MedPath

Phase IIIB-IV Long-Term Follow-up Study for Patients Who Participated in CAMMS03409

Phase 4
Completed
Conditions
Relapsing Remitting Multiple Sclerosis
Interventions
Registration Number
NCT02255656
Lead Sponsor
Genzyme, a Sanofi Company
Brief Summary

Primary Objective:

To evaluate long-term safety of alemtuzumab.

Secondary Objectives:

* To evaluate long term efficacy of alemtuzumab.

* To evaluate the safety profile of participants who received other Disease Modifying Treatment (DMT) following alemtuzumab treatment.

* To evaluate participant-reported Quality of Life (QoL) outcomes and health resource utilization of participant who received alemtuzumab.

* To evaluate as needed re-treatment with alemtuzumab and other DMTs.

Detailed Description

The total duration per participants was up to 5.6 years.

As per Study Investigator discretion, participants can be treated with additional courses of alemtuzumab or any commercialized DMTs.

All participants who completed CAMMS03409 were allowed into the study, which might include specific vulnerable populations. If the investigator decided to treat a participant with a course of alemtuzumab, appropriate cautionary measures were applied as indicated in the approved labelling, or, in ex-European Union countries where Lemtrada was not approved, according to the investigator's brochure.

Recruitment & Eligibility

Status
COMPLETED
Sex
All
Target Recruitment
1062
Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type
INTERVENTIONAL
Study Design
SINGLE_GROUP
Arm && Interventions
GroupInterventionDescription
Alemtuzumabalemtuzumab GZ402673All Participants who completed the study CAMMS03409 (extension study of CAMMS223 \[NCT00050778\], CAMMS323 \[NCT00530348\], or CAMMS324 \[NCT00548405\]) and received alemtuzumab within 48 months prior to enrollment were included in this LPS13649 study. Participants received alemtuzumab, intravenous infusion of 12 milligram per day (mg/day) for 3 consecutive days, at the study investigators' discretion; and at least 12 months after the prior treatment course in the current study (LPS13649).
Primary Outcome Measures
NameTimeMethod
Number of Participants With Treatment-Emergent Adverse Events (TEAEs), and Treatment-Emergent Serious Adverse Events (TESAEs)From Baseline until the end of the study (up to a maximum duration of 5.6 years)

An Adverse Event (AE) was any untoward medical occurrence in a 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 during the 'treatment period (time from Baseline until the end of the study LPS13649 \[i.e. up to a maximum of 5.6 years\]). Serious adverse events (SAEs) 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.

Number of Participants With Infusion-Associated Reactions (IAR)Within 24 hours of any alemtuzumab infusion

Infusion-associated reactions (IAR) was defined as any adverse event occurring during and within 24 hours of alemtuzumab infusion.

Number of Participants With Adverse Events of Special Interest (AESI)From Baseline until the end of the study (up to a maximum duration of 5.6 years)

Adverse events of special interest included the following: hypersensitivity or anaphylaxis; pregnancy of a woman entered in the study; symptomatic overdose (serious or non-serious) with investigational medicinal Product (IMP); increase in alanine transaminase (ALT); autoimmune mediated conditions; hemophagocytic lymphohistiocytosis; progressive multifocal leukoencephalopathy; temporally associated AEs; serious infections; malignancy; and pneumonitis.

Number of Participants With Potentially Clinically Significant Laboratory AbnormalitiesFrom Baseline until the end of the study (up to a maximum duration of 5.6 years)

Criteria for potentially clinically significant laboratory abnormalities included:

* Hemoglobin (Hb): less than or equal to (\<=)115 grams per liter (g/L)(Male \[M\]), \<= 95 g/L (Female\[ F\]); greater than or equal to (\>=)185 g/L (M), \>= 165 g/L (F); Decrease From Baseline (DFB) \>= 20 g/L.

* Hematocrit: \<= 0.37 volume/volume (v/v) (M); \<= 0.32 v/v (F); \>= 0.55 v/v (M); \>= 0.5 v/v (F).

* Red Blood Cells (RBCs): \>=6 \*10\^12/L.

* Platelets: \<100 \*10\^9/L; \>=700 \*10\^9/L. As pre-specified, data collection and analysis for this outcome measure was done on the overall population along with 2 subgroups (DAT and IAT).

Secondary Outcome Measures
NameTimeMethod
Annualized Relapse RateUp to a maximum duration of 5.6 years

Relapse was defined as new neurological symptoms or worsening of previous neurological symptoms with an objective change on neurological examination. Annualized relapse rate was obtained from the total number of confirmed relapses that occurred during the treatment follow up time of all participants divided by the total years of follow-up for all participants. The annualized relapse rate was estimated using a negative binomial model with robust variance estimation.

Change From Baseline in Expanded Disability Status Scale (EDSS) Score at Month 6, 12, 18, 24, 30, 36, 42, 48, 54 and 60Baseline (Month 0 of LPS13649), Month 6, 12, 18, 24, 30, 36, 42, 48, 54 and 60

EDSS is an ordinal scale in half-point increments that qualifies disability in participants with multiple sclerosis (MS). It consists of 8 ordinal rating scales assessing seven functional systems (pyramidal, cerebellar, brainstem, sensory, bowel and bladder, visual, cerebral, and other). EDSS total score ranges from 0 (normal neurological examination) to 10 (death due to MS), where higher scores indicated worst outcomes.

Brain Magnetic Resonance Imaging (MRI) Assessment: Number of New T1 (and New Hypointense T1) Lesions Per MRI ScanUp to a maximum duration of 5.6 years

Number of new T1 lesions per scan was defined as the total number of new T1 lesion (and New Hypointense T1) that occurred during treatment period divided by the total number of scans performed during treatment period.The adjusted cumulative count of lesions was estimated by a repeated negative binomial regression with GEE adjusted for analysis groups and geographic region as covariates.

Brain Magnetic Resonance Imaging (MRI) Assessment: Number of New or Enlarged T2 Lesions Per MRI ScanUp to a maximum duration of 5.6 years

Number of new or enlarged T2 lesions per scan was defined as the total number of new or enlarged T2 lesion that occurred during treatment period divided by the total number of scans performed during treatment period. The adjusted cumulative count of lesions was estimated by a repeated negative binomial regression with GEE adjusted for analysis groups and geographic region as covariates.

HRPQ: Percentage Impact on Work Output Due to Multiple SclerosisBaseline (Month 0 of LPS13649), Month 12, Month 24, Month 36, Month 48 and Month 60

Participants use of healthcare resources, non-medical resources, and informal care as well as their work capacity was assessed at scheduled study visits using a modified questionnaire (HRPQ) designed to evaluate the economic impact of MS. The questionnaire addresses the following content area: participant reported data regarding employment status, work productivity, impact on household chores due to MS. Percentage impact on work output due to MS were reported in this outcome measure.

Proportion of Participants Who Were Relapse FreeUp to a maximum duration of 5.6 years

Relapse was defined as new neurological symptoms or worsening of previous neurological symptoms with an objective change on neurological examination. The proportion of participants who were relapse free (without event) were estimated using the Kaplan-Meier method.

Brain Magnetic Resonance Imaging (MRI) Assessment: Number of Gadolinium Enhancing (Gd-enhancing) Lesions Per MRI ScanUp to a maximum duration of 5.6 years

Number of Gd-enhancing lesions per scan was defined as the total number of Gd-enhancing lesions that occurred during the treatment period divided by the total number of scans performed during the treatment period. The adjusted cumulative count of lesions was estimated by a repeated negative binomial regression with generalized estimating equation (GEE) adjusted for analysis groups and geographic region as covariates.

Brain Magnetic Resonance Imaging (MRI) Assessment: Percent Change From Baseline in Volume of T1 Lesions at Months 12, 24, 36, 48, and 60Baseline (Month 0 of LPS13649), Month 12, Month 24, Month 36, Month 48 and Month 60

The total lesion volume (T1 lesions) was measured by MRI scan.

Brain Magnetic Resonance Imaging (MRI) Assessment: Percent Change From Baseline in Brain Parenchymal Fraction (BPF) at Month 12, 24, 36, 48, and 60Baseline (Month 0 of LPS13649), Month 12, Month 24, Month 36, Month 48 and Month 60

The brain parenchymal fraction was measured by MRI scan.

