A Study of the Safety and Tolerability of GA in the Treatment of Patients With Refractory Neuropathic Pain

NCT06596681 | Recruiting Early Phase 1 DMC

• 1 other identifier: KY2024-157-03
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

Brief Summary

Previous studies have shown that the anterior cingulate cortex is involved in the regulation of pain and its associated negative emotions, that pyramidal neurons are highly excitable in chronic neuropathic pain conditions, and that silencing of pyramidal neurons can eliminate pain. The aim of this study was to evaluate the safety, tolerability, and efficacy of intracranial injection of GA (containing the hM4Di gene) in the anterior cingulate cortex in combination with oral clozapine for the treatment of refractory neuropathic pain.

Conditions

Pain, Intractable

Keywords

Refractory neuropathic pain; GA; clozapine; safety

Outcome Measures

Primary Outcomes (1)

• Incidence and severity of adverse events (AE)/serious adverse events (SAE) as assessed by CTCAE v5.0

  Patient-Reported Adverse Events, Abnormalities on Physical Examination, and Abnormalities in Laboratory Tests

  up to 28 weeks

Secondary Outcomes (13)

• effectiveness: the degree of pain improvement was assessed by visual analogue scale (VAS).

  Weeks 4, 8, and 12 of the effectiveness observation period

• effectiveness: the pain improvement was assessed by Brief pain inventory (BPI) scale.

  Weeks 4, 8, and 12 of the effectiveness observation period

• effectiveness: the degree of sleep quality improvement was assessed by Insomnia Severity Index (ISI).

  Weeks 4, 8, and 12 of the effectiveness observation period

• effectiveness: the sleep quality improvement was assessed by Daily Sleep Interference Scale (DSIS).

  Up to 28 weeks

• effectiveness: the depression improvement was assessed by Hamilton depression (HAMD) scale.

  Weeks 4, 8, and 12 of the effectiveness observation period

Other Outcomes (2)

• fMRI: Neuronal activation in ACC brain regions and connectivity of ACC brain regions with other brain regions

  up to 28 weeks

• Drug Dose Reduction

  up to 28 weeks

Study Arms (1)

GA intracranial injection combined with oral clozapine

EXPERIMENTAL

Patients were first given intracranial injections of GA , followed by the oral clozapine.

Genetic: GA+clozapine

Interventions

GA+clozapine GENETIC

Patients were first given intracranial injections of GA and observed for 14-28 days, followed by a dose-climbing trial of clozapine medication, and finally, after the investigators had determined an effective dose of clozapine, the patients were given a fixed dose of clozapine orally for three months.

GA intracranial injection combined with oral clozapine

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with a definitive diagnosis of neuropathic pain, including but not limited to painful diabetic peripheral neuropathy, trigeminal neuralgia, and post-stroke pain, aged 18-65 years old (regardless of gender), with:
• Regularised treatment with conventional medical therapy (including, but not limited to, medication, physiotherapy, cognitive therapy, nerve blocks and other non-invasive or minimally invasive treatments) for at least 3 months with no symptomatic relief or emergence of tolerance, as assessed by the investigator
• Pharmacological treatment means a full course of treatment with at least two first-line medications, as assessed by the investigator
• Mean visual analogue scale (VAS) value ≥4 cm and/or mean numerical rating scale (NRS) value ≥4 points within one week of baseline at enrolment
• Subjects volunteered to participate in the trial and gave fully informed consent to sign an informed consent form
• Have stable neurological status as assessed by the researcher through motor, sensory and reflex functions
• Subjects are considered reliable and able to comply with the trial protocol (e.g., able to understand and complete relevant scales), visit protocols, and medication administration, according to the investigator's judgement
• Subjects of childbearing potential agree to sign an informed consent form and have no plans to have children during the study period and voluntarily use effective contraception (oral contraceptives are prohibited) and do not plan to donate sperm or eggs

You may not qualify if:

