Intravenous Immunoglobulin for PANDAS
Condition: Obsessive-Compulsive Disorder; Children; Anxiety Disorder; Autoimmune Disease; PANDAS
MeSH terms: Autoimmune Diseases; Anxiety Disorders; Compulsive Personality Disorder; Obsessive-Compulsive Disorder
Intervention: Gamunex Intravenous Immunoglobulin; Placebo
Intervention description: 2.0 gm/kg total, IV (in the vein), over 2 days; Normal saline, IV (in the vein), over 2 days
Intervention MeSH terms: Immunoglobulins; Immunoglobulins, Intravenous; Antibodies; gamma-Globulins; Rho(D) Immune Globulin
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 48.0
Sex: All
Minimum age: 4 Years
Maximum age: 13 Years
Healthy volunteers: No
Keywords: Placebo Controlled; Obsessive-Compulsive Disorder; Children and Adolescents; Intravenous Immunoglobulin; PANDAS

Summary:

      Background:

      - Some children experience a sudden onset of symptoms similar to those found in
      obsessive-compulsive disorder that may be caused by the body s reaction to an infection with
      streptococcal bacteria, most commonly seen as strep throat or scarlet fever. When the body s
      immune system reacts against brain cells following a streptococcal infection, the condition
      is known as PANDAS (pediatric autoimmune neuropsychiatric disorders associated with
      streptococcal infections). The immune system response can be inactivated by treatment with a
      drug known as intravenous immunoglobulin (IVIG). Because there is insufficient research on
      IVIG s effects on the immune system of children with PANDAS, including whether IVIG is
      helpful in treating obsessive-compulsive symptoms related to PANDAS, researchers are
      interested in examining whether IVIG is an appropriate treatment for PANDAS and its
      associated symptoms.

      Objectives:

      - To test the safety and effectiveness of intravenous immunoglobulin for the treatment of
      obsessive-compulsive disorder in children with PANDAS (pediatric autoimmune neuropsychiatric
      disorder associated with streptococcal infection).

      Eligibility:

      - Children between 4 and 12 years of age who have obsessive-compulsive disorder (with or
      without a tic disorder) with sudden onset of symptoms following Group A streptococcal
      bacterial infections.

      Design:

        -  Participants will be screened by telephone to obtain medical history and other
           information, followed by in-person screening at the National Institutes of Health
           Clinical Center.

        -  Participants will be admitted to the hospital to receive 2 days of infusions of either
           IVIG or a placebo. Frequent blood samples, imaging studies, and other tests will be
           performed during this visit.

        -  Six weeks after the inpatient stay, participants will return for further blood samples
           and other tests. Participants who did not receive the study drug, or who received the
           drug but did not respond to the initial IVIG infusion, will have the option to receive
           IVIG at this time.

        -  Followup visits will take place 3 months and 6 months after the first evaluation,
           followed by yearly follow-ups for 5 additional years.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

        Male and female children 4-13 years of age.

        Presence of (Diagnostic and Statistical Manual of Mental Disorders Fourth Edition, Text
        Revision) DSM-IV TR OCD with or without a tic disorder.

        Moderate or greater severity of symptoms, with a score of greater than or equal to 20 on
        the Children s Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) and greater than or equal to
        4 on the Clinical Global Impression Severity scale (CGI-S).

        The acute onset within the previous six months of symptoms in a child previously well, or
        the first acute recurrence within the previous six months, after a period of relatively
        complete remission of symptoms. The acuity of symptom onset/exacerbation is key and must be
        severe, dramatic in onset, and proceed from no/minimal symptoms to maximum severity within
        24-48 hours.

        Symptom onset or first exacerbation preceded within four months by a GAS infection, as
        documented by positive throat culture, exposure to documented GAS infection (in a close
        contact, such as a sibling sharing a bedroom), and/or documented two-fold rise in one or
        more anti-GAS antibody titers such as anti-streptolysin O, anti-streptococcal DNAaseB,
        anti-carbohydrate antibodies and others.

        Onset/exacerbation of OCD is accompanied by at least three of the following 7 clinical
        signs and symptoms. The acuity of the comorbid symptoms must be similar to the OCD symptoms
        and occur in the same time interval.

          1. Markedly increased level of anxiety, particularly new onset of separation anxiety.

          2. Emotional lability, irritability, aggressive behavior and/or personality change.

          3. Sudden difficulties with concentration or learning.

          4. Developmental regression ("baby-talk," temper tantrums; behaviors atypical for actual
             chronological age).

          5. Sleep disorder (insomnia, night terrors, refusal to sleep alone).

          6. Handwriting deterioration or other sign of motoric dysfunction (including new onset of
             motor hyperactivity, or presence of choreiform finger movements).

          7. Urinary frequency or increased urge to urinate; daytime or night-time secondary
             enuresis.

        EXCLUSION CRITERIA:

        History of rheumatic fever, including Sydenham chorea (the neurologic manifestation).

        Presence of symptoms consistent with autism, schizophrenia, or other psychotic disorder
        (unless psychotic symptoms have onset coincident with the possible PANDAS and are
        attributed to OCD).

        Presence of a neurological disorder other than a tic disorder.

        IQ <70. Child subjects need to be able to contribute meaningfully to baseline and follow-up
        ratings, to report adverse effects, and to assent to participation.

        Presence of serious or unstable medical illness or psychiatric or behavioral symptoms that
        would make participation unsafe or study procedures too difficult to tolerate.

        IgA deficiency (<20mg/dL). Intravenous immunoglobulin may contain trace IgA, which may very
        rarely lead to life-threatening anaphylaxis in IgA-deficient participants with anti-IgA
        antibodies (Misbah 1993).

        Hyperviscosity syndromes, which can increase risks associated with IVIG administration.

        Need for live virus vaccine within six months after receiving IVIG (which may be 7.5 months
        from randomization) since IVIG can interfere with effectiveness of such vaccines. IVIG
        should not be administered sooner than two weeks after administration of a live virus
        vaccine, for the same reason.

        Taking nephrotoxic drugs. Every concomitant medication will be subject to scrutiny and
        possible consultation with pediatric safety monitors before randomization to study drug.
        See below as well.

        Recent (less than eight weeks) initiation of cognitive-behavior therapy (CBT).

        Recent (less than eight weeks) initiation or change in dosage of psychotropic medication
        for OCD or tic disorder (e.g., serotonin reuptake inhibitors for OCD, alpha-2 agonists or
        antipsychotics for tic disorders).