Rituximab Therapy in Anti-Myelin Associated Glycoprotein Patients With Characteristics of Good Responders

Официальное название

Rituximab Therapy in Anti-Myelin Associated Glycoprotein Patients With Characteristics of Good Responders:

Обзор

Anti-MAG neuropathy is a progressively disabling orphan rare disorder due to a monoclonal immunoglobulin M(IgM) gammopathy displaying reactivity toward MAG, a glycoprotein of the peripheral nervous system. Its prevalence is around 1/100000 and to date, no treatment has proven efficacy in this disease, including rituximab in 2 Randomized Controlled Trails(RCTs).

Подробное описание

However these trials have included unselected anti-MAG patients and methodological issues have been raised.

In COFRAMAG study, the largest cohort worldwide of anti-MAG patients, predictors of clinical response to rituximab were identified through analysis of 92 treated patients: shorter disease duration and anti-MAG titre above 10000 BTU. Thus this study will focus on rituximab efficacy in a subset of patients with disease duration of less than 2 years and anti-MAG titre above 10000 Buhlmann Titer Units (BTU). The investigators selected Inflammatory Rasch-built Overall Disability Scale (I-RODS) as primary outcome measure because its responsiveness was proven higher than INCAT/ Overall Neuropathy Limitation Score (ONLS) scales to detect clinical meaningful changes in newly treated patients with inflammatory neuropathies.

Вмешательства

• Препарат Rituximab infusion
  2 infusions of 1 gram of rituximab at a 2 week interval (day 1 followed by day 15).
• Препарат Placebo infusion
  2 infusions of placebo at a 2 week interval.
• Препарат Premedications
  Premedications prior to rituximab or placebo infusions: * IV Dexchlorpheniramine Maleate IV: 10 mg * IV Methylprednisolone: 40 mg * PO Paracetamol : 1 gram

Первичные конечные точки

• I-RODS score [Срок оценки: Baseline and 12 months]

Вторичные конечные точки (9)

• Inflammatory Neuropathy Cause and Treatment (INCAT) disability score [Срок оценки: Months: 0, 6, 12]
• Six minute walk test [Срок оценки: Months : 0, 6, 12]
• Timed 25- foot walk (FW) test [Срок оценки: Months : 0, 6, 12]
• 9 hole peg test [Срок оценки: Months : 0, 6, 12]
• ElectroNeuroMyography (ENMG) [Срок оценки: Months : 0, 6, 12]
• ENMG sensory sum score [Срок оценки: Months : 0, 6, 12]
• Score Motor unit number index (MUNIX) [Срок оценки: Months : 0, 6, 12]
• Incidence of Treatment-Emergent Adverse Events of Rituximab [Срок оценки: Months : 0, 6, 12]
• the anti-MAG antibody titre. [Срок оценки: Months : 0, 6, 12]

Критерии участия

Критерии включения

• Disease duration of 5 years or less and documented clinical worsening (clinical or ENMG or disability) over the past 24 months
• IgM gammopathy, either MGUS or Waldenstrom Macroglobulinemia (WM)
• Demyelinating polyneuropathy according to European Federation of Neurological Societies/Peripheral Nerve Society guidelines for chronic inflammatory demyelinating polyneuropathy on nerve conduction studies.
• Anti-MAG titre of 10 000 BTU or more
• Total INCAT score of 1 point or more at baseline
• Absence of immunoglobulin treatment within 3 months prior to inclusion.
• Absence of immunosuppressive therapy within 6 months prior to inclusion, including steroid therapy of 2 months or more as part of the management of neuropathy.
• Negative β-human chorionic gonadotropin (HCG) in women of childbearing potential
• Women of childbearing potential must agree to use contraception for 365 days following administration of rituximab.

Критерии исключения

• \- Unable to give informed consent
• History of severe allergic or anaphylactic reaction to chimeric monoclonal antibody
• Hypersensitivity known to one of the compounds of polaramine or methylprednisolone
• Previous treatment with rituximab
• Diseases known to cause polyneuropathy (e.g. diabetes, uncontrolled thyroid disease, vitamin B1 or B12 deficiency, renal (GFR < 60ml ml/min/1,73 m2- Modification of Diet in Renal Disease (MDRD) formula) or liver disorder, myeloma, amyloidosis, cryoglobulinemia)
• Indication of specific immunosuppressive therapy for WM
• Significant uncontrolled disease at baseline such as cardiovascular (including cardiac arrhythmia), pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine or gastrointestinal or any other significant disease that may prevent patient from participating in the study
• Congestive heart failure (NYHA III or IV)
• Known active bacterial, viral, fungal mycobacterial infection
• History or known presence of recurrent or chronic infection (e.g. viral hepatitis, HIV syphilis, tuberculosis).
• History of cancer, including solid tumors and haematological malignancies (except basal cell and in situ squamous carcinoma of the skin, in situ carcinoma of the cervix of the uterus that have been excised and resolved, with documented clear margins on pathology)
• History of alcohol (more than two drinks a day for a woman, more than 4 glasses a day for a man \[World Health Organization (WHO) definition\]) or other drug abuse within 6 months prior to randomization
• History or currently active primary or secondary immunodeficiency
• White blood cell count < 1500/mm3 or platelet count < 75 000/mm3
• Angle closure glaucoma,
• Urinary retention related to urethroprostatic disorders,
• Uncontrolled psychotic disorders,
• Severe liver failure,
• Recent vaccination with live vaccines (<3months) and vaccination with live virus vaccines is not recommended during the overall study period.

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

Франция · 15 центров

• CHU Brest - La cavale blanche — Brest
• CHU Grenoble - La tronche — Grenoble
• CHU Lille - Roger Salengro — Lille
• CHU Limoges - Dupuytren — Limoges
• HCL lyon — Lyon
• CHU La Timone - APHM — Marseille
• CHU Nancy- Hôpital central — Nancy
• Hôtel-Dieu et Hôpital GR Laënnec - CHU Nantes — Nantes
• … и ещё 7 центров

Идентификаторы

NCT: NCT05136976 · 19PH226 · 2021-000009-25

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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