Acoustic Neuromodulation (ANM) for Youth With Anxiety Disorders

The acoustic neuromodulation trial (ANM-T) is a two-phase, single-site, pilot randomized
clinical trial examining the feasibility of completing a larger scale efficacy study of a
novel treatment of non-linear modulated acoustic stimuli to reduce anxiety severity in youth
with anxiety disorders. Phase I involves a randomized controlled trial comparing active
acoustic neuromodulation to a non-active acoustic stimuli (Placebo or PBO) in youth ages 7-17
years with at least one of the following primary DSM-5 diagnoses: separation anxiety disorder
(SAD), social anxiety disorder and generalized anxiety disorder (GAD).

Additionally, this study will include up to ten healthy volunteer participants in order for
study staff to be appropriately trained to administer the EEG. Furthermore, three pilot cases
will be completed at the start of data collection to ensure effective delivery of all study
procedures and maintenance of blind during the acute study phase. Phase II is a 3-month
treatment maintenance period for Phase I responders. Phase I non-responders to PBO will be
offered active open treatment. Assessments will include those that will likely be used in a
larger efficacy trial including parent on child report, and child self report, and blinded
independent evaluator ratings of the primary outcomes. In addition, in an effort to assess
over all feasibility, monthly recruitment rate, number of consents signed, subjects
randomized, rate of adherence to the treatment protocol, safety of the intervention and
control conditions, patient and family acceptability of the treatment and assessment
protocols will be evaluated. Study Phases Entry Gates: 30 subjects ages 7-17 years will be
enrolled, using a multiple gating procedure designed to ensure that subjects enrolled
evidence a stable, pervasive anxiety diagnosis at the start of treatment.

- Gate A is a 20-minute semi-scripted telephone screening procedure to elicit preliminary
inclusion/exclusion information and to provide additional information to the caller.

- Gate B is a screening assessment that determines "caseness".

After completing informed consent participants and their parents will complete standard
questionnaires and will be interviewed to establish that the child meets all inclusion and no
exclusion criteria and are medically safe to complete the study (clearance from the
pediatrician and pregnancy test for menstruating females). This visit will be videotaped and
will last approximately 2.5 hours.

-Gate C is a baseline assessment of anxiety severity and randomization visit and takes
approximately 2.5 hours and will be videotaped. All subjects will be recruited and screened
and enrolled by investigators at the Weill Cornell Medical College.

Phase I: Phase I is a 6-week randomized (1:1) controlled comparison of ANM and PBO. Subjects
will come in for 20-minute treatment sessions approximately every other day for 2 weeks (5
days in 2 weeks). At each study treatment visit the study coordinator will collect a brief
interim history of anxiety symptoms and adverse events prior to treatment. Formal outcome
assessment by the blind independent evaluator (IE) will be collected at week 6.

Phase II: Phase II is a 17 week treatment maintenance phase (from week 7 to 24). At this
stage, ALL PARTICIPANTS will begin active treatment. Active responders from phase 1 will be
monitored for the durability of the treatment response. Non-responders to the active
treatments will be given a second chance to elicit a response. Non-responders to control
treatment will have a full course of the active treatment. Control treatment responders will
be given the chance to respond to active treatment. At each study visit the coordinator will
collect an interim history and adverse events. Formal outcome assessment by a blind
independent evaluator will occur at weeks 12 and 24

Inclusion Criteria:

- Ages 7-17 years inclusively (i.e., must be at least 7 years) at the point of consent

- Primary DSM 5 diagnosis of SepAD, SocAD, or GAD on the ADIS-RLV (Gate B).

- Anxiety severity of moderate or greater (CGI-S >3 and functional impairment (CGAS
score of <60) (Gate C).

Exclusion Criteria:

- Estimated child Full Scale IQ < 80, as measured by the vocabulary and block design
subtests of the WISC-III) (Gate B). If a potential subject has a verified IQ score in
the three years prior to enrollment as measured by the WISC-III, IIIR, K-ABC, or
Stanford-Binet no IQ assessment is required.

- Child meets criteria for current primary or co-primary Panic Disorder, OCD, PTSD,
conduct disorder or substance abuse (Gate B).

- Child meets criteria for Major Depressive Disorder at greater severity than anxiety
disorder (Gate B). d. Subjects with the following lifetime psychiatric disorders will
be excluded: bipolar disorder, PDD (Asperger's, autism), MDD with psychosis,
schizophrenia, and schizoaffective disorder (Gate B).

- Current use of psychotropic medication or clinical indication for use of psychotropic
medication (except for youth entering on a stable psychostimulant regimen for ADHD)
(Gates A, B).

- Recent treatment with psychotropic medication within 6 weeks of study entry for
fluoxetine, within 2 weeks for other SSRIs, and within 4 weeks for neuroleptics (Gates
A, B).

- Child has failed an adequate trial of CBT for anxiety within the previous 2 years (at
least 10 treatment sessions over a period of less than 1 year conducted by a licensed
provider of CBT) (Gates A, B).

- Child has a major neurological disorder, a major medical illness or hearing impairment
that requires a prohibited episodic or chronic systemic medication or that would
interfere with participation in the study (e.g., frequent hospitalizations, frequent
school absences) (Gates A, B).

- Child is pregnant as indicated by history or a positive pregnancy test at Gate B.
Sexually active girls must agree to use an effective form of birth control, either
hormonal (BCP, Depo-Provera or Norplant), spermicide (foam or vaginal suppository) or
a barrier method (condoms, diaphragm, cervical cap) or a combination of
barrier/spermicide contraception in order to participate in the study.

- Child poses a significant risk for dangerousness to self or to others (Gates A, B, C).

- Child or parent is non-English speaking (unable to complete measures, IE ratings or
treatment without the assistance of a translator) (Gates A, B). NYSPI and UCLA may
recruit Spanish speaking subjects.

- Child is a victim of ongoing or previously undisclosed child abuse requiring new
department of social service report or ongoing department of social service
supervision (Gate B).

- Child, for any reason, has missed more than 50% of school days in the 2 months
preceding randomization. Home schooling does not require exclusion from the study
under this exclusion criterion. Ambiguous cases are referred to Caseness Panel to
avoid truncating the severity range differently across sites (Gates A, B).

- Child has a history of seizures