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

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

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.