Rituximab Treatment for Psychosis And/or Obsessive Compulsive Disorder with Probable Immune System Involvement

NCT04323566 | Enrolling By Invitation Phase 2 DMC

• 3 other identifiers: Ra-P-OCD 1.2, 2020-02-042024-518391-31-002019-000256-33
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

The primary objective for this study is to evaluate whether Rituximab as compared to placebo is a clinically effective treatment for a subgroup of patients suffering from psychosis and/or obsessive-compulsive disorder (OCD) or -behavior (OCB) where there is an indication of immune system involvement. The secondary objectives of this study are

1. 1.To assess whether Rituximab treatment (with the doses and timing described below) as compared to placebo is associated with amelioration in psychiatric symptomatology
2. 2.To assess whether Rituximab treatment as compared to placebo is associated with improvement in executive functions
3. 3.To assess whether Rituximab treatment as compared to placebo is associated with amelioration in neurological symptoms
4. 4.To evaluate the longevity of psychiatric, neurological and executive improvements associated with Rituximab treatment for up to 16 months after the first infusion (i.e. 12 months after the last infusion)
5. 5.To evaluate whether Rituximab treatment as described is safe for these patients.
6. 6.To assess changes in blood and cerebrospinal fluid (CSF) markers for immune activity associated with Rituximab treatment compared to placebo
7. 7.To assess statistical associations between biological markers in blood or CSF and clinical response
8. 8.To describe changes in somatic symptoms associated with treatment with Rituximab vs placebo for patients with initial symptoms in the questionnaires
9. 9.To describe changes on MR and EEG associated with treatment with Rituximab vs placebo for patients with initial pathology in these examination
10. 10.To study immune mechanisms coupled with psychiatric symptoms, possibly identifying novel biomarkers with potential for subtyping encephalopathies with immune engagement, using biobank cells, blood and CSF samples collected from the participants.

Conditions

Obsessive-Compulsive Disorder; Obsessive-Compulsive Behavior; Schizophrenia; Delusional Disorder; Brief Psychotic Disorder; Schizo Affective Disorder; Other Psychoses; Unspecified Psychosis

Outcome Measures

Primary Outcomes (1)

• BPRS

  Brief Psychiatric Rating Scale, is a broad psychiatric interview and evaluation tool comprising 24 items, of which 14 are rated based on the individual´s self-report, and ten based on observed behavior and speech. Each item is rated 1 to 7 (1 = not present, 7 = extremely severe). Minimum score with all items assessed is 24, maximum score is 168. Higher score signifies higher degree of psychiatric symptoms i.e. worse outcome. Primary outcome measure is the mean difference in total score between the trial arms at 8 months.

  8 months

Secondary Outcomes (14)

• WHODAS

  baseline, 4 months, 8 months, 12 months, 16 months

• CGI

  baseline, 4 months, 8 months, 12 months, 16 months

• EQ-VAS

  baseline, 4 months, 8 months, 12 months, 16 months

• Y-BOCS

  baseline, 4 months, 8 months, 12 months, 16 months

• BFCRS

  baseline, 4 months, 8 months, 12 months, 16 months

Study Arms (2)

Treatment-first arm

EXPERIMENTAL

Participants receive i.v. infusions with 500 mg Rituximab at 0 and 4 months, followed by placebo infusions (NaCl) at 8 and at 12 months, Pre-treatment prior to all four infusions consists of injection Solu-Medrol 125 mg i.v., tablet Paracetamol 1000 mg p.o. and tablet Cetirizin 10 mg p.o.

Drug: Rituximab

Placebo-first arm

EXPERIMENTAL

Participants receive placebo (NaCl) i.v. infusions at 0 and 4 months, followed by 500-mg-Rituximab infusions at 8 and 12 months. Pre-treatment prior to all four infusions consists of injection Solu-Medrol 125 mg i.v., tablet Paracetamol 1000 mg p.o. and tablet Cetirizin 10 mg p.o.

Drug: Rituximab

Interventions

Rituximab DRUG

Rituximab 500 mg, dissolved in 250 ml NaCl in an infusion bag, covered with non-see-through plastic * administered iv over a course of max 180 minutes * at 0 and 4 months (treatment-first arme) OR at 8 and 12 months (placebo-first arm)

Placebo-first arm; Treatment-first arm

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• General criteria
• Diagnostic criteria: ICD 10 at least one of the following ICD 10 diagnoses:
• Obsessive-compulsive disorder ICD F42 or
• Obsessive-compulsive behavior ICD R46.81 AND/OR
• Schizophrenia, delusional, and other non-mood psychotic disorders, namely
• F20 Schizophrenia
• F22 Delusional disorders
• F23 Brief psychotic disorder
• F25 Schizoaffective disorders
• F28 Other psychotic disorder not due to a substance or known physiological condition
• F29 Unspecified psychosis not due to a substance or known physiological condition
• Age: 18-55
• Severity: Clinical Global impression (CGI): Minimum score of "4 = Moderately ill"
• Swedish or English proficiency
• The patient has tried at least 2 standard psychiatric medications at maximal tolerable or maximal recommended dosage for his/her current condition over a period of 6 months, but has not improved significantly

You may not qualify if:

• Concomitant malignancies or previous malignancies within the last five years
• Cannot comply with vaccination recommendations
• History of severe allergic or anaphylactic reactions in conjunction with prior treatment with monoclonal antibodies
• Prior antibody therapy including Rituximab (MabThera®/Rituxan®)
• Patient has been treated with clozapine (which may have immunosuppressant effect), systemic corticosteroids or IVIG within 60 days prior to screening visit
• Prior treatment with immunosuppressant medications (not including systemic corticosteroids and IVIG) for other medical condition
• History of or positive screening for HIV, Tuberculosis, Hepatitis B and/or Hepatitis C (ever)
• Heart disease such as previous heart attack, arrhythmia or heart failure, coronary insufficiency
• Current drug, alcohol, or chemical abuse
• Pregnancy at any time during the study
• Known chronical significant bacterial/viral/fungal infections at infusion date
• Diagnosis of well-established neuroinflammatory disease such as Multiple Sclerosis (MS) (ICD codes G00-G09, G35-G37) or systemic lupus erythematosus (SLE) (M32)
• Tested positive for autoantibodies in serum or CSF associated to known and treatable neuroinflammatory disease (such as neuroborreliosis, treatable autoimmune encephalitis). Patients having completed recommended treatment without significant improvement may still be included in this study.
• History of any illness that in the opinion of the investigator may jeopardize the ability of the patient to participate in the study.
• Patient is enrolled in another medical trial.

Sponsors & Collaborators

• Uppsala University Hospital: lead
• Uppsala University: collaborator

Study Sites (1)

Uppsala University Hospital

Uppsala, 75185, Sweden

Location

Related Publications (5)

• Debnath M, Venkatasubramanian G. Recent advances in psychoneuroimmunology relevant to schizophrenia therapeutics. Curr Opin Psychiatry. 2013 Sep;26(5):433-9. doi: 10.1097/YCO.0b013e328363b4da.

  PMID: 23867655 BACKGROUND

• Attwells S, Setiawan E, Wilson AA, Rusjan PM, Mizrahi R, Miler L, Xu C, Richter MA, Kahn A, Kish SJ, Houle S, Ravindran L, Meyer JH. Inflammation in the Neurocircuitry of Obsessive-Compulsive Disorder. JAMA Psychiatry. 2017 Aug 1;74(8):833-840. doi: 10.1001/jamapsychiatry.2017.1567.

  PMID: 28636705 BACKGROUND

• Brimberg L, Benhar I, Mascaro-Blanco A, Alvarez K, Lotan D, Winter C, Klein J, Moses AE, Somnier FE, Leckman JF, Swedo SE, Cunningham MW, Joel D. Behavioral, pharmacological, and immunological abnormalities after streptococcal exposure: a novel rat model of Sydenham chorea and related neuropsychiatric disorders. Neuropsychopharmacology. 2012 Aug;37(9):2076-87. doi: 10.1038/npp.2012.56. Epub 2012 Apr 25.

  PMID: 22534626 BACKGROUND

• Lee WJ, Lee ST, Byun JI, Sunwoo JS, Kim TJ, Lim JA, Moon J, Lee HS, Shin YW, Lee KJ, Kim S, Jung KH, Jung KY, Chu K, Lee SK. Rituximab treatment for autoimmune limbic encephalitis in an institutional cohort. Neurology. 2016 May 3;86(18):1683-91. doi: 10.1212/WNL.0000000000002635. Epub 2016 Apr 1.

  PMID: 27037228 BACKGROUND

• Dazzi F, Shafer A, Lauriola M. Meta-analysis of the Brief Psychiatric Rating Scale - Expanded (BPRS-E) structure and arguments for a new version. J Psychiatr Res. 2016 Oct;81:140-51. doi: 10.1016/j.jpsychires.2016.07.001. Epub 2016 Jul 4.

  PMID: 27451107 BACKGROUND

MeSH Terms

Conditions

Obsessive-Compulsive Disorder; Compulsive Behavior; Schizophrenia; Schizophrenia, Paranoid; Psychotic Disorders; Mental Disorders

Interventions

Rituximab

Condition Hierarchy (Ancestors)

Anxiety Disorders; Impulsive Behavior; Behavior; Schizophrenia Spectrum and Other Psychotic Disorders

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Janet L Cunningham, MD PhD

  Uppsala University Hospital and Uppsala University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: The nurse(s) administering Rituximab or placebo (NaCl) infusions will be prevented from having insight into which of the infusions she/he is administering.
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD Associate Professor Janet Cunningham

Model Details: This is a placebo-controlled, interventional study of parallel groups with 40 participants, randomized to either treatment-first with 500 mg Rituximab i.v. at 0 (infusion 1) and at 4 months (infusion 2), or placebo-first, with NaCl-infusions at 0 and at 4 months. Main evaluation takes place at eight months. The study arms are then crossed over, i.e. those with treatment-first receive placebo at 8 (infusion 3) and 12 months (infusion 4), and those with placebo-first receive Rituximab at these time points. Final evaluation takes place at 16 months. Before each infusion, all patients are pre-treated with Solu-Medrol i.v., Paracetamol p.o. and Cetirizin p.o. Patients are monitored with psychiatric rating scales and blood samples at baseline (-1 month) and every four months. The evaluations at baseline, eight and 16 months also encompass collection of CSF (lumbar puncture), psychologic testing and extended blood samples.

Study Record Dates

• First Submitted: March 10, 2020
• First Posted: March 26, 2020
• Study Start: May 1, 2022
• Primary Completion (Estimated): April 1, 2028
• Study Completion (Estimated): December 1, 2028
• Last Updated: November 19, 2024

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will not share

Locations

SE (1)