The ExTINGUISH Trial of Inebilizumab in NMDAR Encephalitis
- Conditions
- Autoimmune EncephalitisEncephalitis
- Interventions
- Drug: Placebo
- Registration Number
- NCT04372615
- Lead Sponsor
- University of Utah
- Brief Summary
Determine the difference in the modified Rankin score at 16 weeks in participants with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis treated with "first-line" immunomodulatory therapies provided as standard-of-care, and either inebilizumab (investigational agent) or placebo.
- Detailed Description
N-methyl-D-aspartate receptor (NMDAR) encephalitis is one of the most common causes of autoimmune encephalitis, with prevalence exceeding herpes encephalitis in industrialized nations. Typically, the disease affects patients age 10-50 causing prominent psychiatric symptoms, altered consciousness, seizures, movement disorders and life-threatening dysautonomia. Intensive care, including cardiorespiratory support is required in 75% of cases. The diagnosis is confirmed by detection of IgG autoantibodies against central nervous system NMDAR in the cerebrospinal fluid. Despite the severity of the illness, NMDAR encephalitis is a treatable neurological disease, with retrospective case series establishing the benefit of off-label intravenous steroids and immunoglobulins. These treatments are presumed to work through effects on IgG NMDAR autoantibody levels in the CSF, although prospective data informing predictors of treatment responses are limited. Even with prompt treatment, \~50% of patients remain disabled, requiring prolonged hospital admissions. Various off-label therapies have been proposed as "second-line" treatments in NMDAR encephalitis. The majority of second-line treatments target circulating B-cells with various degrees of blood brain penetrance and efficacy, and poor consensus on the timing, dose and route of delivery of candidate agents. High-quality evidence is needed to inform the treatment of NMDAR encephalitis. Inebilizumab is a promising therapeutic monoclonal antibody for the treatment of NMDAR encephalitis. This humanized monoclonal antibody against the B-cell surface antigen CD19 was recently shown to be safe and efficacious in the treatment of neuromyelitis optica spectrum disorder-another antibody-mediated disorder of the central nervous system. Compared to other off label B-cell depleting therapies, such as rituximab, inebilizumab not only depletes CD20+ B-cells, but also CD20- plasmablasts and plasma cells, resulting in robust and sustained suppression of B-cell expression. The ExTINGUISH Trial will randomize 116 participants with moderate-to-severe NMDAR encephalitis to receive either inebilizumab or placebo in addition to first-line therapies. Patient outcomes will be ascertained at standard intervals using the modified Rankin scale and accepted safety measures (primary outcomes at 16 weeks), together with comprehensive validated neuropsychological tests, bedside cognitive screening tools, quality of life/ functional indices, and outcome prediction measures. Clinical data will be combined with quantitative measures of NMDAR autoantibody titers and cytokines implicated in B-cell activation and antibody production within the intrathecal compartment to identify treatment responders, inform the biologic contributors to outcomes, and evaluate for biomarkers that may serve as early predictors of favorable outcomes in future clinical trials in NMDAR encephalitis. The ExTINGUISH Trial will prospectively study an optimized B-cell depletion therapy to promote better long-term outcomes in NMDAR encephalitis, to determine more meaningful cognitive endpoints, and to identify better biologic biomarkers to predict outcome.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 116
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo Placebo Approximately 58 patients will receive placebo in addition to first line immunotherapy. (Approximately 116 participants will be randomized in a 1:1 ratio to 2 treatment groups; approximately 58 participants to each treatment group). All participants will also receive a 3 day course of IVIg. Inebilizumab Inebilizumab Approximately 58 patients will receive Inebilizumab in addition to first line immunotherapy. (Approximately 116 participants will be randomized in a 1:1 ratio to 2 treatment groups; approximately 58 participants to each treatment group). All participants will also receive a 3 day course of IVIg.
- Primary Outcome Measures
Name Time Method Change of modified Rankin score at 16 weeks 16 weeks Change in modified Rankin score (mRS) (0 to 6; 0=normal and 6=death) at 16 weeks determined by rank analyses, integrating need for rescue therapy and time to achievement of the mRS.
