Conditions: Williams Syndrome Anxiety
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 20
Healthy volunteers: no

Brief summary:
The purpose of this study is to do a preliminary assessment of whether buspirone is effective, safe, and tolerable in the treatment of anxiety in children, adolescents, and adults with Williams syndrome.

Detailed description:
After being informed about the study and potential risks, all patients or their legal guardians giving written informed consent will be screened for study eligibility. Patients who meet the eligibility requirements will participate in a 16-week, flexibly-dosed, open-label trial of buspirone. The dose of buspirone will be adjusted over the first 12 weeks of the study and a stable dose will be maintained for the final four weeks of the trial. Adverse effects will be reviewed at each visit and standardized measures of anxiety will be conducted at weeks 4, 8, 12, and 16.

Arms:
arm 1: Subjects will receive buspirone 2.5 mg each morning at the start of the trial. The dose will be increased by 2.5 mg per week in two divided doses daily depending on effectiveness and tolerability. The optimal dose will be reached by week 12 of treatment. The minimum starting dose will be 2.5 mg and the maximum total daily dose will be 30 mg. Medication will be dosed twice daily due to the short half-life (2-3 hours) of this medication.

Interventions: intervention 1: Buspirone
Intervention descriptions: intervention 1: All participants in the study will receive open-label treatment with orally administered buspirone for the full duration of the 16-week trial. Buspirone has high affinity for serotonin 5-HT1A and 5-HT2 receptors and moderate affinity for dopamine D2 receptors. It is approved for the management of generalized anxiety disorder in adults.

Protocol document:
Prot_SAP_000.pdf: 
1 
 
Buspirone treatment of anxiety in individuals with Williams syndrome 
 
PI Name: Robyn P. Thom, MD 
ClinicalTrials.gov ID: NCT04807517 
 
 
 
History of Protocol Revisions 
Version 7.0 Last modified 03/03/2023 
 
 
 


2 
 
Research Plan:  
A. SPECIFIC AIMS: 
Williams syndrome (WS) is a genetic disorder caused by a hemizygous microdeletion spanning 1.5 to 1.8 million 
base pairs containing 26 to 28 genes at chromosome 7q11.23. The prevalence of WS is estimated to be 1/7500 to 
1/10,000. Multiple organ systems are affected by this microdeletion and there is a highly variable range and 
severity of cognitive and medical problems. Common medical comorbidities include cardiovascular disease, 
connective tissue abnormalities, growth abnormalities, and endocrine problems. In addition to the medical 
comorbidities associated with WS, many persons with WS experience high levels of psychiatric symptomatology 
including inattention, hyperactivity, and anxiety.  
One of the areas receiving surprisingly little attention in WS is the diagnosis and treatment of anxiety. While 
children, adolescents, and adults WS frequently experience symptoms of anxiety, it has not yet been fully 
characterized. There are currently no published prospective studies on the pharmacologic treatment of anxiety in 
WS. There continues to be an urgent need for additional studies aimed at the treatment of anxiety in persons with 
WS.  
The long-term goal of this research is to advance the evidence-base behind the pharmacological treatment of WS 
by studying medications that reduce maladaptive symptoms and improve the quality of life of the individual and 
his/her family members. The primary objective of this study is to conduct a preliminary prospective, open-label 
trial of buspirone for the treatment of anxiety associated with WS. The principal investigator (PI) and colleagues 
have completed a retrospective case series of buspirone, a serotonin (5-HT)1A receptor partial agonist and 
dopamine (D3 and D4) antagonist, for the treatment of generalized anxiety disorder in three individuals with WS 
and believe this to be a promising new treatment for the target symptom of anxiety.  
The central hypothesis of this project is that buspirone will improve anxiety when administered to children, 
adolescents, and adults with WS. We also hypothesize that buspirone will be safe and well tolerated. This study 
will provide much needed pilot data regarding the effectiveness and tolerability of buspirone for these symptoms 
in WS and is a necessary first step prior to conducting a larger, more definitive randomized controlled trial.  
We plan to provide preliminary evidence supporting the central hypothesis and accomplish the objectives of this 
study by pursuing the following specific aims:  
1. Determine whether buspirone shows preliminary evidence of effectiveness, safety, and tolerability 
in children, adolescents, and adults with WS. This aim addresses our central hypothesis that buspirone 
will be effective and safe in the treatment of anxiety in persons with WS.   
• For preliminary evidence of effectiveness, we will require a significant decrease in mean PARS 
score from baseline and a ninety-five percent confidence interval for the effect size estimate 
consistent with a standardized effect size (difference in sixteen-week score from baseline divided by 
standard deviation at baseline) of one. 
• For preliminary evidence of safety, we will require no observation of serious or severe adverse 
effects possibly, probably, or definitely associated with buspirone. 
• For preliminary evidence of tolerability, we will require that the 95% confidence interval for drop-
out rate due to side effects of the drug be consistent with a rate of 20% or exclude values >=20%. 
2. Determine which semi-structured interviews and existing anxiety rating scales would be most useful 
for characterizing participants and assessing anxiety treatment effects. A variety of outcome 
measures of anxiety will be used to better assess their applicability and feasibility in the WS population.  
The relative performance of the scales will be evaluated based on their sensitivity to change, their percent 
of item-level missing data, and any feedback on the appropriateness or ease of use of the scales from 
participants or study personnel. 


