Safety and Efficacy Evaluation of GC101 Gene Therapy Via Intrathecal (IT) Injectionin the Treatment of Patients With Type 2 Spinal Muscular Atrophy (SMA) - Phase III

Official title

A Multicenter, Randomized, Open-Label, Standard-of-Care-Controlled, Phase III Clinical Trial to Evaluate the Safety and Efficacy of Intrathecal (IT) Injection of GC101 Adeno-Associated Virus Injection in the Treatment of Patients With Type 2 Spinal Muscular Atrophy (SMA)

Overview

This trial employs a multicenter, randomized, open-label, standard-of-care-controlled design and plans to enroll 50 patients with Type 2 SMA aged 2 to 12 years who have previously received nusinersen. The primary objective of the trial is to evaluate the efficacy of GC101 in treating Type 2 SMA. The secondary objectives are to assess the efficacy, safety, and pharmacokinetic (PK) profile of GC101 in treating Type 2 SMA.

Detailed description

The trial is divided into two groups: one group will receive a single intrathecal injection of GC101 at a dose of 1.2E+14 vg per person and discontinue their previous standard-of-care treatment with nusinersen; the other group will continue their previous standard-of-care treatment with nusinersen. Participants will be randomly assigned to the trial group or the control group in a 1:1 ratio.

Interventions

• Genetic GC101 adeno-associated virus injection
  Self-complementary recombinant adeno-associated viral vector (scAAV) containing a single-stranded transgene encoding a codon-optimized human SMN1 gene

Primary outcome measures

• HFMSE score change from baseline [Time frame: 52 weeks]

Secondary outcome measures (6)

• HFMSE score change from baseline [Time frame: 26 weeks]
• The proportion of participants with an increase in HFMSE score of ≥3 points from baseline. [Time frame: 26 and 52 weeks]
• Changes in WHO-MGRS motor milestones from baseline. [Time frame: 26 and 52 weeks]
• RULM score change from baseline. [Time frame: 26 and 52 weeks]
• SMAIS score change from baseline. [Time frame: 26 and 52 weeks]
• The incidence of adverse events (AEs), serious adverse events (SAEs), and adverse events of special interest (AESIs). [Time frame: 52 weeks]

Eligibility criteria

Inclusion criteria

• Patients with a confirmed diagnosis of Type 2 5q-SMA through clinical phenotype and genetic testing.
• Patients who have been receiving regular treatment with nusinersen for more than one year prior to screening.
• Patients who have not received treatment with risdiplam within 2 months prior to screening and have no plans to receive risdiplam treatment within 12 months after enrollment.
• Patients who can sit independently but cannot walk independently at the time of screening (according to the definitions of independent sitting and walking in the WHO-MGRS motor milestones scale), and have an HFMSE score of ≥10 points.
• Patients and/or their legal guardians are able to understand and are willing to comply with the requirements and procedures of the trial protocol, and voluntarily participate and sign the informed consent form

Exclusion criteria

• Patients with serum anti-AAV9 neutralizing antibody titers > 1:50 at the time of screening.
• Patients who have received nusinersen treatment within 2 months prior to enrollment.
• Patients with any medical conditions that may affect the interpretation of study results or pose a risk to the safety of the participants, including but not limited to organ dysfunction of any cause, acute infectious diseases, primary/acquired immunodeficiency diseases, severe cardiovascular/cerebrovascular diseases, gastrointestinal diseases, diabetes, known epilepsy, meningitis, seizure or convulsion history, or a family history of psychiatric disorders; and those with cerebrospinal fluid circulation disorders.
• Patients with severe liver injury/hepatic insufficiency of any cause, including but not limited to alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≥3 times the upper limit of normal (ULN); total bilirubin (TBil) ≥1.5 times the ULN.
• Patients deemed by the investigator to have contraindications to glucocorticoid use, such as severe hypertension, diabetes, systemic infectious diseases, fungal infections, glaucoma, osteoporosis, peptic ulcer disease, tuberculosis, etc.
• Patients with contraindications to lumbar puncture or intrathecal injection therapy.
• Patients with any medical conditions that may affect the assessment of motor function, such as severe scoliosis, severe joint contracture deformities, planned spinal correction surgery during the trial period, severe osteoporosis, or a history of fractures.
• Patients positive for hepatitis B surface antigen (HBsAg), human immunodeficiency virus (HIV) antibodies, hepatitis C virus (HCV) antibodies, or syphilis antibodies.
• Patients who have received vaccinations within 2 weeks prior to dosing.
• Patients who have previously received gene therapy or participated in any clinical trial within 3 months prior to screening.
• Patients deemed by the investigator to be unsuitable for participation in this study.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 7 centers

• The Seventh Medical Center of Chinese PLA General Hospital — Beijing
• Children's Medical Center of Peking University First Hospital — Beijing
• Beijing Children's Hospital, Capital Medical University — Beijing
• National Children's Medical Center，Shanghai Jiaotong University — Shanghai
• Shenzhen Children's Hospital — Shenzhen
• Children's Hospital of Soochow University — Suzhou
• Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science & Techno — Wuhan

Identifiers

NCT: NCT06971094 · JLJY-GC101-SMA-011

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