Inebilizumab safety measures by the number of treatment-emergent adverse events and serious adverse events 96 weeks Inebilizumab safety, as measured by the number of treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events (TESAEs)
- Secondary Outcome Measures
Name Time Method Clinical Assessment Scale in Autoimmune Encephalitis (CASE) Score (continuous logistic regression), corrected from baseline value to week 24 (weeks 6 and 16). 16 weeks Clinical Assessment Scale in Autoimmune Encephalitis (CASE) Score (ranges of 0 to 27 with 0 being normal and 27 being worse)(continuous logistic regression), corrected from baseline value to week 24 (weeks 6 and 16).
Proportion of participants who meet the protocol-defined criteria for needing rescue therapy at week 6. 6 weeks Proportion of participants who meet the protocol-defined criteria for needing rescue therapy at week 6.
Survival as measured by a Kaplan-Meier analysis. 96 weeks Survival as measured by a Kaplan-Meier analysis.
Time to mRS ≤ 2, corrected for baseline value. 96 weeks Time to mRS ≤ 2, corrected for baseline value.
mRS at week 6 as measured by proportional odds logistic regression/shift analysis. 6 weeks mRS at week 6 as measured by proportional odds logistic regression/shift analysis.
Cognitive outcome at week 24 as measured by mean scaled score on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) + components of Delis-Kaplan Executive Function System (D-KEFS). 24 weeks Cognitive outcome at week 24 as measured by mean scaled score on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) + components of Delis-Kaplan Executive Function System (D-KEFS).
Trial Locations
- Locations (39)
University of Alabama at Birmingham
🇺🇸Birmingham, Alabama, United States
St. Joseph Hospital and Medical Center Barrow Neurological Institute
🇺🇸Phoenix, Arizona, United States
Mayo Clinic in Arizona
🇺🇸Scottsdale, Arizona, United States
UC Irvine
🇺🇸Orange, California, United States
UC Davis
🇺🇸Sacramento, California, United States
Children's Hospital of Orange County
🇺🇸Orange, California, United States
Children's Hospital Colorado Main Campus
🇺🇸Aurora, Colorado, United States
University of Colorado
🇺🇸Aurora, Colorado, United States
Yale University
🇺🇸New Haven, Connecticut, United States
Mayo Clinic Jacksonville
🇺🇸Jacksonville, Florida, United States
University of Miami
🇺🇸Miami, Florida, United States
Emory University
🇺🇸Atlanta, Georgia, United States
Ann and Robert H. Lurie Childrens Hospital of Chicago
🇺🇸Chicago, Illinois, United States
Northwestern University Feinberg School of Medicine
🇺🇸Chicago, Illinois, United States
University of Iowa
🇺🇸Iowa City, Iowa, United States
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
University of Michigan Health System
🇺🇸Ann Arbor, Michigan, United States
Mayo Clinic Rochester
🇺🇸Rochester, Minnesota, United States
Washington University in St. Louis School of Medicine
🇺🇸Saint Louis, Missouri, United States
SUNY Downstate
🇺🇸Brooklyn, New York, United States
Mount Sinai
🇺🇸New York, New York, United States
Columbia University Medical Center
🇺🇸New York, New York, United States
University of Rochester
🇺🇸Rochester, New York, United States
SUNY Buffalo
🇺🇸Williamsville, New York, United States
Wake Forest University Health Sciences
🇺🇸Winston-Salem, North Carolina, United States
University of Cincinnati
🇺🇸Cincinnati, Ohio, United States
Ohio State University
🇺🇸Columbus, Ohio, United States
University of Pennsylvania
🇺🇸Philadelphia, Pennsylvania, United States
University of Pittsburgh
🇺🇸Pittsburgh, Pennsylvania, United States
Vanderbilt University
🇺🇸Nashville, Tennessee, United States
University of Texas Southwestern Medical Center
🇺🇸Dallas, Texas, United States
Texas Children's Hospital
🇺🇸Houston, Texas, United States
University of Utah
🇺🇸Salt Lake City, Utah, United States
University of Virginia
🇺🇸Charlottesville, Virginia, United States
University of Washington
🇺🇸Seattle, Washington, United States
Erasmus Medical University Center
🇳🇱Rotterdam, Netherlands
Erasmus University Rotterdam
🇳🇱Rotterdam, Netherlands
Hospital Clínic Barcelona
🇪🇸Barcelona, Spain
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona
🇪🇸Barcelona, Spain