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The Evaluation of Efficacy and Safety of Rituximab in Refractory CIDP Patients With IgG4 Autoantibodies (RECIPE)

Primary Purpose

Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP)

Status
Completed
Phase
Phase 2
Locations
Japan
Study Type
Interventional
Intervention
Rituximab (genetical recombination)
Placebo
Sponsored by
Nagoya University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP) focused on measuring IgG4 autoantibody, Neurofascin-155, Contactin-1, Rituximab

Eligibility Criteria

12 Years - undefined (Child, Adult, Older Adult)All SexesAccepts Healthy Volunteers

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

Sites / Locations

  • Nagoya University Hospital
  • Chiba University Hospital
  • Kyushu University Hospital
  • Yamaguchi University Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Placebo Comparator

Active Comparator

Arm Label

Rituximab group (IgG4 autoantibody positive)

Placebo group (IgG4 autoantibody positive)

Rituximab group (IgG4 autoantibody negative)

Arm Description

Outcomes

Primary Outcome Measures

Rate of patients with improvement in adjusted Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale
Primary analysis will compare scores of adjusted INCAT Disability Scale evaluated prior to treatment (at the time of enrollment) and scores at each timepoint after week 26 to calculate the proportion of patients who achieve an improvement of one and more from the baseline. The INCAT Disability Scale is an index to evaluate disorders in lower (gait) and upper (elevation of the upper arms and fine movement of the fingertips) extremities. The INCAT score is a 10-point scale and ranges from 0 (normal) to 10 (worst). For the "adjusted" INCAT score, a change in upper extremity score from 0 to 1 or 1 to 0 will not be considered meaningful in this evaluation.

Secondary Outcome Measures

Change in grip strength (kPa)
The differences of Grip strength (kPa) between prior to treatment and at each timepoint are summarized.
Change in Rasch-built Overall Disability Scale (R-ODS) score
The differences of R-ODS score between prior to treatment and at each timepoint are summarized. R-ODS is consist of a 24-item questionnaire about daily living task with 3 response options: (0) "impossible to perform," (1) "performed with difficulty," and (2) "easily performed. The R-ODS score is a 48-point scale (range: 0-48), and is converted into a centile metric score with values ranging from 0 (most severe activity and social participation limitations) to 100 (no activity and social participation limitations).
Change in Medical Research Council (MRC) Sum Score
The differences of MRC Sum Score between prior to treatment and at each timepoint are summarized. The MRC Sum Score is a scale to assess for 8 muscle groups (right and left side) as follow: Shoulder abduction, Elbow flexion, Wrist extension, Index finger abduction, Hip flexion, Knee extension, Foot dorsiflexion, Great toe dorsiflexion.The MRC Sum Score is a 80-point scale and ranges from 0 (paralysis) to 80 (normal strength).
Change in motor nerve distal latency
The differences of distal latency between prior to treatment and at each timepoint are summarized.
Change in motor nerve proximal latency
The differences of proximal latency between prior to treatment and at each timepoint are summarized.
Change in motor nerve compound muscle action potential (CMAP)
The differences of CMAP between prior to treatment and at each timepoint are summarized.
Change in motor nerve conduction velocity
The differences of motor nerve conduction velocity between prior to treatment and at each timepoint are summarized.
Cerebrospinal fluid protein level
Cerebrospinal fluid protein level at each timepoint are summarized.
B cell counts (CD19 positive and CD20 positive cell counts) and T cell counts (CD3 positive, CD4 positive, and CD8 positive cell counts)
B cell counts (CD19 positive and CD20 positive cell counts) and T cell counts (CD3 positive, CD4 positive, and CD8 positive cell counts) at each timepoint are summarized.
Expression of HACA
The number of patients expressing HACA, and the proportion and its 95% confidence interval of these patients at each timepoint are summarized.
Serum rituximab (genetical recombination) level
Serum rituximab (genetical recombination) level at each timepoint are summarized.
Maximum serum concentration (Cmax) of rituximab (genetical recombination)
Cmax of rituximab (genetical recombination) is summarized.
Area under the curve (AUC) of blood concentration of rituximab (genetical recombination)
AUC of blood concentration of rituximab (genetical recombination) is summarized.
Half-life (t1/2) of rituximab (genetical recombination)
t1/2 of rituximab (genetical recombination) is summarized.
Clearance (CL) of rituximab (genetical recombination)
CL of rituximab (genetical recombination) is summarized.
Mean residence time (MRT) of rituximab (genetical recombination)
MRT of rituximab (genetical recombination) is summarized.
Volume of distribution (Vds) of rituximab (genetical recombination) level
Vds of rituximab (genetical recombination) is summarized.
Serum antibody titers of IgG4 (CNTN-1 and NF-155) and these IgG subclass
Serum titers (CNTN-1 and NF-155, and these IgG subclasses 1 to 4) at each timepoint are summarized.
Serum neurofilament
Serum neurofilament level at each timepoint is summarized.

