A Clinical Trial of BAT4406F Injection in Patients With Neuromyelitis Optica Spectrum Disorders

Study Overview
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Brief Summary
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This is a phase II/III multicenter, randomized, double-blind, placebo-controlled study, to investigate the efficacy and safety of BAT4406F injection in patients with neuromyelitis optica lineage disease (NMOSD) who are positive for aquaporin 4 antibody (AQP4-IgG) .

Detailed Description
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This study was a phase II/III multicenter, randomized, double-blind, placebo-controlled study, which was divided into screening period (4 weeks) , randomized control period (RCP) , and open-label period (Olp)A total of 162 subjects were enrolled during the screening period and randomly assigned 2:1 to either the BAT4406F group or the placebo group after randomization on Day 1 of the RCP, subjects would receive BAT4406F (at a dose of 500mg) or placebo, intravenously, at D 1 and D 182, respectively. If any of the following conditions occur, subjects can enter OLP from RCP: 1. Subjects who complete the 52-week RCP study without recurrence of NMOSD can enter Olp within 14 days after the end of the RCP study. 2. In the stage of RCP, NMOSD recurred. After rescue therapy, the patients with stable condition could enter OLP within 28 days after diagnosis. Subjects continued to participate in the RCP study if they were not identified by CEC as having a relapse upon examination. 3. When a protocol-defined first relapse event of 35 cases is observed, or when all 162 subjects have completed randomization and 12 months have elapsed since the first dose in the last of these subjects, or when recommended by the Independent Data Monitoring Committee (IDMC) , the RCP study should be stopped for enrolled subjects, and all enrolled subjects at the RCP stage should stop the RCP study within 14 days of entry into OLP, after which subjects will receive BAT4406F injection at the same dose as RCP, at d 1 of OLP. After termination of the RCP study with BAT4406F every 6 months, subjects were given the option of enrolling in the OLP study.

Official Title
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A Phase II/III Study to Evaluate the Efficacy and Safety of BAT4406F Injection in Patients With Neuromyelitis Optica Lineage Disease

Conditions
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Optic Neuromyelitis Spectrum Disease

Intervention / Treatment
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* Drug: BAT4406F Injection
* Drug: BAT4406F Placebos


