Clinical trial NCT05136976: Rituximab Therapy in Anti-Myelin Associated Glycoprotein Patients With Characteristics of Good Responders
Official title: Rituximab Therapy in Anti-Myelin Associated Glycoprotein Patients With Characteristics of Good Responders:
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Anti-MAG Neuropathy
Keywords: Neuropathy
Anti-MAG
Rituximab
I-RODS
placebo
Lead sponsor: Centre Hospitalier Universitaire de Saint Etienne
Sponsor class: OTHER
Collaborators: name: Ministry of Health, France
First posted: 2021-11-30
Enrollment: 90
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The THERAMAG study is a French academic multicentre, randomized, double-blind trial sponsored by the University Hospital of Saint-Etienne, comparing rituximab infusion to placebo infusion in anti-MAG patients presumed as good clinical responders.
Primary purpose: TREATMENT

Brief summary: 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).

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* 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.

Exclusion Criteria:

* - 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.

Primary outcomes:
measure: I-RODS score
timeFrame: Baseline and 12 months
Secondary outcomes:
measure: Inflammatory Neuropathy Cause and Treatment (INCAT) disability score
timeFrame: Months: 0, 6, 12
measure: Six minute walk test
timeFrame: Months : 0, 6, 12
measure: Timed 25- foot walk (FW) test
timeFrame: Months : 0, 6, 12
measure: 9 hole peg test
timeFrame: Months : 0, 6, 12
measure: ElectroNeuroMyography (ENMG)
timeFrame: Months : 0, 6, 12
measure: ENMG sensory sum score
timeFrame: Months : 0, 6, 12
measure: Score Motor unit number index (MUNIX)
timeFrame: Months : 0, 6, 12
measure: Incidence of Treatment-Emergent Adverse Events of Rituximab
timeFrame: Months : 0, 6, 12
measure: the anti-MAG antibody titre.
timeFrame: Months : 0, 6, 12
Other outcomes:
Locations:
city: Brest
country: France
facility: CHU Brest - La cavale blanche
city: Grenoble
country: France
facility: CHU Grenoble - La tronche
city: Lille
country: France
facility: CHU Lille - Roger Salengro
city: Limoges
country: France
facility: CHU Limoges - Dupuytren
city: Lyon
country: France
facility: HCL lyon
city: Marseille
country: France
facility: CHU La Timone - APHM
city: Nancy
country: France
facility: CHU Nancy- Hôpital central
city: Nantes
country: France
facility: Hôtel-Dieu et Hôpital GR Laënnec - CHU Nantes
city: Nice
country: France
facility: CHU Nice - Pasteur
city: Paris
country: France
facility: APHP Pitié Salpêtrière
city: Paris
country: France
facility: APHP - Kremlin-Bicêtre
city: Saint-Étienne
country: France
facility: CHU de Saint-Etienne
city: Strasbourg
country: France
facility: CHU Strasbourg - Hautepierre
city: Toulouse
country: France
facility: CHU Toulouse - Pierre-Paul Riquet
city: Tours
country: France
facility: CHU Tours - Bretonneau
Study officials:
affiliation: CHU de Saint-Etienne
name: Anne-Laure KAMINSKY, MD
role: PRINCIPAL_INVESTIGATOR
References: