Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities

Current medications for severe behavioural problems (SBP) show equivocal effectiveness and are associated with a high risk of side effects. Innovative and safe treatments are urgently needed. While preclinical studies, anecdotal reports, and uncontrolled studies link SBP with an endocannabinoid mechanism and suggest that medical cannabinoids may be an efficacious and safe alternative to current medications for SBP in adults with IDD, rigorous evidence is still in the very early stages. Unlike cannabidiol (CBD), a cannabinoid with elusive mechanisms and dose ranges, nabilone, a marketed synthetic cannabinoid, has a clearer mechanism, favourable safety profile, and more predictable dosing. Data of safety and efficacy regarding nabilone in this population has never been published.

This study is a Phase I pre-pilot open-label trial of nabilone in adults with IDD and SBP. The trial first includes a screening visit (S-V) for eligibility, then a baseline visit (V 0), followed by a dose titration phase, and then a 4-week open label phase at a stable dose. At the end of the open label phase, participants will undergo a termination visit (V 1), after which nabilone will be tapered off over 8 days. And then, 2 weeks later, participants will undergo a last follow-up visit (V-F) to ensure safety.

At S-V, and before the informed consent process, the participant will be assessed for capacity to provide informed consent. If they cannot pass the competence test using the MacArthur Competence Assessment Tool for Clinical Research (MacCAT-CR), then the written informed consent will be obtained from their substitute decision-maker after seeking participants' assent.

At S-V, participants will also be assessed for eligibility based on the inclusion and exclusion criteria, including SBP defined as a score ≥18 on the Aberrant Behaviour Checklist-Irritability subscale (ABC-I) and a score ≥4 on the Clinical Global Impressions-Severity scale. The SBP should present with a consistent pattern with the frequency of ≥1 time per week for >3 months.

At V 0 the following assessments will be completed:

• Clinical Global Impression - Severity scale (CGI-S) will be rated by the investigator to evaluate the severity of the behavioural problems.
• Measuring baseline vital signs and weight to monitor any AEs of nabilone.
• Assessment of participants' cognitive capacity using the NIH Toolbox® Cognition Battery. Previous evidence suggests that nabilone may cause acute mild decrement in attention and working memory. The investigators will use the NIH Toolbox® Cognition Battery, which has been shown as a good candidate outcome measure to examine broad nonverbal cognitive changes for individuals with IDD (valid and reliable for those with a mental age of ≥5 years; implementable for those with a mental age of ≥3 years), to assess the baseline attention and working memory.
• Assessment of SBP of participants, including behavioural problems using the ABC-I and Modified Overt Aggression Scale (MOAS), as reported by the caregivers. These scales will be the principal measures for detection of changes in SBP.
• Assessment of anxiety using the parent-rated General Anxiety Subscale of the Anxiety, Depression, and Mood Scale (ADAMS). Nabilone and THC at low doses have been shown to alleviate anxiety, thus this measure is used for exploratory aims to detect a signal of behavioural/mood change with nabilone use.
• Assessment of caregiver's stress and crisis using the Stress Subscale of Depression Anxiety Stress Scales (DASS-21) and Brief Family Distress Scale (BFDS). As SBP cause major caregiver burden, the investigators aim to assess whether the caregiver's stress and distress would improve if nabilone also improves participants' SBP.
• Exploratory assessment of autism symptoms using the Social Communication Questionnaire for Adults with Intellectual Disability (SCQ-AID). Prior evidence suggests that autistic symptoms may be associated with the presentation of SBP. The investigators aim to explore whether the baseline autistic symptoms would modulate treatment effects of nabilone.
• Optional assessment of MRI Imaging (dependent on the participant's ability to comply with the following assessments, in the opinion of the carers/parents and investigator).

After V 0, eligible participants will receive open-label nabilone starting with a dosage of 0.25 mg before sleep. During the dose titration phase (which could last up to 15 days), nabilone will be titrated in 0.25 mg increments every two days (with the dosing schedule "twice daily") after consultation with the study team during regular phone calls. The study team will also check whether the participants show any physical or mental changes which are believed to be attributed to AEs (based on the UKU side effect rating scale), and advise the participant and their caregivers on the next step of titration accordingly. Dose adjustments are performed until the participant reaches the maximum permitted dose of 1 mg twice daily or experience intolerable AEs believed to be related to nabilone. If intolerable, the participant will use nabilone at the previous lower dose, entering the open label phase.

Participants will be then on a stable, optimized nabilone dosage for four weeks, and then the trial ends with an on-site termination visit (V1). If there are any changes suspected to be associated with AEs, the UKU side effect rating scale will be assessed during the telephone check-up.

At V 1, the following post-treatment assessments will be completed:

• Assessment of adverse events using the UKU side effect rating scale, examined by the researcher or investigator, to systemically investigate the physical AEs of nabilone.
• Re-measuring of vital signs (including blood pressure to check orthostatic hypotension) and weight to monitor the physical AEs of nabilone.
• Re-assessment of participants' cognitive capacity using the NIH Toolbox® Cognition Battery, to monitor any acute cognitive change (AEs) due to nabilone.
• Re-assessment of caregiver rated ABC-I, MOAS, and General Anxiety Subscale of ADAMS. CGI-S and CGI-I will be rated by the investigator to evaluate the severity and improvement of the behavioural problems after nabilone treatment. These re-assessments are implemented to fulfil the exploratory study aim of assessing behavioural changes pre- and post-treatment of nabilone.
• Re-assessment of caregiver's stress and crisis using the Stress Subscale of DASS-21 and BFDS, to investigate changes in their stress and distress after participants takes nabilone.
• Optional re-assessment of MRI Imaging for those who finish the pre-treatment MRI and are willing to receive the second wave of MRI imaging. This is to investigate the change in brain function and structure pre- and post-treatment of nabilone.

Nabilone will be tapered in 0.25 mg daily decrements to prevent acute withdrawal effects. Phone calls will be held every other day during the dose-tapering phase, to check whether there are any changes which are believed to be attributed to withdrawal effects. A safety follow-up visit (S-F) will be scheduled after 2 weeks of full discontinuation from the study drug.