A Randomized Controlled Trial With Rituximab for Psychotic Disorder in Adults (RCT-RITS)

Immunological factors are assumed to be determinants for some psychiatric disorders, thus anti-inflammatory drugs may be helpful. However, studies on such treatments are scarce. An inflammatory modulating drug rituximab, cluster of differentiation antigen 20 antibodies (anti-CD20 antibodies), is a standard treatment for e.g. multiple sclerosis.

The investigators aim to test rituximab in a randomised placebo-controlled double-blinded, add-on treatment trial in 120 participants (18-55 years) with schizophrenia spectrum disorder. Sampling from blood for analyses of inflammatory mediators are investigated at gene and protein levels and resting state functional magnetic resonance imaging (rsfMRI) and lumbar puncture are optional. Biomarkers will be investigated in relation to treatment response.

Family member(s) to the patient and the patient (separate) will be asked to participate in a qualitative interview by an independent researcher after 3 months.

Study Overview

• Status: Recruiting
• Conditions: Schizophrenia Spectrum and Other Psychotic Disorders
• Intervention / Treatment: Drug: Rituximab

Detailed Description

Immunological factors are assumed to be determinants for some psychiatric disorders, thus anti-inflammatory drugs may be helpful. However, studies on such treatments are scarce. Rituximab (anti-CD20 antibodies), a standard treatment for multiple sclerosis in Sweden, is an inflammatory modulating drug. In a small open pilot trial, markedly ill, treatment-resistant participants with schizophrenia spectrum disorder were treated with a single- dose rituximab (1000 mg), as add-on treatment to antipsychotics in Örebro, Sweden (2019-2022). Large improvements in all types of psychotic symptoms were evident, with long-lasting effects and few side-effects in most of the participants.

This is a proof-of-concept study based on our earlier findings. The investigators will conduct a multicenter, placebo-controlled, double-blinded, add-on intervention study for 120 participants with schizophrenia spectrum disorder (18-55 years). Sampling from blood for analyses of inflammatory mediators are investigated at gene and protein levels and rsfMRI and lumbar puncture are optional at baseline and endpoints. Biomarkers will be investigated in relation to treatment response.

Participants are assessed at five time-points; week 0, 2, 7, 12 (endpoint I) and 24 (endpoint II).

Research questions:

I Does the addition of rituximab to standard psychiatric treatment improve psychotic symptoms in SSD?

II Does overall disability improve with the addition of rituximab?

III Are clinical or biological markers related to treatment response?

IV Is rituximab safe and well tolerated by participants with SSD?

In addition family member(s) to the patient will be asked to participate in a qualitative interview by a researcher after 3 months on changes in the patient's mood and anxiety level, general functioning, behaviours, energy level, psychotic symptoms, motivation, emotional reciprocity and insight to enable a qualitative analysis. We will also ask them about their general thoughts on the study. In addition we will interview the patient after 3 months using qualitative methods.

We also aim study changes in negative symptoms with the Motivation and pleasure- self report (MAP-SR) in addition to the Positive and Negative Syndrome Scale (PANSS) scale and Self-evaluation of Negative Symptoms (SNS). Childhood onset neuropsychiatric symptoms will be investigated retrospectively by the use of Five-to-Fifteen Brief (FTF-Brief).

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Susanne Bejerot, MD,PhD; Phone Number: 46 0701655102; Email: susanne.bejerot@oru.se

Study Locations

• Sweden
  • Örebro, Sweden, 701 85
    • Recruiting
    • Orebro University Hospital
    • Contact: Susanne Bejerot, MD; Phone Number: 0701655102; Email: susanne.bejerot@oru.se
    • Contact: Axel Nordenskjöld, MD; Phone Number: 070-6049589; Email: axel.nordenskjold@oru.se

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 51 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. ages 18 to 55 years
2. duration of illness exceeding 1 year
3. diagnosed with Schizophrenia spectrum disorder (SSD) according to The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5).
4. if female and with any risk for pregnancy, willing to use contraceptives or abstinence if normal and preferred lifestyle.
5. participants should be judged by the investigator to be lucid and oriented to person, place, time, and situation when giving the informed consent.
6. insufficiently recovered from previous antipsychotic treatments.
7. a minimum score of 4 (moderately ill) in Clinical global impression - severity (CGI-S) at baseline.

