Antibiotic Treatment Trial for the PANDAS/PANS Phenotype
Condition: PANS; PANDAS; Obsessive Compulsive Disorder (OCD)
MeSH terms: Obsessive-Compulsive Disorder
Study type: Interventional
Phase: Phase 2

Summary: 
      The purpose of this research study is to know if the antibiotic azithromycin, an antibiotic
      approved by the U.S. Food and Drug Administration (FDA) for treating infections, improves
      symptom severity in children with sudden and severe onset obsessive compulsive symptoms known
      as PANS, Pediatric Acute Onset Neuropsychiatric Syndrome, and PANDAS, Pediatric Autoimmune
      Neuropsychiatric Disorder Associated with Streptococcus. This study seeks to compare the
      effects of placebo vs. azithromycin on Obsessive Compulsive Disorder (OCD) symptom severity
      as well as to assess immune risk factors in children with PANDAS/PANS. Obsessions are
      repetitive, unwanted thoughts or worries that may be unpleasant, silly, or embarrassing.
      Compulsions are repetitive or ritualistic actions that are performed to ease anxiety or
      worries. Doctors think these symptoms may be caused or exacerbated by certain infections such
      as Streptococcus pyogenes, Mycoplasma pneumonia, Borrelia burgordfi, etc. These infections
      commonly cause strep throat, walking pneumonia, and Lyme Disease, among others.

      This study will involve a 4 week double-blind, placebo-controlled randomized trial of
      azithromycin (Double Blind Phase). At the end of this 4 week trial, the child will be
      assigned to azithromycin for 8 weeks (Open Label Phase). At the end of these 12 weeks, a
      Naturalistic Observation phase will assess the child's symptom characteristics for up to 40
      weeks.

      The study hypothesizes that children receiving antibiotic will show significantly greater
      overall improvement in severity compared with placebo, and that children with sudden onset of
      OCD and whose subsequent course shows dramatic fluctuations will have evidence of immune risk
      factors that predisposes to this presentation.
    

Detailed description: 
      Accumulating evidence suggests that a subset of children with obsessive compulsive disorder
      (OCD) have a symptom course that is temporally associated with infections (group A
      Streptococcus, Mycoplasma, Borrelia burgordfi, etc.). The intent of this proposal is to test
      the hypotheses that: 1) this subset of children with OCD known as Pediatric Acute Onset
      Neuropsychiatric Syndrome (PANS) and the specific subset associated with Streptococcus,
      PANDAS (Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcus),
      experience symptom onset and exacerbations due to autoimmune/inflammatory responses to
      infectious triggers and, 2) antibiotic treatment will reduce symptom severity. Investigators
      have reported improvement in neuropsychiatric symptoms of patients presenting with PANDAS
      following antibiotic treatment (Murphy & Pichichero, 2002; Snider, Lougee, Slattery et al.,
      2005). Difficulties with study design and small sample size of early antibiotic trials limit
      the influence of their findings (Kurlan & Kaplan, 2004) although anecdotally, many families
      report often dramatic improvements in OCD symptoms after antibiotic therapy.

      The proposed study is a 4 week double-blind placebo-controlled study of the efficacy of
      azithromycin once daily on OCD symptom severity in children ages 4-14 years presenting with
      the PANS phenotype. An 8 week open label phase will be offered to all subjects completing the
      1-month trial to assess longer term efficacy and tolerability (12 weeks total antibiotics for
      those on active, 8 weeks for those on placebo). At the end of week 8, the child can
      transition to best clinical care practice (cognitive behavioral therapy, additional
      medication trials, etc) if not fully remitted. The rate and timing of any relapse will be
      assessed but are not the primary outcome variables. Evaluations will consist of: 1)
      semi-structured psychiatric diagnostic interviews and rating scales to establish psychiatric
      diagnoses and monitor severity of psychiatric symptoms, particularly obsessive compulsive
      behavior and tics; 2) parent and child-report questionnaires to elicit information regarding
      infections and clinical correlates of PANS attributes; 3) physical and neurological
      examinations; and 4) laboratory studies.

