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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Buspirone | Experimental | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Buspirone | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Mean 16-Week Change in Pediatric Anxiety Rating Scale 5-Item Total Score | The Pediatric Anxiety Rating Scale (PARS) is a clinician-rated instrument that assesses anxiety symptoms that are commonly associated with social anxiety, separation anxiety, and generalized anxiety disorders. Scaled score ranges from 0-25 with higher scores indicating more severe anxiety symptoms. Mean change was estimated using a repeated measures linear regression model with time in categories as the covariate and all non-missing scores for all measurement times as outcomes. A linear contrast estimated mean change between Baseline and Week 16. | Baseline, Week 4, Week 8, Week 12, Week 16; Change from Baseline to Week 16 reported |
| Measure | Description | Time Frame |
|---|---|---|
| Proportion of Participants Who Responded to Treatment at 16 Weeks According to the Improvement Item of the Clinical Global Impression-Scale (Response Defined as CGI-I=1 or CGI-I=2) | The Clinical Global Impressions Global Improvement (CGI-I) is designed to take into account all factors to arrive at an assessment of response to treatment. The CGI-I scale ranges 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), with lower scales indicating improvement (1=very much improved; 2=much improved). In this study, the CGI-I will be focused on the target symptom of anxiety. Participants with a CGI-I score of 1 or 2 will be classified as responders. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Robyn P Thom, MD | Massachusetts General Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Lurie Center for Autism | Lexington | Massachusetts | 02421 | United States |
All 20 enrolled participants met inclusion criteria.
Participants were recruited between May 2021 and March 2023 through the Williams Syndrome Association and the Williams Syndrome Registry, as well as other specialty and primary care clinics. A recruitment letter was also sent to patients diagnosed with Williams Syndrome through the Mass General Brigham Patient Gateway secure online patient portal.
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| ID | Title | Description |
|---|---|---|
| FG000 | Buspirone | 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. Buspirone: 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. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Buspirone | 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. Buspirone: 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Mean 16-Week Change in Pediatric Anxiety Rating Scale 5-Item Total Score | The Pediatric Anxiety Rating Scale (PARS) is a clinician-rated instrument that assesses anxiety symptoms that are commonly associated with social anxiety, separation anxiety, and generalized anxiety disorders. Scaled score ranges from 0-25 with higher scores indicating more severe anxiety symptoms. Mean change was estimated using a repeated measures linear regression model with time in categories as the covariate and all non-missing scores for all measurement times as outcomes. A linear contrast estimated mean change between Baseline and Week 16. | All 20 participants contributed a baseline PARS 5-item total score to the analysis. Due to study discontinuation and a missing assessment, numbers of participants contributing post-baseline scores were 19 at week 4, 18 at week 8, 18 at week 12, and 18 at week 16. | Posted | Mean | 95% Confidence Interval | score on a scale | Baseline, Week 4, Week 8, Week 12, Week 16; Change from Baseline to Week 16 reported |
|
The earlier of 16 weeks or study discontinuation
Adverse event data were collected via a structured side effect rating scale completed with the participant and their primary caregiver.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Buspirone | 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. Buspirone: 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. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Diarrhea | Gastrointestinal disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Lurie Center Research Manager | Massachusetts General Hospital Lurie Center for Autism | 781-860-1711 | luriecenterresearch@mgh.org |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Mar 3, 2023 | Jul 23, 2024 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D018980 | Williams Syndrome |
| D001008 | Anxiety Disorders |
| ID | Term |
|---|---|
| D008607 | Intellectual Disability |
| D019954 | Neurobehavioral Manifestations |
| D009461 | Neurologic Manifestations |
| D009422 | Nervous System Diseases |
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| ID | Term |
|---|---|
| D002065 | Buspirone |
| ID | Term |
|---|---|
| D013141 | Spiro Compounds |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
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|
| 16 weeks |
| Mean 16-Week Change in Child and Adolescent Symptom Inventory Anxiety-Modified Score | The Child and Adolescent Symptom Inventory (CASI) is a caregiver completed questionnaire with items that map directly onto Diagnostic and Statistical Manual of Mental Disorders diagnostic criteria for anxiety disorders in children and adolescents. The CASI-Modified which includes 20 specific items that have been used to assess anxiety in subjects with developmental disabilities will be administered. Total score ranges from 0-20 with higher scores indicating more severe anxiety symptoms. Mean change was estimated using a repeated measures linear regression model with time in categories as the covariate and all non-missing scores for all measurement times as outcomes. A linear contrast estimated mean change between Baseline and Week 16. | Baseline, Week 4, Week 8, Week 12, Week 16; Change from Baseline to Week 16 reported |
| Mean 16-Week Change in Screen for Childhood Anxiety Related Emotional Disorders Total Score | The Screen for Childhood Anxiety Related Emotional Disorders (SCARED) includes both a child/self-report and parent-report form, each containing 41-items. It is used to screen for symptoms of panic disorder, separation anxiety disorder, social phobia, generalized anxiety disorder, and school phobia. Total score ranges from 0-82 and a total score of 25 or greater may indicate the presence of an anxiety disorder. Mean change was estimated using a repeated measures linear regression model with time in categories as the covariate and all non-missing scores for all measurement times as outcomes. A linear contrast estimated mean change between Baseline and Week 16. | Baseline, Week 4, Week 8, Week 12, Week 16; Change from Baseline to Week 16 reported |
| Mean 16-Week Change in Each Subscale of the Aberrant Behavior Checklist | The Aberrant Behavior Checklist (ABC-2) is a caregiver rated instrument that measures psychiatric symptoms and behavioral disturbance in subjects with developmental disability with 5 subscales. Each of its 58 items is scored on a 4-point scale (0=never a problem to 3=severe problem). The 5 subscales and their range of scores are: Irritability 0-45, with higher scores indicating more severe irritability; Social Withdrawal/Lethargy 0-48, with higher scores indicating more severe social withdrawal; Stereotypy 0-21, with higher scores indicating more severe stereotypy; Hyperactivity 0-48, with higher scores indicating more severe hyperactivity; Inappropriate Speech 0-12, with high scores indicating more severe inappropriate speech. Mean change was estimated using a repeated measures linear regression model with time in categories as the covariate and all non-missing scores for all measurement times as outcomes. A linear contrast estimated mean change between Baseline and Week 16. | Baseline, Week 4, Week 8, Week 12, Week 16; Change from Baseline to Week 16 reported |
| Mean 16-Week Change in Pittsburgh Sleep Quality Index Global Score | The Pittsburgh Sleep Quality Index (PSQI) questionnaire that will be completed by the subject's caregiver to assess sleep quality. The global score ranges from 0-21, where a higher score indicates greater sleep difficulty. Mean change was estimated using a repeated measures linear regression model with time in categories as the covariate and all non-missing scores for all measurement times as outcomes. A linear contrast estimated mean change between Baseline and Week 16. | Baseline, Week 4, Week 8, Week 12, Week 16; Change from Baseline to Week 16 reported |
| Participants |
|
| Age, Continuous | Mean | Full Range | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Buspirone |
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. Buspirone: 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. |
|
|
|