3 
 
B. IMPACT AND RELEVANCE: 
The presence of anxiety in people with WS has consistently been identified in population studies of affected 
adolescents and adults (Blomberg, Rosander, & Andersson, 2006; Cherniske et al., 2004; Dykens, 2003; Einfeld, 
Tonge, & Rees, 2001; O. T. Leyfer, Woodruff-Borden, Klein-Tasman, Fricke, & Mervis, 2006; O. Leyfer, 
Woodruff-Borden, & Mervis, 2009; Royston, Howlin, Waite, & Oliver, 2017; Woodruff-Borden, Kistler, 
Henderson, Crawford, & Mervis, 2010). A recent meta-analysis of anxiety disorders in WS demonstrated that 
individuals with WS were significantly more likely to have an anxiety disorder than individuals with heterogenous 
intellectual disability (ID) (RR 4.0, 95% CI 2.27-7.06, p<0.0001) (Royston et al., 2017). The most common 
anxiety disorders identified were specific phobia and generalized anxiety disorder (GAD) (Royston et al., 2017). 
Common phobias included noise; blood, injury, or infection; thunderstorms; and lightning. A longitudinal study of 
anxiety in WS demonstrated that in many cases, anxiety disorders persisted over a 5-year follow-up period. 
Furthermore, of the patients with at least one anxiety disorder, 72.2% developed additional anxiety disorders over 
time (Woodruff-Borden et al., 2010).  
Anxiety represents a common and interfering symptom cluster among individuals with developmental disorders. 
Anxiety may play a role in challenging behaviors including elopement, aggression, self-injury, and 
reclusive/avoidant behavior, that impact participation in school, day programs, and vocational sites. All these 
symptoms/behaviors also contribute to caregiver stress. Untreated anxiety may lead to decreased effectiveness of 
behavior therapy interventions impacting the overall trajectory of achieved independence with activities of daily 
living and other life skills. One study demonstrated an association between high anxiety and attention allocation 
away from eye regions of threatening facial expressions WS (Kirk, Hocking, Riby, & Cornish, 2013). Another 
study demonstrated that anxiety was associated with diminished anger recognition among adults with WS 
compared to typically developed controls (Ng, Bellugi, & Järvinen, 2016). Taken together, these studies suggest 
that anxiety may adversely affect social functioning in individuals with WS.  
Despite documented elevated rates of anxiety in individuals with WS, our current knowledge of efficacious, safe, 
and tolerable pharmacologic treatments for anxiety among individuals with WS remains limited. Empirical 
evidence on psychopharmacologic treatment options for co-morbid anxiety in WS is limited to retrospective case 
series; no prospective studies have been completed. A case series including two adult patients with WS reported 
that the use of low doses of a low-potency first generation antipsychotic (levomepromazine) was helpful for the 
treatment of insomnia and anxiety. Both patients in this case series subsequently developed depressive symptoms 
which responded to a selective serotonin reuptake inhibitor (SSRI) (Urgeles, Alonso, & Ramos-Moreno, 2013). 
Our group completed a retrospective case series describing symptoms of GAD in three adolescents/young adults 
with WS and their course of treatment with buspirone. Treatment with buspirone was well-tolerated and resulted 
in sustained response in all three cases. (Thom, Keary, Waxler, Pober, & McDougle, 2019).  
Buspirone, a non-benzodiazepine, generally non-sedating anxiolytic, is a 5-HT1A receptor agonist and D3/D4 
antagonist. It has a Food and Drug Administration (FDA) indication for the treatment of GAD in adults and is 
currently available as a generic. Multiple double-blind, placebo-controlled trials have demonstrated the efficacy of 
buspirone for treating symptoms of GAD in adults (Feighner, Merideth, & Hendrickson, 1982; Pecknold et al., 
1989; Sramek, Frackiewicz, & Cutler, 1997). Although rare, side effects can include headache, nausea, dizziness, 
and muscle tension (Schatzberg & DeBattista, 2015).  
Our group was the first to report on the potential role of buspirone for the treatment of anxiety in WS (Thom et al., 
2019). Based upon our clinical experience, we have found it helpful for a variety of anxiety symptoms associated 
with WS. Our case series is limited by small sample size, retrospective report, open-label treatment, and no 
control group.  Furthermore, in some cases patients received psychotherapy, changes in the school or living 
environment, and optimization of medical conditions in conjunction with buspirone. Our knowledge base on the 
effect of buspirone for the treatment of anxiety in WS would be enhanced by a prospective study with a larger 


