Evaluation of the Efficacy of Immunomodulatory Therapy in Case of Psychiatric Disorders With Proven Dysimmunity. (TIM-DePisT)

Phase III Randomized, Multicenter Open Label Study to Evaluate the Efficacy of Immunomodulatory Therapy in Case of Psychiatric Disorders With Proven Dysimmunity.

This is an open phase III randomized clinical trial studying the superiority of management by immunomodulator treatment of psychiatric disorders (psychosis and bipolar disorders) for patients previously identified as carriers of autoimmunity such as as the presence of a pathogenic anti-glutamatergic NMDA receptor antibody (NMDAr-Ac).

Study Overview

• Status: Not yet recruiting
• Conditions: Mental Disorder
• Intervention / Treatment: Drug: immunomodulatory treatment by rituximab

Detailed Description

This is an open phase III randomized clinical trial studying the superiority of management by immunomodulator treatment of psychiatric disorders (psychosis and bipolar disorders) for patients previously identified as carriers of autoimmunity such as as the presence of a pathogenic anti-glutamatergic NMDA receptor antibody (NMDAr-Ac). The aim is to assess the clinical efficacy of this treatment associated with the usual recommended psychotropic treatment. To meet this objective, we will use, via a National Center for Scientific Research (CNRS) Research laboratory in Bordeaux, a very sensitive diagnostic platform to detect and demonstrate the pathogenesis of antibodies in patient serum. This platform is operational only within the framework of validation of the results by the reference center for neurological autoimmune diseases in Lyon

• Study Type: Interventional
• Enrollment (Estimated): 174
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Aurore CAPELLI, PhD; Phone Number: 0557820877; Email: aurore.capelli@chu-bordeaux.fr
• Study Contact Backup: Name: Frédéric VILLEGA, MD, PhD; Phone Number: +33 (0)5 56 79 56 41; Email: frederic.villega@chu-bordeaux.fr

Study Locations

• France
  • Bordeaux, France
    • CHU de Bordeaux
    • Contact: Frédéric Villega
    • Sub-Investigator: Valérie Adrian
  • Bordeaux, France
    • Centre Hospitalier Charles Perrens
    • Contact: Bruno Aouizerate
    • Sub-Investigator: Anouck Amestoy
  • Bron, France
    • Centre Hospitalier le Vinatier
    • Contact: Romain Rey
  • Clermont-Ferrand, France
    • CHU de Clermond Ferrand
    • Contact: Pierre-Michel Llorca
  • Colombes, France
    • APHP Louis Mourier
    • Contact: Catherine Dubertet
  • Créteil, France
    • APHP Henri Mondor
    • Contact: Marion Leboyer
  • Le Kremlin-Bicêtre, France
    • Aphp Kremlin Bicetre
    • Contact: Kumaran Deiva
  • Montpellier, France
    • CHU de Montpellier
    • Contact: Delphine CAPDEVIELLE
  • Strasbourg, France
    • CHU de Strasbourg
    • Contact: Fabrice Berna

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• For Adult: First acute or relapse of psychotic disorders defined by the BPRS-E scale with or without standard pharmacological treatment.
• For Children: Child over 6 years old with a first acute or relapse of psychotic disorders defined by the Kiddie sads-PL scale with or without standard pharmacological treatment.
• Biological diagnosis of pathogenic CNS autoantibodies in the blood.
• MDC scale score >3 is required for inclusion in step 2.
• Normal ECG in case of previous heart disease.
• Informed consent of the patient or his legal representatives.
• Effective contraception for women of childbearing potential during the study and for at least 12 months after the last rituximab administration.

Exclusion Criteria:

• Developmental disorder related to a genetic disease.
• Co-existing disorder of severe neurological disease.
• Chronic psychotic disorders receiving ongoing neuroleptic treatment with efficacy.
• Hypersensitivity to the active substance (rituximab) or to murine proteins, or to any of the other excipients
• Blood platelets < 75x109/L
• Neutrophils < 1.5x109/L
• Neoplastic pathology,
• Hepatitis B or HIV infection,
• Contraindication to immunosuppressant treatment (active severe infection, severely immunocompromised state).
• Severe heart failure (New York Heart Association Class IV) or severe, uncontrolled cardiac disease
• Pregnant or breastfeeding women
• Currently receiving an investigational drug or received an investigational drug or device within 30 days (or 5 half-lives for drugs, whichever is longer) prior to screening.
• Previous treatment with rituximab in the past 12 months.
• Patients with a history of recurring or chronic infections or with underlying conditions which may further predispose them to serious infection (e.g. hypogammaglobulinemia).
• Recent vaccination with live viral vaccine (within 3 months).
• Any other medical illness or disability that, in the opinion of the investigator, would compromise effective trial participation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: control group; continuation of ongoing psychiatric care (with or without standard treatment as usual (i.e. antipsychotics, mood stabilisers, antidepressants and/or anxiolytics)).
Experimental: experimental group; immunomodulatory treatment by rituximab, 1g for adults or 375 mg/m2 for children, renewed at 14 days (+/- 3 days), added to stable ongoing psychiatric care (with or without standard treatment as usual ( i.e. antipsychotic, mood stabiliser, antidepressant and/or anxiolytic)). The rituximab is the best immunomodulatory treatment recommended for neurologic encephalitis.	Drug: immunomodulatory treatment by rituximab; 1g for adults or 375 mg/m2 for children, renewed at 14 days (+/- 3 days)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adult patients : the remission of psychiatric symptoms at 3 months	The primary endpoint outcome is the remission of psychiatric symptoms at 3 months, defined as: - For adult patients: 20% decrease from baseline of Brief psychiatric rating scale-Extended (BPRS-E scale).	3 months after randomization
Minor patients : the remission of psychiatric symptoms at 3 months	The primary endpoint outcome is the remission of psychiatric symptoms at 3 months, defined as: - For patients <18years or adults patients included at adolescent age at 2nd step inclusion visit: clinically significant difference ≤3 from baseline of CBCL/6-18 (Child Behavior Checklist) scale.	3 months after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adult Patients : the remission of psychiatric symptoms at 12 months	the remission of psychiatric symptoms defined as: - For adult patients: 20% decrease from baseline of Brief psychiatric rating scale-Extended (BPRS-E scale).	12 months after randomization
Adult Patients : the remission of psychiatric symptoms at 6 months	the remission of psychiatric symptoms defined as: - For adult patients: 20% decrease from baseline of Brief psychiatric rating scale-Extended (BPRS-E scale).	6 months after randomization
Adult Patients : the remission of psychiatric symptoms at 1 month	the remission of psychiatric symptoms defined as: - For adult patients: 20% decrease from baseline of Brief psychiatric rating scale-Extended (BPRS-E scale).	1 month after randomization
Minor patients : the remission of psychiatric symptoms at 12 months	The primary endpoint outcome is the remission of psychiatric symptoms at 12 months, defined as: - For patients <18years or adults patients included at adolescent age at 2nd step inclusion visit: clinically significant difference ≤3 from baseline of CBCL/6-18 (Child Behavior Checklist) scale.	12 months after randomization
Minor patients : the remission of psychiatric symptoms at 6 months	The primary endpoint outcome is the remission of psychiatric symptoms, defined as: - For patients <18years or adults patients included at adolescent age at 2nd step inclusion visit: clinically significant difference ≤3 from baseline of CBCL/6-18 (Child Behavior Checklist) scale.	6 months after randomization
Minor patients : the remission of psychiatric symptoms at 1 month	The primary endpoint outcome is the remission of psychiatric symptoms, defined as: - For patients <18years or adults patients included at adolescent age at 2nd step inclusion visit: clinically significant difference ≤3 from baseline of CBCL/6-18 (Child Behavior Checklist) scale.	1 month after randomization
Adult patients : general functioning at 1 month	for Global assessment of functioning scale (GAF scale), a mean score of 60 and above is expected to be achieved indicating patients experiencing mild to moderate symptoms and functioning pretty well in daily life.	1 month after randomization
Adult patients : general functioning at 3 months	for Global assessment of functioning scale (GAF scale), a mean score of 60 and above is expected to be achieved indicating patients experiencing mild to moderate symptoms and functioning pretty well in daily life.	3 months after randomization
Adult patients : general functioning at 6 months	for Global assessment of functioning scale (GAF scale), a mean score of 60 and above is expected to be achieved indicating patients experiencing mild to moderate symptoms and functioning pretty well in daily life.	6 months after randomization
Adult patients : general functioning at 12 months	for Global assessment of functioning scale (GAF scale), a mean score of 60 and above is expected to be achieved indicating patients experiencing mild to moderate symptoms and functioning pretty well in daily life.	12 months after randomization
Minor patients : Child behaviour check list (CBCL) /6-18 scale at 1 month	For children>6 years old with an acute first episode or relapse of psychotic disorders: clinically significant difference ≤3 from baseline of CBCL/6-18 (Child Behavior Checklist) scale.	1 month after randomization
Minor patients : Child behaviour check list (CBCL) /6-18 scale at 3 months	For children>6 years old with an acute first episode or relapse of psychotic disorders: clinically significant difference ≤3 from baseline of CBCL/6-18 (Child Behavior Checklist) scale.	3 months after randomization
Minor patients : Child behaviour check list (CBCL) /6-18 scale at 6 months	For children>6 years old with an acute first episode or relapse of psychotic disorders: clinically significant difference ≤3 from baseline of CBCL/6-18 (Child Behavior Checklist) scale.	6 months after randomization
Minor patients : Child behaviour check list (CBCL) /6-18 scale at 12 months	For children>6 years old with an acute first episode or relapse of psychotic disorders: clinically significant difference ≤3 from baseline of CBCL/6-18 (Child Behavior Checklist) scale.	12 months after randomization

Collaborators and Investigators

• Sponsor: University Hospital, Bordeaux
• Investigators: Principal Investigator: Frédéric VILLEGA, MD, PhD, University Hospital, Bordeaux

Study record dates

Study Major Dates

• Study Start (Estimated): October 15, 2023
• Primary Completion (Estimated): January 15, 2026
• Study Completion (Estimated): December 15, 2026

Study Registration Dates

• First Submitted: July 7, 2023
• First Submitted That Met QC Criteria: July 7, 2023
• First Posted (Actual): July 14, 2023

Study Record Updates

• Last Update Posted (Actual): July 14, 2023
• Last Update Submitted That Met QC Criteria: July 7, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: psychotic disorders; immunomodulatory therapy; pathogenic central nervous system (CNS) autoantibodies
• Additional Relevant MeSH Terms: Behavioral Symptoms; Problem Behavior; Mental Disorders; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Rituximab
• Other Study ID Numbers: CHUBX 2019/59

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