Immunoadsorption Therapy in Managing NMDAR Antibodies Encephalitis (IANMDAR)

Prospective Assessment of Efficacy of Immunoadsorption Therapy in Managing Childhood NMDA-Receptor (NMDAR) Antibodies Encephalitis

The purpose of the study is to assess the efficacy of immunoadsorption therapy (IA) on improving the neurological status of severe pediatric anti-NMDAR encephalitis patients.

Study Overview

• Status: Recruiting
• Conditions: Anti-NMDAR Encephalitis
• Intervention / Treatment: Drug: IA session; Drug: Rituximab

Detailed Description

Anti-NMDA-Receptor (NMDAR) encephalitis, the most frequent autoimmune encephalitis after Acute Demyelinating encephalomyelitis (ADEM), affects children with predominant movement disorders, decline of consciousness, psychiatric symptoms, language dysfunction, seizures, dysautonomic symptoms. The cerebrospinal fluid (CSF) is most often abnormal with lymphocytic pleocytosis, CSF-specific oligoclonal bands with intrathecal synthesis of anti-NMDAR antibodies. Antibody titres in CSF and serum seem correlated with clinical outcome. Early start of immunotherapy has been reported to improve clinical outcome and associated with less relapses. In a recent large series (211 children/577), 77% of the patients were admitted to Intensive Care Unit (ICU) at the beginning. Within the group of children, first-line immunotherapy (95%) consisted of corticosteroids (89%), and/or intravenous immunoglobulins (IgIV) (83%), and/or plasma exchange (28%) with failure in 46%. The second-line immunotherapy consisting in rituximab (24%) and/or cyclophosphamide (16%) was proposed in 32%, and tended to be associated with good outcome (OR=3.35, CI: 0.86-12.98, p=0.081 for 53 children; statistical significance was achieved for the entire population including adults (OR: 2.69, CI: 1.24-5.80, p = 0.012) and less relapses.

In investigators' experience, the clinical benefit of rituximab is delayed over one month, while children go on worsening (50% admitted in ICU) thus claiming for faster removal of the antibodies. Plasma exchange is proposed in most of the series as alternative or combined treatment in the acute stage (first-line immunotherapy); recently, another plasmatherapy, immunoadsorption therapy (IA), has been reported as an efficient therapeutic approach in 11/13 patients. In this retrospective study, patients received a median of 6 IA sessions within a median period of 8 days with relevant clinical improvement. However these encouraging results and investigators' experience in few children need further prospective and standardized evaluation.

In IANMDAR study, each patient will receive 10 IA sessions during 28 days maximum. Rituximab will be given each week for 4 weeks (one injection by week +/- 3 days):

• at least 1 day before each IA session
• the 4 injections should be done before V2 (Day 28 after the inclusion)

To assess the efficacy of IA-therapy at short term, the neurological status of patients will be evaluated before and after the 10 IA sessions using the Pediatric Cerebral Performance Category Scale (PCPCS) and the modified Rankin Scale (mRS).

To assess the efficacy of IA-therapy at long term, patients will have a standardized follow-up during two years including neuropsychological evaluation at 1 year and at 2 years (see below for further details).

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Aminata TRAORE; Phone Number: +33 1 48 19 27 34; Email: aminata.traore6@aphp.fr
• Study Contact Backup: Name: Isabelle DESGUERRE, MD, PhD; Phone Number: +33 1.44.49.41.42; Email: isabelle.desguerre@aphp.fr

Study Locations

• France
  • Paris, France, 75015
    • Recruiting
    • Hôpital Necker Enfants-Malades
    • Contact: Isabelle DESGUERRE, MD, PhD; Phone Number: +33 1 44 49 41 42; Email: isabelle.desguerre@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 16 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age: 0-18 years inclusive
• Autoimmune encephalitis with positive anti-NMDAR antibodies in CSF (definite anti-NMDAR encephalitis according to Graus's criteria (Graus et al., 2016).
• PCPCS and mRS at 4 or over at the inclusion after first line therapy (steroids and/or IgIV) when Rituximab therapy is warranted
• Parents or legal guardians signed the Informed consent form
• Social insurance affiliation

Exclusion Criteria:

• Autoimmune encephalitis without NMDAR antibodies
• PCPCS and mRS scores under 4 after first-line therapy
• Contraindication to perform central vascular access
• Pregnancy, breastfeeding or absence of effective contraception (including abstinence) in a pubertal patient.

