Rituximab Treatment for Psychosis and/or Obsessive Compulsive Disorder With Probable Immune System Involvement
Rituximab Treatment for Psychosis and/or Obsessive Compulsive Disorder With Probable Immune System Involvement
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. To assess whether Rituximab treatment (with the doses and timing described below) as
 compared to placebo is associated with amelioration in psychiatric symptomatology

 2. To assess whether Rituximab treatment as compared to placebo is associated with
 improvement in executive functions

 3. To assess whether Rituximab treatment as compared to placebo is associated with
 amelioration in neurological symptoms

 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. To evaluate whether Rituximab treatment as described is safe for these patients.

 The exploratory objectives of this study are

 1. To assess changes in blood and cerebrospinal fluid (CSF) markers for immune activity
 associated with Rituximab treatment compared to placebo

 2. To assess statistical associations between biological markers in blood or CSF and
 clinical response

 3. To describe changes in somatic symptoms associated with treatment with Rituximab vs
 placebo for patients with initial symptoms in the questionnaires

 4. To describe changes on MR and EEG associated with treatment with Rituximab vs placebo
 for patients with initial pathology in these examination

 5. 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.
METHODOLOGY:

 This study is planned as a placebo-controlled, interventional study of parallel groups with
 40 participants. Patients will be randomized to either treatment-first arm with 500 mg
 Rituximab i.v. (infusion 1) at 0 and again at 4 months (infusion 2), or placebo-first arm,
 receiving NaCl-infusion at 0 and at 4 months. Main evaluation will take place at eight
 months. The study arms are switched after eight months, i.e. patients starting in the
 treatment-first arm will receive placebo (NaCl) infusions at 8 months (infusion 3) and 12
 months (infusion 4), and patients in the placebo-first arm receive 500 mg-Rituximab infusions
 at these time points. Final evaluation is scheduled at 16 months. Before each infusion, all
 patients in the Rituximab and control groups are pre-treated with injection Solu-Medrol 125
 mg, i.v., tablet Paracetamol 1000 mg, p.o. and tablet Cetirizin 10 mg, orally.

 Patients will be monitored with psychiatric rating scales and blood samples at baseline and
 every four months. In addition, baseline (-1 months), main (8 months) and final evaluation
 (16 months) will encompass collection of CSF (lumbar puncture), psychologic testing and
 extended blood samples. Patient, nurse administering treatment and symptom evaluators are
 blinded to group randomization.

 INVESTIGATIONAL PRODUCT, DOSAGE AND MODE OF ADMINISTRATION:

 -  Treatment: Rituximab (Roche), 500 mg, dissolved in 250 ml NaCl 9 mg/ml, administered
 intravenously twice with 4 months interval.

 -  Placebo: 250 ml NaCl 9 mg/ml, administered intravenously twice with 4 months interval.

 Duration of treatment:

 Patients are observed over the course of 16 months. Main evaluation is conducted after 8
 months. Participants are randomized to either treatment-first (Rituximab infusion at 0 months
 and 4 months) or placebo-first (Rituximab infusion at 8 months and 12 months).

 SITE MONITORING AND SOURCE DATA VERIFICATION

 The Investigator(s)/institution(s) will permit study-related monitoring, audits, review and
 regulatory inspection(s), providing access to source data/hospital records. Sponsor verifies
 that each patient has consented in writing to direct access to the original source
 data/hospital records by the use of written patient information and signed Informed Consent.

 In accordance with the principles of Good Clinical Practice (GCP), monitoring of the study
 will be arranged by the Sponsor. During the study, the Monitor will have regular contacts
 with the study site(s), including visits to ensure that the study is conducted and documented
 properly in compliance with the protocol, GCP and applicable regulatory requirements.

 Prior to the start of the study, the monitor will review the protocol and CRFs with the
 investigator and his/her staff. The investigator will be visited by the monitor, who will
 check study procedures, including safety assessments, study medication handling, and data
 recording.

 To assure the accuracy and completeness of the data recorded in the trial, the monitor will
 compare Case Report Forms (CRFs) with medical records and other relevant documentation during
 the on-site monitoring visits (source data verification, SDV). The monitor will have direct
 access to all source data according to International Council for Harmonisation of Technical
 Requirements for Pharmaceuticals for Human Use (ICH) GCP. Incorrect or missing entries into
 the CRFs will be queried and must be corrected. Any discrepancies of data will be documented
 and explained in the monitoring reports. Study monitoring will not jeopardize patient
 confidentiality.

 The study center may also be subject to inspection by the Swedish Medical Products Agency
 (MPA). The Investigator and other responsible personnel must be available during the
 monitoring visits and a possible inspection, and should devote sufficient time to these
 processes.

 DATA COLLECTION AND MANAGEMENT

 Data management and handling of data will be conducted according to the study specific Data
 Management Plan with ICH guidelines and an assigned CRO's standard operating procedures
 (SOPs). An electronic CRF (eCRF) system will be used to capture data from the study. Data
 entry will be performed by the study site personnel. Validation and data queries will be
 handled by the CRO's Data Management Team. The data will be subjected to validation according
 to the CRO's SOPs in order to ensure accuracy in the collected CRF data.The CRF will have an
 audit trail with appropriate functionality for data capture, tracking and documentation of
 any queries or changes. Electronic signatures will be used to lock the data and identify the
 person entering or changing the data.

 Before database closure a reconciliation will be performed between the Serious Adverse Events
 (SAEs) entered in the safety database and the study database. After database closure, the
 database will be exported as Statistical Analysis System (SAS®) data sets. Any discrepancies
 and additions from the process defined in the Data Management Plan, will be described in a
 study specific Data Management Report.

 STATISTICAL ANALYSIS:

 The trial comprises a fully blinded randomized part, up to and including the 8 month visit,
 and a follow-up part, with preserved blinding but where it is known that the patient has
 received Rituximab treatment either in the fully blinded part of the trial or in the
 follow-up part. The main treatment comparisons will be based on the fully blinded 8 months of
 the trial, analyzed as a parallel group trial as described below. Data from the follow-up
 part will be presented descriptively and will be used for explorative modelling of treatment
 response and duration.

 ANALYSIS POPULATION:

 The full analysis set (FAS) will consist of all randomized patients that received at least
 one dose of investigational treatment, and will be used for all analyses unless specified.
 The number of patients with available data for each outcome analysis will be tabulated. In
 baseline-adjusted analyses, patients that lack baseline data will be excluded.

 DESCRIPTIVE STATISTICS:

 Brief Psychiatric Rating Scale (BPRS) score over time, for both parts of the trial, will be
 described using time series plots of individual data and randomized treatment arm mean
 values. BPRS and BPRS linear change from baseline at each time point will be described by
 randomized treatment using dot plots, scatter plots with baseline value on the x-axis, and
 tables of mean, standard deviation, median, min, max and quartiles.

 PRIMARY ANALYSIS:

 The primary outcome, BPRS at 8 months, will primarily be analyzed using a linear model with
 randomized treatment and baseline BPRS as covariates, and presented as the mean difference
 between the treatment groups with 95% confidence interval (CI) and two-sided p-value.
 Primarily the analysis will be based on observed cases, which gives unbiased estimation under
 a mechanism with random missingness conditional on baseline BPRS and treatment arm.

 SENSITIVITY ANALYSES:

 -  To address missing data,

 1. primary analysis with missing 8-month values imputed by the 4-month value when
 available, and the baseline value otherwise. Under a scenario of no increase in
 BPRS over time and drop-out mainly due to lack of effect, this analysis would be
 biased against superiority of the Rituximab treatment.

 2. analyses of a continuum of scenarios based on a model assuming a treatment group
 dependent missingness propensity estimated from the observed frequencies, and a
 treatment group dependent difference in baseline-adjusted mean BPRS between
 observed and missing outcomes. The results will be presented as contour plots of
 point estimates, lower and upper 95% CI limits, and 2-sided p-values, for each pair
 of treatment arm specific differences between observed and missing outcomes. The
 results will indicate what mean deviations from missing at random conditional on
 treatment and baseline BPRS would be necessary to affect the conclusions.

