Modified Zipper Therapy for AQP4-IgG Positive Neuromyelitis Optica Spectrum Disorder

Phase 4RecruitingNCT07420296

Tianjin Medical University General Hospital198 enrolled

Overview

Study Title: A National, Multicenter, Randomized Controlled Trial of the Modified Zipper Therapy in AQP4 Antibody-Positive Neuromyelitis Optica Spectrum Disorder (ELITE Study) Brief Summary: The goal of this clinical trial is to evaluate the efficacy and safety of a novel sequential immunomodulation strategy, termed "Modified Zipper Therapy," in patients with acute attacks of Aquaporin-4 antibody-positive Neuromyelitis Optica Spectrum Disorder (AQP4-IgG+ NMOSD). The therapy aims to enhance neurological recovery by combining plasma exchange (PE) with immediate complement inhibition using eculizumab, following high-dose corticosteroid pulse therapy. The main questions this trial aims to answer are: Efficacy: Does the Modified Zipper Therapy (high-dose corticosteroids + plasma exchange + eculizumab) lead to a higher rate of neurological improvement at Week 12 compared to standard therapy (high-dose corticosteroids + plasma exchange alone)? For patients with NMOSD-related optic neuritis (NMOSD-ON), improvement is defined as a gain of ≥10 letters on the ETDRS chart or a decrease of ≥0.2 LogMAR in best-corrected visual acuity (BCVA). For patients with NMOSD-related longitudinally extensive transverse myelitis (NMOSD-LETM), improvement is defined as a reduction of ≥2 points on the Expanded Disability Status Scale (EDSS). Safety: What is the nature and frequency of adverse events experienced by participants receiving the Modified Zipper Therapy compared to those receiving standard therapy? Researchers will compare the Modified Zipper Therapy group to the Standard Therapy group to see if the novel combination is more effective in improving visual and functional outcomes in acute AQP4-IgG+ NMOSD. Participants will: Be randomly assigned (like a coin toss) to receive either the Modified Zipper Therapy or the Standard Therapy. Undergo a treatment period involving intravenous corticosteroids and a series of plasma exchange sessions. The Modified Zipper Therapy group will also receive intravenous eculizumab infusions timed around the plasma exchange procedures. Be followed for 24 weeks after treatment completion. Attend scheduled clinic visits for comprehensive assessments including: Visual acuity testing (using ETDRS, Snellen, and low-contrast charts). Neurological function evaluations (EDSS and OSIS scores). Optical coherence tomography (OCT) and visual evoked potential (VEP) tests. Magnetic resonance imaging (MRI) scans of the optic nerves. Safety monitoring (physical exams, lab tests, ECGs).

Study Type

INTERVENTIONAL

Allocation

Interventions

Eculizumab administrationBIOLOGICAL

Complement Inhibitor Therapy (Eculizumab): Initial Dose: Administer 900 mg of eculizumab intravenously immediately after the first PE session. Supplemental Doses: Administer supplemental doses (300-600 mg) after the 2nd, 3rd, and 4th PE sessions. The exact dose will be adjusted in real-time based on drug clearance post-PE. Maintenance Therapy: Administer three additional 900 mg intravenous infusions on the day of the last PE session, and at the 1st and 2nd weeks after its completion, to consolidate efficacy and maintain stable complement inhibition.

High-dose corticosteroid pulse therapyDRUG

High-Dose Corticosteroid Pulse: Intravenous methylprednisolone (IVMP) 1000 mg daily for 3 days, then 500 mg daily for 3 days, followed by 250 mg daily for 3 days, and finally 125 mg daily for 3 days. Subsequently, switch to oral prednisone at 1 mg/kg/day, tapered by 5 mg weekly until a maintenance dose of 10 mg/day is reached, which is continued for 6 months.

Plasma exchange (PE)PROCEDURE

Plasma Exchange (PE) Therapy: Initiated concurrently with corticosteroids. Perform at least 5 PE sessions every other day. Each session exchanges 1.0-1.5 times the plasma volume. Treatment intervals may be adjusted based on fibrinogen levels and bleeding risk.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 80 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Participants ≥ 18 years of age 2. Definite diagnosis according to the 2015 IPND diagnostic criteria for AQP4-IgG-positive NMOSD 3. Seropositivity for anti-AQP4 antibody. 4. Time from onset to enrollment ≤ 30 days. 5. For patients with optic neuritis: visual acuity ≤ 20/200 at screening; for relapse cases, baseline visual acuity prior to this acute episode must have been ≥ 20/60. 6. For patients with longitudinal extensive transverse myelitis (LETM): EDSS score ≥ 5.5 at screening; for relapse cases, baseline EDSS score prior to this acute episode must have been ≤ 3.5. 7. Ability to understand and voluntarily provide written informed consent- Exclusion Criteria: 1. Patients with concurrent neuromuscular disorders. 2. Patients with severe coagulation dysfunction. 3. Patients with known allergy to plasma or intravenous immunoglobulin (IVIG). 4. Patients with active hepatitis B or C virus infection, human immunodeficiency virus (HIV) infection, or those deemed at high risk for the onset or reactivation of syphilis or tuberculosis at screening. 5. Patients with active systemic infection at screening, or a history of severe chronic or recurrent infections. 6. Pregnant or lactating patients. 7. Patients with chronic, severe medical conditions that may affect study compliance. 8. Patients with any clinically significant abnormal laboratory findings as determined by the investigator (e.g., severe anemia, leukopenia, thrombocytopenia, etc.). 9. Patients whom the investigator considers unlikely to complete the study or unlikely to comply with the study requirements (for administrative reasons or otherwise).

Outcomes

Primary Outcomes

Best corrected visual acuity

Time frame: Baseline, Week 12

Expanded Disability Status Scale (EDSS)

The Expanded Disability Status Scale (EDSS) is an ordinal scale ranging from 0 to 10, with higher scores indicating worse neurological impairment and disability in patients with neuromyelitis optica spectrum disorder (NMOSD)

Time frame: Baseline, Week 12

Secondary Outcomes

Best corrected visual acuity

Time frame: Baseline, Week 4, Week 24,

Expanded Disability Status Scale (EDSS)

Time frame: Baseline, Week 4, Week 24,

Optic-Spinal Impairment Score(OSIS)

The Optic-Spinal Impairment Score (OSIS) is a composite scale specifically designed for neuromyelitis optica spectrum disorder (NMOSD), assessing visual function (0-8), motor function (0-7), sensory function (0-5), and sphincter function (0-5). Higher scores reflect greater severity of optic and spinal cord dysfunction, indicating a worse outcome.

Time frame: Baseline, Week 4, Week 12, Week 24

Visual Evoked Potential P100 Wave Latency

Mean change from baseline in P100 wave latency, measured by visual evoked potential (VEP), at Week 12, and Week 24. P100 latency is expressed in milliseconds (ms). Longer latency indicates delayed neural conduction and worse visual pathway function; a greater reduction from baseline reflects a better outcome.