adelaide, Australia
Investigational Site Number 036005
🇦🇺
Campbelltown, Australia
Investigational Site Number 036093
🇦🇺
Murdoch, Australia
Investigational Site Number 036008
🇦🇺
Frankston, Australia
Investigational Site Number 036003
🇦🇺
Nedlands, Australia
Investigational Site Number 036094
🇦🇺
Parkville, Australia
Investigational Site Number 036009
🇦🇺
Prahran, Australia
Investigational Site Number 036006
🇦🇺
Woolloongabba, Australia
Investigational Site Number 056001
🇧🇪
Leuven, Belgium
Investigational Site Number 076001
🇧🇷
Porto Alegre, Brazil
Investigational Site Number 076003
🇧🇷
Salvador, Brazil
Investigational Site Number 076002
🇧🇷
Sorocaba, Brazil
Investigational Site Number 124019
🇨🇦
Burlington, Canada
Investigational Site Number 124003
🇨🇦
Mississauga, Canada
Investigational Site Number 124012
🇨🇦
Montreal, Canada
Investigational Site Number 124010
🇨🇦
Montreal, Canada
Investigational Site Number 124018
🇨🇦
Quebec, Canada
Investigational Site Number 124008
🇨🇦
Sherbrooke, Canada
Investigational Site Number 124015
🇨🇦
Toronto, Canada
Investigational Site Number 124002
🇨🇦
Toronto, Canada
Investigational Site Number 124006
🇨🇦
Vancouver, Canada
Investigational Site Number 124017
🇨🇦
Vancouver, Canada
Investigational Site Number 152007
🇨🇱
Quillota, Chile
Investigational Site Number 152011
🇨🇱
Santiago, Chile
Investigational Site Number 152018
🇨🇱
Santiago, Chile
Investigational Site Number 152002
🇨🇱
Santiago, Chile
Investigational Site Number 152013
🇨🇱
Santiago, Chile
Investigational Site Number 152023
🇨🇱
Talcahuano, Chile
Investigational Site Number 152004
🇨🇱
Talca, Chile
Investigational Site Number 152010
🇨🇱
Valdivia, Chile
Investigational Site Number 152008
🇨🇱
Talca, Chile
Investigational Site Number 152003
🇨🇱
Viña Del Mar, Chile
Investigational Site Number 170001
🇨🇴
Bogota, Colombia
Investigational Site Number 152021
🇨🇱
Viña Del Mar, Chile
Investigational Site Number 170002
🇨🇴
Bogotá, Colombia
Investigational Site Number 250010
🇫🇷
Lille Cedex, France
Investigational Site Number 250006
🇫🇷
Lyon, France
Investigational Site Number 250013
🇫🇷
Lille Cedex, France
Investigational Site Number 250001
🇫🇷
Marseille, France
Investigational Site Number 250002
🇫🇷
Montpellier, France
Investigational Site Number 250005
🇫🇷
Nantes, France
Investigational Site Number 250008
🇫🇷
Strasbourg, France
Investigational Site Number 276006
🇩🇪
Berlin, Germany
Investigational Site Number 250014
🇫🇷
Vandoeuvre-Les-Nancy Cedex, France
Investigational Site Number 276003
🇩🇪
Bochum, Germany
Investigational Site Number 276011
🇩🇪
Großhansdorf, Germany
Investigational Site Number 276005
🇩🇪
Rüdersdorf Bei Berlin, Germany
Investigational Site Number 348303
🇭🇺
Edelény, Hungary
Investigational Site Number 376005
🇮🇱
Petah-Tikva, Israel
Investigational Site Number 380009
🇮🇹
Catania, Italy
Investigational Site Number 380008
🇮🇹
Foggia, Italy
Investigational Site Number 392112
🇯🇵
Chuo-Ku, Japan
Investigational Site Number 392004
🇯🇵
Himeji-Shi, Japan
Investigational Site Number 392108
🇯🇵
Hiroshima-Shi, Japan
Investigational Site Number 392013
🇯🇵
Iizuka-Shi, Japan
Investigational Site Number 392142
🇯🇵
Kasuga-Shi, Japan
Investigational Site Number 392119
🇯🇵
Kishiwada-Shi, Japan
Investigational Site Number 392162
🇯🇵
Kobe-Shi, Japan
Investigational Site Number 392135
🇯🇵
Matsuyama-Shi, Japan
Investigational Site Number 392163
🇯🇵
Nagoya-Shi, Japan
Investigational Site Number 392164
🇯🇵
Muroran-Shi, Japan
Investigational Site Number 392187
🇯🇵
Obihiro-Shi, Japan
Investigational Site Number 392177
🇯🇵
Ome-Shi, Japan
Investigational Site Number 392170
🇯🇵
Osaki-Shi, Japan
Investigational Site Number 392152
🇯🇵
Osaka Sayama-Shi, Japan
Investigational Site Number 392155
🇯🇵
Osaka Sayama-Shi, Japan
Investigational Site Number 392043
🇯🇵
Ota-Shi, Japan
Investigational Site Number 392024
🇯🇵
Sakai-Shi, Japan
Investigational Site Number 392034
🇯🇵
Sapporo-Shi, Japan
Investigational Site Number 392038
🇯🇵
Setagaya-Ku, Japan
Investigational Site Number 392179
🇯🇵
Seto-Shi, Japan
Investigational Site Number 392146
🇯🇵
Tachikawa-Shi, Japan
Investigational Site Number 392006
🇯🇵
Tomakomai-Shi, Japan
Investigational Site Number 392165
🇯🇵
Sumida-Ku, Japan
Investigational Site Number 392173
🇯🇵
Tachikawa-Shi, Japan
Investigational Site Number 392029
🇯🇵
Tsu-Shi, Japan
Investigational Site Number 392168
🇯🇵
Uozu-Shi, Japan
Investigational Site Number 392132
🇯🇵
Urasoe-Shi, Japan
Investigational Site Number 392045
🇯🇵
Uruma-Shi, Japan
Investigational Site Number 392014
🇯🇵
Yokohama-Shi, Japan
Investigational Site Number 410003
🇰🇷
Cheongju-Si, Korea, Republic of
Investigational Site Number 410013
🇰🇷
Incheon, Korea, Republic of
Investigational Site Number 410008
🇰🇷
Seoul, Korea, Republic of
Investigational Site Number 410012
🇰🇷
Seoul, Korea, Republic of
Investigational Site Number 410005
🇰🇷
Seoul, Korea, Republic of
Investigational Site Number 410004
🇰🇷
Seoul, Korea, Republic of
Investigational Site Number 410011
🇰🇷
Seoul, Korea, Republic of
Investigational Site Number 410007
🇰🇷
Seoul, Korea, Republic of
Investigational Site Number 484013
🇲🇽
Chihuahua, Mexico
Investigational Site Number 484006
🇲🇽
Chihuahua, Mexico
Investigational Site Number 410010
🇰🇷
Seoul, Korea, Republic of
Investigational Site Number 484014
🇲🇽
Cuautitlan Izcalli, Mexico
Investigational Site Number 484005
🇲🇽
Distrito Federal, Mexico
Investigational Site Number 484008
🇲🇽
Durango, Mexico
Investigational Site Number 484004
🇲🇽
Mexico City, Mexico
Investigational Site Number 484001
🇲🇽
Guadalajara, Mexico
Investigational Site Number 484007
🇲🇽
Monterrey, Mexico
Investigational Site Number 484010
🇲🇽
México, Mexico
Investigational Site Number 484012
🇲🇽
San Juan Del Rio, Mexico
Investigational Site Number 484011
🇲🇽
Veracruz, Mexico
Investigational Site Number 528001
🇳🇱
Arnhem, Netherlands
Investigational Site Number 528002
🇳🇱
Dordrecht, Netherlands
Investigational Site Number 616004
🇵🇱
Gdansk, Poland
Investigational Site Number 616003
🇵🇱
Gdansk, Poland
Investigational Site Number 616007
🇵🇱
Krakow, Poland
Investigational Site Number 616097
🇵🇱
Krakow, Poland
Investigational Site Number 616005
🇵🇱
Lodz, Poland
Investigational Site Number 616009
🇵🇱
Lodz, Poland
Investigational Site Number 616096
🇵🇱
Poznan, Poland
Investigational Site Number 616098
🇵🇱
Strzelce Opolskie, Poland
Investigational Site Number 616008
🇵🇱
Warszawa, Poland
Investigational Site Number 616011
🇵🇱
Znin, Poland
Investigational Site Number 616010
🇵🇱
Warszawa, Poland
Investigational Site Number 642104
🇷🇴
Bucharest, Romania
Investigational Site Number 642103
🇷🇴
Bucharest, Romania
Investigational Site Number 642102
🇷🇴
Cluj-Napoca, Romania
Investigational Site Number 642107
🇷🇴
Cluj-Napoca, Romania
Investigational Site Number 642105
🇷🇴
Timisoara, Romania
Investigational Site Number 643096
🇷🇺
Moscow, Russian Federation
Investigational Site Number 642106
🇷🇴
Timisoara, Romania
Investigational Site Number 643013
🇷🇺
Ekaterinburg, Russian Federation
Investigational Site Number 643002
🇷🇺
Moscow, Russian Federation
Investigational Site Number 643005
🇷🇺
Moscow, Russian Federation
Investigational Site Number 643007
🇷🇺
Moscow, Russian Federation
Investigational Site Number 643012
🇷🇺
Moscow, Russian Federation
Investigational Site Number 643001
🇷🇺
Moscow, Russian Federation
Investigational Site Number 643006
🇷🇺
Novosibirsk, Russian Federation
Investigational Site Number 643091
🇷🇺
Ryazan, Russian Federation
Investigational Site Number 643008
🇷🇺
Yaroslavl, Russian Federation
Investigational Site Number 643009
🇷🇺
St-Petersburg, Russian Federation
Investigational Site Number 710009
🇿🇦
Brandfort, South Africa
Investigational Site Number 710011
🇿🇦
Cape Town, South Africa
Investigational Site Number 710091
🇿🇦
Cape Town, South Africa
Investigational Site Number 710001
🇿🇦
Cape Town, South Africa
Investigational Site Number 710092
🇿🇦
Cape Town, South Africa
Investigational Site Number 710002
🇿🇦
Cape Town, South Africa
Investigational Site Number 710003
🇿🇦
Cape Town, South Africa
Investigational Site Number 710006
🇿🇦
Durban, South Africa
Investigational Site Number 724014
🇪🇸
Barcelona, Spain
Investigational Site Number 710007
🇿🇦
Pretoria, South Africa
Investigational Site Number 724002
🇪🇸
Barcelona, Spain
Investigational Site Number 724001
🇪🇸
Barcelona, Spain
Investigational Site Number 724006
🇪🇸
Pozuelo De Alarcón, Spain
Investigational Site Number 724003
🇪🇸
Sabadell, Spain
Investigational Site Number 724010
🇪🇸
Palma De Mallorca, Spain
Investigational Site Number 724008
🇪🇸
Sevilla, Spain
Investigational Site Number 724007
🇪🇸
Sant Boi De Llobregat, Spain
Investigational Site Number 724096
🇪🇸
Santiago De Compostela, Spain
Investigational Site Number 724097
🇪🇸
Valencia, Spain
Investigational Site Number 158009
🇨🇳
Taipei, Taiwan
Investigational Site Number 792098
🇹🇷
Ankara, Turkey
Investigational Site Number 792008
🇹🇷
Bursa, Turkey
Investigational Site Number 792001
🇹🇷
Istanbul, Turkey
Investigational Site Number 792003
🇹🇷
Istanbul, Turkey
Investigational Site Number 792005
🇹🇷
Izmir, Turkey
Investigational Site Number 792006
🇹🇷
Mersin, Turkey
Investigational Site Number 792096
🇹🇷
Rize, Turkey
Investigational Site Number 804007
🇺🇦
Chernivtsi, Ukraine
Investigational Site Number 804009
🇺🇦
Ivano-Frankivsk, Ukraine
Investigational Site Number 804005
🇺🇦
Kharkiv, Ukraine
Investigational Site Number 804001
🇺🇦
Kharkiv, Ukraine
Investigational Site Number 804021
🇺🇦
Kharkiv, Ukraine
Investigational Site Number 804003
