Autoimmune Encephalitis
Conditions
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.
Interventions
DRUGOcrelizumab
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.
DRUGSaline
This will be the matching placebo used in the study.
Sponsors
Genentech, Inc.
University of Texas Southwestern Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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: 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Had Clinical Worsening | 12 months | The number of participants who had clinical worsening within 12 months. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Treatment Failure | 12 months | Definition of clinical worsening (treatment failure): 1. Clinician or patient/caregiver perception of clinical decline 2. Worsening of patient/family reported IADL (by one point or more) 3. 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 | 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 |
| 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 |
Countries
United States
Participant flow
Recruitment details
Failed to meet target enrollment and study was discontinued
Participants by arm
| Arm | Count |
|---|---|
| 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.
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. | 2 |
| Treatment Placebo Arm Saline will be used as the matching placebo
Saline: This will be the matching placebo used in the study. | 1 |
| Total | 3 |
Baseline characteristics
| Characteristic | Treatment Arm | Treatment Placebo Arm | Total |
|---|---|---|---|
| Age, Customized Age | 47.5 years | 44 years | 44 years |
| Encephalitis antibody LGI1 Ab | 1 Participants | 0 Participants | 1 Participants |
| Encephalitis antibody NMDAR Ab | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 1 Participants | 2 Participants |
| Region of Enrollment United States | 2 participants | 1 participants | 3 participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Male | 1 Participants | 0 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 2 | 0 / 1 |
| other Total, other adverse events | 2 / 2 | 1 / 1 |
| serious Total, serious adverse events | 0 / 2 | 0 / 1 |
Outcome results
Primary
Number of Participants Who Had Clinical Worsening
The number of participants who had clinical worsening within 12 months.
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment Arm | Number of Participants Who Had Clinical Worsening | 0 Participants |
| Treatment Placebo Arm | Number of Participants Who Had Clinical Worsening | 1 Participants |
Secondary
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
Time frame: Baseline, 12 months
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment Arm | Change in TFLS T Score (Texas Functional Living Scale) Score at 12 Months | 24.5 score on a scale |
Secondary
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
Time frame: Baseline, 6 month
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment Arm | Change in TFLS T-score (Texas Functional Living Scale) Score at 6 Months | 12.75 score on a scale |
Secondary
Time to Treatment Failure
Definition of clinical worsening (treatment failure): 1. Clinician or patient/caregiver perception of clinical decline 2. Worsening of patient/family reported IADL (by one point or more) 3. 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
Population: There were no treatment failures in the treatment arm. Thus, there was no data for this secondary outcome measure in the treatment arm
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment Placebo Arm | Time to Treatment Failure | 12 weeks |