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Cannabinoids for Behavioral Problems in Children With ASD (CBA)

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ClinicalTrials.gov Identifier: NCT02956226
Recruitment Status : Completed
First Posted : November 7, 2016
Last Update Posted : December 27, 2018
Sponsor:
Information provided by (Responsible Party):
Dr. Adi Aran, Shaare Zedek Medical Center

Tracking Information
First Submitted Date  ICMJE November 1, 2016
First Posted Date  ICMJE November 7, 2016
Last Update Posted Date December 27, 2018
Study Start Date  ICMJE January 2017
Actual Primary Completion Date October 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 29, 2018)
  • Change from baseline Home Situations Questionnaire-Autism Spectrum Disorder (HSQ-ASD) score, at three months. Within subject difference between the placebo condition and the whole plant extract condition. [ Time Frame: At onset of each treatment period, at 1 month, 2 months and 3 months (end of treatment period) ]
    This is a 24-item parent-rated measure of noncompliant behavior in children with ASD
  • Clinical Global Impression-Improvement scores (CGI-I ) at three months. Within subject difference between the placebo condition and the whole plant extract condition. [ Time Frame: At 3 months (end of treatment period) ]
    This is a 7-point scale designed to measure overall improvement from baseline (CGI-I).
Original Primary Outcome Measures  ICMJE
 (submitted: November 2, 2016)
  • Change from baseline Home Situations Questionnaire-Autism Spectrum Disorder (HSQ-ASD) score, at three months [ Time Frame: At onset of each treatment period, at 1 month, 2 months and 3 months (end of treatment period) ]
    This is a 24-item parent-rated measure of noncompliant behavior in children with ASD
  • Change in Child Behavior Checklist (CBCL)- externalizing section score, at three months [ Time Frame: At onset of each treatment period, at 1 month, 2 months and 3 months (end of treatment period) ]
    The CBCL generates 3 broad band results—an internalizing score (summing up anxious/depressed scale, somatic complaints scale and withdrawn scale) an externalizing score (summing up non-compliant scale and aggressive behavior scale) and a total score. For this study we will use the externalizing section only.
  • Change in Autism Parenting Stress Index (APSI) score, at three months [ Time Frame: At onset of each treatment period, at 1 month, 2 months and 3 months (end of treatment period) ]
    This is a 13-item parent rated measure designed to assess the effect of interventions to control disruptive behavior in children with ASD on parenting stress.
Change History Complete list of historical versions of study NCT02956226 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: June 29, 2018)
  • Clinical Global Impression-Improvement scores (CGI-I ) at three months. Within subject differences between the placebo condition and the pure cannabinoids condition and between the whole plant extract condition and the pure cannabinoids condition. [ Time Frame: At 3 months (end of treatment period) ]
    This is a 7-point scale designed to measure overall improvement from baseline
  • Change in Social Responsiveness Scale scores-2 (SRS-2, parent and teacher rated) at three months [ Time Frame: At onset of each treatment period and at 3 months (end of treatment period) ]
    This is a 65 item, caregiver (pSRS) or teacher (tSRS) questionnaire, used to determine the severity of social deficit exhibited by participants with ASD. The SRS contains five subscales: Social Awareness, Social Cognition, Social Communication, Social Motivation, and Autistic Mannerisms, which respectively measure the ability to recognize social cues, the ability to interpret social cues, the ability to use expressive verbal and nonverbal language skills, the ability to engage in social-interpersonal behaviors, and the tendency to display stereotypical behaviors and restricted interests characteristic of autism
  • Change in Autism Parenting Stress Index (APSI) score, at three months [ Time Frame: At onset of each treatment period, at 1 month, 2 months and 3 months (end of treatment period) ]
    This is a 13-item parent rated measure designed to assess the effect of interventions to control disruptive behavior in children with ASD on parenting stress.
  • Change from baseline Home Situations Questionnaire-Autism Spectrum Disorder (HSQ-ASD) score, at three months. [ Time Frame: At onset of each treatment period, at 1 month, 2 months and 3 months (end of treatment period) ]
    This is a 24-item parent-rated measure of noncompliant behavior in children with ASD. Within subject differences between the placebo condition and the pure cannabinoids condition and between the whole plant extract condition and the pure cannabinoids condition.
Original Secondary Outcome Measures  ICMJE
 (submitted: November 2, 2016)
  • Change in Clinical Global Impression scores (CGI, improvement and efficacy index items) at three months [ Time Frame: At onset of each treatment period and at 3 months (end of treatment period) ]
    This is a 7-point scale designed to measure severity of illness (CGI-S), overall improvement from baseline (CGI-I) and the drug effects (both therapeutic effect and side effects, CGI-D).
  • Change in Social Responsiveness Scale scores (SRS, parent and teacher rated) at three months [ Time Frame: At onset of each treatment period and at 3 months (end of treatment period) ]
    This is a 69-71 item, caregiver (pSRS) or teacher (tSRS) questionnaire, used to determine the severity of social deficit exhibited by participants with ASD. The SRS contains five subscales: Social Awareness, Social Cognition, Social Communication, Social Motivation, and Autistic Mannerisms, which respectively measure the ability to recognize social cues, the ability to interpret social cues, the ability to use expressive verbal and nonverbal language skills, the ability to engage in social-interpersonal behaviors, and the tendency to display stereotypical behaviors and restricted interests characteristic of autism
Current Other Pre-specified Outcome Measures
 (submitted: November 2, 2016)
Modified Liverpool Adverse Events Profile (LAEP) [ Time Frame: At onset of each treatment period, at 1 month, 2 months and 3 months (end of treatment period) ]
Tolerability and adverse effects will be assessed using this modified Liverpool Adverse Events Profile (LAEP) that includes all 19 items of the original LAEP and another 15 items to cover all reported significant side effects of CBD and THC in former studies.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Cannabinoids for Behavioral Problems in Children With ASD
Official Title  ICMJE Cannabinoids for Behavioral Problems in Autism Spectrum Disorder: A Double Blind, Randomized, Placebo-controlled Trial With Crossover.
Brief Summary This study aims to assess the safety, tolerability and efficacy of cannabinoids mix [cannabidiol (CBD), Δ9-tetrahydrocannabinol (THC) in a 20:1 ratio, BOL Pharma, Israel] for behavioral problems in children and youth with ASD.
Detailed Description

Disruptive behaviors are very common in children and youth with autism spectrum disorder (ASD). Behavioral problems increase social impairment in children with ASD, make interventions more difficult and place considerable strain on families and caregivers. Current treatment is based on behavioral interventions combined with atypical antipsychotics which often have low tolerability and questionable efficacy.

Cannabis exerts profound effects on human social behavior. Research using animal models of ASD indicate a possible dysregulation of the endocannabinoid system, and stress that it may be a novel target for pharmacological interventions. Anecdotal evidence suggest efficacy of various phytocannabinoids in resistant behavioral problems. However controlled human studies are lacking.

Objective: To assess the safety, tolerability and efficacy of cannabinoids mix [cannabidiol (CBD), Δ9-tetrahydrocannabinol (THC) in a 20:1 ratio, BOL Pharma, Israel] for behavioral problems in children and youth with ASD.

Setting: A double blind randomized placebo-controlled trial with crossover.

Methods: One hundred and fifty participants, ages 5-21 years, with ASD and moderate to severe refractory behavioral problems will be randomized to receive 1 out of 3 treatments for 12-weeks and cross-over to another treatment in a second 12 weeks period. Treatment options are: (1) oral placebo (2) cannabis extract, contains cannabidiol and Δ9-tetrahydrocannabinol in a 20:1 ratio, at a cannabidiol dose of 10 mg/kg/d and (3) pure cannabidiol and Δ9-tetrahydrocannabinol in the same ratio and dose.

