Rituximab Versus Ravulizumab, Inebilizumab, Satralizumab, and Eculizumab in NMOSD

Phase 4

Not yet recruiting

• Conditions: NMOSD
• Interventions: Drug: Rituximab (R); Drug: Eculizumab (Soliris®); Drug: Inebilizumab; Drug: Satralizumab; Drug: Ravulizumab

• Registration Number: NCT07010302
• Lead Sponsor: Massachusetts General Hospital

Brief Summary

Neuromyelitis Optica Spectrum Disorder (NMOSD) is a rare autoimmune condition that mainly affects the eyes and spinal cord, causing serious symptoms such as vision loss, paralysis, and severe pain. This trial compares the effectiveness and safety of five medications commonly used to prevent NMOSD relapses: rituximab, ravulizumab, inebilizumab, satralizumab, and eculizumab.

In this study, 160 adults with NMOSD who test positive for a specific antibody (AQP4-IgG) will participate. They will be randomly assigned to receive either rituximab or one of the four other FDA-approved medications. The main goal is to find out which treatment best prevents relapses and has fewer serious side effects. The trial will also measure disability, patient satisfaction, quality of life, and biomarkers that help track disease activity.

Participants will have regular assessments, including medical exams, surveys, and tests for vision, walking ability, and brain function. They will report any side effects or health issues experienced during the study. The trial will last from one to four years for each participant.

This research aims to help patients and doctors make better-informed treatment decisions by providing clear evidence about the best available therapies for NMOSD.

Detailed Description

Neuromyelitis Optica Spectrum Disorder (NMOSD) is an autoimmune inflammatory disorder primarily affecting the optic nerves and spinal cord, leading to symptoms such as blindness, severe muscle weakness, paralysis, and significant pain. This study aims to directly compare the clinical effectiveness and safety profiles of five distinct therapies widely utilized to prevent disease relapses in patients with NMOSD who test positive for aquaporin-4 antibodies (AQP4-IgG): rituximab, ravulizumab, inebilizumab, satralizumab, and eculizumab.

The study is designed as an international, multicenter, randomized, adaptive clinical trial. It involves enrolling 160 adult participants diagnosed with AQP4-IgG positive NMOSD, who will be randomized in equal numbers to receive either rituximab or one of the four other FDA-approved therapies-ravulizumab, inebilizumab, satralizumab, or eculizumab. Patients randomized to the non-rituximab group will undergo further randomization into one of these four comparator medications. Additionally, the study incorporates an observational cohort for patients who decline randomization but agree to be followed according to the same protocol.

The primary objective is to evaluate the comparative effectiveness of rituximab versus the other treatments in preventing NMOSD relapses and treatment failure due to adverse events. Secondary objectives include comparing disability outcomes, evaluating treatment-related adverse events, and assessing impacts on patient-reported quality of life, as well as examining changes in biomarkers relevant to NMOSD disease activity.

Participants will undergo comprehensive evaluations at regular intervals, including detailed neurological examinations, standardized functional assessments (Expanded Disability Status Scale \[EDSS\], Multiple Sclerosis Functional Composite \[MSFC\]), visual acuity and contrast sensitivity testing, and cognitive assessments. Additionally, patient-reported outcomes such as fatigue, pain, mental health status, and overall quality of life will be collected systematically through validated surveys. Safety assessments will include regular monitoring of blood work, clinical evaluations for infections and other complications, and documentation of all adverse events.

Advanced exploratory analyses will also include biomarker studies involving optical coherence tomography (OCT) to assess retinal nerve fiber layer loss, and assays for serum neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) levels. The study will track direct and indirect healthcare costs, as well as impacts on employment and caregiver burden.

The duration of participation will range from one to four years, depending on when participants enroll and their clinical outcomes. All data will be rigorously analyzed using advanced statistical methods, including time-to-event analyses, mixed-effects models, and Bayesian hierarchical approaches to allow robust comparative effectiveness evaluations.

Ultimately, this research aims to provide high-quality, head-to-head data to inform clinical decision-making, optimize treatment strategies, and improve patient outcomes for those living with NMOSD.

