Study of Nusinersen (BIIB058) in Participants With Spinal Muscular Atrophy
- Registration Number
- NCT04089566
- Lead Sponsor
- Biogen
- Brief Summary
The primary objectives of this study are to examine the clinical efficacy of nusinersen administered intrathecally at higher doses to participants with spinal muscular atrophy (SMA), as measured by change in Children's Hospital of Philadelphia-Infant Test of Neuromuscular Disorders (CHOP-INTEND) total score (Part B); to examine the safety and tolerability of nusinersen administered intrathecally at higher doses to participants with SMA (Parts A and C).
The secondary objectives of this study are to examine the clinical efficacy of nusinersen administered intrathecally at higher doses to participants with SMA (Parts A, B and C); to examine the effect of nusinersen administered intrathecally at higher doses to participants with SMA (Parts A and C); to examine the safety and tolerability of nusinersen administered intrathecally at higher doses to participants with SMA, to examine the effect of nusinersen administered intrathecally at higher doses compared to the currently approved dose in participants with SMA (Part B).
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 145
Part A, B and C:
- Genetic documentation of 5q SMA (homozygous gene deletion, mutation, or compound heterozygote)
Part A:
- Onset of clinical signs and symptoms consistent with SMA at > 6 months (> 180 days) of age (i.e., later-onset SMA)
- Age 2 to ≤ 15 years, inclusive, at the time of informed consent
Part B:
-
Participants with SMA symptom onset ≤ 6 months (≤ 180 days) of age (infantile onset) should have age > 1 week to ≤ 7 months (≤ 210 days) at the time of informed consent
-
Participants with SMA symptom onset > 6 months (> 180 days) of age (later onset):
- Age 2 to < 10 years at the time of informed consent
- Can sit independently but has never had the ability to walk independently
- HFMSE score ≥ 10 and ≤ 54 at Screening
Part C:
- Currently on nusinersen treatment at the time of Screening, with the first dose being at least 1 year prior to Screening
Part C Cohort 1:
- Participants of any age (individuals ≥18 years of age at Screening must be ambulatory)
Part C Cohort 2:
- Participants ≥18 years of age at Screening (can be ambulatory or nonambulatory)
- HFMSE total score ≥4 points at Screening
- RULM entry item A score ≥3 points at Screening
Key
Part A, B and C:
- Presence of an untreated or inadequately treated active infection requiring systemic antiviral or antimicrobial therapy at any time during the Screening period
- Presence of an implanted shunt for the drainage of cerebrospinal fluid (CSF) or of an implanted central nervous system (CNS) catheter
- Hospitalization for surgery, pulmonary event, or nutritional support within 2 months prior to Screening or planned within 12 months after the participant's first dose
Part A:
- Respiratory insufficiency, defined by the medical necessity for invasive or noninvasive ventilation for > 6 hours during a 24-hour period, at Screening
- Medical necessity for a gastric feeding tube
- Treatment with an investigational drug given for the treatment of SMA, biological agent, or device within 30 days or 5 half-lives of the agent, whichever is longer, prior to Screening or anytime during the study; any prior or current treatment with any survival motor neuron-2 gene (SMN2)-splicing modifier or gene therapy; or prior antisense oligonucleotide treatment, or cell transplantation
Part B:
-
Treatment with an investigational drug including but not limited to the treatment of SMA, biological agent, or device within 30 days or 5 half-lives of the agent, whichever is longer, prior to Screening or anytime during the study; any prior or current treatment with any SMN2-splicing modifier or gene therapy; or prior antisense oligonucleotide treatment, or cell transplantation
-
Participants with SMA symptom onset > 6 months (> 180 days) of age (later onset):
- Respiratory insufficiency, defined by the medical necessity for invasive or noninvasive ventilation for > 6 hours during a 24-hour period, at Screening
- Medical necessity for a gastric feeding tube
-
Participants with SMA symptom onset ≤ 6 months (≤ 180 days) of age (infantile onset): Signs or symptoms of SMA present at birth or within the first week after birth
Part C:
- Concurrent or previous participation and/or administration of nusinersen in another clinical study
- Concomitant or previous administration of any SMN2-splicing modifier (excluding nusinersen) or gene therapy, either in a clinical study or as part of medical care.
- Concurrent or previous participation in any interventional investigational study for any other drug or device within 30 days or 5 half-lives of the agent, whichever is longer, prior to Screening
NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description 28/28 Milligram (mg) Safety Group Nusinersen Part A: Participants with later-onset SMA will receive loading doses of 28 mg of nusinersen intrathecally on Days 1, 15 and 29 followed by maintenance doses of 28 mg on Days 149 and 269. 12/50/28 mg Titration Group Nusinersen Part C: Participants who have been receiving the approved dose of 12 mg for at least 1 year prior to entry, will receive a single bolus dose of 50 mg of nusinersen intrathecally on Day 1 (4 months after their most recent maintenance dose of 12 mg) followed by maintenance doses of 28 mg on Days 121 and 241. 12/12 mg Active Control Group Nusinersen Part B: Participants with infantile- or later-onset SMA will receive loading doses of 12 mg of nusinersen intrathecally on Days 1, 15, 29, and 64 followed by maintenance doses of 12 mg on Days 183 and 279. Sham procedure will be administered on Day 135. 50/28 mg Active Treatment Group Nusinersen Part B: Participants with infantile- or later-onset SMA will receive loading doses of 50 mg of nusinersen intrathecally on Days 1 and 15 followed by maintenance doses of 28 mg on Days 135 and 279. Sham procedure will be administered on Days 29, 64 and 183.
- Primary Outcome Measures
Name Time Method Part A and C: Change from Baseline in Prothrombin Time (PT) Baseline up to Day 269 Part A and C: Ratio of Weight for Age Baseline up to Day 302 Part B Infantile-onset SMA: Change from Baseline in CHOP-INTEND Total Score for Nusinersen 50/28mg Treatment Group Versus CS3B Matched Sham Control Group Baseline up to Day 183 The CHOP-INTEND test is designed to evaluate the motor skills of infants with significant motor weakness. It includes 16 items (capturing neck, trunk, and proximal and distal limb strength) structured to move from easiest to hardest with the grading including gravity eliminated (lower scores) to antigravity movements (higher scores). All item scores range from 0-4. The change from baseline in the CHOP-INTEND total score will be compared to the study CS3B (NCT02193074) matched sham control group.
Part A and C: Number of Participants with Clinically Significant Shifts from Baseline in Electrocardiograms (ECGs) Screening up to Day 302 Part C Infantile-onset SMA: Change from Baseline in Head Circumference Baseline up to Day 302 Part A and C Later-onset SMA: Change from Baseline in Ulnar Length Baseline up to Day 302 Part A and C: Number of Participants with Clinically Significant Shifts from Baseline in Clinical Laboratory Parameters Screening up to Day 302 Part A and C: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) Screening up to Day 389 An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal assessment such as an abnormal laboratory value), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. An SAE is any untoward medical occurrence that at any dose results in death, in the view of the Investigator, places the participant at immediate risk of death, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, results in a birth defect.
Part A and C: Number of Participants with Clinically Significant Shifts from Baseline in Vital Signs Screening up to Day 302 Part C Infantile-onset SMA: Change from Baseline in Chest Circumference Baseline up to Day 302 Part A and C: Ratio of Weight for Length Baseline up to Day 302 Part A and C: Change in Urine Total Protein Baseline up to Day 302 Part A and C: Change from Baseline in Neurological Examination Outcomes Baseline up to Day 302 Part A and C: Percentage of Participants with a Postbaseline Platelet Count Below the Lower Limit of Normal on at least 2 Consecutive Measurements Baseline up to Day 302 Part A and C: Change from Baseline in Activated Partial Thromboplastin Time (aPTT) Baseline up to Day 269 Part A and C: Change from Baseline in Body Length/Height Baseline up to Day 302 Part C: Ratio of Head-to-chest Circumference Baseline up to Day 302 Part A and C: Change from Baseline in International Normalized Ratio (INR) Baseline up to Day 269 Part C Infantile-onset SMA: Change from Baseline in Arm Circumference Baseline up to Day 302 Part A and C: Percentage of Participants with a Postbaseline Corrected QT Interval Using Fridericia's Formula (QTcF) of > 500 millisecond (msec) and an Increase from Baseline to Any Postbaseline Timepoint in QTcF of > 60 msec Baseline up to Day 302
- Secondary Outcome Measures
Name Time Method Part B Infantile-onset SMA: Time to Death (Overall Survival) for Nusinersen 50/28mg Treatment Group Versus CS3B Matched Sham Control Group Screening up to Day 183 Time to death (overall survival) will be compared to the study CS3B (NCT02193074) matched sham control group.
Part B Infantile-onset SMA: Time to Death (Overall Survival) for Nusinersen 50/28mg Treatment Group Versus 12/12mg Active Control Group Screening up to Day 399 Part B Infantile-onset SMA: Change from Baseline in HINE Section 2 Motor Milestones Total Score for Nusinersen 50/28mg Treatment Group Versus 12/12mg Active Control Group Baseline up to Day 302 Section 2 of the HINE is used to assess motor milestones of the participants It is composed of 8 motor milestone categories: voluntary grasp, ability to kick in supine position, head control, rolling, sitting, crawling, standing, and walking.
Part B Infantile-onset SMA: Time to Death or Permanent Ventilation for Nusinersen 50/28mg Treatment Group Versus CS3B Matched Sham Control Group Screening up to Day 183 Permanent ventilation is defined as tracheostomy or ≥ 16 hours of ventilation/day continuously for \> 21 days in the absence of an acute reversible event. Time to death or permanent ventilation will be compared to the study CS3B (NCT02193074) matched sham control group.
Part B Infantile-onset SMA: Time to Death or Permanent Ventilation for Nusinersen 50/28mg Treatment Group Versus 12/12mg Active Control Group Screening up to Day 399 Permanent ventilation is defined as tracheostomy or ≥ 16 hours of ventilation/day continuously for \> 21 days in the absence of an acute reversible event.
Part B Infantile-onset SMA: Change from Baseline in HINE Section 2 Motor Milestones Total Score for Nusinersen 50/28mg Treatment Group Versus CS3B Matched Sham Control Group Baseline up to Day 183 Section 2 of the HINE is used to assess motor milestones of the participants. It is composed of 8 motor milestone categories: voluntary grasp, ability to kick in supine position, head control, rolling, sitting, crawling, standing, and walking. The change from baseline in the HINE section 2 motor milestones total score will be compared to the study CS3B (NCT02193074) matched sham control group.
Part B Infantile-onset SMA: Change from Baseline in CHOP-INTEND Total Score for Nusinersen 50/28mg Treatment Group Versus 12/12mg Active Control Group Baseline up to Day 302 The CHOP-INTEND test is designed to evaluate the motor skills of infants with significant motor weakness. It includes 16 items (capturing neck, trunk, and proximal and distal limb strength) structured to move from easiest to hardest with the grading including gravity eliminated (lower scores) to antigravity movements (higher scores). All item scores range from 0-4.
Part B Infantile-onset SMA: Change from Baseline in Plasma Concentration of Neurofilament Light Chain (NF-L) for Nusinersen 50/28mg Treatment Group Versus CS3B Matched Sham Control Group Baseline up to Day 183 The change from baseline in the plasma concentration of NF-L will be compared to the study CS3B (NCT02193074) matched sham control group.
Part B Infantile-onset SMA: Percentage of Hammersmith Infant Neurological Examination (HINE) Section 2 Motor Milestone Responders for Nusinersen 50/28mg Treatment Group Versus CS3B Matched Sham Control Group Baseline up to Day 183 Section 2 of the HINE is used to assess motor milestones of the participants It is composed of 8 motor milestone categories: voluntary grasp, ability to kick in supine position, head control, rolling, sitting, crawling, standing, and walking. The percentage of the HINE section 2 motor milestones responders will be compared to the study CS3B (NCT02193074) matched sham control group.
Part B Infantile-onset SMA: Change from Baseline in Plasma Concentration of NF-L for Nusinersen 50/28mg Treatment Group Versus 12/12mg Active Control Group Baseline up to Day 29 Part B Later-onset SMA: Total Number of New World Health Organization (WHO) Motor Milestones for Nusinersen 50/28mg Treatment Group Versus 12/12mg Active Control Group Baseline up to Day 302 Part B: Number of Participants with AEs and SAEs Screening up to Day 399 An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal assessment such as an abnormal laboratory value), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. An SAE is any untoward medical occurrence that at any dose results in death, in the view of the Investigator, places the participant at immediate risk of death, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, results in a birth defect.
Part B: Number of Participants with Clinically Significant Shifts from Baseline in Clinical Laboratory Parameters Screening up to Day 302 Part B Later-onset SMA: Change from Baseline in Assessment of Caregiver Experience with Neuromuscular Disease (ACEND) for Nusinersen 50/28mg Treatment Group Versus 12/12mg Active Control Group Baseline up to Day 302 ACEND is designed to quantify the caregiver impact experienced by parents/caregivers of children affected with severe neuromuscular diseases. It includes domains assessing physical impact (including feeding/grooming/dressing, sitting/play, transfers, and mobility) and general caregiver impact (including time, emotion, and finance).
Part B: Number of Participants with Clinically Significant Shifts from Baseline in ECGs Day 1 up to Day 302 Part B Infantile-onset SMA: Change from Baseline in Head Circumference Baseline up to Day 302 Part B: Change from Baseline in PT Baseline up to Day 279 Part B: Change from Baseline in Neurological Examination Outcomes Baseline up to Day 302 Part A, B and C: Clinical Global Impression of Change (CGIC) Day 302 The CGIC scale is a 7 point scale that requires the clinician to assess how much the participant's illness has changed relative to a baseline state at the beginning of the intervention, where 1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse, 7=very much worse. Higher rating will indicate worsening of the condition.
Part A, B and C: Number of Participants with Serious Respiratory Events Screening up to Day 399 Part B Infantile-onset SMA: Percentage of Time on Ventilation Screening up to Day 302 Parts A, B and C: Ventilator Use Screening up to Day 302 Part A and C: Change from Baseline in PedsQL™ Baseline up to Day 302 PedsQL is used to measure healthrelated quality of life (HRQOL) in children and adolescents. The PedsQL Measurement 4.0 Generic Core Scales include assessment of physical functioning, emotional functioning, social functioning, and school functioning and the PedsQL 3.0 Neuromuscular Module measures HRQOL.
Part B: Number of Participants with Clinically Significant Shifts from Baseline in Vital Signs Screening up to Day 302 Part B Infantile-onset SMA: Change from Baseline in Arm Circumference Baseline up to Day 302 Part B: Change from Baseline in Body Length/Height Baseline up to Day 302 Part B: Change from Baseline in aPTT Baseline up to Day 279 Part A, B and C: Duration of Hospitalizations Day 1 to Day 302 Part B: Infantile SMA-onset: Change from baseline in CSF concentration of NF-L Baseline up to Day 302 Part B Later-onset SMA: Change from Baseline in Hammersmith Functional Motor Scale Expanded (HFMSE) Score for Nusinersen 50/28mg Treatment Group Versus 12/12mg Active Control Group Baseline up to Day 302 HFMSE scale is a tool to assess motor function in children with SMA. The original 20 item Hammersmith Functional Motor Scale was expanded to include 13 additional adapted items from the Gross Motor Function Measure to improve sensitivity for the higher functioning ambulant population.
Part B Later-onset SMA: Change from Baseline in Pediatric Quality of Life Inventory™ (PedsQL) for Nusinersen 50/28mg Treatment Group Versus 12/12mg Active Control Group Baseline up to Day 302 PedsQL is used to measure health related quality of life (HRQOL) in children and adolescents. The PedsQL Measurement 4.0 Generic Core Scales include assessment of physical functioning, emotional functioning, social functioning, and school functioning and the PedsQL 3.0 Neuromuscular Module measures HRQOL.
Part B: Percentage of Participants with a Postbaseline Platelet Count Below the Lower Limit of Normal on at least 2 Consecutive Measurements Baseline up to Day 302 Part A, B and C: Number of Hospitalizations Day 1 to Day 302 Part C: Change from Baseline in HINE Section 2 Motor Milestones Total Score Baseline up to Day 302 Section 2 of the HINE is used to assess motor milestones of the participants. It is composed of 8 motor milestone categories: voluntary grasp, ability to kick in supine position, head control, rolling, sitting, crawling, standing, and walking.
Part B Later-onset SMA: Change from Baseline in Revised Upper Limb Module (RULM) Score for Nusinersen 50/28mg Treatment Group Versus 12/12mg Active Control Group Baseline up to Day 302 The RULM is developed to assess upper limb functional abilities participants with SMA. This test consists of upper limb performance items that are reflective of activities of daily living.
