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.

Study Overview

• Status: Active, not recruiting
• Conditions: Psychosis; Autoimmune Encephalitis
• Intervention / Treatment: Drug: Intravenous immunoglobulin; Drug: Rituximab; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 70
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • Cambridge, United Kingdom
    • Cambridge University Hospitals NH Foundation Trust
  • Exeter, United Kingdom
    • Royal Devon and Exeter NHS Foundation Trust
  • Glasgow, United Kingdom
    • NHS Greater Glasgow and Clyde
  • Liverpool, United Kingdom
    • The Walton Centre NHS Foundation Trust
  • London, United Kingdom
    • King's College Hospital NHS Foundation Trust
  • London, United Kingdom, NW1 2PG
    • University College London Hospitals NHS Foundation Trust
  • Manchester, United Kingdom
    • Salford Royal NHS Foundation Trust
  • Nottingham, United Kingdom
    • Nottingham University Hospitals Nhs Trust
  • Oxford, United Kingdom
    • Oxford University Hospitals NHS Foundation Trust
  • Sheffield, United Kingdom
    • Sheffield Teaching Hospitals NHS Foundation Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 56 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Intravenous immunoglobulin and Rituximab; 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; This is a blood product containing antibodies from thousands of healthy donors.; Other Names: IVIG; Intratect; Drug: Rituximab; Rituximab is a type of biological therapy. It removes B-cells and helps to reduce the inflammation; Other Names: MabThera
Placebo Comparator: Placebo; 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; This is the control, or sham, treatment; Other Names: Saline solution

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Cambridge
• Collaborators: University of Oxford
• Investigators: Principal Investigator: Alasdair Coles, PhD FRCP, University of Cambridge, UK

Publications and helpful links

General Publications

• 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.

Helpful Links

• SINAPPS Group website

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2017
• Primary Completion (Estimated): April 30, 2027
• Study Completion (Estimated): April 30, 2027

Study Registration Dates

• First Submitted: February 2, 2017
• First Submitted That Met QC Criteria: June 19, 2017
• First Posted (Actual): June 21, 2017

Study Record Updates

• Last Update Posted (Actual): May 22, 2026
• Last Update Submitted That Met QC Criteria: May 19, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Psychosis; Immunotherapy; Autoantibodies
• Additional Relevant MeSH Terms: Nervous System Diseases; Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders; Autoimmune Diseases; Immune System Diseases; Psychotic Disorders; Autoimmune Diseases of the Nervous System; Amino Acids, Peptides, and Proteins; Proteins; Pharmaceutical Preparations; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Crystalloid Solutions; Isotonic Solutions; Solutions; Immunoglobulin Isotypes; Immunoglobulin G; Antibodies, Monoclonal, Murine-Derived; Rituximab; Immunoglobulins, Intravenous; Saline Solution
• Other Study ID Numbers: SINAPPS 2

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No