Phase I, open-label, single-arm, single-dose, trial of VGM-R02b (gene replacement therapy) in patients with Glutaric Acidemia Type I (GA-I) who meet enrollment criteria and are genetically confirmed by GCDH gene mutation. 1 to 3 patients aged≤ 6 years at the time of screening will be enrolled in each dose group in the dose escalation part. In the dose expansion part, the sample size will be statistically calculated and adjusted according to the efficacy and safety data in the dose escalation part.
This study consists of screening period, treatment period and postoperative monitoring period and follow-up period. During the screening period (Days -28 to -1), patients whose parent(s)/legal guardian(s) provide informed consent will complete screening procedures to determine eligibility for trial enrollment. Eligible subjects will be admitted to the clinical research center before surgical administration to complete the preoperative examination and determine the surgical plan. Ommaya fluid reservoir capsule implantation will be used in this study (if there were problems with Ommaya implantation, intra-cerebroventricular injection could also be used for drug administration). The day of administration set to be D1. Prophylactic immunosuppressive therapy including Methylprednisolone, Prednisolone and Rapamycin was initiated on D1. Then all the examinations during the 7-day postoperative observation period will be completed based on the evaluation time point specified in the Schedule of Assessments table. Subjects may be discharged 7 days after the infusion, based on Investigator judgment. During the outpatient follow-up period (up to 52 weeks after administration), subjects will return at regularly scheduled intervals for efficacy and safety assessments until the End of Trial. After the End of Trial visit, eligible patients will be asked to participate into the long-term follow up trial.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
12
Administered as specified in the treatment arm.
The Children's Hospital Zhejiang University Shcool of Medicine
Hangzhou, Zhejiang, China
RECRUITINGThe incidence and severity of AEs and SAEs
An AE is any untoward medical occurrence (eg any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a clinical investigation participant after providing written informed consent for participation in the study. Therefore, an AE may or may not be temporally or causally associated with the use of a medicinal (investigational) product.
Time frame: up to 52 weeks
Evaluate changes from baseline in vital signs, and clinical laboratory results
Clinically significant abnormal laboratory values or test results must be identified through a review of values outside of normal ranges/clinically notable ranges, significant changes from baseline or the previous visit, or values which are considered to be non-typical in participant with the underlying disease.
Time frame: up to 52 weeks
Changes in Barry Albright Dystonia Scale from baseline.
The BAD Scale is a 5-point, criterion-based, ordinal scale designed to assess dystonia in eight body regions: eyes, mouth, neck, trunk, and the four extremities. Raters score dystonia as none (0), slight (1), mild (2), moderate (3), or severe (4).
Time frame: up to 52 weeks
Changes in Peabody Developmental Motor Scale (PDMS-2) from baseline.
The Peabody Developmental Motor Scales, a norm referenced tool commonly used to assess infants' fine and gross motor development, also is widely used for children of preschool age.
Time frame: up to 52 weeks
Changes in Bayley Scales of Infant and Toddler Development (BSID) or Wechsler Preschool and Primary Scale of Intelligence (WPPSI) from baseline.
BSID is an extensive formal developmental assessment tool for diagnosing developmental delays in early childhood, this will be used in 1\~42 month patients. The WPPSI uses subtests to determine a child's Verbal and Performance IQ scores as well as the processing speed for children ages over 42 months.
Time frame: up to 52 weeks
Neuroimaging.
Changes in clinically significant abnormalities on brain MRI and MRS compared to Baseline.
Time frame: up to 52 weeks
Biomarkers.
Changes of C5DC GA, 3-OHGA in CSF and plasma.
Time frame: up to 52 weeks
Immunogenicity.
The antibody titer and the number of subjects with positive anti-AAV9 and anti-hGCDH antibodiesin the blood and CSF. The antibody titer and the number of subjects with positive anti-AAV9 and anti-hGCDH specific T cell immune response of peripheral blood mononuclear cells (PBMC).
Time frame: up to 52 weeks
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