E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Obsessive-compulsive disorder (OCD) or Obsessive-compulsive behaviour (OCB) or psychotic disorder (PD) in which there is an indication of immune system involvement. |
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E.1.1.1 | Medical condition in easily understood language |
Obsessive-compulsive or psychotic disorders. |
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E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Behaviours [F01] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10029898 |
E.1.2 | Term | Obsessive-compulsive disorder |
E.1.2 | System Organ Class | 10037175 - Psychiatric disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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. |
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E.2.2 | Secondary objectives of the trial |
1. To assess whether Rituximab treatment (with the doses and timing described in section 8) 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.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
General criteria
1. Diagnostic criteria: ICD 10 at least one of the following ICD 10 diagnoses:
a. Obsessive-compulsive disorder ICD F42 or
b. Obsessive-compulsive behavior ICD R46.81 AND/OR
c. 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:
a. 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
b. Focal neurological symptoms, e.g.
ataxia, dystonia, myoclonus, sensory losses, paresthesia
c. Psychomotor anomaly,
e.g. retardation, catatonic symptoms, parkinsonism
d. Loss of drive (sleep, appetite, libido, motivation)
e. Obsessions, compulsions (OCD/OCB),
f. Hypo- or hypervigilance (for e.g sounds, emotions, other peoples´ or own behavior)
g. Sleeping disorders,
AND
12. At least one of the following criteria:
a. Prodromal phase with infection or symptoms of infection (fever, malaise, etc)
b. Clinical improvement of psychiatric symptoms after treatment with anti-inflammatory medications other than antibody therapy (such as steroids, NSAIDs IVIG, plasmaphereses), or antibiotics
c. Radiological evidence of neuroinflammation (MR)
d. EEG pathology or witnessed epileptic seizure
e. 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 IgG ratio
elevated levels of neurofilament
f. 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
g. Biochemical indication of autoimmunity such as elevated serum anti-TPO, ANA, ANCA, RF or GAD antibodies, PANDAS panel with relationship to symptom development.
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E.4 | Principal 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 significant bacterial/viral/fungal infections at infusion date
24. Diagnosis of well-established neuroinflammatory disease such as MS (ICD codes G00–G09, G35–G37) or 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The clinical efficacy of Rituximab treatment will be evaluated by calculating the average difference between BPRS scores at baseline and main-evaluation (8-month) and comparing it between the treatment-first and the placebo-first group. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
1. The amelioration in psychiatric symptomatology will be assessed by following the
psychiatric rating scales:
o CGI
o WHODAS,
o EQ-VAS,
o Y-BOCS
o BFCS
2. Improvement in executive functions, will be assessed by following neuropsychiatric
tests:
o Neuropsychological tests
o Mismatch negativity
3. The amelioration of neurologic by performing complete, video-recorded neurologic
exams. This procedure is described in section 11.
4. The longevity of psychiatric, neurologic and executive improvements will be examined
by the psychiatric ratings scales named in 1. and blood samples every 4 months up to 16
months, and in addition to that a thorough neurologic exam, the executive tests named in
2. and CSF samples every 8 months up to 16 months.
5. The safety of Rituximab treatment will by adverse events monitoring and questionnaires |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. 8 months
2. 8 months
3. 8 months
4. Every 4 or 8 months up to 16 months
5. Baseline until Close-out visit |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |