A Study Comparing ATB200/AT2221 With Alglucosidase Alfa/Placebo in Adult Subjects With Late-onset Pompe Disease

Phase 3

Completed

Conditions: Pompe Disease (Late-onset)

Interventions: Biological: Cipaglucosidase Alfa
Biological: Alglucosidase Alfa
Drug: Miglustat
Drug: Placebo

Registration Number: NCT03729362

Lead Sponsor: Amicus Therapeutics

Brief Summary: This is a phase 3 double-blind randomized study to study the efficacy and safety of intravenous ATB200 Co-administered with oral AT2221 in adult subjects with Late Onset Pompe Disease compared with Alglucosidase Alfa/placebo.

Detailed Description: This is a double-blind, randomized, multicenter, international study of ATB200/AT2221 in adult subjects with late-onset Pompe disease (LOPD) who have received enzyme replacement therapy with alglucosidase alfa (ie, ERT-experienced) or who have never received ERT (ie, ERT naïve) compared with alglucosidase alfa/placebo.

The study will consist of a screening period up to 30 days, a 12-month treatment period, and a 30 day safety follow-up period. Subjects who complete this study will have the option to participate in an open label extension study to receive ATB200/AT2221 under a separate protocol.

Enzyme replacement therapy-experienced subjects will continue to take alglucosidase alfa during the screening period; treatment with alglucosidase alfa will then be replaced by study drug (ATB200/AT2221 or alglucosidase alfa/placebo) on the same schedule without interruption (ie, every 2 weeks).

Infusion visits will be scheduled every 2 weeks throughout the study; assessments (eg, clinical laboratory tests) for initial safety monitoring will be performed at these visits for the first 6 weeks of the study. Study visits that include efficacy, safety, and other assessments will be scheduled approximately every 3 months and may occur over 2 days, provided all study assessments and procedures (with the exception of pharmacokinetic \[PK\] sample collection) are performed before administration of study drug.

Efficacy assessments (ie, functional assessments) include evaluation of ambulatory function (6MWT), motor function tests (Gait, Stair, Gowers' maneuver, and Chair \[GSGC\] test and Timed Up and Go \[TUG\] test), muscle strength (manual muscle testing and quantitative muscle testing), and pulmonary function tests (forced vital capacity \[FVC\], slow vital capacity \[SVC\], maximal inspiratory pressure \[MIP\], maximal expiratory pressure \[MEP\], and sniff nasal inspiratory pressure \[SNIP\]). Patient reported outcomes (Rasch-built Pompe-specific Activity \[R PAct\] Scale, EuroQol 5 Dimensions 5 Levels Instrument \[EQ-5D-5L\], Patient-Reported Outcomes Measurement Information System \[PROMIS®\] instruments for physical function, fatigue, dyspnea, and upper extremity, and Subject's Global Impression of Change). The Physician's Global Impression of Change will also be performed.

Pharmacodynamic assessments include measurement of biomarkers of muscle injury (creatine kinase \[CK\]) and disease substrate (urinary hexose tetrasaccharide \[Hex4\]). Blood samples will be collected for determination of total GAA protein levels and AT2221 concentrations in plasma for a population PK analysis. Safety assessments include monitoring of adverse events (AEs), including infusion associated reactions (IARs), clinical laboratory tests (chemistry, hematology, and urinalysis), vital signs, physical examinations including weight, electrocardiograms (ECGs), and immunogenicity. Concomitant medications and nondrug therapies will also be recorded.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 125

Inclusion Criteria

Subject must provide signed informed consent prior to any study-related procedures being performed.
Male and female subjects are ≥ 18 years old and weigh ≥ 40 kg at screening.
Female subjects of childbearing potential and male subjects must agree to use medically accepted methods of contraception during the study and for 90 days after the last dose of study drug.
Subject must have a diagnosis of LOPD based on documentation of one of the following:
1. deficiency of GAA enzyme
2. GAA genotyping
Subject is classified as one of the following with respect to ERT status:
1. ERT-experienced, defined as currently receiving standard of care ERT (alglucosidase alfa) at the recommended dose and regimen (ie, 20 mg/kg dose every 2 weeks) for ≥ 24 months
2. ERT-naïve, defined as never having received investigational or commercially available ERT
Subject has a sitting FVC ≥ 30% of the predicted value for healthy adults (National Health and Nutrition Examination Survey III) at screening.
Subject performs two 6MWTs at screening that are valid, as determined by the clinical evaluator, and that meet all of the following criteria:
1. both screening values of 6MWD are ≥ 75 meters
2. both screening values of 6MWD are ≤ 90% of the predicted value for healthy adults
3. the lower value of 6MWD is within 20% of the higher value of 6MWD

