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    Summary
    EudraCT Number:2019-000256-33
    Sponsor's Protocol Code Number:Ra-P-OCD-01
    National Competent Authority:Sweden - MPA
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2019-05-14
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSweden - MPA
    A.2EudraCT number2019-000256-33
    A.3Full title of the trial
    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
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study of Rituximab treatment in patients with Psychosis an/or Obsessive Compulsive Disorder, with a suspected involvement of the immune system
    A.4.1Sponsor's protocol code numberRa-P-OCD-01
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorUppsala University Hospital
    B.1.3.4CountrySweden
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportResearch funding
    B.4.2CountrySweden
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUppsala University Hospital
    B.5.2Functional name of contact pointDept of Neuroscience and Psychiatry
    B.5.3 Address:
    B.5.3.1Street AddressSjukhusvägen 10
    B.5.3.2Town/ cityUppsala
    B.5.3.3Post code751 85
    B.5.3.4CountrySweden
    B.5.4Telephone number+46186112142
    B.5.6E-mailjanet.cunningham@neuro.uu.se
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Mabthera
    D.2.1.1.2Name of the Marketing Authorisation holderRoche
    D.2.1.2Country which granted the Marketing AuthorisationSweden
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRITUXIMAB
    D.3.9.1CAS number 174722-31-7
    D.3.9.4EV Substance CodeSUB12570MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) Yes
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboInfusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical 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.
    E.1.1.1Medical condition in easily understood language
    Obsessive-compulsive or psychotic disorders.
    E.1.1.2Therapeutic area Psychiatry and Psychology [F] - Behaviours [F01]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10029898
    E.1.2Term Obsessive-compulsive disorder
    E.1.2System Organ Class 10037175 - Psychiatric disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main 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.
    E.2.2Secondary 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.
    E.2.3Trial contains a sub-study No
    E.3Principal 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.








    E.4Principal 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.
    E.5 End points
    E.5.1Primary 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.
    E.5.1.1Timepoint(s) of evaluation of this end point
    After 8 months.
    E.5.2Secondary 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
    E.5.2.1Timepoint(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
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial 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
    Last patient last visit.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 40
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state40
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    If response of treatment, but relapse <1.5 years from baseline, the patient is qualified for continuing the treatment.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-06-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-06-25
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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