Stratification and Treatment in Early Psychosis Study -ASSIST

Full Title: Cannabidiol Augmentation of Clozapine in Treatment Resistant Psychosis: a Double-blind, Randomised Controlled Trial

The purpose of this trial is:

• To investigate whether the response to clozapine treatment can be enhanced by adding cannabidiol (CBD), compared to placebo, in treatment resistant psychosis patients.
• To confirm the safety of CBD in people with psychosis.

The trial is a randomised, double-blind, placebo-controlled, multi-centre, international, clinical trial. Individuals with a diagnosis of treatment resistant psychosis in their illness who have had a suboptimal or no response to clozapine treatment will be recruited. These patients are randomised to treatment with oral CBD 500mg twice daily, or a matching placebo for 12 weeks, in addition to clozapine, which is standard care treatment for this population. By using a battery of clinical outcome assessments, the trial will assess several optional biomarkers to predict clinical outcomes and response to treatment with CBD. Biomarkers are being assessed as an exploratory outcome measure. Participants will be invited to provide additional blood samples, stool samples, and complete neuroimaging assessments.

Inclusion Criteria: Participation in the trial requires meeting all of the following inclusion criteria:

1. 16 to 50 years of age (inclusive) who are willing and able to provide written informed consent/assent (country specific requirements apply).
2. The patient has been treated with clozapine for at least 8 weeks with a clozapine plasma concentration of at least 0.35 mg/L at screening. If a patient has a lower plasma concentration at screening, the patient can enter the trial at a later date once their plasma concentration is above the threshold*.
3. Within 10 years of first antipsychotic treatment prescribed for psychosis.
4. The patient meets DSM-5 criteria for schizophrenia, schizoaffective disorder or schizophreniform disorder, as confirmed through the SCID-5-RV. The patient does not meet modified Andreasen et al (2005) criteria for symptomatic remission cross-sectionally (time requirement does not apply), i.e., a severity rating score of no more than mild (score of </=3) on 8 specified Positive and Negative Syndrome Scale (PANSS) positive and negative symptom items: P1 - Delusions, P2 - Conceptual Disorganization, P3 - Hallucinatory Behaviour, N1 - Blunted Affect, N4 - Passive/Apathetic Social Withdrawal, N6 - Lack of Spontaneity and Flow of Conversation, G5 - Mannerisms and Posturing, G9 - Unusual Thought Content.
5. Patients of child-bearing potential** must be willing to ensure that they use highly effective contraception during the trial and as per the requirements in the protocol***.
6. In the Investigator's opinion, is able and willing to comply with all trial requirements.
7. Willing to allow their General Practitioner and/or consultant, if required by local guidelines/regulations, to be notified of participation in the trial.
8. For patients who take part in the optional MRI scans: they must be eligible for MRI scanning as per local requirements, for example concerning e.g. implants, braces etc.

There is inadequate information on the effects of cannabidiol on the foetus in humans. Participants of child-bearing potential** should use a highly effective method of contraception3 for the duration of the trial and for 3 months after the last time the trial intervention was used. There is no special requirement for male participants to use highly effective contraception as there are no known safety concerns in males, such as sperm toxicity, as per the Investigator's Brochure. This trial will also not be collecting pregnancy data from partners of male participants.

*Clozapine levels can be up to 4 weeks old if the clozapine dose remained within 25 mg of the dose used at the time of blood draw.

**A person is considered of child-bearing potential, i.e. fertile, following menarche and until becoming post-menopausal (no menses for 12 months without an alternative medical cause) unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.

***Methods that can achieve a failure rate of less than 1% per year when used consistently and correctly are considered as highly effective birth control methods. Such methods include: 1) combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral; intravaginal; transdermal); 2) progestogen-only hormonal contraception associated with inhibition of ovulation (oral; injectable; implantable); 3) intrauterine device (IUD); 4) intrauterine hormone-releasing system (IUS); 5) bilateral tubal occlusion; 6) vasectomised partner; 7) sexual abstinence (abstinence should only be used as a contraceptive method if it is in line with the subjects' usual and preferred lifestyle).

Periodic abstinence (calendar, symptothermal, post-ovulation methods) is not an acceptable method of contraception. The participant agrees to use an acceptable method of contraception** for the duration of the trial and for 3 months after any trial intervention administration, unless surgically sterile or postmenopausal.

The age range for eligibility has been applied as this corresponds to the usual age range for treatment resistant psychosis; individual cases outside of this age range may have a different aetiology and/or prognosis which could impact on the trial outcomes.

Exclusion Criteria: Individuals are excluded from participation in the trial if they meet one or more of the following exclusion criteria. Rescreening is permitted where the relevant circumstances may have changed.

1. Current treatment with sodium valproate, valproate semisodium, or clobazam. In cases of current use of these medicines, participation is only permitted if they can and will be discontinued or switched to a suitable alternative medication prior to randomisation.

2. Hypersensitivity to the active substance, sesame oil, sesame seed or any of the excipients of the trial intervention.

3. Known hepatic insufficiency and/or transaminase elevations levels exceeding the upper limit of normal 2 times or more and bilirubin greater than 1.5 times the upper limit of normal.

4. Previous neurosurgery or neurological disorder, including epilepsy, which may affect the trial procedures*.

5. IQ <70 as measured by a validated IQ test e.g. Wechsler Abbreviated Scale of Intelligence (WASI), Wechsler Adult Intelligence Scale (WAIS), and Wechsler Intelligence Scale for Children (WISC), as approved for local languages and appropriate for the participant's age.

6. Pregnancy or breastfeeding.

7. The patient has a current diagnosis of 'Substance or medication induced psychotic disorder' or 'Psychotic disorder due to another medical condition' as determined through the SCID-5-RV.

8. Current active suicidal ideation within the last 2 weeks, defined as a score of 1 or higher on CDSS question 8, followed by an assessment by the treating clinician who determines it is not safe for the patient to participate in the trial**

9. The participant meeting DSM-5 criteria for substance use disorder, with the exception of nicotine use disorder (mild, moderate, and severe allowed). Mild cannabis use disorder is allowed (i.e. can meet up to but no more than 3 criteria on the SCID) as long as the subject has not consumed cannabis on average more than three times a week in the past 30 days. Mild alcohol use disorder is also allowed.

10. Patient has participated in another clinical trial in which the participant received an experimental or investigational drug or agent <3 months before Visit 0. Participants who have participated in Type A studies (e.g. trials of standard and within-label treatments including antipsychotic medication) or non CTIMPs (e.g. studies of exercise therapy) must have completed the intervention.

11. The participant refuses any mandatory safety checks during the trial, specifically, refusal of: urine pregnancy test (those of child-bearing potential only); safety blood test; reporting of adverse events; and assessment of suicidality.

12. Any other significant disease or disorder which, in the opinion of the Investigator, may either put the participants at risk because of participation in the trial, or may influence the result of the trial, or the participant's ability to participate in the trial.

    • Minor neurological disorders such as migraine, other minor headache disorders, sleep disorders or nerve palsies which are unlikely to affect trial outcomes including neuroimaging measures can be permitted.

      • The decision to include the patient is at clinician's discretion. The clinician can conclude that it is safe for the patient to participate after the patient is evaluated, in which case this exclusion criterion does not apply and the patient can participate. Either way, the treating clinician needs to record his/her evaluation of suicidal risk in the source documentation or medical file, including his/her considerations, and notify the site PI of the decision.