Efficacy of Ocrelizumab in Autoimmune Encephalitis

• ClinicalTrials.gov Identifier: NCT03835728
• Recruitment Status: Completed
• First Posted: February 11, 2019
• Last Update Posted: November 27, 2020
• Sponsor: University of Texas Southwestern Medical Center
• Collaborator: Genentech, Inc.
• Information provided by (Responsible Party): Steven Vernino, University of Texas Southwestern Medical Center

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Autoimmune Encephalitis	Drug: Ocrelizumab; Drug: Saline	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 3 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Exploratory Study of Efficacy of Ocrelizumab in Autoimmune Encephalitis
• Actual Study Start Date: January 22, 2019
• Actual Primary Completion Date: October 2, 2020
• Actual Study Completion Date: October 2, 2020

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Treatment Arm; Ocrelizumab will be administered 3 times over a 1 year study period. Subjects will receive a dose of 300 mg at week 0 (baseline) and again at week 2. The final dose of 600 mg will be administered at week 24.	Drug: Ocrelizumab; Subjects will be randomized in a 1:1 fashion to receive infusion of Ocrelizumab (2 doses at 300 mg and 1 dose at 600 mg) or matched placebo. The 2 300 mg doses will be administered at day 2 and day 14. The 600 mg dose will be administered during the 6 month visit. The drug will be administered via infusion three times throughout the trial period: after the initial screening, at two weeks from initial infusion, and at 6 months.
Placebo Comparator: Treatment Placebo Arm; Saline will be used as the matching placebo	Drug: Saline; This will be the matching placebo used in the study.

Outcome Measures

Primary Outcome Measures :

1. failure rate [ Time Frame: 12 months ]
   The primary outcome of the treatment trial will be the proportion of patients who fail to complete the 12 month study without clinical worsening.

Secondary Outcome Measures :

1. Treatment failure [ Time Frame: 12 months ]
   Secondary outcome will be time to treatment failure.
2. change in TFLS (Texas Functional Living Scale) scores [ Time Frame: 6-12 months ]

   Secondary outcome: TFLS (Texas Functional Living Scale) scores at 6 and 12 months compared to baseline. - A performance-based measure of functional competence designed to assess instrumental activities of daily living (e.g., managing money) that are thought to be more susceptible to cognitive change than basic activities of daily living (e.g., dressing).

   Content and Structure: The TFLS is comprised of 24 items divided into four subscales assessing abilities related to Time, Money and Calculation, Communication, and Memory. Many items provide a range of possible points allowing the instrument to account for the varying levels of functioning that may be observed in clinical populations.

   Total raw score ranges between 0 and 50 with standardized T-score values between 20 and 66. The higher the score, the better the performance.

   Subscale ranges:

   Time: 0-9 Money and Calculation: 0-8 Communication: 0-28 Memory: 0-5

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

United States, Texas

UT Southwestern Medical Center

Dallas, Texas, United States, 75390

Sponsors and Collaborators

University of Texas Southwestern Medical Center

Genentech, Inc.

Investigators

• Principal Investigator: Steven Vernino, MD, PhD; UT Southwestern Medical Center

More Information

Publications:

Graus F, Titulaer MJ, Balu R, Benseler S, Bien CG, Cellucci T, Cortese I, Dale RC, Gelfand JM, Geschwind M, Glaser CA, Honnorat J, Höftberger R, Iizuka T, Irani SR, Lancaster E, Leypoldt F, Prüss H, Rae-Grant A, Reindl M, Rosenfeld MR, Rostásy 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. Review.

Titulaer MJ, McCracken L, Gabilondo I, Armangué 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.

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.

• Responsible Party: Steven Vernino, PROFESSOR, University of Texas Southwestern Medical Center
• ClinicalTrials.gov Identifier: NCT03835728
• Other Study ID Numbers: STU-2018-0185
• First Posted: February 11, 2019
• Last Update Posted: November 27, 2020
• Last Verified: November 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:

Encephalitis; Hashimoto Disease; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Thyroiditis, Autoimmune; Thyroiditis; Thyroid Diseases; Endocrine System Diseases; Ocrelizumab; Immunologic Factors; Physiological Effects of Drugs