      Aim 1: To compare, in randomized controlled fashion, placebo vs. antibiotic on changes in
      overall symptom severity for obsessive-compulsive symptoms among children with PANS
      phenotype. Changes from baseline and clinical status at end of study will be compared for the
      study arms. Primary endpoint will be change on the Children's Yale Brown Obsessive Compulsive
      scale (CY-BOCS). Secondary measures of interest include severity and improvement measures on
      the Clinical Global Impression Severity/Improvement scale, quality of life measures, and
      weekly ratings of mood, anxiety, attention deficit hyperactivity and tic symptoms.
      Hypothesis: Children receiving antibiotic will show significantly greater overall improvement
      in severity compared with placebo. Children that meet PANDAS/PANS criteria and have current
      OCD symptoms of less than 6 months duration will be enrolled in a double-blind
      placebo-controlled randomized trial of azithromycin for 4 weeks. Subjects will be followed
      weekly during the 3 months (4-week antibiotic treatment trial, 8 weeks open label treatment).
      Although earlier trials have had mixed results, these studies have primarily enrolled
      subjects with longer illness durations and used traditional prophylactic doses in contrast to
      the standard treatment dose of this study. Since treatment doses of antibiotic decrease
      antigenic load, one can speculate that treatment level doses, rather than prophylactic doses,
      may best attenuate neuropsychiatric sequelae. Secondary neuromodulating or immune modulating
      properties at higher dose of antibiotics may also be a possible mode of therapeutic action.
      The timing of treatment response and moderators and predictors of response will also be
      assessed.

      Aim 2: To assess immune risk factors in children with PANDAS/PANS. The data and biological
      specimens (blood, cultures, etc) for all subjects consented for Aim 1 will, be entered into a
      database and repository to assess further these clinical phenotypes. Subjects that do not
      qualify for randomization (medication allergy or current long term antibiotic therapy) or
      decline randomization (e.g. travel required for future visits) will be permitted to
      contribute to Aim 2, i.e. collection of baseline symptom severity and immune marker
      assessment. Hypothesis: It is hypothesized that children with sudden onset of OCD and whose
      subsequent course shows dramatic fluctuations will have evidence of immune risk factors that
      predisposes to this presentation. Certain subject characteristics such as age, duration of
      illness, characteristics of exacerbation episodes, type and number of prior infections, and
      co-occurring disorders may influence treatment response. Immunologic markers that may help
      with determining pathobiology and treatment response will be explored including pathogen
      detection array to identify potential infectious triggers, cytokine array to explore
      inflammatory processes and specific antibody assay to assess potential mediators. In order to
      differentiate those children that may most benefit from antibiotic prophylaxis from those
      that do not benefit, analytic strategies to refine an antibiotic-responsive phenotype will be
      explored.

      Rationale: Based on the PI's observations from research and clinical patients being referred
      for PANDAS (60 patients per year), patients have had most improvement when higher doses of
      antibiotics are used, often relapsing on prophylactic doses. The best response rates have
      been antibiotics designed to treat beta lactamase co-pathogens such as azithromycin,
      cephalosporins or amoxicillin/clavulanic acid. Observed response rates are typically within 3
      weeks although some subjects appear to take longer to gain response. These observations
      deserve further study. Azithromycin was chosen due to improved tolerance, once daily dosing
      regimen, coverage against other microbes implicated in PANS and low risk for allergic
      reaction or exclusion.

      Randomization: Study medication and matching placebo will be provided by the research
      pharmacy. Some of the services provided will include blinding of study drug, packaging and
      labeling, and randomization. Subjects who are randomized will receive either antibiotic or
      placebo in a 1:1 ratio. Both investigator and study participant will be blinded to the
      treatment assignment. Randomization will not be revealed to the investigator or the study
      participants until all participants have completed the study or in the event of serious
      adverse event (SAE).

      Dosing: Azithromycin or placebo every 24 hours will be dispensed. Antibiotic will be
      transferred to identical bottles as placebo and dispensed without the manufacturer label.
      Labels will be identical with matching dose volumes for each. Flavor, color and texture will
      be matched to best of ability. Participants and parents will be instructed to not discuss the
      actual medication with anyone in the study team except the designated person dispensing the
      medication.

      Study participation is entirely voluntary. If at any time a participant wishes to discontinue
      the use of study medication, they can notify the study coordinator and if the family is
      willing, they can choose to enter the naturalistic phase or discontinue the study.

