Study of Dupilumab for the Treatment of Patients With Prurigo Nodularis, Inadequately Controlled on Topical Prescription Therapies or When Those Therapies Are Not Advisable (LIBERTY-PN PRIME)

Phase 3

Completed

Conditions: Neurodermatitis

Interventions: Drug: Dupilumab SAR231893
Drug: Placebo
Drug: Moisturizers
Drug: Low to medium potent topical corticosteroids
Drug: Topical calcineurin inhibitors

Registration Number: NCT04183335

Lead Sponsor: Sanofi

Brief Summary: Primary Objective:

To demonstrate the efficacy of dupilumab on itch response in participants with prurigo nodularis (PN), inadequately controlled on topical prescription therapies or when those therapies are not advisable.

Secondary Objectives:

To demonstrate the efficacy of dupilumab on additional itch endpoints in participants with PN, inadequately controlled on topical prescription therapies or when those therapies are not advisable.

To demonstrate efficacy of dupilumab on skin lesions of PN. To demonstrate the improvement in health-related quality of life. To evaluate safety outcome measures. To evaluate immunogenicity of dupilumab.

Detailed Description: The duration of study for each participant included 2-4 weeks of screening period, 24 weeks of treatment period and 12 weeks of post treatment period.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 151

Inclusion Criteria

Must be 18 to 80 years of age, at the time of signing the informed consent.

With a clinical diagnosis of PN defined by all of the following:

Diagnosed by a dermatologist for at least 3 months before the screening visit.
On the worst-Itch Numeric Rating Scale (WI-NRS) ranged from 0 to 10, participants who had an average worst itch score of greater than or equal to (>=) 7 in the 7 days prior to Day 1.
Participants who had a minimum of 20 PN lesions in total on both legs, and/or both arms and/or trunk, at screening visit and Day 1.
History of failing a 2-week course of medium-to-superpotent TCS or when TCS were not medically advisable.
Had applied a stable dose of topical emollient (moisturizer) once or twice daily for at least 5 out of the 7 consecutive days immediately before Day 1.
Was willing and abled to complete a daily symptom electronic-diary for the duration of the study.

Exclusion Criteria

Participants were excluded from the study if any of the following criteria apply:

Presence of skin morbidities other than PN and mild atopic dermatitis (AD) that interfered with the assessment of the study outcomes.
PN secondary to medications.
PN secondary to medical conditions such as neuropathy or psychiatric disease.
Within 6 months before the screening visit, or documented diagnosis of moderate to severe AD from screening visit to randomization visit.
Severe concomitant illness(es) under poor control that, in the investigator's judgment, would adversely affect the participant's participation in the study.
Severe renal conditions (eg, participants with uremia and/or on dialysis).
Participants with uncontrolled thyroid disease.
Active tuberculosis or non-tuberculous mycobacterial infection, or a history of incompletely treated tuberculosis unless documented adequately treated.
Diagnosed active endoparasitic infections; suspected or high risk of endoparasitic infection, unless clinical and (if necessary) laboratory assessment had ruled out active infection before randomization.
Active chronic or acute infection (except human immunodeficiency virus infection) required treatment with systemic antibiotics, antivirals, antiprotozoals, or antifungals within 2 weeks before the screening visit or during the screening period.
Known or suspected immunodeficiency.
Active malignancy or history of malignancy within 5 years before the baseline visit, except completely treated in situ carcinoma of the cervix, completely treated and resolved non-metastatic squamous or basal cell carcinoma of the skin.

The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Dupilumab	Dupilumab SAR231893	Participants received dupilumab at a loading dose of 600 milligrams (mg), subcutaneously (SC) on Day 1 followed by dupilumab 300 mg once every 2 weeks (q2w) for 24 weeks added to background therapy of topical corticosteroids/topical calcineurin inhibitors (TCS/TCI) at stable dose.
Dupilumab	Moisturizers	Participants received dupilumab at a loading dose of 600 milligrams (mg), subcutaneously (SC) on Day 1 followed by dupilumab 300 mg once every 2 weeks (q2w) for 24 weeks added to background therapy of topical corticosteroids/topical calcineurin inhibitors (TCS/TCI) at stable dose.
Placebo	Moisturizers	Participants received placebo matched to dupilumab 600 mg (loading dose), SC on Day 1 followed by placebo matched to dupilumab 300 mg q2w for 24 weeks added to background therapy of TCS/TCI at stable dose.
Placebo	Low to medium potent topical corticosteroids	Participants received placebo matched to dupilumab 600 mg (loading dose), SC on Day 1 followed by placebo matched to dupilumab 300 mg q2w for 24 weeks added to background therapy of TCS/TCI at stable dose.
Dupilumab	Low to medium potent topical corticosteroids	Participants received dupilumab at a loading dose of 600 milligrams (mg), subcutaneously (SC) on Day 1 followed by dupilumab 300 mg once every 2 weeks (q2w) for 24 weeks added to background therapy of topical corticosteroids/topical calcineurin inhibitors (TCS/TCI) at stable dose.
Dupilumab	Topical calcineurin inhibitors	Participants received dupilumab at a loading dose of 600 milligrams (mg), subcutaneously (SC) on Day 1 followed by dupilumab 300 mg once every 2 weeks (q2w) for 24 weeks added to background therapy of topical corticosteroids/topical calcineurin inhibitors (TCS/TCI) at stable dose.
Placebo	Placebo	Participants received placebo matched to dupilumab 600 mg (loading dose), SC on Day 1 followed by placebo matched to dupilumab 300 mg q2w for 24 weeks added to background therapy of TCS/TCI at stable dose.
Placebo	Topical calcineurin inhibitors	Participants received placebo matched to dupilumab 600 mg (loading dose), SC on Day 1 followed by placebo matched to dupilumab 300 mg q2w for 24 weeks added to background therapy of TCS/TCI at stable dose.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With Improvement (Reduction) in Worst Itch Numeric Rating Scale (WI-NRS) Scores by Greater Than or Equal to (>=) 4 Points From Baseline to Week 24	Baseline, Week 24	WI-NRS is a validated measure of itch severity. Participants were asked daily to rate the intensity of their worst pruritus (itch) over the past 24 hours, using a 11-point scale ranging from 0 (no itch) to 10 (worst imaginable itch). Higher scores indicated more severity. Percentage of participants with improvement (reduction) in WI-NRS scores by \>=4 points from Baseline to Week 24 is reported in this outcome measure.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants With Both an Improvement (Reduction) in WI-NRS Scores by >=4 Points and an IGA PN-S Scores of 0 or 1 From Baseline at Week 24	Baseline, Week 24	WI-NRS is a validated measure of itch severity. Participants were asked daily to rate the intensity of their worst pruritus (itch) over the past 24 hours, using a 11-point scale ranging from 0 (no itch) to 10 (worst imaginable itch), higher scores indicated more severity. IGA PN-S assess the overall number and thickness of PN lesions at a given time point, as determined by the investigator. It consists of a 5-point scale ranging from 0 to 4 where 0 = clear, 1 = almost clear, 2 = mild, 3 = moderate and 4 = severe. Higher scores indicated greater severity. Percentage of participants with both an improvement (reduction) in WI-NRS scores by \>=4 points (from Baseline) and an IGA PN-S scores of 0 or 1 were reported in this outcome measure.
Change From Baseline in Skin Pain-NRS at Week 24	Baseline, Week 24	Skin Pain-NRS was used to measure skin pain intensity. Participants were asked daily to rate the intensity of their worst skin pain over the past 24 hours, using a 11-point scale ranging from 0 ("No pain") to 10 ("Worst possible pain"). Higher scores indicated more severity. LS means and SE were obtained from ANCOVA model.
Percent Change From Baseline in WI-NRS Scores at Week 24	Baseline, Week 24	WI-NRS is a validated measure of itch severity. Participants were asked daily to rate the intensity of their worst pruritus (itch) over the past 24 hours, using a 11-point scale ranging from 0 (no itch) to 10 (worst imaginable itch). Higher scores indicated more severity. Least squares (LS) mean and standard error (SE) were obtained from Analysis of covariance (ANCOVA) model.