 -  To address model misspecification, supplemental comparison of linear change in BPRS from
 baseline between treatment groups using the using Wilcoxon's rank-sum test and the
 Hodges-Lehmann estimate of location change with 95% confidence interval. In addition,
 model assumptions will be assessed by residual plots. Deviations from assumptions are
 not assumed to increase the Type I error, but may affect the interpretation of the
 estimated treatment contrast.

 -  To address non-adherence and protocol deviations, supplemental analysis using the
 primary model, for patients with two doses of treatment and no major protocol deviations
 up to 8 months, as determined at data base lock before unblinding.

 BPRS at four months will be analyzed using the same method as for the primary time point,
 including sensitivity analyses. The main purpose of the four-month measurement is exploration
 of time to response.

 SECONDARY EFFICACY OUTCOMES:

 All analyses will be performed without formal multiplicity adjustment, for observed cases.

 CGI-S over time will be presented by individual time series plots, and for each visit by
 number and percentage of patients in each category, and of patients satisfying the criteria
 for response (at least 2-point reduction from baseline), partial response (a 1 point
 reduction from baseline), and remission (CGI-S score 1-3). The categorical outcome
 response/partial response/no response will be analysed using logistic regression with
 randomized treatment as the only factor and presented as the common odds ratio with 95% CI
 and 2-sided p-value, at 8 months (primary time point) and at 4 months. Remission at the same
 time points will be analysed using logistic regression and presented as odds ratios with 95%
 CI and 2-sided p-value.

 World Health Organization Disability Assessment Schedule (WHODAS) results will be presented
 as domain scores based on item response theory based scoring, and total disability score.
 Domain and total scores over time will be described using individual time series plots and
 mean value plots by randomized treatment. Domain and total scores, and linear change from
 baseline scores, at each time point will be described by randomized treatment using dot
 plots, scatter plots with baseline value on the x-axis, and tables of mean, standard
 deviation, median, min, max and quartiles. Total disability score at 8 months (primary) and 4
 months will be analysed using a linear model with randomized treatment and baseline score as
 covariates and presented as mean difference with 95% CI and 2-sided p-value.

 Yale Brown Obsessive Compulsion Scale (Y-BOCS) results will be presented and analyzed in the
 same way as WHODAS disability score. In addition, the number and proportion of patients with
 score 15 or below will be presented and analyzed in the same way as remission defined by
 CGI-S.

 Bush-Francis Catatonia Rating Scale (BFCRS) total score over time will be described using
 individual time series plots and mean value plots by randomized treatment. Domain and total
 scores, and linear change from baseline scores, at each time point will be described by
 randomized treatment using dot plots, scatter plots with baseline value on the x-axis, and
 tables of mean, standard deviation, median, min, max and quartiles.

 Pittsburgh Sleep Quality Index (PSQI) global sum will be tabulated descriptively by
 randomized treatment for each time point, using mean, standard deviation, median, quartiles,
 min and max, and number and percentage of patients with global sum 5 or higher.

 EuroQol-5D (EQ-5D) domain scores will be presented for each time point using descriptive
 frequency tables and stacked bar charts by randomized treatment. EQ-5D Visual Analogue Scale
 (VAS) scale scores will be presented for each time point using descriptive tables of mean,
 standard deviation, median, min, max and quartiles.

 Mismatch Negativity (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.

 Biomarkers over time will be presented descriptively using individual time series plots and
 plots of geometric mean values over time by randomized treatment, and for each visit scatter
 plots with baseline on the x-axis and tables of geometric mean, geometric coefficient of
 variation (CV), median, quartiles, min and max, based on values over the limit of
 quantification, and number of observations under the limit of quantification. For infusion
 safety markers, the number and proportion of patients with values outside normal will also be
 tabulated. Biomarker concentrations at 8 months (primary) and 4 months will be analysed using
 a linear model for the log-transformed biomarker with randomized treatment and
 log-transformed baseline biomarker as covariates, and presented as the geometric mean ratio
 with 95% CI and two-sided p-value.

 DETERMINATION OF SAMPLE SIZE Within- and between-patient standard deviation was estimated to
 7.1 and 6.7 points respectively, from five case series with in total 35 measurements pre- and
 post-rituximab treatment, using a linear mixed-effect model with random intercept and
 rituximab treatment as a fixed factor.

 Power was estimated using simulation. Baseline and 8 months BPRS were simulated with a 7
 point standard deviation (SD) normally distributed random variation both within and between
 patients (corresponding to a total SD=9.8 points for a single measurement), and a homogenous
 treatment effect, using R v. 3.3.1. 40 patients, 20 patients per group, would give 81% power
 to detect an 8 point adjusted mean difference in BPRS between the rituximab and placebo
 groups, and 89% power to detect a difference of 9 points. Reasonable power would be retained
 under 5% random drop-out, with 79% power to detect an 8 point difference and 87% power to
 detect a 9 point difference between the groups. The power to detect a 9 point difference
 would still be 85% with 10% random drop-out.
INCLUSION CRITERIA

 General criteria

 1. Diagnostic criteria: ICD 10 at least one of the following ICD 10 diagnoses:

 1. Obsessive-compulsive disorder ICD F42 or

 2. Obsessive-compulsive behavior ICD R46.81 AND/OR

 3. 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

 2. Age: 18-55

 3. Severity: Clinical Global impression (CGI): Minimum score of "4 = Moderately ill"

 4. Swedish or English proficiency

 5. 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

 6. Medication has been unchanged for at least one month prior to study start

 7. Signed informed consent

 8. Use of adequate contraception

 9. Radiological evidence of brain atrophy and scarring are absent

 10. 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.

 Specific criteria

 11. Acute (<12 weeks) or atypical debut, or episodes of any of the following:

 1. Symptoms of encephalopathy:

 psychotic symptoms, including hallucinations, delusions, paranoia, disorganized
 speech, disorganized behavior

 agitation, confusion

 sudden change in personality as perceived by the social environment

 drowsiness

 loss of functions in daily Life

 cognitive problems (memory, speech, learning)

 emotional dysregulation

 2. Focal neurological symptoms, e.g. ataxia, dystonia, myoclonus, sensory losses,
 paresthesia

 3. Psychomotor anomaly, e.g.retardation, catatonic symptoms, parkinsonism

 4. Loss of drive (sleep, appetite, libido, motivation)

 5. Obsessions, compulsions (OCD/OCB),

 6. Hypo- or hypervigilance (for e.g sounds, emotions, other peoples´ or own
 behavior)

 7. Sleeping disorders,

 AND

 12. At least one of the following criteria:

 1. Prodromal phase with infection or symptoms of infection (fever, malaise, etc)

 2. Clinical improvement of psychiatric symptoms after treatment with
 anti-inflammatory medications other than antibody therapy (such as steroids,
 NSAIDs IVIG, plasmaphereses), or antibiotics

 3. Radiological evidence of neuroinflammation (MR)

 4. EEG pathology or witnessed epileptic seizure

 5. 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

 6. 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

 7. 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.

 EXCLUSION CRITERIA

 13. Concomitant malignancies or previous malignancies within the last five years

 14. Cannot comply with vaccination recommendations

 15. History of severe allergic or anaphylactic reactions in conjunction with prior
 treatment with monoclonal antibodies

 16. Prior antibody therapy including Rituximab (MabThera®/Rituxan®)

 17. Patient has been treated with clozapine (which may have immunosuppressant effect),
 systemic corticosteroids or IVIG within 60 days prior to screening visit

 18. Prior treatment with immunosuppressant medications (not including systemic
 corticosteroids and IVIG) for other medical condition

 19. History of or positive screening for HIV, Tuberculosis, Hepatitis B and/or Hepatitis C
 (ever)

 20. Heart disease such as previous heart attack, arrhythmia or heart failure, coronary
 insufficiency

 21. Current drug, alcohol, or chemical abuse

 22. Pregnancy at any time during the study

 23. Known chronical significant bacterial/viral/fungal infections at infusion date

 24. Diagnosis of well-established neuroinflammatory disease such as Multiple Sclerosis
 (MS) (ICD codes G00-G09, G35-G37) or systemic lupus erythematosus (SLE) (M32)

 25. 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.

 26. History of any illness that in the opinion of the investigator may jeopardize the
 ability of the patient to participate in the study.

 27. Patient is enrolled in another medical trial.