Clinical trial NCT06217861: A Study to Evaluate the Tolerability, Safety and Efficacy of VGM-R02b
Official title: An Open-Label, Dose-Escalation and Dose-Expansion Phase I Clinical Study to Evaluate the Tolerability, Safety and Efficacy of VGM-R02b in Patients With Glutaric Acidemia Type I
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Glutaric Acidemia Type I
Glutaric Aciduria Type I
Keywords: AAV
gene therapy
ICV
GCDH
Lead sponsor: Shanghai Vitalgen BioPharma Co., Ltd.
Sponsor class: INDUSTRY
First posted: 2024-01-23
Enrollment: 12
Sex: ALL
Maximum age (years): 6
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

1. Subjects must be ≤ 6 years;
2. History of diagnosis of GA-I, and confirmed by gene mutation analysis with biallelic GCDH mutation;
3. At the time of screening, there was one of the obvious neurological manifestations associated with the following diseases, including macrocephaly, dystonia, and motor/intellectual development Poor fertility, epilepsy, abnormal EEG;
4. Those who are receiving standard treatment recommended by the guidelines and whose symptoms remain poorly controlled by the investigator;
5. Plasma GA and 3-OHGA levels were higher than the normal range during screening;

Exclusion Criteria:

1. Participation in gene therapy or stem cell transduction therapy at any time prior to screening for this trial or participation in any other clinical trial within 3 months prior to screening;
2. Recurrent seizures that are not suitable for surgery, based on Investigator judgment;
3. Current severe liver or kidney or cardiovascular disease or coagulation dysfunction, autoimmune deficiency, or uncontrolled autoimmune disease or need immunosuppressive long-term treatment, poorly controlled diabetes (HBA1C ≥7% at screening) or high blood pressure;
4. Active viral infection (includes HIV or serology positive for hepatitis B or C or syphilis);
5. Presence or history of malignancy;
6. Received systemic immunosuppressive therapy within 3 months prior to screening;
7. Received vaccine within 4 weeks prior to administration or plan to receive vaccine within 1 year after administration;
8. Plan to receive surgery during the study;
9. Current using medications including, drugs, herbal or OTC medications that strongly inhibit or induce CYP3A4 or P-glycoprotein (P-gp), e.g., metoclopramide, grapefruit juice, ketoconazole, erythromycin;
10. Abnormal brain structure, not suitable for lateral ventricle administration;
11. Abnormal laboratory test results, which are judged by the investigator not suitable for surgery;
12. History of systemic hypersensitivity reaction to investigational product, the excipients contained in the formulation, or prophylactic immunosuppressant;
13. Contraindicated use of corticosteroids and sirolimus;
14. Contraindicated with general anesthesia or sedation;
15. As judged by the investigator, unable to perform lateral ventricle puncture or Ommaya capsule implantation or lumbar puncture;
16. Unable to perform CT or MRI;
17. Poor compliance;
18. Any other situation where, judged by the investigator, the subject is not suitable for participating in this study.

Primary outcomes:
measure: The incidence and severity of AEs and SAEs
timeFrame: up to 52 weeks
measure: Evaluate changes from baseline in vital signs, and clinical laboratory results
timeFrame: up to 52 weeks
Secondary outcomes:
measure: Changes in Barry Albright Dystonia Scale from baseline.
timeFrame: up to 52 weeks
measure: Changes in Peabody Developmental Motor Scale (PDMS-2) from baseline.
timeFrame: up to 52 weeks
measure: Changes in Bayley Scales of Infant and Toddler Development (BSID) or Wechsler Preschool and Primary Scale of Intelligence (WPPSI) from baseline.
timeFrame: up to 52 weeks
measure: Neuroimaging.
timeFrame: up to 52 weeks
measure: Biomarkers.
timeFrame: up to 52 weeks
measure: Immunogenicity.
timeFrame: up to 52 weeks
Other outcomes:
Locations:
city: Hangzhou
country: China
facility: The Children's Hospital Zhejiang University Shcool of Medicine
state: Zhejiang
Study officials:
affiliation: The Children's Hospital Zhejiang University Shcool of Medicine
name: Qiang Shu
role: PRINCIPAL_INVESTIGATOR
affiliation: The Children's Hospital Zhejiang University Shcool of Medicine
name: Rulai Yang
role: PRINCIPAL_INVESTIGATOR
affiliation: The Children's Hospital Zhejiang University Shcool of Medicine
name: Guanping Dong
role: PRINCIPAL_INVESTIGATOR
References: