IVIG and Rituximab in Antibody-associated Psychosis - SINAPPS2 (SINAPPS2)

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

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.

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.

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.

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.

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

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.

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

Lennox B, Yeeles K, Jones PB, Zandi M, Joyce E, Yu LM, Tomei G, Pollard R, Vincent SA, Shimazaki M, Cairns I, Dowling F, Kabir T, Barnes TRE, Lingford Hughes A, Hosseini AA, Harrower T, Buckley C, Coles A. Intravenous immunoglobulin and rituximab versus placebo treatment of antibody-associated psychosis: study protocol of a randomised phase IIa double-blinded placebo-controlled trial (SINAPPS2). Trials. 2019 Jun 7;20(1):331. doi: 10.1186/s13063-019-3336-1.