Multinational Clinical Study Comparing Isatuximab, Pomalidomide, and Dexamethasone to Pomalidomide and Dexamethasone in Refractory or Relapsed and Refractory Multiple Myeloma Patients
- Conditions
- Plasma Cell Myeloma
- Interventions
- Registration Number
- NCT02990338
- Lead Sponsor
- Sanofi
- Brief Summary
Primary Objective:
To demonstrate the benefit of isatuximab in combination with pomalidomide and low-dose dexamethasone in the prolongation of Progression Free Survival (PFS) as compared to pomalidomide and low-dose dexamethasone in participants with refractory or relapsed and refractory multiple myeloma (MM).
Secondary Objectives:
* To evaluate the Overall Response Rate (ORR) as per International Myeloma Working Group (IMWG) criteria in each arm.
* To compare the Overall Survival (OS) between the two arms.
* To evaluate the Time To Progression (TTP) in each arm.
* To evaluate the PFS in high risk cytogenetic population in each arm.
* To evaluate the Duration of Response (DOR) in each arm.
* To evaluate the safety in both treatment arms.
* To determine the Pharmacokinetic profile of isatuximab in combination with pomalidomide.
* To evaluate the immunogenicity of isatuximab.
* To assess disease-specific and generic health-related quality of life (HRQL), disease and treatment-related symptoms, health state utility, and health status.
- Detailed Description
The duration of the study for the participants included a period for screening of up to 21 days (or up to 28 days for women who can become pregnant). Participants continued study treatment until disease progression, unacceptable adverse reaction, participants' wish or other reason of discontinuation.
During follow-up, participants who discontinued the study treatment due to progression of the disease were followed every 3 months (12 weeks) for survival (or until cut-off date), and participants who discontinued the study treatment prior to documentation of disease progression were followed-up every 4 weeks until disease progression, and then every 3 months (12 weeks) for survival (or until cut-off date).
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 307
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Pd (pomalidomide + dexamethasone) Pomalidomide Participants received pomalidomide 4 milligrams (mg) Per os (PO) on Days 1 to 21 of each 28-day treatment cycle plus dexamethasone 40 mg (participants greater than or equal to (\>=) 75 years of age received 20 mg dexamethasone) PO on Days 1, 8, 15 and 22 of each 28-day treatment cycle until disease progression or unacceptable toxicity or participant's wish to discontinue study treatment, or any other reason, whichever comes first (maximum exposure: 306.6 weeks). Pd (pomalidomide + dexamethasone) Dexamethasone Participants received pomalidomide 4 milligrams (mg) Per os (PO) on Days 1 to 21 of each 28-day treatment cycle plus dexamethasone 40 mg (participants greater than or equal to (\>=) 75 years of age received 20 mg dexamethasone) PO on Days 1, 8, 15 and 22 of each 28-day treatment cycle until disease progression or unacceptable toxicity or participant's wish to discontinue study treatment, or any other reason, whichever comes first (maximum exposure: 306.6 weeks). IPd (isatuximab + pomalidomide + dexamethasone) Isatuximab Participants received isatuximab 10 milligrams per kilogram (mg/kg) intravenous (IV) infusion on Days 1, 8, 15, and 22 at Cycle 1, and then on Days 1 and 15 of subsequent cycles plus pomalidomide 4 mg PO on Days 1 to 21 of each 28-day treatment cycle and dexamethasone 40 mg (participants \>= 75 years of age received 20 mg dexamethasone), PO or IV on Day 1, 8, 15, 22 of each 28-day treatment cycle until disease progression or unacceptable toxicity or participant's wish to discontinue study treatment, or any other reason, whichever comes first (maximum exposure: 311.0 weeks). IPd (isatuximab + pomalidomide + dexamethasone) Pomalidomide Participants received isatuximab 10 milligrams per kilogram (mg/kg) intravenous (IV) infusion on Days 1, 8, 15, and 22 at Cycle 1, and then on Days 1 and 15 of subsequent cycles plus pomalidomide 4 mg PO on Days 1 to 21 of each 28-day treatment cycle and dexamethasone 40 mg (participants \>= 75 years of age received 20 mg dexamethasone), PO or IV on Day 1, 8, 15, 22 of each 28-day treatment cycle until disease progression or unacceptable toxicity or participant's wish to discontinue study treatment, or any other reason, whichever comes first (maximum exposure: 311.0 weeks). IPd (isatuximab + pomalidomide + dexamethasone) Dexamethasone Participants received isatuximab 10 milligrams per kilogram (mg/kg) intravenous (IV) infusion on Days 1, 8, 15, and 22 at Cycle 1, and then on Days 1 and 15 of subsequent cycles plus pomalidomide 4 mg PO on Days 1 to 21 of each 28-day treatment cycle and dexamethasone 40 mg (participants \>= 75 years of age received 20 mg dexamethasone), PO or IV on Day 1, 8, 15, 22 of each 28-day treatment cycle until disease progression or unacceptable toxicity or participant's wish to discontinue study treatment, or any other reason, whichever comes first (maximum exposure: 311.0 weeks).
