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Does cannabidiol reduce severe behavioural problems in children with intellectual disability? Study protocol for a pilot single-site phase I/II randomised placebo controlled trial

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Associated Data

Abstract

Introduction

Severe behavioural problems (SBPs) are a common contributor to morbidity and reduced quality of life in children with intellectual disability (ID). Current medication treatment for SBP is associated with a high risk of side effects. Innovative and safe interventions are urgently needed. Anecdotal reports and preliminary research suggest that medicinal cannabis may be effective in managing SBP in children with developmental disabilities. In particular, cannabidiol (CBD) may be a plausible and safe alternative to current medications. Families who are in urgent need of solutions are seeking cannabis for their ID children with SBP. However there is no evidence from randomised controlled trials to support the use of CBD for SBP. This pilot study aims to investigate the feasibility of conducting a randomised placebo-controlled trial of CBD to improve SBP in children with ID.

Methods and analysis

This is a single-site, double-blind, parallel-group, randomised, placebo-controlled pilot study of 10 participants comparing 98% CBD oil with placebo in reducing SBP in children aged 8–16 years with ID. Eligible participants will be randomised 1:1 to receive either CBD 20 mg/kg/day or placebo for 8 weeks. Data will be collected regarding the feasibility and acceptability of all study components, including recruitment, drop-out rate, study visit attendance, protocol adherence and the time burden of parent questionnaires. Safety outcomes and adverse events will be recorded. All data will be reported using descriptive statistics. These data will inform the design of a full scale randomised controlled trial to evaluate the efficacy of CBD in this patient group.

Ethics and dissemination

This protocol has received ethics approval from the Royal Children’s Hospital ethics committee (Human Research Ethics Committee no. 38236). Results will be disseminated through peer-reviewed journals, professional networks, conferences and social media.

Trial registration number

Strengths and limitations of this study

This is the first study to investigate cannabidiol (CBD) for severe behavioural problem in children with intellectual disability and will contribute to the literature more broadly on the use of cannabinoids in children.

This pilot study will inform the design of a full-scale randomised controlled trial of CBD for this indication, and will inform other CBD trials in children.

Introduction

Intellectual disability with severe behaviour problems and associated burden

Two per cent of children and adolescents have an intellectual disability (ID), 1 and approximately half of these individuals have mental health problems, 2 including many with challenging behaviours. These commonly include aggression, self-injury, agitation, mood changes, screaming and banging objects. We use the term severe behavioural problems (SBP) to describe this clinical phenotype.

SBPs in children with ID are a major contributor to morbidity, functional impairments, missed opportunities for learning and reduced quality of life. SBP also places an enormous burden on families and carers, 3 as well as health, education and disability sectors. Parents and siblings of youth with SBP often live in fear of them and are at increased risk of mental health problems. 4 Expensive long-term residential placement is often the only option. 5 ID is estimated to cost $A15 billion annually in Australia. 6 Much of this cost, including personal expenses, service use, government expenditure and opportunity cost for families, relates to SBP impacting on the health and care needs of these patients. 7 Patients with ID and SBP cause challenging demands for hospitals to manage, with implications for staff training, ward design and safety of both staff and patients.

Problems with current treatment of SBP in youth with ID

Challenging behaviours are extremely difficult to treat in children with ID and SBP. Psychological interventions are often ineffective in patients with ID, 8 leaving environmental modification and medication as the main strategies available. Psychotropic medications are prescribed by Australian paediatricians for almost 50% of youth with ID. 9 The medications—antipsychotics, psychostimulants and antidepressants—carry a high risk of side effects for children and adolescents in general; however, patients with developmental disabilities are at particularly high risk, 10 and less able to report side effects. For example, adults with ID exposed to antipsychotic drugs have a higher incidence of treatment-emergent movement disorders compared with patients without ID. 11 Another common side effect of antipsychotics, weight gain, affects health in a patient group already at increased risk of chronic illness, 12 and is a risk factor for avoidable death. 13 Weight gain also brings practical problems in youth with ID, who are often dependent on carers for everyday activities such as dressing, bathing and toileting, as well as compounding the management of aggressive behaviour.

Current pharmacotherapy in children with ID and SBP is characterised by concerning practices, including polypharmacy and frequent changes to medication regimens 10 ; adding drugs to treat side effects, such as use of metformin to control weight gain caused by antipsychotic medication 14 and long-term use of drugs ‘off-label’, for example, atypical antipsychotics. Innovative and safer interventions are urgently needed for children with ID and SBP.

Medicinal cannabis

The potential for medicinal cannabis products to treat a range of medical and psychiatric conditions is becoming increasingly understood. 15 There has recently been great interest in the potential therapeutic role of cannabinoids. The primary psychoactive compound in the cannabis plant is Δ 9 -tetrahydrocannabinol (∆ 9 -THC), which can cause serious side effects such as paranoia and hallucinations. 16 In contrast cannabidiol (CBD), another cannabis extract, does not have intoxicating properties and may provide benefits with minimal adverse psychological effects.

CBD pharmacology and safety

CBD has been delivered orally in an oil-based capsule or sublingual spray in human trials, in variable ratios with ∆ 9 -THC. The onset and duration of activity depends on the preparation and route of administration. The plasma half-life of CBD following oral administration is approximately 60 hours after two times per day dosing for 7 days in healthy adults. 17 It is highly lipophilic and accumulates in fat. 18 CBD is metabolised by cytochrome P450 enzymes 3A and 2C in the liver.

Both animal and human studies have indicated that CBD does not affect physiological parameters or psychological functions. 19 Studies in healthy adults have shown CBD to be well tolerated across a wide dose range, with no significant adverse effects on vital signs, cognition or mood in oral doses of up to 1500 mg per day. 18 In children with epilepsy up to 50 mg/kg/day of CBD has been prescribed. 20 Reported tolerance in trials has been generally good, with the most common adverse effects, somnolence, diarrhoea and decreased appetite, occurring in a minority of exposed patients. 21

Indications for CBD

Medical cannabis is being advocated for an increasing range of indications. In children, the main indication for CBD is drug-resistant epilepsy, with supportive evidence emerging for its effectiveness as an adjuvant treatment to conventional antiepileptic medications for some specific epileptic syndromes. 21 In 2018, Epidiolex, a pure CBD oral solution manufactured by GW Pharmaceuticals, received approval from the US Food and Drug Administration for patients with Lennox-Gastaut syndrome and Dravet syndrome. 22 It is possible that reported improvements in ‘overall condition’ of children given CBD in epilepsy trials were due to more settled behaviour, although this has not specifically been reported. 23

Biological plausibility of CBD to treat SBP in youth

Neural mechanisms by which CBD may influence mood and behaviour are only partially established, but include alterations in neurotransmission and calcium homeostasis, antioxidant activity and anti-inflammatory effects. 24 Thus, the endocannabinoid system is a novel target for pharmacological treatments of behavioural problems. Alterations in endocannabinoid signalling have been found in mice carrying a mutation related to autism, 25 and in a mouse model of Fragile-X syndrome, 26 so this system appears to play an important role in neurodevelopment and behaviour. 27 While THC has strong affinity for both cannabinoid receptors receptors (CB1 and CB2), CBD appears to exert its effects on the endocannabinoid system through indirect actions, and may also have activity on other neurotransmitter systems. Thus, CBD has biologically plausible potential therapeutic benefits for human behaviour, and there is emerging evidence of benefit from CBD in adult mental health disorders. 28 A recent review described the anticonvulsive, anxiolytic, antipsychotic, anti-inflammatory and neuroprotective properties of CBD, and suggested CBD may be a candidate for the treatment of autism spectrum disorder (ASD). 29 However, the lack of data showing efficacy and safety in this population was noted.

Evidence for cannabis products in treating SBP in youth

The use of medicinal cannabis to treat children and adolescents with behavioural problems has been discussed in the mainstream media (Ellison K. Medical Marijuana: No Longer Just for Adults. New York Times, 21 November 2009), and parents have described ‘the transformative power of medical cannabis’ for their children with ID +SBP (eg, Mothers Advocating Medical Marijuana for Autism). Anecdotally, some parents have reported giving non-prescribed unregulated cannabis products to their children to help with their behaviour, and increasingly Australian parents of children with developmental disabilities and/or mental health disorders are asking their paediatricians if medicinal cannabis would be a useful treatment and whether they can assist them in obtaining it for their child. 23 Research to date suggests that CBD has substantially less side effects than antipsychotic medications, 21 however, there is currently insufficient evidence to inform its use in treating SBP. The American Academy of Pediatrics and the Royal Australasian College of Physicians 30 have highlighted the need for further research into the therapeutic uses of cannabinoids in youth.

A handful of reports in the literature suggest that there may be a legitimate role for medicinal cannabis to treat SBP in youth with developmental disabilities ( table 1 ). Although promising, these uncontrolled reports provide only weak evidence in support of benefit.

