Efficacy of Ocrelizumab in Autoimmune Encephalitis

• Sponsor: University of Texas Southwestern Medical Center (Other)
• Overall Status: Terminated
• CT.gov ID: NCT03835728
• Collaborator: Genentech, Inc. (Industry)
• Enrollment: 3
• Location: 1
• Arms: 2
• Actual Duration (Months): 20.3
• Patients Per Site Per Month: 0.1

Study Details

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
• 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: Jan 22, 2019
• Actual Primary Completion Date: Oct 2, 2020
• Actual Study Completion Date: Oct 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. Number of Participants Who Had Clinical Worsening [12 months]

   The number of participants who had clinical worsening within 12 months.

Secondary Outcome Measures

1. Time to Treatment Failure [12 months]

   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

2. Change in TFLS T-score (Texas Functional Living Scale) Score at 6 Months [Baseline, 6 month]

   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

3. Change in TFLS T Score (Texas Functional Living Scale) Score at 12 Months [Baseline, 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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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:

4. Reasonable exclusion of alternative causes

5. Subacute onset (< 3 months) of memory deficits, altered consciousness, and/or psychiatric symptoms

6. 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)

1. Completed initial treatment with iv steroids (at least 3000mg solumedrol) and plasma exchange (at least 3 exchanges) within the past 8 weeks

2. 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

	Site	City	State	Country	Postal Code
1	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

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 21, 2019

More Information

Publications

• 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.
• 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.

• Responsible Party: Steven Vernino, PROFESSOR, University of Texas Southwestern Medical Center
• ClinicalTrials.gov Identifier: NCT03835728
• Other Study ID Numbers: STU-2018-0185
• First Posted: Feb 11, 2019
• Last Update Posted: Oct 19, 2021
• Last Verified: Sep 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• 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; Ocrelizumab

Study Results

Participant Flow

Recruitment Details	Failed to meet target enrollment and study was discontinued

Arm/Group Title	Treatment Arm	Treatment Placebo Arm
Arm/Group 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. 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.	Saline will be used as the matching placebo Saline: This will be the matching placebo used in the study.
Period Title: Overall Study
STARTED	2	1
COMPLETED	2	1
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Treatment Arm	Treatment Placebo Arm	Total
Arm/Group 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. 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.	Saline will be used as the matching placebo Saline: This will be the matching placebo used in the study.	Total of all reporting groups
Overall Participants	2	1	3
Age, Customized (years) [Median (Full Range) ]
Age	47.5	44	44
Sex: Female, Male (Count of Participants)
Female	1 50%	1 100%	2 66.7%
Male	1 50%	0 0%	1 33.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 50%	0 0%	1 33.3%
White	1 50%	1 100%	2 66.7%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	2 100%	1 100%	3 100%
Encephalitis antibody (Count of Participants)
NMDAR Ab	1 50%	1 100%	2 66.7%
LGI1 Ab	1 50%	0 0%	1 33.3%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment Arm	Treatment Placebo Arm
Arm/Group 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. 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.	Saline will be used as the matching placebo Saline: This will be the matching placebo used in the study.
Measure Participants	2	1
Count of Participants [Participants]	0 0%	1 100%

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

There were no treatment failures in the treatment arm. Thus, there was no data for this secondary outcome measure in the treatment arm

Arm/Group Title	Treatment Arm	Treatment Placebo Arm
Arm/Group 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. 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.	Saline will be used as the matching placebo Saline: This will be the matching placebo used in the study.
Measure Participants	0	1
Number [weeks]	12

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Participant in placebo arm met study endpoint prior to 6 month outcome measure so change in TFLS score at 6 months was not analyzable for efficacy purposes.

Arm/Group Title	Treatment Arm	Treatment Placebo Arm
Arm/Group 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. 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.	Saline will be used as the matching placebo Saline: This will be the matching placebo used in the study.
Measure Participants	2	0
Median (Full Range) [score on a scale]	12.75

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Participant in placebo arm met study endpoint prior to 6 month outcome measure so change in TFLS score at 12 months was not analyzable for efficacy purposes.

Arm/Group Title	Treatment Arm	Treatment Placebo Arm
Arm/Group 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. 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.	Saline will be used as the matching placebo Saline: This will be the matching placebo used in the study.
Measure Participants	2	0
Median (Full Range) [score on a scale]	24.5

Adverse Events

Time Frame	1 year
Arm/Group Title	Treatment Arm		Treatment Placebo Arm
Arm/Group 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. 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.		Saline will be used as the matching placebo Saline: This will be the matching placebo used in the study.
All Cause Mortality
	Treatment Arm		Treatment Placebo Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/2 (0%)		0/1 (0%)
Serious Adverse Events
	Treatment Arm		Treatment Placebo Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/2 (0%)		0/1 (0%)
Other (Not Including Serious) Adverse Events
	Treatment Arm		Treatment Placebo Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/2 (100%)		1/1 (100%)
Hepatobiliary disorders
Elevated transaminases	1/2 (50%)	1	0/1 (0%)	0
Nervous system disorders
Seizures	2/2 (100%)	2	0/1 (0%)	0
Skin and subcutaneous tissue disorders
rash	2/2 (100%)	2	1/1 (100%)	1

Limitations/Caveats

Early termination of trial due to inadequate recruitment. Small numbers of subjects prevents definitive analysis of results

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.