Outcomes and measures: Two co-primary endpoints will compare the whole plant extract treatment to the placebo treatment on a within subject design. 1) The change from baseline Home Situations Questionnaire-ASD score after 3 months of treatment (HSQ-ASD; a parent rated assessment of disruptive behavior). 2) The Clinical Global Impression- improvement (CGI-I; a clinician rated assessment of improvement in disruptive behavior following treatment)

Secondary efficacy outcomes include:

  • Within subject differences between the placebo condition and the pure cannabinoids condition and between the whole plant extract condition and the pure cannabinoids condition in the change from baseline HSQ-ASD score after 3 months of treatment and in the CGI-I.
  • Within subject differences between each pair of the 3 conditions in the Clinical Global Impression- drug effect (CGI-D).
  • Within subject differences between each pair of the 3 conditions in the change from baseline after 3 months of treatment in: Social Responsiveness Scale (SRS) parent and teacher rated, Child Behavior Checklist (CBCL) and autism parenting stress index (APSI).

Safety endpoints will include the proportion of patients with adverse events measured by the investigators and the Liverpool Adverse Events Profile (modified).

Exploratory measures are: markers of the endocannabinoid system in the patients' blood and possible correlation to phytocannabinoids bioavailability and treatment response, change from baseline at the end of treatment in BMI and Children's Sleep Habits Questionnaire (CSHQ) score and quality of parent- child interaction during the study (Emotional Availability- EA).

Long term safety, tolerability and efficacy of cannabidiol-rich medical cannabis will be assessed after 12 and 24 months of open treatment, in a subgroup of patients who will apply for medical license to use cannabis after completing the study.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Autistic Disorder
Intervention  ICMJE
  • Drug: Cannabinoids - 99% pure cannabinoids mix
    99% pure cannabidiol (CBD) and 99% pure Δ9-tetrahydrocannabinol (THC) in a 20:1 ratio (B.O.L Pharma, Israel), in a 160/8.0 mg per mL (CBD/THC) olive oil-based solution.
  • Drug: Placebo
    Olive oil and flavors solution.
  • Drug: Cannabinoids - whole plant extract
    Whole plant extract enriched with cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) to achieve 20:1 ratio (B.O.L Pharma, Israel), in a 160/8.0 mg per mL (CBD/THC) olive oil-based solution.
Study Arms  ICMJE
  • Experimental: Cannabinoids - 99% pure cannabinoids mix
    Oral cannabinoids mix [cannabidiol (CBD), Δ9-tetrahydrocannabinol (THC) in a 20:1 ratio] at 1 mg/kg cannabidiol per day, up-titrated until intolerance or to a maximum dose of 10 mg/kg CBD per day, divided to 3 daily doses, for 3 months.
    Intervention: Drug: Cannabinoids - 99% pure cannabinoids mix
  • Placebo Comparator: Placebo
    Oral olive oil and flavors that mimic in texture and flavor the cannabinoids' solution.
    Intervention: Drug: Placebo
  • Experimental: Cannabinoids - whole plant extract
    Oral cannabinoids mix [cannabidiol (CBD), Δ9-tetrahydrocannabinol (THC) in a 20:1 ratio] at 1 mg/kg cannabidiol per day, up-titrated until intolerance or to a maximum dose of 10 mg/kg CBD per day, divided to 3 daily doses, for 3 months
    Intervention: Drug: Cannabinoids - whole plant extract
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: January 16, 2018)
150
Original Estimated Enrollment  ICMJE
 (submitted: November 2, 2016)
120
Actual Study Completion Date  ICMJE December 2018
Actual Primary Completion Date October 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria: (both are needed)

  • ASD diagnosis (Diagnostic and Statistical Manual of Mental Disorders [Fifth Edition; DSM-V]
  • Moderate or greater behavioral problems as measured by a rating of moderate or higher (≥4) on the Clinical Global Impression-Severity (CGI-S)

Exclusion Criteria:

  • Planned changes in existing interventions for the duration of the trial or such a change in the last 4 weeks.
  • Current treatment with cannabis based therapy or such a treatment in the last 3 months.
  • Heart, liver, renal or hematological disorders
  • History of psychotic disorder in a first degree relative.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 5 Years to 21 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Israel
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02956226
Other Study ID Numbers  ICMJE CBA
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Dr. Adi Aran, Shaare Zedek Medical Center
Study Sponsor  ICMJE Shaare Zedek Medical Center
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Adi Aran, MD Shaare Zedek Medical Center
Principal Investigator: Varda Gross Shaare Zedek Medical Center
PRS Account Shaare Zedek Medical Center
Verification Date December 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP