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    Summary
    EudraCT Number:2019-004758-27
    Sponsor's Protocol Code Number:IVIGPANSOpen
    National Competent Authority:Sweden - MPA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-01-13
    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 number2019-004758-27
    A.3Full title of the trial
    Intravenous immunoglobulin (IVIG) treatment in children with Pediatric Acute-onset Neuropsychiatric Syndrome (PANS): an open-label trial in South-western Sweden
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Intravenous immunoglobulin (IVIG) treatment in children with PANS: a clinical trial in South-western Sweden
    A.3.2Name or abbreviated title of the trial where available
    IVIGPANSOpen
    A.4.1Sponsor's protocol code numberIVIGPANSOpen
    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 SponsorGillberg Neuropsychiatry Centre
    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 supportGillberg Neuropsychiatry Centre
    B.4.2CountrySweden
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGillberg Neuropsychiatry Centre
    B.5.2Functional name of contact pointGNC
    B.5.3 Address:
    B.5.3.1Street AddressKungsgatan 12A
    B.5.3.2Town/ cityGothenburg
    B.5.3.3Post code411 19
    B.5.3.4CountrySweden
    B.5.4Telephone number+46313425970
    B.5.5Fax number+46313425971
    B.5.6E-mailchristopher.gillberg@gnc.gu.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 Privigen
    D.2.1.1.2Name of the Marketing Authorisation holderCSL Behring
    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 Solution for injection/infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    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) No
    D.3.11.7Plasma derived medicinal product Yes
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) is a research diagnosis given to patients who have an abrupt, dramatic onset of neuropsychiatric symptoms including obsessions/compulsions and/or food restriction, and several other neuropsychiatric symptoms.
    E.1.1.1Medical condition in easily understood language
    PANS is a research diagnosis given to patients with an acute onset of neuropsychiatric symptoms including obsessions/compulsions and/or food restriction, and several other neuropsychiatric symptoms.
    E.1.1.2Therapeutic area Psychiatry and Psychology [F] - Mental Disorders [F03]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Primary objective:
    To evaluate the efficacy of intravenous immunoglobulin (IVIG), 2 g/kg given every 4 weeks for 6 months, to patients with post-infectous PANS including the subgroup PANDAS, in improving neuropsychiatric symptoms and impairment (PANS Scale), global functioning (CGI-S) and improvement (CGI-I) in an open-trial design with rigorous clinical monitoring of symptom profiles before, during and after treatment.
    E.2.2Secondary objectives of the trial
    To evaluate changes from baseline to follow-up at 1 month, 3 months, 6 months and 12 months
    o in OCD symptoms, adaptive functioning, quality of life, cognitive functioning, signs of inflammation in MRI and spinal fluid
    • To evaluate number of days of work/school/daily activities missed per subject year due to PANS/PANDAS before and after IVIG therapy
    • To evaluate parental care load, e.g. need for sick leave, before and after IVIG therapy measured by
    • To evaluate through IgG, IgM and IgA levels at baseline, 3 months, 6 months and 12 months
    • Sustainability of any improvement at 12 months after initiation of IVIG measured with the PANS scale, CGI-S and CGI-I

    Safety objective
    • To assess the safety and tolerability of high dose IVIG therapy
    o Clinical signs and symptoms (nausea, headache, local reactions)
    o Liver and kidney function tests, hemoglobin, complete blood count including leucocyte differential
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. The subject and parents/caregivers have given written consent or assent to participate
    in the study.
    2. Children and adolescents between the ages of 4 and 17 years at Baseline.
    3. Documented and confirmed pre-existing diagnosis of post-infectious PANS/PANDAS
    4. The subject has not been treated with IVIG previously or not been treated for the last 6
    months
    5. If the patient is on long-term antibiotic prophylaxis, this should be unchanged one month
    before baseline and during the trial.
    6. Infections occurring during the trial should be treated according to standard clinical
    practice.
    7. Treatment with COX-inhibitors or corticosteroids should be discontinued at least one
    month before baseline and during the trial. Two-three days treatment with corticosteroids
    during and after IVIG treatment is allowed to reduce IVIG side effects such as headache
    and nausea.
    8. Any psychopharmacological treatment (e.g. SSRI, antipsychotics), if considered
    essential for the subject, should be kept at a stable and unchanged dose from one month
    before baseline and during the trial. If not considered essential, it should be discontinued
    at least one month before baseline.
    9. The medical records for all subjects should be available to document diagnosis, previous
    infections and treatment.
    10. For female participants, adequate contraception should be used, see exclusion criteria.
    A negative pregnancy test can possibly be a requirement, specify requirement/type of
    pregnancy test. Contraceptive requirements may also apply to male participants.
    E.4Principal exclusion criteria
    1. Clinical evidence of any significant acute or chronic disease that, in the opinion of the
    Investigator, may interfere with successful completion of the trial or place the subject at
    undue medical risk. Spinal tap results are required before study start to rule out
    encephalitis (which would need to be treated according to encephalitis treatment
    guidelines).
    2. The subject has had a known serious adverse reaction to immunoglobulin or any severe
    anaphylactic reaction to blood or any blood-derived product
    3. Females of childbearing potential who are pregnant, have a positive pregnancy test at
    Baseline (human chorionic gonadotropin [HCG]-based assay), are breastfeeding, or
    unwilling to practice a highly effective method of contraception (oral, injectable or
    implanted hormonal methods of contraception, placement of an intrauterine device [IUD]
    or intrauterine system [IUS], condom or occlusive cap with spermicidal
    foam/gel/film/cream/suppository, male sterilization, or true abstinence) throughout the
    study Note: True abstinence: When this is in line with the preferred and usual lifestyle of
    the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods], declaration of abstinence for the duration of a trial, and withdrawal
    are not acceptable methods of contraception.)
    4. The subject has significant proteinuria (dipstick proteinuria ≥ 3+, known urinary protein
    loss > 1 g/24 hours, or nephrotic syndrome), has a history of acute renal failure, has
    severe renal impairment (blood urea nitrogen [BUN] or creatinine more than 2.5 times
    the upper limit of normal [ULN]), and/or is on dialysis
    5. The subject has Screening Visit values of aspartate aminotransferase (AST) or alanine
    aminotransferase (ALT) levels exceeding 2.5 times the ULN for the expected normal
    range for the testing laboratory.
    6. The subject has hemoglobin < 90 g/L at Screening
    7. The subject has a known previous infection with or clinical signs and symptoms
    consistent with current hepatitis B virus (HBV) or hepatitis C virus (HCV) infection
    8. The subject has a history of or current diagnosis of deep venous thrombosis or
    thromboembolism (e.g., myocardial infarction, cerebrovascular accident, or transient
    ischemic attack); history refers to an incident in the year prior to Baseline or 2 episodes
    over lifetime.
    9. The subject currently has a known hyperviscosity syndrome
    10. The subject has an acquired medical condition that is known to cause secondary immune
    deficiency, such as chronic lymphocytic leukemia, lymphoma, multiple myeloma, chronic
    or recurrent neutropenia (absolute neutrophil count less than 1.0 x 109
    /L], or HIV
    infection/acquired immune deficiency syndrome (AIDS).
    11. The subject is HIV positive by NAT based on a Screening blood sample.
    12. The subject has non-controlled arterial hypertension at a level of greater than or equal
    to the 90th percentile blood pressure (either systolic or diastolic) for their age and height
    13. The subject is receiving any of the following medications: (a) immunosuppressants
    including chemotherapeutic agents, (b) immunomodulators, (c) long-term systemic
    corticosteroids defined as daily dose > 1 mg of prednisone equivalent/kg/day for > 30 days.
    Note: Intermittent courses of corticosteroids of not more than 10 days would not
    exclude a subject. Inhaled or topical corticosteroids are allowed.
    14. The subject has known substance or prescription drug abuse.
    15. The subject has participated in another clinical trial within 30 days prior to Baseline
    (observational studies without investigative treatments [non-interventional] are
    permitted) or has received any investigational blood product within the previous 3
    months
    16. The subject/caregiver is unwilling to comply with any aspect of the protocol, including IV
    infusions, blood sampling
    17. Mentally challenged subjects who cannot give independent informed consent
    In the opinion of the Investigator the subject may have compliance problems with the
    protocol and the procedures of the protocol.
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy variables are:
    o changes in symptom severity and impairment on the investigator-rated Pediatric Acute Neuropsychiatric Symptom (PANS) scale (Swedo, Leckman et al.). Clinical response is defined as >30% reduction in symptoms and impairment, respectively.
    o changes in global symptoms and functioning measured by CGI-S (Clinical Global Impression-Severity) and in global improvement measured by CGI-I (Clinical Global Impression-Improvement). Clinical response is defined as a score of 1-2 on CGI-S and CGI-I, respectively.

    E.5.1.1Timepoint(s) of evaluation of this end point
    Baseline, 1, 3, 6 and 12 months
    E.5.2Secondary end point(s)
    Changes in:
    • OCD symptoms measured with the CY-BOCS scale
    • Level of functioning in everyday life assessed by the ABAS II scale (rated by parent or other caregiver and from the responsible teacher/preschool teacher)
    • Quality of life assessment (CHIP-CE scale - Parent report, rated by parent or other caregiver.
    • Neuropsychiatric and neurodevelopmental symptoms assessed by the parent-rated 5-15 scale (Kadesjö et al 2004).
    • Motor/neurologic functioning (neurologic assessment of choreiform movements, balance (Rombergs test with extended arms), diadochokinesis, finger-nose tapping, eye movements, muscle tone, reflexes, figure copying, drawing, handwriting).
    • Cognitive functioning (auditory working memory subtest from WISC-V. Visual working memory. VMI (visual perception test).
    • School-PANS (short version of PANS-scale rated by teacher or school assistant; Murphy, personal communication)
    • Days absent from school during the study period (3 months stage 1, 12 months stage 2) compared to previous 3 months
    • Parental situation, e.g. sick leave, reduced working hours
    • Trough concentrations of total IgG, IgA, IgM and at 3 mo, 6 mo
    • AEs, suspected adverse drug reactions (suspected ADRs), serious AEs (SAEs), and discontinuations due to AEs and SAEs
    • Vital signs during clinic visits (temperature [T], respiratory rate [RR], heart rate [HR], systolic blood pressure [SBP] and diastolic blood pressure [DBP]).
    • Physical assessments: physical exams will be recorded as normal or abnormal, according to the physician’s judgment criteria, and findings will be recorded.
    • Laboratory assessments including chemistry, hematology, and urinalysis.
    • In a subgroup of participants who can tolerate Cerebral Magnetic Resonance Tomography (MRI) without general anesthesia, MRI will be done according to a specific protocol (Hadjikani, personal communication)
    E.5.2.1Timepoint(s) of evaluation of this end point
    Baseline, 3, 6 and 12 months
    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) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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 No
    E.8.2.3Other No
    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
    LVLS
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 10
    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) Yes
    F.1.1.5.1Number of subjects for this age range: 5
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 5
    F.1.2Adults (18-64 years) No
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state10
    F.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 10
    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)
    Subjects will be followed and treated according to standard clinical guidelines
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-03-02
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-02-20
    P. End of Trial
    P.End of Trial StatusOngoing
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