      Naturalistic Observation Phase: After the subject's completion of the active phase of the
      study (baseline to end of week 12 as determined by subject eligibility, medication tolerance,
      etc), the family will be given the choice to opt in or opt out of a naturalistic follow up on
      a monthly basis until end of week 52. The family will be provided a monthly PANS scale and
      questionnaire regarding the child's current treatment. Depending on which option works best
      for them, they can return by the forms by mail or complete online.

      Compliance Monitoring: Azithromycin, with daily dosing, has higher rates of adherence than
      other antibiotics with more frequent dosing. The parent of the child will be educated about
      optimal dosing and compliance. Each unit dose will be labeled specifically with the
      participants identification number. The clinical coordinator will document each batch of
      medication on the dispensing log. Each batch of study medication will include supply until
      next scheduled visit plus one week to cover any difficulty returning to study in the
      scheduled interval. All study medication will be accounted for throughout the study by the
      investigator or the designee.

      End of Treatment Alternatives: Standard of care treatment options are unavailable for the
      initial 8 weeks, after which point families will have multiple options for post-study care if
      needed. Until better guidelines are developed, children in the PANDAS/PANS subgroup should
      also be given the chance to benefit from evidence based treatments that may lessen the
      severity of a future flare up. From our previous work (Storch, Murphy, Geffken et al., 2006),
      we believe that remaining OCD symptoms are best treated with CBT unless the child is still
      too severe to engage in therapy. CBT can help children remodel automatic responses to
      obsessions, teach skills that should prove helpful if symptoms do recur and also help
      families with behavioral strategies to lessen the risk of disrupted functioning and
      accommodation. Children often report feeling empowered from coping, relaxation, and
      resiliency skills learned in cognitive behavioral therapy (CBT). Antidepressants approved for
      OCD are an option to consider for those that appear to have a chronic stable course but many
      youth with a PANS presentation are incapacitated by these sudden and severe symptoms, with
      many parents feeling too desperate (Murphy, observations) to wait the typical 10-12 weeks for
      SSRIs to achieve full efficacy. Many of these children are highly sensitive to usual starting
      doses (Murphy, Storch, & Strawser, 2006) but do well when started on a low dose (e.g.
      sertraline at 6.25mg) and gradually increased as tolerated. Patients with tics respond well
      to a variety of evidence based pharmacologic agents and behavioral treatments if needed due
      to symptom severity and impairment. Following the study all subjects with incomplete
      remission will be referred for CBT in the outpatient clinics or the community based on parent
      preference. The investigative team has considerable experience in the application of this
      approach for pediatric OCD (Murphy et al., 2007) and collaborates closely with outpatient
      providers.

      Adverse effects: Every effort should be made to identify prior history of adverse effects to
      antibiotics prior to the randomization phase (exclusion criterion). In the event of
      Candidiasis, other opportunistic overgrowth or allergic reaction, the recommendations by the
      primary care physician (PCP) of the child will be followed. As this adverse event is unlikely
      except during treatment with antibiotics, blinding will be compromised and the child will be
      considered a drop due to adverse event. Open label probiotics will be provided to subjects in
      both study arms in all phases to be taken daily. In the event of an SAE, the blind should be
      broken only if knowing the treatment status is of significance to the course of treatment. If
      at any time the blinding becomes otherwise compromised, the subject will exit the randomized
      control trial (RCT) portion of the study. The date, time, and reason or situation surrounding
      unblinding must be documented as completely as possible. All SAEs should also be reported to
      the institutional review board (IRB) as soon as possible. Laboratory tests (CBC, metabolic
      panel, urine toxicology and pregnancy test [for post-pubescent females]) and an EKG will be
      obtained at baseline. Every 2 weeks, liver function testing will be done to monitor for
      hepatic toxicity risks as well as an EKG to monitor for cardiac risks (increased QTc).
    

Intervention name(s): Azithromycin; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Antibiotic used to treat infections; Thickening compound with sugar and flavoring
Other intervention name(s): Zithromax; Zmax
Intervention MeSH terms: Azithromycin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: PANS; PANDAS; OCD; Tics; Azithromycin; Antibiotic Treatment