Percentage of Participants With Investigator's Global Assessment For Prurigo Nodularis-Stage (IGA PN-S) Scores of 0 or 1 at Week 24	At Week 24	IGA PN-S is an instrument used to assess the overall number and thickness of PN lesions at a given time point, as determined by the investigator. It consists of a 5-point scale ranging from 0 to 4 where 0 = clear, 1 = almost clear, 2 = mild, 3 = moderate and 4 = severe. Higher scores indicate severe prurigo nodularis (PN). In this outcome measure, percentage of participants with IGA PN-S score of either 0 (clear) or 1 (almost clear) has been reported.
Change From Baseline in Health-Related Quality of Life (HRQoL) as Measured by Dermatology Life Quality Index (DLQI) at Week 24	Baseline, Week 24	DLQI is developed to measure dermatology specific HRQoL in adult participants. It comprises of set of 10 questions assessing the impact of skin disease on participants' HRQoL over the previous week. Responses to each question were assessed on a 4-point Likert scale ranged from 0 (not at all) to 3 (very much). Scores from all 10 questions added up to give total DLQI scores ranged from 0 (not at all) to 30 (very much), higher scores indicated more impact on quality of life. LS means and SE were obtained from ANCOVA model.
Change From Baseline in Hospital Anxiety and Depression Scale (HADS) Total Score at Week 24	Baseline, Week 24	HADS is a 14-item self-administered questionnaire that consists of 2 scales, one measuring anxiety (HADS-A), and the other measuring depression (HADS-D). Each subscale comprised of 7 items with a scoring range from 0 (less severity of anxiety and depression) to 21 (greater severity of anxiety and depression symptoms) for each subscale. The total HADS score ranges from 0 (less severity) to 42 (more severity), with a high score indicative of severe anxiety and/or depression level. LS means and SE were obtained from ANCOVA model.
Probability of Participants With an Improvement (Reduction) in WI-NRS Scores by >=4 Points From Baseline at Week 24	Baseline, Week 24	WI-NRS is a validated measure of itch severity. Participants were asked daily to rate the intensity of their worst pruritus (itch) over the past 24 hours, using a 11-point scale ranging from 0 (no itch) to 10 (worst imaginable itch). Higher scores indicated more severity. Probability of participants with an improvement (reduction) in WI-NRS at Week 24 was based on Kaplan-Meier estimates and was reported in this outcome measure.
Change From Baseline in WI-NRS Scores at Week 12 and 24	Baseline, Weeks 12 and 24	WI-NRS is a validated measure of itch severity. Participants were asked daily to rate the intensity of their worst pruritus (itch) over the past 24 hours, using a 11-point scale ranging from 0 (no itch) to 10 (worst imaginable itch). Higher scores indicated more severity. LS means and SE were obtained from ANCOVA model.
Percent Change From Baseline in WI-NRS Scores at Weeks 2, 4 and 12	Baseline, Weeks 2, 4 and 12	WI-NRS is a validated measure of itch severity. Participants were asked daily to rate the intensity of their worst pruritus (itch) over the past 24 hours, using a 11-point scale ranging from 0 (no itch) to 10 (worst imaginable itch). Higher scores indicated more severity. LS means and SE were obtained from ANCOVA model.
Percent Change From Baseline in WI-NRS Scores at Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24	Baseline, Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24	WI-NRS is a validated measure of itch severity. Participants were asked daily to rate the intensity of their worst pruritus (itch) over the past 24 hours, using a 11-point scale ranging from 0 (no itch) to 10 (worst imaginable itch). Higher scores indicated more severity. LS means and SE were obtained from ANCOVA model.
Percentage of Participants With Improvement (Reduction) in WI-NRS Scores by >=4 Points From Baseline at Week 12	Baseline, Week 12	WI-NRS is a validated measure of itch severity. Participants were asked daily to rate the intensity of their worst pruritus (itch) over the past 24 hours, using a 11-point scale ranging from 0 (no itch) to 10 (worst imaginable itch). Higher scores indicated more severity. Percentage of participants with improvement (reduction) in WI-NRS score by \>=4 points from Baseline to Week 12 is reported in this outcome measure.
Percentage of Participants With Improvement (Reduction) in WI-NRS Scores by >=4 Points From Baseline at Week 4	Baseline, Week 4	WI-NRS is a validated measure of itch severity. Participants were asked daily to rate the intensity of their worst pruritus (itch) over the past 24 hours, using a 11-point scale ranging from 0 (no itch) to 10 (worst imaginable itch). Higher scores indicated more severity. Percentage of participants with improvement (reduction) in WI-NRS scores by \>=4 Points at Week 4 is reported in this outcome measure.
