Antibiotic Treatment Trial for the PANDAS/PANS Phenotype

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).

Inclusion Criteria:

- Ages 4 -14 years.

- Presence of OCD and at least two of the following:

1. Anxieties e.g. new onset separation anxiety

2. Sensory abnormalities (tactile/auditory/visual defensiveness or visual
misperceptions)

3. Behavioral Regression (e.g. new onset impulsivity, hyperactivity, meltdowns)

4. Deterioration in school performance or in handwriting

5. Emotional lability and/or depression

6. Urinary symptoms (frequent urination or enuresis)

7. Sleep disturbances Anorexia

- Current episode OCD of recent onset (less or equal to 6 months) associated with
infection

- Symptom onset appears temporally related to infection or exposure

- Symptoms are of moderate severity with significant impairment (CGI of moderate or
worse) and CY-BOCS of more or equal to 16.

- Parental willingness to accompany their child for multiple study visits and be
responsible for medication compliance.

Exclusion Criteria:

- History of Rheumatic Fever including Sydenham's Chorea (heart murmur, frank chorea,
EKG PR or QTc prolongation, abnormal reflexes (Gordon-Hey reflex)).

- Diagnosis of autism (moderate - severe), schizophrenia, mental retardation or chronic
degenerative neurological disease.

- Any illness for which antibiotic treatment may be contraindicated (e.g. Liver
disease).

- Personal history of adverse reaction or allergy to azithromycin.

- Recent or planned psychopharmacologic (4 weeks for most medications or 8 weeks for
SSRIs) treatment changes.

- Antibiotic prophylaxis therapy or history of neuropsychiatric non-response to prior
antibiotic trial.

- Currently participating in cognitive behavioral therapy or habit reversal therapy for
OCD and/or tics.

- Weight less than 15 kilograms

- Concurrent therapy with medications that may increase adverse effects (eg. pimozide,
citalopram, tricyclic antidepressants, etc).