4 
 
sample size, standardized enrollment procedures and dose titration, and prospective assessments of treatment 
outcomes.  
In summary, anxiety frequently occurs in WS yet no prospective treatment studies have been conducted which can 
guide treatment. Buspirone appears promising in the treatment of anxiety disorders in WS. A prospective, pilot 
study is urgently needed to address this large gap in treatment knowledge. This project is extremely relevant to 
advancing the knowledge about WS and its treatment. The proposal will characterize anxiety in a sample of 
individuals with WS and each participant will receive open-label treatment with buspirone 
C. INNOVATION  
Studying the treatment of anxiety in WS is highly novel. Anxiety is a common co-morbidity in WS though it 
hasn’t received attention in terms of characterization or treatment. This trial when completed will be the first 
prospective study of a medication for the treatment of anxiety in WS. Buspirone itself has a unique mechanism 
with a benign side effect profile and appears promising in treating anxiety in WS.  
Our group has published a case series with this drug in adolescents/young adults with WS. We continue to use it 
clinically at our neurodevelopmental disorders center, often as the first-line pharmacotherapy for interfering 
anxiety in WS. Over the years, we have found buspirone to be particularly effective as a first-line agent for the 
treatment of disabling anxiety. This project represents a novel avenue of study and we expect that it will advance 
knowledge on how best to treat anxiety in WS. This data could also be used to obtain future funding for a more 
definitive randomized controlled trial.  
D. RESEARCH STRATEGY  
Study Design: 
A 16-week, flexibly-dosed, open-label trial of buspirone was chosen as the optimal way of gathering quality 
preliminary data. Participants will be seen at screen, baseline, and following 4, 8, 12, and 16 weeks of treatment. 
The duration of the trial will allow us to adjust the dose of study drug over the first 12 weeks and allow for stable 
dosing during the final 4 weeks of the trial. We may complete visits remotely utilizing Partners approved secure 
videoconferencing platforms such as Zoom or by phone.   
Participants:  
Twenty children, adolescents, and adults, 5 to 65 years of age, with a genetic or clinical diagnosis of WS 
exhibiting clinically significant anxiety on standardized rating scales will be recruited for this trial. All caregivers 
calling for an appointment at our Center are asked if they have any interest in participating in research. The Lurie 
Center’s IRB-approved research registry will also be searched to identify participants eligible for this project. The 
approved study research invitation letter will be sent will also be sent via patient gateway to Mass General 
Brigham patients diagnosed with Williams syndrome and meeting age criteria utilizing a queried list from the 
Mass General Brigham Research Patient Data Registry (RPDR). Given the size of the Lurie Center, we do not 
expect significant difficulty in recruiting 20 subjects over the 3 years of the project.  
Subjects and their legal guardians interested in participating in the study will have a face-to-face interview with 
the PI and/or the research coordinator/assistant where the nature of the project, the risks, the benefits, and the 
alternatives to participation in the project are discussed. Prior to engaging in research, formal written consent will 
be obtained from the parent(s)/legal guardian(s) on an IRB-approved consent form. An IRB-approved assent form 
will also be used for the subjects under the age of 18 years of age. The only exception will be for younger children 
with lower developmental levels who are assessed as incapable of participating in even a simplified discussion of 
benefits, risks, and alternatives.  


