Clinical trial NCT03274375: Immunoadsorption Therapy in Managing NMDAR Antibodies Encephalitis
Official title: Prospective Assessment of Efficacy of Immunoadsorption Therapy in Managing Childhood NMDA-Receptor (NMDAR) Antibodies Encephalitis
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Anti-NMDAR Encephalitis
Keywords: Anti-NMDAR encephalitis
IA adsorption
Paediatric
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2017-09-06
Enrollment: 20
Sex: ALL
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

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).

Eligibility criteria: 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

Primary outcomes:
measure: Change in Neurological status evaluated with the Pediatric Cerebral Performance Category Scale (PCPCS)
timeFrame: before and after the 10 IA sessions, 28 days maximum
measure: Change in Neurological status evaluated with the modified Rankin Scale (mRS)
timeFrame: before and after the 10 IA sessions, 28 days maximum
Secondary outcomes:
measure: Need of hospitalization in ICU and pediatric neurology unit
timeFrame: 28 days
measure: Duration of hospitalization in ICU and pediatric neurology unit
timeFrame: 28 days
measure: Need for mechanical ventilation
timeFrame: 28 days
measure: Need for vasopressive treatment
timeFrame: 28 days
measure: Time of recovery of independent daily-life activities
timeFrame: 28 days
measure: Name and duration of medication for behavioral disorders and sleep disorders
timeFrame: 28 days
measure: Evolution of movement disorders assessed by the Movement Disorder Childhood Scale with video-taping, performed before and after IA therapy
timeFrame: 28 days
measure: Biological evolution of NMDAR antibodies tested in serum
timeFrame: 28 days
measure: Biological evolution of NMDAR antibodies tested in CSF
timeFrame: 28 days
measure: Titration of NMDAR antibodies in serum before and after the first and the last (tenth) IA session
timeFrame: 28 days
measure: Duration of each immunoadsorption treatment
timeFrame: 28 days
measure: Duration of use of medication for sedation by pharmaceutical class
timeFrame: 28 days
measure: Occurrence of hypotension with need for vasopressive treatment
timeFrame: 28 days
measure: Occurrence of dysautonomic events (linked to the pathology): cardiac arrhythmia and heart rate events, flush, apnea
timeFrame: 28 days
measure: Occurrence of vascular access complications : Infections (number, duration of antibiotics used), inadvertent removal, inefficiency (duration of retention of each vascular access)
timeFrame: 28 days
measure: Total duration of the immunoadsorption therapy
timeFrame: 28 days
measure: Total number of sessions
timeFrame: 28 days
measure: Number of adsorbers used for each patient
timeFrame: 28 days
measure: Adverse events of associated treatments
timeFrame: 28 days
measure: PCPCS score
timeFrame: 3 months
measure: mRS score
timeFrame: 3 months
measure: PCPCS score
timeFrame: 6 months
measure: mRS score
timeFrame: 6 months
measure: PCPCS score
timeFrame: 1 year
measure: PCPCS score
timeFrame: at 2 years
measure: mRS score
timeFrame: 1 year
measure: mRS score
timeFrame: at 2 years
measure: Need of hospitalization in functional rehabilitation unit
timeFrame: 2 years
measure: Duration of hospitalization in functional rehabilitation unit
timeFrame: 2 years
measure: School attendance (special school or not) and rehabilitation attendance
timeFrame: 2 years
measure: Neuropsychological assessment for cognitive and behavioral status with Wechsler scales
timeFrame: 1 year
measure: Neuropsychological assessment for cognitive and behavioral status with Wechsler scales
timeFrame: at 2 years
measure: Neuropsychological assessment for cognitive and behavioral status with Child Behavior Checklist (CBCL)
timeFrame: 1 year
measure: Neuropsychological assessment for cognitive and behavioral status with Child Behavior Checklist (CBCL)
timeFrame: at 2 years
measure: Neuropsychological assessment for cognitive and behavioral status with Brief Inventory of Executive Functions (BRIEF)
timeFrame: 1 year
measure: Neuropsychological assessment for cognitive and behavioral status with Brief Inventory of Executive Functions (BRIEF)
timeFrame: at 2 years
measure: Neuropsychological assessment for cognitive and behavioral status with Pediatric Quality of Life questionnaire (PedsQL)
timeFrame: 1 year
measure: Neuropsychological assessment for cognitive and behavioral status with Pediatric Quality of Life questionnaire (PedsQL)
timeFrame: at 2 years
measure: Visual attention evaluated with NEPSY scale
timeFrame: 1 year
measure: Visual attention evaluated with NEPSY scale
timeFrame: at 2 years
measure: Rey's figure test to evaluate visuospatial abilities and memory
timeFrame: 1 year
measure: Rey's figure test to evaluate visuospatial abilities and memory
timeFrame: 2 years
measure: CMS to assess memory
timeFrame: 1 year
measure: CMS to assess memory
timeFrame: 2 years
measure: Digit span to assess memory
timeFrame: 1 year
measure: Digit span to assess memory
timeFrame: 2 years
measure: Movement disorders assessment with the Movement Disorder Childhood Scale
timeFrame: 3 months
measure: Movement disorders assessment with video-taping
timeFrame: 3 months
measure: Movement disorders assessment with the Movement Disorder Childhood Scale
timeFrame: 6 months
measure: Movement disorders assessment with video taping
timeFrame: 6 months
measure: Movement disorders assessment with the Movement Disorder Childhood Scale
timeFrame: 1 year
measure: Movement disorders assessment with the Movement Disorder Childhood Scale
timeFrame: 2 years
measure: Movement disorders assessment with video-taping
timeFrame: 1 year
measure: Movement disorders assessment with video-taping
timeFrame: at 2 years
measure: Occurrence and date of relapses
timeFrame: 2 years
measure: Presence of NMDAR antibodies in CSF
timeFrame: 6 months
measure: Presence of NMDAR antibodies in CSF
timeFrame: 1 year
measure: Presence of NMDAR antibodies in serum
timeFrame: 3 months
measure: Presence of NMDAR antibodies in serum
timeFrame: 6 months
measure: Presence of NMDAR antibodies in serum
timeFrame: 1 year
measure: Proteinorachia
timeFrame: 6 months
measure: Proteinorachia
timeFrame: 1 year
measure: Presence of oligoclonal bands in serum
timeFrame: 1 year
measure: Presence of oligoclonal bands in serum
timeFrame: 3 months
measure: Presence of oligoclonal bands in serum
timeFrame: 6 months
measure: Presence of oligoclonal bands in CSF
timeFrame: 6 months
measure: Presence of oligoclonal bands in CSF
timeFrame: 1 year
measure: Number of lymphocytes in serum
timeFrame: 3 months
measure: Number of lymphocytes in serum
timeFrame: 6 months
measure: Number of lymphocytes in serum
timeFrame: 1 year
measure: Number of lymphocytes in CSF
timeFrame: 6 months
measure: Number of lymphocytes in CSF
timeFrame: 1 year
Other outcomes:
Locations:
city: Paris
country: France
facility: Hôpital Necker Enfants-Malades
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Rémi SALOMON, Md, PhD
role: STUDY_CHAIR
References: