Low Recruitment in a Double-Blind, Placebo-Controlled Trial of Ocrelizumab for Autoimmune Encephalitis: A Case Series and Review of Lessons Learned

Abstract

Introduction: Observational data suggest that B-cell-depleting therapies are effective for antibody-mediated autoimmune encephalitis. However, randomized controlled trials are needed. Here, we report challenges encountered in a randomized, placebo-controlled trial of ocrelizumab for autoimmune encephalitis that failed to meet recruitment goals.

Methods: This was a single-center, 12-month, randomized, double-blind, placebo-controlled trial. Patients with autoimmune encephalitis were randomized in 1:1 fashion to placebo or ocrelizumab infusion after receiving first-line immunotherapy. The primary endpoint of the study was clinical worsening, defined as a perceived decline by the patient or clinician or a decrease in the Lawton and Brody Instrumental Activities of Daily Living Scale (IADL), along with either worsening on the Texas Functional Living Scale (TFLS) or hospitalization for symptoms of encephalitis.

Results: Among 16 eligible patients, only three enrolled in the study, which closed due to poor recruitment. Two participants were randomized to the ocrelizumab arm and one to the placebo arm. The single patient in the placebo arm (NMDAR+) met the primary endpoint at 12 weeks and received open-label ocrelizumab with improvement. In the ocrelizumab arm, one participant (NMDAR+) demonstrated marked improvement, and the second (LGI1+) remained clinically stable. There were no serious adverse events associated with ocrelizumab.

Conclusion: Clinical trial recruitment for autoimmune encephalitis is challenging, and our trial did not meet recruitment goals. Large, multicenter clinical trials are still needed, and careful attention must be given to study design, endpoints, and patient selection. Instrumented functional rating scales will be valuable outcome measures for future studies.

Trial registration: ClinicalTrials.gov identifier: NCT03835728.

Keywords: Autoimmune encephalitis; Clinical trial; Encephalitis; Neuroimmunology.

© 2022. The Author(s).

Figures

Fig. 1

CONSORT [Consolidated Standards of Reporting Trials] flow diagram

Fig. 2

Functional and neuropsychological assessments. Data for study participants were derived from direct assessments (TFLS and MoCA), telephone survey (IADL) or chart review (modified Rankin scale [mRS]) over the course of the study. Treatment infusions were given at weeks 0, 2, and 24. Data at week 0 were collected prior to treatment. The arrow for participant 2 indicates the point of worsening that met criteria for study endpoint. Participant 2 received an open-label infusion of ocrelizumab at week 14. The asterisk (*) indicates missing data at week 24 for participant 3 due to COVID-19 restrictions. a Treatment timeline. Filled symbols = ocrelizumab; open symbols = placebo. b Instrumental Activities of Daily Living (IADL, full score = 8) scores. c Texas Functional Living Scale (TFLS). d Montreal Cognitive Assessment (MoCA, full score = 30). e Modified Rankin scale (mRS). LGI1 = leucine-rich glioma-inactivated protein 1; NMDAR = N-methyl-d-aspartate receptor; OCR = ocrelizumab