• Contraindication to perform IA therapy :

  • Clinical conditions that prohibit transitory volume changes
  • Indications that prohibit anticoagulation using Heparin and/or ACD-A solutions
  • History of hypercoagulability
  • Generalized viral, bacterial and/or mycotic infections
  • Severe immune deficiencies (e.g. AIDS)
  • Suspected allergies against sheep antibodies or agarose

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: IA session; 4 Rituximab injections; 10 IA sessions

Drug: IA session; 10 IA sessions performed in 28 days maximum, using TherasorbTM adsorbers which contain sheep derived polyvalent antihuman-immunoglobulin coupled to SepharoseTM CL-4B.; Drug: Rituximab; Concomitantly, Rituximab will be given each week for 4 weeks (one injection by week +/- 3 days): at least 1 day before each IA session; the last injection will occur after the last session IA (minimum one day after)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Neurological status evaluated with the Pediatric Cerebral Performance Category Scale (PCPCS)	at least reduction of 1 point in PCPCS between the two evaluations is expected	before and after the 10 IA sessions, 28 days maximum
Change in Neurological status evaluated with the modified Rankin Scale (mRS)	at least reduction of 1 point in mRS between the two evaluations is expected	before and after the 10 IA sessions, 28 days maximum

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Need of hospitalization in ICU and pediatric neurology unit	To assess immunoadsorption therapy at short term in pediatric severe anti-NMDAR encephalitis patients	28 days
Duration of hospitalization in ICU and pediatric neurology unit	To assess immunoadsorption therapy at short term in pediatric severe anti-NMDAR encephalitis patients	28 days
Need for mechanical ventilation	To assess immunoadsorption therapy at short term in pediatric severe anti-NMDAR encephalitis patients	28 days
Need for vasopressive treatment	To assess immunoadsorption therapy at short term in pediatric severe anti-NMDAR encephalitis patients	28 days
Time of recovery of independent daily-life activities	independent ambulation, enteral feeding, responsiveness to simple instructions and verbal communication (first word)	28 days
Name and duration of medication for behavioral disorders and sleep disorders	To assess immunoadsorption therapy at short term in pediatric severe anti-NMDAR encephalitis patients	28 days
Evolution of movement disorders assessed by the Movement Disorder Childhood Scale with video-taping, performed before and after IA therapy	To assess immunoadsorption therapy at short term in pediatric severe anti-NMDAR encephalitis patients	28 days
Biological evolution of NMDAR antibodies tested in serum	before and after IA sessions	28 days
Biological evolution of NMDAR antibodies tested in CSF	at diagnosis and after IA sessions	28 days
Titration of NMDAR antibodies in serum before and after the first and the last (tenth) IA session	To assess immunoadsorption therapy at short term in pediatric severe anti-NMDAR encephalitis patients	28 days
Duration of each immunoadsorption treatment	To assess tolerance of IA therapy	28 days
Duration of use of medication for sedation by pharmaceutical class	to assess need of sedation	28 days
Occurrence of hypotension with need for vasopressive treatment	To assess tolerance of IA therapy	28 days
Occurrence of dysautonomic events (linked to the pathology): cardiac arrhythmia and heart rate events, flush, apnea	To assess tolerance of IA therapy	28 days
Occurrence of vascular access complications : Infections (number, duration of antibiotics used), inadvertent removal, inefficiency (duration of retention of each vascular access)	To assess tolerance of IA therapy	28 days
Total duration of the immunoadsorption therapy	To assess tolerance of IA therapy	28 days
Total number of sessions	To assess tolerance of IA therapy	28 days
Number of adsorbers used for each patient	To assess tolerance of IA therapy	28 days
Adverse events of associated treatments	To assess tolerance of IA therapy	28 days
PCPCS score	To assess Immunoadsorption therapy at long term	3 months
mRS score	To assess Immunoadsorption therapy at long term	3 months
PCPCS score	To assess Immunoadsorption therapy at long term	6 months
mRS score	To assess Immunoadsorption therapy at long term	6 months
PCPCS score	To assess Immunoadsorption therapy at long term	1 year
PCPCS score	To assess Immunoadsorption therapy at long term	at 2 years
mRS score	To assess Immunoadsorption therapy at long term	1 year
mRS score	To assess Immunoadsorption therapy at long term	at 2 years
Need of hospitalization in functional rehabilitation unit	To assess Immunoadsorption therapy at long term	2 years
Duration of hospitalization in functional rehabilitation unit	To assess Immunoadsorption therapy at long term	2 years
School attendance (special school or not) and rehabilitation attendance	To assess Immunoadsorption therapy at long term	2 years
Neuropsychological assessment for cognitive and behavioral status with Wechsler scales		1 year
Neuropsychological assessment for cognitive and behavioral status with Wechsler scales		at 2 years
Neuropsychological assessment for cognitive and behavioral status with Child Behavior Checklist (CBCL)		1 year
Neuropsychological assessment for cognitive and behavioral status with Child Behavior Checklist (CBCL)		at 2 years
Neuropsychological assessment for cognitive and behavioral status with Brief Inventory of Executive Functions (BRIEF)		1 year
Neuropsychological assessment for cognitive and behavioral status with Brief Inventory of Executive Functions (BRIEF)		at 2 years
Neuropsychological assessment for cognitive and behavioral status with Pediatric Quality of Life questionnaire (PedsQL)		1 year
Neuropsychological assessment for cognitive and behavioral status with Pediatric Quality of Life questionnaire (PedsQL)		at 2 years
Visual attention evaluated with NEPSY scale		1 year
Visual attention evaluated with NEPSY scale		at 2 years
Rey's figure test to evaluate visuospatial abilities and memory		1 year
Rey's figure test to evaluate visuospatial abilities and memory		2 years
CMS to assess memory		1 year
CMS to assess memory		2 years
Digit span to assess memory		1 year
Digit span to assess memory		2 years
Movement disorders assessment with the Movement Disorder Childhood Scale	To assess Immunoadsorption therapy at long term	3 months
Movement disorders assessment with video-taping	To assess Immunoadsorption therapy at long term	3 months
Movement disorders assessment with the Movement Disorder Childhood Scale	To assess Immunoadsorption therapy at long term	6 months
Movement disorders assessment with video taping	To assess Immunoadsorption therapy at long term	6 months
Movement disorders assessment with the Movement Disorder Childhood Scale	To assess Immunoadsorption therapy at long term	1 year
Movement disorders assessment with the Movement Disorder Childhood Scale	To assess Immunoadsorption therapy at long term	2 years
Movement disorders assessment with video-taping	To assess Immunoadsorption therapy at long term	1 year
Movement disorders assessment with video-taping	To assess Immunoadsorption therapy at long term	at 2 years
Occurrence and date of relapses		2 years
Presence of NMDAR antibodies in CSF	titration at 6 months	6 months
Presence of NMDAR antibodies in CSF	titration at 1 year	1 year
Presence of NMDAR antibodies in serum	titration at 3 months	3 months
Presence of NMDAR antibodies in serum	titration at 6 months	6 months
Presence of NMDAR antibodies in serum	titration at 1 year	1 year
Proteinorachia	titration at 6 months	6 months
Proteinorachia	titration at 1 year	1 year
Presence of oligoclonal bands in serum	checked at 1 year	1 year
Presence of oligoclonal bands in serum	checked at 3 months	3 months
Presence of oligoclonal bands in serum	checked at 6 months	6 months
Presence of oligoclonal bands in CSF	checked at 6 months	6 months
Presence of oligoclonal bands in CSF	checked at 1 year	1 year
Number of lymphocytes in serum	checked at 3 months	3 months
Number of lymphocytes in serum	checked at 6 months	6 months
Number of lymphocytes in serum	checked at 1 year	1 year
Number of lymphocytes in CSF	checked at 6 months	6 months
Number of lymphocytes in CSF	checked at 1 year	1 year

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Study Chair: Rémi SALOMON, Md, PhD, Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Actual): June 23, 2021
• Primary Completion (Estimated): July 1, 2024
• Study Completion (Estimated): June 1, 2026

Study Registration Dates

• First Submitted: July 24, 2017
• First Submitted That Met QC Criteria: September 4, 2017
• First Posted (Actual): September 6, 2017

Study Record Updates

• Last Update Posted (Actual): July 13, 2023
• Last Update Submitted That Met QC Criteria: July 12, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: Paediatric; Anti-NMDAR encephalitis; IA adsorption
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Immune System Diseases; Neoplasms; Autoimmune Diseases of the Nervous System; Autoimmune Diseases; Neoplasms by Site; Neurodegenerative Diseases; Nervous System Neoplasms; Paraneoplastic Syndromes, Nervous System; Paraneoplastic Syndromes; Neuroinflammatory Diseases; Encephalitis; Anti-N-Methyl-D-Aspartate Receptor Encephalitis; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Rituximab
• Other Study ID Numbers: P150919; 2016-A00259-42 (Other Identifier: IDRCB)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No