| Secondary | Proportion of Participants Who Responded to Treatment at 16 Weeks According to the Improvement Item of the Clinical Global Impression-Scale (Response Defined as CGI-I=1 or CGI-I=2) | The Clinical Global Impressions Global Improvement (CGI-I) is designed to take into account all factors to arrive at an assessment of response to treatment. The CGI-I scale ranges 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), with lower scales indicating improvement (1=very much improved; 2=much improved). In this study, the CGI-I will be focused on the target symptom of anxiety. Participants with a CGI-I score of 1 or 2 will be classified as responders. | Participants who completed the study | Posted | Number | 95% Confidence Interval | Proportion of participants | 16 weeks |
|
|
|
| Secondary | Mean 16-Week Change in Child and Adolescent Symptom Inventory Anxiety-Modified Score | The Child and Adolescent Symptom Inventory (CASI) is a caregiver completed questionnaire with items that map directly onto Diagnostic and Statistical Manual of Mental Disorders diagnostic criteria for anxiety disorders in children and adolescents. The CASI-Modified which includes 20 specific items that have been used to assess anxiety in subjects with developmental disabilities will be administered. Total score ranges from 0-20 with higher scores indicating more severe anxiety symptoms. Mean change was estimated using a repeated measures linear regression model with time in categories as the covariate and all non-missing scores for all measurement times as outcomes. A linear contrast estimated mean change between Baseline and Week 16. | All 20 participants contributed a baseline CASI modified score to the analysis . Due to study discontinuation and missing assessments, numbers of participants contributing post-baseline scores were 19 at week 4, 18 at week 8, 17 at week 12, and 18 at week 16. | Posted | Mean | 95% Confidence Interval | score on a scale | Baseline, Week 4, Week 8, Week 12, Week 16; Change from Baseline to Week 16 reported |
|
|
|
| Secondary | Mean 16-Week Change in Screen for Childhood Anxiety Related Emotional Disorders Total Score | The Screen for Childhood Anxiety Related Emotional Disorders (SCARED) includes both a child/self-report and parent-report form, each containing 41-items. It is used to screen for symptoms of panic disorder, separation anxiety disorder, social phobia, generalized anxiety disorder, and school phobia. Total score ranges from 0-82 and a total score of 25 or greater may indicate the presence of an anxiety disorder. Mean change was estimated using a repeated measures linear regression model with time in categories as the covariate and all non-missing scores for all measurement times as outcomes. A linear contrast estimated mean change between Baseline and Week 16. | All 20 participants contributed a baseline parent-report SCARED total score to the analysis . Due to study discontinuation and missing or incomplete assessments, numbers of participants contributing post-baseline parent-report scores were 19 at week 4, 18 at week 8, 17 at week 12, and 18 at week 16, and numbers contributing child-report scores were 9 at baseline, 8 at week 4, 10 at week 8, 7 at week 12, and 8 at week 16, with 10 contributing a score at either baseline or week 16. | Posted | Mean | 95% Confidence Interval | score on a scale | Baseline, Week 4, Week 8, Week 12, Week 16; Change from Baseline to Week 16 reported |
|
|
|
| Secondary | Mean 16-Week Change in Each Subscale of the Aberrant Behavior Checklist | The Aberrant Behavior Checklist (ABC-2) is a caregiver rated instrument that measures psychiatric symptoms and behavioral disturbance in subjects with developmental disability with 5 subscales. Each of its 58 items is scored on a 4-point scale (0=never a problem to 3=severe problem). The 5 subscales and their range of scores are: Irritability 0-45, with higher scores indicating more severe irritability; Social Withdrawal/Lethargy 0-48, with higher scores indicating more severe social withdrawal; Stereotypy 0-21, with higher scores indicating more severe stereotypy; Hyperactivity 0-48, with higher scores indicating more severe hyperactivity; Inappropriate Speech 0-12, with high scores indicating more severe inappropriate speech. Mean change was estimated using a repeated measures linear regression model with time in categories as the covariate and all non-missing scores for all measurement times as outcomes. A linear contrast estimated mean change between Baseline and Week 16. | All 20 participants contributed baseline ABC subscale scores to the analysis . Due to study discontinuation and missing assessments, numbers of participants contributing post-baseline scores were 19 at week 4, 18 at week 8, 17 at week 12, and 18 at week 16. | Posted | Mean | 95% Confidence Interval | score on a scale | Baseline, Week 4, Week 8, Week 12, Week 16; Change from Baseline to Week 16 reported |
|
|
|
| Secondary | Mean 16-Week Change in Pittsburgh Sleep Quality Index Global Score | The Pittsburgh Sleep Quality Index (PSQI) questionnaire that will be completed by the subject's caregiver to assess sleep quality. The global score ranges from 0-21, where a higher score indicates greater sleep difficulty. Mean change was estimated using a repeated measures linear regression model with time in categories as the covariate and all non-missing scores for all measurement times as outcomes. A linear contrast estimated mean change between Baseline and Week 16. | All 20 participants contributed a baseline PSQI global score to the analysis . Due to study discontinuation and missing assessments, numbers of participants contributing post-baseline scores were 19 at week 4, 18 at week 8, 16 at week 12, and 17 at week 16. | Posted | Mean | 95% Confidence Interval | score on a scale | Baseline, Week 4, Week 8, Week 12, Week 16; Change from Baseline to Week 16 reported |
|
|
|
| 0 |
| 20 |
| 0 |
| 20 |
| 19 |
| 20 |
| Appetite decrease | General disorders | Systematic Assessment |
|
| Stomach or abdominal discomfort | Gastrointestinal disorders | Systematic Assessment |
|
| Nasal congestion or cold | Infections and infestations | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | Systematic Assessment |
|
| Sadness | Psychiatric disorders | Systematic Assessment |
|
| Headache | Nervous system disorders | Systematic Assessment |
|
| Flu or other respiratory problems | Infections and infestations | Systematic Assessment |
|
| Dry mouth | General disorders | Systematic Assessment |
|
| Interrupted sleep/ other sleep problems | Psychiatric disorders | Systematic Assessment |
|
| Tiredness/fatigue | General disorders | Systematic Assessment |
|
| Constipation | Gastrointestinal disorders | Systematic Assessment |
|
| Irritability | Psychiatric disorders | Systematic Assessment |
|
| Sedation/drowsiness | General disorders | Systematic Assessment |
|
| Weakness | General disorders | Systematic Assessment |
|
| Dizziness/faintness | Nervous system disorders | Systematic Assessment |
|
| Asthmatic symptoms | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Appetite increase | General disorders | Systematic Assessment |
|
| Indigestion | Gastrointestinal disorders | Systematic Assessment |
|
| Localized rash | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Sweating | General disorders | Systematic Assessment |
|
| Change in speech | Psychiatric disorders | Systematic Assessment |
|
| Confusion | Nervous system disorders | Systematic Assessment |
|
| Disinhibition | Psychiatric disorders | Systematic Assessment |
|
| Suicidal ideas | Psychiatric disorders | Systematic Assessment |
|
| Fever | General disorders | Systematic Assessment |
|
| Acid reflux | Gastrointestinal disorders | Systematic Assessment |
|
| Ataxia | Nervous system disorders | Systematic Assessment |
|
| Belching | Gastrointestinal disorders | Systematic Assessment |
|
| Hand pain | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Lip picking | Psychiatric disorders | Systematic Assessment |
|
| Paresthesia | Nervous system disorders | Systematic Assessment |
|
| Pneumonia | Infections and infestations | Systematic Assessment |
|
| Shoulder injury | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Social withdrawal | Psychiatric disorders | Systematic Assessment |
|
| Stuttering | Nervous system disorders | Systematic Assessment |
|
| Urinary tract infection | Renal and urinary disorders | Systematic Assessment |
|
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| D021921 | Aortic Stenosis, Supravalvular |
| D001024 | Aortic Valve Stenosis |
| D000082862 | Aortic Valve Disease |
| D006349 | Heart Valve Diseases |
| D006331 | Heart Diseases |
| D002318 | Cardiovascular Diseases |
| D025063 | Chromosome Disorders |
| D000013 | Congenital Abnormalities |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D030342 | Genetic Diseases, Inborn |
| D001523 | Mental Disorders |
| D010879 |
| Piperazines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D011743 | Pyrimidines |
| D011083 | Polycyclic Compounds |
|
| Title | Measurements |
|---|---|
|
| Hyperactivity |
|
| Inappropriate speech |
|