- Primary Outcome Measures
Name Time Method Progression Free Survival (PFS) From the date of randomization to the date of first documentation of progression, or the date of death from any cause, or initiation of further anti-myeloma treatment or data cut-off whichever comes first (maximum duration: 76.7 weeks) PFS:time from date of randomization to date of first documentation of progressive disease (PD) determined by Independent Response Committee (IRC) or date of death from any cause, whichever comes first. If progression or death was not observed, participant was censored at date of last progression-free tumor assessment prior to study cut-off date. Analysis was performed by Kaplan-Meier method. PD as per International Myeloma Working Group (IMWG) criteria was defined as increase of \>=25% from lowest confirmed value in any one of the following criteria: serum M-protein (the absolute increase must be \>=0.5gram(g)/dL), serum M-protein increase \>=1g/dL if lowest M component was \>=5g/dL; urine M-component (absolute increase must be \>=200mg/24hour), appearance of new lesion(s),\>=50% increase from nadir in sum of the products of the maximal perpendicular diameters of measured lesions (SPD) of \>1 lesion, or \>=50% increase in the longest diameter of a previous lesion \>1 centimeter in short axis.
- Secondary Outcome Measures
Name Time Method Progression Free Survival in High Risk Cytogenetic Population From the date of randomization to the date of first documentation of progression, or the date of death from any cause, or initiation of further anti-myeloma treatment or data cut-off whichever comes first (maximum duration 76.7 weeks) PFS in high risk cytogenetic population was defined as PFS in subgroup of participants carrying high risk cytogenetic changes including del(17p), translocation (t)(4;14) or translocation t(14;16) assessed by fluorescence in situ hybridization (FISH). PFS was defined as the time from date of randomization to date of first documentation of PD (determined by IRC) or date of death from any cause, whichever comes first. PD defined as per IMWG criteria as: increase of \>=25% from lowest confirmed value in any one of following criteria: serum M-protein (absolute increase must be \>=0.5 g/dL), serum M-protein increase \>=1 g/dL if lowest M component was \>=5 g/dL; urine M-component (absolute increase must be \>=200 mg/24hour), appearance of new lesion(s), \>=50% increase from nadir in SPD of \>1 lesion, or \>=50% increase in the longest diameter of previous lesion \>1 centimeter (cm) in short axis.
Overall Response Rate (ORR): Percentage of Participants With Disease Response as Per Independent Response Committee (IRC) From the date of randomization to the date of first documentation of progression or initiation of further anti-myeloma treatment or data cut-off whichever comes first (maximum duration 76.7 weeks) ORR (IMWG criteria): percentage of participants with stringent complete response(sCR), complete response (CR), very good partial response (VGPR), and partial response (PR) as best overall response, assessed by IRC. sCR:negative immunofixation on serum and urine,disappearance of any soft tissue plasmacytomas,\<5% plasma cells in bone marrow aspirates plus normal free light chain(FLC)ratio(0.26-1.65), absence of clonal cells in bone marrow biopsy.CR:negative immunofixation on serum and urine,disappearance of any soft tissue plasmacytomas,\<5% plasma cells in bone marrow aspirates.VGPR: serum and urine M-protein detectable by immunofixation, not on electrophoresis/,\>=90% reduction in serum M-protein plus urine M-protein level \<100mg/24h/,\>=90% decrease in SPD compared to baseline in soft tissue plasmacytoma. PR: \>=50% reduction of serum M-protein and reduction in 24h urinary M-protein by \>=90%/\<200mg/24h,if present at baseline,\>=50% reduction in the size (SPD) of soft tissue plasmacytomas.