Part B Later-onset SMA: Change from Baseline in Cerebral Spinal Fluid (CSF) Concentration of NF-L for Nusinersen 50/28mg Treatment Group Versus 12/12mg Active Control Group Baseline up to Day 302 Part B Later-onset SMA: Change from Baseline in Plasma Concentration of NF-L for Nusinersen 50/28mg Treatment Group Versus 12/12mg Active Control Group Baseline up to Day 302 Part B Infantile-onset SMA: Change from Baseline in Chest Circumference Baseline up to Day 302 Part B: Ratio of Weight for Length Baseline up to Day 302 Part B: Ratio of Head-to-chest Circumference Baseline up to Day 302 Part B: Change in Urine Total Protein Baseline up to Day 302 Part B: Percentage of Participants with a Postbaseline QTcF of > 500 msec and an Increase from Baseline to Any Postbaseline Timepoint in QTcF of > 60 msec Baseline up to Day 302 Part A and C: Change from Baseline in HFMSE Score Baseline up to Day 302 HFMSE scale is a tool to assess motor function in children with SMA. The original 20 item Hammersmith Functional Motor Scale was expanded to include 13 additional adapted items from the Gross Motor Function Measure to improve sensitivity for the higher functioning ambulant population.
Part B Later-onset SMA: Change from Baseline in Ulnar Length Baseline up to Day 302 Part B: Ratio of Weight for Age Baseline up to Day 302 Part B: Change from Baseline in INR Baseline up to Day 279 Parts A and B: Change from Baseline in the Parent Assessment of Swallowing Ability (PASA) Scale Baseline up to Day 302 PASA questionnaire is developed to assess the signs and symptoms of dysphagia. It includes 33 items across 4 domains. General feeding, drinking liquids and eating solid foods will be assessed with 5 levels of response (Never, Rarely, Sometimes, Often, and Always), and 2 items will be assessed with 'Yes'/'No'. The assessment of swallowing concerns has 4 levels of response: Strongly Agree, Agree, Disagree, and Strongly Disagree. For Part A, it will be assessed in participants with later-onset SMA and in Part B, it will be assessed in participants with infantile- and later-onset SMA.
Part A and C: Change from Baseline in RULM Score Baseline up to Day 302 The RULM is developed to assess upper limb functional abilities participants with SMA. This test consists of upper limb performance items that are reflective of activities of daily living.
Part A and C: Total Number of New WHO Motor Milestones Baseline up to Day 302 Part A and C: Change from Baseline in ACEND Baseline up to Day 302 ACEND is designed to quantify the caregiver impact experienced by parents/caregivers of children affected with severe neuromuscular diseases. It includes domains assessing physical impact (including feeding/grooming/dressing, sitting/play, transfers, and mobility) and general caregiver impact (including time, emotion, and finance).
Part C: Change from Baseline in CHOP-INTEND Total Score Baseline to up Day 302 The CHOP-INTEND test is designed to evaluate the motor skills of infants with significant motor weakness. It includes 16 items (capturing neck, trunk, and proximal and distal limb strength) structured to move from easiest to hardest with the grading including gravity eliminated (lower scores) to antigravity movements (higher scores). All item scores range from 0-4.
Trial Locations
- Locations (66)
Tokyo Women's Medical University Hospital
🇯🇵Shinjuku-ku, Tokyo-To, Japan
Uniwersyteckie Centrum Kliniczne
🇵🇱Gdansk, Poland
Regional Pediatric Clinical Hospital #1
🇷🇺Ekaterinburg, Russian Federation
Russian Children Neuromuscular Center of Veltischev
🇷🇺Moskva, Russian Federation
King Fahad Specialist Hospital
🇸🇦Dammam, Saudi Arabia
King Faisal Specialist Hospital & Research Center
🇸🇦Riyadh, Saudi Arabia
Magyarorszagi Reformatus Egyhaz Bethesda Gyermekkorhaz
🇭🇺Budapest, Hungary
Clinica MEDS La Dehesa
🇨🇱Santiago, Chile
Hospital Universitario San Ignacio
🇨🇴Bogota, Colombia
Hospital Infantil de Mexico Federico Gomez
🇲🇽Mexico, Distrito Federal, Mexico
UMC Utrecht
🇳🇱Utrecht, Netherlands
Instytut Pomnik - Centrum Zdrowia Dziecka
🇵🇱Warszawa, Poland
Royal Children's Hospital
🇦🇺Parkville, Victoria, Australia
Clinica Las Condes
🇨🇱Santiago, Chile
Semmelweis Egyetem
🇭🇺Budapest, Hungary
Children's Clinical University Hospital
🇱🇻Riga, Latvia
Schneider Children's Medical Center
🇮🇱Petach-Tikva, Israel
Hospital Sant Joan de Deu
🇪🇸Esplugues Del Llobregat, Barcelona, Spain
National Guard Health Affairs: King Abdulaziz Medical City
🇸🇦Jeddah, Saudi Arabia
Children's Hospital Colorado
🇺🇸Aurora, Colorado, United States
The Johns Hopkins Hospital
🇺🇸Baltimore, Maryland, United States
Stanford Hospital and Clinics
🇺🇸Palo Alto, California, United States
Boston Children's Hospital
🇺🇸Boston, Massachusetts, United States
St. Jude Children's Research Hospital
🇺🇸Memphis, Tennessee, United States
HC-UFMG - Hospital das Clinicas da Universidade Federal de Minas Gerais
🇧🇷Belo Horizonte, Minas Gerais, Brazil
Hospital de Clínicas de Porto Alegre
🇧🇷Porto Alegre, Rio Grande Do Sul, Brazil
McGill University Health Centre/Glen Site/Montreal Children's Hospital
🇨🇦Montreal, Quebec, Canada
BC Children's Hospital
🇨🇦Vancouver, British Columbia, Canada
London Health Sciences Centre (LHSC) - Children's Hospital
🇨🇦London, Ontario, Canada
Hospital Luis Calvo Mackenna
🇨🇱Santiago, Chile
Children's Hospital Chongqing University of Medical Science
🇨🇳Chongqing, Chongqing, China
Beijing Children's Hospital
🇨🇳Beijing, Beijing, China
Peking University First Hospital
🇨🇳Beijing, Beijing, China
Xiangya Hospital, Central South University
🇨🇳Changsha, Hunan, China
Qilu Hospital of Shandong University
🇨🇳Jinan, Shandong, China
The Second Hospital affiliated to West China Medical University
🇨🇳Chendu, Sichuan, China
Fundacion Hospitalaria San Vicente de Paul
🇨🇴Medellin, Colombia
Tallinn Children's Hospital
🇪🇪Tallinn, Estonia
Universitaetsklinikum Freiburg
🇩🇪Freiburg, Baden Wuerttemberg, Germany
University General Hospital "Attikon"
🇬🇷Athens, Greece
General Hospital of Thessaloniki "Hippokration"
🇬🇷Thessaloniki, Greece
Universitaetsklinikum Giessen und Marburg GmbH
🇩🇪Giessen, Hessen, Germany
The Children's University Hospital
🇮🇪Dublin, Ireland
Tel Aviv Sourasky Medical Center
🇮🇱Tel Aviv, Israel
Fondazione Policlinico Universitario Agostino Gemelli IRCCS
🇮🇹Roma, Italy
Fondazione Serena Onlus - Centro Clinico Nemo
🇮🇹Milano, Italy
Kurume University Hospital
🇯🇵Kurume-shi, Fukuoka-Ken, Japan
Seoul National University Hospital
🇰🇷Seoul, Korea, Republic of
Hyogo College of Medicine Hospital
🇯🇵Nishinomiya-shi, Hyogo-Ken, Japan
Kyungpook National University Chilgok Hospital
🇰🇷Daegu, Gyeongsangbuk-do, Korea, Republic of
Saint George University Hospital Medical Center
🇱🇧Beirut, Lebanon
Instituto Nacional de Pediatria
🇲🇽Mexico City, Distrito Federal, Mexico
Antiguo Hospital Civil de Guadalajara Fray Antonio Alcalde
🇲🇽Guadalajara, Jalisco, Mexico
National Taiwan University Hospital
🇨🇳Taipei, Taiwan
Akdeniz Univesity Medical Faculty
🇹🇷Antalya, Turkey
Hospital Universitario La Paz
🇪🇸Madrid, Spain
Hospital Universitari Vall d'Hebron
🇪🇸Barcelona, Spain
Hospital Universitari i Politecnic La Fe
🇪🇸Valencia, Spain
Kaohsiung Medical University Chung-Ho Memorial Hospital
🇨🇳Kaohsiung, Taiwan
The University of Texas Southwestern Medical Center
🇺🇸Dallas, Texas, United States
Ann & Robert H. Lurie Children's Hospital of Chicago
🇺🇸Chicago, Illinois, United States
Hopital Purpan
🇫🇷Toulouse cedex 9, Haute Garonne, France
Hospital das Clínicas da Faculdade de Medicina da USP
🇧🇷São Paulo, Sao Paulo, Brazil
Guangzhou Woman and Children's Medical Center
🇨🇳Guangzhou, Guangzhou, China
Hôpital Raymond Poincaré
🇫🇷Garches, Hauts De Seine, France
Great Ormond Street Hospital for Children
🇬🇧London, Greater London, United Kingdom
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