• In patients with painful diabetic peripheral neuropathy, amputation due to diabetes mellitus or large (≥3cm) and/or gangrenous ulcers on the lower limbs 2.Currently diagnosed with progressive neurological disorders such as multiple sclerosis, chronic inflammatory demyelinating polyneuropathy, tumours of the brain or spinal cord, and neurodegenerative disorders, as determined by the investigators 3.Have a chronic systemic disease that, as assessed by the investigator, may affect the subject's participation in the study, including but not limited to:
• suffering from severe cardiopulmonary disease such as unstable angina, myocardial infarction, severe arrhythmia, recurrent asthma attacks, etc;
• Malignant tumours of the central nervous system or other systems. 4.Current status such as coagulation disorders, bleeding tendencies, platelet dysfunction, severely reduced function due to underlying cardiac/pulmonary disease, progressive peripheral vascular disease, or poorly controlled diabetes mellitus, and subjects who may be suffering from a relevant disease state that affects surgery as assessed by the investigator 5.Currently on anticoagulants and unable to stop them 6.Localised infection or active systemic infection at the anticipated surgical access site 7.History of previous intracranial surgical treatment (except for minimally invasive paracentesis for diagnostic tests, etc.) 8.Patients with severe psychiatric symptoms (e.g., major depression, schizophrenia, etc.) or significant suicidal tendencies or assessed by the investigator to be unable to complete the clinical trial 9. Pre-existing or concomitant severe hepatic dysfunction, renal dysfunction, cardiac dysfunction (in which severe hepatic dysfunction is defined as ALT ≥ 2.0 times the upper limit of normal or AST ≥ 2.0 times the upper limit of normal; severe renal dysfunction refers to a CRE ≥ 1.5 times the upper limit of normal or an eGFR \< 40mL/min/1.73m2; and severe cardiac dysfunction refers to an NYHA score of grade 3-4) ，delirium, hypotension, epilepsy, glaucoma, myelosuppression or leukopenia, severe central nervous system depression, or coma from any cause 10. Subjects with abnormal laboratory test values:
• <!-- -->
• white blood cell count \<3.5 x 109/L and neutrophil count \<1.0 x 109/L
• Platelet (PLT) \<75 x 109/L
• Coagulation: prothrombin time and activated partial thromboplastin time \>1.5 x ULN
• Blood adeno-associated virus (AAV) antibody titre \>1:1000 11.Patients taking drugs that cause granulocyte deficiency or have myelosuppressive effects 12.Patients with granulocyte deficiency or severe granulocytopenia due to prior clozapine use 13.Patients with contraindications and/or allergies to medications during the trial (e.g. clozapine or other components of clozapine, contrast agents, etc.) 14.Have gastrointestinal diseases (Crohn's disease, acute or chronic pancreatitis, paralytic intestinal obstruction, etc.) or major gastrointestinal surgeries that affect the absorption, metabolism and excretion of drugs, etc.
• Subjects had received any gene or cellular therapy 16. Known history of alcohol, drug abuse 17.Patients participating in other clinical trials or applying other investigational biologics, drugs or devices within six months prior to screening 18.Contraindications to MRI and functional MRI (e.g. claustrophobia, metallic foreign bodies in the body) 19.Clozapine-related serious adverse reactions are considered a screening failure if they occur during the screening period, at the judgement of the investigator

Sponsors & Collaborators

• Beijing Tiantan Hospital: lead

Study Sites (1)

Beijing Tiantan Hospital

Beijing, Beijing Municipality, 100070, China

RECRUITING

MeSH Terms

Conditions

Pain, Intractable; Neuralgia

Condition Hierarchy (Ancestors)

Pain; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Peripheral Nervous System Diseases; Neuromuscular Diseases; Nervous System Diseases

Study Officials

• Yilong Wang, Doctor

  Beijng tiantan hospital

  STUDY CHAIR

• Hua Pan, Doctor

  Beijng tiantan hospital

  STUDY DIRECTOR

• Fang Luo, Doctor

  Beijng tiantan hospital

  STUDY DIRECTOR

Central Study Contacts

Yahui Zhu, Doctor

CONTACT

13439182912; zhuyahuidr@sina.com

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: chief physician, professor

Model Details: A group of patients with refractory neuropathic pain

Study Record Dates

• First Submitted: August 27, 2024
• First Posted: September 19, 2024
• Study Start: September 11, 2024
• Primary Completion: March 31, 2026
• Study Completion (Estimated): June 30, 2026
• Last Updated: January 22, 2026

Record last verified: 2025-10

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)