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Efficacy of Ocrelizumab in Autoimmune Encephalitis

Primary Purpose

Autoimmune Encephalitis

Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Ocrelizumab
Saline
Sponsored by
University of Texas Southwestern Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Autoimmune Encephalitis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • UT Southwestern Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Treatment Arm

Treatment Placebo Arm

Arm Description

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.

Saline will be used as the matching placebo

Outcomes

Primary Outcome Measures

Number of Participants Who Had Clinical Worsening
The number of participants who had clinical worsening within 12 months.

Secondary Outcome Measures

Time to Treatment Failure
Definition of clinical worsening (treatment failure): Clinician or patient/caregiver perception of clinical decline Worsening of patient/family reported IADL (by one point or more) One of the following additional features: Significant worsening of Texas Functional Living Scale (by ≥ 5 T points, 0.5 st deviation) Other clinical worsening leading to hospitalization
Change in TFLS T-score (Texas Functional Living Scale) Score at 6 Months
Change in TFLS T-score (Texas Functional Living Scale) scores at 6 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. Change in TFLS T-score was used in this study
Change in TFLS T Score (Texas Functional Living Scale) Score at 12 Months
Change in TFLS T-score (Texas Functional Living Scale) scores at 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. Change in TFLS T-score was used in this study

Full Information

First Posted
February 5, 2019
Last Updated
September 21, 2021
Sponsor
University of Texas Southwestern Medical Center
Collaborators
Genentech, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT03835728
Brief Title
Efficacy of Ocrelizumab in Autoimmune Encephalitis
Official Title
Exploratory Study of Efficacy of Ocrelizumab in Autoimmune Encephalitis
Study Type
Interventional

2. Study Status

Record Verification Date
September 2021
Overall Recruitment Status
Terminated
Why Stopped
Failed to meet target enrollment and study was discontinued
Study Start Date
January 22, 2019 (Actual)
Primary Completion Date
October 2, 2020 (Actual)
Study Completion Date
October 2, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Texas Southwestern Medical Center
Collaborators
Genentech, Inc.

4. Oversight

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
Data Monitoring Committee
No

5. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Autoimmune Encephalitis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
3 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment Arm
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Treatment Placebo Arm
Arm Type
Placebo Comparator
Arm Description
Saline will be used as the matching placebo
Intervention Type
Drug
Intervention Name(s)
Ocrelizumab
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Saline
Intervention Description
This will be the matching placebo used in the study.
Primary Outcome Measure Information:
Title
Number of Participants Who Had Clinical Worsening
Description
The number of participants who had clinical worsening within 12 months.
Time Frame
12 months
Secondary Outcome Measure Information:
Title
Time to Treatment Failure
Description
Definition of clinical worsening (treatment failure): Clinician or patient/caregiver perception of clinical decline Worsening of patient/family reported IADL (by one point or more) One of the following additional features: Significant worsening of Texas Functional Living Scale (by ≥ 5 T points, 0.5 st deviation) Other clinical worsening leading to hospitalization
Time Frame
12 months
Title
Change in TFLS T-score (Texas Functional Living Scale) Score at 6 Months
Description
Change in TFLS T-score (Texas Functional Living Scale) scores at 6 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. Change in TFLS T-score was used in this study
Time Frame
Baseline, 6 month
Title
Change in TFLS T Score (Texas Functional Living Scale) Score at 12 Months
Description
Change in TFLS T-score (Texas Functional Living Scale) scores at 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. Change in TFLS T-score was used in this study
Time Frame
Baseline, 12 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age 18 or greater Able to obtain informed consent from patient or appropriate designee Possible autoimmune encephalitis as defined by Table 1: Reasonable exclusion of alternative causes Subacute onset (< 3 months) of memory deficits, altered consciousness, and/or psychiatric symptoms 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) Completed initial treatment with iv steroids (at least 3000mg solumedrol) and plasma exchange (at least 3 exchanges) within the past 8 weeks Presence of one (or more) of the following autoantibodies in serum or CSF NMDA receptor LGI1 CASPR2 DPPX Exclusion Criteria: Prior immunosuppression treatment in past year (other than steroids, intravenous immunoglobulin and plasma exchange) Active malignancy requiring chemotherapy Pregnancy Evidence of active hepatitis or tuberculosis infection Medical condition that (in investigators opinion) precludes the use of ocrelizumab
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Steven Vernino, MD, PhD
Organizational Affiliation
UT Southwestern Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
UT Southwestern Medical Center
City
Dallas
State/Province
Texas
ZIP/Postal Code
75390
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Yes
Citations:
PubMed Identifier
26906964
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.
Results Reference
background
PubMed Identifier
23290630
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.
Results Reference
background
PubMed Identifier
26439968
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.
Results Reference
background
PubMed Identifier
35129803
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.
Results Reference
derived

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Efficacy of Ocrelizumab in Autoimmune Encephalitis

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