Exclusion Criteria:

1. pregnancy or breast-feeding
2. weight below 40 kg
3. clinically relevant ongoing infection at the discretion of the physician
4. chronic infections
5. positive test for hepatitis B, hepatitis C, HIV, or tuberculosis
6. malignancy currently or within 2 years prior to inclusion
7. current severe heart failure (NYHA grade IV) or any other severe heart disease (e.g. or history of cardiac arrhythmia or myocardial infarction)
8. any change of antipsychotic medication within the previous 4 weeks
9. unable to make an informed decision to consent to the trial
10. ongoing clozapine treatment
11. ongoing immunomodulatory treatment
12. treatments with monoclonal antibodies within 1 year before the inclusion

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
Experimental: Rituximab; Rituximab 1000 mg, infusion	Drug: Rituximab; Infusion; Other Names: Saline
Placebo Comparator: Placebo; Saline infusion	Drug: Rituximab; Infusion; Other Names: Saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in psychotic symptoms	Change in scores in the measure for psychotic symptoms "the Positive and Negative Syndrome Scale (PANSS)"	Baseline up to 12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Improvement in functioning	Measuring overall disability with Personal and Social Performance Scale (PSP)	Baseline up to week 12 and 24
Proportion of responders to treatment, rated as much or very much improved with CGI-I	Improvement according to clinical rated Clinical Global Impression-Improvement (CGI-I)	Baseline up to week 12 and 24
Improvement since baseline	Improvement according to clinical rated Clinical Global Impression-Improvement (CGI-I)	Baseline up to week 12 and 24
Change in severity since baseline	Improvement according to clinical rated Clinical Global Impression-Severity (CGI-S)	Baseline up to week 12 and 24
Improvement in psychotic symptoms since baseline	Change in scores in the measure for psychotic symptoms "the Positive and Negative Syndrome Scale (PANSS)".	Baseline up to week 24
Change in self-rated overall health	Differences in patient self-rated health (VAS-health)	Baseline up to week 12 and 24
Patient-rated improvement	Patient's Global Evaluation of improvement (PGE) corresponding to the CGI-I scores	Baseline up to week 12 and 24
Inflammatory markers in blood and/or cerebro spinal fluid (CSF)	Baseline levels of inflammatory markers in relation to treatment response (optional)	Baseline up to week 12 and 24
Safety and tolerability of rituximab	Open questions and a questionnaire (AAR-Revised)	Baseline up to week 12 and 24
fMRI	Change in brain morphology and/or activity in fMRI (optional)	Baseline up to week 12 and 24
Patient-rated change in psychiatric symptoms	Mental health symptom domains (Level 1 Cross-cutting symptom measure of global symptom severity) in relationship to response.	Baseline up to week 12 and 24

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Depression	The depression item A6 in PANSS will be investigated separately	Baseline up to week 12 and 24
Negative symptoms	The Negative Syndrome Scale assessed by the clinician will be compared to self-rated negative symptoms measured with the Motivation and pleasure- self report (MAP-SR) in order to study how well they are correlated.	Baseline week 12 and week 24
Qualitative assessment	An informant will be interviewed on whether they can see changes in patients and patient will be interviewed separately on symptoms after 12 weeks	12-18 weeks after infusion

Collaborators and Investigators

• Sponsor: Region Örebro County
• Investigators: Principal Investigator: Susanne Bejerot, MD, PhD, Region Örebro Län

Study record dates

Study Major Dates

• Study Start (Actual): March 21, 2023
• Primary Completion (Estimated): June 30, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: November 14, 2022
• First Submitted That Met QC Criteria: November 14, 2022
• First Posted (Actual): November 18, 2022

Study Record Updates

• Last Update Posted (Actual): October 12, 2023
• Last Update Submitted That Met QC Criteria: October 9, 2023
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: psychosis; rituximab; RCT; immunomodulatory treatment; CD20 antibodies
• Additional Relevant MeSH Terms: Mental Disorders; Schizophrenia; Psychotic Disorders; Mental Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Rituximab
• Other Study ID Numbers: 278825

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