Percentage of Participants With Best Overall Response (BOR) as Per Independent Response Committee From the date of randomization until disease progression, or death, initiation of further anti-myeloma treatment or data cut-off whichever comes first (maximum duration 76.7 weeks) BOR:best sequential response from start of treatment until disease progression, death, initiation of further anti-myeloma treatment/data cut-off, whichever comes first. Ordering of evaluations from best to worse was: sCR,CR,VGPR,PR, minimal response (MR), stable disease (SD), PD, and not evaluable.CR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas,\<5% plasma cells in bone marrow aspirates. sCR:CR as defined previously plus normal FLC ratio (0.26 to 1.65), absence of clonal cells in bone marrow biopsy. VGPR: serum and urine M-protein detectable by immunofixation,\>=90% reduction in serum M-protein plus urine M-protein level \<100mg/24h,\>=90% decrease in SPD compared to baseline in soft tissue plasmacytoma. PR: \>=50% reduction of serum M-protein and reduction in 24h urinary M-protein by \>=90%/\<200mg/24h. MR:\>=25% but \<=49% reduction in serum M-protein and reduction in 24h urine M-protein by 50-89%. SD: Not meeting criteria for CR,VGPR,PR,MR/PD.
Percentage of Participants With Very Good Partial Response (VGPR) or Better as Per Independent Response Committee From the date of randomization to the date of first documentation of progression, death, initiation of further anti-myeloma treatment, or data cut-off whichever comes first (maximum duration 76.7 weeks) VGPR rate was defined as the percentage of participants achieving a VGPR or better as BOR. VGPR was defined as serum and urine M-protein detectable by immunofixation but not on electrophoresis or \>=90% reduction in serum M-protein plus urine M-protein level \<100 mg/24 h or \>=90% decrease in the sum of maximal perpendicular diameter compared to baseline in soft tissue plasmacytoma. BOR was defined as the best sequential response, using the IRC's assessment of response, from the start of treatment until disease progression (provided that the progression is subsequently confirmed in case of progression requiring confirmation), death, initiation of further anti-myeloma treatment, or cut-off date, whichever occurs first. CR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas,\<5% plasma cells in bone marrow aspirates.
Number of Participants With Minimal Residual Disease (MRD) Up to 76.7 weeks MRD was assessed by next-generation sequencing in bone marrow samples from participants who achieved CR, to determine the depth of response at the molecular level. IMWG criteria for CR: Negative immunofixation on the serum and urine, disappearance of any soft tissue plasmacytomas, and \<5% plasma cells in bone marrow aspirates. MRD was classified as positive or negative at the minimum sensitivity of 1 in 10\^5 nucleated cells. MRD negativity was defined as the absence of the dominant clonotype sequence(s) identified in the bone marrow aspirate collected at screening. MRD positivity was defined as the presence of the dominant clonotype sequence(s) identified in the bone marrow aspirate collected at screening.
Clinical Benefit Rate (CBR): Percentage of Participants With Clinical Benefit as Per Independent Response Committee From the date of randomization to the date of first documentation of progression, death, initiation of further anti-myeloma treatment or data cut-off whichever comes first (maximum duration 76.7 weeks) CBR was defined as the percentage of participants achieving a MR or better as BOR. MR was defined as \>= 25% but \<= 49% reduction in serum M-protein and reduction in 24h urine M-protein by 50-89%, which still exceed 200 mg/24h; if present at baseline, \>=50% reduction in size (SPD) of soft tissue plasmacytomas was also required. BOR was defined as the best sequential response, using the IRC's assessment of response, from the start of treatment until disease progression (provided that the progression is subsequently confirmed in case of progression requiring confirmation), death, initiation of further anti-myeloma treatment, or cut-off date, whichever occurs first.
