Phase 3 Efficacy Study With Concurrent Control of IT MELPIDA in SPG50.Concurrent Controls.

Inclusion criteria

• Inclusion:
• For the treatment group
• Male and females between the ages of 4 months to 72 months at the time of screening.
• Molecularly-confirmed diagnosis of SPG50 (confirmed by a CLIA certified, CE-marked, or equivalent lab): Genomic DNA mutation analysis demonstrating bi-allelic pathogenic or likely pathogenic variants in the AP4M1 gene.
• Subjects must have features of neurologic dysfunction by clinical history and physical examination.
• Stable doses of concomitant medications?concomitant medications Other medicines a participant takes during the study. Some must be reported; some are restricted. such as anti-spasticity medications, anti-seizure medications, behavioral management medications, sleep medications, and special diets, supplements, or nutritional support for at least 3 months prior to Screening?prior to Screening The checks done before enrolment to see whether a person qualifies, such as tests, scans or a review of medical history.. If recent changes (< 3 months) in medications, the subject may be allowed per Investigator judgement.
• Parent/legal guardian?legal guardian A person who is legally allowed to make decisions, including consent to research, on behalf of someone who cannot consent for themselves. willing to provide written informed consent?written informed consent The process of explaining a study, including its risks and what participation involves, so that a person can decide freely whether to take part. Consent is usually documented in writing, and a participant can choose to leave the study later. for their child prior to participation in the study,
• Subjects and caregivers must demonstrate the ability to travel to the study center. For the 30 days post treatment subjects must reside within 100 miles (approximately 160 km) of the clinical site.
• For the control group?control group The group the study treatment is compared with. It may receive a placebo, an existing treatment (active comparator), a sham procedure, or no intervention.
• Male and females between the ages of 4 to 72 months at the time of screening.
• A molecularly confirmed diagnosis of SPG47, SPG50 or SPG52 (confirmed by a CLIA certified, CE-marked, or equivalent lab). Genomic DNA mutation analysis demonstrating bi-allelic pathogenic variants in the AP4B1, AP4M1, or AP4S1 gene,
• Subjects must have features of neurologic dysfunction by clinical history and physical examination.
• 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.
• Subjects and caregivers must demonstrate the ability to travel to the study center.
• Exclusion
• For the treatment group
• Loss of one of the 8 major motor milestones within the last 12 months. Milestones defined as:
• #24: Sit on mat: Maintain, arms free, 3 seconds
• #44: 4 Point: Crawls or hitches forward 1.8m (6')
• #53: Standing: Maintains, arms free, 3 seconds
• #67: Standing: 2 hands held: walks forward 10 steps
• #69: Standing: Walks forward 10 steps
• #84: Standing: Holding 1 rail: walks up 4 steps, holding 1 rail, alternating feet
• #85: Standing: Holding 1 rail: walks down 4 steps, holding 1 rail, alternating feet
• #88: Standing on 15cm (6") step: Jumps off, both feet simultaneously
• Inability to participate in the clinical evaluation as determined by the principal investigators.
• Clinically significant abnormal laboratory values (hemoglobin < 6 or > 20 g/dL; white blood cell > 20,000 per cmm, platelets count < 100,000 per cmm; INR > ULN?ULN The highest value of a blood test that a laboratory considers normal. Criteria such as '≤ 3 × ULN' mean the result must be no more than three times that value.; GGT, ALT, and AST or total bilirubin > 1.5 × ULN, creatinine ≥ 1.5 mg/dL) prior to gene replacement therapy.
• Presence of a concomitant medical condition (eg, scoliosis or bleeding disorder) that precludes a lumbar puncture?lumbar puncture A procedure in which a needle is placed between the bones of the lower back to collect spinal fluid or to give a treatment. or use of anesthetics for sedated procedures.
• Documented cardiomyopathy or significant congenital heart abnormalities.
• History of severe/life-threatening allergic reaction to sirolimus, tacrolimus, corticosteroids?corticosteroids Steroid medicines, such as prednisone, that reduce inflammation. Studies often require a stable dose at entry or measure whether the study treatment allows the dose to be reduced., or gadolinium.
• Concomitant illness or requirement for chronic drug treatment that in the opinion of the PI creates unnecessary risks for gene transfer, or interactions with the immunosuppressive?immunosuppressive A medicine that reduces the activity of the immune system. Studies of autoimmune conditions often require a stable dose, a prior failure, or a washout of such medicines. agents.
• Any item which would exclude the subject from being able to undergo MRI?MRI A scan that uses magnets and radio waves, not X-rays, to make detailed pictures of the inside of the body. Some implants and metal objects mean a person cannot have one. according to local institutional policy, or any other procedure.
• The presence of significant AP-4 related CNS impairment or behavioral disturbances that would confound the scientific rigor or interpretation of results of the study.
• Recent or planned elective surgical procedures (within 6 months) that would confound the scientific rigor or interpretation of results of the study.
• Failure to obtain appropriate informed consent.
• Reason to believe that the subject or parents of the subject will not comply with the study procedures outlined in the study protocol.
• Have received an investigational drug?investigational drug A treatment that is being tested and has not been approved for this use. It may be approved for a different condition. Being studied does not mean it works or is available outside the study. within 30 days prior to screening or plan to receive an investigational drug (other than gene therapy) during the study.
• Enrollment?Enrollment The number of participants a study plans to include, or has included. 'Estimated' means the planned number; 'actual' means the number who joined. and participation in another interventional?interventional A study in which researchers assign participants to one or more interventions, such as a drug, procedure, device, behavioural programme or other approach, to measure their effects. clinical trial 90 days before first visit (screening).
• For the control group
• Loss of one of the 8 major motor milestones within the last 12 months. Milestones defined as:
• #24: Sit on mat: Maintain, arms free, 3 seconds
• #44: 4 Point: Crawls or hitches forward 1.8m (6')
• #53: Standing: Maintains, arms free, 3 seconds
• #67: Standing: 2 hands held: walks forward 10 steps
• #69: Standing: Walks forward 10 steps
• #84: Standing: Holding 1 rail: walks up 4 steps, holding 1 rail, alternating feet
• #85: Standing: Holding 1 rail: walks down 4 steps, holding 1 rail, alternating feet
• #88: Standing on 15cm (6") step: Jumps off, both feet simultaneously
• Inability to participate in the clinical evaluation as determined by the principal investigators.
• Any other situation that would exclude the subject from undergoing any other procedure required in this study.
• The presence of significant AP-4 related CNS impairment or behavioral disturbances that would confound the scientific rigor or interpretation of results of the study.
• Recent or planned elective surgical procedures that would confound the scientific rigor or interpretation of results of the study.
• Failure to obtain appropriate informed consent.
• Reason to believe that the subject or parents of the subject will not comply with the study procedures outlined in the study protocol.
• Have received an investigational drug within 30 days prior to screening or plans to receive an investigational drug (other than gene therapy) during the study.
• Enrollment and participation in another interventional clinical trial 90 days before first visit (screening).