🇺🇦
Kyiv, Ukraine
Investigational Site Number 804004
🇺🇦
Kyiv, Ukraine
Investigational Site Number 804008
🇺🇦
Kyiv, Ukraine
Investigational Site Number 804017
🇺🇦
Kyiv, Ukraine
Investigational Site Number 804018
🇺🇦
Kyiv, Ukraine
Investigational Site Number 804002
🇺🇦
Poltava, Ukraine
Investigational Site Number 804022
🇺🇦
Zaporizhzhya, Ukraine
Investigational Site Number 804012
🇺🇦
Zaporizhzhya, Ukraine
Investigational Site Number 826001
🇬🇧
Bradford, United Kingdom
Investigational Site Number 826006
🇬🇧
South Shields, United Kingdom
Investigational Site Number 826009
🇬🇧
Oxford, United Kingdom
Investigational Site Number 826010
🇬🇧
London, United Kingdom
Investigational Site Number 826007
🇬🇧
Portsmouth, United Kingdom
Investigational Site Number 840099
🇺🇸
Gilbert, Arizona, United States
Investigational Site Number 840029
🇺🇸
Los Angeles, California, United States
Investigational Site Number 840064
🇺🇸
Bangor, Maine, United States
Investigational Site Number 840109
🇺🇸
Bakersfield, California, United States
Investigational Site Number 840019
🇺🇸
Los Angeles, California, United States
Investigational Site Number 840101
🇺🇸
Chicago, Illinois, United States
Investigational Site Number 840022
🇺🇸
Los Angeles, California, United States
Investigational Site Number 840067
🇺🇸
Philadelphia, Pennsylvania, United States
Investigational Site Number 840030
🇺🇸
Owensboro, Kentucky, United States
Investigational Site Number 840928
🇺🇸
Pittsburgh, Pennsylvania, United States
Investigational Site Number 840091
🇺🇸
Pittsburgh, Pennsylvania, United States
Investigational Site Number 840023
🇺🇸
Dallas, Texas, United States
Investigational Site Number 840040
🇺🇸
Colorado Springs, Colorado, United States
Investigational Site Number 208002
🇩🇰
Hvidovre, Denmark
Investigational Site Number 208001
🇩🇰
København Nv, Denmark
Investigational Site Number 840047
🇺🇸
Birmingham, Alabama, United States
Investigational Site Number 840403
🇺🇸
Denver, Colorado, United States
Investigational Site Number 840006
🇺🇸
Denver, Colorado, United States
Investigational Site Number 840024
🇺🇸
Denver, Colorado, United States
Investigational Site Number 840130
🇺🇸
Denver, Colorado, United States
Investigational Site Number 840018
🇺🇸
Minneapolis, Minnesota, United States
Investigational Site Number 840015
🇺🇸
Cincinnati, Ohio, United States
Investigational Site Number 840031
🇺🇸
Portland, Oregon, United States
Investigational Site Number 840108
🇺🇸
Durham, North Carolina, United States
Investigational Site Number 840146
🇺🇸
Cincinnati, Ohio, United States
Investigational Site Number 840008
🇺🇸
San Antonio, Texas, United States
Investigational Site Number 840132
🇺🇸
Little Rock, Arkansas, United States
Investigational Site Number 840115
🇺🇸
Ocoee, Florida, United States
Investigational Site Number 840401
🇺🇸
Boston, Massachusetts, United States
Investigational Site Number 840071
🇺🇸
Gainesville, Florida, United States
Investigational Site Number 032012
🇦🇷
San Miguel De Tucuman, Argentina
Investigational Site Number 076009
🇧🇷
Florianópolis, Brazil
Investigational Site Number 076013
🇧🇷
São Bernardo Do Campo, Brazil
Investigational Site Number 124009
🇨🇦
Calgary, Canada
Investigational Site Number 124016
🇨🇦
Hamilton, Canada
Investigational Site Number 152005
🇨🇱
Santiago, Chile
Investigational Site Number 250009
🇫🇷
Brest, France
Investigational Site Number 250004
🇫🇷
La Tronche, France
Investigational Site Number 276010
🇩🇪
Frankfurt Am Main, Germany
Investigational Site Number 348003
🇭🇺
Gödöllö, Hungary
Investigational Site Number 392009
🇯🇵
Asahi-Shi, Japan
Investigational Site Number 392012
🇯🇵
Edogawa-Ku, Japan
Investigational Site Number 840052
🇺🇸
Chevy Chase, Maryland, United States
Investigational Site Number 840073
🇺🇸
Gaithersburg, Maryland, United States
Investigational Site Number 840087
🇺🇸
Scottsdale, Arizona, United States
Investigational Site Number 840077
🇺🇸
Murray, Utah, United States
Investigational Site Number 032007
🇦🇷
Rosario, Argentina
Investigational Site Number 032005
🇦🇷
Rosario, Argentina
Investigational Site Number 056002
🇧🇪
Brussels, Belgium
Investigational Site Number 124007
🇨🇦
Trois-Rivieres, Canada
Investigational Site Number 152024
🇨🇱
Santiago, Chile
Investigational Site Number 276009
🇩🇪
Koblenz, Germany
Investigational Site Number 376002
🇮🇱
Rehovot, Israel
Investigational Site Number 380004
🇮🇹
Ferrara, Italy
Investigational Site Number 840082
🇺🇸
Charleston, South Carolina, United States
Investigational Site Number 840117
🇺🇸
Greenville, South Carolina, United States
Investigational Site Number 840079
🇺🇸
Twin Falls, Idaho, United States
Investigational Site Number 840034
🇺🇸
Medford, Oregon, United States
Investigational Site Number 076012
🇧🇷
Sao Paulo, Brazil
Investigational Site Number 076006
🇧🇷
São Paulo, Brazil
Investigational Site Number 840068
🇺🇸
Ocean City, New Jersey, United States
Investigational Site Number 840011
🇺🇸
Princeton, New Jersey, United States
Investigational Site Number 840057
🇺🇸
South Burlington, Vermont, United States
Investigational Site Number 032006
🇦🇷
Rosario, Argentina
Investigational Site Number 056003
🇧🇪
Gent, Belgium
Investigational Site Number 076007
🇧🇷
Porto Alegre, Brazil
Investigational Site Number 124001
🇨🇦
Montreal, Canada
Investigational Site Number 152014
🇨🇱
Santiago, Chile
Investigational Site Number 250007
🇫🇷
Nimes Cedex 9, France
Investigational Site Number 380002
🇮🇹
Genova, Italy
Investigational Site Number 392002
🇯🇵
Chuo-Ku, Japan
Investigational Site Number 392030
🇯🇵
Habikino-Shi, Japan
Investigational Site Number 392040
🇯🇵
Kodaira-Shi, Japan
Investigational Site Number 392131
🇯🇵
Koushi-Shi, Japan
Investigational Site Number 392153
🇯🇵
Kyoto-Shi, Japan
Investigational Site Number 392127
🇯🇵
Ota-Ku, Japan
Investigational Site Number 392169
🇯🇵
Sagamihara-Shi, Japan
Investigational Site Number 392011
🇯🇵
Sakaide-Shi, Japan
Investigational Site Number 124013
🇨🇦
Ottawa, Canada
Investigational Site Number 376003
🇮🇱
Haifa, Israel
Investigational Site Number 376001
🇮🇱
Kfar Saba, Israel
Investigational Site Number 380007
🇮🇹
Padova, Italy
Investigational Site Number 392037
🇯🇵
Chiyoda-Ku, Japan
Investigational Site Number 392137
🇯🇵
Fukuoka-Shi, Japan
Investigational Site Number 392032
🇯🇵
Hirakata-Shi, Japan
Investigational Site Number 392042
🇯🇵