Overall Survival (OS): Final Analysis From the date of randomization to date of death from any cause or data cut-off date, whichever was earlier (maximum duration 245.6 weeks) OS was defined as the time from the date of randomization to death from any cause. In the absence of confirmation of death, survival time was censored at the last date participant was known to be alive or at the cut-off date, whichever comes first. This pre-specified final analysis was performed when the 220 OS events were met.
Time to Progression (TTP) as Per Independent Response Committee From the date of randomization to the date of first documentation of progression, or initiation of further anti-myeloma treatment or data cut-off whichever comes first (maximum duration 76.7 weeks) TTP was defined as time from randomization to the date of first documentation of PD, as determined by the IRC. As per IMWG criteria, PD was defined for participants with increase of \>= 25% from lowest confirmed value in any one of the following criteria: serum M-protein (the absolute increase must be \>= 0.5 g/dL), serum M-protein increase \>=1 g/dL if the lowest M component was \>=5 g/dL; urine M-component (the absolute increase must be \>=200 mg/24hour), appearance of new lesion(s), \>=50% increase from nadir in SPD of \>1 lesion, or \>=50% increase in the longest diameter of a previous lesion \>1 centimeter in short axis.
Duration of Response (DOR) as Per Independent Response Committee From the date of the first IRC determined response to the date of first IRC progression or death, whichever occurred first (maximum duration 76.7 weeks) DOR:time from date of first IRC determined response(PR or better) to date of first IRC-PD or death, whichever occurred first.DOR was determined only for participants who had achieved a response of PR or better based on disease assessment by IRC.If progression or death was not observed,participant was censored at date of participants last progression-free tumor assessment prior to initiation of further anti-myeloma treatment(if any)and study cut-off date. PD(IMWG criteria):increase of \>=25% from lowest confirmed value in any one of following criteria: serum M-protein (absolute increase must be \>=0.5 g/dL), serum M-protein increase \>=1g/dL if lowest M component was \>=5g/dL;urine M-component (absolute increase must be \>=200mg/24 hour),appearance of new lesion(s), \>=50% increase from nadir in SPD of \>1 lesion,or \>=50% increase in the longest diameter of a previous lesion \>1 cm in short axis. PR:\>=50% reduction of serum M-protein and reduction in 24h urinary M-protein by \>=90%/\<200mg/24h.
Time to First Response (TT1R) as Per Independent Response Committee From the date of randomization to the date of first IRC determined response, or death or data cut-off whichever comes first (maximum duration 76.7 weeks) TT1R was defined as the time from randomization to the date of first IRC determined response (PR or better) that is subsequently confirmed. PR was defined as \>=50% reduction of serum M-protein and reduction in 24 hours urinary M-protein by \>=90% or to \<200 mg/24 h. In addition to the above listed criteria, if present at baseline, a \>=50% reduction in the size (SPD) of soft tissue plasmacytomas was also required.
Pharmacokinetics (PK) Parameter: Plasma Concentration of Isatuximab at End of Infusion (CEOI) End of infusion on Cycle(C)1 Day(D)1 and Cycle1 Day 15; Cycle 2 Day 1; and Cycle 4 Day 1 CEOI was defined as the plasma concentration at end of infusion.
Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Cancer Specific Questionnaire With 30 Items (EORTC QLQ-C30): Global Health Status (GHS)/Quality of Life (QOL) Score Baseline, Day 1 of each cycle (Cycle 3, Cycle 6, Cycle 9, and Cycle 17) EORTC-Quality of Life Questionnaire (QLQ)-C30 is a cancer-specific instrument with 30 questions for evaluation of new chemotherapy and provides an assessment of participant reported outcome dimensions. EORTC QLQ-C30 included GHS/ QOL, functional scales (physical, role, cognitive, emotional, social), symptom scales (fatigue, pain, nausea/vomiting), and 6 single items (dyspnea, appetite loss, insomnia, constipation, diarrhea, financial difficulties). Most questions from QLQ-C30 were a 4-point scale (1/Not at All to 4/Very Much), except Items 29-30, which comprise GHS scale and were a 7-point scale (1/Very Poor to 7/Excellent). Answers were converted into grading scale, with values between 0 and 100. A high score represented a favorable outcome with a best quality of life for participant.
Change From Baseline in European Quality of Life Working Group Health Status Measure 5 Dimensions (5D), 5 Levels (5L) (EQ-5D-5L) Score: Health State Utility Index Value Baseline, Day 1 of each cycle (Cycle 3, Cycle 6, Cycle 9, and Cycle 17) The EQ-5D-5L is a standardized measure of health status that provides a general assessment of health and wellbeing. The EQ-5D descriptive system comprises 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has a 5-level response: no problems, slight problems, moderate problems, severe problems, and extreme problems. Response options are measured with a 5-point Likert scale (for the 5L version). The 5D-5L systems are converted into a single index utility score between 0 to 1, where higher score indicates a better health state and lower score indicate worse health state.
Time to Best Response (TTBR) as Per Independent Response Committee From the date of randomization to date of first occurrence of IRC determined best overall response or data cut-off whichever comes first (maximum duration 76.7 weeks) TTBR was defined as the time from randomization to the date of first occurrence of IRC determined BOR (PR or better) that was subsequently confirmed. PR was defined as \>=50% reduction of serum M-protein and reduction in 24 hours urinary M-protein by \>=90% or to \<200 mg/24 h. In addition to the above listed criteria, if present at baseline, a \>=50% reduction in the size (SPD) of soft tissue plasmacytomas was also required. BOR was defined as the best sequential response, using the IRC's assessment of response, from the start of treatment until disease progression (provided that the progression is subsequently confirmed in case of progression requiring confirmation), death, initiation of further anti-myeloma treatment, or cut-off date, whichever occurs first.
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) From randomization up to 30 days after last dose of study drug (maximum duration up to 241.6 weeks for Pd arm and 245.6 weeks for IPd arm) Adverse Event (AE) was defined as any untoward medical occurrence in a participant who received study drug and did not necessarily had a causal relationship with the treatment. TEAEs were defined as AEs that developed, worsened (according to the Investigator opinion), or became serious during the treatment period (time from the first dose of study treatments up to 30 days after last dose of study treatments). An SAE is any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, is a medically important event.
Pharmacokinetic Parameter: Accumulation Ratio of Isatuximab at Concentration at the End of Infusion (CEOI) End of infusion on Cycle 1 Day 1, Cycle 2 Day 1, and Cycle 4 Day 1 Accumulation Ratio was defined as the ratio of CEOI of Cycle 2 Day 1 versus Cycle 1 Day 1 and Cycle 4 Day 1 versus Cycle 1 Day 1, where CEOI was the plasma concentration at the end of infusion.
Number of Participants With Anti-drug Antibodies (ADA) From randomization up to 60 days after last dose of study drug (maximum duration 76.7 weeks) ADA were categorized as: pre-existing, treatment induced and treatment boosted response. Pre-existing ADA was defined as ADA that were present in samples drawn during the pretreatment period (i.e., before the first isatuximab administration). Treatment-induced ADA was defined as ADA that developed at any time during the ADA on-study observation period in participants without preexisting ADA, including participants without pretreatment samples. Treatment boosted ADA was defined as pre-existing ADA that increased at least 2 titer steps between pre-treatment and post-treatment.
Change From Baseline in European Quality of Life Working Group Health Status Measure 5 Dimensions, 5 Levels (EQ-5D-5L) Score: Visual Analogic Scale (VAS) Baseline, Day 1 of each cycle (Cycle 3, Cycle 6, Cycle 9, and Cycle 17) EQ-5D-5L is a standardized, participant-rated questionnaire to assess health-related quality of life. The EQ-5D-5L includes 2 components: the EQ-5D-5L health state utility index (descriptive system) and the EQ-5D-5L Visual Analog Scale. The Visual Analogue Scale is designed to rate the participant's current health state on a scale from 0 to 100, where 0 represents the worst imaginable health state and 100 represents the best imaginable health state.