Study Timeline

• Study First Submitted: 2025-05-21
• Study First Submitted QC: 2025-05-29
• Status Verified: 2025-06
• Last Update Submitted: 2025-06-06
• Study First Posted: 2025-06-08
• Last Update Posted: 2025-06-11
• Study Start: 2025-11
• Primary Completion: 2029-02
• Study Completion: 2030-02

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 160

Inclusion Criteria

• Diagnosis of NMOSD according to the 2015 International Panel for NMO Diagnosis (IPND) consensus criteria.
• Seropositivity for AQP4 immunoglobulin G (AQP4-IgG) confirmed by a cell-based assay (either live or fixed) that meets the threshold for positivity set by the local testing laboratory.
• Age ≥18 years at the time of consent.
• Ability and willingness to provide informed consent and comply with all study procedures, including scheduled visits, laboratory tests, and assessments.
• Eligible to receive any of the study drugs based on clinical judgment

Exclusion Criteria

• Known active hepatitis B virus (HBV) infection, defined as a positive hepatitis B surface antigen or detectable HBV DNA by PCR.
• Known active hepatitis C virus (HCV) infection, defined as detectable HCV RNA by PCR.
• Known active or latent tuberculosis, evidenced by a positive interferon-gamma release assay (IGRA) unless fully treated per local guidelines before enrollment.
• Known or suspected immunodeficiency disorders, including but not limited to HIV infection with CD4 count <200 cells/mm³ or any condition requiring chronic immunosuppressive therapy outside the scope of the study drugs.
• Pregnancy or breastfeeding, or intention to conceive during the study period. Pregnancy is excluded due to insufficient safety data for the investigational treatments in this population. Women of childbearing potential must agree to use effective contraception throughout the study and for a defined period following the last dose of study drug, per product labeling or institutional guidance.
• Any medical, psychiatric, or neurological condition that, in the investigator's opinion, may interfere with study participation, pose additional risk to the participant, or confound interpretation of study results.
• Inability or unwillingness to comply with the requirements of the protocol, including scheduled visits, evaluations, or procedures, based on investigator assessment.
• Known hypersensitivity or severe allergic reaction to any component of the study drugs or pre-medications required for infusion.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Rituximab	Rituximab (R)	-
Complement inhibitors	Eculizumab (Soliris®)	Ravulizumab or eculizumab
Complement inhibitors	Ravulizumab	Ravulizumab or eculizumab
Inebilizumab	Inebilizumab	-
Satralizumab	Satralizumab	-
Open-label, non-randomized	Rituximab (R)	Open-label, non-randomized
Open-label, non-randomized	Eculizumab (Soliris®)	Open-label, non-randomized
Open-label, non-randomized	Ravulizumab	Open-label, non-randomized
Open-label, non-randomized	Satralizumab	Open-label, non-randomized
Open-label, non-randomized	Inebilizumab	Open-label, non-randomized

Primary Outcome Measures

Name	Time	Method
Time to treatment discontinuation due to any reason	From date of randomization until the date of first treatment discontinuation or adjudicated relapse, whichever comes first, assessed up to 48 months	Includes adverse events, tolerability, patient preference, or logistical barriers.
Time to adjudicated relapse	From date of randomization until the date of adjudicated relapse or first treatment discontinuation, whichever comes first, assessed up to 48 months	As determined by the blinded Relapse Adjudication Committee using pre-specified clinical and imaging criteria

Secondary Outcome Measures

Name	Time	Method
McGill Pain Questionnaire Short Form	Baseline and every 6 months through study completion, an average of 30 months and a maximum of 48 months	Assesses both the intensity and quality of pain using 15 descriptors (11 sensory, 4 affective), a visual analog scale, and a present pain intensity index. Higher scores indicate more severe pain experience.
Brief Pain Inventory	Baseline and every 6 months through study completion, an average of 30 months and a maximum of 48 months	Evaluates pain severity and the impact of pain on daily functions. It includes both numeric rating scales and interference items related to activity, mood, walking, and sleep. Higher scores on severity and interference scales indicate more severe and impactful pain.
Expanded Disability Status Scale (EDSS)	Baseline and every 12 months through study completion, an average of 30 months and a maximum of 48 months	Quantifies the severity of disability in patients with neuroinflammatory disorders such as NMOSD. The scale ranges from 0 to 10 in half-point increments, where 0 indicates normal neurological function and 10 represents death due to neurological causes. Higher scores reflect greater disability.
Timed 25-Foot Walk	Baseline and every 12 months through study completion, an average of 30 months and a maximum of 48 months	Measures ambulatory function. Participants are instructed to walk 25 feet as quickly and safely as possible. The time to complete the walk is recorded; lower times indicate better function.
9-Hole Peg Test	Baseline and every 12 months through study completion, an average of 30 months and a maximum of 48 months	Assesses upper extremity function and fine motor coordination. Participants place and remove nine pegs into a pegboard as quickly as possible using one hand. The test is performed separately for each hand. The time to complete the task is recorded; shorter times reflect better performance.
Symbol Digit Modalities Test (SDMT)	Baseline and every 12 months through study completion, an average of 30 months and a maximum of 48 months	Evaluates cognitive processing speed. Participants are presented with a series of symbols matched with numbers and asked to substitute the corresponding number for each symbol within 90 seconds. The total number of correct responses is recorded; higher scores indicate better cognitive performance.
Landolt High Contrast Visual Acuity	Baseline and every 12 months through study completion, an average of 30 months and a maximum of 48 months	Assessed using Landolt ring optotypes under standard lighting conditions. Participants identify the orientation of the ring (gap in one of four cardinal directions). The number of correct responses is converted to a visual
Landolt Low Contrast Visual Acuity	Baseline and every 12 months through study completion, an average of 30 months and a maximum of 48 months	Assessed using Landolt ring optotypes at 2.5% contrast. Participants identify the orientation of the ring (gap in one of four cardinal directions). The number of correct responses is converted to a visual acuity ratio (Snellen equivalent). Higher ratios indicate better low contrast vision.
Treatment Satisfaction Questionnaire for Medication II (TSQM-II)	Baseline and every 6 months through study completion, an average of 30 months and a maximum of 48 months	Assesses patient satisfaction with medication across multiple domains, including effectiveness, side effects, convenience, and global satisfaction. Higher scores indicate greater satisfaction with treatment.
EuroQol 5-Dimension 5-Level (EQ-5D-5L)	Baseline and every 6 months through study completion, an average of 30 months and a maximum of 48 months	The descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression . Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. The patient is asked to indicate his/her health state by ticking the box next to the most appropriate statement in each of the five dimensions. This decision results in a 1-digit number that expresses the level selected for that dimension. The digits for the five dimensions can be combined into a 5-digit number that describes the patient's health state. Index values, calculated using country-specific value sets, range from less than 0 (health states considered worse than death) to 1 (full health). An associated visual analog scale (VAS) records the respondent's self-rated health on a scale from 0 (worst imaginable health) to 100 (best imaginable health).
Beck Depression Inventory-II	Baseline and every 6 months through study completion, an average of 30 months and a maximum of 48 months	21-item self-report questionnaire used to assess the severity of depressive symptoms in adults. Total scores categorize depression as minimal, mild, moderate, or severe.
General Anxiety Disorder-7	Baseline and every 6 months through study completion, an average of 30 months and a maximum of 48 months	7-item questionnaire used to screen for and measure the severity of generalized anxiety disorder. Scores range from 0 to 21, with higher scores indicating more severe anxiety symptoms.
Fatigue Scale for Motor and Cognitive Function	Baseline and every 6 months through study completion, an average of 30 months and a maximum of 48 months	20-item patient-reported measure assessing both motor and cognitive fatigue in individuals with neuroinflammatory diseases. It yields separate subscale scores and a total fatigue score; higher scores indicate greater fatigue.
Katz Index of Independence in Activities of Daily Living	Baseline and every 6 months through study completion, an average of 30 months and a maximum of 48 months	Assesses functional independence in six basic activities of daily living: bathing, dressing, toileting, transferring, continence, and feeding. Higher scores reflect greater independence.
Visual Function Questionnaire 25	Baseline and every 6 months through study completion, an average of 30 months and a maximum of 48 months	Neasures vision-related quality of life across 12 subscales, including general vision, ocular pain, and social functioning. It is designed for individuals with chronic eye diseases. Higher scores indicate better self-reported visual function.
Pittsburgh Sleep Quality Index	Baseline and every 6 months through study completion, an average of 30 months and a maximum of 48 months	19-item instrument that assesses sleep quality over a one-month period. It generates a global score based on seven domains. Higher scores indicate poorer sleep quality.
PainDETECT	Baseline and every 6 months through study completion, an average of 30 months and a maximum of 48 months	Sreening tool used to identify neuropathic components of pain. It includes questions about pain quality and pattern. Scores ≥19 suggest likely neuropathic pain.

Trial Locations

Locations (3)

Massachusetts General Hospital; 🇺🇸 Boston, Massachusetts, United States

Brigham and Women's Hospital; 🇺🇸 Boston, Massachusetts, United States

Charité - Universitätsmedizin Berlin; 🇩🇪 Berlin, Germany