Rituximab Treatment for Psychosis and/or Obsessive Compulsive Disorder With Probable Immune System Involvement (Ra-P-OCD)
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|ClinicalTrials.gov Identifier: NCT04323566|
Recruitment Status : Enrolling by invitation
First Posted : March 26, 2020
Last Update Posted : May 17, 2022
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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
- To assess whether Rituximab treatment (with the doses and timing described below) as compared to placebo is associated with amelioration in psychiatric symptomatology
- To assess whether Rituximab treatment as compared to placebo is associated with improvement in executive functions
- To assess whether Rituximab treatment as compared to placebo is associated with amelioration in neurological symptoms
- 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)
- To evaluate whether Rituximab treatment as described is safe for these patients.
The exploratory objectives of this study are
- To assess changes in blood and cerebrospinal fluid (CSF) markers for immune activity associated with Rituximab treatment compared to placebo
- To assess statistical associations between biological markers in blood or CSF and clinical response
- To describe changes in somatic symptoms associated with treatment with Rituximab vs placebo for patients with initial symptoms in the questionnaires
- To describe changes on MR and EEG associated with treatment with Rituximab vs placebo for patients with initial pathology in these examination
- 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.
|Condition or disease||Intervention/treatment||Phase|
|Obsessive-Compulsive Disorder Obsessive-Compulsive Behavior Schizophrenia Delusional Disorder Brief Psychotic Disorder Schizo Affective Disorder Other Psychoses Unspecified Psychosis||Drug: Rituximab||Phase 2|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||40 participants|
|Intervention Model:||Crossover Assignment|
|Intervention Model Description:||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.|
|Masking:||Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)|
|Masking Description:||The nurse(s) administering Rituximab or placebo (NaCl) infusions will be prevented from having insight into which of the infusions she/he is administering.|
|Official Title:||A Randomized, Double-blinded, Placebo-controlled Study of Rituximab in Patients With Psychosis and/or Obsessive Compulsive Disorder, With an Indication of Immune System Involvement|
|Actual Study Start Date :||May 1, 2022|
|Estimated Primary Completion Date :||April 1, 2026|
|Estimated Study Completion Date :||May 1, 2026|
Experimental: Treatment-first arm
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.
Rituximab 500 mg, dissolved in 250 ml NaCl in an infusion bag, covered with non-see-through plastic
Experimental: Placebo-first arm
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.
Rituximab 500 mg, dissolved in 250 ml NaCl in an infusion bag, covered with non-see-through plastic
- BPRS [ Time Frame: 8 months ]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.
- WHODAS [ Time Frame: baseline, 4 months, 8 months, 12 months, 16 months ]World Heath Organization Disability Assessment Schedule (36 questions self-rated by participant). Each item is assigned a score from 1 ("none") to five ("extreme"). Minimum score is 36, maximum score 180 with higher score meaning worse outcome.
- CGI [ Time Frame: baseline, 4 months, 8 months, 12 months, 16 months ]Clinical global impressions of severity (CGI-S) and improvement (CGI-I) as rated by investigator. Severity of illness (CGI-S) is rated from 1 = "normal, not ill" to 7 = "among the most extremely ill patients", i.e. higher score means worse outcome. Global improvement (CGI-I) is rated from 1 = "Very much improved" to 7 = "Very much worse" i.e. higher score meaning worse outcome.
- EQ-VAS [ Time Frame: baseline, 4 months, 8 months, 12 months, 16 months ]EuroQol Visual analogue scale; measures self-rated health on a visual analogue scale. Score ranges from 0 to 100, with higher score meaning better outcome.
- Y-BOCS [ Time Frame: baseline, 4 months, 8 months, 12 months, 16 months ]Yale Brown Obsessive Compulsive Scale; using 10-item investigator-administered assessment of the frequency of obsessions and compulsions. Each item is scored from 0 to 4, with higher score indicating more severe symptoms i.e. worse outcome. Minimum score is 0, maximum is 40.
- BFCRS [ Time Frame: baseline, 4 months, 8 months, 12 months, 16 months ]Bush Francis Catatonia Rating Scale, an investigator-rated 23-item scale for catatonic signs and their severity. Each item is rated from 0 to 3 (items 13, 17, 18, 19, 20 and 21 can only be assigned 0 or 3), with higher score indicating more severe symptoms, i.e. worse outcome. Minimum score is 0, maximum is 69.
- MMN [ Time Frame: baseline, 8 months, 16 months ]
Mismatch negativity (MMN); measuring differences in brain reactions to infrequently ("deviant") vs frequently occuring ("standard") auditory stimuli. EEG is recorded during a 12-minute session with the patient listening to an odd-ball paradigm of 1440 standard tones and 360 duration variants. 400 ms-windows are averaged and the maximum difference in negativity between standards and deviants is recorded as the MMN.
MMN amplitude and latency will be measured as the most negative data point within the 80-130 ms latency window, post-stimulus onset and compared between time points. Previous data is not available for this population.
- Neurological exam [ Time Frame: baseline, 8 months, 16 months ]
The following items will be examined and judged normal or abnormal. Outcome is change in number of pathological items over time. More abnormal items means worse outcome.
- verbal coherence
- awareness of person, place and time
- involuntary movements
- walking pattern
- heel-to-toe gait
- heel walking and toe walking
- squatting and raising up
- knee extension
- tone of knee joints, elbows, wrists
- reflexes: patellar, achilles, biceps, triceps
- plantar response (Babinski´s sign)
- finger-to-nose test
- light-touch sensation on hands and feet
- pin-prick sensation on hands and feet
- vibration sensation on ankles and wrists
- eye movement (including nystagmus, ptosis)
- pupil size and reaction to light
- Donder´s field-of-view-test
- friction sound hearing test
- facial motor functions
- uvula asymmetry
- tongue motor functions
- finger and shoulder abduction
- Grassets test
- Rombergs test
- Change in plasma/serum and CSF markers for immune activity [ Time Frame: baseline, 8 months, 16 months ]
The concentration of diverse markers for immune activity e.g. autoantibodies, cytokines, chemokines, immunoregulatory molecules, will be measured at baseline, 8 months and 16 months.
Biomarker concentrations over time will be presented descriptively using individual time series plots, and plots of geometric mean values over time by randomized treatment. The exact biomarkers to be analyzed will be specified before data collection for this study is completed and before the code is broken.
- BPRS [ Time Frame: 4 months, 12 months, 16 months ]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 (0 = not assessed, 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. BPRS at 4, 12 and 16 months will be analyzed using the same method as for the primary time point.
- SWM [ Time Frame: baseline, 8 months, 16 months ]CANTAB digital version of Spatial Working Memory (SWM). Among a number of digital colored squares, participants are to find yellow tokes and use them to fill up an empty column. Outcome is measured by number of errors (revisiting squares), with higher error number meaning worse outcome.
- RTI [ Time Frame: baseline, 8 months, 16 months ]CANTAB digital version of Reaction Time (RTI). Participants must react as soon as possible to indicate a yellow dot that appears in one of five circles. Outcome measures are divided into reaction time and movement time. Longer time means worse outcome.
- PAL [ Time Frame: baseline, 8 months, 16 months ]CANTAB digital version of paired associates learning (PAL). Several boxes displayed on a screen. Some of them contain a pattern. Participants must allocate a displayed pattern to the correct box. Outcome is measured by number of errors (higher number means worse outcome), number of trials required to locate pattern(s) correctly (higher number means worse outcome), memory scores (higher score means better outcome) and stages completed (more stages means better outcome).
- MTT [ Time Frame: baseline, 8 months, 16 months ]
CANTAB digital version of Multitasking Test (MTT). The test displays an arrow which can appear on either the right or left side of the screen, and can point either to the right or to the left.