Pharmacokinetic Parameter: Plasma Concentration of Isatuximab at 1 Hour After End of Infusion (CEOI+1 Hour) Cycle 1:1 hour after End of Infusion on Day 1; Cycle 4:1 hour after End of Infusion on Day 1 CEOI+1 hour was defined as the plasma concentration of isatuximab at 1 hour after end of infusion.
PK Parameter: Plasma Concentration of Isatuximab at Ctrough Pre-infusion on C1D1, C1D8, C1D15, C1D22, C2D1, C2D15, C3D1, C3D15, C4D1, C4D15, C5D1, C6D1, C7D1, C8D1, C9D1, C10D1, C11D1, C12D1, C13D1, C14D1, C15D1, C16D1, C17D1, C18D1, C19D1, C20D1; End of treatment (EOT [30 days after last drug administration]) Trough Concentration (Ctrough) is the concentration prior to study drug administration.
PK Parameter: Accumulation Ratio of Isatuximab at Trough Concentration (Ctrough) Pre-infusion on Cycle 1 Day 8, Cycle 2 Day 1, and Cycle 4 Day 1 Accumulation Ratio was defined as the ratio of Ctrough of Cycle 2 Day 1 versus Cycle 1 Day 8 and Cycle 4 Day 1 versus Cycle 1 Day 8, where Ctrough is the concentration prior to study drug administration.
Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Multiple Myeloma Specific Module With 20 Items (EORTC QLQ-MY20): Disease Symptoms Domain Score Baseline, Day 1 of each cycle (Cycle 3, Cycle 6, Cycle 9, and Cycle 17) EORTC QLQ-MY20 is a validated questionnaire to assess the overall quality of life in participants with multiple myeloma. Disease symptoms domain is one of the four domain scores. Disease symptoms domain score used 4-point scale (1 'Not at All' to 4 'Very Much'). Scores are averaged, and transformed to 0 -100 scale, where higher scores = more symptoms and lower health-related quality of life (HRQL) and lower score = less symptoms and more HRQL
Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Multiple Myeloma Specific Module With 20 Items (EORTC QLQ-MY20): Side Effects of Treatment Domain Score Baseline, Day 1 of each cycle (Cycle 3, Cycle 6, Cycle 9, and Cycle 17) EORTC QLQ-MY20 is a validated questionnaire to assess the overall quality of life in participants with multiple myeloma. Side effects of treatment domain is one of the four domain scores. Side effects of treatment domain score used 4-point scale (1 'Not at All' to 4 'Very Much'). Scores are averaged, and transformed to 0-100 scale, where higher scores = more side effects and lower HRQL and lower scores = less side effects and better HRQL.