Table 1

Completed and ongoing studies reporting behavioural outcomes of youth treated with medicinal cannabis products

Published studies
Sample size Population Study design Product used Findings
1 Child with ID+SBP Case report Dronabinol (∆9-THC) Improvements in hyperactivity, irritability and speech 38
10 Adolescents with ID+SBP Open-label case series Dronabinol (∆9-THC) Reductions in self-injurious behaviour in 7 out of 10 participants 39
75 Children with epilepsy (heterogeneous sample) Retrospective chart review ‘Oral cannabis ’ Improvements in behaviour 40
19 Children with epilepsy: Dravet syndrome (n=13), Doose syndrome (n=4), Lennox-Gastaut syndrome (n=1) and idiopathic epilepsy (n=1) Facebook survey ‘CBD-enriched cannabis’ Improvements in mood, sleep and self-stimulation 41
53 Children with ASD Open-label, symptoms graded as improvement, no change, worsening CBD:∆9-THC 20:1 Improvements in self-injury, rage-attacks, hyperactivity, sleep and anxiety. 42 Adverse events were mildQ
60 Children with ASD+SBP Retrospective open label ‘CBD-rich cannabis’ ‘Much improved’ or ‘very much improved’ behaviour in 61% of patients. 43 Only one serious adverse event was noted, a transient psychotic event, which was considered to be related to an increase in ∆9-THC.
188 Children with ASD Prospective open label ‘CBD-enriched cannabis’ (mostly 30% CBD and 1.5% ∆9-THC) Significant or moderate improvements in anxiety, agitation and rage attacks for 79.8% of 119 participants assessed after 1 month. 44 The most common side effect was restlessness
Ongoing registered trials
Sample size Population Study design Product used ClinicalTrials.gov Identifier
150 Youth with ASD+SBP Double-blind, cross-over RCT Cannabis oil with a 20:1 ratio of CBD to ∆9-THC > NCT02956226
100 Children with ASD+SBP Double-blind RCT Cannabidivarin (CBDV; a homolog of CBD) > NCT03202303
26 Youth with Prader-Willi Syndrome +SBP Double-blind RCT CBDV > NCT03848481
204 Children with Fragile X Syndrome Double-blind RCT Synthetic CBD > NCT03614663

ASD, autism spectrum disorder; CBD, cannabidiol; ID, intellectual disability; RCT, randomised controlled trial; SBP, severe behavioural problem; ∆9-THC, Δ9-tetrahydrocannabinol.

There are currently four registered trials of medicinal cannabis products use for behavioural problems in youth (also summarised in table 1 ). In contrast to these, our study will include all children with ID and SBP, regardless of aetiology, and irrespective whether they have been diagnosed with ASD. Whereas one currently registered trial uses a ∆9-THC containing product, our study will use CBD alone, thus avoiding the potential risks associated with ∆9-THC. Two registered studies describe randomised controlled trials (RCTs) comparing cannabidivarin (a homolog of CBD) to placebo. CBD has a more established safety profile, is more commonly known and sought by consumers and more readily available commercially. Given the larger number of pharmaceutical companies manufacturing CBD, it would be expected that CBD is also more competitively priced—an important consideration for both research funding bodies and patients.

This pilot study will assess the feasibility of conducting a large scale, randomised, double-blind, placebo-controlled study of oral CBD in children with ID and SBP. We will also collect preliminary data on the safety and tolerance of CBD in children with ID and SBP.

Methods and analysis

Study objective

The primary objective of this pilot study is to evaluate all elements of the study design (recruitment strategy, tolerability of the study medication, study duration, study procedures and outcome measures) to assess if they are acceptable and feasible for the conduct of a full-scale RCT of CBD to reduce SBP in children with ID. The secondary objective is to collect preliminary data on the safety of oral administration of CBD in children aged 8–16 years with ID and SBP, by assessing adverse event signals. An exploratory aim of this study is to assess for a signal of behavioural change in participants treated with CBD, through completion of a parent-reported behavioural questionnaire pretreatment and post-treatment.

Patient and public involvement

Two clinician stakeholder forums have been held with groups of paediatricians and child and adolescent psychiatrists who manage children with ID. There was a strong and consistent expression of the need for evidence regarding the efficacy and safety of CBD in these patients, and a belief, based on the common experience of parents inquiring in consultations, that parents would be interested in participating in a trial.

Prior to development of this protocol, we conducted brief, semistructured telephone interviews with eight parents of children with ID and SBPs, in which they were asked whether they would be willing to enrol their child in an 8-week placebo-controlled trial of CBD. Responses were uniformly enthusiastic, with all parents indicating a willingness to participate if such a trial was conducted.

In this pilot study, parents will complete a brief questionnaire poststudy completion regarding their experience participating in the research study. Parents will be asked to rate their experience with recruitment, study visits, drug tolerability and questionnaires using Likert scales. They will also be invited to provide suggestions for improvements to the study design. This information will inform the design of the definitive trial.