A cue at the top of the screen indicates to the participant which rule they are to follow to select the right or left button: either according to "the side on which the arrow appeared" or according to "the direction in which the arrow was pointing".
Outcome measures include response latencies and error scores. Longer latency and higher error score mean worse outcome.
- OTS [ Time Frame: baseline, 8 months, 16 months ]CANTAB digital version of One Touch Stockings of Cambridge (OTS). The participant is shown an upper and a lower display containing three colored balls each. The participant is to work out in their head how many moves that are required to copy the pattern in the upper display to the lower display. Outcome measures are number of problems solved on first choice (higher number means better outcome), mean choices to correct (higher number means worse outcome), speed of response to first choice (if the first choice was correct, longer time means worse outcome) and mean latency to correct (loger latency means worse outcome)
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
|Ages Eligible for Study:||18 Years to 55 Years (Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
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
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
- Medication has been unchanged for at least one month prior to study start
- Signed informed consent
- Use of adequate contraception
- Radiological evidence of brain atrophy and scarring are absent
The clinical picture indicates active inflammatory activity (see specific criteria below), potential for rehabilitation and time from disease and/or episode debut is no longer than 10 years.
Acute (<12 weeks) or atypical debut, or episodes of any of the following:
Symptoms of encephalopathy:
psychotic symptoms, including hallucinations, delusions, paranoia, disorganized speech, disorganized behavior
sudden change in personality as perceived by the social environment
loss of functions in daily Life
cognitive problems (memory, speech, learning)
- Focal neurological symptoms, e.g. ataxia, dystonia, myoclonus, sensory losses, paresthesia
- Psychomotor anomaly, e.g.retardation, catatonic symptoms, parkinsonism
- Loss of drive (sleep, appetite, libido, motivation)
- Obsessions, compulsions (OCD/OCB),
- Hypo- or hypervigilance (for e.g sounds, emotions, other peoples´ or own behavior)
- Sleeping disorders,
At least one of the following criteria:
- Prodromal phase with infection or symptoms of infection (fever, malaise, etc)
- Clinical improvement of psychiatric symptoms after treatment with anti-inflammatory medications other than antibody therapy (such as steroids, NSAIDs IVIG, plasmaphereses), or antibiotics
- Radiological evidence of neuroinflammation (MR)
- EEG pathology or witnessed epileptic seizure
Biochemical evidence of inflammation, autoimmunity or blood-brain barrier dysfunction in blood or CSF samples, such as one of the following:
presence of oligoclonal bands
elevated CSF cell count
elevated albumin quotient, or elevated albumin in CSF
elevated Immunoglobulin G (IgG) ratio
elevated levels of neurofilament
- Patient history of autoimmune disorder not associated with neuroinflammation, such as type 1 diabetes, rheumatoid arthritis, Sjögren´s syndrome, inflammatory bowel disease (IBD, comprising Crohn´s disease and ulcerative colitis), celiac disease, Grave´s disease, Hashimoto's thyroiditis
- Biochemical indication of autoimmunity such as elevated serum anti-thyroid peroxidase (TPO) antibody, antinuclear antibody (ANA), anti-neutrophil cytoplasmic antibody (ANCA), rheumatoid factor (RF) or glutamic acid decarboxylase (GAD) antibodies, PANDAS panel with relationship to symptom development.
- 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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04323566
|Uppsala University Hospital|
|Uppsala, Sweden, 75185|
|Principal Investigator:||Janet L Cunningham, MD PhD||Uppsala University Hospital and Uppsala University|
|Responsible Party:||Janet Cunningham, MD Associate Professor Janet Cunningham, Uppsala University Hospital|
|Other Study ID Numbers:||
Ra-P-OCD 1.1, 2019-06-18
2019-000256-33 ( EudraCT Number )
|First Posted:||March 26, 2020 Key Record Dates|
|Last Update Posted:||May 17, 2022|
|Last Verified:||May 2022|
|Individual Participant Data (IPD) Sharing Statement:|
|Plan to Share IPD:||No|
|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|
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