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age greater than or equal to the age of 18 and less than or equal to 65 patients, gender not limited; Met the 2015 international NMO diagnostic panel (IPND) criteria for NMOSD, And AQP4-IGG positive patients Screening before 2 times at least 2 years experience with clinical records of relapse，or experienced at least 1 clinically documented recurrence within 1 year prior to screening For subjects who had a relapse before screening, symptoms needed to be stable for at least 4 weeks before randomization Into the group of former dosage of corticosteroids under 30 mg and prednisone equivalent，and the trial drug must be used within a month after the withdrawal of hormones The score of EDSS 7 or less Has the fertility of men and women must agree during treatment and 6 months after the last dose of using effective birth control method; Agreed to participate in trials, and books to sign the informed consent Exclusion Criteria: CD19 + b-cell count below the lower limit of normal, b-cell-scavenger drugs used 6 months before baseline or within 5 half-lives of the drug, whichever is older (including but not limited to Rituximab, enalizumab, etc.) ; 6 months prior to the baseline used other monoclonal antibody therapy;Baseline used within five half-life before other biological preparation; Used it for 3 months prior to the baseline McCaw phenol ester, azathioprine and methotrexate;6 months prior to the baseline using cyclophosphamide;Baseline before five half-life Within a month before the filter used intravenous immunoglobulin (IVIG), plasma exchange (PE); Within 4 weeks before screening received vaccine or live attenuated;Within 2 weeks before the baseline received inactivated vaccine;Baseline received within 4 weeks before the new coronavirus vaccine In another clinical study and the baseline from the test drug treatment under three months or 5 half-life of the drug (the long time limit shall prevail); This test for monoclonal antibody has a history of allergies, known in drug allergy patients;Serious drug allergy or for two or over two kinds of food or drugs； 6 months prior to screening, except NMOSD need continuous oral or intravenous glucocorticoid dose > 20 mg/day of any more than 21 days Abnormal liver, kidney and bone marrow reserve HIV positive at HIV history or enrollment screening; History of hepatitis B Andor hepatitis C or Hepatitis B surface antigen (HBSAG) positivity at screening [ or Hepatitis B core antibody positive, hepatitis B surface antibody negative, Hepatitis B virus deoxynucleotides (HBV DNA) quantification exceeding normal range ] ; Or Hepatitis C virus (HCV) antibody positive [ with HCV-rna quantitation exceeding the normal range ] , Treponema pallidum antibody positive at the time of enrollment; Comply with any of the following subjects a latent or active TB infection related standards: Current or past people with active TB; In history and/or physical examination during filter tip physical signs or symptoms of active TB; Recent close contact with people with active TB; At the time of screening, the positive result of TB infected T cells was found. A test could be repeated if the subject's first tb-infected t-cell test result was inconclusive, and the patient was excluded from this study if the test result was inconclusive (or positive) again. Covid-19 infection was diagnosed with clinical symptoms or signs consistent with 2019 coronavirus (COVID-19) infection (eg, fever, dry cough, dyspnea, sore throat, and fatigue) within 4 weeks before screening or during screening, or upon appropriate laboratory testing (at the discretion of the investigator or in accordance with local regulations) . If COVID-19 infection is confirmed before screening, appropriate laboratory testing is required to confirm that the infection has been cured; Suffering from metabolic, hematological, renal, hepatic, pulmonary, neuroendocrine, cardiac, infectious, gastrointestinal or other autoimmune diseases, the researchers believe there is an unacceptable risk to patients, or it may affect NMOSD assessment; According to the researchers, there was a history of drug and alcohol abuse (drinking 14 units of alcohol per week: 1 unit = 285 mL of beer, or 25 mL of spirits, or 125 mL of wine) in the 12 months before screening； Subjects who are unable to undergo an MRI scan (for example, are allergic to Gd-containing MRI contrast media, have a pacemaker, defibrillator, or other metallic object with internal or external limitations to performing an MRI scan) ; Pregnant or lactating women, and screening or baseline pregnancy test positive female subjects; Researchers think that the other does not fit to participate in this study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental group：BAT4406F<br>RCP：Intravenous infusion; Dosage:500mg/time; Time of administration:The drug was given at D 1 and D 182 respectively OLP：Intravenous infusion; Dosage:500mg/time; Time of administration: After D1 dosing, Every 6 months to 1 times | Drug: BAT4406F Injection<br>* Intravenous infusion; Dosage:500mg/time<br>|
| Active Comparator: Control group：BAT4406F Placebos<br>RCP：Intravenous infusion; Dosage:500mg/time; Time of administration:The drug was given at D 1 and D 182 respectively OLP：Intravenous infusion; Dosage:500mg/time; Time of administration: After D1 dosing, Every 6 months to 1 times | Drug: BAT4406F Placebos<br>* Intravenous infusion; Dosage:500mg/time<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacodynamics | The follow-up time point of peripheral blood before and after the analysis to the medicine CD19 + B lymphocytes proportion/count change | RCP: Day7, Day14, Day28, Day56, Day84, Day112, Day140, Day182, Day280, Day364. OLP:D7, D28, Day84, Day182, Day280, Day364. Week 40+26n (n=1, 2, 3.....) , Week 52+26n (n=1, 2, 3.....). And OLP maximum period for 3 years | 
| Pharmacodynamics | Serum immunoglobulin (IgG and IgM) levels were measured. | RCP:in Day84、Day182、Day280、Day364. OLP: in Day1、Day84、Day182、Day280、Day364 of every years.And OLP maximum period for 3 years | 
| Pharmacodynamics | AQP4-IgG levels were measured. | RCP:in Day84、Day182、Day280、Day364. OLP: in Day1、Day84、Day182、Day280、Day364 of every years.And OLP maximum period for 3 years | 
| Pharmacokinetics（PK） | Cmax | Through study completion,up to 49 months. And OLP maximum period for 3 years. | 
| Pharmacokinetics（PK） | Tmax | Through study completion,up to 49 months. And OLP maximum period for 3 years. | 
| Pharmacokinetics（PK） | Cmin | Through study completion,up to 49 months. And OLP maximum period for 3 years. | 
| Pharmacokinetics（PK） | AUC0-tau | Through study completion,up to 49 months. And OLP maximum period for 3 years. | 
| Pharmacokinetics（PK） | t1/2 | Through study completion,up to 49 months. And OLP maximum period for 3 years. | 
| Pharmacokinetics（PK） | CL | Through study completion,up to 49 months. And OLP maximum period for 3 years. | 
| Pharmacokinetics（PK） | Vd | Through study completion,up to 49 months. And OLP maximum period for 3 years. | 
| Immunogenicity evaluation | Resistant antibody positive rate (ADA) | RCP:in Day84、Day181、Day252、Day364. OLP: in Day84、Day181、Day252、Day364 of every years.And OLP maximum period for 3 years | 
| Immunogenicity evaluation | The titers of Ada positive samples | RCP:in Day84、Day181、Day252、Day364. OLP: in Day84、Day181、Day252、Day364 of every years.And OLP maximum period for 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Vital signs | Number of participants with abnormal vital signs | Through study completion,up to 49 months. And OLP maximum period for 3 years. | 
| physical examination | Number of participants with abnormal physical examination findings | Through study completion,up to 49 months. And OLP maximum period for 3 years. | 
| Laboratory tests | Number of participants with abnormal laboratory test results | Through study completion,up to 49 months. And OLP maximum period for 3 years. | 
| electrocardiogram（ ECG ） | Number of participants with abnormal ECG readings | Through study completion,up to 49 months. And OLP maximum period for 3 years. | 
| Adverse events（AE） | Adverse events (AE) is happening, is happening because of adverse events leading to withdrawal Adverse events associated with drugs The occurrence of Serious adverse events (SAE) | Through study completion,up to 49 months. And OLP maximum period for 3 years. | 
| Injection site reactions | Number of participants with injection site reactions | Through study completion,up to 49 months. And OLP maximum period for 3 years. |