Isesaki-Shi, Japan
Investigational Site Number 392025
🇯🇵
Kobe-Shi, Japan
Investigational Site Number 392044
🇯🇵
Kokubunji-Shi, Japan
Investigational Site Number 392133
🇯🇵
Machida-Shi, Japan
Investigational Site Number 124014
🇨🇦
Quebec, Canada
Investigational Site Number 348301
🇭🇺
Balassagyarmat, Hungary
Investigational Site Number 380010
🇮🇹
Ancona, Italy
Investigational Site Number 380003
🇮🇹
Modena, Italy
Investigational Site Number 380099
🇮🇹
Palermo, Italy
Investigational Site Number 392023
🇯🇵
Kanazawa-Shi, Japan
Investigational Site Number 380001
🇮🇹
Pisa, Italy
Investigational Site Number 392185
🇯🇵
Akashi-Shi, Japan
Investigational Site Number 392007
🇯🇵
Chuo-Ku, Japan
Investigational Site Number 392021
🇯🇵
Fukuyama-Shi, Japan
Investigational Site Number 392158
🇯🇵
Hiroshima-Shi, Japan
Investigational Site Number 392144
🇯🇵
Minato-Ku, Japan
Investigational Site Number 392186
🇯🇵
Shibuya-Ku, Japan
Investigational Site Number 392010
🇯🇵
Kurashiki-Shi, Japan
Investigational Site Number 392122
🇯🇵
Minato-Ku, Japan
Investigational Site Number 392106
🇯🇵
Mizunami-Shi, Japan
Investigational Site Number 392020
🇯🇵
Naka-Gun, Japan
Investigational Site Number 392130
🇯🇵
Shinjuku-Ku, Japan
Investigational Site Number 792004
🇹🇷
Istanbul, Turkey
Investigational Site Number 792090
🇹🇷
Izmir, Turkey
Investigational Site Number 804094
🇺🇦
Ivano-Frankivsk, Ukraine
Investigational Site Number 410006
🇰🇷
Seoul, Korea, Republic of
Investigational Site Number 392036
🇯🇵
Kyoto-Shi, Japan
Investigational Site Number 643011
🇷🇺
Saint-Petersburg, Russian Federation
Investigational Site Number 643010
🇷🇺
Saint-Petersburg, Russian Federation
Investigational Site Number 158008
🇨🇳
New Taipei City, Taiwan
Investigational Site Number 792002
🇹🇷
Ankara, Turkey
Investigational Site Number 804014
🇺🇦
Ternopil, Ukraine
Investigational Site Number 804019
🇺🇦
Vinnytsya, Ukraine
Investigational Site Number 392005
🇯🇵
Naruto-Shi, Japan
Investigational Site Number 392008
🇯🇵
Sapporo-Shi, Japan
Investigational Site Number 392167
🇯🇵
Shinagawa-Ku, Japan
Investigational Site Number 410001
🇰🇷
Suwon, Korea, Republic of
Investigational Site Number 484003
🇲🇽
Monterrey, Mexico
Investigational Site Number 616001
🇵🇱
Lodz, Poland
Investigational Site Number 792013
🇹🇷
Kirikkale, Turkey
Investigational Site Number 616006
🇵🇱
Bialystok, Poland
Investigational Site Number 643099
🇷🇺
St-Petersburg, Russian Federation
Investigational Site Number 158007
🇨🇳
Taichung, Taiwan
Investigational Site Number 792007
🇹🇷
Istanbul, Turkey
Investigational Site Number 804023
🇺🇦
Dnipro, Ukraine
Investigational Site Number 804020
🇺🇦
Kyiv, Ukraine
Investigational Site Number 804016
🇺🇦
Kyiv, Ukraine
Investigational Site Number 804006
🇺🇦
Odesa, Ukraine
Investigational Site Number 804015
🇺🇦
Yalta, Ukraine
Investigational Site Number 410002
🇰🇷
Bucheon-Si, Korea, Republic of
Investigational Site Number 840902
🇺🇸
New Haven, Connecticut, United States
Investigational Site Number 840017
🇺🇸
Louisville, Kentucky, United States
Investigational Site Number 840078
🇺🇸
Omaha, Nebraska, United States
Investigational Site Number 840404
🇺🇸
Winston-Salem, North Carolina, United States