Investigating The Effects Of Full-Spectrum Medicinal Cannabis Plant Extract 0.08% THC (NTI164) On Paediatric Acute-onset Neuropsychiatric Syndrome (PANS)

This open-label study spans 18 to 54 weeks and aims to assess the efficacy of Full-Spectrum Medicinal Cannabis Plant Extract containing 0.08% THC (NTI164) for treating pediatric acute-onset neuropsychiatric syndrome (PANS) in children. The main objective is to evaluate how effective the NTI164 treatment is over the specified duration.

The study protocol involves several phases:

• **Up-titration phase:** Participants will start with a daily dosage of 5 mg/kg of NTI164, incrementally increasing this dose over a four-week period until reaching either the maximum tolerated dose or 20 mg/kg per day.
• **Treatment phase:** Following the up-titration, participants will continue at their maximum tolerated dose for eight weeks.
• **Extension phase:** After the initial eight-week treatment phase, participants have the option to continue at their maximum dose for up to an additional 46 weeks, totaling a possible 54 weeks of treatment.
• **Down-titration phase:** At the conclusion of the treatment or extension phases, the dosage will be gradually reduced by 5 mg/kg over four weeks until the participant's involvement in the study ends.

The effectiveness of NTI164 will be monitored through both participant- and psychologist-led questionnaires, which are designed to track changes in the emotions and behavior of the patients with PANS. Additionally, the study will employ whole blood RNA sequencing as a method to validate the presence of an immune dysfunction signature, aiming to provide a biomarker for response to treatment. This comprehensive approach seeks to ensure a thorough evaluation of NTI164's potential benefits in alleviating the symptoms of PANS.

Inclusion criteria

• 1 - 17 years of age
• Patients who fulfil PANS criteria
• Acute onset of OCD or severely restricted food intake
• Concurrent presentation of additional neuropsychiatric symptoms from at least 2 of the following 7 categories: anxiety, emotional lability/depression, irritability, aggression or severely oppositional behaviours, behavioural regression, deterioration in school performance, sensory or motor abnormalities (e.g. tics), somatic symptoms (e.g. sleep disturbances, enuresis or increase in urinary frequency)
• Symptoms not better explained by a known neurologic or medical disorder (e.g. Sydenham's chorea)
• RCADS-P scores of >65 (a scale of anxiety, social phobia, panic disorder, OCD, and low mood, a score of >65 infers moderate-significant impairment)
• Other patient medications (e.g. anti-psychotics) must be stable for at least 12 weeks prior to trial participation

Exclusion criteria

• Infection and/or antibiotic use in the 2 weeks prior to trial participation (i.e. baseline blood tests and commencement of NTI164)
• Recent changes to other patient medication (e.g. addition or escalation of anxiolytics, anti-depressants etc; medication dosage must be stable for at least 12 weeks prior to trial participation)
• Intellectual disability preventing adequate assent from patient, or that would affect reporting throughout trial; patients with intellectual disability must still have the capacity to verbalise their symptoms/experiences
• Ongoing immunomodulating or immunosuppressive treatment use in the previous 12 weeks, including steroids, IVIG, antibiotics, low-dose naltrexone, mycophenolate, Rituximab etc.
• Currently using or has used recreational or medicinal cannabis or cannabinoid-based medications (e.g. Sativex ®, Epidiolex ®) in the previous 12 weeks and/or is unwilling or unable to abstain for the duration of the trial
• Underlying renal impairment, cardiovascular issues (e.g. arrhythmia), current or previous thrombosis
• Impaired hepatic function, defined as serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2 x upper limit of normal (ULN) or total bilirubin (TBL) > 2 x ULN; this criterion can only be confirmed once baseline laboratory results are available and participants who fail this criterion will not proceed in this study
• Other diagnosed neurological condition likely to be contributing to OCD/neuropsychiatric symptoms (e.g. Huntington's disease)