Exclusion Criteria

Subject has received any investigational therapy or pharmacological treatment for Pompe disease, other than alglucosidase alfa, within 30 days or 5 half-lives of the therapy or treatment, whichever is longer, before Day 1 or is anticipated to do so during the study.
Subject has received gene therapy for Pompe disease
Subject is taking any of the following prohibited medications within 30 days before Day 1:
- miglitol (eg, Glyset)
- miglustat (eg, Zavesca)
- acarbose (eg, Precose or Glucobay)
- voglibose (eg, Volix, Vocarb, or Volibo)
Note: None of these medications have a half-life that, when multiplied by 5, is longer than 30 days.
Subject requires the use of invasive or noninvasive ventilation support for > 6 hours per day while awake.
Subject has a hypersensitivity to any of the excipients in ATB200, alglucosidase alfa, or AT2221.
Subject has a medical condition or any other extenuating circumstance that may, in the opinion of the investigator or medical monitor, pose an undue safety risk to the subject or may compromise his/her ability to comply with or adversely impact protocol requirements. This includes clinical depression (as diagnosed by a psychiatrist or other mental health professional) with uncontrolled or poorly controlled symptoms.
Subject, if female, is pregnant or breastfeeding at screening.
Subject, whether male or female, is planning to conceive a child during the study.
Subject does not have documentation of diagnosis of Pompe disease and refuses to undergo genetic testing.

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cipaglucosidase Alfa/Miglustat	Cipaglucosidase Alfa	Participants received cipaglucosidase alfa co-administered with miglustat every 2 weeks (Q2W).
Cipaglucosidase Alfa/Miglustat	Miglustat	Participants received cipaglucosidase alfa co-administered with miglustat every 2 weeks (Q2W).
Alglucosidase Alfa/Placebo	Alglucosidase Alfa	Participants received alglucosidase alfa co-administered with placebo Q2W.
Alglucosidase Alfa/Placebo	Placebo	Participants received alglucosidase alfa co-administered with placebo Q2W.

Primary Outcome Measures

Name	Time	Method
Change From Baseline to Week 52 in 6 Minute Walk Distance (6MWD)	Baseline, Week 52	The efficacy of cipaglucosidase alfa/miglustat co-administration on ambulatory function was measured by the 6MWT. The 6MWD, measured in meters, is the distance walked on the 6MWT. A greater distance indicated greater endurance. An increase from baseline indicated improvement.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline to Week 52 in the Total Score for the PROMIS® - Fatigue	Baseline, Week 52	Fatigue Short Form 8a consisted of 6 questions, each scored on a scale from 1 to 5 as follows: 1 = not at all; 2 = a little bit; 3 = somewhat; 4 = quite a bit; 5 = very much; and 2 questions, each scored on a scale from 1 to 5 as follows: 1 = never; 2 = rarely; 3 = sometimes; 4 = often; 5 = always. The total score was calculated by summing up scores (1 to 5) across all items. A lower score represented lower fatigue symptoms.
Change From Baseline to Week 52 in the Total Score for the Gait, Stairs, Gowers' Maneuver, and Chair (GSGC)	Baseline, Week 52	The GSGC consisted of a 10-meter walk for evaluation of gait, a 4-stair climb, Gowers' maneuver, and arising from a chair. Results of the GSGC included the time required to complete the individual tests, individual scores for each of the tests (1 to 7 points for each of gait, 4-stair climb, and Gowers' maneuver, and 1 to 6 points for arising from a chair), and a total score. GSGC total score was the sum of the component scores from the 4 functional tests. The total score ranged from a minimum of 4 points (normal performance) to a maximum of 27 points (worst performance).
Change From Baseline to Week 52 in European Quality of Life-5 Dimensions 5 Response Levels (EQ-5D-5L) Based on the EuroQol Visual Analogue Scale (EQ VAS) Quantitative Score	Baseline, Week 52	The EuroQol Visual Analogue Scale (EQ VAS) is a vertical visual analogue scale that records the respondent's own assessment of his or her overall health status at the time of completion. Scores range from 0 (the worst health you can imagine) to 100 (the best health you can imagine). Higher EQ VAS scores represent an improved sense of overall health while lower scores represent a worsening of overall health.
Change From Baseline to Week 52 in Rasch-Built Pompe-Specific Activity (R-PAct) Total Score	Baseline, Week 52	The R-PAct scale was an 18-item questionnaire to measure limitations in activities and restriction in social participation. Possible responses to questions were as follows: unable to perform, able to perform, but with difficulty, and able to perform without difficulty. The total score was calculated by summing up the observed scores across the 18 items and it ranged from 0 to 36, with higher values representing lower level of disease impact on the muscles.
Change From Baseline to Week 52 in Maximal Expiratory Pressure (MEP) % Predicted	Baseline, Week 52	The percent predicted values of MEP were calculated as: % predicted = (actual result / predicted result) \* 100, where the predicted results were obtained using the reference equations from Uldry and Fitting (1995).
Change From Baseline to Week 52 in Sniff Nasal Inspiratory Pressure (SNIP) % Predicted	Baseline, Week 52	The percent predicted values of SNIP were calculated as: % predicted = (actual result / predicted result) \* 100, where the predicted results were obtained using the reference equations from Evans and Whitelaw (2009).
Change From Baseline to Week 52 in Maximal Inspiratory Pressure (MIP) % Predicted	Baseline, Week 52	The percent predicted values of MIP were calculated as: % predicted = (actual result / predicted result)\* 100, where the predicted results were obtained using the reference equations from Uldry and Fitting (1995).
Change From Baseline to Week 52 in Maximum Vital Capacity (Maximum VC) % Predicted	Baseline, Week 52	Maximum VC is the greater of the two VC values (FVC or SVC).
Population Pharmacokinetics (PK): Maximum Observed Concentration (Cmax) of Cipaglucosidase Alfa and Alglucosidase Alfa in ERT-Experienced Participants Using Plasma Total GAA Protein Level by Signature Peptide Assay and Plasma Miglustat Concentration	Days 1 and 364 (Week 52)	On Days 1 and 364 (Week 52), sparse blood samples were collected for PK analysis in ERT-experienced participants at 0, 1, 4, 6, 12, and 24 hours post-dose. Collection of the 12-hour sample was optional.
Population PK: Cmax of Cipaglucosidase Alfa and Alglucosidase Alfa in ERT-Naïve Participants	Days 1 and 364 (Week 52)	On Days 1 and 364 (Week 52), sparse blood samples were collected for PK analysis in ERT-naïve participants at 0, 1, 4, 6, 12, and 24 hours post-dose. Collection of the 12-hour sample was optional.