5 
 
Inclusion Criteria:  
1. Age 5 to 65 years of age  
2. Diagnosis of WS confirmed via genetic testing or a clinical diagnosis made by a clinician with significant 
experience treating patients with WS  
3. Clinically significant anxiety as evidenced by a Pediatric Anxiety Rating Scale (PARS) score of 10 or 
greater (5-item scale). The PARS (“The Pediatric Anxiety Rating Scale (PARS): Development and 
psychometric properties.” 2002) was chosen as an inclusion criterion (and outcome measure) since it 
assesses severity across common anxiety disorders in children including generalized anxiety, social anxiety, 
separation anxiety, and transition-associated anxiety. In addition, it is an instrument that allows the clinician 
to incorporate both child and parent report into a final clinician-rated score for each item.  
4. A Clinical Global Impression Severity Item score > 4 (moderate) for anxiety symptoms at Screen and 
Baseline.  
Exclusion Criteria:  
1. Diagnosis of OCD, posttraumatic stress disorder, major mood disorder, psychotic disorder, or 
substance use disorder. These disorders are exclusionary since the primary treatment of these disorders 
may require acute psychosocial treatments or other medications that would confound the assessments.  
2. Presence of any past or present conditions that would make treatment with buspirone unsafe. This 
includes allergy to buspirone, liver or kidney disease, and pregnancy (or being sexually active without using 
acceptable methods to prevent pregnancy).  
3. Use of selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors 
(SNRIs), benzodiazepines, antihistamines (as needed use of an antihistamine for the treatment of 
allergies will be permitted), or antipsychotics. Subjects will need to be off medications from these classes 
for at least 5 elimination half-lives prior to beginning the trial.  
4. Use of other psychotropic medications which are ineffective, poorly tolerated, or sub-optimal in terms 
of dose. A board-certified child and adolescent psychiatrist will assess any other psychotropic medications 
being used and determine whether they are effective, tolerated, and optimal in terms of dose. Concurrent use 
of a psychotropic medication (other than SSRIs, SNRIs, benzodiazepines, antihistamines, or antipsychotics) 
will be allowed if the dose has been stable for 30 days and if they meet the criteria of effectiveness, 
tolerability, and dose.  
5. Previous adequate trial of buspirone. An adequate trial will be defined as a total daily dose of ≥20 mg for 
at least 4 weeks. In addition, subjects who developed significant adverse effects during a trial of buspirone 
at any dose or duration will be excluded.  
6. Severe or profound intellectual disability based on clinical assessment and review of standardized 
assessment of cognitive skills. Subjects will undergo standardized testing and be evaluated by study staff to 
determine cognitive capabilities. Participants determined to have severe or profound intellectual disability 
will be excluded.  
Baseline Characterization:  
All subjects will have a baseline psychiatric diagnostic evaluation done to gather a thorough developmental, 
medical, and psychiatric history, as well as a mental status exam and height and weight will be obtained for 
subjects evaluated in the clinic, and additionally provided by a caregiver at the week 16 visit if completed 
remotely. The medical history and exam will be aimed at ruling out other medical conditions that could exacerbate 
anxiety or behavioral symptoms (e.g., chronic gastrointestinal disease, obstructive sleep apnea, thyroid disease). 
The following standardized scales and testing will also be conducted.  


6 
 
1. Stanford-Binet Intelligence Scales, Fifth Edition (SB-5). The SB-5 will be used to calculate an 
abbreviated battery IQ. The abbreviated IQ was chosen to limit subject burden given that a number of 
other measures will be conducted at screening and can be administered remotely.  
2. The Weschler Abbreviated Scale of Intelligence, Second Edition (WASI-II).  The WASI-II can also 
be administered remotely and will be used for subjects depending on age and ability.  
3. Developmental Profile, Fourth Edition (DP-4). If patients are unable to obtain a valid score on the SB-5 
ABIQ or WASI-II due to constraints of a virtual visit, significantly delayed cognitive skills, or inability of 
participant to cooperate with testing, the Cognitive and Adaptive Behavior subscales of the 
Developmental Profile (DP-4) Parent/Caregiver Interview Form will be administered. 
 
