Clinical trial NCT03835728: Efficacy of Ocrelizumab in Autoimmune Encephalitis
Official title: Exploratory Study of Efficacy of Ocrelizumab in Autoimmune Encephalitis
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Autoimmune Encephalitis
Lead sponsor: University of Texas Southwestern Medical Center
Sponsor class: OTHER
Collaborators: name: Genentech, Inc.
First posted: 2019-02-11
Enrollment: 3
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This pilot study is a randomized, double-blind, placebo controlled study of the efficacy of ocrelizumab in autoimmune encephalitis. Subjects with new diagnosis of autoimmune encephalitis will be invited to enroll in this study. Subjects will be randomized to receive ocrelizumab (an anti-CD20 therapy) or matched placebo, and will undergo three infusions over a six month period. Subjects will complete clinical visits over the study period, during which safety monitoring and neuropsychological assessments will be performed to assess for signs of clinical worsening from encephalitis. The primary outcome of this study is the proportion of patients who fail to complete the twelve month period without clinical worsening, as defined by the protocol. Subjects who experience early clinical worsening during the study may be offered open-label treatment with ocrelizumab at the discretion of the investigators.


Eligibility criteria: Inclusion Criteria:

1. Age 18 or greater
2. Able to obtain informed consent from patient or appropriate designee
3. Possible autoimmune encephalitis as defined by Table 1:

   1. Reasonable exclusion of alternative causes
   2. Subacute onset (\< 3 months) of memory deficits, altered consciousness, and/or psychiatric symptoms
   3. One or more of the following:

      * CSF (cerebrospinal fluid) pleocytosis (\>5 cells/µl corrected, if necessary, for traumatic lumbar puncture)
      * EEG (electroencephalogram) with epileptiform or focal slow wave abnormalities involving temporal lobes
      * Brain abnormalities on T2/FLAIR MRI restricted to the mesial temporal (limbic) lobes
      * Associated dyskinesias (faciobrachial dystonic movements or orofacial dyskinesias)
4. Completed initial treatment with iv steroids (at least 3000mg solumedrol) and plasma exchange (at least 3 exchanges) within the past 8 weeks
5. Presence of one (or more) of the following autoantibodies in serum or CSF

   * NMDA receptor
   * LGI1
   * CASPR2
   * DPPX

Exclusion Criteria:

1. Prior immunosuppression treatment in past year (other than steroids, intravenous immunoglobulin and plasma exchange)
2. Active malignancy requiring chemotherapy
3. Pregnancy
4. Evidence of active hepatitis or tuberculosis infection
5. Medical condition that (in investigators opinion) precludes the use of ocrelizumab

Primary outcomes:
measure: Number of Participants Who Had Clinical Worsening
timeFrame: 12 months
Secondary outcomes:
measure: Time to Treatment Failure
timeFrame: 12 months
measure: Change in TFLS T-score (Texas Functional Living Scale) Score at 6 Months
timeFrame: Baseline, 6 month
measure: Change in TFLS T Score (Texas Functional Living Scale) Score at 12 Months
timeFrame: Baseline, 12 months
Other outcomes:
Locations:
city: Dallas
country: United States
facility: UT Southwestern Medical Center
state: Texas
Study officials:
affiliation: UT Southwestern Medical Center
name: Steven Vernino, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Graus F, Titulaer MJ, Balu R, Benseler S, Bien CG, Cellucci T, Cortese I, Dale RC, Gelfand JM, Geschwind M, Glaser CA, Honnorat J, Hoftberger R, Iizuka T, Irani SR, Lancaster E, Leypoldt F, Pruss H, Rae-Grant A, Reindl M, Rosenfeld MR, Rostasy K, Saiz A, Venkatesan A, Vincent A, Wandinger KP, Waters P, Dalmau J. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016 Apr;15(4):391-404. doi: 10.1016/S1474-4422(15)00401-9. Epub 2016 Feb 20.
citation: Titulaer MJ, McCracken L, Gabilondo I, Armangue T, Glaser C, Iizuka T, Honig LS, Benseler SM, Kawachi I, Martinez-Hernandez E, Aguilar E, Gresa-Arribas N, Ryan-Florance N, Torrents A, Saiz A, Rosenfeld MR, Balice-Gordon R, Graus F, Dalmau J. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol. 2013 Feb;12(2):157-65. doi: 10.1016/S1474-4422(12)70310-1. Epub 2013 Jan 3.
citation: Dubey D, Sawhney A, Greenberg B, Lowden A, Warnack W, Khemani P, Stuve O, Vernino S. The spectrum of autoimmune encephalopathies. J Neuroimmunol. 2015 Oct 15;287:93-7. doi: 10.1016/j.jneuroim.2015.08.014. Epub 2015 Aug 28.
citation: Blackburn KM, Denney DA, Hopkins SC, Vernino SA. Low Recruitment in a Double-Blind, Placebo-Controlled Trial of Ocrelizumab for Autoimmune Encephalitis: A Case Series and Review of Lessons Learned. Neurol Ther. 2022 Jun;11(2):893-903. doi: 10.1007/s40120-022-00327-x. Epub 2022 Feb 7.