Full Information

First Posted
February 19, 2019
Last Updated
August 19, 2021
Sponsor
Nagoya University
Collaborators
Japan Agency for Medical Research and Development, Zenyaku Kogyo Co., Ltd.
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1. Study Identification

Unique Protocol Identification Number
NCT03864185
Brief Title
The Evaluation of Efficacy and Safety of Rituximab in Refractory CIDP Patients With IgG4 Autoantibodies
Acronym
RECIPE
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

2. Study Status

Record Verification Date
August 2021
Overall Recruitment Status
Completed
Study Start Date
March 28, 2019 (Actual)
Primary Completion Date
May 27, 2021 (Actual)
Study Completion Date
May 27, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Nagoya University
Collaborators
Japan Agency for Medical Research and Development, Zenyaku Kogyo Co., Ltd.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP)
Keywords
IgG4 autoantibody, Neurofascin-155, Contactin-1, Rituximab

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
25 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Rituximab group (IgG4 autoantibody positive)
Arm Type
Active Comparator
Arm Title
Placebo group (IgG4 autoantibody positive)
Arm Type
Placebo Comparator
Arm Title
Rituximab group (IgG4 autoantibody negative)
Arm Type
Active Comparator
Intervention Type
Biological
Intervention Name(s)
Rituximab (genetical recombination)
Intervention Description
Administer 375 mg/m2 of rituximab (genetical recombination) IV infusion once weekly for 4 doses.
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
Administer placebo IV infusion once weekly for 4 doses.
Primary Outcome Measure Information:
Title
Rate of patients with improvement in adjusted Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale
Description
Primary analysis will compare scores of adjusted INCAT Disability Scale evaluated prior to treatment (at the time of enrollment) and scores at each timepoint after week 26 to calculate the proportion of patients who achieve an improvement of one and more from the baseline. The INCAT Disability Scale is an index to evaluate disorders in lower (gait) and upper (elevation of the upper arms and fine movement of the fingertips) extremities. The INCAT score is a 10-point scale and ranges from 0 (normal) to 10 (worst). For the "adjusted" INCAT score, a change in upper extremity score from 0 to 1 or 1 to 0 will not be considered meaningful in this evaluation.
Time Frame
Up to 52 weeks
Secondary Outcome Measure Information:
Title
Change in grip strength (kPa)
Description
The differences of Grip strength (kPa) between prior to treatment and at each timepoint are summarized.
Time Frame
Up to 52 weeks
Title
Change in Rasch-built Overall Disability Scale (R-ODS) score
Description
The differences of R-ODS score between prior to treatment and at each timepoint are summarized. R-ODS is consist of a 24-item questionnaire about daily living task with 3 response options: (0) "impossible to perform," (1) "performed with difficulty," and (2) "easily performed. The R-ODS score is a 48-point scale (range: 0-48), and is converted into a centile metric score with values ranging from 0 (most severe activity and social participation limitations) to 100 (no activity and social participation limitations).
Time Frame
Up to 52 weeks
Title
Change in Medical Research Council (MRC) Sum Score
Description
The differences of MRC Sum Score between prior to treatment and at each timepoint are summarized. The MRC Sum Score is a scale to assess for 8 muscle groups (right and left side) as follow: Shoulder abduction, Elbow flexion, Wrist extension, Index finger abduction, Hip flexion, Knee extension, Foot dorsiflexion, Great toe dorsiflexion.The MRC Sum Score is a 80-point scale and ranges from 0 (paralysis) to 80 (normal strength).
Time Frame
Up to 52 weeks
Title
Change in motor nerve distal latency
Description
The differences of distal latency between prior to treatment and at each timepoint are summarized.
Time Frame
Up to 52 weeks
Title
Change in motor nerve proximal latency
Description
The differences of proximal latency between prior to treatment and at each timepoint are summarized.
Time Frame
Up to 52 weeks
Title
Change in motor nerve compound muscle action potential (CMAP)
Description
The differences of CMAP between prior to treatment and at each timepoint are summarized.
Time Frame
Up to 52 weeks
Title
Change in motor nerve conduction velocity
Description
The differences of motor nerve conduction velocity between prior to treatment and at each timepoint are summarized.
Time Frame
Up to 52 weeks
Title
Cerebrospinal fluid protein level
Description
Cerebrospinal fluid protein level at each timepoint are summarized.
