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    The EU Clinical Trials Register currently displays   44043   clinical trials with a EudraCT protocol, of which   7319   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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    Summary
    EudraCT Number:2020-001109-22
    Sponsor's Protocol Code Number:PBGM01-001
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:
    Date on which this record was first entered in the EudraCT database:2020-10-21
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2020-001109-22
    A.3Full title of the trial
    A Phase 1/2 Open-Label, Multicenter, Dose Ranging and Confirmatory Study to Assess the Safety, Tolerability and Efficacy of a Single Dose of PBGM01 Delivered into the Cisterna Magna of Pediatric Subjects Aged 4 to 24 Months with Type 1 (Early Onset Infantile) and Aged 6 to 24 Months with Type 2a (Late Onset Infantile) GM1 Gangliosidosis (IMAGINE-1 Study)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of Safety, Tolerability, Efficacy and of PBGM01 in Pediatric Subjects with GM1 Gangliosidosis
    A.4.1Sponsor's protocol code numberPBGM01-001
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorPassage Bio, Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportPassage Bio, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPassage Bio, Inc.
    B.5.2Functional name of contact pointDavid Weinstein
    B.5.3 Address:
    B.5.3.1Street AddressCommerce Square Two, 2001 Market Street
    B.5.3.2Town/ cityPhiladelphia
    B.5.3.3Post codePA 19103
    B.5.3.4CountryUnited States
    B.5.6E-mailinfo@passagebio.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.2Product code PBGM01
    D.3.4Pharmaceutical form Injection
    D.3.4.1Specific paediatric formulation Yes
    D.3.7Routes of administration for this IMPIntracisternal use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Yes
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product Yes
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms Yes
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.2Product code ITFFBD01 (ICM Diluent)
    D.3.4Pharmaceutical form Injection
    D.3.4.1Specific paediatric formulation Yes
    D.3.7Routes of administration for this IMPIntracisternal use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product Yes
    D.3.11.13.1Other medicinal product typeDiluent for PBGM01
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    GM1 gangliosidosis (GM1) is an autosomal recessive disorder that results from mutations in the human galactosidase beta 1 gene (GLB1), which encodes beta-galactosidase (β-gal).
    E.1.1.1Medical condition in easily understood language
    When people have GM1, the gene (GLB1) that carries instructions to make a specific protein, called an enzyme, does not work properly.
    E.1.1.2Therapeutic area Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    - To assess the safety and tolerability of PBGM01 following administration of a single dose into the cisterna magna
    E.2.2Secondary objectives of the trial
    - To assess the efficacy of PBGM01 following administration of a single dose into the cisterna magna
    - To assess the pharmacodynamic effects of PBGM01 following administration of a single dose into the cisterna magna
    - To assess the effects of PBGM01 following administration of a single dose into the cisterna magna on disease progression
    - To assess the effects of PBGM01 following administration of a single dose into the cisterna magna on quality of life and healthcare resource utilization
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    This study will include infants who have confirmed biallelic pathological GLB1 mutations AND β-gal activity below the lower bound of the normal range. Subjects will be >4 months to <24 months of age at enrollment, with either symptoms of Type 1 (Early Onset Infantile) GM1 characterized by early onset (<6 months of age), predictive of rapid progression; or subjects aged >6 months to <24 months of age with symptoms of Type 2a (Late Onset Infantile) GM1 characterized by later onset presentation (>6 to 18 months of age), predictive of slower progression.

    Inclusion Criteria
    Subjects who are homozygous or compound heterozygous for GLB1 gene deletion or pathological mutation.

    Type 1 (Early Onset Infantile) GM1
    Subjects with medical record documentation of onset of signs or symptoms of GM1 before 6 months of age, with hypotonia and/or developmental delay and/or other signs consistent with GM1 (e.g., hepatosplenomegaly, skeletal dysplasia, cherry-red maculae, cardiomyopathy, and coarse facial features) AND must have at least two of the following remaining developmental skills within the past week confirmed/observed by the site examiner at the time of screening:
    • Shows ability to move arms and legs intentionally. 
    • Looks at an object of interest for at least 3 continuous seconds. 
    • When held upright against a caregiver’s chest, can roll their head from one side to the other (e.g., if the child is lying with their left ear on the caregiver’s shoulder, they can switch to lying with their right ear on the caregiver’s shoulder without assistance or repositioning).
    • Vocalizes a specific mood such as pleasure during activity with toys, free play, or social interaction; or displeasure when play is interrupted, toys removed, or child restrained.
    • Throaty, gurgling or nasal sounds elicited by interaction with caregiver.
    • Child’s eyes track a moving person through midline to the left and right.

    Type 2a (Late Onset Infantile) GM1
    Subjects with medical record documentation of onset of signs or symptoms of GM1 at age >6 months to 18 months of age, with hypotonia and/or plateauing or delay in achieving further developmental milestones and/or any other documented signs consistent with GM1 (e.g., hepatosplenomegaly, skeletal dysplasia, cherry-red maculae, cardiomyopathy, and coarse facial features) AND must meet age-dependent developmental criteria for symptomatic Late Onset Infantile GM1 subjects below:

    Symptomatic subjects ≤ 12 months of age are required to have at least 1 of the 4 age appropriate gross motor, fine motor, language/cognitive or social developmental milestones listed for their age in the table below within the past week confirmed/observed by the site examiner at the time of screening.

    Symptomatic subjects >12 and <24 months are required to have at least 2 of the 4 developmental milestones for a child 50% of their age (see table on page 67 of the protocol) within the past week confirmed/observed by the site examiner at the time of screening. For example, a 16-month-old child would need to have at least 2 of the 4 developmental milestones of an 8-month old child.
    E.4Principal exclusion criteria
    Subjects should be reevaluated throughout the course of the study to ensure that they have not acquired any condition that might qualify them for exclusion from study procedures. If they develop any condition (s) that would exclude them from the study prior to receiving PBGM01, they should be withdrawn from the study. If after receiving PBGM01, a subject develops a contraindication to a procedure (e.g. MRI), investigators should refrain from performing such procedures (which could potentially cause harm) for the duration of the study (all other study procedures and data collection will continue).
    1. Any clinically significant neurocognitive deficit not attributable to GM1 or any other condition that may, in the opinion of the investigator, confound interpretation of study results.
    2. If any 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 chronic ventilation-assisted respiratory support or a need for tracheostomy as a result of their disease.
    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.
    5. Any contraindication to 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 space occupying lesion causing mass effect 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 anomaly such as a large midline cerebellar vein or occipital sinus, congenital anatomical abnormalities such as Chiari malformation.
    6. Any contraindication to MRI or 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 therapy is prohibited throughout the study.
    10. Receipt of a vaccine within 14 days of dosing
    11. Estimated 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. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 x upper limit of normal (ULN) or total bilirubin >1.5 x 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 (Temperature > 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, 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 interfere with evaluation of PBGM01 or interpretation of subject safety or study results. This includes:
    a. Abnormal laboratory values considered clinically significant by the investigator
    b. Failure to thrive, defined as: Falling 20 percentiles (20/100) in body weight in the 3 months preceding Screening/Baseline
    c. Underlying defect in immune function
    d. History of multiple and severe life-threatening infections.
    E.5 End points
    E.5.1Primary end point(s)
    Adverse events, neurological examination, nerve conduction studies, Total Neuropathy Score-Nurse, hematology, serum chemistry, liver tests, coagulation (PT, aPTT, INR), CSF anti-AAVhu68 NAbs, vector shedding, urinalysis, physical examination, vital signs, ECG, brain MRI, and CSF cytology and chemistry (cell counts, protein, glucose) will be assessed over 5 years.
    E.5.1.1Timepoint(s) of evaluation of this end point
    over 5 years
    E.5.2Secondary end point(s)
    Key Secondary Endpoint will be assessed at 2 years and over 5 years:
    • Vineland Adaptive Behavior Scales, Second Edition

    Other Secondary Endpoints will be assessed at 2 years and over 5 years:
    • Bayley Scale of Infant and Toddler Development, Third Edition (up to 42 months of age); Kaufman Assessment Battery for Children, Second Edition (>42 months of age)
    • WHO Multicenter Growth Reference Study Motor Development Milestones Assessment
    • Hammersmith Infant Neurodevelopment Examination
    • Clinician and Caregiver Global Impression of Severity and Change
    • Peabody Developmental Motor Scales, Second Edition (starting at 3 years of age)

    • β-galactosidase activity, hexosaminidase activity, and neurofilament light chain levels in CSF and serum
    • β-galactosidase substrates, which may include GM1 ganglioside, dp5, A2G2’, and keratan sulfate in CSF and/or serum and/or urine
    All will be assessed over 5 years.

    • Total brain volume, brain substructure volume, and ventricle volume and T1/T2 signal intensity as measured by MRI
    • Skeletal abnormalities as measured by lateral spinal x-rays
    • Cardiomyopathy measured by cardiac echocardiogram
    • Hepatosplenomegaly measured by abdominal ultrasound
    • Changes in EEG background features as measured by serial EEG
    • Assessment of mechanical ventilation-free survival
    • Assessment of nutrition status by need of placement and use of feeding tubes
    • Seizure diary
    • Hearing and vision testing
    All will be assessed at pre-specified time points over 5 years

    • Quality of life: Pediatric Quality of Life Inventory/ Pediatric Quality of Life Inventory-Infant Scale, version 4.0
    • Healthcare resource utilization: chart review for hospital days, ER visits, ICU admissions, surgeries, need for hearing and visual aids
    All will be assessed at pre-specified time points over 5 years

    E.5.2.1Timepoint(s) of evaluation of this end point
    at 2 years and over 5 years
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans Yes
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA1
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Brazil
    Canada
    Turkey
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years8
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years8
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 28
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) Yes
    F.1.1.4.1Number of subjects for this age range: 28
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state3
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 3
    F.4.2.2In the whole clinical trial 28
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    As the study is designed to be a single open-label dosing, there will be no other therapies provided after the end of the subject participation in the trial.  The subject should continue seeking and receiving standard of care as clinically indicated.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-12-08
    N.Ethics Committee Opinion of the trial application
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion
    P. End of Trial
    P.End of Trial Status
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