Trial Locations
- Locations (111)
BRCR Medical Center Inc. Site Number : 8400002
🇺🇸Plantation, Florida, United States
Dana Farber Site Number : 8400006
🇺🇸Boston, Massachusetts, United States
Investigational Site Number : 0360004
🇦🇺St Leonards, New South Wales, Australia
Investigational Site Number : 0360001
🇦🇺Waratah, New South Wales, Australia
Investigational Site Number : 0360005
🇦🇺Melbourne, Victoria, Australia
Investigational Site Number : 0360002
🇦🇺Melbourne, Victoria, Australia
Investigational Site Number : 0360006
🇦🇺Richmond, Victoria, Australia
Investigational Site Number : 0560003
🇧🇪Antwerpen, Belgium
Investigational Site Number : 0560002
🇧🇪Brussel, Belgium
Investigational Site Number : 0560004
🇧🇪Gent, Belgium
Investigational Site Number : 0560001
🇧🇪Leuven, Belgium
Investigational Site Number : 1240001
🇨🇦Montreal, Quebec, Canada
Investigational Site Number : 1240004
🇨🇦Montreal, Quebec, Canada
Investigational Site Number : 1240005
🇨🇦Sherbrooke, Quebec, Canada
Investigational Site Number : 2030005
🇨🇿Brno, Czechia
Investigational Site Number : 2030004
🇨🇿Hradec Kralove, Czechia
Investigational Site Number : 2030001
🇨🇿Olomouc, Czechia
Investigational Site Number : 2030002
🇨🇿Ostrava - Poruba, Czechia
Investigational Site Number : 2030003
🇨🇿Praha 2, Czechia
Investigational Site Number : 2080002
🇩🇰Ålborg, Denmark
Investigational Site Number : 2500021
🇫🇷Bayonne, France
Investigational Site Number : 2500008
🇫🇷Caen, France
Investigational Site Number : 2500009
🇫🇷Dijon, France
Investigational Site Number : 2500017
🇫🇷Grenoble, France
Investigational Site Number : 2500013
🇫🇷La Roche Sur Yon, France
Investigational Site Number : 2500003
🇫🇷Lille, France
Investigational Site Number : 2500023
🇫🇷Limoges, France
Investigational Site Number : 2500019
🇫🇷Montpellier Cedex, France
Investigational Site Number : 2500002
🇫🇷Nantes, France
Investigational Site Number : 2500015
🇫🇷Paris, France
Investigational Site Number : 2500016
🇫🇷Paris, France
Investigational Site Number : 2500005
🇫🇷Pessac, France
Investigational Site Number : 2500004
🇫🇷Pierre Benite, France
Investigational Site Number : 2500007
🇫🇷POITIERS Cedex, France
Investigational Site Number : 2500025
🇫🇷Reims, France
Investigational Site Number : 2500014
🇫🇷Rennes, France
Investigational Site Number : 2500001
🇫🇷TOULOUSE Cedex 9, France
Investigational Site Number : 2500012
🇫🇷Tours, France
Investigational Site Number : 2500018
🇫🇷Vandoeuvre-les-nancy, France
Investigational Site Number : 2760001
🇩🇪Leipzig, Germany
Investigational Site Number : 3000002
🇬🇷Athens, Greece
Investigational Site Number : 3000005
🇬🇷Athens, Greece
Investigational Site Number : 3000001
🇬🇷Athens, Greece
Investigational Site Number : 3000004
🇬🇷Patra, Greece
Investigational Site Number : 3000003
🇬🇷Thessaloniki, Greece
Investigational Site Number : 3480001
🇭🇺Budapest, Hungary
Investigational Site Number : 3480003
🇭🇺Budapest, Hungary
Investigational Site Number : 3480002
🇭🇺Debrecen, Hungary
Investigational Site Number : 3800001
🇮🇹Bologna, Italy
Investigational Site Number : 3800010
🇮🇹Catania, Italy
Investigational Site Number : 3800009
🇮🇹Firenze, Italy
Investigational Site Number : 3800008
🇮🇹Genova, Italy
Investigational Site Number : 3800007
🇮🇹Milano, Italy
Investigational Site Number : 3800002
🇮🇹Milano, Italy
Investigational Site Number : 3800006
🇮🇹Padova, Italy
Investigational Site Number : 3800004
🇮🇹Terni, Italy
Investigational Site Number : 3800003
🇮🇹Torino, Italy
Investigational Site Number : 3920001
🇯🇵Nagoya-shi, Aichi, Japan
Investigational Site Number : 3920005
🇯🇵Shibukawa-shi, Gunma, Japan
Investigational Site Number : 3920004
🇯🇵Sapporo-shi, Hokkaido, Japan
Investigational Site Number : 3920006
🇯🇵Kyoto-shi, Kyoto, Japan
Investigational Site Number : 3920008
🇯🇵Suwa-shi, Nagano, Japan
Investigational Site Number : 3920003
🇯🇵Okayama-shi, Okayama, Japan
Investigational Site Number : 3920007
🇯🇵Sunto-gun, Shizuoka, Japan
Investigational Site Number : 3920002
🇯🇵Shibuya-ku, Tokyo, Japan
Investigational Site Number : 4100007
🇰🇷Hwasun-gun, Jeollanam-do, Korea, Republic of
Investigational Site Number : 4100001
🇰🇷Seoul, Seoul-teukbyeolsi, Korea, Republic of
Investigational Site Number : 4100002
🇰🇷Seoul, Seoul-teukbyeolsi, Korea, Republic of
Investigational Site Number : 4100006
🇰🇷Incheon, Korea, Republic of
Investigational Site Number : 4100005
🇰🇷Seoul, Korea, Republic of
Investigational Site Number : 5540001
🇳🇿Takapuna, Auckland, New Zealand
Investigational Site Number : 5540004
🇳🇿Dunedin, Otago, New Zealand
Investigational Site Number : 5540003
🇳🇿Hamilton, Waikato, New Zealand
Investigational Site Number : 5540002
🇳🇿Auckland, New Zealand
Investigational Site Number : 5780001
🇳🇴Oslo, Norway
Investigational Site Number : 6160003
🇵🇱Lublin, Lubuskie, Poland
Investigational Site Number : 6160005
🇵🇱Krakow, Malopolskie, Poland
Investigational Site Number : 6160001
🇵🇱Warszawa, Mazowieckie, Poland
Investigational Site Number : 6160002
🇵🇱Chorzow, Slaskie, Poland
Investigational Site Number : 6200004
🇵🇹Coimbra, Portugal
Investigational Site Number : 6200002
🇵🇹Lisboa, Portugal
Investigational Site Number : 6200001
🇵🇹Porto, Portugal
Investigational Site Number : 6430004
🇷🇺Moscow, Russian Federation
Investigational Site Number : 6430001
🇷🇺Moscow, Russian Federation
Investigational Site Number : 6430002
🇷🇺Moscow, Russian Federation
Investigational Site Number : 7030001
🇸🇰Bratislava, Slovakia
Investigational Site Number : 7240005
🇪🇸Santiago de Compostela, A Coruña [La Coruña], Spain
Investigational Site Number : 7240001
🇪🇸Barcelona, Barcelona [Barcelona], Spain
Investigational Site Number : 7240006
🇪🇸Santander, Cantabria, Spain
Investigational Site Number : 7240002
🇪🇸Pamplona, Navarra, Spain
Investigational Site Number : 7240003
🇪🇸Madrid, Spain
Investigational Site Number : 7240004
🇪🇸Salamanca, Spain
Investigational Site Number : 7520004
🇸🇪Luleå, Sweden
Investigational Site Number : 7520005
🇸🇪Uddevalla, Sweden
Investigational Site Number : 1580004
🇨🇳Kaohsiung, Taiwan
Investigational Site Number : 1580002
🇨🇳Taichung, Taiwan
Investigational Site Number : 1580001
🇨🇳Taipei, Taiwan
Investigational Site Number : 1580003
🇨🇳Taoyuan, Taiwan
Investigational Site Number : 7920001
🇹🇷Ankara, Turkey
Investigational Site Number : 7920002
🇹🇷Antalya, Turkey
Investigational Site Number : 7920005
🇹🇷Istanbul, Turkey
Investigational Site Number : 7920006
🇹🇷Istanbul, Turkey
Investigational Site Number : 7920003
🇹🇷Istanbul, Turkey
Investigational Site Number : 7920004
🇹🇷Istanbul, Turkey
Investigational Site Number : 7920008
🇹🇷Izmir, Turkey
Investigational Site Number : 7920010
🇹🇷Izmir, Turkey
Investigational Site Number : 7920009
🇹🇷Kayseri, Turkey
Investigational Site Number : 7920007
🇹🇷Kocaeli, Turkey
Investigational Site Number : 8260002
🇬🇧London, London, City Of, United Kingdom
Investigational Site Number : 8260003
🇬🇧London, London, City Of, United Kingdom
Investigational Site Number : 8260001
🇬🇧London, London, City Of, United Kingdom