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Open Label Study of Safety and Tolerability of Rituximab in Neuromyelitis Optica, Recurrent Transverse Myelitis and Recurrent Bilateral Simultaneous Optic Neuritis

Phase 1
12 Years
86 Years
Not Enrolling
Neuromyelitis Optica

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Trial Information

Open Label Study of Safety and Tolerability of Rituximab in Neuromyelitis Optica, Recurrent Transverse Myelitis and Recurrent Bilateral Simultaneous Optic Neuritis

Rituximab is a genetically engineered, chimeric, murine/human monoclonal antibody directed
against the CD20 antigen found on the surface of normal and malignant pre-B and mature B
cells. The antibody is an IgG1 immunoglobulin containing murine light- and heavy chain
variable region sequences and human constant region sequences. Rituximab is composed of two
heavy chains of 451 amino acids and two light chains of 213 amino acids (based on cDNA
analysis) and has an approximate molecular mass of 145 kD. Rituximab has a binding affinity
for the CD20 antigen of ~8.0 nM.

Rituximab was developed by Biogen Idec and Genentech, Inc. It was approved by the FDA in
1997 for the treatment of relapsed or refractory low grade or follicular, CD20+, B-cell
non-Hodgkin's lymphoma (NHL).

Rituximab has also been studied in a variety of non-malignant autoimmune disorders where B
cells and auto antibodies appear to play a role in pathophysiology. Rituximab has been
reported to relieve signs and symptoms of rheumatoid arthritis , lupus , immune
thrombocytopenia , autoimmune anemia , autoimmune neuropathy , and paraneoplastic
opsoclonus/myoclonus .

A Phase II study (WA16291) has been completed in patients with rheumatoid arthritis (RA) .
A total of 161 patients were randomized to 4 treatment arms: Methotrexate, Rituximab alone,
Rituximab and Methotrexate, Rituximab and Cyclophosphamide. Two doses of Rituximab, 1 gm
each, were administered IV two weeks apart. Infusion reactions were observed in 36% of
patients during their first infusion of Rituximab compared to 30% for placebo . Four
Rituximab-treated patients developed serious infections, for a rate of 4.6 per 100 patient
years. For context, the rate of infections requiring hospital admission was 9.57 per 100
patient years in a community based epidemiologic study in RA.

We treated 8 patients with NMO with Rituximab and observed that Rituximab appears to be well
tolerated with 0/8 of the patients suffering serious adverse reactions that could be
directly related to Rituximab administration. Moreover, 7/8 patients experienced decrease
in neurological disability following treatment, suggesting that B-cell depletion may enhance
neurological recovery from attacks. 7/8 of the patients remained attack-free within a
period of 18 months of follow-up on average (range 3 to 12 months) following treatment. We
observed one attack following treatment in a single patient, whereas 14 attacks would have
been predicted by the pre-treatment attack rate (p=0.012, paired t test comparing pre- and
post-treatment attack rates). Nevertheless, the observed impact of treatment on recovery is
more than what would be expected from spontaneous recovery and deserves further
investigation. If B cells are essential for pathogenesis of recurrent attacks in NMO, B
cell depletion may induce sustained remission. We also observed in one case, a dramatic
recovery of electrophysiological conduction in the optic nerves (visual evoked potentials),
which implies that in this case, rituxan did not impair repair mechanisms, for example,
demyelination following the acute attack.

Inclusion Criteria

Inclusion criteria

1. Criteria for neuromyelitis optica:

1. acute transverse myelitis and optic neuritis occurring within 30 days of each
other followed by a second attack of either optic neuritis and/or acute
transverse myelitis at least 3 months following the heralding attack OR

2. acute transverse myelitis followed by optic neuritis at least 3 months later OR

3. optic neuritis followed by acute transverse myelitis at least 3 months later

2. Criteria for high risk for neuromyelitis optica:

1. recurrent idiopathic recurrent acute transverse myelitis with at least 3 months
time between each attack OR

2. recurrent bilateral simultaneous optic neuritis with at least 3 months time
between each attack.

- Subjects should also have no clinical evidence of disease outside the optic
nerve or spinal cord.

- In addition patients should have one major supportive criteria OR two minor
supportive criteria:

1. Negative brain MRI at onset (Does not meet criteria for multiple
sclerosis (Paty, 1998)

2. Spinal cord MRI with signal abnormality extending over ≥3 vertebral

3. CSF pleocytosis of > 50 WBC/mm3 OR > 5 PMNs/mm3

- Minor supportive criteria:

1. Bilateral optic neuritis

2. Severe optic neuritis with fixed visual acuity worse than 20/200 in at
least one eye

3. Severe, fixed, attack-related weakness (MRC ≤2) in one or more limbs

- Subjects must have exhibited evidence of treatment failure, defined as at
least one attack of either acute transverse myelitis or optic neuritis
within six months of screening despite treatment within steroids or other
immunomodulatory drug for the preceding attack.

- Able and willing to give written informed consent and comply with the
requirements of the study protocol.

- Adequate renal function as indicated by normal serum sodium, potassium,
chloride, bicarbonate, creatinine, and blood urea nitrogen studies.

- Adequate liver function, as indicated by normal bilirubin and alkaline
phosphatase, and transaminases (AST and ALT) within 2X upper limit of

- Negative serum pregnancy test (for women of child bearing age).

- 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.

Exclusion Criteria:

1. Treatment with broad-spectrum immunosuppressant medications such as cyclophosphamide,
mitoxantrone, methotrexate, azathioprine, and cladribine, within 60 days of

2. Treatment with any investigational agent within 4 weeks of screening

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

4. Previous Treatment with Rituximab (MabThera® / Rituxan®)

5. Prior antibody therapy

6. History of exposure to clioquinol

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

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

9. History of Hepatitis B and/or Hepatitis C (Hep B/C at screening)

10. History of recurrent significant infection or history of recurrent bacterial

11. Known active bacterial, viral fungal mycobacterial, or other infection or any major
episode of infection requiring hospitalization

12. Ongoing daily steroid use

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

14. Pregnancy (a negative serum pregnancy test should be performed for all women of
childbearing potential within 7 days of treatment) or lactation

15. Concomitant malignancies or previous malignancies within the last five years, with
the exception of adequately treated basal or squamous cell carcinoma of the skin or
carcinoma in situ of the cervix.

16. History of psychiatric disorder

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Safety and Tolerability of Rituximab in NMO (monitor for any AE during two years of follow up)

Outcome Time Frame:

96 weeks

Safety Issue:


Principal Investigator

Bruce Cree, MD, PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

MS Center , UCSF


United States: Institutional Review Board

Study ID:




Start Date:

January 2004

Completion Date:

December 2010

Related Keywords:

  • Neuromyelitis Optica
  • Neuromyelitis Optica
  • acute transverse myelitis
  • Myelitis, Transverse
  • Neuromyelitis Optica



UCSF MS Center , 350 Parnassus Ave , suite #908San Francisco, California  94117
The Neurological Institute of New York MS CenterColumbia University Medical Center 710 West 168th Street,, New York  10032