Back to resultsAdministration of MELPIDA to Determine the Safety and Efficacy for Patients With Spastic Paraplegia Type 50
Primary Purpose
Spastic Paraplegia Type 50
Status
Active
Phase
Phase 1
Locations
Canada
Study Type
Interventional
Intervention
MELPIDA
Sponsored by
About this trial
This is an interventional other trial for Spastic Paraplegia Type 50
Eligibility Criteria
Inclusion Criteria: Age < 5 years old Confirmed diagnosis of SPG50 disease by: Genomic DNA mutation analysis demonstrating homozygous or compound heterozygous, pathogenic and/or potentially pathogenic variants in the AP4M1 gene Clinical history or examination features consistent with SPG50 and that include neurologic dysfunction Parent/legal guardian willing to provide written informed consent for their child prior to participation in the study Subject able to comply with all protocol requirements and procedures Exclusion Criteria: Inability to participate in study procedures (as determined by the site investigator) Presence of a concomitant medical condition that precludes lumbar puncture (LP) or use of anesthetics History of bleeding disorder or any other medical condition or circumstance in which lumbar puncture is contraindicated according to local institutional policy Inability to be safely sedated in the opinion of the clinical anesthesiologist Active infection, at the time of dosing, based on clinical observations Concomitant illness or requirement for chronic drug treatment that in the opinion of the PI creates unnecessary risks for gene transfer Inability of the patient to undergo MRI according to local institutional policy Inability of the patient to undergo any other procedure required in this study The presence of significant non-SPG50 related central nervous system (CNS) impairment or behavioral disturbances that would confound the scientific rigor or interpretation of results of the study Have received an investigational drug within 30 days prior to screening or plan to receive an investigational drug (other than gene therapy) during the study. Enrollment and participation in another interventional clinical trial Contraindication to MELPIDA or any of its ingredients Contraindication to any of the immune suppression medications used in this study Clinically significant abnormal laboratory values (GGT, ALT, and AST, or total bilirubin > 3 × Upper Limit of Normal (ULN), creatinine ≥ 1.5 mg/dL, hemoglobin [Hgb] < 6 or > 20 g/dL; white blood cell (WBC) > 20,000 per cmm) prior to gene replacement therapy. Patients with an elevated bilirubin level that is unequivocally the result of neonatal jaundice shall not be excluded
Sites / Locations
- The Hospital for Sick Children
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
MELPIDA
Arm Description
A single intrathecal infusion of 10 mL at 1E14 vg/mL for a total dose of 1E15 vg (open-label)
Outcomes
Primary Outcome Measures
Incidence of unanticipated anticipated treatment-related toxicities, Grade 3 or higher
collection of occurrence and severity of serious adverse events. Incidence of serious adverse events and adverse events throughout the study, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Higher grade values indicated greater severity. Grade 1 - Grade 5.
Change from baseline in nerve conduction velocity
Nerve conduction studies will be used to determine nerve conduction velocity. Nerve conduction studies involve providing a small electrical stimulus to either a motor or sensor nerve and then measuring the resulting action potential at distal point of that nerve (for sensory nerve studies) or at the muscle that the nerve innervates (motor nerve studies). Velocity of conduction (measured between the two points and represented in m/s) will be obtained. The value is compared to standard reference values for age.
Determination of liver safety
Changes in Liver Ultrasound findings from baseline. Incidence of serious adverse events and adverse events throughout the study, as assessed by CTCAE v5.0
Determination of liver safety
Liver laboratory test: alanine transaminase (ALT) in U/L
Determination of liver safety
Liver laboratory test: aspartate aminotransferase (AST) in U/L
determination of liver safety
Liver laboratory test: Total bilirubins in umol/L
Determination of liver safety
Liver laboratory test: direct bilirubins in umol/L
Determination of liver safety
Liver laboratory test: alkaline phosphatase (ALP) in U/L
Determination of liver safety
Liver laboratory test: gamma-glutamyl transferase (GGT) in U/L
Change from baseline in nerve conduction amplitude
Nerve conduction study will be done to assess nerve conduction amplitude. Nerve conduction studies involve providing a small electrical stimulus to either a motor or sensor nerve and then measuring the resulting action potential at distal point of that nerve (for sensory nerve studies) or at the muscle that the nerve innervates (motor nerve studies). Amplitude of the action potential (measured at the distal site and represented in uV for sensory amplitudes and mV for motor amplitudes) will be obtained. The value is compared to standard reference values for age.
Secondary Outcome Measures
Stability or improvement in spasticity
Modified Ashworth scale (0-4). 0: no increase in muscle tone; 1: slight increase in muscle tone, manifested by a catch and release or by minimal resistance at the end of the range of motion when the affected part(s) is moved in flexion or extension; 1+: slight increase in muscle tone, manifested by a catch, followed by minimal resistance throughout the remainder (less than half) of the range of motion; 2: more marked increase in muscle tone through most of the range of motion, but affected part(s) easily moved; 3: considerable increase in muscle tone, passive movement difficult; 4: affected part(s) rigid in flexion or extension. Values reported separately for right and left upper and lower limbs.
Stability or improvement in spasticity
Tardieu scale (0-5). 0: no resistance throughout passive movement; 1: slight resistance throughout with no clear catch at a precise angle; 2: clear catch at a precise angle, followed by release; 3: fatiguable clonus (<10 seconds) occurring at a precise angle; 4: unfatiguable clonus (>10 seconds) occurring at a precise angle; 5: joint immobile. Values reported separately for right and left upper and lower limbs.
Full Information
NCT ID
NCT06069687
First Posted
August 17, 2023
Last Updated
October 5, 2023
Sponsor
The Hospital for Sick Children
1. Study Identification
Unique Protocol Identification Number
NCT06069687
Brief Title
Administration of MELPIDA to Determine the Safety and Efficacy for Patients With Spastic Paraplegia Type 50
Official Title
A Phase 1 Open-label Intrathecal Administration of MELPIDA to Determine the Safety and Efficacy for Patients With Spastic Paraplegia Type 50 (SPG50) Caused by a Mutation in the AP4M1 Gene
Study Type
Interventional
2. Study Status
Record Verification Date
October 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
March 11, 2022 (Actual)
Primary Completion Date
March 2027 (Anticipated)
Study Completion Date
March 2027 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
The Hospital for Sick Children
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
This will be a first-in-human Phase I, open-label, single dose clinical study of MELPIDA administered intrathecally (IT) through a lumbar puncture (LP) to a single subject with confirmed pathogenic mutations in the Adaptor Related Protein Complex 4 Subunit Mu 1 (AP4M1) gene. The primary outcome will be the determination of the safety and tolerability of MELPIDA in patients with SPG50, based on development of toxicity.
The secondary outcome will be a preliminary exploration of efficacy of the treatment.
MELPIDA, is a recombinant serotype 9 adeno-associated virus (AAV) encoding a codon-optimized human AP4M1 transgene and will be administer to the patient via a single intrathecal infusion of 10 mL at 1E14 vg/mL for a total dose of 1E15 vg.
The total study duration is 5 years post dosing and the participant will be tested at screening/baseline (-28 to -7 days), return for dosing, and then follow-up visits post-dosing on Days 7 (+/-2), 30 (+/-2), 60 (+/-2), 90 (+/-14), 180 (+/-14), 270 (+/-14), 360 (+/-14), 540 (+/-14), and 720 (+/-14) days, then annually for the last 3 years.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Spastic Paraplegia Type 50
7. Study Design
Primary Purpose
Other
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
1 (Actual)
8. Arms, Groups, and Interventions
Arm Title
MELPIDA
Arm Type
Experimental
Arm Description
A single intrathecal infusion of 10 mL at 1E14 vg/mL for a total dose of 1E15 vg (open-label)
Intervention Type
Biological
Intervention Name(s)
MELPIDA
Intervention Description
A single intrathecal infusion of 10 mL at 1E14 vg/mL for a total dose of 1E15 vg
Primary Outcome Measure Information:
Title
Incidence of unanticipated anticipated treatment-related toxicities, Grade 3 or higher
Description
collection of occurrence and severity of serious adverse events. Incidence of serious adverse events and adverse events throughout the study, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Higher grade values indicated greater severity. Grade 1 - Grade 5.
Time Frame
through study completion, an average of 5 years
Title
Change from baseline in nerve conduction velocity
Description
Nerve conduction studies will be used to determine nerve conduction velocity. Nerve conduction studies involve providing a small electrical stimulus to either a motor or sensor nerve and then measuring the resulting action potential at distal point of that nerve (for sensory nerve studies) or at the muscle that the nerve innervates (motor nerve studies). Velocity of conduction (measured between the two points and represented in m/s) will be obtained. The value is compared to standard reference values for age.
Time Frame
Screening, Day 21, and Month 3, 6, 12, 24, 36, 48 and 60
Title
Determination of liver safety
Description
Changes in Liver Ultrasound findings from baseline. Incidence of serious adverse events and adverse events throughout the study, as assessed by CTCAE v5.0
Time Frame
Screening, Month 6, 12, 24, 36, 48 and 60
Title
Determination of liver safety
Description
Liver laboratory test: alanine transaminase (ALT) in U/L
Time Frame
Screening, Day -1, 2, 7, 14, 21 and 28, and Month 3, 6, 9, 12, 18, 24, 36, 48 and 60
Title
Determination of liver safety
Description
Liver laboratory test: aspartate aminotransferase (AST) in U/L
Time Frame
Screening, Day -1, 2, 7, 14, 21 and 28, and Month 3, 6, 9, 12, 18, 24, 36, 48 and 60
Title
determination of liver safety
Description
Liver laboratory test: Total bilirubins in umol/L
Time Frame
Screening, Day -1, 2, 7, 14, 21 and 28, and Month 3, 6, 9, 12, 18, 24, 36, 48 and 60
Title
Determination of liver safety
Description
Liver laboratory test: direct bilirubins in umol/L
Time Frame
Screening, Day -1, 2, 7, 14, 21 and 28, and Month 3, 6, 9, 12, 18, 24, 36, 48 and 60
Title
Determination of liver safety
Description
Liver laboratory test: alkaline phosphatase (ALP) in U/L
Time Frame
Screening, Day -1, 2, 7, 14, 21 and 28, and Month 3, 6, 9, 12, 18, 24, 36, 48 and 60
Title
Determination of liver safety
Description
Liver laboratory test: gamma-glutamyl transferase (GGT) in U/L
Time Frame
Screening, Day -1, 2, 7, 14, 21 and 28, and Month 3, 6, 9, 12, 18, 24, 36, 48 and 60
Title
Change from baseline in nerve conduction amplitude
Description
Nerve conduction study will be done to assess nerve conduction amplitude. Nerve conduction studies involve providing a small electrical stimulus to either a motor or sensor nerve and then measuring the resulting action potential at distal point of that nerve (for sensory nerve studies) or at the muscle that the nerve innervates (motor nerve studies). Amplitude of the action potential (measured at the distal site and represented in uV for sensory amplitudes and mV for motor amplitudes) will be obtained. The value is compared to standard reference values for age.
Time Frame
Screening, Day 21, and Month 3, 6, 12, 24, 36, 48 and 60
Secondary Outcome Measure Information:
Title
Stability or improvement in spasticity
Description
Modified Ashworth scale (0-4). 0: no increase in muscle tone; 1: slight increase in muscle tone, manifested by a catch and release or by minimal resistance at the end of the range of motion when the affected part(s) is moved in flexion or extension; 1+: slight increase in muscle tone, manifested by a catch, followed by minimal resistance throughout the remainder (less than half) of the range of motion; 2: more marked increase in muscle tone through most of the range of motion, but affected part(s) easily moved; 3: considerable increase in muscle tone, passive movement difficult; 4: affected part(s) rigid in flexion or extension. Values reported separately for right and left upper and lower limbs.
Time Frame
Screening, Day -1, and Month 3, 6, 9, 12, 18, 24, 36, 48 and 60.
Title
Stability or improvement in spasticity
Description
Tardieu scale (0-5). 0: no resistance throughout passive movement; 1: slight resistance throughout with no clear catch at a precise angle; 2: clear catch at a precise angle, followed by release; 3: fatiguable clonus (<10 seconds) occurring at a precise angle; 4: unfatiguable clonus (>10 seconds) occurring at a precise angle; 5: joint immobile. Values reported separately for right and left upper and lower limbs.
Time Frame
Screening, Day -1, and Month 3, 6, 9, 12, 18, 24, 36, 48 and 60.
Other Pre-specified Outcome Measures:
Title
Motor function, neuropsychological, and disease burden assessments
Description
Bayley 4 (Fine Motor, Gross Motor, Cognitive & Language). Scores are aggregated for each domain into a scaled score. The highest possible score on a subtest or subdomain is 19, and the lowest possible score is 1. Scores from 8 to 12 are considered average.
Time Frame
Screening, Day -1, and Month 3, 6, 9, 12, 18, 24, 36, 48 and 60.
Title
Motor function, neuropsychological, and disease burden assessments
Description
Number of seizures per day (numerical value)
Time Frame
Screening, Day -1, 7, 14, 21 and 28, and Month 3, 6, 9, 12, 18, 24, 36, 48 and 60.
Title
Motor function, neuropsychological, and disease burden assessments
Description
Type of seizures, if applicable
Time Frame
Screening, Day -1, 7, 14, 21 and 28, and Month 3, 6, 9, 12, 18, 24, 36, 48 and 60.
Title
Motor function, neuropsychological, and disease burden assessments
Description
Seizure triggers, if applicable.
Trigger will be defined by any observer or the participant. An open answer format will be collected.
Time Frame
Screening, Day -1, 7, 14, 21 and 28, and Month 3, 6, 9, 12, 18, 24, 36, 48 and 60.
Title
Motor function, neuropsychological, and disease burden assessments
Description
Seizure rescue medication used, if applicable
Time Frame
Screening, Day -1, 7, 14, 21 and 28, and Month 3, 6, 9, 12, 18, 24, 36, 48 and 60.
Title
Motor function, neuropsychological, and disease burden assessments
Description
Clinical Global Impression of Overall Change by Physician (1-7); 1: very much improved to 7: very much worse. Single value reported.
Time Frame
Screening, Day -1, and Month 3, 6, 9, 12, 18, 24, 36, 48 and 60.
Title
Motor function, neuropsychological, and disease burden assessments
Description
Vineland (Comprehensive Parent/Caregiver Form). The domain scores are expressed as standard scores with a mean of 100 and standard deviation of 15; domains: communication, daily living skills, socialization and motor skills.
Time Frame
Screening, Day -1, and Month 3, 6, 9, 12, 18, 24, 36, 48 and 60.
Title
motor function, neuropsychological, and disease burden assessments
Description
Number of falls per day
Time Frame
Screening, Day -1, 7, 14, 21 and 28, and Month 3, 6, 9, 12, 18, 24, 36, 48 and 60.
Title
Motor function, neuropsychological, and disease burden assessments
Description
Causes of any falls reported, as applicable
Time Frame
Screening, Day -1, 7, 14, 21 and 28, and Month 3, 6, 9, 12, 18, 24, 36, 48 and 60.
Title
Motor function, neuropsychological, and disease burden assessments
Description
Clinical Severity of Illness by Physician (1-7); 1: normal, shows no sign of illness to 7: among the most extremely ill of patients. Single value reported.
Time Frame
Screening, Day -1, and Month 3, 6, 9, 12, 18, 24, 36, 48 and 60.
10. Eligibility
Sex
Male
Minimum Age & Unit of Time
0 Years
Maximum Age & Unit of Time
4 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Age < 5 years old
Confirmed diagnosis of SPG50 disease by:
Genomic DNA mutation analysis demonstrating homozygous or compound heterozygous, pathogenic and/or potentially pathogenic variants in the AP4M1 gene
Clinical history or examination features consistent with SPG50 and that include neurologic dysfunction
Parent/legal guardian willing to provide written informed consent for their child prior to participation in the study
Subject able to comply with all protocol requirements and procedures
Exclusion Criteria:
Inability to participate in study procedures (as determined by the site investigator)
Presence of a concomitant medical condition that precludes lumbar puncture (LP) or use of anesthetics
History of bleeding disorder or any other medical condition or circumstance in which lumbar puncture is contraindicated according to local institutional policy
Inability to be safely sedated in the opinion of the clinical anesthesiologist
Active infection, at the time of dosing, based on clinical observations
Concomitant illness or requirement for chronic drug treatment that in the opinion of the PI creates unnecessary risks for gene transfer
Inability of the patient to undergo MRI according to local institutional policy
Inability of the patient to undergo any other procedure required in this study
The presence of significant non-SPG50 related central nervous system (CNS) impairment or behavioral disturbances that would confound the scientific rigor or interpretation of results of the study
Have received an investigational drug within 30 days prior to screening or plan to receive an investigational drug (other than gene therapy) during the study.
Enrollment and participation in another interventional clinical trial
Contraindication to MELPIDA or any of its ingredients
Contraindication to any of the immune suppression medications used in this study
Clinically significant abnormal laboratory values (GGT, ALT, and AST, or total bilirubin > 3 × Upper Limit of Normal (ULN), creatinine ≥ 1.5 mg/dL, hemoglobin [Hgb] < 6 or > 20 g/dL; white blood cell (WBC) > 20,000 per cmm) prior to gene replacement therapy. Patients with an elevated bilirubin level that is unequivocally the result of neonatal jaundice shall not be excluded
Facility Information:
Facility Name
The Hospital for Sick Children
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 1X8
Country
Canada
12. IPD Sharing Statement
Learn more about this trial
Administration of MELPIDA to Determine the Safety and Efficacy for Patients With Spastic Paraplegia Type 50
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