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Trial record 5 of 19 for:    gm1 gangliosidosis

Study of Safety, Tolerability and Efficacy of PBGM01 in Pediatric Participants With GM1 Gangliosidosis (Imagine-1)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04713475
Recruitment Status : Active, not recruiting
First Posted : January 19, 2021
Last Update Posted : January 17, 2024
Sponsor:
Information provided by (Responsible Party):
Passage Bio, Inc.

Brief Summary:
PBGM01 is a gene therapy for GM1 gangliosidosis intended to deliver a functional copy of the GLB1 gene to the brain and peripheral tissues. This study will assess in a 2 part design the safety, tolerability and efficacy of PBGM01 in patients with early onset infantile (Type 1) and late onset infantile (Type 2a) GM1 gangliosidosis

Condition or disease Intervention/treatment Phase
GM1 Gangliosidosis GM1 Gangliosidosis, Type I GM1 Gangliosidosis, Type 2 Beta-Galactosidase-1 (GLB1) Deficiency Biological: PBGM01 Phase 1 Phase 2

Detailed Description:

GM1 gangliosidosis (GM1) is an autosomal recessive disorder that results from mutations in the galactosidase beta 1 gene (GLB1), which encodes beta-galactosidase (β-gal). β-gal is a lysosomal enzyme that catalyzes the first step in the degradation of GM1 ganglioside and keratan sulfate, and GM1 patients carry GLB1 alleles that produce little or no residual β-gal activity. PBGM01 is an adeno-associated viral vector serotype hu68 carrying GLB1, the gene encoding for human beta-galactosidase, formulated as a solution for injection into the cisterna magna. This is a global interventional, multicenter, single-arm, dose escalation, adaptive design study of PBGM01 delivered as a one-time dose administered into the cisterna magna to patients with early onset infantile (Type 1) and late onset infantile (Type 2a) GM1 gangliosidosis.

In Part 1 of the study, the dose-escalation phase will assess three dose levels of PBGM01 as a one-time dose in six independent cohorts of patients with either Type 1 or Type 2a GM1 gangliosidosis. The cohorts for patients with Type 1 and Type 2a will be assessed independently from each other.

Part 2 of the study will test the safety and efficacy of PBGM01 in confirmatory cohorts for Types 1 and Type 2a GM1 gangliosidosis with a dose chosen based on the data obtained in part 1 of the study. This will be a 2-year study with a 3-year safety extension.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 26 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: Open-label, multi-center, dose escalation
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 1/2 Open-Label, Multicenter Study to Assess the Safety, Tolerability and Efficacy of a Single Dose of PBGM01 Delivered Into the Cisterna Magna of Pediatric Type 1 (Early Onset) and Type 2a (Late Onset) Infantile GM1 Gangliosidosis
Actual Study Start Date : March 17, 2021
Estimated Primary Completion Date : February 2026
Estimated Study Completion Date : February 2029


Arm Intervention/treatment
Experimental: Part 1: Dose I of Dose Escalation Cohorts designed to identify the optimal dose of PBGM01

Assigned Intervention:

PBGM01 Dose I: 3.3 x 10^10 GC/g estimated brain weight, single dose of PBGM01 via intra cisterna magna in Late Onset Infantile GM1 Gangliosidosis (Type 2a) and Early Onset Infantile GM1 Gangliosidosis (Type 1)

Biological: PBGM01
AAVhu68 viral vector

Experimental: Part 1: Dose II of Dose Escalation Cohorts designed to identify the optimal dose of PBGM01

Assigned Intervention:

PBGM01 Dose II: 1.1 x 10^11 GC/g estimated brain weight, single dose of PBGM01 via intra cisterna magna in Late Onset Infantile GM1 Gangliosidosis (Type 2a) and Early Onset Infantile GM1 Gangliosidosis (Type 1)

Biological: PBGM01
AAVhu68 viral vector

Experimental: Part 1: Dose III of Dose Escalation Cohorts designed to identify the optimal dose of PBGM01

Assigned Intervention:

PBGM01 Dose III: 2.2 x 10^11 GC/g estimated brain weight, single dose of PBGM01 via intra cisterna magna in Late Onset Infantile GM1 Gangliosidosis (Type 2a) and Early Onset Infantile GM1 Gangliosidosis (Type 1)

