Immunoadsorption Therapy in Managing NMDAR Antibodies Encephalitis

Anti-NMDAR Encephalitis Clinical Trial

— IANMDAR  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03274375
• Other study ID #: P150919
• Secondary ID: 2016-A00259-42
• Status: Recruiting
• Phase: Phase 2
• Start date: June 23, 2021
• Est. completion date: June 2026

Study information

• Verified date: July 2023
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: Isabelle DESGUERRE, MD, PhD
• Phone: +33 1.44.49.41.42
• Email: isabelle.desguerre[@]aphp.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 20
• Est. completion date: June 2026
• Est. primary completion date: July 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 18 Years

Eligibility

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

Related Conditions & MeSH terms

• Anti-N-Methyl-D-Aspartate Receptor Encephalitis
• Anti-NMDAR Encephalitis
• Encephalitis

Intervention

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.
• 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)

Locations

Country	Name	City	State
France	Hôpital Necker Enfants-Malades	Paris

Sponsors (1)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris

Country where clinical trial is conducted

France, 

Outcome

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