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The Evaluation of Efficacy and Safety of Rituximab (Genetical Recombination) in Refractory Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) Patients with Immunoglobulin G4 (IgG4) Autoantibodies in the Exploratory Clinical Trial (RECIPE Trial)

RECIPE Trial (RECIPE Trial)

Iijima Masahiro

Nagoya University Hospial

65 Tsurumai-cho, Showa-ku, Nagoya, Aich

ijama@med.nagoya-u.ac.jp

Shimizu Shinobu

Nagoya University Hospial

65 Tsurumai-cho, Showa-ku, Nagoya, Aich

+81-52-744-2942

s-shimizu@med.nagoya-u.ac.jp

Complete

Mar. 14, 2019

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

treatment purpose

1. Patients with definite CIDP diagnosed according to the modified diagnostic criteria of European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) (2010) by the time of enrollment in the study
2. Patients meeting one of the following conditions:
1) Patients with positive serum IgG4 autoantibody (CNTN-1 or NF-155) confirmed by the time of enrollment in the study
2) Patients with negative serum IgG4 autoantibody (CNTN-1 and NF-155) confirmed by the time of enrollment in the study
3. Patients with refractory CIDP not responding adequately to treatment with corticosteroids for 12 weeks, and intravenous immunoglobulin therapy (IVIg) for 8 weeks by the time of enrollment in the study, or those who are unable to administer or continue corticosteroids and IVIg
4. Patients with total adjusted Inflammatory Neuropathy Cause and Treatment (INCAT) Disability Scale scores of 2 to 8 at both preliminary enrollment and enrollment, and with the total score at enrollment equal to or worse than that at preliminary enrollment
5. Patients aged 12 years or older at informed consent
6. Patients who give their voluntary written consent after having received adequate information on this study (legally acceptable representatives should also give consent for underage patients, and informed assent should be obtained from children aged 12 to 15)

1. Patients with disease meeting one of the following exclusion criteria defined in the modified EFNS/PNS diagnostic criteria (2010).
1) Borrelia burgdorferi infection (Lyme disease), diphtheria, drug or toxin exposure probably to have caused the neuropathy Hereditary demyelinating neuropathy
2) Prominent sphincter disturbance
3) Diagnosis of multifocal motor neuropathy
4) IgM monoclonal gammopathy with high antibody titers to myelin-associated glycoprotein
5) Other causes for a demyelinating neuropathy including POEMS syndrome, osteosclerotic myeloma, diabetic and non-diabetic lumbosacral radiculoplexus neuropathy
PNS lymphoma and amyloidosis may occasionally have demyelinating features
2. Patients who have started or have increased the dose of corticosteroids for CIDP within 12 weeks prior to the enrollment
3. Patients who have started or have increased the dose of IVIg within 8 weeks prior to the enrollment
4. Patients who have undergone plasmapheresis within 8 weeks prior to the enrollment or patients with refractory disease not responding adequately to 8 weeks of plasmapheresis (plasma exchange or double-filtration plasmapheresis)
5. Patients who have started or have increased the dose of an immunosuppressant (azathioprine, cyclophosphamide, cyclosporine, mycophenolate mofetil, interferon alpha, interferon beta, etanercept, methotrexate, mitoxantrone, alemtuzumab, cladribine, tacrolimus, fingolimod) within 12 weeks prior to the enrollment
6. Patients who have undergone hematopoietic stem cell transplant prior to the enrollment
7. Patients who have used rituximab (genetical recombination) prior to the enrollment
8. Patients who have participated in another clinical study within 3 months prior to the enrollment (enrollment is allowed for those participating in a clinical study in the range of Indications or Dosage and Administration in Japan) or patients who are participating in another study
9. Patients with poorly controlled diabetes (HbA1c of 7 % or higher)
10. Patients who have or are suspected to have active infection (infection requiring treatment with systemic antimicrobial, antifungal, or antiviral agents) at the time of the enrollment
11. Patients tested positive for HBs antigen, HBs antibody, HBc antibody, and/or HCV antibody (patients with positive hepatitis B surface antibody or core antibody can be enrolled when a hepatitis B virus-DNA test is negative [below the limit of detection], and hepatitis B virus-DNA and aspartate/alanine transaminase levels are monitored at fixed intervals), or patients with positive HIV antibody or HTLV-1 antibody at the time of the enrollment
12. Patients with leukopenia (less than 2,000 /mm3), neutropenia (less than 1,000 /mm3), or lymphopenia (less than 500 /mm3) at the time of the enrollment
13. Patients with history of serious hypersensitivity or anaphylactic reaction to one of the ingredients in the investigational drug or murine protein-containing products
14. Patients with serious comorbidity (e.g., hepatic, renal, cardiac, lung, hematologic, or brain disease)
15. Female patients who are pregnant, lactating, or potentially pregnant, or patients who are not willing to use contraceptive measures during the study period
16. Patients who are judged to be unsuitable by the investigator or a sub-investigator

Both

Chronic Inflammatory Demyelinating Polyneuropathy

CIDP patients with positive IgG4 autoantibody (CNTN-1 or NF-155):
Administer 375 mg/m2 of rituximab (genetical recombination) or placebo IV infusion once weekly for 4 doses.
CIDP patients with negative IgG4 autoantibody (CNTN-1 and NF-155):
Administer 375 mg/m2 of rituximab (genetical recombination) IV infusion once weekly for 4 doses.

Chronic Inflammatory Demyelinating Polyneuropathy

Adjusted INCAT Disability Scale

1) Grip strength (left/right)
2) Rasch-built Overall Disability Scale (R-ODS)
3) Medical Research Council (MRC) Sum Score
4) Nerve conduction study (motor nerves: median, ulnar, tibial, and peroneal nerves)
5) Cerebrospinal fluid protein level
6) B cell counts (CD19 positive and CD20 positive cell counts) and T cell counts (CD3 positive, CD4 positive, and CD8 positive cell counts)
7) Expression of human antichimeric antibodies (HACA)
8) Serum rituximab (genetical recombination) level
9) Titer of serum IgG4 autoantibody (CNTN-1 and NF-155) and these IgG subclasses
10) Serum neurofilament
11) Adverse events
12) Vital signs, laboratory values

+81-52-744-1958

Dec. 21, 2018

+81-43-226-2616

Dec. 21, 2018

+81-836-22-2428

Dec. 21, 2018

+81-92-642-5774

Dec. 21, 2018

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