Rituximab in Chronic Inflammatory Demyelinating Polyneuropathy

Rituximab in Chronic Inflammatory Demyelinating Polyneuropathy: A Phase II Study

CIDP is a heterogeneous disease with variable responses to therapy. Recently, a distinctive subgroup of patients with serum autoantibodies to the paranodal proteins contactin and neurofascin have been identified. Although they present with active and serious disease, multiple clinical reports suggest that these patients can be cured with a treatment that depletes B cells and presumably eliminates pathogenic autoantibodies. However, beyond that subgroup of CIDP patients, which CIDP patients might benefit from Rituximab and B cell depletion is unknown. This Phase II study will treat 3 homogenous groups of 16 CIDP patients each with Rituximab in order to determine if there are subgroups that can be taken off current medications and put into long-term remission. The results from this study will be used to design a future larger trial. Biomarkers including paranodal antibodies, serum neurofilament light chains, anti-ganglioside antibodies will be obtained in order to learn about disease pathogenesis and possibly target therapy

INCLUSION CRITERIA

1. Written informed consent obtained from subjects indicating that they understand the purpose of and procedures required for the study and are willing to participate

2. Male or female, aged ≥18 years

3. Documented diagnosis of typical CIDP according to the European Academy of Neurology/Peripheral Nerve Society criteria 202127

4. Must be willing to complete the study and return for follow-up visits.

5. Men and women of reproductive potential must agree to use an acceptable method of birth control during treatment and for twelve months (1 year) after completion of treatment.

6. Successfully treated CIDP patients. Data at or prior to the screening visit must show evidence that during the course of therapy either the INCAT score improved by 1 or more points or improvement occurred according to the physician opinion.

7. CIDP disease stability is based on 2 visits that are 3 or more months apart documented at or prior to the screening visit by assessing unchanged CIDP status per physician opinion. The subject must be at the same dosage and frequency of CIDP therapy in between these 2 timepoints.

8. Belonging to 1 of the following 2 treatment groups:

   1. IVIg/SCIg for up to 3 years.
   2. IVIg/SCIg for more than 3 years.

9. Off steroids for at least 3 months before screen visit. Topical steroids and infrequent intraarticular steroids are allowed.

10. No anticipated change in dosage or CIDP therapy from week 0 to week 24.

11. Off concurrent immunosuppressive agents (such as azathioprine, methotrexate, mycophenolate mofetil, or cyclosporine or cyclophosphamide or any other agent) for at least 6 months prior to screening visit.

EXCLUSION CRITERIA

1. Female subjects who are premenopausal and are

   1. pregnant on the basis of a serum pregnancy test,
   2. breast-feeding, or
   3. not using an effective method of double barrier (1 hormonal plus 1 barrier method or 2 simultaneous barrier methods) or birth control (birth control pills, male condom, female condom, intrauterine device, Norplant, tubal ligation, or other sterilization procedures).

2. Participation in another clinical study within 30 days before entering the study or during the study

3. Employee or direct relative of an employee of the study site or Sponsor

4. Other medical condition, laboratory finding, or physical exam finding that precludes participation

5. A neuropathy of other causes, including:

   1. A motor syndrome that fulfils criteria for multifocal motor neuropathy (MMN) with conduction block
   2. CIDP with monoclonal gammopathy of uncertain significance (CIDP-MGUS) or monoclonal gammopathy associated with an oncologic diagnosis
   3. Neuropathies secondary to infections, disorders, or systemic diseases
   4. Drug-, biologic-, chemotherapy-, or toxin-induced peripheral neuropathy
   5. Hereditary demyelinating neuropathies
   6. Central demyelinating disorders (e.g. multiple sclerosis)
   7. Others, like polyneuropathy, lumbosacral radiculoplexus neuropathy

6. Patients with known history prior to screening visit of nodal and paranodal (anti-NF155, anti- CNTN1, anti- Caspr1 or anti-NF140/186 antibody) performed at a laboratory meeting quality standards for cell-based assay method and if required other confirmatory assays

7. Any chronic or debilitating disease, or central nervous disorder that causes neurological symptoms or may interfere with assessment of CIDP or outcome measures

8. Cardiac insufficiency (New York Heart Association Classes III/IV), cardiomyopathy, significant cardiac arrhythmia requiring treatment, unstable or advanced ischemic heart disease, congestive heart failure or severe hypertension

9. Subjects with current malignancy requiring chemotherapy and/or radiotherapy, or history of malignancy with less than 2 years of complete remission prior to screening. Exceptions are: adequately treated basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the cervix, and stable prostate cancer not requiring treatment

10. Plasma exchange within the last 3 months of screen visit.

11. Any prior treatment with a biologic (e.g. rituximab (MabThera®/Rituximab®), ocrelizumab (Ocrevus®), natalizumab (Tysabri®), alemtuzumab, TNF-α inhibitor)

12. Abnormal laboratory parameters:

    1. creatinine >1.5 times the upper normal limit (UNL)
    2. hemoglobin (Hb) <10 g/dL
    3. absolute neutrophil count (ANC) <1000 cells/μl
    4. elevated liver enzymes (AST or ALT >2.5 x Upper Limit of Normal).
    5. platelets < 100,000/mL

13. History of bone marrow hypoplasia, leucopenia, thrombocytopenia, significant anemia, clinical or laboratory evidence of immunodeficiency syndromes, that are not transient events or side effects related to a clinical procedure (i.e. plasmapheresis) and within one year of screening.

14. Positive Hepatitis B or C serology (Hep B surface antigen and Hep C antibody). For patients who are negative for surface antigen [HBsAg] and positive for HB core antibody [HBcAb+], we will consult liver disease experts before starting and during treatment

15. History of positive HIV (HIV conducted during screening if applicable)

16. Receipt of a live vaccine within 4 weeks prior to randomization

17. Contraindication to receiving rituximab

18. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies

19. History of recurrent significant infection or history of recurrent bacterial infections

20. Known active bacterial, viral fungal mycobacterial, or other infection (including tuberculosis or atypical mycobacterial disease, but excluding fungal infections of nail beds) or any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks prior to screening

21. Lack of venous access

22. History of drug, alcohol, or chemical abuse within 6 months prior to screening

23. Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the subject at high risk from treatment complications

24. Levels of IgG or IgM that are below 30% of the lower limit of normal.