Population PK: Area Under the Concentration-Time Curve (AUC) of Cipaglucosidase Alfa and Alglucosidase Alfa in ERT-Experienced Participants Using Plasma Total GAA Protein Level by Signature Peptide Assay and Plasma Miglustat Concentration	Days 1 and 364 (Week 52)	On Days 1 and 364 (Week 52), sparse blood samples were collected for PK analysis in ERT-experienced participants at 0, 1, 4, 6, 12, and 24 hours post-dose. Collection of the 12-hour sample was optional.
Change From Baseline to Week 52 in the Quantitative Muscle Test (QMT) Values	Baseline, Week 52	QMT was measured using the hand-held dynamometer. Larger values (in kg) indicated greater muscle strength.
Change From Baseline in the Time to Complete Individual GSGC Component Tests and Timed Up and Go (TUG) Test at Week 52	Baseline, Week 52	Motor function test assessed the time to complete individual GSGC component tests (10-meter walk, 4- stair climb, Gowers' maneuver, and arise from a chair) and the TUG test. The TUG test assessed the time a subject needed to rise from a chair, walk 3 meters, turn around, walk back to the chair, and sit down.
Physician's Global Impression of Change (PGIC) Overall Status at Week 52	Week 52	Physician's Global Impression of Change is based on a single item that is scored on a 7-point rating scale ranging from 1 "very much worse" to 7 "very much improved". A tertiary response variable (improving, declining, stable) was defined as follows: "Improving", which consisted of improved, moderately improved, and very much improved; "Declining", which consisted of worse, moderately worse, and very much worse; and "Stable", which equaled to no change.
Subject's Global Impression of Change (SGIC) at Week 52	Week 52	The SGIC is designed to record the participants' impression of their functional status since starting study drug using a 7-point scale ranging from 1 "very much worse" to 7 "very much improved". A tertiary response variable (improving, declining, stable) was defined as follows: "Improving", which consisted of improved, moderately improved, and very much improved; "Declining", which consisted of worse, moderately worse, and very much worse; and "Stable", which equaled to no change.
Comparison of AUC of Cipaglucosidase Alfa in ERT- Experienced and ERT-Naïve Populations	Days 1 and 364 (Week 52)	On Days 1 and 364 (Week 52), sparse blood samples were collected for PK analysis at 0, 1, 4, 6, 12, and 24 hours post-dose. Collection of the 12-hour sample was optional.
Number of Participants Improving on Both 6MWD and % Predicted FVC at Week 52	Week 52	A composite subject-level response of the 2 relevant clinical outcomes, 6MWD and FVC (% predicted), was assessed. Prespecified thresholds were used for assessment of improvement consistent with published minimal clinically important difference values for comparable instruments in similar disease.
Number of Participants With Treatment-Emergent Anti-Drug Antibodies (ADAs)	Baseline up to Week 52	Treatment-emergent ADAs were defined as participants who had seroconverted or boosted their preexisting ADA during the study period.
Population PK: AUC of Cipaglucosidase Alfa and Alglucosidase Alfa in ERT-Naïve Subjects	Days 1 and 364 (Week 52)	On Days 1 and 364 (Week 52), sparse blood samples were collected for PK analysis in ERT-naïve participants at 0, 1, 4, 6, 12, and 24 hours post-dose. Collection of the 12-hour sample was optional.
Noncompartmental Analysis: Cmax of Plasma Total GAA Protein by Signature Peptide T09 in ERT-Naïve Subjects	Day 1	A noncompartmental analysis was performed on ERT-naïve subjects, who underwent serial PK sampling during the study. On Day 1, serial blood samples were collected for ERT-naïve participants just prior to initiation of cipaglucosidase alfa/alglucosidase alfa infusion (time 0) and at 1, 2, 3, 3.5, 4, 4.5, 6, 8, 10, and 24 hours after the start of cipaglucosidase alfa/alglucosidase alfa infusion for plasma total human acid α-glucosidase (GAA) protein signature peptide T09 and plasma miglustat determinations.
Noncompartmental Analysis: AUC From Time 0 (Predose) to the Time of Last Quantifiable Concentration of Plasma Total GAA Protein by Signature Peptide T09 in ERT-Naïve Subjects	Day 1	A noncompartmental analysis was performed on ERT-naïve subjects, who underwent serial PK sampling during the study. On Day 1, serial blood samples were collected for ERT-naïve participants just prior to initiation of cipaglucosidase alfa/alglucosidase alfa infusion (time 0) and at 1, 2, 3, 3.5, 4, 4.5, 6, 8, 10, and 24 hours after the start of cipaglucosidase alfa/alglucosidase alfa infusion for plasma total GAA protein signature peptide T09 and plasma miglustat determinations.