Time Frame
Up to 52 weeks
Title
B cell counts (CD19 positive and CD20 positive cell counts) and T cell counts (CD3 positive, CD4 positive, and CD8 positive cell counts)
Description
B cell counts (CD19 positive and CD20 positive cell counts) and T cell counts (CD3 positive, CD4 positive, and CD8 positive cell counts) at each timepoint are summarized.
Time Frame
Up to 52 weeks
Title
Expression of HACA
Description
The number of patients expressing HACA, and the proportion and its 95% confidence interval of these patients at each timepoint are summarized.
Time Frame
Up to 52 weeks
Title
Serum rituximab (genetical recombination) level
Description
Serum rituximab (genetical recombination) level at each timepoint are summarized.
Time Frame
Up to 52 weeks
Title
Maximum serum concentration (Cmax) of rituximab (genetical recombination)
Description
Cmax of rituximab (genetical recombination) is summarized.
Time Frame
Up to 52 weeks
Title
Area under the curve (AUC) of blood concentration of rituximab (genetical recombination)
Description
AUC of blood concentration of rituximab (genetical recombination) is summarized.
Time Frame
Up to 52 weeks
Title
Half-life (t1/2) of rituximab (genetical recombination)
Description
t1/2 of rituximab (genetical recombination) is summarized.
Time Frame
Up to 52 weeks
Title
Clearance (CL) of rituximab (genetical recombination)
Description
CL of rituximab (genetical recombination) is summarized.
Time Frame
Up to 52 weeks
Title
Mean residence time (MRT) of rituximab (genetical recombination)
Description
MRT of rituximab (genetical recombination) is summarized.
Time Frame
Up to 52 weeks
Title
Volume of distribution (Vds) of rituximab (genetical recombination) level
Description
Vds of rituximab (genetical recombination) is summarized.
Time Frame
Up to 52 weeks
Title
Serum antibody titers of IgG4 (CNTN-1 and NF-155) and these IgG subclass
Description
Serum titers (CNTN-1 and NF-155, and these IgG subclasses 1 to 4) at each timepoint are summarized.
Time Frame
Up to 52 weeks
Title
Serum neurofilament
Description
Serum neurofilament level at each timepoint is summarized.
Time Frame
Up to 52 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
12 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: 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 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 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 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 Patients aged 12 years or older at informed consent 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: 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 Patients who have started or have increased the dose of corticosteroid for CIDP within 12 weeks prior to the enrollment Patients who have started or have increased the dose of IVIg within 8 weeks prior to the enrollment 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) 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 Patients who have underwent hematopoietic stem cell transplant prior to the enrollment Patients who have used rituximab (genetical recombination) prior to the enrollment 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 Patients with poorly controlled diabetes (HbA1c of 7 % or higher) 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 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 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 Patients with history of serious hypersensitivity or anaphylactic reaction to one of the ingredients in the investigational drug or murine protein-containing products Patients with serious comorbidity (e.g., hepatic, renal, cardiac, lung, hematologic, or brain disease) Female patients who are pregnant, lactating, or potentially pregnant, or patients who are not willing to use contraceptive measures during the study period Patients who are judged to be unsuitable by the investigator or a sub-investigator
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Masahiro Iijima, Ph. D
Organizational Affiliation
Nagoya University Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Nagoya University Hospital
City
Nagoya
State/Province
Aich
ZIP/Postal Code
466-8560
Country
Japan
Facility Name
Chiba University Hospital
City
Chiba
Country
Japan
Facility Name
Kyushu University Hospital
City
Fukuoka
Country
Japan
Facility Name
Yamaguchi University Hospital
City
Ube
Country
Japan

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
32234705
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.
Results Reference
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The Evaluation of Efficacy and Safety of Rituximab in Refractory CIDP Patients With IgG4 Autoantibodies

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