Rituximab Therapy in Anti-Myelin Associated Glycoprotein Patients With Characteristics of Good Responders:
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 90
- 试验地点
- 15
- 主要终点
- I-RODS score
研究概览
简要总结
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).
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
盲法说明
The randomization will be performed by the pharmacy. The treatment group will not be mentioned to the clinicians.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •- 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.
研究组 & 干预措施
Placebo
Patient with anti-MAG neuropathy will be included. They will randomized in placebo or Rituximab group.
They will have the same premedications prior to rituximab or placebo infusions:
- IV Dexchlorpheniramine Maleate IV: 10 mg
- IV Methylprednisolone: 40 mg
- PO Paracetamol : 1 gram
干预措施: Placebo infusion (Drug)
Placebo
Patient with anti-MAG neuropathy will be included. They will randomized in placebo or Rituximab group.
They will have the same premedications prior to rituximab or placebo infusions:
- IV Dexchlorpheniramine Maleate IV: 10 mg
- IV Methylprednisolone: 40 mg
- PO Paracetamol : 1 gram
干预措施: Premedications (Drug)
Rituximab
Patient with anti-MAG neuropathy will be included. They will randomized in placebo or Rituximab group.
They will have the same premedications prior to rituximab or placebo infusions:
- IV Dexchlorpheniramine Maleate IV: 10 mg
- IV Methylprednisolone: 40 mg
- PO Paracetamol : 1 gram
干预措施: Rituximab infusion (Drug)
Rituximab
Patient with anti-MAG neuropathy will be included. They will randomized in placebo or Rituximab group.
They will have the same premedications prior to rituximab or placebo infusions:
- IV Dexchlorpheniramine Maleate IV: 10 mg
- IV Methylprednisolone: 40 mg
- PO Paracetamol : 1 gram
干预措施: Premedications (Drug)
结局指标
主要结局
I-RODS score
时间窗: Baseline and 12 months
Clinical response defined as a 4 points (or more) change of I-RODS between baseline and 12 months. I-RODS is a 24-item patient-reported outcome measure which maximum score is 48. It is a linearly weighted scale that specifically captures activity and social participation limitations in patients with inflammatory neuropathies, including Monoclonal Gammopathy of Unknown Significance (MGUS) related polyneuropathies.
次要结局
- ElectroNeuroMyography (ENMG)(Months : 0, 6, 12)
- Score Motor unit number index (MUNIX)(Months : 0, 6, 12)
- the anti-MAG antibody titre.(Months : 0, 6, 12)
- Inflammatory Neuropathy Cause and Treatment (INCAT) disability score(Months: 0, 6, 12)
- Six minute walk test(Months : 0, 6, 12)
- 9 hole peg test(Months : 0, 6, 12)
- Incidence of Treatment-Emergent Adverse Events of Rituximab(Months : 0, 6, 12)
- Timed 25- foot walk (FW) test(Months : 0, 6, 12)
- ENMG sensory sum score(Months : 0, 6, 12)