Change From Baseline in EQ-5D Visual Analogue Scale (VAS) Scores at Month 12, 24, 36, 48, and 60Baseline (Month 0 of LPS13649), Month 12, Month 24, Month 36, Month 48 and Month 60

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 to 100), where 0=worst imaginable health state to 100=best imaginable health state, and higher score indicated better outcome.

Modified Healthcare Resource Utilization Questionnaire (HRUQ): Number of Participants Who Reported Change in Employment Situation, Availing of Sick Leaves, Admissions and Stays in Hospital, Rehabilitation Centers or Nursing Homes Due to Multiple SclerosisBaseline (Month 0 of LPS13649), Month 12, Month 24, Month 36, Month 48 and Month 60

Participants use of healthcare resources, non-medical resources, and informal care as well as their work capacity was assessed at scheduled study visits using a modified questionnaire (HRUQ) designed to evaluate the economic impact of MS. Questionnaire addresses the following content areas: employment situation and changes in employment situation due to MS;sick leaves,admissions and stays in hospital, rehabilitation centers, or nursing homes; typical MS-related investments (eg, stair and bed lift, ramps,rails) and devices (eg,walking aids,wheelchairs); assistance by community or social services (e.g. home nurse, transportation), or help from family or friends. Each question requires a binary answer (yes/no). Number of participants who reported "Yes" as an answer to "employment situation change; had sick leaves; had hospital admission; had spent time in rehabilitation center and had spent time in a nursing home or a similar institution" questions were reported in this outcome measure.

Health Related Productivity Questionnaire (HRPQ): Number of Participants Reporting Current Employment Status (Part Time/Full Time/Not Employed) Due to Multiple SclerosisBaseline (Month 0 of LPS13649), Month 12, Month 24, Month 36, Month 48 and Month 60

Participants use of healthcare resources, non-medical resources, and informal care as well as their work capacity was assessed at scheduled study visits using a modified questionnaire (HRPQ) designed to evaluate the economic impact of MS. The questionnaire addresses the following content area: participant reported data regarding employment status, work productivity, impact on household chores due to MS. Current employment status of participants (i.e. Part Time/Full Time/Not Employed) was reported in this outcome measure.

Brain Magnetic Resonance Imaging (MRI) Assessment: Percent Change From Baseline in Volume of T2 Lesions at Months 12, 24, 36, 48, and 60Baseline (Month 0 of LPS13649), Month 12, Month 24, Month 36, Month 48 and Month 60

The total lesion volume (T2 lesions) was measured by MRI scan.

HRPQ: Percentage Impact on Work Output for Household Chores Due to Multiple SclerosisBaseline (Month 0 of LPS13649), Month 12, Month 24, Month 36, Month 48 and Month 60

Participants use of healthcare resources, non-medical resources, and informal care as well as their work capacity was assessed at scheduled study visits using a modified questionnaire (HRPQ) designed to evaluate the economic impact of MS. The questionnaire addresses the following content area: participant reported data regarding employment status, work productivity, impact on household chores due to MS. Percentage impact on work output for household chores due to MS were reported in this outcome measure.

Change From Baseline in Self-reported Quality of Life (QoL) as Assessed by the Medical Outcome Study (MOS) 36-Item Short-Form Health Survey (SF-36): Physical Component Summary (PCS) and Mental Component Summary (MCS) Scores at Month 12, 24, 36, 48, and 60Baseline (Month 0 of LPS13649), Month 12, Month 24, Month 36, Month 48 and Month 60

The MOS SF-36 is an extensively validated and widely used measure of QoL that assesses participants' perceptions of health status and its impact on their lives. It consisted of 36 items organized into 8 scales (physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional and mental health). Two summary measures of physical and mental health, the PCS and MCS, respectively, were derived from scale aggregates, and were reported in this outcome measure. The score range for each of these 2 summary scores was from 0 (worst) to 100 (best), higher scores indicated better QoL.

Modified HRUQ: Number of Participants Who Reported Other Changes/Changes in Lifestyle Due to Multiple SclerosisBaseline (Month 0 of LPS13649), Month 12, Month 24, Month 36, Month 48 and Month 60

Participants use of healthcare resources, non-medical resources, and informal care as well as their work capacity was assessed at scheduled study visits using a modified questionnaire (HRUQ) designed to evaluate the economic impact of MS.Questionnaire addresses following content areas: employment situation and changes in employment situation due to MS; admissions and stays in hospital, rehabilitation centers, or nursing homes; typical MS-related investments(e.g.stair and bed lift,ramps,rails) and devices(e.g.walking aids,wheelchairs);assistance by community or social services(e.g.home nurse, transportation), or help from family or friends. Each question requires a binary answer (yes/no). Number of participants who reported other changes/changes in lifestyle due to MS, i.e."Yes" as an answer to "had made changes to your house, apartment, car or did you require any special equipment or aids; assistance required; other assistance required" questions were reported in this outcome measure.

Change From Baseline in Functional Assessment of Multiple Sclerosis (FAMS) Score at Month 12, 24, 36, 48, and 60Baseline (Month 0 of LPS13649), Month 12, Month 24, Month 36, Month 48 and Month 60

The FAMS is a self-reported multidimensional index comprising a total of 58 items on 7 subscales: mobility (7 items); symptoms (7 items); emotional well-being (7 items); general contentment (7 items); thinking and fatigue (9 items); family/social well-being (7 items); and additional concerns (14 items, these are not scored). Each item (except those for "additional concerns") was rated on a 5-point scale of 0 (lower quality of life) to 4 (higher quality of life). Total FAMS score was the sum of 44 scored items, which ranged from 0 (poor) to 176 (best), with higher numbers reflecting a higher quality of life.

Change From Baseline in European Quality of Life -5 Dimension (EQ-5D) Score: Utility Scores at Month 12, 24, 36, 48, and 60Baseline (Month 0 of LPS13649), Month 12, Month 24, Month 36, Month 48 and Month 60

The EQ-5D is a generic, standardized instrument that provides a simple, descriptive profile and a single index value for health status used in the clinical and economic evaluation of health care as well as in population health surveys. The EQ-5D comprises 5 dimensions of health: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension measured on 3 levels: some, moderate, and extreme problems. The 5 dimensional 3-level systems was converted into single index utility score ranges from 0 to 100, where 100=best health state; and 0=worst health state; higher scores indicated better outcome.

HRPQ: Total Scheduled Working Hours and Number of Hours Missed From Work Due to Multiple SclerosisBaseline (Month 0 of LPS13649), Month 12, Month 24, Month 36, Month 48 and Month 60

Participants use of healthcare resources, non-medical resources, and informal care as well as their work capacity was assessed at scheduled study visits using a modified questionnaire (HRPQ) designed to evaluate the economic impact of MS. The questionnaire addresses the following content area: participant reported data regarding employment status, work productivity, impact on household chores due to MS. Data for "total scheduled working hours of participants; number of hours missed from work by participants due to MS" were reported in this outcome measure.

HRPQ: Total Scheduled Household Chores Hours; Number of Hours Missed From Household Chores Due to Multiple SclerosisBaseline (Month 0 of LPS13649), Month 12, Month 24, Month 36, Month 48 and Month 60

Participants use of healthcare resources, non-medical resources, and informal care as well as their work capacity was assessed at scheduled study visits using a modified questionnaire (HRPQ) designed to evaluate the economic impact of MS. The questionnaire addresses the following content area: participant reported data regarding employment status, work productivity, impact on household chores due to MS. Data for "total scheduled household chores hours; number of hours missed from planned household chores by participants due to MS" were reported in this outcome measure.

HRPQ: Duration of Disease (in Months) Since Development of Multiple SclerosisBaseline up to end of the study (up to a maximum duration of 5.6 years)

Participants use of healthcare resources, non-medical resources, and informal care as well as their work capacity was assessed at scheduled study visits using a modified questionnaire (HRPQ) designed to evaluate the economic impact of MS. The questionnaire addresses the following content area: participant reported data regarding employment status, work productivity, impact on household chores due to MS. Mean and standard deviation data for duration of MS disease (in months) since the start of MS development in participants was reported in this outcome measure.

HRPQ: Number of Participants Who Reported Impact on Work Due to Multiple SclerosisBaseline up to end of the study (up to a maximum duration of 5.6 years)

Participants use of healthcare resources, non-medical resources, and informal care as well as their work capacity was assessed at scheduled study visits using a modified questionnaire (HRPQ) designed to evaluate the economic impact of MS. The questionnaire addresses the following content area: participant reported data regarding employment status, work productivity, impact on household chores due to MS. Number of participants who reported "Yes" as an answer to questions related to impact on work: "forced me to work part-time when I wanted to work full-time; kept me from having a job when I wanted to work full-time; kept me from having a job when I wanted to work part-time; none of the above" questions were reported in this outcome measure.

Trial Locations

Locations (131)

Investigational Site Number 1054

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Traverse City, Michigan, United States

Investigational Site Number 1086

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Cullman, Alabama, United States

Investigational Site Number 1040

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Berkeley, California, United States

Investigational Site Number 1059

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Maitland, Florida, United States

Investigational Site Number 1093

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Pasadena, California, United States

Investigational Site Number 1152

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Fullerton, California, United States

Investigational Site Number 1027

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Fort Collins, Colorado, United States

Investigational Site Number 1078

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Jacksonville, Florida, United States

Investigational Site Number 1173

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Sarasota, Florida, United States

Investigational Site Number 1034

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Sunrise, Florida, United States

Investigational Site Number 1008

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Northbrook, Illinois, United States

Investigational Site Number 1001

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Fort Wayne, Indiana, United States

Investigational Site Number 1024

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Indianapolis, Indiana, United States

Investigational Site Number 1017

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Des Moines, Iowa, United States

Investigational Site Number 1022

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Kansas City, Kansas, United States

Investigational Site Number 1039

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Lexington, Kentucky, United States

Investigational Site Number 1028

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Worcester, Massachusetts, United States

Investigational Site Number 1061

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Wellesley, Massachusetts, United States

Investigational Site Number 1092

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Saint Louis, Missouri, United States

Investigational Site Number 1073

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Teaneck, New Jersey, United States

Investigational Site Number 1014

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Albuquerque, New Mexico, United States

Investigational Site Number 1081

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Mineola, New York, United States

Investigational Site Number 1026

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New York, New York, United States

Investigational Site Number 1160

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Patchogue, New York, United States

Investigational Site Number 1035

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Cleveland, Ohio, United States

Investigational Site Number 1015

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Rochester, New York, United States

Investigational Site Number 1053

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Syracuse, New York, United States

Investigational Site Number 1058

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Uniontown, Ohio, United States

Investigational Site Number 1097

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Allentown, Pennsylvania, United States

Investigational Site Number 1057

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Providence, Rhode Island, United States

Investigational Site Number 1002

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Round Rock, Texas, United States

Investigational Site Number 1018

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Houston, Texas, United States

Investigational Site Number 1037

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Vienna, Virginia, United States

Investigational Site Number 1068

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Seattle, Washington, United States

Investigational Site Number 03208

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Caba, Argentina

Investigational Site Number 2012

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Kogarah, Australia

Investigational Site Number 2003

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Melbourne, Australia

Investigational Site Number 2001

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Heidelberg, Australia

Investigational Site Number 2011

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Hobart, Australia

Investigational Site Number 2002

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Parkville, Australia

Investigational Site Number 2009

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Sydney, Australia

Investigational Site Number 2006

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Westmead, Australia

Investigational Site Number 5004

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Esneux, Belgium

Investigational Site Number 3006

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Porto Alegre, Brazil

Investigational Site Number 1102

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Calgary, Canada

Investigational Site Number 1105

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Gatineau, Canada

Investigational Site Number 3001

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São Paulo, Brazil

Investigational Site Number 3003

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São Paulo, Brazil

Investigational Site Number 1104

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Greenfield Park, Canada

Investigational Site Number 1110

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London, Canada

Investigational Site Number 1109

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Kingston, Canada

Investigational Site Number 1106

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Vancouver, Canada

Investigational Site Number 1101

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Ottawa, Canada

Investigational Site Number 4804

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Hradec Kralove, Czechia

Investigational Site Number 4801

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Praha 2, Czechia

Investigational Site Number 4803

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Brno, Czechia

Investigational Site Number 5302

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Aarhus N, Denmark

Investigational Site Number 4802

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Teplice, Czechia

Investigational Site Number 4634

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Frankfurt am Main, Germany

Investigational Site Number 4602

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Berlin, Germany

Investigational Site Number 4607

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Dresden, Germany

Investigational Site Number 4622

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Hamburg, Germany

Investigational Site Number 4609

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Hennigsdorf, Germany

Investigational Site Number 4605

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Hannover, Germany

Investigational Site Number 4608

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München, Germany

Investigational Site Number 4610

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Rostock, Germany

Investigational Site Number 4304

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Sevilla, Spain

Investigational Site Number 4613

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Wermsdorf, Germany

Investigational Site Number 5505

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Tel Aviv, Israel

Investigational Site Number 4102

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Gallarate (VA), Italy

Investigational Site Number 4106

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Orbassano (TO), Italy

Investigational Site Number 4110

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Roma, Italy

Investigational Site Number 4202

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Sittard-Geleen, Netherlands

Investigational Site Number 3102

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Mexico, Mexico

Investigational Site Number 4902

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Krakow, Poland

Investigational Site Number 4901

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Lodz, Poland

Investigational Site Number 4903

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Lublin, Poland

Investigational Site Number 4904

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Poznan, Poland

Investigational Site Number 4905

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Warszawa, Poland

Investigational Site Number 6009

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Kazan, Russian Federation

Investigational Site Number 6005

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Moscow, Russian Federation

Investigational Site Number 6003

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Moscow, Russian Federation

Investigational Site Number 6002

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Saint-Petersburg, Russian Federation

Investigational Site Number 6010

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Pyatigorsk, Russian Federation

Investigational Site Number 4301

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Barcelona, Spain

Investigational Site Number 6004

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Saint-Petersburg, Russian Federation

Investigational Site Number 6016

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Ufa, Russian Federation

Investigational Site Number 4305

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Málaga, Spain

Investigational Site Number 4303

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Madrid, Spain

Investigational Site Number 4701

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Göteborg, Sweden

Investigational Site Number 4702

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Umeå, Sweden

Investigational Site Number 6102

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Kharkov, Ukraine

Investigational Site Number 6103

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Lviv, Ukraine

Investigational Site Number 6104

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Kiev, Ukraine

Investigational Site Number 4004

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Bristol, United Kingdom

Investigational Site Number 4001

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Cambridge, United Kingdom

Investigational Site Number 4005

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Cardiff, United Kingdom

Investigational Site Number 4006

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London, United Kingdom

Investigational Site Number 4008

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Salford, United Kingdom

Investigational Site Number 4007

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Sheffield, United Kingdom

Investigational Site Number 1083

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Lenexa, Kansas, United States

Investigational Site Number 1009

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Knoxville, Tennessee, United States

Investigational Site Number 6008

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Saint-Petersburg, Russian Federation

Investigational Site Number 5005

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Bruxelles, Belgium

Investigational Site Number 1163

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Cordova, Tennessee, United States

Investigational Site Number 5001

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Leuven, Belgium

Investigational Site Number 5501

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Ramat Gan, Israel

Investigational Site Number 3105

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Chihuahua, Mexico

Investigational Site Number 1090

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Tucson, Arizona, United States

Investigational Site Number 1055

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Franklin, Tennessee, United States

Investigational Site Number 6006

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Nizhny Novgorod, Russian Federation

Investigational Site Number 6013

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Samara, Russian Federation

Investigational Site Number 6001

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Moscow, Russian Federation

Investigational Site Number 2005

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Southport, Australia

Investigational Site Number 2013

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Auchenflower, Australia

Investigational Site Number 5301

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København Ø., Denmark

Investigational Site Number 4112

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Cagliari, Italy

Investigational Site Number 1020

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Detroit, Michigan, United States

Investigational Site Number 1031

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Phoenix, Arizona, United States

Investigational Site Number 1171

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Phoenix, Arizona, United States

Investigational Site Number 1067

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Oklahoma City, Oklahoma, United States

Investigational Site Number 1042

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Nashville, Tennessee, United States

Investigational Site Number 1046

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San Antonio, Texas, United States

Investigational Site Number 3002

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Recife, Brazil

Investigational Site Number 1049

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Tampa, Florida, United States

Investigational Site Number 1005

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Tampa, Florida, United States

Investigational Site Number 1021

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Louisville, Kentucky, United States

Investigational Site Number 1025

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Ann Arbor, Michigan, United States

Investigational Site Number 1095

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Chapel Hill, North Carolina, United States

Investigational Site Number 1084

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Kansas City, Missouri, United States

Investigational Site Number 1082

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Winston-Salem, North Carolina, United States

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