Ublituximab for Acute Neuromyelitis Optica (NMO) Relapses

• ClinicalTrials.gov Identifier: NCT02276963
• Recruitment Status: Completed
• First Posted: October 28, 2014
• Results First Posted: June 6, 2019
• Last Update Posted: June 6, 2019
• Sponsor: Johns Hopkins University
• Information provided by (Responsible Party): Johns Hopkins University

Tracking Information

• First Submitted Date: October 21, 2014
• First Posted Date: October 28, 2014
• Results First Submitted Date: February 22, 2019
• Results First Posted Date: June 6, 2019
• Last Update Posted Date: June 6, 2019
• Actual Study Start Date: January 2016
• Actual Primary Completion Date: July 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 5, 2019)

Change in 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 demyelinating disease. 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 where 0 is normal and 10 is deceased. Increasing disability is reflected in an increasing EDSS score.

Original Primary Outcome Measures (submitted: October 27, 2014)

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

All adverse events and side effects related to this drug will be recorded.

• Current Secondary Outcome Measures: Not Provided

Original Secondary Outcome Measures (submitted: October 27, 2014)

• 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.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Ublituximab for Acute Neuromyelitis Optica (NMO) Relapses
• 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) and Neuromyelitis Optica Spectrum Disorder (NMOSD)

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-Aquaporin-4 (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 Description

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.

• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Neuromyelitis Optica
• Neuromyelitis Optica Spectrum Disorder

Intervention

Drug: Ublituximab

Monoclonal antibody that specifically binds to the trans-membrane antigen CD20, which induces immune response that causes lysis of B cells.

Other Name: LFB-R603

Study Arms

Experimental: Ublituximab Plus Glucocorticoids

Ublituximab 450 mg intravenously once on day 1, plus glucocorticoids 1000 mg intravenously daily on days 1-5

Intervention: Drug: Ublituximab

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 5, 2019): 6
• Original Estimated Enrollment (submitted: October 27, 2014): 5
• Actual Study Completion Date: February 15, 2019
• Actual Primary Completion Date: July 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Able and willing to provide written informed consent.
2. 18-100 years of age.
3. New acute optic neuritis and/or transverse myelitis. A clinical event is defined as an episode of inflammation in the spinal cord and/or optic nerve leading to neurologic deficits on physical exam not attributable to another disease process.
4. Confirmed or highly suspected diagnosis of NMO according to the 2006 revisions of the Wingerchuk diagnostic criteria for NMO (Wingerchuk, 2006), or AQP4 positive NMOSD.
5. The B cell count must be normal (5-20% of total lymphocytes) in subjects who have not received another B cell depleting therapy in the past year. For those on B cell depleting therapy within the past year, a B cell count of at least 0.5% is necessary.

6. A female subject is eligible to enter the trial if she is:

   • Not pregnant or nursing;
   • Of non-childbearing potential OR of child-bearing potential

7. Subject has a negative serum pregnancy test at screening and agrees to one of the following:

   • Complete abstinence from intercourse for the period from consent into the trial until 6 months after the last dose of investigational product; or,

   • Consistent and correct use of one of the following acceptable methods of birth control for the period from consent into the trial until 6 months after the last dose of investigational product:

     • Oral contraceptives
     • Injectable progesterone
     • Levonorgestrel implants
     • Estrogenic vaginal ring
     • Percutaneous contraceptive patches
     • Intrauterine device (IUD) or intrauterine system (IUS)
     • Male partner sterilization
     • Double barrier method

Exclusion Criteria:

1. Current evidence or known history of clinically significant infection including:

   • Chronic or ongoing active infectious disease
   • Previous serious opportunistic or atypical infections.
   • Hepatitis B
   • Tuberculosis (TB)
   • HIV
2. History of clinically significant central nervous system (CNS) trauma (e.g. spinal cord compression).

3. Past or current history of medically significant adverse effects from:

   • Corticosteroids
   • Diphenhydramine
   • Murine or mouse/human chimeric antibodies

4. Past or current malignancy, except for

   • Cervical carcinoma Stage 1B or less
   • Non-invasive basal cell and squamous cell skin carcinoma
   • Cancer diagnoses with a duration of complete response (remission) >5 years A history of hematologic malignancy excludes a subject from participation, regardless of response.
5. Significant concurrent, uncontrolled medical condition including, but not limited to, cardiac, renal, hepatic, hematological, gastrointestinal, endocrine, immunodeficiency syndrome, pulmonary, cerebral, psychiatric, or neurological disease which could affect the subject's safety, impair the subject's reliable participation in the trial, impair the evaluation of endpoints, or necessitate the use of medication not allowed by the protocol, as determined by the PI of the trial.
6. Use of an investigational drug or other experimental therapy for a condition other than NMO within 4 weeks, 5 pharmacokinetic half lives or duration of biological effect (whichever is longer) prior to screening.
7. Current participation in any other interventional clinical trial. Participation in non-interventional trial requires approval of the protocol by investigator.
8. Subjects who are concurrently receiving any other investigational agents, or have participated in an interventional clinical trial within the last 21 days, or subjects who have been vaccinated with a live vaccine < 2 months prior to trial inclusion.
9. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with ublituximab breastfeeding should be discontinued if the mother is treated with ublituximab.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 100 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02276963
• Other Study ID Numbers: IRB00052958
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Johns Hopkins University
• Study Sponsor: Johns Hopkins University
• Collaborators: Not Provided

Investigators

• Principal Investigator: Michael Levy, MD, PhD; Johns Hopkins University

• PRS Account: Johns Hopkins University
• Verification Date: June 2019