Clinical trial NCT03864185: The Evaluation of Efficacy and Safety of Rituximab in Refractory CIDP Patients With IgG4 Autoantibodies
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP)
Keywords: IgG4 autoantibody
Neurofascin-155
Contactin-1
Rituximab
Lead sponsor: Nagoya University
Sponsor class: OTHER
Collaborators: name: Japan Agency for Medical Research and Development
name: Zenyaku Kogyo Co., Ltd.
First posted: 2019-03-06
Enrollment: 25
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: To evaluate the efficacy and safety of rituximab (genetical recombination) intravenously administered to CIDP patients with positive or negative IgG4 autoantibody.


Eligibility criteria: Inclusion Criteria:

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:

   (i) Patients with positive serum IgG4 autoantibody (CNTN-1 or NF-155) confirmed by the time of enrollment in the study

   (ii) 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 corticosteroid 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 corticosteroid 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)

Exclusion Criteria:

1. Patients with disease meeting one of the following exclusion criteria defined in the modified EFNS/PNS diagnostic criteria (2010).

   (i) Borrelia burgdorferi infection (Lyme disease), diphtheria, drug or toxin exposure probably to have caused the neuropathy Hereditary demyelinating neuropathy

   (ii) Prominent sphincter disturbance

   (iii) Diagnosis of multifocal motor neuropathy

   (iv) IgM monoclonal gammopathy with high titre antibodies to myelin-associated glycoprotein

   (v) 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 corticosteroid 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 underwent 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 underwent 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 HBs antibody or HBc 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

Primary outcomes:
measure: Rate of patients with improvement in adjusted Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale
timeFrame: Up to 52 weeks
Secondary outcomes:
measure: Change in grip strength (kPa)
timeFrame: Up to 52 weeks
measure: Change in Rasch-built Overall Disability Scale (R-ODS) score
timeFrame: Up to 52 weeks
measure: Change in Medical Research Council (MRC) Sum Score
timeFrame: Up to 52 weeks
measure: Change in motor nerve distal latency
timeFrame: Up to 52 weeks
measure: Change in motor nerve proximal latency
timeFrame: Up to 52 weeks
measure: Change in motor nerve compound muscle action potential (CMAP)
timeFrame: Up to 52 weeks
measure: Change in motor nerve conduction velocity
timeFrame: Up to 52 weeks
measure: Cerebrospinal fluid protein level
timeFrame: Up to 52 weeks
measure: B cell counts (CD19 positive and CD20 positive cell counts) and T cell counts (CD3 positive, CD4 positive, and CD8 positive cell counts)
timeFrame: Up to 52 weeks
measure: Expression of HACA
timeFrame: Up to 52 weeks
measure: Serum rituximab (genetical recombination) level
timeFrame: Up to 52 weeks
measure: Maximum serum concentration (Cmax) of rituximab (genetical recombination)
timeFrame: Up to 52 weeks
measure: Area under the curve (AUC) of blood concentration of rituximab (genetical recombination)
timeFrame: Up to 52 weeks
measure: Half-life (t1/2) of rituximab (genetical recombination)
timeFrame: Up to 52 weeks
measure: Clearance (CL) of rituximab (genetical recombination)
timeFrame: Up to 52 weeks
measure: Mean residence time (MRT) of rituximab (genetical recombination)
timeFrame: Up to 52 weeks
measure: Volume of distribution (Vds) of rituximab (genetical recombination) level
timeFrame: Up to 52 weeks
measure: Serum antibody titers of IgG4 (CNTN-1 and NF-155) and these IgG subclass
timeFrame: Up to 52 weeks
measure: Serum neurofilament
timeFrame: Up to 52 weeks
Other outcomes:
Locations:
city: Nagoya
country: Japan
facility: Nagoya University Hospital
state: Aich
city: Chiba
country: Japan
facility: Chiba University Hospital
city: Fukuoka
country: Japan
facility: Kyushu University Hospital
city: Ube
country: Japan
facility: Yamaguchi University Hospital
Study officials:
affiliation: Nagoya University Hospital
name: Masahiro Iijima, Ph. D
role: PRINCIPAL_INVESTIGATOR
References:
citation: Shimizu S, Iijima M, Fukami Y, Tamura N, Nakatochi M, Ando M, Nishi R, Koike H, Kaida K, Koga M, Kanda T, Ogata H, Kira JI, Mori M, Kuwabara S, Katsuno M. Efficacy and Safety of Rituximab in Refractory CIDP With or Without IgG4 Autoantibodies (RECIPE): Protocol for a Double-Blind, Randomized, Placebo-Controlled Clinical Trial. JMIR Res Protoc. 2020 Apr 1;9(4):e17117. doi: 10.2196/17117.