Questionnaires to be piloted in this study include child-specific outcomes, as well as those assessing parent/carer quality of life and mental health.

Following completion of the study, participating families will be sent a summary of the study findings. Dissemination of findings will include distribution through community resources, including those accessed by carers such as support groups, and the Murdoch Children’s Research Institute (MCRI) Facebook page.

Trial design

This is a single-site, double-blind, parallel-group, randomised, placebo-controlled pilot study of 10 participants comparing 98% CBD oil with placebo in reducing SBP in children aged 8–16 years with ID. Eligible participants will be randomised 1:1 to receive either CBD or placebo.

Investigational product

This study will use 98% CBD in grapeseed oil provided by Tilray, Canada as a 100 mg/mL CBD oral solution, and a placebo grapeseed oil matched for smell, taste and appearance.

Participants

Inclusion criteria

Each patient must meet all of the following criteria to be enrolled in this study:

Full scale IQ

Deficit in adaptive function (basis for severity rating of ID in DSM-5) in at least one activity of life: Vineland Adaptive Behaviour Scales completed by interview with the parent or carer; derives scores in Communication, Daily Living Skills and Socialisation domains and a Global Adaptive score.

Exclusion criteria

Procedure

Recruitment procedure

Participants will be recruited from the Royal Children’s Hospital’s (RCH) Paediatric Clinics and Child and Adolescent Mental Health Service, as well as paediatric private practices in Victoria. The study will be advertised to clinicians in relevant departments and private clinics with a request to consider whether they have eligible patients. Paediatricians and psychiatrists will send standard study-designed letters, signed by the doctor, to potentially eligible families that briefly outline the study and invite interested parents to contact the study coordinator for further information. Potential participants will then attend a screening visit to determine eligibility. The researchers will obtain written informed consent from parents at the screening assessment (refer to online supplementary material 1 for a sample consent form).

Supplementary data
Randomisation, allocation concealment and double-blind conditions

A randomisation schedule will be generated by an independent statistician at the Clinical Epidemiology and Biostatistics Unit at the MCRI.

The randomisation schedule will be provided to the trials pharmacist at the RCH. Treatment allocation will be conducted by the pharmacy and will be blinded to all members of the study team and participants. Study medication codes will only be available once all data collected have been entered into the study database for every participant and the database has been finalised. In the event of a medical emergency, a pharmacist will be available to break the blind.

Study procedures

This study will be conducted at RCH, Melbourne. Study visits and assessments will be conducted as per table 2 . To maximise protocol adherence and minimise treatment dropouts, a dedicated study coordinator will be available to respond to parent queries or concerns between study visits.

Table 2

Schedule of study visit procedures and assessments

Screening Baseline/start of uptitration Double-blind evaluation End of study (phone call)
Start of maintenance Maintenance mid-point Start of down-titration End of down-titration
Day −14 to −1 1 Day 9–13 Day 36–40* Day 66–70 Day 74* Day 104
WASI-II X
Vineland-3 X
A-TAC X
SCQ X
ABC-I X
Parent survey X
Medical history X
Concomitant medications X X X X
Physical examination (including vital signs) X X X X
Weight measurement X X X X
Height measurement X
Haematology X X X
Biochemistry X X X
Randomisation X
Dispense study medication X X X X
Study drug administration X—————————————————X
Dispense diary cards X X X X
Collect diary cards X X X X
Evaluation measures X X
Safety outcome measure (MOSES) X X X
Adverse events X X X X X
Compliance check X X X X
Pilot evaluation questionnaire X

*Maintenance midpoint and end of down-titration visits require only the parent or carer to attend to return study medication.

ABC-1, Aberrant Behaviour Checklist-Irritability subscale; A-TAC, Autism Tics ADHD and Comorbidities; MOSES, Monitoring of Side Effects Scale; SCQ, Social Communication Questionnaire; WASI-II, Wechsler Abbreviated Scale of Intelligence-II.

Further description of the assessments included in table 2 are as follows:

WASI-II. The WASI-II 32 is a general intelligence, or IQ test designed to assess specific and overall cognitive capabilities and is individually administered to children, adolescents and adults (ages 6–89). This will be administered to children who have not had an IQ test in the 2 years prior to screening.

Vineland-3. Vineland Adaptive Behaviour Scales V.3 will be completed by interview with the parent or carer of children who have not had an IQ test in the 2 years prior to screening. This instrument derives scores in Communication, Daily Living Skills and Socialisation domains, and a Global Adaptive score.

