- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT05518188
Melpida: Recombinant Adeno-associated Virus (Serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
A Phase 1/2 Open-label Intrathecal Administration of MELPIDA to Determine Its Safety and Efficacy for Patients With Spastic Paraplegia Type 50 (SPG50) Caused by Mutation in the AP4M1 Gene.
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
MELPIDA is a gene therapy product being developed for the treatment of Spastic Paraplegia Type 50 (SPG50), which is one of a group of four genetic disorders (SPG47, SPG50, SPG51 and SPG52) comprising AP-4 related Spastic Paraplegia (AP4-SPG). Inherited in an autosomal recessive pattern, AP-4- SPG is caused by biallelic pathogenic variants in one of 4 genes that encode components of the heterotrimeric adaptor protein complex 4 (AP4). Mutations in any of the components result in disrupted AP-4 function, and result in a common, shared clinical phenotype. Adaptor protein complexes such as AP-4 play key roles in signal-mediated trafficking of integral membrane proteins. They mediate vesicle formation and the cargo contained within these vesicles. While the precise function of the AP-4 complex is not fully understood, recent data suggests it plays an important role in protein sorting through the golgi, including regulation of trafficking of components required for autophagy. Deficiency in AP-4 leads to progressive neurodegeneration.
AP-4-HSP is an ultra-rare autosomal recessive disease with ~156 patients identified worldwide, 59 of which have the SPG50 subtype. There are approximately 9 patients with SPG50 in North America (OMIM #612936), ClinicalTrials.gov Identifier: NCT04712812. SPG50 is caused by biallelic pathogenic variants in the AP4M1 gene.
The AP4-deficiency syndrome (AP-4-HSP) is characterized by progressive spasticity, microcephaly, intellectual deficiency, dysmorphic traits, and growth retardation. Symptoms of AP-4-HSP begin in infancy, though patients are often not correctly identified and diagnosed until age 5 to 10 years. Patients experience progressive spastic paraplegia in the first decade of life, resulting in quadriplegia by adolescence or early adulthood with associated wheelchair dependence. There is also the presence of severe, progressive cognitive impairment. Epilepsy is an important co-morbidity present in the majority of cases. Only a few affected individuals have been identified to survive beyond age 30 year, though the extent of early mortality is yet to be fully elucidated.
Based on an AP-4-HSP natural history study currently in progress at Boston Children's Hospital (BCH), it is evident that disease severity ranges from child to child, but that most children fall into the severely affected (i.e. severe spasticity with paralysis and severe cognitive impairment) category. A small proportion of children, considered least severe, are able to speak in short sentences, walk with an abnormal gait, and have few to no seizures early on in the disease (less than 10 years of age). However, most children in this less severe category still experience progressive decline, ultimately losing the ability to walk and becoming quadriplegic between the ages of 10 and 20 years.
The majority of children with the SPG50 subtype of AP-4-HSP conform to a severe presentation, and are completely non-verbal, have microcephaly, never walk, have epilepsy and are severely cognitively impaired by the age of 10. It is not known how patients are affected later in life as very few have been identified beyond the age of 30. SPG50 is thus a degenerative neurological disease, affecting both cognitive and motor capabilities. Importantly, there is significant care giver burden, as all patients eventually require complete support for all activities of daily living from family and/or caregivers. There are no treatments currently available for patients with SPG50.
Study Type
Enrollment (Estimated)
Phase
- Phase 2
- Phase 1
Contacts and Locations
Study Contact
- Name: Sydney Cooper, MSc
- Phone Number: 214-250-0174
- Email: Sydney.Cooper@UTSouthwestern.edu
Study Locations
-
-
Texas
-
Dallas, Texas, United States, 75235
- Recruiting
- Children's Medical Center Dallas
-
Contact:
- SUSAN IANNACCONE, MD
- Phone Number: 214-456-5220
- Email: SUSAN.IANNACCONE@UTSouthwestern.edu
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- Age 1-10 years old
Confirmed diagnosis of SPG50 disease by:
- Genomic DNA mutation analysis demonstrating homozygous or compound heterozygous, confirmed 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
- Ability to stand for more than 5 seconds OR
- Ability to take 5 steps independently or with a walker OR
- Modified Ashworth Scale score 2 or below (Ankles).
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 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 × 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.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Treatment Arm
MELPIDA, a gene therapy product
|
MELPIDA, a recombinant serotype 9 adeno-associated virus (AAV) encoding a codon-optimized human AP4M1 transgene
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Incidence of unanticipated treatment-related toxicities, Grade 3 or higher in participants with SPG50
Time Frame: 60 months
|
Incidence of unanticipated treatment-related toxicities, Grade 3 or higher, in participants with SPG50 will be determined from the collection of occurrence and severity of serious adverse events (SAEs).
Adverse events will be determined according to Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.
|
60 months
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Stability or improvement in spasticity in participants with SPG50 as measured by the Modified Ashworth scale (MAS)
Time Frame: 60 months
|
Stability or improvement in spasticity in participants with SPG50 is measured by the Modified Ashworth scale (MAS) which is a muscle tone assessment scale used to assess the resistance experienced during passive range of motion.
Possible scores range from 0-4 where lower scores indicate better outcome.
|
60 months
|
Stability or improvement in spasticity in participants with SPG50 as measured by the Tardieu scale
Time Frame: 60 months
|
Stability or improvement in spasticity in participants with SPG50 is measured by the Tardieu scale which quantifies muscle spasticity by assessing the response of the muscle to stretch applied at specified velocities.
Possible scores range from 0-5 where lower scores indicate better outcome.
|
60 months
|
Collaborators and Investigators
Collaborators
Investigators
- Principal Investigator: Susan T. Iannaccone, MD, FAAN, UT Southwestern Medical Center
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Nervous System Diseases
- Neurologic Manifestations
- Congenital Abnormalities
- Musculoskeletal Diseases
- Muscular Diseases
- Neuromuscular Manifestations
- Craniofacial Abnormalities
- Musculoskeletal Abnormalities
- Malformations of Cortical Development, Group I
- Malformations of Cortical Development
- Nervous System Malformations
- Paralysis
- Muscle Hypertonia
- Microcephaly
- Muscle Spasticity
- Paraplegia
Other Study ID Numbers
- IND No 028202; Serial No 0000
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
IPD Sharing Time Frame
IPD Sharing Supporting Information Type
- STUDY_PROTOCOL
- SAP
- ICF
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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