Clinical Trial: Ublituximab for Acute Neuromyelitis Optica (NMO) Relapses

Study Status: Active, not recruiting
Recruit Status: Active, not recruiting
Study Type: Interventional

Official Title: Phase I, Single-Center, Open Label Trial of Ublituximab + Glucocorticoids for the Treatment of Acute Optic Neuritis and/or Transverse Myelitis in Neuromyelitis Optica (NMO

Brief Summary:

Ublituximab (also known as LFB-R603) is a monoclonal antibody that specifically binds to the trans-membrane antigen CD20. The binding induces immune response that causes lysis of B cells.

The rationale for using ublituximab in neuromyelitis optica (NMO) and neuromyelitis optica spectrum disorder (NMOSD) is based on the known roles of B cells, antibody production and plasma cells in the pathophysiology of NMO. NMO is characterized by the presence of an anti-AQP4 antibody, which can only be produced by differentiation of B cells to plasma cells. Because these anti-AQP4 antibodies may be pathogenic, B cells recognizing AQP4 may be directly involved in the disease process as well. B cells also play a role as potent antigen presenting cells in NMO. The strongest evidence of the importance of B cells in NMO comes from studies of B cell depletion, most commonly with anti-CD20 monoclonal antibody, rituximab (Rituxan®).

Rituximab has been shown in five retrospective and two prospective studies to be effective in reducing NMO relapses up to 90% and achieving remission in up to 80% of patients solely by its action on CD20+ B cells, despite no change in plasma cell population and anti-AQP4 antibody titers. These human trials strongly suggest a critical role for B cells in the pathophysiology of human disease. While typically used in the prevention of disease, B-cell depletion may be beneficial in the treatment of an acute relapse as well. Emerging evidence indicates that peripheral B cells are activated during a relapse and plasmablast production of anti-AQP4 antibodies spikes. B cells are also found within acute lesions of the spinal cord and optic nerve suggesting roles both in the blood and in the central nervous system during a relapse.

Detailed Summary:

The overall objective is to assess the safety of ublituximab as add-on therapy to steroids for treatment of acute optic neuritis and/or transverse myelitis in NMO and NMOSD.

Primary Objective To assess safety of acute B cell depletion in NMO subjects with acute relapse of optic neuritis or transverse myelitis who are treated with ublituximab + glucocorticoids beginning on dose administration and ending with recovery of B cells.

Secondary Objectives

• To determine the B cell depletion pharmacokinetics of ublituximab in the NMO patients population with monthly B cell counts for up to 9 months.
• To determine the frequency of adverse events with ublituximab in this patient population.

Trial Design Given the severity and the consequences of relapse in NMO, placebo treatment without steroid treatment is unethical and use of an active treatment is considered mandatory. The potential of currently utilized drugs and techniques to reduce the inflammation in NMO has been established primarily through expert consensus and small open label and retrospective studies.

This is a Phase 1 open-label, standard-of-care, single treatment arm, unblinded, single center interventional trial in NMO/NMOSD patients in which experimental subjects will receive one (1) infusion of 450 mg of intravenous ublituximab at the onset of an NMO exacerbation in addition to standard of care treatment with daily intravenous glucocorticoid at 1000 mg for five days.

Current Primary Outcome: Number of Participants with Adverse Events [ Time Frame: Through the entire study duration from day 1 through day 90. ]

Original Primary Outcome: Same as current

Current Secondary Outcome:

• MRI spine [ Time Frame: On admission to the hospital and day 1 and on follow up 90 days later ]
  MRIs will be performed for standard of care purposes and will be used to make clinical decisions about escalation of immunosuppressive treatment. For this trial, the MRIs will also be analyzed for two parameters: length and T2 hyperintensity in the spinal cord and optic nerve and volume of T1 post-contrast enhancement if available.
• Neurological Disability - Expanded Disability Scale Score [ Time Frame: On admission to the hospital on day 1, on discharge 5-21 days later and on follow up at 90 days ]
  The Kurtzke Expanded Disability Status Scale (EDSS) was developed to measure the disability status of subjects with multiple sclerosis. It allows an objective quantification of the level of functioning that could be widely and reproducibly used by researchers and health care providers. The EDSS provides a total score on a scale that ranges from 0 to 10. The first levels 1.0 to 4.5 refer to people with a high degree of ambulatory ability and the subsequent levels 5.0 to 9.5 refer to the loss of ambulatory ability. The range of main categories include (0) = normal neurologic exam; to (5) = ambulatory without aid or rest for 200 meters; disability severe enough to impair full daily activities; to (10) = death due to MS. In addition, it also provides eight subscale measurements called Functional System (FS) scores.
• High Contrast Visual Acuity [ Time Frame: On admission to the hospital on day 1, on discharge 5-21 days later and on follow up 90 days later. ]

  High Contrast Visual Acuity: High-contrast Sloan letter charts are readily available and provide a practical, quantitative, and standardized assessment of visual function. Each chart consists of rows of black letters (decreasing in size from top to bottom) on a white background.

  For this trial, 100% monocular low contrast visual acuity will be measured on days 1 and 5 during the steroid phase and weekly during the plasma exchange phase. Charts will be read at a 2-meter distance by trained examiners in the hospital room with constant lighting of 80-100 foot-candles accomplished using standard fluorescent hospital room overhead lighting. Binocular testing will be recorded as total number of letter identified correctly (maximum 60).

• Timed 25-foot Walk [ Time Frame: On admission to the hospital on day 1, on discharge 5-21 days later and on follow up 90 days later. ]
  Timed 25-foot walking trials will be assessed on days 1 and 5 during the steroid phase and weekly in the plasma exchange phase. The Timed 25-Foot Walk test is a quantitative measure of lower extremity function. If required, the subject may use an appropriate assistive device to walk as quickly as he/she can from one end to the other end of a clearly marked, unobstructed, 25-foot course. Timing will begin when any part of the subject's foot crosses the tape. Timing will end when any part of the subject's foot crosses the finish line (identified by a taped mark on the floor). Time will be recorded in seconds. The task is immediately administered again (a maximum five-minute rest period is allowed between trials) by having the subject walk back the same distance. The average of the two values will be recorded.

Original Secondary Outcome: Same as current

Information By: Johns Hopkins University

Dates:
Date Received: October 21, 2014
Date Started: September 2015
Date Completion: December 2017
Last Updated: December 20, 2016
Last Verified: December 2016