Autism-Tics attention deficit/hyperactivity disorder (ADHD) and Comorbidities (A-TAC). A-TAC 33 34 inventory is a comprehensive screening interview for ASD, attention deficit/hyperactivity disorder (ADHD), tic disorders, developmental coordination disorder, learning disorders and other childhood mental disorders. Modules screening for Motor skills, ADHD, Tics, Compulsions, Mood, Anxiety and Oppositional defiance will be administered with the participants’ parent or carer by a study doctor.

Social Communication Questionnaire (SCQ). The ‘current’ version of the SCQ 35 will be used to screen for ASD symptoms. This will be administered online with the outcome measures.

ABC-I. The ABC 31 is an informant-rated questionnaire assessing severity of behavioural symptoms commonly seen in youth with ID that includes five subscales: Irritability, Social Withdrawal, Stereotypic Behaviour, Hyperactivity/Non-compliance and Inappropriate Speech. The Irritability subscale (ABC-I), which covers symptoms such as agitation, aggression, meltdowns and self-harm, will be used to determine eligibility.

Parent survey and Medical history. Demographic details will be collected from parents, along with details of the child’s medical history, previous medications, allied health service utilisation and any non-pharmacological behaviour management strategies that have been tried.

Concomitant medications. At each visit, the investigators will ask about changes in participants’ medications.

Physical examination. Physical examination including vital signs (temperature, heart rate, respiratory rate and blood pressure) and height and weight measurement will be conducted by a study doctor.

Haematology and Biochemistry. Blood will be collected by finger prick and tested for full blood count, electrolytes, creatinine, liver function tests and lipase. Participants with clinically significant abnormalities will be excluded from participating at the judgement of the investigators. Any abnormal results will be communicated to the families immediately, and to the paediatrician at the conclusion of the study (or immediately if considered clinically significant).

Study drug administration. Investigational product will be administered orally at a starting dose of 5 mg/kg/day in two divided doses. The dose will be increased in increments of 5 mg/kg every 3 days for 9 days up to the maintenance dose of 20 mg/kg/day (up titration phase). This dose was chosen to be consistent with a recent Dravet syndrome trial, 21 and because good human pharmacokinetic data are available for 20 mg/kg. 36 A ceiling dose of 1000 mg/day will be administered to all participants weighing 50 kg or greater. Participants will continue to receive investigational product at the maintenance dose for 8 weeks (maintenance phase). The treatment duration was chosen because the RCT of CBD in Dravet syndrome reported that ‘the difference in favour of CBD was seen in the first month of the maintenance period’. 21 This was corroborated by personal correspondence with both researchers and clinicians experienced in prescribing CBD for youth with ASD. The 8-week maintenance period, therefore, will allow 4 weeks for treatment effects to emerge, followed by an additional 4 weeks, which corresponds with the period over which parents are required to reflect when completing the behavioural outcome questionnaire. On completion of the maintenance phase, the dose will be decreased in increments of 5 mg/kg for 9 days at which time administration will cease.

Diary cards. Diary cards will be provided to parents to record each administration of study medication, including administration time, dosage and any noteworthy comments such as incomplete administration of medication or possible side effects.

Evaluation measures. Parent-report questionnaires will be trialled for feasibility, burden and acceptability for this population, with a view to include these as outcome measures in a future full-scale randomised clinical trial of CBD to reduce SBP in children with ID. These will be administered online through Research Electronic Data Capture (REDCap). See table 3 for further details of these questionnaires.

Table 3

Construct Measurement Source
SBP Summary score from the ABC-I 31 (15 items) Parent report
Behaviour Other subscales of the ABC 31 (4 outcomes) Parent report
Overall clinical impression Clinical Global Impressions 37 : 2-item clinician-rated summary measures of (a) severity of psychopathology and (b) improvement Clinician-rating
Participation Child and Adolescent Scale of Participation 45 (20 items). Participation in home, school and community activities Parent report
Quality of life Child Health Utility 9D 46 47 (9 items). Preference-weighted measure used to calculate quality adjusted life years for children. Parent report
Sleep Sleep Disturbance Scale for Children 48 (26 items) Parent report
Parent quality of life Assessment of Quality of Life 8D 49 (35 items). Health-related instrument used to calculate quality adjusted life years for parents. Parent report
Family quality of life Beach Centre Family Quality of Life 50 (25 items). Family interaction, parenting, emotional and material well-being, disability-related support Parent report
Parent mental health Depression Anxiety Stress Scale −21 51 (21 items). Report of symptoms over the past week. Parent report
Parenting stress Autism Parenting Stress Index 52 (13 items). Measures three categories of stress drivers: core social disability, difficult behaviour, physical issues Parent report

ABC-1, Aberrant Behaviour Checklist-Irritability subscale; SBP, severe behavioural problems.

