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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| MELPIDA | Experimental | A single intrathecal infusion of 10 mL at 1E14 vg/mL for a total dose of 1E15 vg (open-label) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| MELPIDA | Biological | A single intrathecal infusion of 10 mL at 1E14 vg/mL for a total dose of 1E15 vg |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | through study completion, an average of 5 years |
| 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. | Screening, Day 21, and Month 3, 6, 12, 24, 36, 48 and 60 |
| 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 | Screening, Month 6, 12, 24, 36, 48 and 60 |
| Determination of liver safety | Liver laboratory test: alanine transaminase (ALT) in U/L | Screening, Day -1, 2, 7, 14, 21 and 28, and Month 3, 6, 9, 12, 18, 24, 36, 48 and 60 |
| Determination of liver safety | Liver laboratory test: aspartate aminotransferase (AST) in U/L | Screening, Day -1, 2, 7, 14, 21 and 28, and Month 3, 6, 9, 12, 18, 24, 36, 48 and 60 |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Motor function, neuropsychological, and disease burden assessments | 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. | Screening, Day -1, and Month 3, 6, 9, 12, 18, 24, 36, 48 and 60. |
Inclusion Criteria:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| The Hospital for Sick Children | Toronto | Ontario | M5G 1X8 | Canada |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 38942994 | Derived | Dowling JJ, Pirovolakis T, Devakandan K, Stosic A, Pidsadny M, Nigro E, Sahin M, Ebrahimi-Fakhari D, Messahel S, Varadarajan G, Greenberg BM, Chen X, Minassian BA, Cohn R, Bonnemann CG, Gray SJ. AAV gene therapy for hereditary spastic paraplegia type 50: a phase 1 trial in a single patient. Nat Med. 2024 Jul;30(7):1882-1887. doi: 10.1038/s41591-024-03078-4. Epub 2024 Jun 28. |
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| determination of liver safety | Liver laboratory test: Total bilirubins in umol/L | Screening, Day -1, 2, 7, 14, 21 and 28, and Month 3, 6, 9, 12, 18, 24, 36, 48 and 60 |
| Determination of liver safety | Liver laboratory test: direct bilirubins in umol/L | Screening, Day -1, 2, 7, 14, 21 and 28, and Month 3, 6, 9, 12, 18, 24, 36, 48 and 60 |
| Determination of liver safety | Liver laboratory test: alkaline phosphatase (ALP) in U/L | Screening, Day -1, 2, 7, 14, 21 and 28, and Month 3, 6, 9, 12, 18, 24, 36, 48 and 60 |
| Determination of liver safety | Liver laboratory test: gamma-glutamyl transferase (GGT) in U/L | Screening, Day -1, 2, 7, 14, 21 and 28, and Month 3, 6, 9, 12, 18, 24, 36, 48 and 60 |
| 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. | Screening, Day 21, and Month 3, 6, 12, 24, 36, 48 and 60 |
| Screening, Day -1, and Month 3, 6, 9, 12, 18, 24, 36, 48 and 60. |
| 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. | Screening, Day -1, and Month 3, 6, 9, 12, 18, 24, 36, 48 and 60. |
| Motor function, neuropsychological, and disease burden assessments | Number of seizures per day (numerical value) | Screening, Day -1, 7, 14, 21 and 28, and Month 3, 6, 9, 12, 18, 24, 36, 48 and 60. |
| Motor function, neuropsychological, and disease burden assessments | Type of seizures, if applicable | Screening, Day -1, 7, 14, 21 and 28, and Month 3, 6, 9, 12, 18, 24, 36, 48 and 60. |
| Motor function, neuropsychological, and disease burden assessments | Seizure triggers, if applicable. Trigger will be defined by any observer or the participant. An open answer format will be collected. | Screening, Day -1, 7, 14, 21 and 28, and Month 3, 6, 9, 12, 18, 24, 36, 48 and 60. |
| Motor function, neuropsychological, and disease burden assessments | Seizure rescue medication used, if applicable | Screening, Day -1, 7, 14, 21 and 28, and Month 3, 6, 9, 12, 18, 24, 36, 48 and 60. |
| Motor function, neuropsychological, and disease burden assessments | Clinical Global Impression of Overall Change by Physician (1-7); 1: very much improved to 7: very much worse. Single value reported. | Screening, Day -1, and Month 3, 6, 9, 12, 18, 24, 36, 48 and 60. |
| Motor function, neuropsychological, and disease burden assessments | 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. | Screening, Day -1, and Month 3, 6, 9, 12, 18, 24, 36, 48 and 60. |
| motor function, neuropsychological, and disease burden assessments | Number of falls per day | Screening, Day -1, 7, 14, 21 and 28, and Month 3, 6, 9, 12, 18, 24, 36, 48 and 60. |
| Motor function, neuropsychological, and disease burden assessments | Causes of any falls reported, as applicable | Screening, Day -1, 7, 14, 21 and 28, and Month 3, 6, 9, 12, 18, 24, 36, 48 and 60. |
| Motor function, neuropsychological, and disease burden assessments | 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. | Screening, Day -1, and Month 3, 6, 9, 12, 18, 24, 36, 48 and 60. |