Buspirone Treatment:  
Subjects will receive buspirone 2.5 mg each morning at the start of the trial. The dose will be increased by 2.5 mg 
per week in two divided doses daily depending on effectiveness and tolerability. During the first 12 weeks, 
patients will be seen monthly with additional telephone visits conducted in between clinical visits for additional 
monitoring of adverse effects and for dosing adjustment as necessary. The optimal dose will be reached by week 
12 of treatment. A final visit will be conducted at week 16. The minimum starting dose will be 2.5 mg and the 
maximum total daily dose will be 30 mg. Buspirone is prepared in 5 mg tablets and will be dosed twice daily due 
to the short half-life (2-3 hours) of this medication (see example of dosing schedule below).   
Example Dosing Schedule* 
 
Morning  Dose 
(mg) 
Afternoon Dose  
(mg) 
Week 1 
2.5 
None 
Week  2 
2.5 
2.5 
Week  3 
5 
2.5 
Week  4 
5 
5 
Week  5 
7.5 
5 
Week  6 
7.5 
7.5 
Week  7 
10 
7.5 
Week  8 
10 
10 
Week  9 
12.5 
10 
Week  10 
12.5 
12.5 
Week  11 
15 
12.5 
Week  12 
15 
15 
Week 13-16 
Stable dose for last 4 weeks of study 
*The schedule is a guide and may be adjusted depending on 
tolerability and effectiveness. 
 
Outcome Measures:  
1. Pediatric Anxiety Rating Scale (PARS). The PARS will be the primary outcome measure. It will be 
conducted at screening, baseline, and each follow-up visit.  
2. Child and Adolescent Symptom Inventory (CASI) Anxiety Items. These include 20 parent-rated items 
from the Child and Adolescent Symptom Inventory. It will be conducted at baseline and each follow-up visit.  
3. Screen for Childhood Anxiety Related Emotional Disorders (SCARED).  The SCARED (Birmaher et al 
1999) is a 41-item scale that includes both a child/self-report and parent-report form.  It is used to screen for  
symptoms of panic disorder, separation anxiety disorder, social phobia, and generalized anxiety disorder, as 
well as school phobias.  It will be conducted at baseline and each follow-up visit. 