Percentage of Participants With Investigator's Global Assessment for PN-Stage (IGA PN-S) 0 or 1 Score at Weeks 4, 8, and 12	At Weeks 4, 8 and 12	IGA PN-S is an instrument used to assess the overall number and thickness of PN lesions at a given time point, as determined by the investigator. It consists of a 5-point scale ranging from 0 to 4: where 0 = clear, 1 = almost clear, 2 = mild, 3 = moderate and 4 = severe. Higher scores indicate severe PN. In this outcome measure, percentage of participants with IGA PN-S score of either 0 (clear) or 1 (almost clear) has been reported.
Percentage of Participants Achieving >=4 Points Improvement (Reduction) From Baseline in WI-NRS Scores at Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 and 24	Baseline, Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 and 24	WI-NRS is a validated measure of itch severity. Participants were asked daily to rate the intensity of their worst pruritus (itch) over the past 24 hours, using a 11-point scale ranging from 0 (no itch) to 10 (worst imaginable itch). Higher scores indicated more severity. Percentage of participants achieving \>=4 points improvement (reduction) from Baseline in WI-NRS scores at Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 and 24 is reported in this outcome measure.
Percentage of Participants With Investigator's Global Assessment for PN-Activity (IGA PN-A) 0 or 1 Score at Weeks 4, 8, 12 and 24	At Weeks 4, 8, 12 and 24	The IGA PN-A is an instrument used to assess the overall activity of PN lesions at a given time point, as determined by the investigator. It consists of a 5-point scale ranging from 0 to 4: where 0 = clear (0% nodules showing excoriations/crusts), 1 = almost clear (up to 10% nodules showing excoriations/crusts), 2 = mild (11-25% nodules showing excoriations/crusts), 3 = moderate (26-75% nodules showing excoriations/crusts) and 4 = severe (76-100% of nodules showing excoriations/crusts). Higher scores indicate severe PN. In this outcome measure, percentage of participants with IGA PN-A score of either 0 (clear) or 1 (almost clear) has been reported.
Number of Participants With Treatment-emergent and Treatment Boosted Antidrug Antibodies (ADA)	From the first IMP administration to the last IMP administration + 14 weeks (i.e., up to 36 weeks)	ADA response was categorized as: Treatment emergent and Treatment-boosted. Treatment emergent ADAs were defined as a participant with no positive assay response at Baseline but with a positive assay response during the entire TEAE period. Treatment boosted ADAs: defined as participants with a positive ADA assay response at Baseline and with at least a 4-fold increase in titer compared to Baseline during the TE period (time from the first IMP administration to the last IMP administration + 14 weeks). Titer values were defined as low titer (\< 1,000); moderate (1,000 \<= titer \<=10,000) and high titer (\> 10,000).
Onset of Action Based on Change From Baseline in WI-NRS Scores at Week 3	Baseline, Week 3	Onset of action was defined as the first p\<0.05 difference from placebo in the weekly average WI-NRS that remained significant at subsequent measurements. WI-NRS is a validated measure of itch severity. Participants were asked daily to rate the intensity of their worst pruritus (itch) over the past 24 hours, using a 11-point scale ranging from 0 (no itch) to 10 (worst imaginable itch). Higher scores indicated greater severity. LS means and SE were obtained from ANCOVA model.
Change From Baseline in IGA PN-S Scores at Weeks 4, 8, 12, and 24	Baseline, Weeks 4, 8, 12, and 24	IGA PN-S is an instrument used to assess the overall number and thickness of PN lesions at a given time point, as determined by the investigator. It consists of a 5-point scale ranging from 0 to 4: where 0 = clear, 1 = almost clear, 2 = mild, 3 = moderate and 4 = severe. Higher scores indicate severe PN. LS means and SE were obtained from ANCOVA model.
Change From Baseline in HRQoL as Measured by DLQI at Week 12	Baseline, Week 12	DLQI is developed to measure dermatology specific HRQoL in adult participants. It comprises of set of 10 questions assessing the impact of skin disease on participants' HRQoL over the previous week. Responses to each question were assessed on a 4-point Likert scale ranged from 0 (not at all) to 3 (very much). Scores from all 10 questions added up to give total DLQI scores ranged from 0 (not at all) to 30 (very much), higher scores indicated more impact on quality of life. LS means and SE were obtained from ANCOVA model.
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)	From the first IMP administration to the last IMP administration + 14 weeks (i.e., up to 36 weeks)	An Adverse Event (AE) was defined as any untoward medical occurrence in a participant who received study drug and did not necessarily have to have a causal relationship with the treatment. Serious adverse events (SAEs) was defined as 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. TEAEs were defined as AEs that developed, worsened or became serious during the treatment-emergent (TE) period (from the first investigational medicinal product \[IMP\] administration to the last IMP administration + 14 weeks).

Trial Locations

Locations (63): Investigational Site Number :8400001
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Dublin, Ohio, United States
Investigational Site Number :8400025
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Houston, Texas, United States
Investigational Site Number :8400011
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Gilbert, Arizona, United States
Investigational Site Number :8400022
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Fort Smith, Arkansas, United States
Investigational Site Number :0320009
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Mendoza, Argentina
Investigational Site Number :4100001
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Incheon, Korea, Republic of
Investigational Site Number :3920007
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Nagasaki-shi, Nagasaki, Japan
Investigational Site Number :4100004
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Seoul, Seoul-teukbyeolsi, Korea, Republic of
Investigational Site Number :8400014
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Miami, Florida, United States
Investigational Site Number :6430007
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Krasnodar, Russian Federation
Investigational Site Number :0320007
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Caba, Ciudad De Buenos Aires, Argentina
Investigational Site Number :4100002
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Seoul, Seoul-teukbyeolsi, Korea, Republic of
Investigational Site Number :4100003
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Seoul, Seoul-teukbyeolsi, Korea, Republic of
Investigational Site Number :2500005
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Reims, France
Investigational Site Number :4100005
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Incheon, Incheon-gwangyeoksi, Korea, Republic of
Investigational Site Number :4840001
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Monterrey, Nuevo León, Mexico
Investigational Site Number :8400003
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Newnan, Georgia, United States
Investigational Site Number :0320008
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Caba, Buenos Aires, Argentina
Investigational Site Number :0320004
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Caba, Ciudad De Buenos Aires, Argentina
Investigational Site Number :0320001
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Buenos Aires, Argentina
Investigational Site Number :3920003
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Tokorozawa-shi, Saitama, Japan
Investigational Site Number :1560004
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Beijing, China
Investigational Site Number :0320005
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Caba, Buenos Aires, Argentina
Investigational Site Number :8400010
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Philadelphia, Pennsylvania, United States
Investigational Site Number :8400018
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Clarkston, Michigan, United States
Investigational Site Number :0320002
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Caba, Buenos Aires, Argentina
Investigational Site Number :0320006
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Caba, Argentina
Investigational Site Number :3920010
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Izumo-shi, Shimane, Japan
Investigational Site Number :1560001
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Chengdu, China
Investigational Site Number :1560002
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Hangzhou, China
Investigational Site Number :1560003
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Wuxi, China
Investigational Site Number :3920006
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Itabashi-ku, Tokyo, Japan
Investigational Site Number :3920004
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Bunkyo-ku, Tokyo, Japan
Investigational Site Number :3920009
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Yokohama-shi, Kanagawa, Japan
Investigational Site Number :6430006
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Moscow, Russian Federation
Investigational Site Number :6430010
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Moscow, Russian Federation
Investigational Site Number :8400004
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Columbus, Georgia, United States
Investigational Site Number :8400007
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Tulsa, Oklahoma, United States
Investigational Site Number :8400009
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Athens, Ohio, United States
Investigational Site Number :8400006
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Bellaire, Texas, United States
Investigational Site Number :8400005
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Norfolk, Virginia, United States
Investigational Site Number :3920001
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Shinagawa-Ku, Tokyo, Japan
Investigational Site Number :8400026
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Sacramento, California, United States
Investigational Site Number :8400016
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Indianapolis, Indiana, United States
Investigational Site Number :8400013
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Saint Louis, Missouri, United States
Investigational Site Number :8400017
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Sandy Springs, Georgia, United States
Investigational Site Number :8400024
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East Windsor, New Jersey, United States
Investigational Site Number :8400002
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Pflugerville, Texas, United States
Investigational Site Number :8400015
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Charleston, South Carolina, United States
Investigational Site Number :8400019
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San Antonio, Texas, United States
Investigational Site Number :0320003
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San Miguel de Tucuman, Tucumán, Argentina
Investigational Site Number :3920005
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Kyoto-shi, Kyoto, Japan
Investigational Site Number :4100007
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Seongnam-si, Gyeonggi-do, Korea, Republic of
Investigational Site Number :3920002
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Nagoya-shi, Japan
Investigational Site Number :4840002
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Guadalajara, Jalisco, Mexico
Investigational Site Number :4840005
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Monterrey, Nuevo León, Mexico
Investigational Site Number :4840006
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Guadalajara, Mexico
Investigational Site Number :4840003
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Veracruz, Mexico
Investigational Site Number :6430008
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Chelyabinsk, Russian Federation
Investigational Site Number :6430005
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Moscow, Russian Federation
Investigational Site Number :6430009
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Saratov, Russian Federation
Investigational Site Number :6430002
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St-Petersburg, Russian Federation
Investigational Site Number :6430001
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Stavropol, Russian Federation