Comparison of Cmax of Cipaglucosidase Alfa in ERT-Experienced and ERT-Naïve Populations	Days 1 and 364 (Week 52)	On Days 1 and 364 (Week 52), sparse blood samples were collected for PK analysis at 0, 1, 4, 6, 12, and 24 hours post-dose. Collection of the 12-hour sample was optional.
Change From Baseline to Week 52 in Sitting Forced Vital Capacity (FVC; % Predicted)	Baseline, Week 52	The efficacy of cipaglucosidase alfa/miglustat co-administration on pulmonary function was measured by sitting FVC (% predicted). FVC is a standard pulmonary function test used to quantify respiratory muscle weakness.
Change From Baseline to Week 52 in the Manual Muscle Test (MMT) Score for the Lower Extremities	Baseline, Week 52	The total score for the MMT lower extremity strength included the following 8 body parts: right/left hip flexion, right/left hip abduction, right/left knee flexion and right/left knee extension. The MMT lower extremity score ranged from 0 to 40, with lower scores indicating weaker muscle strength. An increase from baseline indicated increased muscle strength.
Change From Baseline to Week 26 in 6MWD	Baseline, Week 26	The 6MWD, measured in meters, is the distance walked on the 6MWT.
Change From Baseline to Week 52 in the Total Score for the Patient- Reported Outcomes Measurement Information System (PROMIS®) - Physical Function	Baseline, Week 52	Physical Function Short Form 20a (v2.0) consisted of 20 questions. The first 14 questions were each scored on a scale from 1 to 5 as follows: 1 = unable to do; 2 = with much difficulty; 3 = with some difficulty; 4 = with a little difficulty; 5 = without any difficulty; the next 6 questions were each scored on a scale from 1 to 5 as follows: 1 = cannot do; 2 = quite a lot; 3 = somewhat; 4 = very little; 5 = not at all. The total score was calculated by summing up scores (1 to 5) across all items. Total scores range from 20 to 100. A higher score represented a better outcome.
Change From Baseline to Week 52 in Sitting Slow Vital Capacity (SVC) % Predicted	Baseline, Week 52	SVC is a standard pulmonary function test used to quantify respiratory muscle weakness.
Change From Baseline to Week 52 in % Predicted 6MWD	Baseline, Week 52	The % predicted 6MWD = (actual 6MWD / predicted 6MWD) \* 100. The predicted values were calculated using Enright And Sherrill 1998 Reference Equations.
Change From Baseline to Week 52 in Other MMT Scores	Baseline, Week 52	Each manual muscle test was evaluated on a scoring scale from 0 to 5, as follows: 0 = no muscle movement; 1 = visible muscle movement, but no movement at the joint; 2 = movement at the joint, but not against gravity; 3 = movement against gravity, but not against added resistance; 4 = movement against resistance, but less than normal; 5 = normal strength. Upper extremity score was the sum of scores for right/left shoulder abduction, right/left shoulder adduction, right/left elbow extension, and right/left elbow flexion, with the total score ranging from 0 to 40. Proximal muscle group score, the sum of scores for right/left hip flexion, right/left hip abduction, right/left shoulder abduction, and right/left shoulder adduction, with the total score ranging from 0 to 40. MMT total score was the sum of the lower and upper extremity scores and ranged from 0 to 80. Lower scores indicated lower overall muscle strength. An increase from baseline indicated improvement in muscle strength.
Change From Baseline to Week 52 in PROMIS-Dyspnea and Upper Extremities Total Scores	Baseline, Week 52	The Upper Extremities Short Form 7a consisted of 7 items each scored on a decreasing scale from 1 to 5 as follows: 1 = unable to do; 2 = with much difficulty; 3 = with some difficulty; 4 = with a little difficulty; 5 = without any difficulty. Dyspnea Severity Short Form 10a consisted of 10 items each scored on a scale from 0 to 3 as follows: 0 = no shortness of breath; 1 = mildly short of breath; 2 = moderately short of breath; 3 = severely short of breath. A total score was generated for each instrument by adding up each item. Total scores for upper extremities range from 7 to 35. Total scores for dyspnea range from 0 to 30. A higher score for upper extremities represented improvement in symptoms. A lower score for dyspnea severity represented improvement in symptoms.
Change From Baseline to Week 52 in Urinary Hexose Tetrasaccharide (Hex4) Level	Baseline, Week 52	Levels of urinary Hex4, a biomarker of disease substrate, were measured. The assay specifically targets Hex4, the glucose tetrasaccharide (Glc4), which is a biomarker of glycogen storage.
Change From Baseline to Week 52 in Serum Creatine Kinase (CK) Level	Baseline, Week 52	Change from baseline to Week 52 in serum CK level. CK levels were measured as part of the serum chemistry panel.