Biological: PBGM01
AAVhu68 viral vector

Experimental: Part 2: Expansion Cohort designed to confirm the safety and efficacy of PBGM01

Confirmatory Cohorts: Late Onset Infantile GM1 Gangliosidosis (Type 2a) and Early Onset Infantile GM1 Gangliosidosis (Type 1)

Assigned Intervention:

PBGM01 Single dose of PBGM01, via intra cisterna magna Dose to be determined

Biological: PBGM01
AAVhu68 viral vector




Primary Outcome Measures :
  1. Number of Participants with Treatment Related AEs and SAEs as Characterized by CTCAEv5.0 [ Time Frame: Up to 5 years (multiple visits) ]
    Assess the number of treatment-related adverse events (AEs) and serious adverse events (SAEs) as characterized by CTCAEv5.0

  2. Change from Baseline in Developmental Milestones as Assessed by the Bayley Scale of Infant and Toddler Development, Third Edition [ Time Frame: From baseline to 2 years (multiple visits) ]
    Assess changes in the developmental age and the total number of developmental milestones using the Bayley Scale of Infant and Toddler Development, Third Edition instrument


Secondary Outcome Measures :
  1. Change from Baseline in Developmental Milestones as Assessed by the Vineland Adaptive Behavior Scale-II [ Time Frame: From baseline to 2 years (multiple visits) ]
    Assess changes in the developmental age and the total number of developmental milestones using the Vineland Adaptive Behavior Scale-II instrument

  2. Change in Baseline in Biomarkers of Beta-Galactosidase Activity in Blood and CSF [ Time Frame: From baseline to 2 years (multiple visits) ]
    Assess change in biomarkers of beta-galactosidase activity including enzyme activity in blood and CSF

  3. Change in Baseline in Biomarkers of Beta-Galactosidase Substrates in Blood and CSF [ Time Frame: From baseline to 2 years (multiple visits) ]
    Assess change in concentration of beta-galactosidase substrates including GM1 ganglioside in blood and CSF

  4. Change in Concentration of Biomarker of Disease Progression in Plasma and CSF [ Time Frame: From baseline to 2 years (multiple visits) ]
    Assess change in neurofilament light chain (NfL) concentration as a marker for neurodegeneration and disease progression in plasma and CSF

  5. Change in Brain Anatomy as Assessed by MRI [ Time Frame: From baseline to 2 years (multiple visits) ]
    Assess change in disease severity, volumetric MRI measures, brain diffusivity, and white matter lesions by MRI imaging

  6. Change in Quality of Life Using Pediatric Quality of Life Scales [ Time Frame: From baseline to 2 years (multiple visits) ]
    Assess change in quality of life as measured by Pediatric Quality of Life Scale (Peds QL) and the Pediatric Quality of Life-Infant Scale (PedsQL-IS)

  7. Change in Ventilator-Free Survival Compared with Natural History Data [ Time Frame: From baseline to 2 years (multiple visits) ]
    Assess change compared with natural history data in ventilator-free survival and chronic ventilatory support



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   1 Month to 24 Months   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • All Patients: Documented GM1 gangliosidosis diagnosis based on genotyping confirming 2 mutations in the GLB1 gene and documented deficiency of beta-galactosidase enzyme by laboratory testing.
  • Early onset infantile (Type 1) must be ≥1 month and <12 months of age at enrollment and have signs and/or symptoms of GM1 gangliosidosis that started before 6 months of age with specific minimum developmental milestones remaining.
  • Late onset infantile (Type 2a) must be ≥6 months and ≤24 months of age at enrollment and have signs and/or symptoms of GM1 gangliosidosis that started between 6 and 18 months of age with specific minimum developmental milestones remaining including the ability to sit independently at screening as defined by the WHO Multicenter Growth Reference Study (WHO-MGRS) criteria of being able to sit up unsupported with head erect for at least 10 seconds.

Exclusion Criteria:

  1. Any clinically significant neurocognitive deficit not attributable to GM1 gangliosidosis or any other condition that may, in the opinion of the investigator, confound interpretation of study results.
  2. If a subject had an acute illness requiring hospitalization within 30 days of enrollment, the history must be discussed with the sponsor's medical monitor before allowing the subject to be enrolled.
  3. History of ventilation assisted respiratory support or a need for tracheostomy as a result of their disease. Chronic ventilatory support is defined as use of invasive or noninvasive (BiPAP) mechanical ventilation. Note: This does not exclude participants who use respiratory vests or noninvasive (BiPAP) mechanical ventilation for obstructive sleep apnea regardless of cause for less than 12 hours per day.
  4. Intractable seizure or uncontrolled epilepsy defined as having had an episode of status epilepticus, or seizures requiring hospitalization within 30 days prior to dosing of PBGM01. Note: This does not exclude participants who have a history of staring spells that have not been associated with EEG findings.
  5. Any contraindication to the ICM administration procedure, including contraindications to fluoroscopic imaging and anesthesia or any condition that would increase the risk of adverse outcomes from the ICM procedure including, but not limited to, the presence of a space occupying lesion causing mass effects or signs of increased intracranial pressure, space occupying lesion in the posterior fossa or foramen magnum, aberrant vascular anatomy such as a large midline posterior inferior cerebellar artery, aberrant venous anatomy such as a large cerebellar vein or occipital sinus, or congenital anatomical abnormalities such as a Chiari malformation.
  6. Any contraindication to MRI or lumbar puncture (LP).
  7. Prior gene therapy.
  8. Use of miglustat within 48 hours prior to dosing of PBGM01. The use of miglustat is prohibited throughout the study.
  9. Use of enzyme replacement therapy or other investigational therapy within 5 half-lives prior to dosing of PBGM01. The use of enzyme replacement is prohibited throughout the study.
  10. Receipt of a vaccine within 14 days prior to dosing and/or scheduled vaccine within 30 days after dosing.
  11. Estimate glomerular filtration rate (eGFR) <30 mL/minute based on creatinine
  12. Coagulopathy (INR > 1.5) or activated partial thromboplastin time [aPTT] > 40 seconds
  13. Thrombocytopenia (platelet count < 100,000 per μL.
  14. AST or ALT > 3 times the upper limit of normal (ULN) or total bilirubin > 1.5x ULN
  15. Cardiomyopathy (screening troponin level above the ULN).
  16. Peripheral neuropathy
  17. Medical conditions or laboratory or vital sign abnormalities that would increase risk of complications from intra-cisterna magna injection, anesthesia, fluoroscopy, LP, and/or MRI including temperature over 38°C, oxygen saturation below 95% on room air or baseline oxygen requirement, heart rate or respiratory rate abnormal for age of the subject, abnormal blood pressure for age, or evidence of infection.
  18. Any condition (e.g., history of any disease, evidence of any current disease, any finding upon physical examination, or any laboratory abnormality) that, in the opinion of the investigator, would put the subject at undue risk during the administration procedure or would interfere with evaluation of PBGM01 or interpretation of subject safety or study results.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04713475


Locations
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United States, California
Benioff Children's Hospital
Oakland, California, United States, 94158
United States, Minnesota
University of Minnesota
Minneapolis, Minnesota, United States, 55455
United States, New Jersey
Children's Hospital at St. Peter's University Hospital
New Brunswick, New Jersey, United States, 08901
United States, Pennsylvania
The Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104
Brazil
Hospital de Clínicas de Porto Alegre (HCPA)
Porto Alegre, Brazil
Canada
Montreal Children's Hospital
Montréal, Canada
The Hospital for Sick Children
Toronto, Canada
Turkey
Gazi University
Ankara, Turkey
United Kingdom
Great Ormond Street Hospital
London, United Kingdom
Sponsors and Collaborators
Passage Bio, Inc.
Investigators
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Study Director: Samiah Al-Zaidy, MD Passage Bio, Inc.
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Responsible Party: Passage Bio, Inc.
ClinicalTrials.gov Identifier: NCT04713475    
Other Study ID Numbers: PBGM01-001
2020-001109-22 ( EudraCT Number )
First Posted: January 19, 2021    Key Record Dates
Last Update Posted: January 17, 2024
Last Verified: January 2024

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Passage Bio, Inc.:
Infantile
Late Infantile
Rare disease
Lysosomal storage disease
Additional relevant MeSH terms:
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Gangliosidoses
Gangliosidosis, GM1
Sphingolipidoses
Lysosomal Storage Diseases, Nervous System
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Lipidoses
Lipid Metabolism, Inborn Errors
Lysosomal Storage Diseases
Metabolic Diseases
Lipid Metabolism Disorders