University Hospitals Enrolls First U.S. Patient in International Phase 3 Clinical Trial for ‘autoimmune Encephalitis
June 28, 2023
Innovations in Neurology & Neurosurgery | Summer 2023
“We are delighted that University Hospitals has enrolled the first U.S. patient in CIELO, the first and only phase 3 clinical trial aimed at identifying an evidence-based treatment for autoimmune encephalitis [AE],” says Hesham Abboud, MD, PhD, Director of the Multiple Sclerosis and Neuroimmunology Program at University Hospitals Neurological Institute.
AE is a rare immune-mediated disorder of the brain, and conventional medical management has depended on empiric evidence, expert opinion and retrospective studies. CIELO is a randomized, double-blind study evaluating the safety and efficacy of satralizumab, an interleukin-6 inhibitor, versus placebo. Satralizumab is currently FDA-approved for the treatment of adults with aquaporin-4 (AQP4) antibody-positive neuromyelitis optica spectrum disorder (NMOSD), a rare inflammatory disease most often affecting the optic nerves and spinal cord.
CIELO investigators are recruiting patients at over 80 sites in 15 countries. Dr. Abboud serves on the international steering committee and has collaborated with a team of experts on the trial’s design. In 2021, he was the lead author of two manuscripts published by the Autoimmune Encephalitis Alliance Clinicians Network that amalgamated expert consensus and best practice recommendations for the diagnosis and management of AE.1
“Within those manuscripts, we identified the need for clinical trials — especially involving the most promising mechanisms of action. That was the nucleus upon which this study was developed,” says Dr. Abboud.
Epidemiology of AE
Individuals of any age can be affected by AE. While paraneoplastic AE is more common in the elderly, idiopathic AE is diagnosed more frequently in young adults. A personal or family history of other autoimmune disorders is common. The prevalence rate of 13.7/100,0002 is likely underestimated.
“For many years, it was thought that infectious encephalitis, particularly herpetic encephalitis, was more common,” says Dr. Abboud. “However, epidemiological studies suggest that AE is becoming one of the leading causes of encephalitis and is increasingly recognized as a reason for neurological hospitalization and neuro-ICU admissions.”
CIELO Design and Targeted Outcomes
With a goal of enrolling 152 adolescent and adult patients worldwide, investigators are focused on individuals with the two most common subtypes of AE.
- Anti-N-Methyl-D-Aspartic Acid Receptor (NMDAR) Encephalitis
- Anti-Leucine-Rich Glioma-Inactivated 1 (LGI1) Encephalitis
“We are testing satralizumab as an add-on to standard medical management because this condition can be fatal if not treated early,” says Dr. Abboud. “Patients must receive anti-inflammatory treatment such as high-dose steroids, intravenous immunoglobulin and/or plasma exchange. While not evidence-based, these three interventions are considered first-line therapy for AE.”
The novel study design will enroll both new-onset and refractory patients. Every patient will receive one or more anti-inflammatory treatments at the investigator’s discretion. Individuals who respond to first-line therapy and consent to the study will be randomized to either Satralizumab or placebo.
“We call these new-onset patients,” says Dr. Abboud. “There is another arm of the study in which patients who do not respond to first-line immunotherapy and remain symptomatic will be prescribed second-line therapy, typically rituximab, a long-acting monoclonal antibody.” Those patients can then participate in the refractory arm of the study. The primary endpoint, a modified Rankin score (mRS) score improvement ≥ 1 from baseline and no use of rescue therapy, will be assessed at week 24. Some secondary endpoints include:
- Cessation of status epilepticus without rescue therapy
- Change in the Clinical Assessment Scale of Encephalitis (CASE) score
- Cognitive and verbal learning assessments
“We are hopeful that satralizumab shows effectiveness in the management of these two subtypes of AE,” says Dr. Abboud. “We also hope to justify using the same molecule against even rarer subtypes of AE that have similarities to NMDAR and LGI1.”
For more information, contact Dr. Abboud at Hesham.Abboud@UHhospitals.org.
1 Abboud H, Probasco JC, Irani S, Ances B, Benavides DR, Bradshaw M, Christo PP, Dale RC, Fernandez-Fournier M, Flanagan EP, Gadoth A, George P, Grebenciucova E, Jammoul A, Lee ST, Li Y, Matiello M, Morse AM, Rae-Grant A, Rojas G, Rossman I, Schmitt S, Venkatesan A, Vernino S, Pittock SJ, Titulaer MJ; Autoimmune Encephalitis Alliance Clinicians Network. Autoimmune encephalitis: proposed best practice recommendations for diagnosis and acute management. J Neurol Neurosurg Psychiatry. 2021 Jul;92(7):757-768. doi: 10.1136/jnnp-2020-325300. Epub 2021 Mar 1. PMID: 33649022; PMCID: PMC8223680.
2 Dubey D, Pittock SJ, Kelly CR, et al. Autoimmune encephalitis epidemiology and a comparison to infectious encephalitis. Ann Neurol. 2018 Jan;83(1):166-177. doi: 10.1002/ana.25131. PMID: 29293273; PMCID: PMC6011827.
Hesham Abboud, MD, PhD
Director of the Multiple Sclerosis and Neuroimmunology Program
University Hospitals Neurological Institute
University Hospitals Cleveland Medical Center
Associate Professor of Neurology
Case Western Reserve University School of Medicine