7 
 
4. Aberrant Behavior Checklist (ABC-2). The ABC-2 is a 58-item questionnaire with 5 subscales derived by 
factor analysis: Irritability, Social Withdrawal, Stereotypy, Hyperactivity, and Inappropriate Speech. It has 
been extensively used in psychopharmacological studies of autism and other developmental disorders and 
assesses many symptoms that are either central to autism (Social Withdrawal, Stereotypy, Inappropriate 
Speech) or frequently a target of treatment (Irritability, Hyperactivity). It will be conducted at baseline and 
each follow-up visit.  
5. Pittsburgh Sleep Quality Index (PSQI). The PSQI is a self-rated 19 item questionnaire which assesses 
sleep quality and disturbances over a one-month time interval (Buysse et al., 1989). It will be used to assess 
the sleep quality of study participants by parent/caregiver report. 
6. Clinical Global Impressions (CGI). A trained clinician will perform the CGI. The CGI is designed to take 
into account all factors to arrive at an assessment of severity and response to treatment, including parent 
report, parent-rated measures, and clinician-rated measures (as described below). The CGI Severity (CGI-S) 
item is rated on a scale from 1 to 7 (1 = normal, not at all ill; 2 = borderline ill; 3 = mildly ill; 4 = moderately 
ill; 5 = markedly ill; 6 = severely ill; 7 = among the most extremely ill patients). The CGI Global 
Improvement (CGI-I) item is also rated from 1 to 7 (1 = very much improved; 2 = much improved; 3 = 
minimally improved; 4 = no change; 5 = minimally worse; 6 = much worse; 7 = very much worse). Subjects 
receiving a CGI-I rating of 1 or 2 will be classified as responders to treatment. The severity ratings will be 
conducted at screen, baseline and the last follow-up visit. The improvement ratings will be conducted at each 
follow-up visit. 
Safety Monitoring: 
According to the buspirone package insert, common adverse events associated with the use of buspirone not seen 
at an equivalent incidence among placebo-treated patients include dizziness, nausea, headache, nervousness, 
lightheadedness, and excitement. Treatment-emergent adverse events in placebo-controlled clinical trials 
occurring at a rate of at least 1% of patients taking buspirone include tachycardia, drowsiness, insomnia, 
decreased concentration, anger/hostility, confusion, depression, blurred vision, dry mouth, abdominal/gastric 
distress, diarrhea, constipation, vomiting, musculoskeletal pain, numbness, paresthesia, incoordination, tremor, 
skin rash, fatigue, and sweating/clamminess. Adverse events will be collected via a structured side effect rating 
scale completed with the participant and their primary caregiver. This will include a list of adverse experiences 
that have been reported with buspirone at a rate greater than 1% including but not limited to dizziness, drowsiness, 
nausea, headache, nervousness, fatigue, insomnia, xerostomia, impaired concentration, hostility, confusion, 
blurred vision, diarrhea, abdominal pain, numbness, and weakness. Each of these side-effects plus any additional 
complaints will be rated at baseline on a 4-point scale by the caregiver as follows: 0 = none; 1 = mild; 2 = 
moderate; 3 = severe. This scale is similar to that used by the RUPP Autism Network. Suicidality will be assessed 
at each visit by directly asking the subject (when verbal skills are sufficient) and the caregiver about any thoughts 
or behaviors that directly or indirectly might indicate suicidality (e.g., morbid thoughts, self-injury, statements 
about life not worth living), when indicated by positive responses. At baseline, the Columbia-Suicide Severity 
Rating Scale (C-SSRS) will be administered per the instructions at www.cssrs.columbia/ed/clinical_trials.html. 
The C-SSRS will also be administered at each subsequent visit following the first report of suicidality. Subjects 
and caregivers will also have information on how to contact the on-call physician from our practice group who 
provides coverage 24 hours/day and 365 days/year. Physicians taking call are familiar with research protocols and 
can contact the principal investigator at any time.  
All adverse events picked up on the rating scale as new will be recorded by the physician. The physician will also 
ask about any visits to the doctor, new medication use (e.g. OTC cold medicine), or any other complaints, in order 
to be confident that most adverse events are uncovered. The physician will keep a running log of adverse events 
that will record the date of onset, date of resolution, seriousness, severity, and relationship to study intervention 


8 
 
(e.g., definite, probable, possible, remote, or none) as well as whether the adverse event led to a change in study 
intervention or other treatment.  
A physician will review vital signs as they become available. All significant adverse events as well as the progress 
of the study will be reviewed and discussed in detail at the biannual meetings of the Data and Safety Monitoring 
Board (DSMB). The DSMB includes rotating members of MGH faculty and/or affiliates including physicians, 
researchers, and a biostatistician familiar with the study population and design.  All serious or unexpected AEs 
that are possibly related to drug treatment will be reported to the MassGeneral Brigham IRB within 5 working 
days from notification of the event.   
 
Sample Size Considerations: 
Taking into account a likely placebo response, we consider a clinically meaningful decrease in mean PARS score 
16 weeks after the start of buspirone to be equivalent to a standardized effect size (mean change/baseline standard 
deviation) of 1.0.  Assuming a standardized effect size of 1.0, a correlation between baseline and week 16 
measurements of 0.5, and a total loss to follow up of 30% (resulting in 14 participants providing complete data), a 
sample size of 20 participants provides greater than 90% power to detect a decrease in mean PARS score from 
baseline.   In addition, for a standardized effect size of 0.2, a sample size of 20 provides nearly 80% power to rule 
out an effect size as large as 1.0. 
 
For safety outcomes, if there is a serious or severe adverse event associated with buspirone treatment in 
the population that occurs with a frequency of 10% or more, we will have an 85% or greater chance of observing 
it in the study and concluding there are safety concerns with buspirone use in the population, assuming at least 
90% (n=18) of participants remain in the study long enough to experience the event. 
 
For tolerability, for discontinuation rates due to side effects of 50% or greater, a sample size of 20 
provides 80% power to detect a difference from 20%, assuming no more than 10% dropout for unrelated reasons 
(n=18).  All sample size calculations assume two-sided testing with alpha=0.05. 
Statistical Analysis Plan:  
 
Demographic and clinical characteristics of the sample will be tabulated using means (SDs) for 
continuous characteristics and clinical scale scores treated as continuous and frequencies and percents for 
categorical and ordinal variables. 
 
Change in PARS 5-item total score between baseline and week 16 will provide our primary preliminary 
estimate of efficacy.  To estimate changes in PARS score and all other clinical outcomes but the CGI-I between 
baseline and week 16, we will use repeated measures linear regression models, as implemented in PROC MIXED 
in SAS and fit using REML estimation, with repeated measurements of clinical scores as outcomes and time, in 
categories, as the predictor.  Our primary interest will be only in the difference between baseline and week 16 
scores, but all observed scores will be included as outcomes, given that partially observed scores may be 
informative for estimation.  We will obtain an estimate of 16-week change and corresponding 95% CI using a 
contrast of the week 16 and baseline model parameters.  A contrast of the same parameters will provide a 
statistical test of the null hypothesis that there was no change in outcome between baseline and 16 weeks.  For the 
CGI-I, we will estimate the percentage who respond to treatment and corresponding 95% CI using the proportion 
of participants with CGI-I scores <=2 at 16 weeks.  For this calculation, participants who withdrew prior 16 weeks 
due to side effects will be included as non-responders, and participants who withdrew for other reasons will be 
excluded.   Sensitivity to change will be compared between scales using standardized effect sizes, calculated using 
the estimated 16-week change in each outcome divided by the SD of the outcome at baseline.  We will also 
tabulate and compare the percent of item-level missing data for each scale. 


9 
 
 
Frequency of all side effects and adverse events and corresponding 95% CIs will be tabulated.  Tolerance 
and corresponding 95% CI will be estimated using the proportion of participants who did not withdraw from the 
study before 16 weeks due to reasons other than side effects or an adverse event who discontinue treatment due to 
side effects or an adverse event.  We will also use the 16-week study retention rate and corresponding 95% CI, 
calculated as the proportion of the participants enrolling in the study who remain in the study for 16 weeks, as a 
measure of feasibility.  
 
Confidence intervals for binomial proportions will be calculated using Wilson’s method.   Confidence 
intervals and statistical tests will be two-sided, with test-wise alpha=0.05. 
Data Management:  
When a participant is enrolled in the study, he or she will be assigned a unique identification number that is used 
to identify all data associated with that person, including hard copy, and computerized data. Data will be collected 
on hard-copy forms and then verified by data entry personnel. All of the hard copy research data is kept in locked 
file cabinets at the Lurie Center. Only the PI and primary research assistants will have access to these files, 
ensuring security of the hard copy records.  
Once data is obtained, the clinician will review the form to make sure that all required items are completed and to 
clarify any ambiguous notations before giving it to the research assistant responsible for data entry. Several 
quality control measures are built into our computerized data management. Data entry forms have been designed 
that correspond to the measures used in this study. These forms are configured so that out-of-range values cannot 
be entered; data entry prompts appear in the correct order, including skipping questions when appropriate; and 
entered values cannot be inadvertently overwritten. Immediately after data entry, a series of logic check programs 
are run automatically, indicating any entered values that appear incorrect and the reason why. Logic check reports 
will be reconciled with the hardcopy and, if necessary, the clinician. Changes will then be entered, and the logic 
check programs executed again in order to detect any new errors resulting from the changed values. The process 
will continue until no further errors are detected by the logic check programs.  
Project Milestones:  
Year 1: The trial will be initiated after obtaining IRB approval. Eight subjects will enroll into the protocol.  
Year 2: Trial enrollment continues. An additional 8 subjects will be enrolled into the protocol.  
Year 3: Trial enrollment continues. The final 4 subjects will be enrolled into the protocol. Data will be analyzed.  
Schedule of Measures: 
Table 1. Schedule of Measures 
 
Treatment Phase 
Measure 
Screen 
Baseline 
Week 
2* 
Week 
4 
Week 
6* 
Week 
8 
Week 
10* 
Week 
12 
Week 
16 
Parent Ratings [1] 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
PARS [2] 
X 
X 
 
X 
 
X 
 
X 
X 
SCARED [3] 
 
X 
 
X 
 
X 
 
X 
X 
CASI Anxiety [4] 
 
X 
 
X 
 
X 
 
X 
X 
ABC-2 [5] 
 
X 
 
X 
 
X 
 
X 
X 
PSQI [6] 
 
X 
 
X 
 
X 
 
X 
X 
Subject Assessments 
 
 
 
 
 
 
 
 
 
Height, Weight 
X 
 
 
 
 
 
 
 
 
Urine Pregnancy Test [7] 
X 
 
 
 
 
 
 
 
 


10 
 
PARS** 
X 
X 
 
X 
 
X 
 
X 
X 
SCARED** 
 
X 
 
X 
 
X 
 
X 
X 
Stanford-Binet-5 (SB-5), 
WASI-II [8], or 
Developmental Profile-4 (DP-
4)  
X 
 
 
 
 
 
 
 
 
Treating Clinician 
 
 
 
 
 
 
 
 
 
WS Diagnosis [9] 
 
 
 
 
 
 
 
 
 
Diagnostic Exam including 
medical/psychiatric History 
X 
 
 
 
 
 
 
 
 
Health/Behavior Review 
X 
 
 
 
 
 
 
 
 
Adverse Effects Review 
 
X 
X 
X 
X 
X 
X 
X 
X 
CGI-Severity [10] 
X 
X 
 
 
 
 
 
 
X 
CGI-Improvement [11] 
 
 
 
X 
 
X 
 
X 
X 
Suicide Assessment [12] /  
C-SSRS* [13] 
X* 
X* 
X 
X* 
X 
X* 
X 
X* 
X* 
Concomitant Treatments 
X 
X 
X 
X 
 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
 
X 
X 
X 
X 
*Telephone Visit; [1] Parent or primary caretaker ratings; [2] PARS = Pediatric Anxiety Rating Scale; [3] 
SCARED = Screen for Child Anxiety Related Disorders; [4] CASI Anxiety = Child & Adolescent 
Symptom Inventory; [5] ABC-2 = Aberrant Behavior Checklist, Second Edition; [6] PSQI = Pittsburgh 
Sleep Quality Index; [7] Females of child-bearing potential only; [8] WASI-II = Weschler Abbreviated 
Scale of Intelligence, Second Edition; [9] genetic testing or clinical diagnosis; [10] CGI-S = Clinical 
Global Impression for Severity; [11] CGI-1 = Clinical Global Impression for Improvement [12] Suicide 
Assessment included in Adverse Effect Review; [13] Columbia-Suicide Severity Rating Scale (C-SSRS)* 
will be administered to participant and/or parent if any positive suicidal ideation is reported during clinical 
assessment.  Each visit following the first report of suicidal ideation will include the administration of the 
C-SSRS.; ** when subject’s communication abilities allows 
 
F. ENVIRONMENT 
The performance site is the Lurie Center in Lexington, Massachusetts. It serves as the major referral site for 
children, adolescents, and adults with autism and other neurodevelopmental disorders from throughout the State of 
Massachusetts, as well as neighboring states. Research is a major focus of the Center’s mission. Approximately 20 
patients with WS are seen annually for an initial evaluation, thus ensuring an adequate sample from which to 
recruit.  
H. REFERENCES  
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American Academy of Child and Adolescent Psychiatry, 38(10), 1230–6. https://doi.org/10.1097/00004583-
199910000-00011  
Blomberg, S., Rosander, M., & Andersson, G. (2006). Fears, hyperacusis and musicality in Williams syndrome. 
Research in Developmental Disabilities, 27(6), 668–680. https://doi.org/10.1016/j.ridd.2005.09.002 
Buysse, D. J., Reynolds, C. F., Charles, F., Monk, T. H., Berman, S. R., & Kupfer, D. J. (1989). The Pittsburgh sleep 
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Cherniske, E. M., Carpenter, T. O., Klaiman, C., Young, E., Bregman, J., Insogna, K., … Pober, B. R. (2004). 
Multisystem study of 20 older adults with Williams syndrome. American Journal of Medical Genetics, 
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Dykens, E. M. (2003). Anxiety, Fears, and Phobias in Persons With Williams Syndrome. Developmental 
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Einfeld, S. L., Tonge, B. J., & Rees, V. W. (2001). Longitudinal Course of Behavioral and Emotional Problems in 
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and Developmental Disorders, 47(12), 3765–3777. https://doi.org/10.1007/s10803-016-2909-z 
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