Cannabidiol for ASD Open Trial

Study Overview
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Brief Summary
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This is a 6-week open trial to identify the optimal dosing of cannabidiol (CBD) in youth with autism spectrum disorder (ASD) and to identify primary and secondary outcomes for future controlled studies. This study evaluates change in symptoms commonly associated with ASD, as evidence suggests that CBD may be eﬀective in addressing diﬃculties such as irritability and anxiety, while maintaining a benign adverse eﬀect (AE) proﬁle in children and adolescents. 30 male and female participants with ASD between the ages of 7 and 17 years old are being recruited. Participants have ﬂuent speech and an estimated IQ greater than or equal to 80. Study intervention is 98% pure CBD. The CBD is Greenwich Biosciences, Inc.'s 100mg/mL oral solution, brand name EPIDIOLEX. First, a Bayesian optimal interval (BOIN) design was used, such that participants were assigned to cohorts of size 3 receiving doses of 3, 6, or 9 mg/kg/day, depending on the treatment response of participants in prior cohorts. The BOIN design ended after the fifth cohort of participants, and the two lower doses, 3 and 6 mg/kg/day, were eliminated. The highest dose, 9 mg/kg/day, was not tested. Therefore, in subsequent cohorts, we will be examining 9 mg/kg/day exclusively in up to 15 additional participants with co-occurring ASD and attention-deficit/hyperactivity disorder (ADHD) diagnoses, as this clinical profile appears to most closely resemble youth classified as responders within the BOIN design.

Official Title
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A Phase 2 Study of Cannabidiol as a New Treatment for Autism Spectrum Disorder in Children and Adolescents

Conditions
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ASD, Autism Spectrum Disorder

Intervention / Treatment
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* Drug: 98% pure CBD


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female pediatric outpatients aged between and including 7 to 17.9 years old Diagnosis of ASD confirmed by the ADOS-2 and DSM-5 criteria Diagnosis of ADHD confirmed by clinician review of K-SADS-COMP and DSM-5 Criteria SRS-2 Total T-score of 66 or higher CGI-S score of 4 or higher Physical exam and laboratory results that are within normal range for their age Fluent speech Estimated IQ of at least 80 Presence of a parent/legal guardian who is able to consent for their participation and complete assessments regarding the child's development and behavior throughout the study Exclusion Criteria: History or current evidence of significantly impaired liver function, defined as 1) Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) > 5 × upper limit of normal (ULN); 2) ALT or AST > 3 × ULN with concomitant total bilirubin > 2.0 × ULN; or 3) ALT or AST ≥ 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia History of active seizure disorder or epilepsy; patients seizure free for >5 years off of antiepileptic drugs and other than uncomplicated febrile seizures are not excluded Exposure to any investigational agent in the 30 days prior to initiation of trial Treatment with CBD or other cannabinoid within the previous two months Current use of medications metabolized primarily by CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A4, or CYP2D6 isoenzymes. Methylphenidate is not contraindicated. History of drug abuse including marijuana/cannabis use in the past 3 months Positive urine sample results from drug screening indicating presence of the following drugs: THC, opiates, methamphetamine, or cocaine Diagnosis of a known genetic disorder (e.g., Prader-Willi Syndrome, Angelman Syndrome, etc.). Active suicidality (ideation and plan) is present A current psychiatric diagnosis of bipolar disorder, major depressive disorder (MDD), psychosis, schizophrenia, or post-traumatic stress disorder (PTSD) Pregnant or lactating patients or patients who will not agree to be abstinent or use contraception A medical condition that severely impacts the subject's ability to participate in the study, interferes with the conduct of the study, confounds interpretation of study results or endangers the subject's well-being Diagnosis of Rett Syndrome or Childhood Disintegrative Disorder or marked sensory impairment such as deafness or blindness Subjects who have had changes in allied health therapies, behavioral or educational interventions within 4 weeks prior to initiation of trial, other than those associated with school holidays Subjects who have had changes in non-exclusionary psychotropic medications within 4 weeks of initiation of trial

