IVIG and Rituximab in Antibody-associated Psychosis - SINAPPS2

Study Overview
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Brief Summary
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A randomised phase II double-blinded placebo-controlled trial designed to explore the utility of immunotherapy for patients with acute psychosis associated with anti-neuronal membranes (NMDA-receptor or Voltage Gated Potassium Channel). Primary objective: To test the efficacy of immunotherapy (IVIG and rituximab) for patients with acute psychosis associated with anti-neuronal membranes. Secondary objective: To test safety of immunotherapy (IVIG and rituximab) for patients with acute psychosis associated with anti-neuronal membranes.

Detailed Description
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Investigators propose a randomised double-blinded placebo-controlled trial to test the hypothesis that immunotherapy is an effective treatment of antibody-associated psychosis, either first episode of psychosis or relapse following previous remission. Immunotherapy for the trial consists of one cycle of intravenous immunoglobulin (IVIG: 2g/kg over days 1-4) followed by two infusions of 1g rituximab (at day 28-35, and then 14 days after the first infusion). The rationale for this regime is that it combines a rapid-action treatment (IVIG) to induce remission with a longer-action therapy (rituximab) to maintain remission. It is based on a protocol where elimination of circulating antibodies is the treatment goal, namely desensitisation of potential transplant patients who have multiple anti-HLA antibodies capable of inducing hyperacute rejection and also being tested in various trials on clinicaltrials.gov (NCT00642655, NCT01178216, and NCT01502267). Blinding is required to minimise placebo responses in a trial based on symptomatology.

Official Title
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A Randomised Phase II Double-blinded Placebo-controlled Trial of Intravenous Immunoglobulins and Rituximab in Patients With Antibody-associated Psychosis (SINAPPS2)

Conditions
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Psychosis, Autoimmune Encephalitis

Intervention / Treatment
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* Drug: Intravenous immunoglobulin
* Drug: Placebo
* Drug: Rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Acute psychosis >2 weeks. This may either be first episode or relapse after remission (remission defined as having mild or absent symptoms of psychosis for at least 6 months) Serum or CSF neuronal membrane autoantibodies at pathological levels (including NMDAR, LGI1 and other) Psychosis symptoms as defined by PANSS ≥4 on at least one of the following items: P1, P2, P3, N1, N4, N6, G5 and G9. Exclusion Criteria: Current episode of psychosis greater than 24 months duration Co-existing severe neurological disease Evidence of current acute encephalopathy Hepatitis or HIV infection, pregnancy Contraindications to any trial drug Concurrent enrolment in another CTIMP

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Intravenous immunoglobulin and Rituximab<br>One cycle of intravenous immunoglobulin (IVIG) 2g/kg over 2-5 days (days 1-5) followed by (b) two infusions of 1g rituximab (the first infusion starting between days 28-35, and the second infusion 14 days later), each with 100mg methylprednisolone. | Drug: Intravenous immunoglobulin<br>* This is a blood product containing antibodies from thousands of healthy donors.<br>* Other names: Intratect;Drug: Rituximab<br>* Rituximab is a type of biological therapy. It removes B-cells and helps to reduce the inflammation<br>* Other names: MabThera;|
| Placebo Comparator: Placebo<br>One cycle of 0.9% saline solution over 2-5 days (days 1-5) followed by (b) two infusions of placebo solution alongside placebo pill - in equal volumes to steroid pre-medication and rituximab. | Drug: Placebo<br>* This is the control, or sham, treatment<br>* Other names: Saline solution;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to start of symptomatic recovery (symptomatic remission sustained for at least 6 months) | remission defined as Positive and Negative Syndrome Scale (PANSS) score 3 or less on PANSS items P1, P2, P3, N1, N4, N6, G5 and G9 sustained for 6 months | up to 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to first treatment response (whether sustained or not) | Treatment response defined as score of 3 or less on each of the following PANSS items: P1, P2, P3, N1, N4, N6, G5, and G9. | up to 18 months | 
| Relapse rate | Relapse rate is defined as a score 4 or more on PANSS items P1, P2, P3, N1, N4, N6, G5, and G9. | 18 months | 
| Number of adverse effects | total number of patient reported adverse effects | 18 months | 
| Proportion of patients reaching 20% reduction in PANSS total score | 20% reduction in the PANSS total score (all PANNS items included) | 12 months | 
| Proportion of patients reaching 30% reduction in PANSS total score | 30% reduction in the PANSS total score (all PANNS items included) | 12 months | 
| Proportion of patients reaching 40% reduction in PANSS total score | 40% reduction in the PANSS total score (all PANNS items included) | 12 months | 
| Changes in the Clinical Global Impression Scale in Schizophrenia (CGI-Schizophrenia) | Change in CGI-Schizophrenia scores from baseline to month 12 | 12 months | 
| Changes in the Young Mania Rating Scale (YMRS) | Change in YMRS total score from baseline to month 12 | 12 months | 
| Changes in the Antipsychotic Non-Neurological Side-Effects Rating Scale (ANNSERS) | Change in ANNSERS total score from baseline to month 12 | 12 months | 
| Changes in the Brief Assessment of Cognition in Schizophrenia (BACS) | Change in BACS scores from baseline to month 12 | 12 months | 
| Changes in the Global Assessment of Functioning scale (GAF) | Change in the GAF score from baseline to month 12 | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Psychosis, Immunotherapy, Autoantibodies