Trial Locations

Locations (73): The Ohio State University Wexner Medical Center
🇺🇸
Columbus, Ohio, United States
Hôpital Salengro
🇫🇷
Lille, France
Hôpital Pasteur
🇫🇷
Nice, France
Hackensack University Medical Center
🇺🇸
Hackensack, New Jersey, United States
Emory Clinic
🇺🇸
Atlanta, Georgia, United States
Royal Brisbane & Women's Hospital
🇦🇺
Herston, Queensland, Australia
Heritage Medical Research Clinic, University of Calgary
🇨🇦
Calgary, Alberta, Canada
NYU School of Medicine
🇺🇸
New York, New York, United States
Monash Medical Centre
🇦🇺
Melbourne, Victoria, Australia
Hôpital Raymond Poincaré
🇫🇷
Garches, France
Billings Clinic
🇺🇸
Billings, Montana, United States
Hôpital Neurologique Pierre Wertheimer
🇫🇷
Bron, France
Hospital Universitario Austral
🇦🇷
Buenos Aires, Argentina
Royal Adelaide Hospital
🇦🇺
Adelaide, South Australia, Australia
Szpital Uniwersytecki w Krakowie
🇵🇱
Małogoskie, Poland
Sahlgrenska University Hospital
🇸🇪
Gothenburg, Sweden
Universitätsklinikum Bonn
🇩🇪
Bonn, NRW, Germany
Kagoshima University Hospital
🇯🇵
Kagoshima, Japan
University of Pécs
🇭🇺
Pécs, Hungary
Hôpital de la Timone
🇫🇷
Marseille, France
Lysosomal and Rare Disorders Research
🇺🇸
Fairfax, Virginia, United States
Semmelweis University, Institute of Genomic Medicine and Rare Disease
🇭🇺
Budapest, Hungary
The Jikei University Hospital
🇯🇵
Tokyo, Japan
Fukuoka University Hospital
🇯🇵
Fukuoka, Japan
Westmead Hospital
🇦🇺
Westmead, Australia
UMHAT Alexandrovska
🇧🇬
Sofia, Bulgaria
Eginition Hospital
🇬🇷
Athens, Attica, Greece
University of Auckland
🇳🇿
Auckland, New Zealand
University of Szeged
🇭🇺
Szeged, Hungary
Universitätsklinikum Halle (Saale)
🇩🇪
Halle (Saale), Sachsen-Anhalt, Germany
Hokkaido University Hospital
🇯🇵
Sapporo, Hokkaido, Japan
Hospital de la Santa Creu I Sant Pau
🇪🇸
Barcelona, Spain
Erasmus MC
🇳🇱
Rotterdam, Netherlands
Centrum Medyczne
🇵🇱
Rzeszów, Poland
Pusan National University
🇰🇷
Yangsan, Gyeongsangnam-do, Korea, Republic of
Cambridge University Hospitals
🇬🇧
Cambridge, United Kingdom
National Taiwan University Hospital
🇨🇳
Taipei, Taiwan
Salford Royal NHS Foundation Trust
🇬🇧
Salford, United Kingdom
Queen Elizabeth Hospital Birmingham
🇬🇧
Birmingham, United Kingdom
Washington University School of Medicine
🇺🇸
Saint Louis, Missouri, United States
Aarhus Universitets Hospital
🇩🇰
Aarhus N, Denmark
Rigshospitalet Copenhagen Neuromuscular Center
🇩🇰
Copenhagen, Denmark
Neuromuscular Research Center
🇺🇸
Phoenix, Arizona, United States
Indiana University Health Neuroscience Center
🇺🇸
Indianapolis, Indiana, United States
University of Minnesota Clinical Research Unit
🇺🇸
Minneapolis, Minnesota, United States
Duke University Medical Center
🇺🇸
Durham, North Carolina, United States
University of Cincinnati Neurology
🇺🇸
Cincinnati, Ohio, United States
Cincinnati Children's Hospital Medical Center
🇺🇸
Cincinnati, Ohio, United States
University of Texas Health Science Center San Antonio
🇺🇸
San Antonio, Texas, United States
University of Utah, Center for Clinical and Translational Sciences
🇺🇸
Salt Lake City, Utah, United States
University of California, Irvine
🇺🇸
Irvine, California, United States
University of Pittsburgh
🇺🇸
Pittsburgh, Pennsylvania, United States
Izumi City General Hospital
🇯🇵
Osaka, Japan
University of Arkansas for Medical Sciences
🇺🇸
Little Rock, Arkansas, United States
The Feinstein Institute for Medical Research
🇺🇸
Manhasset, New York, United States
Penn State Health Milton S. Hershey Medical Center
🇺🇸
Hershey, Pennsylvania, United States
University of Pennsylvania
🇺🇸
Philadelphia, Pennsylvania, United States
UZ Leuven
🇧🇪
Leuven, Belgium
University Clinical Centre of the Republic of Srpska
🇧🇦
Banja Luka, Bosnia and Herzegovina
McMaster University Medical Centre
🇨🇦
Hamilton, Ontario, Canada
Friedrich-Baur Institut
🇩🇪
Munich, Bavaria, Germany
UOC di Neurologia e Malattie Neuromuscolari
🇮🇹
Messina, NAP, Italy
UOC Genetica Medica
🇮🇹
Napoli, NAP, Italy
Universitätsklinikum Münster
🇩🇪
Münster, NRW, Germany
Royal Free Hospital NHS
🇬🇧
London, United Kingdom
National Center of Neurology and Psychiatry
🇯🇵
Tokyo, Japan
University Medical Centre Ljubljana
🇸🇮
Ljubljana, Slovenia
Seoul National University Hospital
🇰🇷
Seoul, Korea, Republic of
University of South Florida Research Center
🇺🇸
Tampa, Florida, United States
Oregon Health & Science University
🇺🇸
Portland, Oregon, United States
UF Helath: University of Florida Clinical Research Center
🇺🇸
Gainesville, Florida, United States
University of Kansas Medical Center
🇺🇸
Kansas City, Kansas, United States
Medizinische Universität Innsbruck
🇦🇹
Innsbruck, Austria