Ages Eligible for Study
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Minimum Age: 7 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 98% pure CBD<br>98% pure CBD. The CBD will be 100mg/mL oral solution provided by Greenwich Biosciences, Inc. | Drug: 98% pure CBD<br>* A Bayesian optimal interval (BOIN) design was used, such that participants were assigned to cohorts of size 3 receiving doses of 3, 6, or 9 mg/kg/day, depending on the treatment response of participants in prior cohorts. The BOIN design has ended, and two doses have been tested and eliminated (3 and 6 mg/kg/day). We are now examining 9 mg/kg/day exclusively.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Global Impression Scale -Improvement (CGI-I) | The physician-rated CGI-I comprises one question asking how much a participant's condition has changed since baseline. The item is answered using a 7-point Likert scale, where 1 = very much improved; 2 = much improved; 3 = minimally improved; 4 = no change; 5 = minimally worse; 6 = much worse; and 7 = very much worse. The total score is the item response; lower scores indicate greater improvement. | Week 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Repetitive Behavior Scale-Revised (RBS-R) Score | The RBS-R is a 43-item self report used to measure the breadth of repetitive behavior in children. For each item, behaviors are rated on a 4-point scale: 0-Behavior does not occur, 1-Behavior occurs and is a mild problem, 2-Behavior occurs and is a moderate problem, 3-Behavior occurs and is a severe problem. On the last question, participants are asked to lump together all of the behaviors described in the questionnaire, and provide a rating for how much of a problem these repetitive behaviors are overall, on a scale from 1-100: 1-Not a problem at all, to 100-As bad as you can imagine. The total score is the sum of all items and ranges from 0 to 229. | Baseline, Week 6 | 
| Change in Social Responsiveness Scale, 2nd Edition (SRS-2), School-Age Form Score | The SRS-2 is a 65-item questionnaire assessing Social Awareness, Social Cognition, Social Communication, Social Motivation, and Restricted Interests and Repetitive Behavior. Items are scored on a 4-point scale (ranging from 1=not true to 4=almost always true). The raw score is the sum of responses and is converted to a T-score; the final T-score has a mean of 50 points with a standard deviation of 10 points, where lower scores indicate greater social responsiveness: Less than or equal to 59 = Low-to-no symptom impacts Between 60-65 = Mild-to-moderate defcits in social interaction Between 66-75 = Moderate defcit in social interaction Greater than or equal to 76 = Severe | Baseline, Week 6 | 
| Change in Aberrant Behavior Checklist (ABC) - Irritability Subscale Score | The ABC Irritability subscale comprises 15 items rated on a 4-point scale (ranging from 0=no problem at all to 3 = problem is severe in degree). The total score is the sum of responses and ranges from 0 to 45; higher scores indicate greater presences of irritability related behavior. | Baseline, Week 6 | 
| Change in Aberrant Behavior Checklist (ABC) - Social Withdrawal Subscale Score | The ABC Social Withdrawal subscale comprises 16 items rated on a 4-point scale (ranging from 0=no problem at all to 3 = problem is severe in degree). The total score is the sum of responses and ranges from 0 to 48; higher scores indicate greater presences of irritability related behavior. | Baseline, Week 6 | 
| Change in Anxiety, Depression and Mood Scale (ADAMS) Score | 28 symptom items assessing Manic/Hyperactive Behavior, Depressed Mood, Social Avoidance, General Anxiety, and Compulsive Behavior. Items are rated on 4-point scale ranging from 0=not a problem to 3=severe problem. The total score is the sum of responses and ranges from 0 to 84; lower scores indicate better outcomes and lesser symptoms. | Baseline, Week 6 | 
| Change in Screen for Child Anxiety Related Disorders (SCARED), Parent Version Score | The SCARED, Parent Version is a 41-item parent-report measure developed to measure child anxiety symptoms. Subscales include Somatic Symptoms/Panic Disorder, Generalized Anxiety Disorder, Separation Anxiety, Social Phobia, and School Phobia. Items are rated on a 3-point scale ranging from 0=not true or hardly ever true to 2=very true or often true. The total score is the sum of responses and ranges from 0 to 82; lower scores indicate lesser child anxiety symptoms. | Baseline, Week 6 | 
| Change in Sleep Disturbance Scale for Children (SDSC) Score | The SDSC is a 26-item parent-completed assessment of their child's sleep-wake rhythm. The questionnaire measures Disorders of Initiating and Maintaining Sleep, Sleep Breathing Disorders, Disorders of Arousal, Sleep Wake Transition Disorders, Disorders of Excessive Somnolence, and Sleep Hyperhydrosis. Items are rated on 5-point scale where 1=never and 5=always (daily). The total score is the sum of responses and ranges from 26 to 130; lower scores indicate healthier sleep-wake rhythms. | Baseline, Week 6 | 
| Change in Vineland Adaptive Behavior Scales, Third Edition (Vineland-3) Parent/Caregiver Form Score | Used to measure adaptive functioning across three core domains (Communication, Daily Living Skills, and Socialization), and two optional domains (Motor Skills and Maladaptive Behavior); items are rated on a 3-point scale (0=never; 1=sometimes; 2=usually or often). The core domains sum to a total Adaptive Behavior Composite. The range of possible composite scores ranges from 20-140, with a higher score indicating higher levels of adaptive functioning. | Baseline, Week 6 | 
| Change in Clinical Global Impression-Severity (CGI-S) Score | 1-item assessment of clinicians impression of severity of illness. Illness severity is rated on a 7-point scale ranging from 1=not at all to 7=among the most extremely ill. | Baseline, Week 6 | 
| Change in Autism Family Experience Questionnaire (AFEQ) Score | Parent/Caregiver form used to measure impact of autism interventions on family experience and quality of life. Items are rated on a 5-point scale where 1=always and 5=never. The total score is the sum of responses and ranges from 48 - 240; lower scores indicate better outcomes. | Baseline, Week 6 | 
| Change in Anxiety Scale for Children - Autism Spectrum Disorder - Parent Versions (ASC-ASD-P) Score | 24-item Parent/Caregiver-completed form developed to detect symptoms of anxiety in youth with ASD. Items are rated on a 4-point scale (0=never and 3=always). The total score is the sum of responses and ranges from 0 to 72; lower scores indicate lesser symptoms of anxiety. | Baseline, Week 6 | 
| Anxiety Scale for Children - Autism Spectrum Disorder (ASC-ASD-C) - Child Version | 24-item Child-completed form developed to detect symptoms of anxiety in youth with ASD. Items are rated on a 4-point scale (0=never and 3=always). The total score is the sum of responses and ranges from 0 to 72; lower scores indicate lesser symptoms of anxiety. | Baseline, Week 6 | 
| Change in Ohio State University (OSU) Autism Clinical Global Impressions: Severity | Reflects clinicians impression of severity of illness on a 7-point scale ranging from 1=not present to 7=classic autism. | Baseline, Week 6 | 
| OSU Autism Clinical Global Impressions: Improvement | Reflects clinicians impression of improvement on a 7-point scale ranging from 1=very much improved to 7=very much worse. | Week 6 | 
| Change in Behavioral Inflexibility Scale (BIS) Score | 38-item Parent/Caregiver-completed measure designed to assess rigid patterns of behavior commonly associated with ASD. Items are rated on a 6-point Likert scale where 0=Not at all a problem and 5=Very severe or extreme problem. The total score is the sum of responses and ranges from 0 to 228; higher scores indicate greater behavioral inflexibility. | Baseline, Week 6 | 
| Change in Home Situations Questionnaire - Modified for ASD (HSQ-ASD) Score | 24-item Parent/Caregiver-completed questionnaire measuring behavioral noncompliance in everyday settings over the past four weeks. Severity of non-compliance is rated on a 9-point Likert scale (where 1 = no interruption, and 9 = frequent/consistent interruption). The total score is the sum of responses and ranges from 24 to 216; higher scores indicate greater behavioral noncompliance. | Baseline, Week 6 | 
| Change in Strengths and Weaknesses of Attention-Deficit/Hyperactivity Disorder Symptoms and Normal Behavior (SWAN) Score | SWAN is an 18-item Parent/Caregiver-completed measure designed to assess symptoms of ADHD in children and adolescents. Items are rated on a 7-point Likert scale, where Far Below Average = 3, Below Average = 2, Somewhat Below Average = 1, Average = 0, Somewhat Above Average = -1, Above Average = -2, and Far Above Average = -3. The total score is the sum of responses and ranges from -54 to 54; the lower the score, the higher the severity of ADHD symptoms. | Baseline, Week 6 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cannabidiol (CBD)