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

Официальное название

A Comparative Clinical Effectiveness Trial of Rituximab Versus Ravulizumab, Inebilizumab, Satralizumab and Eculizumab To Prevent Relapses in Neuromyelitis Optica Spectrum Disorder

Обзор

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.

Подробное описание

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.

Вмешательства

• Препарат Rituximab (R)
  1000 mg at weeks 0 and 2 followed by 1000 mg every 6 months
• Препарат Eculizumab (Soliris®)
  900 mg weekly for 4 weeks, followed by 1200 mg every 2 weeks
• Препарат Ravulizumab
  * 40 to \< 60 kg: 2400 mg * 60 to \< 100 kg: 2700 mg * 100 kg: 3000 mg as an induction dose, followed by * 40 to \< 60 kg: 3000 mg * 60 to \< 100 kg: 3300 mg * 100 kg: 3600 mg Every 8 weeks starting 15 days after loading dose
• Препарат Satralizumab
  120 mg at Weeks 0, 2, 4, followed by 120 mg every 4 weeks
• Препарат Inebilizumab
  300 mg on Day 1 and Day 15, followed by 300 mg every 6 months

Первичные конечные точки

• Time to adjudicated safety or tolerability failure [Срок оценки: From date of randomization until the date of first adjudicated safety or tolerability failure or adjudicated relapse, whichever comes first, assessed up to 48 months]
• Time to adjudicated relapse [Срок оценки: From date of randomization until the date of adjudicated relapse or first treatment discontinuation, whichever comes first, assessed up to 48 months]

Вторичные конечные точки (12)

• Expanded Disability Status Scale (EDSS) [Срок оценки: Baseline and every 12 months through study completion, an average of 30 months and a maximum of 48 months]
• Timed 25-Foot Walk [Срок оценки: Baseline and every 12 months through study completion, an average of 30 months and a maximum of 48 months]
• 9-Hole Peg Test [Срок оценки: Baseline and every 12 months through study completion, an average of 30 months and a maximum of 48 months]
• Symbol Digit Modalities Test (SDMT) [Срок оценки: Baseline and every 12 months through study completion, an average of 30 months and a maximum of 48 months]
• Landolt High Contrast Visual Acuity [Срок оценки: Baseline and every 12 months through study completion, an average of 30 months and a maximum of 48 months]
• Landolt Low Contrast Visual Acuity [Срок оценки: Baseline and every 12 months through study completion, an average of 30 months and a maximum of 48 months]
• Treatment Satisfaction Questionnaire for Medication II (TSQM-II) [Срок оценки: Baseline and every 6 months through study completion, an average of 30 months and a maximum of 48 months]
• EuroQol 5-Dimension 5-Level (EQ-5D-5L) [Срок оценки: Baseline and every 6 months through study completion, an average of 30 months and a maximum of 48 months]
• PROMIS Depression Short form [Срок оценки: Baseline and every 6 months through study completion, an average of 30 months and a maximum of 48 months]
• Fatigue Scale for Motor and Cognitive Function [Срок оценки: Baseline and every 6 months through study completion, an average of 30 months and a maximum of 48 months]
• Visual Function Questionnaire 25 [Срок оценки: Baseline and every 6 months through study completion, an average of 30 months and a maximum of 48 months]
• Brief Pain Inventory [Срок оценки: Baseline and every 6 months through study completion, an average of 30 months and a maximum of 48 months]

Критерии участия

Критерии включения

• 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

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Двойное слепое

Основная цель

Лечение

Центры проведения

США · 2 центра

• Massachusetts General Hospital — Boston
• Brigham and Women's Hospital — Boston

Германия · 1 центр

• Charité - Universitätsmedizin Berlin — Berlin

Публикации

• Barreras P, Vasileiou ES, Filippatou AG, Fitzgerald KC, Levy M, Pardo CA, Newsome SD, Mowry EM, Calabresi PA, Sotirchos ES. Long-term Effectiveness and Safety of Rituximab in Neuromyelitis Optica Spectrum Disorder and MOG Antibody Disease. Neurology. 2022 Nov 29;99(22):e2504-e2516. doi: 10.1212/WNL.0000000000201260. Epub 2022 Aug 31. PMID 36240094
• Yamamura T, Weinshenker B, Yeaman MR, De Seze J, Patti F, Lobo P, von Budingen HC, Kou X, Weber K, Greenberg B. Long-term safety of satralizumab in neuromyelitis optica spectrum disorder (NMOSD) from SAkuraSky and SAkuraStar. Mult Scler Relat Disord. 2022 Oct;66:104025. doi: 10.1016/j.msard.2022.104025. Epub 2022 Jul 5. PMID 36007339
• Rensel M, Zabeti A, Mealy MA, Cimbora D, She D, Drappa J, Katz E. Long-term efficacy and safety of inebilizumab in neuromyelitis optica spectrum disorder: Analysis of aquaporin-4-immunoglobulin G-seropositive participants taking inebilizumab for ⩾4 years in the N-MOmentum trial. Mult Scler. 2022 May;28(6):925-932. doi: 10.1177/13524585211047223. Epub 2021 Oct 1. PMID 34595983
• Kumpfel T, Giglhuber K, Aktas O, Ayzenberg I, Bellmann-Strobl J, Haussler V, Havla J, Hellwig K, Hummert MW, Jarius S, Kleiter I, Klotz L, Krumbholz M, Paul F, Ringelstein M, Ruprecht K, Senel M, Stellmann JP, Bergh FT, Trebst C, Tumani H, Warnke C, Wildemann B, Berthele A; Neuromyelitis Optica Study Group (NEMOS). Update on the diagnosis and treatment of neuromyelitis optica spectrum disorders (N PMID 37676297
• Nosadini M, Alper G, Riney CJ, Benson LA, Mohammad SS, Ramanathan S, Nolan M, Appleton R, Leventer RJ, Deiva K, Brilot F, Gorman MP, Waldman AT, Banwell B, Dale RC. Rituximab monitoring and redosing in pediatric neuromyelitis optica spectrum disorder. Neurol Neuroimmunol Neuroinflamm. 2016 Jan 21;3(1):e188. doi: 10.1212/NXI.0000000000000188. eCollection 2016 Feb. PMID 26819962
• Rover C, Friede T. Dynamically borrowing strength from another study through shrinkage estimation. Stat Methods Med Res. 2020 Jan;29(1):293-308. doi: 10.1177/0962280219833079. Epub 2019 Mar 1. PMID 30821201
• Wingerchuk DM, Banwell B, Bennett JL, Cabre P, Carroll W, Chitnis T, de Seze J, Fujihara K, Greenberg B, Jacob A, Jarius S, Lana-Peixoto M, Levy M, Simon JH, Tenembaum S, Traboulsee AL, Waters P, Wellik KE, Weinshenker BG; International Panel for NMO Diagnosis. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology. 2015 Jul 14;85(2):177-89. doi: 10.1212 PMID 26092914
• Marcinno A, Marnetto F, Valentino P, Martire S, Balbo A, Drago A, Leto M, Capobianco M, Panzica G, Bertolotto A. Rituximab-induced hypogammaglobulinemia in patients with neuromyelitis optica spectrum disorders. Neurol Neuroimmunol Neuroinflamm. 2018 Sep 13;5(6):e498. doi: 10.1212/NXI.0000000000000498. eCollection 2018 Nov. PMID 30258855

Идентификаторы

NCT: NCT07010302 · 40200

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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