Safety Outcome Measure. Safety outcomes will be collected using the Monitoring of Side Effects Scale (MOSES), 37 which will be completed by the parent or carer with the assistance of a study doctor. The MOSES is an 83-item measure that includes known side effects of psychotropic medications.

Assessment of adverse events. Adverse events will be evaluated at baseline (to exclude pre-existing problems) and throughout the study. Adverse events will be documented from physical examination findings, clinically significant lab results and diary cards. Documentation for all adverse events will include the specific event/condition, the dates and times of occurrence, the event severity, duration, likely relationship to CBD, action taken and date of resolution. In the event any participant (or their parent/carer) reports an intolerability to study medication, or there is a clinical or laboratory observation suggesting an intolerability to study medication, dose modification or cessation may be initiated in consultation with the Study Management Group.

In the event, any clinical observation suggests a severe intolerability of an individual participant to the study medication, study medication discontinuation will be considered. Any adverse event still ongoing at the time of study medication discontinuation will be monitored until it has returned to baseline status, stabilised, or, in the opinion of the Investigator and the Study Management Group agree that follow-up is no longer required.

Serious adverse events will be reported to the research governance office within 72 hours of becoming aware of the event and in accordance with local governance authorisation.

Compliance check. Parents will be instructed to return all medication bottles, empty or otherwise, for weighing by pharmacy staff to measure compliance. Compliance between 80% and 120% will be considered acceptable.

Pilot evaluation questionnaire. At the conclusion of the study, parents will complete a questionnaire specifically designed for this study to assess parent acceptability of study procedures (recruitment approach, number of study visits, questionnaire completion and blood tests) and medication tolerability. Refer to the online supplementary material 2 for a copy of this questionnaire.

Supplementary data
Data collection and analysis

Data will be collected regarding the feasibility and acceptability of all study components, including recruitment, withdrawal rate, study visit attendance, protocol adherence and the time burden of parent questionnaires.

Data will be entered directly into an online database (REDCap) at the time of collection and cross-checked for completion by the study coordinator. Only de-identified data will be entered into REDCap. Identifiable data (such as contact details) will be held in a separate, confidential, secure document accessible only to the investigators.

As this is a pilot study, all data will be reported using descriptive statistics. The recruitment rate will be presented as the percentage of eligible participants enrolled, and the reasons for not participating will be summarised. Study visit attendance and protocol adherence, medication compliance, study withdrawals, treatment discontinuations and protocol violations will be summarised by treatment arm. The acceptability of study visits and procedures, and tolerability of the study medication will be presented as mean scores with ranges and SD.

MOSES assessed safety outcomes and adverse events will also be summarised.

Scores from the evaluation measures listed in table 3 will be summarised as means and SD by treatment group.

Ethics and dissemination

Study-specific unique identifiers will to be used to identify trial subjects. Data will be deidentified and associated with study specific identification numbers. Data will be captured and stored directly in REDCap, Vanderbilt University, a secure, web-based application for building and managing online databases and surveys. REDCap is hosted on MCRI infrastructure. Data will be kept for at least 15 years after the completion of the trial in accordance with the requirements of the Therapeutic Goods Administration or until the 25th birthday of the youngest participant, whichever is the later date (Victorian Health Records Act 2001).

Research data for this project will be presented at conferences and published in peer-reviewed journals. Aggregated data only will be reported in publications and presentations, with individual identifying information removed. We will endeavour to make these research data/resources as widely available as possible, while safeguarding the privacy of participants, protecting confidential and proprietary data, and third-party intellectual property.

Discussion

This pilot study aims to investigate the feasibility of conducting a double-blind RCT of CBD to reduce SBP in children with ID. This study is not sufficiently powered to evaluate the efficacy of CBD in this population, however, the findings of this pilot study will inform the design of a fully powered RCT of CBD for reducing SBP in ID. The secondary aim of collecting preliminary safety data of CBD in this population, and the exploratory aim of examining for a signal of behavioural change in those treated with CBD, may also be informative for future study design. The planned RCT will address an identified evidence-practice gap in the use of CBD to meet an important need for services, the community and families, the safe and effective treatment of SBP in children and adolescents with ID. If safe and effective the transition into medical practice will require dissemination of research findings, education and training of prescribers, and support material solutions such as evidence-based clinical practice guidelines.

Supplementary Material

Footnotes

Contributors: All authors (DE, KT, JMP, JLF, NC, MM, CP, KJL and KW) made substantial contributions to the design of this study and the writing of the protocol. All authors (DE, KT, JMP, JLF, NC, MM, CP, KJL and KW) made substantial contributions to drafting the work and revising it critically for intellectual content. All authors (DE, KT, JMP, JLF, NC, MM, CP, KJL and KW) approved the final version submitted. All authors (DE, KT, JMP, JLF, NC, MM, CP, KJL and KW) agreed to be accountable for the accuracy or integrity of the work

Funding: This work was supported by an internal grant scheme available to employees of MCRI. This research received no specific grant from any external funding agency in the public, commercial or not-for-profit sectors.

Disclaimer: Investigational product was supplied in kind from Tilray, who had no role in the conception or design of the study and will have no role in data collection, management, analysis, or interpretation, preparation, review, or approval of the manuscript; nor in thedecision to submit the manuscript for publication.

Competing interests: None declared.

Patient consent for publication: Not required.

Ethics approval: This project has ethics approval from the Human Research Ethics Committee of the Royal Children’s Hospital, Melbourne (38236)

Provenance and peer review: Not commissioned; externally peer reviewed.

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Press Release Details

BOSTON , July 23, 2021 (GLOBE NEWSWIRE) — A correction has been issued for a release disseminated under the same headline on July 22nd at 9:00 am EST by Radius Health, Inc. (RDUS), please note that the corrected release contains the revised statement with the typographical correction as follows: “RAD011 is not scheduled as it does not have traceable amounts of THC,” which has been corrected from “does have.” This information is located in the last sentence of the last paragraph of the main body of the press release.

Radius Health, Inc. (“Radius” or the “Company”) (NASDAQ: RDUS) today announced that it has recently received the written meeting minutes from a June Type C meeting held with the U.S. Food and Drug Administration (“FDA”) regarding RAD011, a synthetic cannabidiol oral solution.

RAD011 is initially to be utilized for the treatment of Prader-Willi Syndrome (“PWS”). RAD011 has previously been granted Orphan Drug and Fast Track Designation by the FDA. Based on the feedback received, Radius plans on initiating a pivotal Phase 2/3 global study for patients with PWS.

The main highlights from the FDA meeting minutes are set out below:

  • Design characteristics and endpoints for a single seamless, pivotal Phase 2/3 study for PWS
  • Results dependent, a single adequate and well-controlled study could serve as the basis for marketing approval
  • Acceptability of 505(b)(2) regulatory pathway subject to completion and review of PK bridging and dedicated food effect studies
  • Acceptability of nonclinical package to support the pivotal Phase 2/3 study

, CEO of Prader-Willi Syndrome Association USA said, “We are encouraged by Radius’ commitment to advance RAD011 for the treatment of debilitating symptoms associated with PWS, particularly hyperphagia. We look forward to supporting their team throughout their study by raising awareness of their planned study with key opinion leaders, caregivers and individuals within the PWS community, and providing a means to gather perspective of individuals with PWS and critical caregivers.”

Phase 2/3 Study
Radius plans to initiate the pivotal Phase 2/3 study, to be branded as “SCOUT” (Synthetic Cannabidiol Oral Solution), by end of this year or early first quarter of 2022. With this current initiation timeline, it is anticipated top line results would be available in the second half of 2024.

The proposed study parameters, informed by several global advisory board meetings completed with leading KOLs, PWS advocacy organizations, and feedback from the FDA, are highlighted below:

  • The pivotal Phase 2/3 study (SCOUT-015) will be a double-blind, placebo-controlled, seamless pivotal Phase 2/3 study in individuals with genetically-confirmed PWS, ages 8 to 65
  • The seamless design will evaluate safety and tolerability across multiple dose groups in the Phase 2 portion, narrow the dose selection for the Phase 3 portion, and anticipated to enable one study to evaluate efficacy, safety and tolerability
  • A screening and placebo lead-in period will precede the 26-week maintenance period
  • Approximately 200 PWS individuals at 30+ global sites are planned for inclusion in SCOUT-015
  • Primary endpoint: change in Hyperphagia Questionnaire for Clinical Trials (HQ-CT) from baseline
  • Eligible individuals have the option to enroll in a long-term extension safety study (SCOUT-016)

, Ph.D. in Neuroscience and Senior Vice President at Radius stated, “We have established an exceptionally strong and highly experienced team of dedicated clinical, medical, biometrics, advocacy, regulatory and CMC talent to execute the pivotal study for PWS.”

added further that, “We intend to use PWS as the anchor indication for RAD011. Additional disease opportunities and clinical trial initiatives will be shared in due course.”

Strategic CRO Partner Selected & DEA Scheduling Guidance Received
The Company is working closely with CTI Clinical Trial & Consulting, a world-leading CRO in rare and orphan disease research, to initiate and execute SCOUT-015 and SCOUT-016.

Important to the initiation and execution of the SCOUT program, Radius will move forward with RAD011 as not scheduled under the Controlled Substance Act (“CSA”) based on guidance from the Drug Enforcement Administration (“DEA”). The guidance states if a product does not contain any quantity of synthetic THC (or any other controlled substance), it is not controlled under the CSA. RAD011 is not scheduled as it does not have traceable amounts of THC.

About Prader-Willi Syndrome
PWS, an orphan disease, is a complex genetic disorder with clinical manifestations on the endocrine and neurological systems. Clinical signs of PWS develop throughout childhood, with hyperphagia and anxiety ranked as the key clinical features seeking medical attention by caregivers of individuals with PWS. Hyperphagia is a relentless, insatiable, pathological drive to eat that requires caregivers to strictly manage access to food through the locking of cabinets and refrigerators. PWS is recognized as the leading genetic cause of life-threatening obesity in children. As life-threatening hyperphagia persists into adulthood, metabolic syndrome expressed through obesity and diabetes can develop and contribute to morbidity and mortality. In addition to food-related behaviors, the behavioral symptoms commonly observed in PWS include high irritability, habitual skin picking, oppositional defiance and cognitive rigidity. There are currently no approved therapies to treat this disorder’s hyperphagia, irritability, or metabolic aspects. In the U.S. , PWS occurs in approximately one out of every 15,000 births.

About RAD011
Investigational drug RAD011 is a pharmaceutical-grade synthetic cannabidiol oral solution, manufactured utilizing traditional pharmaceutical manufacturing processes. The product has purity specifications that meet standardized regulatory and quality control requirements and, compared to the process of developing a plant-derived product, the synthetic manufacturing process usually enables increased consistency and greater precision in the product supply. RAD011 has been assessed in over 150 patients across multiple indications and has potential utilization in multiple endocrine and metabolic orphan diseases. Radius is initially targeting Prader-Willi syndrome (PWS) and anticipates initiating a seamless pivotal Phase 2/3 study for patients with PWS in the second half of 2021.

About Radius
Radius is a commercial biopharmaceutical company committed to serving patients with unmet medical needs in endocrinology and other therapeutic areas. Radius’ lead product, TYMLOS® (abaloparatide) injection, was approved by the U.S. Food and Drug Administration for the treatment of postmenopausal women with osteoporosis at high risk for fracture. The Radius clinical pipeline includes investigational abaloparatide injection for potential use in the treatment of men with osteoporosis; an investigational abaloparatide transdermal system for potential use in the treatment of postmenopausal women with osteoporosis; the investigational drug, elacestrant (RAD1901), for potential use in the treatment of hormone-receptor positive breast cancer out-licensed to Menarini Group ; and the investigational drug RAD011, a synthetic cannabidiol oral solution with potential utilization in multiple endocrine and metabolic orphan diseases, initially targeting Prader-Willi syndrome.

Forward-Looking Statements
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements contained in this press release that do not relate to matters of historical fact should be considered forward-looking statements, including without limitation statements regarding our expectations with respect to our SCOUT-15 and SCOUT-16 clinical trials and timing of receipt of topline results therefrom.

These forward-looking statements are based on management’s current expectations. These statements are neither promises nor guarantees, but involve known and unknown risks, uncertainties and other important factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements, including, but not limited to, the following: the adverse impact the ongoing COVID-19 pandemic is having and is expected to continue to have on our business, financial condition and results of operations, including our commercial operations and sales, clinical trials, preclinical studies, and employees; quarterly fluctuation in our financial results; our dependence on the success of TYMLOS, and our inability to ensure that TYMLOS will obtain regulatory approval outside the U.S. or be successfully commercialized in any market in which it is approved, including as a result of risk related to coverage, pricing and reimbursement; risks related to competitive products; risks related to our ability to successfully enter into collaboration, partnership, license or similar agreements; risks related to clinical trials, including our reliance on third parties to conduct key portions of our clinical trials and uncertainty that the results of those trials will support our product candidate claims; the risk that adverse side effects will be identified during the development of our product candidates or during commercialization, if approved; risks related to manufacturing, supply and distribution; and the risk of litigation or other challenges regarding our intellectual property rights. These and other important risks and uncertainties discussed in our filings with the Securities and Exchange Commission , or SEC , including under the caption “Risk Factors” in our Annual Report on Form 10-K for the year ending December 31, 2020 and subsequent filings with the SEC , could cause actual results to differ materially from those indicated by the forward-looking statements made in this press release. Any such forward-looking statements represent management’s estimates as of the date of this press release. While we may elect to update such forward-looking statements at some point in the future, we disclaim any obligation to do so, even if subsequent events cause our views to change. These forward-looking statements should not be relied upon as representing our views as of any date subsequent to the date of this press release.