IVIG and Rituximab in Antibody-associated Psychosis - SINAPPS2

Sponsor

University of Cambridge (Other)

Overall Status

Recruiting

CT.gov ID

NCT03194815

Collaborator

University of Oxford (Other)

Enrollment

Locations

Arms

Anticipated Duration (Months)

8.9

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Psychosis Autoimmune Encephalitis	Drug: Intravenous immunoglobulin Drug: Placebo Drug: Rituximab	Phase 2

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 Design

Study Type:

Interventional

Anticipated Enrollment :

80 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Nov 1, 2017

Anticipated Primary Completion Date :

Oct 1, 2023

Anticipated Study Completion Date :

Mar 1, 2024

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

Time to start of symptomatic recovery (symptomatic remission sustained for at least 6 months) [up to 18 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

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

16 Years to 60 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Cambridge University Hospitals NH Foundation Trust	Cambridge	United Kingdom
2	Royal Devon and Exeter NHS Foundation Trust	Exeter	United Kingdom
3	The Walton Centre NHS Foundation Trust	Liverpool	United Kingdom
4	University College London Hospitals Nhs Foundation Trust	London	United Kingdom	NW1 2PG
5	King's College Hospital NHS Foundation Trust	London	United Kingdom
6	Salford Royal NHS Foundation Trust	Manchester	United Kingdom
7	Nottingham University Hospitals NHS Trust	Nottingham	United Kingdom
8	Oxford University Hospitals NHS Foundation Trust	Oxford	United Kingdom
9	Sheffield Teaching Hospitals NHS Foundation Trust	Sheffield	United Kingdom